PaperPlayer biorxiv neuroscience: Recent Episodes
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.29.505018v1?rss=1
Authors: Lu, X., Wang, Y., Liu, Z., Gou, Y., Jaeger, D., St-Pierre, F.
Abstract: Widefield imaging with genetically encoded voltage indicators (GEVIs) is a promising approach for understanding the role of large cortical networks in the neural coding of behavior. However, the slow kinetics of current GEVIs limit their deployment for single-trial imaging of rapid neuronal voltage dynamics. Here, we developed a high-throughput platform to screen for GEVIs that combine fast kinetics with high brightness, sensitivity, and photostability under widefield one-photon illumination. Rounds of directed evolution produced JEDI-1P, a green-emitting fluorescent indicator whose performance is improved for all metrics. Next, we optimized a neonatal intracerebroventricular delivery method to achieve cost-effective and wide-spread JEDI-1P expression in mice. We also developed an approach to effectively correct optical measurements from hemodynamic and motion artifacts. Finally, we achieved stable brain-wide voltage imaging and successfully tracked gamma-frequency whisker and visual stimulations in awake mice in single trials, opening the door to investigating the role of high-frequency signals in brain computations.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.28.504668v1?rss=1
Authors: Mu, S., Turner, N. L., Silversmith, W. M., Jordan, C. S., Kemnitz, N., Sorek, M., David, C., Jones, D. L., Bland, D., Moore, M., Sterling, A. R., Seung, H. S., the Eyewirers
Abstract: We observed novel classes of cell-cell contacts between retinal starburst amacrine neurons, from finely detailed morphological reconstructions of cells from an electron microscopic image volume of a mouse retina. These contacts have peculiar morphological patterns and traits, different among the respective On and Off starburst amacrine subpopulations, but both occur within the soma layers as opposed to their regular laminae of contact within the inner plexiform layer.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.29.505313v1?rss=1
Authors: Rosenthal, I. A., Bashford, L., Kellis, S., Pejsa, K., Lee, B., Liu, C., Andersen, R. A.
Abstract: The responsiveness of primary somatosensory cortex (S1) to physical tactile stimuli is well documented but the extent to which it is modulated by vision is unresolved. Additionally, recent literature has suggested that tactile events are represented in S1 in a more complex, generalized manner than its long-established topographic organization. To better characterize S1 function, neural activity was recorded from a tetraplegic patient implanted with microelectrode arrays in S1 during 1s stroking touches to the forearm (evoking numb sensation) or finger (naturalistic sensation). Touch conditions included visually observed first person physical touches, physical touches without vision, and visual touches without physical contact which occurred either to a third person, an inanimate object, or the patient's own body in virtual reality. Two major findings emerged from this dataset. The first was that vision strongly modulates S1 activity, but only if there is a physical element to the touch, suggesting that passive observation of touches is not sufficient to recruit S1 neurons. The second was that despite the location of the recording arrays in a putative arm area of S1, neural activity was able to represent both arm and finger touches in physical touch conditions. Arm touches were encoded more strongly and specifically, supporting the idea that S1 encodes tactile events primarily through its topographic organization, as well as in a more general manner encompassing larger areas of the body.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.30.505842v1?rss=1
Authors: Reimann, M. W., Guyonnet-Hencke, T.
Abstract: The brain comprises several anatomically clearly separated structures. This parcellation is often extended into the isocortex, where border demarcations are less clear due to its relatively homogeneous structure. Yet, established parcellation schemes exist, based on anatomical, physiological or functional differences. Here, we derive a parcellation scheme based purely on connectomics, that is, the spatial structure of long-range synaptic connections within the cortex. To that end, we analyze a publicly available dataset of average mouse brain connectivity, and split the isocortex into disjunct regions. Instead of clustering connectivity based on similarity or modularity, our scheme is inspired by methods that split sensory cortices into subregions where gradients of neuronal response properties, such as the location of the receptive field, reverse. We developed a method to calculate comparable gradients from voxelized brain connectivity data and automatically detect reversals in them. This approach better respects the known presence of functional gradients within brain regions than clustering-based approaches. Placing borders at the reversals resulted in a parcellation into 41 subregions that differs significantly from an established scheme in nonrandom ways, but is comparable in terms of the modularity of connectivity between regions. It revealed unexpected trends of connectivity, such a a tripartite split of somatomotor regions along an anterior to posterior gradient. The method can be readily adapted to other organisms and data sources, such as human functional connectivity.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.29.505464v1?rss=1
Authors: Samavat, M., Bartol, T. M., Bromer, C., Bowden, J. B., Hubbard, D. D., Hanka, D. C., Kuwajima, M., Mendenhall, J. M., Parker, P. H., Abraham, W. C., Harris, K. M., Sejnowski, T. J.
Abstract: Synapses from the same axon onto the same dendrite have a common history of coactivation and have similar spine head volumes, suggesting that synapse function precisely modulates structure. We have applied Shannon information theory to obtain a new analysis of synaptic information storage capacity (SISC) using non-overlapping dimensions of dendritic spine head volumes as a measure of synaptic weights with distinct states. Spine head volumes in the stratum radiatum of hippocampal area CA1 occupied 24 distinct states (4.1 bits). In contrast, spine head volumes in the middle molecular layer of control dentate gyrus occupied only 5 distinct states (2 bits). Thus, synapses in different hippocampal regions had different synaptic information storage capacities. Moreover, these were not fixed properties but increased during long-term potentiation, such that by 30 min following induction, spine head volumes in the middle molecular layer increased to occupy 10 distinct states (3 bits), and this increase lasted for at least 2 hours. Measurement of the Kullback-Liebler divergence revealed that synaptic states evolved closer to storing the maximum amount of information during long-term potentiation. These results show that our new SISC analysis provides an improved and reliable estimate of information storage capacity of synapses. SISC revealed that the Shannon information after long-term potentiation is nearly maximized for the number of distinguishable states.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.29.505726v1?rss=1
Authors: Jun, N. Y., Field, G. D., Pearson, J. M.
Abstract: Among the most striking features of retinal organization is the grouping of its output neurons, the retinal ganglion cells (RGCs), into a diversity of functional types. Each of these types exhibits a mosaic-like organization of receptive fields (RFs) that tiles the retina and visual space. Previous work has shown that many features of RGC organization, including the existence of ON and OFF cell types, the structure of spatial RFs, and their relative arrangement, can be predicted on the basis of efficient coding theory. This theory posits that the nervous system is organized to maximize information in its encoding of stimuli while minimizing metabolic costs. Here, we use efficient coding theory to present a comprehensive account of mosaic organization in the case of natural videos as the retinal channel capacity---the number of simulated RGCs available for encoding---is varied. We show that mosaic density increases with channel capacity up to a series of critical points at which, surprisingly, new cell types emerge. Each successive cell type focuses on increasingly high temporal frequencies and integrates signals over large spatial areas. In addition, we show we show theoretically and in simulation that a transition from mosaic alignment to anti-alignment across pairs of cell types is observed with increasing output noise and decreasing input noise. Together, these results offer a unified perspective on the relationship between retinal mosaics, efficient coding, and channel capacity that can help to explain the stunning functional diversity of retinal cell types.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.31.505131v1?rss=1
Authors: Kunimatsu, J., Akiyama, Y., Toyoshima, O., Matsumoto, M.
Abstract: Respiration is strongly linked to internal states such as arousal, emotion, and even cognitive processes and provides objective biological information to estimate these states in humans and animals. However, the measurement of respiration has not been established in macaque monkeys that have been widely used as model animals for understanding various higher brain functions. In the present study, we developed a method to monitor the respiration of behaving monkeys. We first measured the temperature of their nasal breathing, which changes between inspiration and expiration phases, in an anesthetized condition and estimated the respiration pattern. We compared the estimated pattern with that obtained by a conventional chest band method that has been used in humans and applies to anesthetized, but not behaving, monkeys. These respiration patterns matched well, suggesting that the measurement of nasal air temperature can be used to monitor the respiration of monkeys. Furthermore, we confirmed that the respiration frequency in behaving monkeys monitored by the measurement of nasal air temperature was not affected by the orofacial movement of licking to obtain the liquid reward. We next examined the frequency of respiration when they listened to music or white noise. The respiratory frequency was higher when the monkeys listened to music than the noise. This result is consistent with a phenomenon in humans and indicates the accuracy of our monitoring method. These data suggest that the measurement of nasal air temperature enables us to monitor the respiration of behaving monkeys and thereby estimate their internal states.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.30.505858v1?rss=1
Authors: Ballard, H. K., Jackson, T. B., Hicks, T. H., Cox, S. J., Miller, A. C., Maldonado, T., Bernard, J. A.
Abstract: Sex hormones fluctuate over the course of the female lifespan and are associated with brain health and cognition. Thus, hormonal changes throughout female adulthood, and with menopause in particular, may contribute to sex differences in brain function and behavior. Further, sex hormones have been correlated with sleep patterns, which also exhibit sex-specific impacts on the brain and behavior. As such, the interplay between hormones and sleep may contribute to late-life brain and behavioral outcomes in females. Here, in a sample of healthy middle-aged and older females (n = 79, ages 35-86), we evaluated the effect of hormone-sleep interactions on cognitive and motor performance as well as cerebellar-frontal network connectivity. Salivary samples were used to measure 17{beta}-estradiol, progesterone, and testosterone levels while overnight actigraphy was used to quantify sleep patterns. Cognitive behavior was quantified using the composite average of standardized scores on memory, processing speed, and attentional tasks, and motor behavior was indexed with sequence learning, balance, and dexterity tasks. We analyzed resting-state connectivity correlations for two specific cerebellar-frontal networks: a Crus I to dorsolateral prefrontal cortex network and a Lobule V to primary motor cortex network. In sum, results indicate that sex hormones and sleep patterns interact to predict cerebellar-frontal connectivity and behavior in aging females. Together, the current findings further highlight the potential consequences of endocrine aging in females and suggest that the link between sex hormones and sleep patterns may contribute, in part, to divergent outcomes between sexes in advanced age.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.30.505888v1?rss=1
Authors: orhan, p., Duszkiewicz, A. J., Peyrache, A.
Abstract: Understanding the relationship between circuit properties and the organization of neuronal population activity is a fundamental question in neuroscience. The fine tuning of neuronal activity to specific values of environmental or internal features are canonical examples of how information is encoded in the brain, possibly resulting from precisely organized inputs. Yet, in the cortex, finely tuned neurons are often recorded together with neurons whose tuning is much less specific, for example those of inhibitory neurons, and the connectivity statistics accounting for the overall distribution of tuning curves is unclear. Here, using recordings in the mouse head-direction system, we first show both in simulation and analytically that random linear combinations of ideal finely tuned inputs reproduce the distribution of fast-spiking neuron tuning curves, a class of neurons believed to operate in the linear regime. This transformation preserves, on the population level, the singular spectrum of the input tuning curves but the relative power of each singular component is independently distributed in each output cell, leading to a distribution ranging from uni-modal to symmetrically tuned cells. We then generalize the model to a non-linear transformation of the inputs, combined with background inhibition. Using recordings from input neurons in the thalamus, where tuning curves are near-ideal, the model reproduces for various levels of inhibition the entire range of observed neuronal responses in the cortex, from precisely and narrowly tuned neurons to multipeak excitatory cells, as well as symmetrical tuning curves of inhibitory neurons. We replicate these findings in a dataset of hippocampal recordings. In conclusion, the full distribution of tuning curves is a signature of input connectivity statistics, which, for fast-spiking neurons and thalamocortical circuits, is likely to be random rather than specifically organized.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.30.505941v1?rss=1
Authors: Wong, A., Bhuiyan, M. I. H., Rothman, J., Drew, K., Pourrezaei, K., Sun, D., Barati, Z.
Abstract: Timely and sensitive in vivo estimation of ischemic stroke-induced brain infarction are necessary to guide diagnosis and evaluation of treatments efficacy. The gold standard for estimation of the cerebral infarction volume is magnetic resonance imaging (MRI), which is expensive and not readily accessible. Measuring regional cerebral blood flow (rCBF) with Laser Doppler flowmetry (LDF) is the status quo for confirming reduced blood flow in experimental ischemic stroke models. However, rCBF reduction following cerebral artery occlusion often does not correlate with subsequent infarct volume. In the present study, we employed the continuous-wave near infrared spectroscopy (NIRS) technique to monitor cerebral oxygenation during 90 min of the intraluminal middle cerebral artery occlusion (MCAO) in Sprague-Dawley rats (n=8, male). The NIRS device consisted of a controller module and an optical sensor with two LED light sources and two photodiodes making up two parallel channels for monitoring left and right cerebral hemispheres. Optical intensity measurements were converted to deoxyhemoglobin (Hb) and oxyhemoglobin (HbO2) changes relative to a 2-min window prior to MCAO. Area under the curve (auc) for Hb and HbO2 was calculated for the 90-min occlusion period for each hemisphere (ipsilateral and contralateral). To obtain a measure of total ischemia, auc of the contralateral side was subtracted from the ipsilateral side resulting in {Delta}Hb and {Delta}HbO2 parameters. Infarct volume (IV) was calculated by triphenyl tetrazolium chloride (TTC) staining at 24h reperfusion. Results showed a significant negative correlation (r = -0.81, p = 0.03) between {Delta}Hb and infarct volume. In conclusion, our results show feasibility of using a noninvasive optical imaging instrument, namely NIRS, in monitoring cerebral ischemia in a rodent stroke model. This cost-effective, non-invasive technique may improve the rigor of experimental models of ischemic stroke by enabling in vivo longitudinal assessment of cerebral oxygenation and ischemic injury.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.31.505522v1?rss=1
Authors: Portales, A., Chamero, P., Jurado, S.
Abstract: Normal aging and many age-related diseases such as Alzheimer disease cause deficits in olfaction, however it is currently unknown how natural and pathological aging impact the detection of social odors which might contribute to the impoverishment of social behavior at old age further worsening overall health. Here, we investigated the effect of aging in the recognition of social cues and the display of social behavior. Our findings indicate that aging distinctively disrupts the processing of social olfactory cues decreasing social odor exploration, discrimination and habituation in both wild type senescent (2-year-old) mice and in 1-year-old double mutant model of Alzheimer disease (APP/PS1). Furthermore, social novelty was diminished in 1-year-old APP/PS1 mice, indicating that alterations in the processing of social cues are accelerated during pathological aging. Analysis of the vomeronasal organ, the main gateway to pheromone-encoded information, indicated that natural and pathological aging distinctively reduce the neurogenic ability of the vomeronasal sensory epithelium. Cell proliferation remained majorly preserved in 1-year model of Alzheimer disease (APP/PS1), whereas naturally aged animals exhibited significant deficiencies in the number of mature, proliferative and progenitor cells. This study reveals fundamental differences in the cellular processes by which natural and pathological aging disrupt the exploration of social cues and social behavior.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.30.505868v1?rss=1
Authors: Martin-Cortecero, J., Isaias-Camacho, E. U., Boztepe, B., Ziegler, K., Mease, R. A., Groh, A.
Abstract: Most brain circuits comprise intermingled neuronal populations with heterogeneous input and output connectivity, which limits the ability to unambiguously map how the circuit of interest synaptically links specific input pathways to specific downstream targets. By applying newly available transsynaptic and intersectional tracing tools to investigate input-output connectivity of the superior colliculus (SC), a conserved midbrain-node with extensive long-range connectivity throughout the brain, we identify hitherto unknown connectivity features underlying cortical control of SC sensory-motor transformations. We pinpoint a whisker region in the SC of mice as a node for the integration of somatosensory and motor cortical signals. Tracing input-defined pathways from brainstem, motor- and somatosensory cortices to the whisker SC and further on to collicular downstream targets in the midbrain and brainstem revealed that long-range inputs establish synaptic contacts with inhibitory and excitatory SC-output neurons, thereby providing monosynaptic trans-collicular pathways between specific cortical and subcortical circuits for somato-motor integration.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.29.505728v1?rss=1
Authors: Miyano, R., Sakamoto, H., Hirose, K., Sakaba, T.
Abstract: Synaptic vesicles dock and fuse at the presynaptic active zone (AZ), the specialized site for transmitter release. AZ proteins play multiple roles such as recruitment of Ca2+ channels as well as synaptic vesicle docking, priming and fusion. However, the precise role of each AZ protein type remains unknown. At phasic synapses having high release probability, Rab3-interacting molecule-binding protein2 (RIM-BP2) is known to affect Ca2+ channel localization at AZs. In order to dissect the role of RIM-BP2 at tonic synapses having low release probability, we applied electrophysiological recording and super-resolution imaging to hippocampal mossy fiber terminals of RIM-BP2 KO mice. By using whole cell capacitance measurements, we found that reduced Ca2+ currents were responsible for the decreased rates of transmitter release in RIM-BP2 KO terminals. Consistently, STED microscopy pictured lower densities of P/Q-type Ca2+ channels at AZs deficient in RIM-BP2. Our results suggest that the RIM-BP2 function differs between phasic and tonic synapses.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.30.505807v1?rss=1
Authors: Maggi, S., Hock, R. M., O'Neill, M., Buckley, M. J., Moran, P. M., Bast, T., Sami, M., Humphries, M. D.
Abstract: Investigating the strategies engaged by subjects in decision making and learning requires tracking their choice strategies on a trial-by-trial basis. Here we present a simple but effective probabilistic approach to tracking choice strategies at trial resolution, using Bayesian evidence accumulation. We show this approach identifies both successful learning and the exploratory strategies used in decision tasks performed by humans, non-human primates, rats, and synthetic agents. We find learning occurs earlier and more often than estimated using classical approaches. Also, win-stay and lose-shift strategies, often considered as complementary, are consistently used independently, with the adoption of lose-shift preceding both learning new rules and switching away from old rules. Our approach can be extended to any discrete choice strategy, and its low computational cost is ideally suited for real-time analysis and closed-loop control.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.29.505733v1?rss=1
Authors: Raghavan, R. T., Kelly, J. G., Hasse, J. M., Levy, P., Hawken, M., Movshon, J. A.
Abstract: In natural scenes, there is substantial variation in the mean and variance of light levels (luminance and contrast). Retinal ganglion cells maintain their sensitivity despite this variation and their limited signaling bandwidth using two adaptive mechanisms, which control luminance and contrast gain. However, the signature of each mechanism and their interactions further downstream of the retina are unknown. We recorded neurons in the magnocellular and parvocellular layers of the lateral geniculate nucleus (LGN) in anesthetized adult male macaques and characterized how they adapt to changes in contrast and luminance. As contrast increases, neurons in the magnocellular layers maintain sensitivity to high temporal frequency stimuli but attenuate sensitivity to low temporal-frequency stimuli. Neurons in the parvocellular layers do not adapt to changes in contrast. As luminance increases, magnocellular and parvocellular cells increase their sensitivity to high temporal frequency stimuli. Adaptation to luminance is independent of adaptation to contrast, as previously reported for LGN neurons in the cat. Our results are similar to those previously reported for macaque retinal ganglion cells, suggesting that adaptation to luminance and contrast result from two independent mechanisms that are retinal in origin.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.31.506056v1?rss=1
Authors: Lynn, M. B., Geddes, S., Chahrour, M., Maille, S., Harkin, E., Harvey-Girard, E., Haj-Dahmane, S., Naud, R. B., Beique, J.-C.
Abstract: Serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) receive a diverse constellation of long-range synaptic inputs, yet unifying principles of local circuitry and its dynamics are largely unknown - a crucial component of understanding how 5-HT output controls behavior. Here, we developed a formalism bridging optogenetic, electrophysiological, computational and behavioral strategies to reveal how the dynamics of local circuitry in DRN control the expression of reward associations. Using long-range input from lateral habenula (LHb) to interrogate functional DRN circuitry, we uncover 5-HT1A receptor-mediated local recurrent connections between 5-HT neurons, refuting classical theories of autoinhibition by 5-HT1A receptors. These inhibitory 5-HT connections were slow, stochastic, strongly facilitating, and gated spike output of 5-HT neurons. Targeted physiology and modeling approaches revealed that these functional connectivity features collectively support the emergence of a paradoxical excitation-driven inhibition in response to high frequency LHb activation, and of a winner-take-all computation over protracted timescales. In vivo, we found that optogenetic activation of LHb inputs to DRN transiently disrupted expression of a reward-conditioned response in an auditory conditioning task. In accordance with quantitative model predictions, this disruption occurred exclusively at the conjunction of high frequency LHb activation and high predicted reward value, and was not due to a modulation of the underlying reward association. Thus, we propose that recurrent dynamics in the DRN support a contextual value computation, where stable learned associations are integrated with dynamic environmental inputs to support sharp behavioral state transitions in changing environments.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.31.506020v1?rss=1
Authors: Devoght, J., Comhair, J., Morelli, G., Rigo, J.-M., D'Hooge, R., Touma, C., Palme, R., Dewachter, I., vandeVen, M., Harvey, R. J., Schiffmann, S., Piccart, E., Brone, B.
