bioRxiv Subject Collection: Neuroscience's Journal
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Monday, April 28th, 2025
| Time |
Event |
| 11:33p |
Pathogenic O-GlcNAc dyshomeostasis associated with cortical malformations and hyperactivity
Missense variants in the O-GlcNAc transferase (OGT) gene have recently been shown to segregate with a syndromic form of intellectual disability (OGT-ID), underscoring the importance of protein O-GlcNAcylation in brain function. However, the underlying pathophysiological mechanisms linking ID to potential OGT malfunction--whether developmental, neurophysiological, or both--remain unclear. Here, we present comprehensive analyses encompassing behaviour and brain architecture in a rodent model carrying the C921Y OGT-ID variant. These mice show a range of behavioural deficits, including hyperactivity, impulsivity, and associative learning phenotypes. Structural studies, using micro-computed tomography and magnetic resonance imaging, revealed reduced skull size, microcephaly, reduced cortical thickness and hypoplastic corpus callosum. These were associated with nodular cortical dysplasia affecting the superficial layers of the cingulate cortex. Mechanistically, quantitative proteomic analyses revealed O-GlcNAc dyshomeostasis associated with distinct perturbed molecular pathways involved in brain development. Taken together, these data reveal neurodevelopmental defects associated with O-GlcNAc dyshomeostasis and provide a platform for dissecting mechanism and treatments of OGT-ID. | | 11:33p |
Differential changes in the effective neural drive following new motor skill acquisition between vastus lateralis and medialis
Purpose: To investigate whether short-term learning of a new motor task is mediated by changes in common synaptic inputs to motor neurons within and between synergistic muscles. Methods: Seventeen healthy individuals performed 15 repetitions of a complex force-matching task at 10% of a maximal voluntary contraction. Two trials were selected for analysis, the one with the highest force-target error (pre-learning) and the one with the lowest (post-learning). High-density surface electromyograms recorded from vastus medialis (VM) and vastus lateralis (VL) were decomposed into their constituent motor unit spike trains, with individual motor units being tracked between trials. Motor unit discharge behavior and common synaptic oscillations across the delta, alpha, and beta bands were calculated and compared between pre- and post-learning. Results: Force-target matching improved across trials, accompanied by a significant decrease in the coefficient of variation of the inter-spike interval (p < 0.01), while the mean discharge rate remained similar (p > 0.85). The area under the curve within delta (p < 0.003) and alpha (p < 0.004) bands decreased between trials, with no significant changes in the beta band (p > 0.05). Notably, reductions in the alpha band correlated significantly with performance improvements in VL (R = 0.81) but not in VM (R = 0.12). Conclusion: The acquisition of a new motor task is mediated by modulations in common synaptic inputs to motor units, leading to improved force control. Our findings further suggest that these changes in common synaptic inputs, particularly in the alpha band, differ between VM and VL. | | 11:33p |
Tanycyte Bmal1 sex-specifically regulates weight gain and hypothalamic neurogenesis in female mice
The hypothalamic radial-glia-like tanycyte population plays important and intertwined roles in feeding and metabolism, reproduction, and seasonality. Although these processes are circadian-regulated and clock genes reportedly show robust cycling along the 3rd ventricle, the role of the clock in tanycytes has not yet been examined. We report here that clock genes cycle with much higher amplitude in ventral tanycytes compared to more dorsal ependymocytes of the 3rd ventricle, and that specific disruption of the tanycyte clock can be achieved by adult Bmal1 deletion using the RaxCreER driver. Adult tanycyte Bmal1 deletion did not affect circadian rhythms of wheel-running and sleep, but did inhibit weight gain on high-fat diet in female mice. Altered tanycyte-derived hypothalamic neurogenesis, which can regulate feeding and weight gain by contributing new neurons to nearby feeding-relevant nuclei, is one mechanism that likely contributes to this phenotype. Fate mapping studies showed that female mice have higher baseline tanycyte-derived neurogenesis than males, with many of the resulting neurons localizing to the feeding-relevant arcuate nucleus. Female but not male mice show reduced tanycyte-derived arcuate neurogenesis after adult tanycyte Bmal1 deletion and an increased percentage of newborn arcuate neurons take on a feeding-suppressing POMC neuropeptidergic fate. Thereby, skewing of feeding and satiety promoting fates link the weight homeostasis and neurogenesis effects. Together, our data establish tanycyte Bmal1 as a sexually dimorphic regulator of weight homeostasis, likely mediated at least in part by a female-specific neurogenesis effect in the feeding circuitry. | | 11:33p |