Abstract: Distinct developmental pathologies, including autism spectrum disorder and schizophrenia, exhibit impaired reward-motivated behavior. Key to proper reward-motivated behavior is the integration of dopaminergic and glutamatergic inputs to the striatum. The glycine alpha 2 receptor (GlyR2) is the single functionally expressed glycine receptor in adult striatum, and is therefore ideally positioned to modulate striatal behavior and cellular signal integration. Here, we report excessive appetitive conditioning in GlyR2 knockout animals. We next show that depletion of GlyR2 enhances dopamine-induced increases in the activity of putative dopamine D1-expressing striatal projection neurons, while not affecting dopamine neuron activity. These in vivo behavioral changes are tied to enhanced striatal activation in GlyR2 KO mice, since we found excessive locomotor responses to amphetamine in GlyR2 KO mice that correlate with immediate early gene c-fos expression in the dorsal striatum. 3-D modeling revealed activation of cell ensembles in the striatum in response to D-amphetamine, an increase in number of cells but no shift in intercell distance histograms, in agreement with unaltered dopamine release, in GlyR2 KO mice. Taken together, we show that depletion of GlyR2 impairs reward-motivated behavior and altered striatal signal integration. This sheds important light onto the cellular mechanisms that underlie reward function, and pave the way towards novel therapeutics for the treatment of e.g. schizophrenia and autism spectrum disorder.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.31.506041v1?rss=1
Authors: Khatib, D., Ratzon, A., Sellevoll, M., Barak, O., Morris, G., Derdikman, D.
Abstract: Memories of past events can be recalled long after the event, indicating stability. But new experiences are also integrated into existing memories, indicating plasticity. In the hippocampus, spatial representations are known to remain stable, but have also been shown to drift over long periods of time. We hypothesized that experience, more than the passage of time, is the driving force behind memory plasticity. We compared the stability of place cells in the hippocampus of mice traversing two similar, familiar tracks for different durations. We found that the more time spent in an environment, the greater the representational drift, regardless of the total elapsed time. Our results suggest that spatial representation is a dynamic process, related to the ongoing experiences within a specific context, and is related to the accumulation of new memories rather than to passive forgetting.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.31.506080v1?rss=1
Authors: Munz, M., Bharioke, A., Kosche, G., Moreno-Juan, V., Brignall, A., Graff-Meyer, A., Ulmer, T., Rodrigues, T., Haeuselmann, S., Pavlinic, D., Ledergerber, N., Gross-Scherf, B., Rozsa, B., Krol, J., Picelli, S., Cowan, C. S., Roska, B.
Abstract: Cortical circuits are composed predominantly of pyramidal-to-pyramidal neuron connections, yet their assembly during embryonic development is not well understood. We show that embryonic layer 5 pyramidal neurons, identified through single cell transcriptomics, display two phases of circuit assembly in vivo. At E14.5, a multi-layered circuit motif, composed of a single layer 5 cell type, forms. This motif is transient, switching to a second circuit motif, involving all three types, by E17.5. In vivo targeted single cell recordings and two-photon calcium imaging of embryonic layer 5 neurons reveal that, in both phases, neurons have active somas and neurites, tetrodotoxin-sensitive voltage-gated conductances, and functional glutamatergic synapses. Embryonic layer 5 neurons strongly express autism-associated genes, and perturbing these genes disrupts the switch between the two motifs. Hence, layer 5 pyramidal neurons form transient active pyramidal-to-pyramidal circuits, at the inception of neocortex, and studying these circuits could yield insights into the etiology of autism.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.31.505985v1?rss=1
Authors: de Melo, G. D., Perraud, V., Alvarez, F., Vieites-Prado, A., Kim, S., Kergoat, L., Trueb, B. S., Tichit, M., Piazza, A., Thierry, A., Hardy, D., Wolff, N., Munier, S., Koszul, R., Simon-Loriere, E., Thiel, V., Lecuit, M., Lledo, P.-M., Renier, N., Larrous, F., Bourhy, H.
Abstract: Anosmia was identified as a hallmark of COVID-19 early in the pandemic, however, with the emergence of variants of concern, the clinical profile induced by SARS-CoV-2 infection has changed, with anosmia being less frequent. Several studies have focused on the neuropathogenesis of the original SARS-CoV-2, but little is known about the neuropathological potential of the variants. Here, we assessed the clinical, olfactory and inflammatory conditions of golden hamsters infected with the original SARS-CoV-2, its ORF7-deleted mutant, and three variants: Gamma, Delta and Omicron/BA.1. We show that infected animals developed a variant-dependent clinical disease, and that the ORF7 of SARS-CoV-2 contribute to causing olfactory disturbances. Conversely, all SARS-CoV-2 variants were found to be neuroinvasive, regardless of the clinical presentation they induce. With newly-generated nanoluciferase-expressing SARS-CoV-2, we validated the olfactory pathway as a main entry point towards the brain, confirming that neuroinvasion and anosmia are independent phenomena upon SARS-CoV-2 infection.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.29.505682v1?rss=1
Authors: Willemen, H., Ribeiro, P., Broeks, M., Meijer, N., Versteeg, S., Malecki, J., Falnes, P., Jans, J., Eijkelkamp, N.
Abstract: Pain often persists in patients with inflammatory diseases, even when the inflammation has subsided. The molecular mechanisms leading to this failure in resolution of inflammatory pain and the transition to chronic pain are poorly understood. Mitochondrial dysfunction in sensory neurons has been linked to chronic pain, but its role in resolution of inflammatory pain is unclear. Transient inflammation causes neuronal plasticity, called hyperalgesic priming, which impairs resolution of hyperalgesia induced by a subsequent inflammatory stimulus. We identified that hyperalgesic priming in mice caused disturbances in mitochondrial respiration, oxidative stress, and redox balance in dorsal root ganglia (DRG) neurons. Preventing these priming-induced disturbances restored resolution of inflammatory hyperalgesia. Concurrent with these mitochondrial and metabolic changes, the expression of ATPSc-KMT, a mitochondrial methyltransferase, was increased in DRG neurons in primed mice. ATPSc-KMT overexpression in DRG neurons of naive mice induced similar mitochondrial and metabolic changes as observed after priming, leading to failure in pain resolution. Inhibition of mitochondrial respiration, knockdown of ATPSCKMT expression, or NAD+ supplementation were sufficient to restore resolution of inflammatory pain and prevent chronic pain development. Thus, inflammation-induced mitochondrial-dependent disturbances in DRG neurons promote failure in inflammatory pain resolution and drive the transition to chronic pain.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.28.505627v1?rss=1
Authors: Luo, L., Wang, X., Lu, J., Chen, G., Luan, G., Li, W., Wang, Q., Fang, F.
Abstract: The concept of receptive field (RF) is central to sensory neuroscience. Neuronal RF properties have been substantially studied in animals, while those in humans remain nearly unexplored. Here, we measured neuronal RFs with intracranial local field potentials (LFPs) and spiking activity in human visual cortex (V1/V2/V3). We recorded LFPs via macro-contacts and discovered that RF sizes estimated from low-frequency activity (LFA, 0.5 to 30 Hz) were larger than those estimated from low-gamma activity (LGA, 30 to 60 Hz) and high-gamma activity (HGA, 60 to 150 Hz). We then took a rare opportunity to record LFPs and spiking activity via microwires in V1 simultaneously. We found that RF sizes and temporal profiles measured from LGA and HGA closely matched those from spiking activity. In sum, this study reveals that spiking activity of neurons in human visual cortex could be well approximated by LGA and HGA in RF estimation and temporal profile measurement, implying the pivotal functions of LGA and HGA in early visual information processing.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.29.505635v1?rss=1
Authors: Han, L. K., Dinga, R., Leenings, R., Hahn, T., Cole, J., Aftanas, L., Amod, A., Besteher, B., Colle, R., Corruble, E., Couvy-Duchesne, B., Danilenko, K., Fuentes-Claramonte, P., Saffet Gonul, A., Gotlib, I., Goya-Maldonado, R., Groenewold, N., Hamilton, P., Ichikawa, N., Ipser, J., Itai, E., Koopowitz, S.-M., Li, M., Okada, G., Okamoto, Y., Olga, C., Osipov, E., Penninx, B., Pomarol-Clotet, E., Rogriguez-Cano, E., Sacchet, M., Shinzato, H., Sim, K., Stein, D., Uyar-Demir, A., Veltman, D., Schmaal, L.
Abstract: Background: Several studies have evaluated whether depressed persons have older appearing brains than their nondepressed peers. However, the estimated neuroimaging derived brain age gap has varied from study to study, likely driven by differences in training and testing sample (size), age range, and used modality/features. To validate our previously developed ENIGMA brain age model and the identified brain age gap, we aim to replicate the presence and effect size estimate previously found in the largest study in depression to date (N=2,126 controls & N=2,675 cases; +1.08 years [SE 0.22], Cohen's d=0.14, 95% CI: 0.08 to 0.20), in independent cohorts that were not part of the original study. Methods: A previously trained brain age model (www.photon-ai.com/enigma_brainage) based on 77 FreeSurfer brain regions of interest was used to obtain unbiased brain age predictions in 751 controls and 766 persons with depression (18-75 years) from 13 new cohorts collected from 20 different scanners. Results: Our ENIGMA MDD brain age model generalized reasonably well to controls from the new cohorts (predicted age vs. age: r = 0.73, R2=0.47, MAE=7.50 years), although the performance varied from cohort to cohort. In these new cohorts, on average, depressed persons showed a significantly higher brain age gap of +1 year (SE 0.35) (Cohen's d=0.15, 95% CI: 0.05 to 0.25) compared with controls, highly similar to our previous finding. Conclusions: This study further validates our previously developed ENIGMA brain age algorithm. Importantly, we replicated the brain age gap in depression with a comparable effect size. Thus, two large-scale independent mega-analyses across in total 32 cohorts and >3,400 patients and >2,800 controls worldwide show reliable but subtle effects of brain aging in adult depression.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.26.505489v1?rss=1
Authors: Dabaghian, Y. A.
Abstract: Grid cells play a principal role in enabling mammalian cognitive representations of ambient environments. The key property of these cells---the regular arrangement of their firing fields---is commonly viewed as means for establishing spatial scales or encoding specific locations. However, using grid cells' spiking outputs for deducing spatial orderliness proves to be a strenuous task, due to fairly irregular activation patterns triggered by the animal's sporadic visits to the grid fields. The following discussion addresses statistical mechanisms enabling emergent regularity of grid cell firing activity, from the perspective of percolation theory. In particular, it is shown that the range of neurophysiological parameters required for spiking percolation phenomena matches experimental data, which points at biological viability of the percolation approach and casts a new light on the role of grid cells in organizing the hippocampal map.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.27.505287v1?rss=1
Authors: He, L., He, Y., Lun, K., Ma, L., Du, K., Huang, T.
Abstract: Retina ribbon synapses are the first synapses in the visual system. Unlike the conventional synapses in the central nervous system triggered by action potentials, ribbon synapses are uniquely driven by graded membrane potentials and are thought to transfer early sensory information faithfully. However, how ribbon synapses compress the visual signals and contribute to visual adaptation in retina circuits is less understood. To this end, we introduce a physiologically constrained module for the ribbon synapse, termed Ribbon Adaptive Block (RAB), and an extended "hierarchical Linear-Nonlinear-Synapse" (hLNS) framework for the retina circuit. Our models can elegantly reproduce a wide range of experimental recordings on synaptic and circuit-level adaptive behaviors across different cell types and species. In particular, it shows strong robustness to unseen stimulus protocols. Intriguingly, when using the hLNS framework to fit intra-cellular recordings from the retina circuit under stimuli similar to natural conditions, we revealed rich and diverse adaptive time constants of ribbon synapses. Furthermore, we predicted a frequency-sensitive gain-control strategy for the synapse between the photoreceptor and the CX bipolar cell, which differ from the classic contrast-based strategy in retina circuits. Overall, our framework provides a powerful analytical tool for exploring synaptic adaptation mechanisms in early sensory coding.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.29.504748v1?rss=1
Authors: Pini, L., de Lange, S., Pizzini, F. B., Boscolo Galazzo, I., Manenti, R., Cotelli, M., Galluzzi, S., Cotelli, M. S., Corbetta, M., Van den Heuvel, M., Pievani, M.
Abstract: Network neuroscience is a promising approach to explore cognitive processes in neurological disorders. Alzheimer's disease (AD) and frontotemporal dementia (FTD) show network dysfunctions linked with cognitive deficits. Within this framework, network abnormalities between AD and FTD show both convergent and divergent patterns. However, these functional patterns are far from being established and their relevance to cognitive processes remains to be elucidated. In this study, we aimed to investigate the relationship between cognition and functional connectivity of major cognitive networks in these diseases. Twenty-three bvFTD, 22 AD and 20 controls underwent cognitive evaluation and resting-state functional MRI. Principal component analysis was used to describe cognitive variance across participants. Brain network connectivity was estimated with connectome analysis. Connectivity matrices were created assessing correlations between parcels within each functional network. The following cognitive networks were considered: default mode (DMN), dorsal attention (DAN), ventral attention (VAN) and frontoparietal (FPN) networks. The relationship between cognition and connectivity was assessed using a robust convergent correlation-wise and interaction analyses. Three principal cognitive components explained more than 80% of the cognitive variance: the first component (cogPC1) loaded on memory, the second component (cogPC2) loaded on emotion and language, the third component (cogPC3) loaded on the visuo-spatial and attentional domains. Compared to HC, AD and bvFTD showed impairment in all cogPCs (p<0.002), and bvFTD scored worse than AD in cogPC2 (p=0.031). At the network level, the DMN showed a robust association in the whole group with cogPC1 and cogPC2, and the VAN with cogPC2. By contrast, DAN and FPN showed a divergent pattern between diagnosis and connectivity for cogPC2. We confirmed these results by means of a multivariate analysis (canonical correlation). These results suggest that a low-dimensional representation can account for a large variance in cognitive scores in the continuum from normal to pathological aging. Moreover, cognitive components showed both convergent and divergent patterns with connectivity across AD and bvFTD. The convergent pattern was observed across the networks primarily involved in these diseases (i.e., the DMN and VAN), while a divergent FC-cognitive pattern was mainly observed between attention/executive networks and the language/emotion cognitive component, suggesting the co-existence of compensatory and detrimental mechanisms underlying these components.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.29.505742v1?rss=1
Authors: Zheng, X. Y., Hebart, M. N., Dolan, R. J., Doeller, C. F., Cools, R., Garvert, M. M.
Abstract: The hippocampal-entorhinal system uses cognitive maps to represent spatial knowledge and other types of relational information, such as the transition probabilities between objects. However, objects can often be characterized in terms of different types of relations simultaneously, e.g. semantic similarities learned over the course of a lifetime as well as transitions experienced over a brief timeframe in an experimental setting. Here we ask how the hippocampal formation handles the embedding of stimuli in multiple relational structures that differ vastly in terms of their mode and timescale of acquisition: Does it integrate the different stimulus dimensions into one conjunctive map, or is each dimension represented in a parallel map? To this end, we reanalyzed functional magnetic resonance imaging (fMRI) data from Garvert et al. (2017) that had previously revealed an entorhinal map which coded for newly learnt statistical regularities. We used a triplet odd-one-out task to construct a semantic distance matrix for presented items and applied fMRI adaptation analysis to show that the degree of similarity of representations in bilateral hippocampus decreases as a function of semantic distance between presented objects. Importantly, while both maps localize to the hippocampal formation, this semantic map is anatomically distinct from the originally described entorhinal map. This finding supports the idea that the hippocampal-entorhinal system forms parallel cognitive maps reflecting the embedding of objects in diverse relational structures.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.29.505731v1?rss=1
Authors: Togoli, I., Fornaciai, M., Visibelli, E., Piazza, M., Bueti, D.
Abstract: Magnitude dimensions such as time and numerosity are fundamental components of our visual experience, allowing us to understand the environment and interact with it. Different magnitudes are however not processed independently from each other, but show a relationship whereby the perception of one dimension depends on the others (magnitude integration). In this study, we use electroencephalography (EEG) to address whether such integration may arise from a shared brain processing stage where different dimensions are integrated together, or from independent parallel processes interfering with each other. In the experiment, participants judged either the average numerosity or duration of dynamic dot-array stimuli concurrently modulated in both dimensions. First, the behavioural results show a magnitude integration effect in both tasks, with duration affecting the judgement of numerosity and vice versa. The EEG results further show that both numerosity and duration significantly modulate event-related potentials at several distinct latencies. Crucially, however, we identified a significant interaction between numerosity and duration emerging in a specific latency window (360-460 ms) irrespective of the task performed by participants. In this latency window, the modulation of ERPs provided by the interfering magnitude dimension can be predicted by the strength of the behavioural bias. Our results thus support the idea of different magnitude dimensions converging onto a shared perceptual processing stage mediating their integration. Overall, our results demonstrate a clear electrophysiological signature of magnitude integration between numerosity and time, and provide new evidence for a shared representational system encompassing different magnitude dimensions.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.29.505672v1?rss=1
Authors: Grimm, C., Duss, S. N., Privitera, M., Munn, B. N., Frassle, S., Chernysheva, M., Patriarchi, T., Razansky, D., Wenderoth, N., Shine, J., Bohacek, J., Zerbi, V.
Abstract: Noradrenaline (NA) release from the brainstem nucleus locus coeruleus (LC) changes activity and connectivity in neuronal networks across the brain, thus modulating multiple behavioural states. NA release is mediated by both tonic and burst-like neuronal LC activity. However, it remains unknown whether the functional changes in downstream projection areas depend on these firing patterns. Using optogenetics, pupillometry, photometry, and functional MRI in mice, we show that tonic and burst LC firing patterns elicit brain responses that are specific to the activation frequency and temporal pattern. Tonic activation of the LC evokes nonlinear responses in prefrontal, limbic, and cerebellar regions, in line with the proposed inverted-U relationship between LC activity and behaviour. We further demonstrate that LC activity enhances network integration and acts as a facilitator of brain state transitions, hence increasing brain flexibility. Together, these findings reveal how the LC-NA system achieves a nuanced regulation of global circuit operations.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.29.505760v1?rss=1
Authors: Fortin-Houde, J., Henderson, F., Ducharme, G., Amilhon, B.
Abstract: The hippocampus (HP) receives neurochemically diverse inputs from the raphe nuclei, including glutamatergic fibers characterized by the expression of the vesicular glutamate transporter VGLUT3. These raphe-HP VGLUT3 (VGLUT3HP) projections have been suggested to play a critical role in HP functions, yet a complete anatomical overview of raphe VGLUT3 projections to the forebrain, and in particular the HP, is lacking. Using anterograde viral tracing, we describe largely non-overlapping VGLUT3-positive projections from the dorsal raphe (DR) and median raphe (MnR) to the forebrain, with the HP receiving inputs from the MnR. A limited subset of forebrain regions such as the amygdaloid complex, claustrum and hypothalamus receive projections from both the DR and MnR that remain largely segregated. This highly complementary anatomical pattern suggests contrasting roles for DR and MnR VGLUT3 neurons. To further analyse the topography of VGLUT3 raphe projections to the HP, we used retrograde tracing and found that VGLUT3HP neurons distribute over several raphe sub-regions (including the MnR, paramedian raphe and B9 nucleus) and lack co-expression of serotonergic markers. Strikingly, two-color retrograde tracing unraveled two parallel streams of VGLUT3-positive projections targeting the dorsal and ventral poles of the HP. These results demonstrate highly organized and segregated VGLUT3-positive projections to the HP, suggesting independent modulation of HP functions such as spatial memory and emotion-related behavior.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.28.505618v1?rss=1
Authors: Zhou, X., Xiao, Q., Chen, S., Xu, X., Hong, Y., Chen, Y., Wang, L., Chen, Y., Yang, F., Tu, J.
Abstract: Many mental illnesses are accompanied by abnormal risk-avoidance behavior, yet we have only a limited understanding of the neuronal regulatory mechanisms involved. We previously established an inducible DISC1-N terminal fragment transgenic mouse (DISC1-NTM) model which has exhibited risk-avoidance deficiency. Using this model, we analyzed differentially expressed genes (DEGs) using snRNA-seq and the results indicate impaired neuron-astrocyte interactions. We used optogenetic tools to modulate astrocytes in the basolateral amygdala (BLA) and found that ChR2-expressing astrocytes were able to rescue risk-avoidance impairment in DISC1-NTM mice. Using patch clamp recordings combined with signal-cell qPCR, we found impaired excitability of BLAWFS1 neurons in DISC1-NTM mice and that ChR2-expressing astrocytes can induce action potentials (APs) in WFS1 neurons, which restores WFS1 neuronal activity. WFS1 neurons are necessary for BLA astrocytes to modulate impaired risk-avoidance behavior. These finding provide new insights into mechanisms of astrocyte-neuron interactions and suggest that BLA astrocytes may be a promising target for impaired risk avoidance in mental illness.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.28.502233v1?rss=1
Authors: Sonobe, Y., Yamagata, T., Yang, H., Haruki, Y., Ogawa, K.
Abstract: The sense of body ownership, defined as the sensation that one's body belongs to oneself, is a fundamental component of bodily self-consciousness. Several studies have shown the importance of multisensory integration for the emergence of the sense of body ownership, together with the involvement of the parieto-premotor and extrastriate cortices in bodily awareness. However, whether the sense of body ownership elicited by different sources of signal, especially visuotactile and visuomotor inputs, is represented by common neural patterns remains to be elucidated. We used functional magnetic resonance imaging (fMRI) to investigate the existence of neural correlates of the sense of body ownership independent of the sensory modalities. Participants received tactile stimulation or executed finger movements while given synchronous and asynchronous visual feedback of their hand. We used multi-voxel patterns analysis (MVPA) to decode the synchronous and asynchronous conditions with cross-classification between two modalities: the classifier was first trained in the visuotactile sessions and then tested in the visuomotor sessions and vice versa. Regions of interest-based and searchlight analyses revealed significant above-chance cross-classification accuracies in the bilateral intraparietal sulcus (IPS), the bilateral ventral premotor cortex (PMv), and the left extrastriate body area (EBA). Moreover, we observed a significant positive correlation between the cross-classification accuracy in the left PMv and the difference in subjective ratings of the sense of body ownership between the synchronous and asynchronous conditions. Our findings revealed the neural representations of the sense of body ownership in the IPS, PMv, and EBA that is invariant to the sensory modalities.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.29.505633v1?rss=1
Authors: Mannam, V., Howard, S.
Abstract: Machine learning (ML) models based on convolutional neural networks (CNNs) have been used to significantly increase microscopy resolution, speed (signal-to-noise ratio), and data interpretation. The bottleneck in developing effective ML systems is often the need to acquire large datasets to train the neural network. This paper demonstrates how adding a dense encoder-decoder block can be useful to effectively train a CNN that provides super-resolution images from conventional diffraction-limited microscopy images when trained using a small dataset containing 15 field-of-views (FOVs). DenseED blocks use a dense layer that concatenates features from the previous convolutional layer to the next convolutional layer. Demonstrate using DenseED blocks in fully convolutional networks (FCNs) to estimate the super-resolution images when trained with a small training dataset (15 FOVs) of human cells from the Widefield2SIM dataset and the fluorescent-labeled fixed bovine pulmonary artery endothelial cells (BPAE samples). Conventional ML models without DenseED blocks trained on small datasets fail to accurately estimate super-resolution images while models, including the DenseED blocks can. The average resolution and peak signal-to-noise ratio (PSNR) improvements achieved using DenseED blocks in FCNs when trained with 15 FOVs are 2 times and ~3.2 dB, respectively. In addition, we evaluated various configurations of target image generation methods (experimentally captured target and computationally generated target) that are used to train the FCNs with and without DenseED blocks and showed with DenseED blocks outperform compared to simple FCNs without DenseED blocks. Hence, the proposed approach indicates that microscopy applications can use DenseED blocks to train on smaller datasets that are application specific/experimental modality specific imaging platforms such as MRI/X-ray and other in vivo imaging modalities.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.505077v1?rss=1
Authors: Marinelli, I., Walker, J. J., Seneviratne, U., DSouza, W., Cook, M. J., Anderson, C., Bagshaw, A. P., Lightman, S. L., Woldman, W., Terry, J. R.
Abstract: Epilepsy is a serious neurological disorder characterised by a tendency to have recurrent, spontaneous, seizures. Classically, seizures are assumed to occur at random. However, recent research has uncovered underlying rhythms both in seizures and in key signatures of epilepsy - so-called interictal epileptiform activity - with timescales that vary from hours and days through to months. Understanding the physiological mechanisms that determine these rhythmic patterns of epileptiform discharges remains an open question. Many people with epilepsy identify precipitants of their seizures, the most common of which include stress, sleep deprivation and fatigue. To quantify the impact of these physiological factors, we analysed 24-hour EEG recordings from a cohort of 107 people with idiopathic generalized epilepsy. We found two subgroups with distinct distributions of epileptiform discharges: one with highest incidence during sleep and the other during day-time. We interrogated these data using a mathematical model that describes the transitions between background and epileptiform activity in large-scale brain networks. This model was extended to include a time-dependent forcing term, where the excitability of nodes within the network could be modulated by other factors. We calibrated this forcing term using independently-collected human cortisol (the primary stress-responsive hormone characterised by circadian and ultradian patterns of secretion) data and sleep-staged EEG from healthy human participants. We found that either the dynamics of cortisol or sleep stage transition, or a combination of both, could explain most of the observed distributions of epileptiform discharges. Our findings provide conceptual evidence for the existence of underlying physiological drivers of rhythms of epileptiform discharges. These findings should motivate future research to explore these mechanisms in carefully designed experiments using animal models or people with epilepsy.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.29.505641v1?rss=1
Authors: Newman, A. G., Sharif, J., Bessa, P., Zaqout, S., Brown, J., Nakayama, M., Mueller, S., Böhm-Sturm, P., Ohara, O., Koseki, H., Singh, P., Tarabykin, V.
Abstract: In aging cells and animal models of premature aging, heterochromatin loss coincides with the transcriptional activation of normally silenced endogenous retroviruses (ERVs). Here we show that loss of heterochromatin maintenance and de-repression of ERVs results in neurodegeneration via the Complement cascade in an age dependent manner. We discovered differential contributions of HP1 proteins to ERV silencing where HP1{gamma} is necessary and sufficient for H4K20me3 deposition and HP1{beta} deficiency is detrimental to DNA maintenance methylation. Progressive ERV de-repression in HP1{beta}/{gamma} DKO mice was followed by stimulation of the integrated stress response, the induction of Complement 3+ reactive astrocytes and increased infiltration and activation of microglia. This chronic inflammatory state coincided with age-dependent reductions in dendrite complexity and cognition. Our results demonstrate the importance of preventing loss of epigenetic maintenance, as this will be the only way postmitotic neuronal genomes can be protected and/or renewed.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.29.505610v1?rss=1
Authors: Broadhead, M. J., Doucet, K., Kantelberg, O. G., Zhu, F., Grant, S. G. N., Horrocks, M. H., Miles, G. B.
Abstract: Cellular inclusions of hyperphosphorylated TAR-DNA-Binding Protein 43 (TDP-43) are a key hallmark of neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS). ALS is characterised by a loss of motor neurons in the brain and spinal cord that is preceded by early-stage changes in synaptic function that may be associated with TDP-43 pathology. However, there has been little characterisation of the synaptic expression of TDP-43 in spinal cord synapses. This study utilises a range of high-resolution and super-resolution microscopy techniques with immunolabelling, as well as an aptamer-based TDP-43 labelling strategy visualised with single-molecule localisation microscopy, to characterise and quantify the presence of phosphorylated TDP-43 (pTDP-43) in spinal cord synapses. We observe that TDP-43 is expressed in the majority of spinal cord synapses as nanoscale clusters as small as 60 nm in diameter. Synaptic TDP-43 expression is more frequently associated with presynaptic terminals than postsynaptic densities, and is more enriched in VGLUT1-associated synapses, compared to VGLUT2-associated synapses. Our nanoscopy techniques showed no difference in the subsynaptic expression of pTDP-43 in the ALS mouse model, SOD1G93a compared to healthy controls. This research characterizes the basic synaptic expression of TDP-43 with nanoscale precision and provides a framework with which to investigate the potential relationship between TDP-43 pathology and synaptic pathology in neurodegenerative diseases.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.28.505585v1?rss=1
Authors: Bruel, B. M., Katopodis, V. G., de Vries, R., Donner, T. H., McGinley, M. J., de Gee, J. W.
Abstract: Recent work indicates that pupil-linked phasic arousal signals reduce the impact of prior expectations and biases on decision formation. It has remained unclear whether phasic arousal (i) causes the bias reduction, if (ii) choosing against one's bias causes phasic arousal, or if (iii) a third variable is driving both. Here, using an auditory accessory stimulus, we found evidence for the first scenario: on accessory stimulus vs normal trials, pupil-linked phasic arousal was robustly elevated and choice bias was reduced. With computational modeling of behavior, we established that the bias reduction was not due to a change in response caution (i.e., speed-accuracy tradeoff), but due to a change in a bias in the accumulation of evidence leading up to a choice. Thus, pupil-linked phasic arousal shapes choice behavior.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.27.505553v1?rss=1
Authors: Tsong, H., Holzbaur, E., Stavoe, A. K.
Abstract: Misregulation of neuronal autophagy has been implicated in age-related neurodegenerative diseases including Parkinson's disease and Huntington's disease. We compared autophagosome formation and maturation in primary murine neurons during development and through aging to elucidate how aging affects neuronal autophagy. We observed an age-related decrease in the rate of formation of LC3B-positive autophagosomes leading to a significant decrease in the density of autophagosomes along the axon. Next, we assessed the maturation of autophagic vesicles and identified a surprising increase in their maturation in neurons from aged mice. While we did not detect notable changes in endolysosomal content in the distal axon during aging, we found that autophagic vesicles were transported more efficiently in neurons from adult mice than in neurons from young mice. This efficient transport of autophagic vesicles in both the distal and proximal axon is maintained in neurons from aged mice and indicates that aging alone does not impair transport nor negatively impact the later stages of autophagy. However, the pronounced deficit in autophagosome biogenesis in aged neurons may contribute to a decreased capacity to clear aggregated proteins or dysfunctional organelles and thus contribute to age-related degeneration.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.26.505475v1?rss=1
Authors: Dossat, A., Kokoska, M. M., Whitaker-Fornek, J., Kulkarni, A. S., Levitt, E. S., Wesson, D. W.
Abstract: The gustatory region of the insular cortex (GC) processes taste information in manners important for taste-guided behaviors, including food intake itself. In addition to oral gustatory stimuli, GC activity is also influenced by physiological states including hunger. The specific cell-types and molecular mechanisms that afford with GC with such influences on food intake are unclear. Glucagon-like peptide 1 (GLP-1) is produced by neurons in the brain whereafter it can act upon GLP-1 receptor-expressing (GLP-1R+) neurons found in several brain regions. In these brain regions, GLP-1R agonism suppresses homeostatic food intake and dampens the hedonic value of food. Here, we report in mice of both sexes that cells within the GC express GLP-1R mRNA and further, by ex vivo brain slice recordings, that GC GLP-1R+ neurons are depolarized by the selective GLP-1R agonist, exendin-4 (Ex-4). Next we found that chemogenetic stimulation of GLP-1R+ neurons, and also pharmacological stimulation of GC-GLP-1Rs themselves, both reduced homeostatic food intake. When maintained on a high-fat diet, obese mice exhibited impaired food intake responses when Ex-4 was administered into the GC. Yet, when obese mice were switched to a low-fat diet, the effect of GC Ex-4 was restored, indicating that GC GLP-1R influences may depend upon palatability of the food. Together, these results provide evidence for a specific cell population in the GC which may hold roles in both homeostatic and hedonic food intake.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.27.505441v1?rss=1
Authors: Delamare, G., Feitosa Tome, D., Clopath, C.
Abstract: Memories are thought to be stored in neural ensembles known as engrams that are specifically reactivated during memory recall. Recent studies have found that memory engrams of two events that happened close in time tend to overlap in the hippocampus and the amygdala, and these overlaps have been shown to support memory linking. It has been hypothesised that engram overlaps arise from the mechanisms that regulate memory allocation itself, involving neural excitability, but the exact process remains unclear. Indeed, most theoretical studies focus on synaptic plasticity and little is known about the role of intrinsic plasticity, which could be mediated by neural excitability and serve as a complementary mechanism for forming memory engrams. Here, we developed a rate-based recurrent neural network that includes both synaptic plasticity and neural excitability. We obtained structural and functional overlap of memory engrams for contexts that are presented close in time, consistent with experimental studies. Moreover, we showed that enhancing the initial excitability of a subset of neurons just before presenting a context biases the memory allocation to these neurons. We then explored the role of inhibition as a way of controlling competition among neurons from two ensembles. This work suggests mechanisms underlying the role of intrinsic excitability in memory allocation and linking, and yields predictions regarding the dynamics of memory engrams.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.28.505586v1?rss=1
Authors: Elshahabi, A., Ethofer, s., Lerche, H., Wehrl, H., la Fougere, C., Braun, C., Focke, N. K.
Abstract: Despite several studies investigating the relationship between blood-oxygen-level-dependent functional MRI (BOLD-fMRI) and neuroelectric activity, our understanding is rather incomplete. For instance, the canonical hemodynamic response function (HRF) is commonly used, regardless of brain region, frequency of electric activity and functional networks. We studied this relationship between BOLD-fMRI and electroencephalography (EEG) signal of the human brain in detail using simultaneous fMRI and EEG in healthy awake human subjects at rest. Signals from EEG sensors were filtered into different frequency bands and projected into three-dimensional source space. The correlation of the time courses of the two modalities were quantified on a voxel-by-voxel basis on full-brain level as well as separately for each resting state network, with different temporal shifts and EEG frequency bands. We found highly significant correlations between the BOLD-fMRI signal and simultaneously measured EEG, yet with varying time-lags for different frequency bands and different resting state networks. Additionally, we found significant negative correlations with a much longer delay in the fMRI BOLD signal. The positive correlations were mostly around 6-8 seconds delayed in the BOLD time course while the negative correlations were noticed with a BOLD offset of around 20 to 26 seconds. These positive and negative correlation patterns included the commonly reported alpha and gamma bands but also extend in other frequency bands giving characteristic profiles for different resting state networks. Our results confirm recent works that suggest that the relationship between the two modalities is rather brain region / network-specific than a global function and suggest that applying a global canonical HRF for electrophysiological data is probably insufficient to account for the different spatial and temporal dynamics of different brain networks. Moreover, our results suggest that the HRF also varies in different frequency bands giving way to further studies investigating cross-frequency coupling and its interplay with resting state networks.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.28.505598v1?rss=1
Authors: Palmigiano, A., Engelken, R., Wolf, F.
Abstract: Cortical networks exhibit highly irregular spiking activity to repeated stimuli. One source of such variability is network chaos, ever-present in spiking network models. In order to reliably and robustly represent and transmit information, cortical networks must implement active mechanisms to quench undesired changes in spiking patterns. Neuronal oscillations have been proposed as a mechanism to flexibly gate information flow across the cortex, but whether these collective rhythms would actually contribute to quenching spiking unreliability and tame network chaos by synchronizing activity, or on the contrary, intensify chaos by acting as a common drive to the network, is not easily predictable. Here we investigate the dynamical properties of network models with respect to two known control parameters regulating collective oscillatory activity: delayed recurrent inhibition and an external periodic drive. To do so, we advanced the tractability of large spiking networks of exactly solvable neuronal models by developing a strategy that allows for exact characterization of the dynamics on the attractor of effectively delayed network models in a system with fixed and finite degrees of freedom. We find that, below the transition to collective oscillations, neuronal networks have a stereotypical dependence on the delay so far only described for scalar systems and low-dimensional maps. We demonstrate that the emergence of internally generated oscillations induces a complete dynamical reconfiguration, by increasing the dimensionality of the chaotic attractor, the speed at which nearby trajectories separate from one another, and the rate at which the network produces entropy. Our results suggest that simple temporal dynamics of the mean activity can have a profound effect on the structure of the spiking patterns and therefore on the information processing capability of neuronal networks.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.25.505251v1?rss=1
Authors: Millar, P. R., the Dominantly Inherited Alzheimer Network,, Gordon, B. A., Luckett, P. H., Benzinger, T., Cruchaga, C., Fagan, A. M., Hassenstab, J., Perrin, R. J., Schindler, S. E., Allegri, R. F., Day, G. S., Farlow, M. R., Mori, H., Nübling, G., Bateman, R., Morris, J., Ances, B.
Abstract: Background: Estimates of "brain-predicted age" quantify apparent brain age compared to normative trajectories of neuroimaging features. The brain age gap (BAG) between predicted and chronological age is elevated in symptomatic Alzheimer disease (AD), but has not been well explored in preclinical AD. Prior studies have typically modeled BAG with structural magnetic resonance imaging (MRI), but more recently other modalities, including functional connectivity (FC) and multimodal MRI, have been explored. Methods: We trained three models to predict age from FC, volumetric (Vol), or multimodal MRI (Vol+FC) in 390 control participants (18-89 years old). In independent samples of 144 older adult controls, 154 preclinical AD participants, and 154 cognitively impaired (CI; CDR > 0) participants, we tested relationships between BAG and AD biomarkers of amyloid, tau, and neurodegeneration, as well as a global cognitive composite. Results: All models predicted age in the control training set, with the multimodal model outperforming the unimodal models. All three BAG estimates were significantly elevated in CI compared to controls. FC-BAG and Vol+FC-BAG were marginally reduced in preclinical AD participants compared to controls. In CI participants only, elevated Vol-BAG and Vol+FC-BAG were associated with more advanced AD pathology and lower cognitive performance. Conclusions: Both FC-BAG and Vol-BAG are elevated in CI participants. However, FC and volumetric MRI also capture complementary signals. Specifically, FC-BAG may capture a unique biphasic response to preclinical AD pathology, while Vol-BAG may capture pathological progression and cognitive decline in the symptomatic stage. A multimodal age-prediction model captures these modality-specific patterns, and further, improves sensitivity to healthy age differences. Funding: This work was supported by the National Institutes of Health (P01-AG026276, P01-AG03991, P30-AG066444, 5-R01-AG052550, 5-R01-AG057680, 1-R01-AG067505, 1S10RR022984-01A1, U19-AG032438), the BrightFocus Foundation (A2022014F), and the Alzheimers Association (SG-20-690363-DIAN).
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.26.505307v1?rss=1
Authors: Li, D., Hu, Y., Qi, M., Zhao, C., Jensen, O., Huang, J., Song, Y.
Abstract: Previous work has proposed two potentials benefits of retrospective attention on working memory (WM): target strengthening and non-target inhibition. It remains unknown which hypothesis contributes to the improved WM performance, yet the neural mechanisms responsible for this attentional benefit are unclear. Here, we recorded electroencephalography (EEG) signals while 33 participants performed a retrospective-cue WM task. Multivariate pattern classification analysis revealed that only representations of target features were enhanced by valid retrospective attention during the retention, supporting the target strengthening hypothesis. Further univariate analysis found that mid-frontal theta inter-trial phase coherence (ITPC) and ERP components were modulated by valid retrospective attention and correlated with individual differences and moment-to-moment fluctuations on behavioral outcomes, suggesting that both trait- and state-level variability in attentional preparatory processes influence goal-directed behavior. Furthermore, task-irrelevant target spatial location could be decoded from EEG signals, indicating that enhanced spatial binding of target representation promotes high WM precision. Importantly, frontoparietal theta-alpha phase-amplitude-coupling was increased by valid retrospective attention and predicted the reduced randomly guessing rates. This long-range connection supported top-down information flow in engagement of frontoparietal networks, which might organize attentional states to integrate target features. Altogether, these results provide neurophysiological bases that retrospective attention improves WM precision through enhancing representation of target and emphasize the critical role of frontoparietal attentional network in the control of WM representations.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.26.505477v1?rss=1
Authors: Zheng, X. Y., Piai, V.