The representational geometry of out-of-distribution generalization in primary visual cortex and artificial neural networks
Humans and other animals display a remarkable ability to generalize learned knowledge to novel domains, a phenomenon known as out-of-distribution (OOD) generalization. This capability is thought to depend on the format of neural population representations; however, the specific geometrical properties that support OOD generalization and the learning objectives that give rise to them remain poorly understood. Here, we examine the OOD generalization of neural population representations of static grating orientations in the mouse visual cortex. We show that a decoder trained on neural responses within a restricted orientation domain can generalize to held-out orientation domains. The quality of generalization correlates with both the dimensionality and the curvature of the underlying neural representation manifold. Notably, similar OOD-generalizable geometry emerges in a deep neural network trained to predict the next frame in natural video sequences. These findings reveal the representational geometric properties underlying OOD generalization, and suggest that predictive learning objectives offer a promising approach for acquiring generalizable representation geometry. | | 11:33p |
Cortical interneurons require JNK signaling for migration regardlessof substrate and topographical environment
During embryonic development, cortical interneurons travel tangentially in migratory streams to reach the cerebral cortex, then turn radially to exit their streams and invade the cortical plate. Migrating cortical interneurons remain in constant communication with both extracellular signals and intracellular machinery to maintain a directed migration into the cortical rudiment. In order to engage in directed migration, cortical interneurons undergo the cell biological process termed nucleokinesis in which interneurons translocate their cell bodies into a cytoplasmic swelling formed in the leading process. Many of the intracellular mechanisms governing the timing of migratory stream exit and cortical plate invasion are poorly understood yet are of fundamental importance to cortical development. We previously uncovered a requirement for the c-Jun NH2-terminal kinase (JNK) signaling pathway in cortical interneuron migration. Disruption of the JNK signaling pathway resulted in a delayed entry of cortical interneurons into the cortex, as well as a premature departure from migratory streams. We are interested in uncovering the mechanisms by which JNK activity coordinates the intracellular processes essential for the guided migration of cortical interneurons. Our data shows, through the use of multiple ex vivo and in vitro assays, that cortical interneurons treated with JNK inhibitor exhibit major deficiencies in nucleokinesis. Additionally, we developed a novel tool to explore cortical interneuron migration using a nanopattern topography. Interneurons grown on nanopatterns have significantly faster migratory speeds and translocate further distances than cells cultured on a flat substrate. Interneurons grown on nanopatterns also display a different subcellular distribution of doublecortin, a known target of JNK signaling involved in microtubule stability and the guided migration of cortical interneurons. Overall, our results highlight the importance of JNK signaling in the guided migration of cortical interneurons. | | 11:33p |
Slow Mechanical Filtering by Outer Hair Cells Enhances Rather than Limits Receptor Potential Kinetics
Mammals achieve extraordinarily sensitive hearing through the active amplification of sound vibrations in the cochlea. Central to this process is the electromotility of outer hair cells (OHCs)-their somatic length changes powered by the membrane motor protein prestin, which converts receptor potentials into mechanical forces. Yet the intrinsic RC (resistance-capacitance) low-pass filtering of the OHC membrane poses a paradox: how can OHCs generate the rapid force changes necessary for effective amplification? One hypothesis suggests that hair bundle adaptation, operating on sub- to tens-of-millisecond timescales, might compensate for the comparatively slower somatic response. In this study, we resolve the paradox by simultaneously recording sound-evoked electrical and mechanical responses in the guinea pig cochlear apex during adaptation-inducing intense sound stimulation. High-speed