Abstract: Speaking is not only about retrieving words and structuring them into sentences, but it also requires top-down control to plan and execute speech. In previous electrophysiological research with young-adult speakers, mid-frontal theta oscillations have been observed using a picture-word interference paradigm. With this paradigm, participants name pictures while ignoring superimposed distractor words. In particular, mid-frontal theta power increases for categorically related distractors relative to other types of distractors, reflecting the top-down interference control in resolving the competition between processing streams during word production (Piai, Roelofs, Jensen, Schoffelen, & Bonnefond, 2014). In the present study, we conceptually replicated the magnetoencephalography study by Piai et al. (2014) with an older group of healthy adults (mean age of 60 years). Behaviorally, we replicated distractor semantic interference and Stroop-like interference effects usually observed in young adults. However, we did not find the corresponding theta modulation associated with these interference effects on the neural level. Instead, we found beta power decreases for both effects, mostly pronounced in the left posterior temporal and inferior parietal cortex. The distinct spectro-spatial-temporal profile of the oscillatory effects in the older population suggests different underlying dynamics relative to the midline frontal effect previously found in young-adult speakers. Our results indicate that the neural underpinnings of top-down interference control may be modified by aging, and that the mid-frontal theta cannot be the exclusive mechanism enabling interference control during spoken word production.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.27.504533v1?rss=1
Authors: Shaw, G., Madorsky, I., Li, Y., Wang, Y., Rana, S., Fuller, D.
Abstract: Recent work shows that certain immunological assays for the neurofilament light chain NF-L detect informative signals in the CSF and blood of human and animals affected by a variety of CNS injury and disease states. Much of this work has been performed using two mouse monoclonal antibodies to NF-L, UD1 and UD2, also known as 2.1 and 47.3 respectively. These are the essential components of the Uman Diagnostics NF-Light ELISA kit, the Quanterix Simoa bead based NF-L assay and others. We show here that the antibodies bind to neighboring epitopes in a short, conserved and unusual peptide in the NF-L "rod" Coil 2 region. We also describe a surprising and useful feature of Uman and similar reagents. While other well characterized NF-L antibodies show robust staining of countless cells and processes in CNS sections from healthy rats, both Uman antibodies reveal only a minor subset of presumably spontaneously degenerating or degenerated neurons and their processes. However following experimental mid-cervical injuries to rat spinal cord both Uman antibodies recognize numerous profiles in tissue sections. The Uman positive material was associated with fiber tracts expected to be damaged by the injury administered and the profiles had the swollen, beaded, discontinuous and sinusoidal morphology expected for degenerating and degenerated processes. We also found that several antibodies to the C terminal "tail" region of NF-L stain undamaged axonal profiles but fail to recognize the Uman positive material. The unmasking of the Uman epitopes and the loss of the NF-L tail epitopes can be mimicked by treating sections from healthy animals with proteases suggesting that the immunological changes we have discovered are due to neurodegeneration induced proteolysis. We have also generated a novel panel of monoclonal and polyclonal antibody reagents directed against the region of NF-L including the Uman epitopes which have staining properties identical to the Uman reagents. Using these we show that the NF-L region to which the Uman reagents bind contains further hidden epitopes distinct from those recognized by the two Uman reagents. We speculate that the Uman type epitopes are part of a binding region important for higher order neurofilament assembly. The work provides important insights into the properties of the NF-L biomarker, describes novel and useful properties of Uman type and NF-L tail binding antibodies and provides a hypothesis relevant to further understanding of neurofilament assembly.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.26.505502v1?rss=1
Authors: Wei, X., Cheng, Z., Chen, W., Guo, H., Liu, Z., Hu, T., Zhang, Y., Cai, Q., Ge, F., Fan, Y., Chang, J., Guan, X.
Abstract: Cocaine abuse during adolescence increases the risk for developing drug addiction in later life, but the underlying molecular mechanism remains unclear. Here, adolescent cocaine-exposed (ACE) male mice models were established by giving once-daily intraperitoneal injections of 15 mg/kg cocaine to mice during adolescence (P28-P42). We found that ACE mice exhibited a higher sensitivity to subthreshold dose of cocaine (1 mg/kg) in adulthood, accompanied with triggered activities and dendritic spine density of pyramidal neuron, increased Dusp1 gene, as well as reduced protein levels and activity of dual specificity phosphatase 1 (DUSP1) in mPFC. Specific overexpression of DUSP1 on mPFC glutamatergic neurons efficiently blocked cocaine-preferred behaviors and reduced mPFC activity, while knockdown of DUSP1 maintained cocaine-preferred behaviors and increased mPFC activity in ACE mice. MAPK-related signals, especially ERK1/2, might underlie the mediating effects of DUSP1. Collectively, these findings suggested that targeting mPFC DUSP1 may represent a promising therapeutic strategy for the treatment and attenuation of addiction susceptibility, particularly in addicts with a history of adolescent drugs exposure.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.27.505547v1?rss=1
Authors: Yeh, S.-Y., Estill, M., Lardner, C. K., Browne, C. J., Minier-Toribio, A., Futamura, R., Beach, K., McManus, C. A., Xu, S.-j., Zhang, S., Heller, E. A., Shen, L., Nestler, E. J.
Abstract: The ability of neurons to respond to external stimuli involves adaptations of gene expression. The transcription factor, {Delta}FOSB, is important for the development of drug addiction, however, its gene targets have not been identified. Here we use CUT&RUN to map the genome-wide enrichment of {Delta}FOSB binding in the two major neuronal cell types of the nucleus accumbens, a key brain reward region, after cocaine exposure. The binding landscape shows that the majority of {Delta}FOSB peaks occur outside of promoter regions, including intergenic regions, and are surrounded by epigenetic marks indicative of active enhancers. BRG1, the core subunit of the SWI/SNF chromatin remodeling complex, overlaps with {Delta}FOSB peaks, consistent with earlier studies of {Delta}FOSB's interacting proteins. In addition, in silico analyses predict that {Delta}FOSB cooperatively regulates gene expression with homeobox and T-box transcription factors. These novel findings uncover key elements of {Delta}FOSB's molecular mechanisms in transcriptional regulation.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.26.505472v1?rss=1
Authors: Morrone Parfitt, G., Coccia, E., Goldman, C., Whitney, K., Reyes, R., Sarrafha, L., Nam, K. H., Jones, D., crary, J. F., Ordureau, A., Blanchard, J., Ahfeldt, T. D.
Abstract: Accumulation of advanced glycation end products (AGEs) on biopolymers accompany cellular aging and drives poorly understood disease processes. Here, we studied how AGEs contribute to development of early on-set Parkinson's Disease (PD) caused by loss-of-function of DJ1, a protein deglycase. In induced pluripotent stem cell (iPSC)-derived midbrain organoid models deficient for DJ1 activity, we find that lysosomal proteolysis is impaired, causing AGEs to accumulate, -synuclein (-syn) phosphorylation to increase, and proteins to aggregate. These processes are at least partly driven by astrocytes, as DJ1 loss reduces their capacity to provide metabolic support and triggers acquisition of a pro-inflammatory phenotype. Consistently, in co-cultures, we find that DJ1-expressing astrocytes are able to reverse the proteolysis deficits of DJ1 knockout midbrain neurons. In conclusion, astrocytes' capacity to clear toxic damaged proteins is critical to preserve neuronal function and their dysfunction contributes to the neurodegeneration observed in PD.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.26.505381v1?rss=1
Authors: van Beest, E. H., Abdelwahab, M. A., Cazemier, J. L., Baltira, C., Maes, M. C., Peri, B. D., Self, M. W., Willuhn, I., Roelfsema, P. R.
Abstract: The striatum, input nucleus of the basal ganglia, receives topographically organized input from the cortex and gives rise to the direct and indirect pathways with antagonistic effects on the output of the basal ganglia. We optogenetically stimulated the direct and indirect pathways in mice and measured their influence on perceptual decisions and neuronal activity in the cortex. In a task in which mice had to detect a visual stimulus, unilateral direct-pathway stimulation increased the probability of lick responses to the non-stimulated side and increased cortical activity globally. In contrast, indirect-pathway stimulation increased the probability of licks to the stimulated side and decreased activity in visual cortical areas. To probe the possible role of the two pathways in working memory, we trained the mice to report the location of a stimulus with licking one of two spouts, after a memory delay. Direct-pathway stimulation prior to and during the memory delay enhanced both the neural representation of a contralateral visual stimulus and the number of contraversive choices, whereas indirect-pathway stimulation had the opposite effects, in accordance with an antagonistic influence of the direct and indirect pathways on licking direction. Our results demonstrate how these two pathways influence perceptual decisions and working memories, and modify activity in the cerebral cortex.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.26.502106v1?rss=1
Authors: Reuschenbach, J., Reinert, J. K., Fukunaga, I.
Abstract: Knowing what factors affect the acquisition of a behavioural task is central to understanding the mechanisms of learning and memory. It also has practical implications, as animal behavioural experiments used to probe cognitive functions often require lengthy training. Delayed Match (or Non-Match)-to-Sample (DMS/DNMS) tasks are relatively complex tasks used to study working memory and sensory perception, but their use in the mouse remains hampered by the lengthy training involved. In this study, we assessed two aspects of stimulus timing on the acquisition of an olfactory DNMS task: how the sample-test odour delay durations and the reward timing affect the acquisition rate. We demonstrate that head-fixed mice learn to perform an olfactory DNMS task more quickly when the initial training uses a shorter sample-test odour delay without detectable loss of generalisability. Unexpectedly, we observed a slower task acquisition when the odour-reward interval was shorter. This effect was accompanied by a shortening of reaction times and more frequent sporadic licking. Analysis of this result using a drift-diffusion model indicated that a primary consequence of early reward delivery is a lower decision bound. Since an accurate performance with a lower decision bound requires greater discriminability in the sensory representations, this may underlie the slower learning rate with early reward arrival. Together, our results reflect the possible effects of stimulus timing on stimulus encoding and its consequence on the acquisition of a complex task.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.26.505388v1?rss=1
Authors: Meissner, S. N., Baechinger, M., Kikkert, S., Imhof, J., Missura, S., Carro Dominguez, M., Wenderoth, N.
Abstract: The brain's state of arousal influences cognitive functioning and mental well-being. It is controlled by several neuromodulatory nuclei in the brainstem and, particularly, by the locus coeruleus (LC). The LC is the main source of noradrenaline (NA) in the central nervous system where it exerts powerful effects on neural processing and autonomic function. Here, we investigate whether human participants can gain volitional control of their brain's arousal state using a new neurofeedback approach which exploits the mechanism that the eye's pupil diameter provides an indirect readout of arousal if light conditions are controlled. We show that pupil-based neurofeedback training is essential for learning how to self-regulate pupil size. Once acquired, pupil self-regulation significantly modulates neuromodulatory brainstem centers involved in arousal control and particularly the LC-NA system when carefully measured with functional magnetic resonance imaging. Further, it modulates heart rate, a cardiovascular marker of autonomic function, and it has a significant effect on behavior and specific psychophysiological responses during an oddball task, an attention task that has been shown to be evoke stimulus-dependent LC-NA activity. Considering the modulatory effects of the LC-NA system and other arousal-regulating centers on cognitive functioning and various behaviors including stress-related responses, pupil-based neurofeedback has a tremendous potential to be translated to behavioral and clinical applications across various domains.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.25.505306v1?rss=1
Authors: Berners-Lee, A., Shtrahman, E., Grimaud, J., Murthy, V. N.
Abstract: Rodents can learn from exposure to rewarding odors to make better and quicker decisions. The piriform cortex is thought to be important for learning complex odor associations, however it is not understood exactly how it learns to remember discriminations between many, sometimes overlapping, odor mixtures. We investigated how odor mixtures are represented in the posterior piriform cortex (pPC) of mice while they learn to discriminate a unique target odor mixture against hundreds of nontarget mixtures. We find that a significant proportion of pPC neurons discriminate between the target and all other nontarget odor mixtures. Neurons that prefer the target odor mixture tend to respond with brief increases in firing rate at odor onset compared to other neurons, which exhibit sustained and/or decreased firing. We allowed mice to continue training after they had reached high levels of performance and find that pPC neurons become more selective for target odor mixtures as well as for randomly chosen repeated nontarget odor mixtures that mice did not have to discriminate from other nontargets. These single unit changes during overtraining are accompanied by better categorization decoding at the population level, even though behavioral metrics of mice such as reward rate and latency to respond do not change. However, when difficult ambiguous trial types are introduced, the robustness of the target selectivity is correlated with better performance on the difficult trials. Taken together, these data reveal pPC as a dynamic and robust system that can optimize for both current and possible future task demands at once.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.25.504678v1?rss=1
Authors: Borjigin, A., Kokkinakis, K., Bharadwaj, H. M., Stohl, J. S.
Abstract: Despite excellent performance in quiet, cochlear implants (CIs) only partially restore normal levels of intelligibility in noisy settings. Recent developments in machine learning have resulted in deep neural network (DNN) models that achieve noteworthy performance in speech enhancement and separation tasks. However, there are no commercially available CI audio processors that utilize DNN models for noise reduction. We implemented two DNN models intended for applications in CIs: (1) a recurrent neural network (RNN), which is a lightweight template model, and (2) SepFormer, which is the current top-performing speech separation model in the literature. The models were trained with a custom training dataset (30 hours) that included four configurations: speech in non-speech noise and speech in 1-talker, 2-talker, and 4-talker speech babble backgrounds. The enhancement of the target speech (or the suppression of the noise) by the models was evaluated by commonly used acoustic evaluation metrics of quality and intelligibility, including (1) signal-to-distortion ratio, (2) ``perceptual'' evaluation of speech quality, and (3) short-time objective intelligibility. Both DNN models yielded significant improvements in all acoustic metrics tested. The two DNN models were also evaluated with thirteen CI users using two types of background noise: (1) CCITT noise (speech-shaped stationary noise) and (2) 2-talker babble. Significant improvements in speech intelligibility were observed when the noisy speech was processed by the models, compared to the unprocessed conditions. This work serves as a proof of concept for the application of DNN technology in CIs for improved listening experience and speech comprehension in noisy environments.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.26.505367v1?rss=1
Authors: Meseguer-Beltran, M., Sanchez-Sarasua, S., Landry, M., Kerekes, N., Sanchez-Perez, A. M.
Abstract: Aims: Attention deficit/ hyperactivity disorder (ADHD) is a neurodevelopmental syndrome characterized by dopaminergic dysfunction. In this study, we aimed to demonstrate the link between dopaminergic deficit and neuroinflammation underlying ADHD symptoms. Subjects and Treatment: We used a validated ADHD mice model, that involves perinatal 6-OHDA lesion. Animals were treated with 20mg/L (drinking water) of Abscisic acid (ABA) for one month. We tested behaviour (learning and memory, anxiety, social interactions, and pain) in both females and male mice, in all eight groups (control and lesioned, with/without ABA). Postmortem, we analyzed microglia morphology and Ape1 expression in specific brain areas related to the descending pain inhibitory pathway. Results: In females, dopaminergic deficit increased pain sensitivity, but not hyperactivity, in contrast to males. This behaviour was associated with inflammatory microglia and lower Ape1 levels in the anterior cingulate cortex (ACC) and posterior insula cortex (IC). ABA treatment reduced inflammation and alleviated pain. In males, ABA reduced hyperactivity, but had no significant effect on inflammation. Conclusions: This is the first study proving a sex-dependent association between dopamine dysfunction and inflammation in specific brain areas, leading to different behavior outcomes in a mouse model of ADHD. These findings provide new clues for potential treatments.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.25.505296v1?rss=1
Authors: Vandrey, B., Armstrong, J., Brown, C. M., Garden, D. L. F., Nolan, M. F.
Abstract: Standard models for spatial and episodic memory suggest that the lateral entorhinal cortex (LEC) and medial entorhinal cortex (MEC) send parallel independent inputs to the hippocampus, each carrying different types of information. Here, we evaluate the possibility that information is integrated between divisions of the entorhinal cortex prior to reaching the hippocampus. We demonstrate that fan cells in layer 2 (L2) of LEC that receive neocortical inputs, and that project to the hippocampal dentate gyrus, also send axon collaterals to layer 1 (L1) of the MEC. Activation of fan cell inputs evokes monosynaptic glutamatergic excitation of stellate and pyramidal cells in L2 of the MEC, typically followed by inhibition that contains fast and slow components mediated by GABAA and GABAB receptors, respectively. Fan cell inputs also directly activate interneurons in L1 and L2 of MEC, with synaptic connections from L1 interneurons accounting for slow feedforward inhibition of L2 principal cell populations. The relative strength of excitation and inhibition following fan cell activation differs substantially between neurons and is largely independent of anatomical location. Our results demonstrate that the LEC, in addition to directly influencing the hippocampus, can activate or inhibit major hippocampal inputs arising from the MEC. Thus, local circuits in the superficial MEC may combine spatial information with sensory and higher order signals from the LEC, providing a substrate for integration of what and where components of episodic memories.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.25.505357v1?rss=1
Authors: Madrid, L. I., Badhavkar, S., Hafey, K., Jimenez-Martin, J., Milne, M., Coulson, E. J., Jhaveri, D.
Abstract: Cholinergic signaling plays a crucial role in the regulation of adult hippocampal neurogenesis and hippocampus-dependent cognitive and mood-related functions. However, the contribution of basal forebrain medial septum (MS) and diagonal band of Broca (DBB) cholinergic neurons that innervate the hippocampus and the identity of the cholinergic receptor(s) that regulate the production and maturation of new neurons are not completely understood. Using a targeted, selective ablation approach, we show that MS/DBB cholinergic neurons support both the survival and morphological maturation of adult-born neurons in the mouse hippocampus. We demonstrate that the muscarinic acetycholine receptor subtype M4 (M4 mAChR) is expressed on a population of quiescent neural precursor cells (NPCs) and that its pharmacological stimulation via intra-hippocampal or systemic administration of M4-selective modulators leads to their activation, thereby enhancing neurogenesis in vivo. Furthermore, we show that the activation of M4 mAChR-expressing quiescent NPCs ameliorates the MS/DBB cholinergic lesion-induced decrease in hippocampal neurogenesis. In contrast, the impairment in the morphological maturation of adult-born neurons due to MS/DBB cholinergic neuron loss is further exacerbated by the systemic administration of an M4-selective allosteric potentiator. These findings reveal novel and stage-specific roles of cholinergic signaling in regulating adult hippocampal neurogenesis. They also uncouple the positive role of selective M4 potentiators in enhancing the production of new neurons from the M4-induced inhibition of their morphological maturation, at least in the context of cholinergic dysfunction.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.25.505358v1?rss=1
Authors: Becchi, S., Chieng, B., Bradfield, L., Capallan, R., Leung, B., Balleine, B. W.
Abstract: The loss of neurons in parafascicular thalamus (Pf) and of their inputs to dorsomedial striatum (DMS) are associated with Lewy body disease (LBD) and Parkinsons disease dementia (PDD) and have been linked to the effects of neuroinflammation. In rats, these inputs regulate the function of striatal cholinergic interneurons (CINs) that are necessary for the flexible encoding of the action-outcome (AO) associations for goal-directed action. We found that these inputs modify the encoding, not retrieval, of new AO associations and cause burst-pause firing of CINs in the DMS during AO remapping. These adaptive effects were abolished by neuroinflammation in the Pf, resulting in the loss of goal-directed control when the rats were required to update AO associations after a change in contingency. We found that the neuronal and behavioral deficits induced by inflammation in the Pf were rescued by administration of selegiline, a MAO-B inhibitor that we found also enhances ATPase activity in CINs, suggesting a potential treatment for cognitive deficits associated with inflammation affecting the function of midline thalamic nuclei and related structures.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.505140v1?rss=1
Authors: Mokalled, M. H.
Abstract: Unlike mammals, adult zebrafish undergo spontaneous recovery after major spinal cord injury. Whereas reactive gliosis presents a roadblock for mammalian spinal cord repair, glial cells in zebrafish elicit pro-regenerative bridging functions after injury. Here, we perform genetic lineage tracing, assessment of regulatory sequences, and inducible cell ablation to define mechanisms that direct the molecular and cellular responses of glial cells after spinal cord injury in adult zebrafish. Using a newly generated CreERT2 transgenic line, we show that cells that direct expression of the bridging glial marker ctgfa give rise to regenerating glia after injury, with negligible contribution to either neuronal or oligodendrocyte lineages. A 1 kb sequence upstream of the ctgfa gene was sufficient to direct expression in early bridging glia after injury. Finally, ablation of ctgfa-expressing cells using a transgenic nitroreductase strategy impaired glial bridging and recovery of swim behavior after injury. This study identifies key regulatory features, cellular progeny, and requirements of glial cells during innate spinal cord regeneration.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.505069v1?rss=1
Authors: Ertl, N., Lawn, W., Mokrysz, C., Freeman, T., Alnagger, N., Borissova, A., Fernandez-Vinson, N., Lees, R., Ofori, S., Petrilli, K., Trinci, K., Viding, E., Curran, H. V., Wall, M. B.
Abstract: Cannabis use is highly prevalent in adolescents however little is known about its effects on adolescent brain function. Resting-state functional Magnetic Resonance Imaging was used in matched groups of adolescents (16-17 years old, N=70, 35 users/35 controls) and young adults (26-29 years old, N=70, 35 users/35 controls). Pre-registered analyses examined the connectivity of cortical and sub-cortical brain networks. Cannabis users (across both age-groups) showed localised increases in connectivity in the default mode, executive, and limbic striatum networks. Localised decreases in connectivity were seen in the salience network, and the sensorimotor striatal network showed both localised increases and decreases in connectivity. Mean connectivity across entire networks was significantly decreased in the default mode network in cannabis users. There were no significant interactions found between age-group and user-group. Cannabis use is associated with changes to connectivity in cortical and sub-cortical brain networks, however adolescence does not appear to modify these effects.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.505113v1?rss=1
Authors: Larbi, M. C., Messa, G., Jalal, H., Koutsikou, S.
Abstract: Vertebrate locomotion is heavily dependent on descending control originating in the midbrain and subsequently influencing central pattern generators in the spinal cord. However, the midbrain neuronal circuitry and its connections with other brainstem and spinal motor circuits has not been fully elucidated. Basal vertebrates with very simple nervous system, like the hatchling Xenopus laevis tadpole, have been instrumental in unravelling fundamental principles of locomotion and its suspraspinal control. Here, we use behavioral and electrophysiological approaches in combination with lesions of the midbrain to investigate its contribution to the initiation and control of the tadpole swimming in response to trunk skin stimulation. None of the midbrain lesions studied here blocked the tadpole's sustained swim behavior following trunk skin stimulation. However, we identified that distinct midbrain lesions led to significant changes in the latency and trajectory of swimming. These changes could partly be explained by the increase in synchronous muscle contractions on the opposite sides of the tadpole's body and permanent deflection of the tail from its normal position, respectively. Furthermore, the midbrain lesions led to significant changes in the tadpole's ability to stop swimming when it bumps head on to solid objects. We conclude that the tadpole's embryonic trunk skin sensorimotor pathway involves the midbrain, which harbors essential neuronal circuitry to significantly contribute to the appropriate, timely and coordinated selection and execution of locomotion, imperative to the animal's survival.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.504155v1?rss=1
Authors: Hanna, J., Floel, A.
Abstract: Manual sleep analysis for research purposes and for the diagnosis of sleep disorders is labor- intensive and often produces unreliable results, which has motivated many attempts to design automatic sleep stage classifiers. With the recent introduction of large, publicly available hand-scored polysomnographic data, and concomitant advances in machine learning methods to solve complex classification problems with supervised learning, the problem has received new attention, and a number of new classifiers that provide excellent accuracy. Most of these however have non-trivial barriers to use. We introduce the Greifswald Sleep Stage Classifier (GSSC), which is free, open source, and can be relatively easily installed and used on any moderately powered computer. In addition, the GSSC has been trained to perform well on a large variety of electrode set-ups, allowing high performance sleep staging with portable systems. The GSSC can also be readily integrated into brain-computer interfaces for real-time inference. These innovations were achieved while simultaneously reaching a level of accuracy equal to, or exceeding, recent state of the art classifiers and human experts, making the GSSC an excellent choice for researchers in need of reliable, automatic sleep staging.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.505176v1?rss=1
Authors: Linsley, J. W., Perez, N., Hsu, I.-U., Yu, Y., Jasti, N., Waalkes, M., Horstick, E. J., Kuwada, J. Y.
Abstract: The stac family of genes are expressed by several cell types including neurons and muscles in a wide variety of animals. In vertebrates, stac3 encodes an adaptor protein specifically expressed by skeletal muscle that regulates L-type calcium channels (CaChs) and excitation-contraction coupling. The function of Stac proteins expressed by neurons in the vertebrate CNS, however, is unclear. To better understand neuronal Stac proteins, we identified the stac1 gene in zebrafish. stac1 is expressed selectively in the embryonic CNS including in Kolmer-Agduhr (KA) neurons, the cerebral fluid-contacting neurons (CSF-cNs) in the spinal cord. Previously CSF-cNs in the spinal cord were implicated in locomotion by zebrafish larvae. Thus, expression of stac1 by CSF-cNs and the regulation of CaChs by Stac3 suggest the hypothesis that Stac1 may be important for normal locomotion by zebrafish embryos. We tested to see if optogenetic activation of CSF-cNs was sufficient to induced swimming in embryos as it is in larvae. Indeed, optogenetic activation of CSF-cNs in embryos induced swimming in embryos. Next, we generated stac1-/- null embryos and found that both mechanosensory and noxious stimulus-induced swimming were decreased. We further found that zebrafish embryos respond more vigorously to tactile stimulation in the light compared to the dark. Interestingly, light enhancement of touch-induced swimming was eliminated in stac1 mutants. Thus, Stac1 regulates escape locomotion in zebrafish embryos perhaps by regulating the activity of CSF-cNs.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.505211v1?rss=1
Authors: Ozcan, F., Alkan, A.
Abstract: Natural sounds are easily perceived and identified by humans and animals. Despite this, the neural transformations that enable sound perception remain largely unknown. Neuroscientists are drawing important conclusions about neural decoding that may eventually aid research into the design of brain-machine interfaces (BCIs). It is thought that the time-frequency correlation characteristics of sounds may be reflected in auditory assembly responses in the midbrain and that this may play an important role in identification of natural sounds. In our study, natural sounds will be predicted from multi-unit activity (MUA) signals collected in the inferior colliculus. The temporal correlation values of the MUA signals are converted into images. We used two different segment sizes and thus generated four subsets for the classification. Using pre-trained convolutional neural networks (CNNs), features of the images were extracted and the type of sound heard was classified. For this, we applied transfer learning from Alexnet, GoogleNet and Squeezenet CNNs. The classifiers support vector machines (SVM), k-nearest neighbour (KNN), Naive Bayes and Ensemble were used. The accuracy, sensitivity, specificity, precision and F1 score were measured as evaluation parameters. Considering the trials one by one in each, we obtained an accuracy of 85.69% with temporal correlation images over 1000 ms windows. Using all trials and removing noise, the accuracy increased to 100%.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.505201v1?rss=1
Authors: Shen, X., Ozen, A. C., Monsivais, H., Sunjar, A., Ilbey, S., Zheng, W., Du, Y., Chiew, M., emir, u.
Abstract: Background: The iron concentration increases during normal brain development and is identified as a risk factor for many neurodegenerative diseases, it is vital to monitor iron content in the brain non-invasively. Purpose: This study aimed to quantify in vivo brain iron concentration with a 3D rosette-based ultra-short echo time (UTE) magnetic resonance imaging (MRI) sequence. Methods: A cylindrical phantom containing nine vials of different iron concentrations (iron (II) chloride) from 0.5 millimoles to 50 millimoles and six healthy subjects were scanned using 3D high-resolution (0.94x0.94x0.94 mm3) rosette UTE sequence at an echo time (TE) of 20 us. Results: Iron-related hyperintense signals (i.e., positive contrast) were detected based on the phantom scan, and were used to establish an association between iron concentration and signal intensity. The signal intensities from in vivo scans were then converted to iron concentrations based on the association. The deep brain structures, such as the substantia nigra, putamen, and globus pallidus, were highlighted after the conversion, which indicated potential iron accumulations. Conclusion: This study suggested that T1-weighted signal intensity could be used for brain iron mapping.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.505193v1?rss=1
Authors: Takagi, A., Gomi, H., Burdet, E., Koike, Y.
Abstract: Humans are adept at moving the arm to interact with objects and surfaces. The brain is thought to regulate motion and interactions using two different controllers, one specialized for movements and the other for force regulation. However, it remains unclear whether different control mechanisms are necessary. Here we show that the brain can employ a single high-level control strategy for both movement and interaction control. The Model Predictive Control (MPC) strategy introduced in this paper uses an internal model of the environment to plan the arm's muscle activity whilst updating its predictions using periodic feedback. Computer simulations demonstrate MPC's ability to produce human-like movements and after-effects in free and force field environments. It can simultaneously regulate both force and stiffness during interactions, and can accomplish motor tasks demanding transitions between motion and interaction control. Model Predictive Control promises to be an important tool to test ideas of motor control as it can handle nonlinear dynamics with changing environments and goals without having to specify the movement duration.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.505180v1?rss=1
Authors: Diaz-deLeon, G., Alvarez, M., Bayones, L., Zainos, A., Zizumbo, J., Parra, S., Pujalte, S., Romo, R., Rossi-Pool, R., De Lafuente, V.
Abstract: The dorsal premotor cortex (DPC) has classically been associated with a role in preparing and executing the physical motor variables during cognitive tasks. While recent work has provided nuanced insights into this role, here we propose that DPC also participates more actively in decision-making. We recorded neuronal activity in DPC while two trained monkeys performed a vibrotactile categorization task, utilizing two distinct ranges of stimuli values that varied on two physical attributes: vibrotactile frequency and amplitude. We observed a broad heterogeneity across DPC neurons, the majority of which maintained the same response patterns across attributes and ranges, coding in the same periods, mixing temporal and categorical dynamics. The predominant categorical signal was maintained throughout the delay, movement periods and notably during the inter-trial period. Putting the entire population's data through two dimensionality reduction techniques, we found that imposing the sensory structure yielded pure categorical and temporal representations. Furthermore, projecting the activity of one population over the population axes of the other yielded identical categorical and temporal responses. Finally, we sought to identify functional subpopulations based on the combined activity of all stimuli, neurons, and time points, however we found a continuum of single-unit responses mixing temporal and categorical dynamics. All this points to DPC playing a more decision-related role than previously anticipated.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.505172v1?rss=1
Authors: Uruk, G., Ozcan, S. Y., Aktas, C. C., Taskiran-Sag, A., Donmez-Demir, B., Duran, J., Guinovart, J. J., Karatas-Kursun, H., Dalkara, T., Ozkan, M. Y.
Abstract: Ischemic stroke results in sudden blood flow cessation, thus, unmet energy requirements. Although the clotted artery can be recanalized and blood flow is restored, brain perfusion may not be fully attained due to microvascular constrictions. Under glucose-deprived and hypoxic conditions, glucose derived from the glycogen stored around peri-microvascular astrocyte end-feet may serve as an emergency fuel to meet the metabolic demand during the acute period of ischemic stroke. To elucidate the impact of glycogen utilization on brain microcirculation, we administered glycogen phosphorylase inhibitor 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) intracerebroventricularly. Transgenic mice in which glycogen synthase-1 expression was selectively knocked out in central nervous system (GYS1Nestin-KO) were also used. Both approaches caused microvascular constrictions mediated by CD13-positive pericyte contractions. When mice with disrupted glycogen utilization were subjected to MCA ischemia, pericyte-mediated microvascular constrictions and the infarct volumes were further increased compared to untreated controls or wild-type littermates. Peri-microvascular glycogen depletions were highly correlated with microvascular constrictions as shown by Periodic acid Schiff (PAS) staining and immunolabeling with anti-glycogen antibodies. Imaging of regional cortical blood flow changes during ischemia disclosed severely compromised blood flow dynamics in mice with disrupted glycogen metabolism. In conclusion, disrupting glycogen utilization causes ischemic-like microvascular constrictions under non-ischemic circumstances and increases susceptibility to brain ischemia. Understanding the role of glycogen at neurogliovascular level in brain may provide novel insight to the pathophysiology of ischemic stroke and therapeutic opportunities.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.25.505122v1?rss=1
Authors: Shao, Y., Ostojic, S.
Abstract: How the connectivity of cortical networks determines the neural dynamics and the resulting computations is one of the key questions in neuroscience. Previous works have pursued two complementary strategies to quantify the structure in connectivity, by specifying either the local statistics of connectivity motifs between small groups of neurons, or by defining network-wide low-rank patterns of connectivity that determine the resulting low-dimensional dynamics. A direct relationship between these two approaches is however currently missing, and in particular it remains to be clarified how local connectivity statistics are related to the global connectivity structure and shape the low-dimensional activity. To bridge this gap, here we develop a method for mapping local connectivity statistics onto an approximate global low-rank structure. Our method rests on approximating the global connectivity matrix using dominant eigenvectors, which we compute using perturbation theory for random matrices. This approach demonstrates that multi-population networks defined from local connectivity properties can in general be approximated by low-rank connectivity with Gaussian-mixture statistics. We specifically apply this method to excitatory-inhibitory networks, and show that it leads to accurate predictions for both the low-dimensional dynamics, and for the activity of individual neurons. Altogether, our approach allows us to disentangle the effects of mean connectivity and reciprocal motifs on the global recurrent feedback, and provides an intuitive picture of how local connectivity shapes global network dynamics.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.25.505166v1?rss=1
Authors: Lendemeijer, B., Unkel, M., Mossink, B., Hijazi, S., Sampedro, S. G., Shpak, G., Slump, D. E., van den Hout, M. C. G. N., van IJcken, W. F. J., Bindels, E. M. J., Hoogendijk, W. J. G., Nadif Kasri, N., de Vrij, F. M. S., Kushner, S. A.
Abstract: Astrocytes are essential for the formation and maintenance of neural networks through metabolic support, facilitation of synaptic function, and optimization of electrophysiological activity. However, a major technical challenge for investigating astrocyte function and disease-related pathophysiology has been the limited ability to obtain functional human astrocytes. Here we present a novel method to efficiently differentiate human pluripotent stem cell (hPSC)-derived neural progenitors to functional astrocytes in 28 days using a culture medium containing leukemia inhibitory factor (LIF) and bone morphogenetic protein 4 (BMP4). This approach yields highly pure populations of astrocytes expressing canonical astrocyte markers, which we confirmed by immunofluorescence, flow cytometry and RNA sequencing. Human PSC-derived astrocytes efficiently buffer glutamate and robustly support neural network activity. Co-cultures of hPSC-derived astrocytes and neurons on multi-electrode arrays generated robust network activity within 2 days and synchronous network bursts after 6 days. Whole cell patch-clamp recordings revealed an increased frequency of postsynaptic currents in human hPSC-derived neurons co-cultured with hPSC-derived versus primary rodent astrocytes, consistent with a corresponding increase in synapse density. Furthermore, hPSC-derived astrocytes retained their hominid morphology when transplanted into a mouse brain. In conclusion, we present a novel protocol to obtain functional astrocytes from human pluripotent stem cells, providing a platform for investigating human astrocyte function and neuronal-glial interactions.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.25.505270v1?rss=1
Authors: Hutt, A., Rich, S., Valiante, T. A., Lefebvre, J.
Abstract: Heterogeneity is the norm in biology. The brain is no different: neuronal cell-types are myriad, reflected through their cellular morphology, type, excitability, connectivity motifs and ion channel distributions. While this biophysical diversity enriches neural systems' dynamical repertoire, it remains challenging to reconcile with the robustness and persistence of brain function over time. To better understand the relationship between heterogeneity and resilience, we analyzed both analytically and numerically a non-linear sparse neural network with balanced excitatory and inhibitory connections evolving over long time scales. We examined how neural diversity expressed as excitability heterogeneity in this network influences its dynamic volatility (i.e., its susceptibility to critical transitions). We exposed this network to slowly-varying modulatory fluctuations, continuously interrogating its stability and resilience. Our results show that excitability heterogeneity implements a homeostatic control mechanism tuning network stability in a context-dependent way. Such diversity was also found to enhance network resilience, quenching the volatility of its dynamics, effectively making the system independent of changes in many control parameters, such as population size, connection probability, strength and variability of synaptic weights as well as modulatory drive. Taken together, these results highlight the fundamental role played by cell-type heterogeneity in the robustness of brain function in the face of change.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.25.505232v1?rss=1
Authors: Colenbier, N., Sareen, E., del-Aguila Puntas, T., Griffa, A., Pellegrino, G., Mantini, D., Marinazzo, D., Arcara, G., Amico, E.
Abstract: The discovery that human brain connectivity data can be used as a 'fingerprint' to identify a given individual from a population, has become a burgeoning research area in the neuroscience field. Recent studies have identified the possibility to extract these brain signatures from the temporal rich dynamics of resting-state magnetoencephalography (MEG) recordings. However, to what extent MEG signatures constitute a marker of human identifiability when engaged in task-related behavior remains an open question. Here, using MEG data from naturalistic and neurophysiological tasks, we show that identification improves in tasks relative to resting-state, providing compelling evidence for a task dependent axis of MEG signatures. Notably, improvements in identifiability were more prominent in strictly controlled tasks. Lastly, the brain regions contributing most towards individual identification were also modified when engaged in task activities. We hope that this investigation advances our understanding of the driving factors behind brain identification from MEG signals.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.25.505256v1?rss=1
Authors: Matsunaga, M., Yamamoto, R., Kita, T., Ohnishi, H., Yamamoto, N., Okano, T., Omori, K., Nakagawa, T.
Abstract: In contrast to mammals, the avian cochlea, specifically the basilar papilla, can regenerate sensory hair cells, which involves fate conversion of supporting cells to hair cells. To determine the mechanisms for converting supporting cells to hair cells, we used single-cell RNA sequencing during hair cell regeneration in explant cultures of chick basilar papillae. We identified dynamic changes in the gene expression of supporting cells, and the pseudotime trajectory analysis demonstrated the stepwise fate conversion from supporting cells to hair cells. Initially, supporting cell identity was erased and transition to the precursor state occurred. A subsequent gain in hair cell identity progressed together with downregulation of precursor-state genes. Transforming growth factor beta receptor 1-mediated signaling was involved in induction of the initial step, and its inhibition resulted in suppression of hair cell regeneration. Our data provide new insights for understanding fate conversion from supporting cells to hair cells in avian basilar papillae.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.25.505246v1?rss=1
Authors: Mason, S. L., Junges, L., Woldman, W. L., Facer-Childs, E. R., de Campos, B. M., Bagshaw, A. P., Terry, J. R.
Abstract: Chronotype - the relationship between the internal circadian physiology of an individual and the external 24-hour light-dark cycle - is increasingly implicated in mental health and cognition. Individuals presenting with a late chronotype have an increased likelihood of developing depression, and can display reduced cognitive performance during the societal 9-5 day. However, the interplay between physiological rhythms and the brain networks that underpin cognition and mental health are not well understood. To address this issue, we use resting state fMRI collected from 16 people with an early chronotype and 22 people with a late chronotype to study if differentiable information about chronotype is embedded in functional brain networks. We develop a classifier utilising the Network Based-Statistic (NBS) methodology, using rigorous selection criteria to select t-statistic thresholds within the NBS approach. We find significant differences in functional networks measured in early and late chronotypes and describe conditions under which the classifier achieves 97.3% accuracy. Revealing differences in functional brain networks based on extreme chronotype suggests future avenues of research that may ultimately better characterise the relationship between internal physiology, external perturbations, brain networks and disease.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.505080v1?rss=1
Authors: Gilbert, J., Purnama, U., Molnar, Z., James, W. S.
Abstract: Neuronal progenitor subtypes have distinct fate restrictions regulated by time-dependent activation of energetic pathways during development. Thus, the hijacking of cellular metabolism by Zika virus (ZIKV) to support its replication may contribute to damage in the developing fetal brain. Here, we showed that 2D in vitro differentiation of human induced pluripotent stem cells into cortical neuronal progenitors (hi-NPCs) produces metabolically distinct populations that resemble the metabolic profile of forebrain progenitor subtypes. These progenitor subtypes showed differential replication rates of neurotropic ZIKV. This differential replication alters the transcription of metabolic genes and upregulates the glycolytic capacity of progenitor subtypes. Analysis using Imagestream revealed subtype-specific metabolic alterations at different stages during ZIKV replication. During early stages of infection, ZIKV replication in early progenitors increases lipid droplet abundance and decreases mitochondrial size and membrane potential. During later stages infection, early progenitors show increased subcellular distribution of lipid droplets, whilst late progenitors show decreased mitochondria size. The finding that there are hi-NPC subtype-specific alterations of cellular metabolism during ZIKV infection provide a platform to investigate the mechanisms on how ZIKV differentially dysregulate the metabolism of forebrain progenitor subtypes which may help explain the differences in brain damage over each trimester.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.25.505068v1?rss=1
Authors: Tecilla, M., Grossbach, M., Gentile, G., Holland, P., Antonini, A., Ruiz, M. H.