confocal microscopy paired with AI-based segmentation enabled two-dimensional quantification of the OHC mechanical response-tracking changes in length, width, and area-while extracellular recordings captured receptor potentials. Under control conditions, the inherently slow kinetics of prestin-mediated mechanical changes serve to sharpen receptor potential kinetics. Notably, pharmacological blockade of prestin with salicylate reversed this relationship: the mechanical response kinetics became markedly sharper, while receptor potential kinetics shifted into a sluggish, low-pass regime. These findings demonstrate that the intrinsic low-pass filtering of electromotility is not a limitation but rather a critical feature that preserves rapid electrical transduction, thereby underpinning the exquisite sensitivity of the mammalian auditory system. | | 11:33p |
Patient-derived Brain Organoids Reveal Divergent Neuronal Activity Across Subpopulations of Autism Spectrum Disorder
Patient-derived brain organoids have emerged as a powerful model for investigating the mechanisms underlying neurological and psychiatric disorders. They provide novel insights into autism spectrum disorder (ASD), a heterogeneous neurodevelopmental condition whose underlying mechanisms remain poorly understood. Recent advancements in generating electrophysiological functional 3D brain organoids enable the study of molecular and network-level neuronal activity. Here, we aimed to characterize the neurophysiological underpinnings of ASD by comparing electrophysiological properties of brain organoids derived from eleven individuals diagnosed with autism spectrum disorder - 10 with monogenic syndromic ASD across five genetic subtypes, and 1 with idiopathic ASD - to organoids derived from 4 neurotypical control individuals. We identified distinct differences in baseline activity (resting state) and evoked responses (synaptic plasticity and network dynamics) across ASD subgroups. To comprehensively assess these differences, we applied dimensionality reduction and machine learning (principal component analysis, PCA) to integrate multiple electrophysiological features into a unified framework. Our findings reveal subtype-specific neurophysiological alterations in ASD brain organoids, offering mechanistic insights into ASD heterogeneity and potential applications for early diagnostics, drug screening, and therapeutic development. | | 11:33p |
Structure-Function Mapping of Olfactory Bulb Circuits with Synchrotron X-ray Nanotomography
Information is routed between brain areas via parallel streams. Neurons may share common inputs yet convey distinct information to different downstream targets. Here, we leverage the anatomical organisation of the mouse olfactory bulb (OB), where dozens of projection neurons (mitral and tufted cells, M/TCs) affiliate with a single input unit, a glomerulus. To link functional properties of M/TCs to their anatomical glomerular association at scale, we combine in vivo two-photon (2P) imaging with synchrotron CT anatomical analysis and targeted X-ray nano-holotomography (XNH). Improving XNH resolution for mm3 volumes enables us to reliably identify subcellular features, automatically segment >80,000 cell nuclei in individual experiments, and delineate several hundred functionally imaged projection neurons and their detailed morphology, including up to 20 M/TCs per individual glomerulus ('sister' cells). In over 2400 sister cell pairs, we consistently find that odour response amplitudes to a panel of 47 monomolecular odours are conserved between sister cells, with, however, distinct responses to individual odours. Responses correlated with anatomical features such as cell body position and lateral dendritic arborisation. Thus, sister cells neither simply relay glomerular inputs nor are they dominated by network activity. Instead, they show a 'balanced diversity' in their responses, enabling efficient encoding of odour stimuli whilst retaining the overall structure of odour space. Thus, synchrotron X-ray tomography can reliably link subcellular anatomy to function in a non-destructive way across the mm3 scale. With recent advances in X-ray optics and the emergence of 4th generation synchrotrons, it becomes conceivable to extend this highly accessible approach to entire brain regions with increasing resolution. | | 11:33p |
The impact of nerve injury on the immune system across the lifespan is sexually dimorphic