Abstract: Motor improvements, such as faster movement times or increased velocity, have been consistently associated with reward magnitude in deterministic contexts. Yet whether individual inferences on reward probability influence motor vigour dynamically remains undetermined. Here we investigated how dynamically inferring volatile action-reward contingencies modulated motor performance trial-by-trial in healthy younger (HYA, 37) and older adults (HOA, 37), and in medicated Parkinson's Disease patients (PD, 20). We conducted an online study that coupled a standard one-armed bandit decision-making paradigm with a motor sequence task and used a validated hierarchical Bayesian model to fit trial-by-trial data. Our results showed that stronger predictions about the tendency of the action-reward contingency led to faster performance tempo on a trial-by-trial basis without modulating reaction times (RT). Using Bayesian linear mixed models, we demonstrated in HYA, HOA and PD a similar sensitivity (slope) of execution tempo to inferences about the reward probabilities, despite HOA and PD being generally slower than HYA (intercept). In a second experiment in HYA (39), we additionally showed that subjective inferences about credit assignment - whether lack of reward is associated with an incorrect decision or execution error - led to a similar modulation of motor vigour by reward expectation. Our study is the first to reveal that the dynamic updating of beliefs about volatile action-reward contingencies positively biases motor performance through faster execution tempo, without affecting RT. We also provide novel evidence for a preserved sensitivity of motor vigour to inferences about the action-reward mapping in ageing and medicated PD.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.26.505426v1?rss=1
Authors: Birolini, G., Valenza, M., Ottonelli, I., Talpo, F., Minoli, L., Cappelleri, A., Bombaci, M., Caccia, C., Leoni, V., Passoni, A., Favagrossa, M., Nucera, M. R., Colombo, L., Paltrinieri, S., Bagnati, R., Duskey, J. T., Caraffi, R., Vandelli, M. A., Taroni, F., Salmona, M., Scanziani, E., Biella, G., Ruozi, B., Tosi, G., Cattaneo, E.
Abstract: Huntingtons disease (HD) has been linked to reduced synthesis of cholesterol in the brain. Its exogenous delivery to the brain has been shown to be beneficial in the rapidly progressing R6/2 mouse model. Here we used an advanced formulation of brain-permeable nanoparticles (NPs) loaded with cholesterol and called hybrid-g7-NPs-chol, to explore the long-term therapeutical potential of cholesterol administration to the brain of the slow-progressing zQ175DN knock-in HD mouse model.
We show that one cycle treatment with hybrid-g7-NPs-chol, administered in the pre-symptomatic or symptomatic phases, is sufficient to completely normalize cognitive defects up to 5 months, as well as to improve other behavioral and neuropathological parameters. Instead, two cycles of hybrid-g7-NPs-chol are needed to achieve long-lasting therapeutic benefits for 12 months without severe inflammatory side-effects. Sustained cholesterol delivery to the brain of zQ175DN mice also reduces mutant Huntingtin aggregates both in striatum and cortex and completely normalizes glutamatergic communication in the striatal medium spiny neurons compared to saline-treated HD mice.
These results show that cholesterol delivery via brain-permeable NPs is a safe and versatile therapeutic option for lastingly reversing HD-related behavioral decline and neuropathological signs, highlighting the translational potential of cholesterol-based strategies in HD patients.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.26.505274v1?rss=1
Authors: Hänisch, B., Hansen, J. Y., Bernhardt, B. C., Eickhoff, S. B., Dukart, J., Misic, B., Valk, S. L.
Abstract: The relationship between brain areas based on neurotransmitter receptor and transporter molecule expression patterns may provide a link between brain structure and its function. Here, we studied the organization of the receptome, a measure of regional neurotransmitter receptor/transporter molecule (NTRM) similarity, derived from in vivo PET imaging studies of 19 different receptors and transporters. Nonlinear dimensionality reduction revealed three main spatial gradients of receptor similarity in the cortex. The first gradient differentiated the somato-motor network from the remaining cortex. The second gradient spanned between temporo-occipital and frontal anchors, differentiating visual and limbic networks from attention and control networks, and the third receptome gradient was anchored between the occipital and temporal cortices. In subcortical structures, the receptome delineated a striato-thalamic axis, separating functional communities. Moreover, we observed similar organizational principles underlying receptome differentiation in cortex and subcortex, indicating a link between subcortical and cortical NTRM patterning. Overall, we found that the cortical receptome shared key organizational traits with brain structure and function. Node-level correspondence of receptor similarity to functional, microstructural, and diffusion MRI-based measures decreased along a primary-to-transmodal gradient. Compared to primary and paralimbic regions, we observed higher receptomic diversification in unimodal and heteromodal regions, possibly supporting functional flexibility. In sum, we show how receptor similarity may form an additional organizational layer of human brain architecture, bridging brain structure and function.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.26.505432v1?rss=1
Authors: Andriatsilavo, M., Dumoulin, A., Dutta, S., Stoeckli, E. T., Hiesinger, P. R., Hassan, B. A.
Abstract: Developmental variation in brain-wiring contributes to behavioural individuality1,2. However, how and when individualized wiring diagrams emerge and become stable during development remains largely unknown. Here, we explored axon targeting dynamics in individual brains using live-imaging of a developing Drosophila visual circuit and discovered that targeting choice is an algorithmic multi-step growth process with variable outcomes. Using optogenetics, we found that temporally restricted Notch lateral-inhibition defines a subset of neurons with a probabilistic potential to innervate distal targets. Next, axons from NotchOFF neurons amplify into long actin-rich multi-fibre structures necessary for distal growth. A subset of these NotchOFF neurons create distal targeting axons by stabilizing microtubule growth in one of their actin fibres. Amplified axons without tubulin-stabilized fibres retract, resulting in the stochastic selection of a different number of distal targeting axons in each brain. Pharmacological microtubule destabilization suffices to inhibit this targeting. We observed a similar axonal amplification-stabilization process in the developing chick spinal cord, suggesting a conserved mechanism. Finally, early microtubule patterns predict the adult brain- wiring of an individual in a target-independent manner prior to synapse formation3,4. Thus, we show that a temporal succession of genetically encoded stochastic processes explains the emergence of individual wiring variation.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.505157v1?rss=1
Authors: Mustaly-Kalimi, S., Marr, R. A., Gilman-Sachs, A., Peterson, D. A., Sekler, I., Stutzmann, G. E.
Abstract: Impairments in neural lysosomal- and autophagic-mediated degradation of cellular debris contribute to neuritic dystrophy and synaptic loss. While these are well-characterized features of neurodegenerative disorders such as Alzheimer's disease (AD), the upstream cellular processes driving deficits in pathogenic protein mishandling are less understood. Using a series of fluorescent biosensors and optical imaging in model cells, AD mouse models and human neurons derived from AD patients, we reveal a novel cellular signaling cascade underlying protein mishandling mediated by intracellular calcium dysregulation, an early component of AD pathogenesis. Increased Ca2+ release via the endoplasmic reticulum (ER) resident ryanodine receptor (RyR) is associated with reduced expression of the lysosome proton pump vATPase subunits (V1B2 and V0a1), resulting in lysosome deacidification and disrupted proteolytic activity in AD mouse models and human induced neurons (HiN). As a result of impaired lysosome digestive capacity, mature autophagosomes with hyperphosphorylated tau accumulated in AD murine neurons and AD HiN, exacerbating proteinopathy. Normalizing AD-associated aberrant RyR-Ca2+ signaling with the negative allosteric modulator, dantrolene (Ryanodex), restored vATPase levels, lysosomal acidification and proteolytic activity, and autophagic clearance of intracellular protein aggregates in AD neurons. These results highlight that prior to overt AD histopathology or cognitive deficits, aberrant upstream Ca2+ signaling disrupts lysosomal acidification and contributes to pathological accumulation of intracellular protein aggregates. Importantly, this is demonstrated in animal models of AD, and in human iPSC-derived neurons from AD patients. Furthermore, pharmacological suppression of RyR-Ca2+ release rescued proteolytic function, revealing a target for therapeutic intervention that has demonstrated effects in clinically-relevant assays.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.26.505430v1?rss=1
Authors: Saenen, L., Verheyden, G., Orban de Xivry, J.-J.
Abstract: Sensory processing consists in the integration and interpretation of somatosensory information. It builds upon proprioception but is a distinct function requiring complex processing by the brain over time. Currently little is known about the effect of aging on sensory processing ability, nor the influence of other covariates such as motor function, proprioception, or cognition. In this study, we measured upper limb passive and active sensory processing, motor function, proprioception, and cognition in 40 healthy younger adults and 54 older adults. We analyzed age differences across all measures and evaluated the influence of covariates on sensory processing through regression. Our results showed larger effect sizes for age differences in sensory processing (r=0.39-0.40) compared to motor function (r=0.18-0.22) and proprioception (r=0.10-0.27), but smaller than for cognition (r=0.56-0.63). Aside from age, we found no evidence that sensory processing performance was influenced by motor function or proprioception, but active sensory processing was influenced by cognition ({beta}=0.32-0.46). In conclusion, sensory processing showed an age-related decline, while some proprioceptive and motor abilities were preserved across age.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.26.504777v1?rss=1
Authors: Ma, X., Rizzoglio, F., Perreault, E. J., Miller, L. E., Kennedy, A.
Abstract: Existing intracortical brain computer interfaces (iBCIs) transform neural activity into control signals capable of restoring movement to persons with paralysis. However, the accuracy of the "decoder" at the heart of the iBCI typically degrades over time due to turnover of recorded neurons. To compensate, decoders can be recalibrated, but this requires the user to spend extra time and effort to provide the necessary data, then learn the new dynamics. As the recorded neurons change, one can think of the underlying movement intent signal being expressed in changing coordinates. If a mapping can be computed between the different coordinate systems, it may be possible to stabilize the original decoder's mapping from brain to behavior without recalibration. We previously proposed a method based on Generalized Adversarial Networks (GANs), called "Adversarial Domain Adaptation Network" (ADAN), which aligns the distributions of latent signals within underlying low-dimensional neural manifolds. However, ADAN was tested on only a very limited dataset. Here we propose a method based on Cycle-Consistent Adversarial Networks (Cycle-GAN), which aligns the distributions of the full-dimensional neural recordings. We tested both Cycle-GAN and ADAN on data from multiple monkeys and behaviors and compared them to a linear method based on Procrustes Alignment of axes provided by Factor Analysis (PAF). Both GAN-based methods outperformed PAF. Cycle-GAN and ADAN (like PAF) are unsupervised and require little data, making them practical in real life. Overall, Cycle-GAN had the best performance and was easier to train and more robust than ADAN, making it ideal for stabilizing iBCI systems over time.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.26.505422v1?rss=1
Authors: Mender, M. J., Nason-Tomaszewski, S. R., Temmar, H., Costello, J. T., Wallace, D. M., Willsey, M. S., Ganesh Kumar, N., Kung, T. A., Patil, P. G., Chestek, C. A.
Abstract: A key factor in the clinical translation of brain-machine interfaces (BMIs) for restoring hand motor function will be their robustness to changes in a task. With functional electrical stimulation (FES) for example, the patient's own hand will be used to produce a wide range of forces in otherwise similar movements. To investigate the impact of task changes on BMI performance, we trained two rhesus macaques to control a virtual hand with their physical hand while we added springs to each finger group (index or middle-ring-small) or altered their wrist posture. Using simultaneously recorded intracortical neural activity, finger positions, and electromyography, we found that predicting finger kinematics and finger-related muscle activations across contexts led to significant increases in prediction error, especially for muscle activations. However, with respect to online BMI control of the virtual hand, changing either training task context or the hand's physical context during online control had little effect on online performance. We explain this dichotomy by showing that the structure of neural population activity remained similar in new contexts, which could allow for fast adjustment online. Additionally, we found that neural activity shifted trajectories proportional to the required muscle activation in new contexts, possibly explaining biased kinematic predictions and suggesting a feature that could help predict different magnitude muscle activations while producing similar kinematics.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.26.505458v1?rss=1
Authors: Alamri, Y., Jennings, S.
Abstract: The auditory nerve (AN) compound action potential (CAP) is an important tool for assessing auditory disorders and monitoring the health of the auditory periphery during surgical procedures. The CAP has been mathematically conceptualized as the convolution of a unit response (UR) waveform with the firing rate of a population of AN fibers. Here, an approach for predicting experimentally recorded CAPs in humans is proposed, which involves the use of human-based computational models to simulate AN activity. CAPs elicited by clicks, chirps, and amplitude-modulated carriers were simulated and compared with empirically recorded CAPs from human subjects. In addition, narrowband CAPs derived from noise-masked clicks and tone bursts were simulated. Many morphological, temporal, and spectral aspects of human CAPs were captured by the simulations for all stimuli tested. These findings support the use of model simulations of the human CAP to refine existing human-based models of the auditory periphery, aid in the design and analysis of auditory experiments, and predict the effects of hearing loss, synaptopathy, and other auditory disorders on the human CAP.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.26.505408v1?rss=1
Authors: Manenti, G. L., Dizaji, A. S., Schwiedrzik, C. M.
Abstract: Stimulus and location specificity are long considered hallmarks of visual perceptual learning. This renders visual perceptual learning distinct from other forms of learning, where generalization can be more easily attained, and unsuitable for practical applications, where generalization is key. Based on hypotheses derived from the structure of the visual system, we test here whether stimulus variability can unlock generalization in perceptual learning. We train subjects in orientation discrimination, while we vary the amount of variability in a task-irrelevant feature, spatial frequency. We find that independently of task difficulty, this manipulation enables generalization of learning to new stimuli and locations, while not negatively affecting the overall amount of learning on the task. We then use deep neural networks which recapitulate our findings in humans to investigate how variability unlocks generalization. We find that networks develop invariance to the task-irrelevant feature when trained with variable inputs. The degree of learned invariance strongly predicts generalization. A reliance on invariant representations can explain variability-induced generalization in visual perceptual learning, suggests new targets for understanding the neural basis of perceptual learning in high-order visual cortex, and presents an easy to implement modification of common training paradigms that may benefit practical applications.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.26.505413v1?rss=1
Authors: Biojone, C., Cannarozzo, C., Seiffert, N., Diniz, C., Brunello, C., Castren, E., Casarotto, P.
Abstract: Brain-derived neurotrophic factor (BDNF) acting upon its receptor Neurotrophic tyrosine kinase receptor 2 (NTRK2, TRKB) plays a central role in the development and maintenance of synaptic function and activity- or drug-induced plasticity. TRKB possesses an inverted cholesterol-recognition and alignment consensus sequence (CARC), suggesting this receptor can act as a cholesterol sensor. We have recently shown that antidepressants drugs directly bind to the CARC domain of TRKB dimers, and that this binding as well as biochemical and behavioral responses to antidepressants are lost with a mutation in the TRKB CARC motif (Y433F). However, it is not clear if this mutation can also compromise the receptor function and lead to behavioral alterations. Here, we observed that Y433F mutation does not alter BDNF binding to TRKB, or BDNF-induced dimerization of TRKB. In this line, primary cultures from embryos of heterozygous Y433F mutant mice (hTRKB.Y433F) are responsive to BDNF-induced activation of TRKB, and samples from adult mice do not show any difference on TRKB activation compared to wild-type littermates (TRKB.wt). The behavioral phenotype of hTRKB.Y433F mice is indistinguishable from the wild-type mice in cued fear conditioning, contextual discrimination task or the elevated plus maze, whereas mice heterozygous to BDNF null allele show a phenotype in context discrimination task. Taken together, our results indicate that Y433F mutation in the TRKB CARC motif does not show signs of loss-of-function of BDNF responses, while antidepressant binding to TRKB and responses to antidepressants are lost in Y433F mutants, making them an interesting mouse model for antidepressant research.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.26.504147v1?rss=1
Authors: Knoll, A., Tabbaa, M., Levitt, P.
Abstract: Preclinical models of neurodevelopmental disorders typically use single inbred strains which fail to capture human genetic and symptom heterogeneity that is common clinically. We tested if systematically modeling human genetic diversity in mouse genetic reference panels would recapitulate population and individual differences in responses to a syndromic mutation in the high-confidence autism risk gene, CHD8. Trait disruptions mimicked those seen in human populations, including high penetrance of macrocephaly and disrupted behavior, but with robust strain and sex differences. For every trait, some strains exhibited a range of large effect size disruptions, sometimes in opposite directions, and remarkably others expressed resilience. Thus, systematically introducing genetic diversity into mouse models of neurodevelopmental disorders provides a better framework for discovering individual differences in symptom etiologies and improved treatments.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.26.505452v1?rss=1
Authors: Mahmoudian, B., Dalal, H., Lau, J. C., Corrigan, B. W., Barker, K., Rankin, A., Chen, E. C. S., Peters, T., Martinez-Trujillo, J. C.
Abstract: Precise targeting of deep brain structures in humans and large animal models has been a challenge for neuroscientists. Conventional protocols used in animal models typically require large access chambers which are prone to infection and involve assembly and implantation of complex microdrives for semi-chronic applications. Here we present a methodology for improving targeting of subcortical structures in large animals such as macaque monkeys, using image guided neuronavigation. Design of custom cranial caps allowed for incorporation of stable fiducial markers, required for increased targeting accuracy in neuronavigation procedures, resulting in an average targeting error of 1.6 mm over three implantations. Incorporation of anchor bolt chambers, commonly used in human neurosurgery, provided a minimally invasive entrance to the brain parenchyma, allowing for chronic recordings. By leveraging existing 3D printing technology, we fabricated an anchor bolt-mounted microdrive for semi-chronic applications. Our protocol leverages commercially available tools for implantation, decreases the risk of infection and complications of open craniotomies, and improves the accuracy and precision of chronic electrode implantations targeting deep brain structures in large animal models.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.26.505400v1?rss=1
Authors: Roland, A., Coelho, C., Haun, H., Gianessi, C., Lopez, M., D'Ambrosio, S., Machinski, S., Kroenke, C., Frankland, P., Becker, H., Kash, T.
Abstract: High-level alcohol consumption causes neuroplastic changes in the brain that lead to negative affective and somatic symptoms when alcohol is withdrawn, promoting relapse drinking. We have some understanding of these plastic changes in defined brain circuits and cell types, but unbiased approaches are needed to explore broader patterns of adaptations. Here, we employed whole-brain c-fos mapping and network analysis to assess how brain-wide patterns of neuronal activity are altered during acute alcohol abstinence and reaccess in a well-characterized model of alcohol dependence. Mice underwent four cycles of chronic intermittent ethanol vapor exposure (CIE) with alternating weeks of voluntary alcohol drinking, and a subset of mice underwent forced swim stress (FSS) prior to drinking sessions to further escalate alcohol consumption. After four CIE cycles, brains were collected from mice in each group either 24 hours (abstinence) or immediately following a one-hour period of alcohol reaccess. Brains from CIE mice during acute abstinence displayed widespread neuronal activation relative to those from AIR mice, independent of FSS, and this increase in c-fos was reversed by reaccess drinking. For network analysis, mice were then classified as high or low drinkers (HD or LD). We computed Pearson correlations for all pairs of brain regions and used graph theoretical methods to identify changes in network properties associated with high-drinking behavior. Network modularity, a measure of network segregation into communities, was increased in HD mice after alcohol reaccess relative to abstinence. Within-community strength and diversity measures were computed for each region and condition, and highly coactive regions were identified. One high-diversity region, the cortical amygdala (COA), was further interrogated using a chemogenetic approach. COA silencing in CIE mice reduced voluntary drinking, validating our network analysis and indicating that this region may play an important but underappreciated role in alcohol dependence.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.25.505325v1?rss=1
Authors: Jung, Y., Forest, T. A., Walther, D. B., Finn, A. S.