Although nerve injury-associated neuroinflammation contributes to neuropathic pain, the long-term impact of such injury on systemic homeostasis and its potential role in pain remains elusive. In this study, we aim to understand the systemic changes that are present alongside chronic pain in nerve-injured male and female mice across their lifespan. We monitored mechanical and cold sensitivity in male and female mice starting at the age of 3-4 months old when they received spared nerve injury (SNI), up to 20-month post-injury. Alongside, we collected blood samples to track changes in immune cells with flow cytometry, and to assess inflammation-related serum proteome using a 111-target Proteome Profiler. We also transferred serum from sham/SNI mice to naive mice to determine the potential of systemic contribution to pain. While nerve injury did not affect immune cell composition in the blood, it triggered a long-lasting disturbance of molecular profile in the serum of sham/SNI mice, in a sex-dependent manner. Compared to sham surgery, nerve injury amplified regulation of inflammatory proteins in males, but slightly reduced it in females. These changes in the serum occurred in parallel with long-lasting mechanical and cold hypersensitivity in the nerve-injured mice. Both male and female SNI serum induced hypersensitivity when transferred to naive mice, regardless of a sex-matched or sex-crossed transfer. Our results highlight that a local nerve injury can have persistent systemic impact. Injury-associated systemic inflammation could contribute to neuropathic pain, but the underlying mechanisms may be sexually dimorphic. | | 11:33p |
Deployment of endocytic machinery to periactive zones of nerve terminals is independent of active zone assembly and evoked release
In presynaptic nerve terminals, the endocytic apparatus rapidly restores synaptic vesicles after neurotransmitter release. Many endocytic proteins localize to the periactive zone, a loosely defined area adjacent to active zones. A prevailing model posits that recruitment of these endocytic proteins to the periactive zone is activity-dependent. We here show that periactive zone targeting of endocytic proteins is largely independent of active zone machinery and synaptic activity. At periactive zones of mouse hippocampal synapses and Drosophila neuromuscular junctions, pharmacological or genetic silencing resulted in unchanged or increased levels of endocytic proteins including Dynamin, Amphiphysin, Nervous Wreck, PIPK1{gamma} and AP-180. Similarly, disruption of active zone assembly via genetic ablation of active zone scaffolds at each synapse did not impair the localization of endocytic proteins. Overall, our work indicates that endocytic proteins are constitutively deployed to the periactive zone and supports the existence of independent assembly pathways for active zones and periactive zones. | | 11:33p |
Neuralace: Manufacture, Parylene-C Coating, and Mechanical Properties
Subdural electrode arrays have traditionally been used for epilepsy monitoring and surgical planning. With the emergence of brain-computer interface (BCI) applications, these arrays are now being explored for chronic use, leveraging their ability to record subdural signals for neural decoding. Transitioning from short-term implantation in epilepsy monitoring to long-term use in BCIs requires advancements through consideration of the foreign body response to ensure long-term durability and functionality. Biocompatibility challenges, such as fibrotic encapsulation and reactive astrogliosis, highlight the need for conformal subdural implant designs that minimize mechanical stress on neural tissue. This study investigates the mechanical properties of the Neuralace, a novel ultra-thin, high-channel-count mesh-type surface grid. We characterized the stiffness of the silicon-based interposer electrode meshes and evaluated the effects of various geometric configurations and polymeric encapsulation layers on the mechanical performance. Using a full factorial design of experiments framework and a custom low-force four-point bending setup, we identified the design factors that impact the stiffness of Neuralace structures. The results showed highly consistent stiffness measurements. The stiffness values of Neuralace structures ranged from 2.99 N/m to 7.21 N/m, depending on the cell-wall thickness (CWT) of the lace, the orientation angle, and whether the structures were encapsulated with parylene-C (PPXC). Orientation and CWT had the largest impact on the stiffness of the structures, while the effects of PPXC encapsulation were statistically significant but more subtle. The stiffest Neuralace configuration is expected to exert forces approximately 10 to 100 times lower than commercially available subdural implants would when conforming to the radius of the smallest anatomical gyrus. This work demonstrates the feasibility of tailoring the mechanical properties of Neuralace to improve its suitability for chronic neural implantation, providing insights for future design iterations and conformable implant development. |
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