Abstract: One critical feature of children's cognition is their relatively immature attention. Decades of research have shown that children's attentional abilities mature slowly over the course of development, including the ability to filter out distracting information. Despite such rich behavioral literature, little is known about how developing attentional abilities modulate neural representations in children. This information is critical to understanding exactly how attentional development shapes the way children process information. One intriguing possibility is that attention might be less likely to impact neural representations in children as compared with adults. In particular, representations of attended items may be less likely to be sharpened relative to unattended items in children as compared to adults. To investigate this possibility, we measured brain activity using fMRI while adults (21-31 years) and children (7-9 years) performed a one-back working memory task in which they were directed to attend to either motion direction or an object in a complex display where both were present. We used multivoxel pattern analysis and compared decoding accuracy of attended and unattended information. Consistent with attentional sharpening, we found higher decoding accuracy for task-relevant information (i.e., objects in the object-attended condition) than for task-irrelevant information (i.e., motion in the object-attended condition) in adults- visual cortices. However, in children's visual cortices, both task-relevant and task-irrelevant information were decoded equally well. What's more, exploratory whole-brain analysis showed that the children represent task-irrelevant information more than adults in multiple regions across the brain, including the prefrontal cortex. These findings show that 1) attention does not sharpen neural representations in the child visual cortex, and further 2) that the developing brain can represent more information than the adult brain.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.23.505030v1?rss=1
Authors: Dhinagar, N. J., Thomopoulos, S. I., Rajagopalan, P., Stripelis, D., Ambite, J. L., Steeg, G. V., Thompson, P. M.
Abstract: Deep neural networks show great promise for classifying brain diseases and making prognostic assessments based on neuroimaging data, but large, labeled training datasets are often required to achieve high predictive accuracy. Here we evaluated a range of transfer learning or pre-training strategies to create useful MRI representations for downstream tasks that lack large amounts of training data, such as Alzheimer's disease (AD) classification. To test our models, we analyzed 4,098 3D T1-weighted brain MRI scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort and independently validated our proposed methods for detecting AD with an out-of-distribution test set of 600 scans from the Open Access Series of Imaging Studies (OASIS3) cohort. First, we trained 3D and 2D convolutional neural network (CNN) architectures. We tested combinations of multiple pre-training strategies based on (1) supervised, (2) contrastive learning, and (3) self-supervised learning - using pre-training data within versus outside the MRI domain. In our experiments, the 3D CNN pre-trained with contrastive learning provided the best overall results - when fine-tuned on T1-weighted scans for AD classification - outperformed the baseline by 2.8% when trained with all of the training data from ADNI. We also show test performance as a function of the training dataset size and the chosen pre-training method. Transfer learning offered significant benefits in low data regimes, with a performance boost of 7.7%. When the pre-trained model was used for AD classification, we were able to visualize an improved clustering of test subjects' diagnostic groups, as illustrated via a uniform manifold approximation (UMAP) projection of the high-dimensional model embedding space. Further, saliency maps indicate the additional activation regions in the brain scan using pre-training, that then maximally contributed towards the final prediction score.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.23.504918v1?rss=1
Authors: Pons-Espinal, M., Blasco-Agell, L., Fernandez-Carasa, I., di Domenico, A., Richaud, Y., Mosquera, J. L., Marruecos, L., Espinosa, L., Garrido, A., Tolosa, E., Edel, M. J., Juan Otero, M., Ferrer, I., Raya, A., Consiglio, A.
Abstract: Parkinson's disease (PD) is associated with premature death of dopamine-producing neurons in the brain. Previous studies have shown that astrocytes of PD patients may contribute to neuronal degeneration by mechanisms involving both direct cell-to-cell contact and transfer of soluble molecules. Since it has been proposed that PD patients exhibit an overall pro-inflammatory state, and since astrocytes are key mediators of the inflammation response in the brain, here we sought to address whether astrocyte-mediated inflammatory signaling could contribute to PD neuropathology. For this purpose, we generated astrocytes from induced pluripotent stem cells (iPSCs) representing PD patients and healthy controls. Transcriptomic analyses identified a unique inflammatory gene expression signature in PD astrocytes compared to controls. In particular, the pro-inflammatory cytokine IL-6 was found to be highly expressed and released by PD astrocytes, and to induce toxicity in dopamine neurons. Mechanistically, neuronal cell death was mediated by IL-6 signaling via IL-6 receptor (IL-6R) expressed in human PD neurons, leading to downstream activation of STAT3. Importantly, astrocyte-induced cell death in PD disease midbrain neurons could be prevented by blocking IL6R-mediated signaling using clinically available antibodies. Moreover, examination of postmortem tissue brain of early-stage PD patients uncovered increased numbers of dopamine neurons overexpressing IL-6R and of reactive astrocytes overexpressing IL-6, compared to healthy brains. Our findings highlight the potential role of astrocyte-mediated inflammatory signaling in neuronal loss in PD, and open the way for new therapies based on IL-6 immunomodulation for preventing PD pathogenesis.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.23.505002v1?rss=1
Authors: Sharma, S., Borski, C., Hanson, J., Garcia, M. A., Link, C. D., Hoeffer, C. A., Chatterjee, A., Nagpal, P.
Abstract: Acute activation of innate immune response in the brain, or neuroinflammation, protects this vital organ from a range of external pathogens and promotes healing after traumatic brain injury. However, chronic neuroinflammation leads to the activation of immune cells like microglia and astrocytes causes damage to the nervous tissue, and is causally linked to a range of neurodegenerative diseases such as Alzheimers diseases (AD), Multiple Sclerosis (MS), Parkinsons diseases (PD), and many others. While neuroinflammation is a key target for a range of neuropathological diseases, there is a lack of effective countermeasures to tackle it, and existing experimental therapies require fairly invasive intracerebral and intrathecal delivery due to difficulty associated with the therapeutic crossover between the blood-brain barrier (BBB), making such treatments impractical to treat neuroinflammation long-term. Here, we present the development of an optimal neurotherapeutic using our NanoligomerTM discovery engine, by screening downregulation of several proinflammatory cytokines (e.g., Interleukin-1{beta} or IL-1{beta}, tumor necrosis factor-alpha or TNF-, TNF receptor 1 or TNF-R1, Interleukin 6 or IL-6), inflammasomes (e.g., NLRP1), key transcription factors (e.g., nuclear factor kappa-B or NF-{kappa}{beta}) and their combinations, as upstream regulators and canonical pathway targets, to identify and validate the best-in-class treatment. Using our high-throughput drug discovery, target validation, and lead molecule identification using a bioinformatics and AI-based ranking method to design sequence-specific peptide molecules to up-or down-regulate gene expression of the targeted gene at will, we used our discovery engine to perturb and identify most effective upstream regulators and canonical pathways for therapeutic intervention to reverse neuroinflammation. The lead neurotherapeutic was a combination of NanoligomersTM targeted to NF-{kappa}{beta} (SB.201.17D.8_ NF-{kappa}{beta}1) and TNFR1 (SB.201.18D.6_TNFR1), which were identified using in vitro cell-based screening in donor-derived human astrocytes, and further validated in vivo using a mouse model of lipopolysaccharide (LPS)-induced neuroinflammation. The combination treatment SB_NI_111 was delivered without any special formulation using a simple intraperitoneal injection of low-dose (5mg/kg) and was found to significantly suppress the expression of LPS-induced neuroinflammation in mouse hippocampus. These results point to the broader applicability of this approach towards the development of therapies for chronic neuroinflammation-linked neurodegenerative diseases, sleep countermeasures, and others, and the potential for further investigation of the lead neurotherapeutic molecule as reversible gene therapy.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.23.505010v1?rss=1
Authors: Meng, J. H., Schuman, B., Rudy, B., Wang, X.-J.
Abstract: Neocortical Layer 1 (L1) consists of GABAergic interneurons (INs) and receives extensive long-range "top down" projections, but L1 INs remain poorly understood. In this work, we systematically examined the distinct dominant electrophysiological features for four unique IN subtypes in L1 that were previously identified: Canopy cells show an irregular firing pattern near rheobase; Neurogliaform cells (NGFCs) are late-spiking, and their firing rate accelerates during current injections; cells with strong expression of the 7 nicotinic receptor (7 cells), display initial (rebound) bursting; vasoactive intestinal peptide (VIP) expressing cells exhibit high input resistance, strong adaptation, and irregular firing. Computational modelling revealed that these neurophysiological diverse features could be explained by an extended exponential-integrate-and-fire neuron model with varying contributions of a slowly inactivating K+ channel (SIK), a T-type Ca2+ channel, and a spike-triggered Ca2+-dependent K+ channel. In particular, we show that irregular firing results from square-wave bursting through a fast-slow analysis. Furthermore, we demonstrate that irregular firing is frequently observed in VIP cells due to the interaction between strong adaptation and a SIK channel. The reported findings of single neuron dynamics should be incorporated to elucidate how different L1 cell types contribute to the integration of top-down signaling and local processes.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.23.503975v1?rss=1
Authors: Mazor, M., Gong, C., Fleming, S. M.
Abstract: Previously, we identified a subset of regions where the relation between decision confidence and univariate fMRI activity was quadratic, with stronger activation for both high and low compared to intermediate levels of confidence. We further showed that, in a subset of these regions, this quadratic modulation appeared only for confidence in detection decisions about the presence or absence of a stimulus, and not for confidence in discrimination decisions about stimulus identity (Mazor, Friston & Fleming, 2021). Here, in a pre-registered follow-up experiment, we sought to replicate our original findings and identify the origins of putative detection-specific confidence signals by introducing a novel asymmetric-discrimination condition: a discrimination task with the signal-detection properties of a detection task. This task required discriminating two alternatives (two different grating tilts) but was engineered such that the distribution of perceptual evidence was asymmetric, just as in yes/no detection. We successfully replicated the quadratic modulation of subjective confidence in prefrontal, parietal and temporal cortices. However, in contrast to our original report, this quadratic effect was similar in detection and discrimination responses, but stronger in the novel asymmetric-discrimination condition. We interpret our findings as weighing against the detection-specificity of confidence signatures and speculate about possible alternative origins of a quadratic modulation of decision confidence.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.23.504980v1?rss=1
Authors: Reyes, R. G., Martinez-Montes, E.
Abstract: In recent years, a vertiginous advance has occurred within the Neural Field Theory with the development of the so-called Next Generation Neural Field models. Unlike the phenomenological models, these models manage to describe neuronal activity, macroscopically, from the thermodynamic limit of microscopic laws under the assumption of a homogeneous density of neurons. The study of neural activity during neurodegenerative processes associated to Alzheimer's, Parkinson's or Glioblastomas, should include a variable density of neurons. In this work, we propose an update of the Next Generation Neural Field model, extracted from the thermodynamic limit of the quadratic integration-and-fire model with realistic synaptic coupling and a variable density of neurons at the microscopic level. The thermodynamic limit of the system will allow us to study the patterns of synchronized neural activity that appear as the result of different spatial distribution of neurodegeneration. In particular, we demonstrate that during neurodegenerative processes, the relationship established between the thermodynamic states of the Neural Field and the Kuramoto order parameter (Measure of Neural Synchronization) differs from the classic results of the Next Generation Neural Field literature. Instead, the variation in neuron density directly modifies the Kuramoto order parameter. This might help us explain the diverse patterns of activity that can be found in different neurodegenerative processes and that could become experimental biomarkers of such pathologies.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.23.505015v1?rss=1
Authors: Rafiei, F., Rahnev, D.
Abstract: Convolutional neural networks currently provide the best models of biological vision. However, their decision behavior, including the facts that they are deterministic and use equal number of computations for easy and difficult stimuli, differs markedly from human decision-making, thus limiting their applicability as models of human perceptual behavior. Here we develop a new neural network, RTNet, that generates stochastic decisions and human-like response time (RT) distributions, and also reproduces all foundational features of human accuracy, RT, and confidence. To test RTNet's ability to predict human behavior on novel images, we collected accuracy, RT, and confidence data from 60 human subjects performing a digit discrimination task. We found that the accuracy, RT, and confidence produced by RTNet for individual novel images correlated with the same quantities produced by human subjects. Critically, human subjects who were more similar to the average human performance were also found to be closer to RTNet's predictions. Overall, RTNet is the first neural network that exhibits all basic signatures of perceptual decision making, and therefore provides the most detailed model of all critical features of human behavior for novel images.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.23.505021v1?rss=1
Authors: Cui, J., Carey, J. S., Pera, R. A. R.
Abstract: Parkinsons disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra region of the midbrain. Diagnostic criteria for PD require that at least two of three motor signs are observed: tremor, rigidity, and/or bradykinesia. The most common and effective treatment for PD is Levodopa (L-DOPA) which is readily converted to DA and has been the primary treatment since the 1960s. Dopamine agonists have also been developed but are less effective than L-DOPA. Although the lack of a model system to study PD has hampered efforts to identify treatments, diverse screening strategies have been proposed for identification of new pharmaceutical candidates. Here, we describe a pilot screen to identify candidate molecules from a bioactive compound library, that might increase formation, maintenance and/or survival of DA neurons in vitro. The screen used a previously characterized reporter construct consisting of the luciferase gene inserted downstream of the endogenous tyrosine hydroxylase (TH) gene and neurons differentiated from human pluripotent stem cells for 18 days. The reporter mimics expression of TH and includes a secreted luciferase whose activity can be measured non-invasively over multiple timepoints. Screening of the bioactive compound library resulted in the identification of a single molecule, SGC0946, that is an inhibitor of DOT1L (Disruptor Of Telomeric silencing 1-Like) which encodes a widely-conserved histone H3K79 methyltransferase that is able to both activate and repress gene transcription. Our results indicate that SGC0946 increased reporter luciferase activity with a single treatment at 8-hours post-plating being equivalent to continuous treatment. Moreover, data suggested that the total number of neurons differentiated in the assays was comparable from experiment to experiment under different SGC0946 treatments over time. In contrast, data suggested that the survival and/or maintenance of DA neurons might be specifically enhanced by SGC0946 treatment. These results confirm other reports that indicate inhibition of DOT1L may play an important role in maintenance and survival of neural progenitor cells (NPCs) and their lineage-specific differentiation.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.23.504875v1?rss=1
Authors: Lieber, J. D., Lee, G. M., Majaj, N. J., Movshon, J. A.
Abstract: Natural images contain information at multiple spatial scales. Although we understand how early visual mechanisms split multi-scale images into distinct spatial frequency channels, we do not know how the outputs of these channels are processed further by mid-level visual mechanisms. We have recently developed a naturalness discrimination task that uses synthesized, multi-scale textures to isolate these mid-level mechanisms (Freeman et. al. 2013). Here, we use three experimental manipulations (image blur, image rescaling, and eccentric viewing) to show that naturalness sensitivity is strongly dependent on image features at high object spatial frequencies (measured in cycles/image). As a result, sensitivity depends on a texture acuity limit, a property of the visual system that sets the highest retinal spatial frequency (measured in cycles/degree) that can be used to solve the task. A model observer analysis shows that high object spatial frequencies carry more task-relevant information than low object spatial frequencies. Comparing the outcome of this analysis with human performance reveals that human observers' efficiency is similar for all object spatial frequencies. We conclude that the mid-level mechanisms that underlie naturalness sensitivity effectively extract information from all image features below the texture acuity limit, regardless of their retinal and object spatial frequency.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.23.504998v1?rss=1
Authors: Brown, T. C., McGee, A. W.
Abstract: Abnormal visual experience during a developmental critical period degrades cortical responsiveness. Yet how experience-dependent plasticity alters the response properties of individual neurons and composition of visual circuitry is unclear. Here we measured with calcium imaging in alert mice how monocular deprivation (MD) during the developmental critical period affects binocularity, orientation, and spatial frequency tuning for neurons in primary visual cortex. Tracking the tuning properties for several hundred neurons revealed that the interconversion of monocular and binocular neurons relies on the quality of visual experience to determine the ratio of monocular neurons responsive to the contralateral and ipsilateral eye. In addition, a population of neurons more responsive to the closed eye were exchanged for neurons with tuning properties more similar to the responsive neurons altered by MD. Thus, plasticity during the critical period adapts to recent experience by both altering the tuning of responsive neurons and recruiting neurons with matching tuning properties.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.505066v1?rss=1
Authors: Decourt, M., Balado, E., Francheteau, M., Solinas, M., Benoit-Marand, M., Fernagut, P.-O.
Abstract: Subtle cognitive impairment can occur early in the course of Parkinson's disease (PD) and may manifest under different forms of executive dysfunction such as impaired cognitive flexibility. The precise contribution of nigrostriatal dopaminergic neurodegeneration to these non-motor features of the disease is poorly known. Whether such cognitive impairment associated with the disease process may also predate and contribute to the development of neuropsychiatric side-effects following dopamine replacement therapy remains largely unknown. To address these issues, we investigated the respective contributions of nigrostriatal degeneration and chronic treatment with the dopamine D3-preferring agonist pramipexole on behavioural flexibility in a rat model of PD. Flexible, intermediate and inflexible rats were identified based on baseline assessment of behavioural flexibility using an operant set-shifting task. Nigrostriatal degeneration was induced by bilateral viral-mediated expression of A53T mutated human -synuclein in the substantia nigra pars compacta and behavioural flexibility was assessed after induction of nigrostriatal degeneration, and during chronic pramipexole treatment. Nigrostriatal degeneration impaired behavioural flexibility in flexible but not in inflexible rats. Pramipexole induced a decrease of behavioural flexibility that was exacerbated in lesioned rats and in the most flexible individuals. Furthermore, the deficits induced by pramipexole in lesioned rats affected different components of the task between flexible and inflexible individuals. This study demonstrates that nigrostriatal degeneration and pramipexole unequally impair behavioural flexibility, suggesting that the susceptibility to develop non-motor impairments upon treatment initiation could primarily depend on premorbid differences in behavioural flexibility.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.23.505001v1?rss=1
Authors: Sharma, S., Fallgren, C., Weil, M. M., Chatterjee, A., Nagpal, P.
Abstract: Galactic cosmic rays (GCR) in space induce increase in cerebral amyloid-{beta} levels and elevated levels of microgliosis and astrocytosis, causing accelerated neurodegeneration from this increased neuroinflammation. Even exposure to low-levels of high-Z high-energy (HZE) radiation (50 cGy) has been shown to induce biochemical and immunohistochemical changes in short-term leading to degradation in cognition, motor skills, and development of space-induced neuropathy. There is lack of effective neuroinflammation countermeasures, and current experimental therapies require invasive intracerebral and intrathecal delivery due to difficulty associated with therapeutic crossover between blood-brain barrier. Here, we present a new countermeasure development approach for neurotherapeutics using high-throughput drug-discovery, target validation, and lead molecule identification with nucleic acid-based molecules. These NanoligomerTM molecules are rationally designed using a bioinformatics and AI-based ranking method and synthesized as a single-modality combining 6-different design elements to up- or down-regulate gene expression of target gene at will, resulting in elevated or diminished protein expression of intended target. This platform approach was used to perturb and identify most effective upstream regulators and canonical pathways for therapeutic intervention to reverse radiation-induced neuroinflammation. The lead NanoligomerTM and corresponding target granulocyte-macrophage colony-stimulating factor (GM-CSF) were identified using in vitro cell-based screening in human astrocytes and donor derived peripheral blood mononuclear cells (PBMCs) and further validated in vivo using a mouse model of radiation-induced neuroinflammation. GM-CSF transcriptional downregulator Nanoligomer 30D.443_CSF2 downregulated proinflammatory cytokine GM-CSF (or CSF2) using simple intraperitoneal injection of low-dose (3mg/kg) and completely reversed expression of CSF2 in cortex tissue, as well as other neuroinflammation markers. These results point to the broader applicability of this approach towards space countermeasure development, and potential for further investigation of lead neurotherapeutic molecule as a reversible gene therapy.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.505107v1?rss=1
Authors: Bauza, M., Krstulovic, M., Krupic, J.
Abstract: Spatial working memory and image recognition tests are commonly used to facilitate the diagnosis of hippocampal-related neurological disorders such as Alzheimers disease due to their relatively high specificity and sensitivity to damage to the medial temporal lobes compared to standard commonly used clinical tests. Pathological changes in Alzheimers disease start years before the formal diagnosis is made, partially due to testing too late. To address this challenge, we developed a novel digital platform, hAge (healthy Age), which integrates double spatial alternation, image recognition and visuospatial tasks for frequent remote unsupervised assessment of spatial and non-spatial working memory. 191 healthy adults (67% females, 18-81 years old) participated in the study. In line with findings using standard laboratory tests, we showed that performance on the spatial alternation task negatively correlated with inter-trial periods and performance levels on image recognition and visuospatial tasks can be controlled by varying image similarity. Importantly, we demonstrated that frequent engagement with the double spatial alternation task leads to a strong practice effect, previously identified as a potential measure of cognitive decline in MCI patients. Finally, we discuss how lifestyle and motivation confounds may present a serious challenge for cognitive assessment in real-world uncontrolled environments.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.505087v1?rss=1
Authors: R Villamayor, P., Gullon, J., Quintela, L., Sanchez-Quinteiro, P., Martinez, P., Robledo, D.
Abstract: Background: Chemosensory cues are vital for social and sexual behaviours and are primarily detected and processed by the vomeronasal system (VNS), whose plastic capacity has been investigated in mice. However, studying chemosensory plasticity outside of laboratory conditions may give a more realistic picture of how the VNS adapts to a changing environment. Rabbits are a well-described model of chemocommunication since the discovery of the rabbit mammary pheromone and their vomeronasal organ (VNO) transcriptome was recently characterized, a first step to further study plasticity-mediated transcriptional changes. In this study, we assess the plastic capacity of the rabbit male and female VNO under sex-separation vs sex-combined scenarios, including adults and juveniles, to determine whether the rabbit VNO is plastic and, if so, whether such plasticity is already established at early stages of life. Results: First, we characterized the number of differentially expressed genes (DEGs) between the VNO of rabbit male and female under sex-separation and compared it to sex-combined individuals, both in adults and juveniles, finding that differences between male and female were larger in a sex-separated scenario. Secondly, we analyzed the number of DEGs between sex-separated and sex-combined scenarios, both in males and females. In adults, both sexes showed a high number of DEGs while in juveniles only females showed differences. Additionally, the vomeronasal receptor genes were strikingly down-regulated in sex-separated adult females, whereas in juveniles up-regulation was shown for the same condition, suggesting a role of VRs in puberty onset. Finally, we described the environment-modulated plastic capacity of genes involved in reproduction, immunity and VNO functional activity, including G-protein coupled receptors. Conclusions: Our results show that sex-separation induces sex- and stage- specific gene expression differences in the VNO of male and female rabbit, both in adults and juveniles. These results bring out for the first time the plastic capacity of the rabbit VNO, supporting its functional adaptation to specifically respond to a continuous changing environment. Finally, species-specific differences and individual variability should always be considered in VNO studies and overall chemocommunication research.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.505085v1?rss=1
Authors: Taylor, S., Kobayashi, M., Vilella, A., Tiwari, D., Zolboot, N., Hartzell, A., Girgiss, C., Abaci, Y., De Sanctis, C., Bellenchi, G. C., Darnell, R. B., Gross, C., Zoli, M., Berg, D. K., Lippi, G.
Abstract: The assembly of the mammalian brain is orchestrated by temporally coordinated waves of gene expression. A key aspect of this developmental program is mediated at the post-transcriptional level by microRNAs (miRNAs). Deletion of neuronal enriched miRNAs induces strong developmental phenotypes, and multiple reports have found altered levels of miRNAs in patients with neurodevelopmental disorders. However, cellular and molecular mechanisms used by miRNAs to instruct proper brain development remain largely unexplored. Here, through multiple screens, we identified miR-218 as a critical regulator of hippocampal assembly in mice. MiR-218 is highly expressed in the hippocampus and enriched in both excitatory principal neurons and GABAergic inhibitory interneurons. Transient inhibition of miR-218 in early life results in an adult brain with heightened network activity and a predisposition to seizures. We used RNA-seq and FACS-seq (fluorescence-activated cell sorting followed by RNA-seq) to identify global and cell type-specific changes in gene expression in the absence of miR-218 and narrow down which altered developmental processes would lead to long-term network instability. We find that miR-218 inhibition results in the disruption of early depolarizing GABAergic signaling, structural defects in dendritic spines, and altered intrinsic membrane excitability. Finally, conditional knockout of miR-218 in interneurons, but not pyramidal neurons is sufficient to recapitulate the effects on long-term stability. Taken together, the data suggest that miR-218 orchestrates hippocampal network assembly to produce a stable network in the adult, primarily by regulating interneuron function in early postnatal life.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.23.505049v1?rss=1
Authors: Fraza, C. J., Zabihi, M., Beckmann, C. F., Marquand, A. F.
Abstract: In this paper, we propose a new framework for understanding and modelling neurobiological extreme atypicalities for individual participants. We combine the strength of normative models, to make predictions for individual patients, with multivariate extreme value statistics, which allows us to model the outer centiles accurately, enabling accurate estimation of risk and detection of atypicality. In general, most statistical methods focus principally on estimating the mean of the distribution and are not appropriate to capture the tails of the distribution. We believe that the tails carry most of the information for predicting psychopathy in neurological and psychiatric disorders and should therefore be modelled carefully. In the univariate case, we demonstrate how to fit a generalized Pareto distribution with the peaks over threshold method. For the multivariate case, we present a novel framework that allows us to capture the multivariate tails of the distribution fully. The model relies on the so-called tail pairwise dependence matrix (TPDM). The TPDM is similar to a covariance matrix, but specified for the tails. From the TPDM we can create a reduced basis of vectors that explain most of the structure underlying the extreme values. The method is similar to covariance principal component analysis, but uniquely made for the extreme values. To evaluate this framework, we use a range of neuroimaging-derived measures from the UK Biobank dataset, including structural, functional and diffusion image-derived phenotypes. We find that the first extreme principal component mostly consists of whole-brain volume and area measures and the second extreme principal component is mostly compromised of white matter tracts. We further demonstrate the link between extreme brain deviations in the individual from a reference cohort to behaviour.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.23.504847v1?rss=1
Authors: Parker, P. R. L., Martins, D. M., Leonard, E. S. P., Casey, N. M., Sharp, S. L., Abe, E. T. T., Smear, M. C., Yates, J. L., Mitchell, J. F., Niell, C. M.
Abstract: Animals move their head and eyes as they explore and sample the visual scene. Previous studies have demonstrated neural correlates of head and eye movements in rodent primary visual cortex (V1), but the sources and computational roles of these signals are unclear. We addressed this by combining measurement of head and eye movements with high density neural recordings in freely moving mice. V1 neurons responded primarily to gaze shifts, where head movements are accompanied by saccadic eye movements, but not to head movements where compensatory eye movements stabilize gaze. A variety of activity patterns immediately followed gaze shifts, including units with positive, biphasic, or negative responses, and together these responses formed a temporal sequence following the gaze shift. These responses were greatly diminished in the dark for the vast majority of units, replaced by a uniform suppression of activity, and were similar to those evoked by sequentially flashed stimuli in head-fixed conditions, suggesting that gaze shift transients represent the temporal response to the rapid onset of new visual input. Notably, neurons responded in a sequence that matches their spatial frequency preference, from low to high spatial frequency tuning, consistent with coarse-to-fine processing of the visual scene following each gaze shift. Recordings in foveal V1 of freely gazing head-fixed marmosets revealed a similar sequence of temporal response following a saccade, as well as the progression of spatial frequency tuning. Together, our results demonstrate that active vision in both mice and marmosets consists of a dynamic temporal sequence of neural activity associated with visual sampling.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.23.505043v1?rss=1
Authors: Kobayashi, T., Takemi, M., Nozaki, D.
Abstract: Even experts can sometimes fail while performing fully learned movements. Do such failures suddenly arise, or are there any forecasting signs? It has been reported that the kinematics of the early phase of movements can predict the failure, and brain activity patterns specific to failures are observed just before the movement onset. The presence of abnormal brain activity patterns long before (> 30 s) a failure in a cognitive task leads us to question if signs of a failure in action could exist in trials preceding the failure. Here, we examined this question using a reaching movement adaptation paradigm conventionally used to test motor learning dynamics. Firstly, the presence of a behavioral sign that preceded failures was observed: the peak velocity of the reaching movement significantly decreased in the preceding two trials. Secondly, specific theta and alpha band activity of EEG were observed in the failure trials and the trials preceding the failure. These results suggest that a failure in actions does not occur suddenly, and some signs preceding failures can be observed in the prior trials. Our approach may pave the way to investigate how we prevent failures and improve motor performance.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.23.505040v1?rss=1
Authors: Pull, K., Folk, R., Kang, J., Jackson, S., Guesk, B., Esfandiarei, M., Jadavji, N. M.
Abstract: A maternal diet that provides adequate nutrition during pregnancy and lactation is vital to the neurodevelopment of offspring. One-carbon metabolism plays an important role in the closure of the neural tube of the developing embryo; however, the impact of maternal one-carbon dietary deficiencies on offspring neurological function later in life remains relatively unknown. Stroke is one of the leading causes of death globally, and its prevalence is expected to increase in younger age groups as the incidence of various risk factors for stroke increases. The aim of our study was to determine the impact of maternal nutritional deficiencies on cerebral blood flow and peripheral hemodynamics after ischemic stroke in adult offspring. In this study, adult female C57BL/6J mice were placed on either control (CD), choline (ChDD) or folic acid (FADD) deficient diets for four weeks to deplete stores prior to mating and maintained on the assigned diet during pregnancy and lactation. Female offspring were weaned and transitioned to a CD for the duration of the study. Ischemic stroke was induced in the sensorimotor cortex of 2- and 10-month-old female offspring using the photothrombosis model. Six weeks after induction of stroke, cerebral and peripheral blood flow was measured using the Vevo2100 Pulse Wave Doppler tracing modality. Our data showed that 3.5-month-old female offspring from a ChDD mothers had reduced blood flow in the posterior cerebral artery compared to CD mice; this effect disappeared in older offspring. In 11.5-month-old females we observed changes in peripheral hemodynamics, but not in young animals. Our findings suggest that a maternal dietary deficiency in choline results in reduced cerebral blood flow in adult female offspring after ischemic stroke, but the long-term effects are not present. This result points to the key role of the maternal diet in early life neuro-programming, while emphasizing its effects on both fetal development and long-term cerebrovascular health.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.505112v1?rss=1
Authors: Cappelloni, M. S. S., Shivkumar, S., Haefner, R. M., Maddox, R. K.
Abstract: The brain combines information from multiple sensory modalities to interpret the environment. These processes, collectively known as multisensory integration, have been modeled as ideal Bayesian causal inference, proposing that perception involves the combination of information from different sensory modalities based on their reliability and their likelihood of stemming from the same causes in the outside world. Bayesian causal inference has explained a variety of multisensory effects in simple tasks but is largely untested in complex sensory scenes where multisensory integration can provide the most benefit. Recently, we presented data challenging the ideal Bayesian model from a new auditory spatial discrimination task in which spatially aligned visual stimuli improve performance despite providing no information about the correct response. Here, we present two modifications of our original experiment to explore potential effects of the stimulus duration, and thus relative reliability of the stimuli, on the multisensory effect we previously measured. While our results replicate the original effect, we do not find clear evidence that the reliability of the stimuli impacts effect size within or across subjects.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.505091v1?rss=1
Authors: Kirchner, J., Watson, T., Bauer, J., Lappe, M.
Abstract: Vision requires that we rotate our eyes frequently to look at informative structures in the scene. Eye movements are planned by the brain but their execution depends on the mechanical properties of the oculomotor plant, i.e, the arrangement of eyeball position, muscle insertions and pulley locations. Therefore, the biomechanics of rotations is sensitive to eyeball translation because it changes muscle levers. Eyeball translations are little researched as they are difficult to measure with conventional techniques. Here we study the effects of eyeball translation on the coordination of gaze rotation by high-speed MRI recordings of saccadic eye movements during blinks, which are known to produce strong translations. We found that saccades during blinks massively overshoot their targets, and that these overshoots occur in a transient fashion such that the eye is back on target at the time the blink ends. These dynamic overshoots were tightly coupled to the eyeball translation, both in time and in size. Saccades made without blinks were also accompanied by small amounts of transient eyeball retraction, the size of which scaled with saccade amplitude. These findings demonstrate the complex interaction between rotation and translation movements of the eye. The mechanical consequences of eyeball translation on oculomotor control should be considered along with the neural implementation in the brain to understand the generation of eye movements and their disorders.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.505057v1?rss=1
Authors: Noguchi, J., Watanabe, S., Oga, T., Isoda, R., Nakagaki, K., Sakai, K., Sumida, K., Hoshino, K., Saito, K., Miyawaki, I., Sugano, E., Tomita, H., Mizukami, H., Watakabe, A., Yamamori, T., Ichinohe, N.
Abstract: Impairments in the experience-dependent elaboration of neural circuits are assumed to underlie autism spectrum disorder (ASD). However, the phenotype underlying synaptic plasticity is poorly understood. Here, we used a valproic acid-induced ASD marmoset model and in vivo two-photon microscopy to investigate the structural dynamics of dendritic spines in the dorsomedial prefrontal cortex, which is involved in ASD core symptoms. In model marmosets compared to controls, spine turnover was upregulated and spines were actively generated in clusters. Clustered emerging spines were predominant in carryover of generated spines in the model marmosets. Presynaptic boutons of local axons, but not long-range commissural axons, showed hyperdynamic turnover. Furthermore, nasal oxytocin administration reduced the clustered emergence of spines. Finally, we confirmed the high molecular conformity of adult animal models with human ASD. Our study suggests that an altered balance between synaptic plasticity and consolidation underlies ASD, and may be a potential therapeutic target.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.505074v1?rss=1
Authors: Nagel, M., Noss, M., Xu, J., Horn, N., Ueffing, M., Boldt, K., Schuele, R.
Abstract: Neurons critically depend on regulated RNA localization and tight control of spatio-temporal gene expression to maintain their morphological and functional integrity. Mutations in the kinesin motor protein gene KIF1C cause Hereditary Spastic Paraplegia, an autosomal recessive disease leading to predominant degeneration of the long axons of central motoneurons. In this study we aimed to gain insight into the molecular function of KIF1C and understand how KIF1C dysfunction contributes to motoneuron degeneration. We used affinity proteomics in neuronally differentiated neuroblastoma cells (SH-SY5Y) to identify the protein complex associated with KIF1C in neuronal cells; candidate interactions were then validated by immunoprecipitation and mislocalization of putative KIF1C cargoes was studied by immunostainings. We found KIF1C to interact with all core components of the exon junction complex (EJC); expression of mutant KIF1C in neuronal cells leads to loss of the typical localization distally in neurites. Instead, EJC core components accumulate in the pericentrosomal region, here co-localizing with mutant KIF1C. These findings suggest KIF1C as a neuronal transporter of the EJC. Interestingly, the binding of KIF1C to the EJC is RNA-mediated, as treatment with RNAse prior to immunoprecipitation almost completely abolishes the interaction. Silica-based solid-phase extraction of UV-crosslinked RNA-protein complexes furthermore supports direct interaction of KIF1C with RNA, as recently also demonstrated for kinesin heavy chain. Taken together, our findings are consistent with a model where KIF1C transports mRNA in an EJC-bound and therefore transcriptionally silenced state along neurites, thus providing the missing link between the EJC and mRNA localization in neurons.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.505089v1?rss=1
Authors: Ainslie, A. P., Klaver, M., Voshart, D. C., Gerrits, E., Eggen, B. J., Bergink, S., Barazzuol, L.
Abstract: Progressive neurocognitive dysfunction is the leading cause of a reduced quality of life in patients with primary brain tumours. Understanding the mechanisms underlying cognitive impairments that occur in response to a brain tumour and its treatment is essential to improve patients' quality of life. Here, we show that normal-appearing non-tumour brain regions of patients with glioblastoma display hallmarks of accelerated ageing and share multiple features with Alzheimer's disease patients. Integrated transcriptomic and tissue analysis shows that normal-appearing brain tissue from glioblastoma patients has a significant overlap with brain tissue from Alzheimer's disease patients, revealing shared mitochondrial and neuronal dysfunction, and proteostasis deregulation. Overall, the brain of glioblastoma patients undergoes Alzheimer's disease-like accelerated ageing, providing novel or repurposed therapeutic targets for managing brain cancer-related side effects.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.505165v1?rss=1
Authors: Pak, C., Sebastian, R., Jin, K., Pavon, N., Bansal, R., Potter, A., Song, Y., Babu, J., Gabriel, R., Sun, Y., Aronow, B. J.
Abstract: De novo mutations and copy number variations (CNVs) in NRXN1 (2p16.3) pose a significant risk for schizophrenia (SCZ). How NRXN1 CNVs impact cortical development in a cell type-specific manner and how disease genetic background modulates these phenotypes are unclear. Here, we leveraged human pluripotent stem cell-derived brain organoid models carrying NRXN1 heterozygous deletions in isogenic and SCZ patient genetic backgrounds and conducted single cell transcriptomic analysis over the course of cortical brain organoid development from 3 weeks to 3.5 months. We identified maturing glutamatergic and GABAergic neurons as being consistently impacted due to NRXN1 CNVs irrespective of genetic background, contributed in part by altered gene modules in ubiquitin-mediated pathways, splicing, and synaptic signaling. Moreover, while isogenic NRXN1 CNVs impact differentiation and maturation of neurons and astroglia, cell composition and developmental trajectories of early neural progenitors are affected in SCZ-NRXN1 CNVs. Our study reveals developmental timing dependent NRXN1 CNV-induced cellular mechanisms in SCZ at single cell resolution and highlights the emergence of disease-specific transcriptomic signatures and cellular vulnerabilities, which can arise from interaction between genetic variants and disease background.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.505210v1?rss=1
Authors: Ikezoe, K., Hidaka, N., Manita, S., Murakami, M., Tsutsumi, S., Isomura, Y., Kano, M., Kitamura, K.
Abstract: Cerebellar climbing fibers (CFs) convey sensorimotor information and their errors, which are used for motor control and learning. Furthermore, they represent reward-related information. Despite such functional diversity of CF signals, it is still unclear whether each CF conveys the information of single or multiple modalities and how the CFs conveying different information are distributed over the cerebellar cortex. We performed two-photon calcium imaging from cerebellar Purkinje cells (PCs) in mice engaged in a voluntary forelimb lever-pull task and demonstrated that CF responses in 93% of PCs could be explained by the combination of multiple behavioral variables, such as lever movement, licking, and reward delivery. Neighboring PCs exhibited similar CF response properties, formed functional clusters, and shared noise fluctuations of responses. Taken together, individual CFs convey behavioral information on multiplex variables and are spatially organized into the functional modules of the cerebellar cortex.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.24.505144v1?rss=1
Authors: Keshavarzi, M., M. Di Liberto, G., Gabrielczyk, F., Wilson, A., Macfarlane, A., Goswami, U.
Abstract: Cross-language data show that children with dyslexia are poor at recognizing syllable stress patterns, yet their speech production appears normal, suggesting an unexpected disconnect between speech input and output processes. Here we utilized a novel computerized speech copying task based on the speech amplitude envelope (AE) to investigate this disconnect. Seventy-five children with and without dyslexia copied familiar spoken targets like "Aladdin". Children with dyslexia were significantly worse at producing the multi-syllabic targets as indexed by two similarity metrics for computing the AE. They did not differ from other children in producing the pitch contours of items. Accordingly, impaired AE perception in dyslexia is matched by impaired AE production. Children with dyslexia are heard to produce multi-syllabic words normally because their pitch contours are intact.
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.25.505119v1?rss=1
Authors: Lu, T.-Y., Hanumaihgari, P., Hsu, E. T., Agarwal, A., Bergles, D. E.
Abstract: Oligodendrocytes are generated from a widely distributed population of progenitors that express neurotransmitter receptors, but the mechanisms that alter activity of these oligodendrocyte precursor cells (OPCs) in vivo have not been determined. We generated a novel line of transgenic mice to express membrane-anchored GCaMP6s in OPCs and used longitudinal two-photon microscopy to monitor their calcium changes in the cerebral cortex of awake mice. OPCs exhibited high rates of spontaneous activity, consisting of focal, transient calcium increases within their highly ramified processes. Unexpectedly, these events occurred independent of excitatory neuron activity, but were inhibited by anesthesia, sedative agents, and antagonists of noradrenergic signaling. These norepinephrine enhanced calcium dynamics rapidly declined as with differentiation. Selective knockout of alpha-1A adrenergic receptors in OPCs suppressed both spontaneous and locomotion-induced calcium increases, indicating that OPCs are directly modulated by norepinephrine in vivo, providing a means to alter their dynamics and lineage progression during distinct brain states.
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