bioRxiv Subject Collection: Neuroscience's Journal
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Friday, January 10th, 2025
| Time |
Event |
| 1:31a |
Age-dependent alterations in the head-direction signal in a rat model of Fragile X Syndrome
Fragile X Syndrome (FXS) is a common monogenic cause of autism spectrum disorder and intellectual disability (ASD/ID), but the neural mechanisms underlying its symptoms remain unclear. Here, we investigate the development of the head-direction (HD) system in a rat model of FXS (Fmr1-/y rats). Using high-density silicon probes, we recorded neuronal activity in the postsubiculum (PoSub), a cortical hub of the HD system, during exploration and sleep in juvenile and adult Fmr1-/y and wild-type (WT) rats. Juvenile Fmr1-/y rats exhibited enhanced HD tuning characterized by sharper directional tuning curves and improved stability of the HD signal in relation to the external environment. This enhancement was intrinsic to the HD circuit and persisted across behavioral and sleep states. However, by adulthood, HD tuning in Fmr1-/y rats became unstable, with increased drift in the allocentric reference frame despite intact intrinsic HD dynamics. These findings reveal a transient enhancement of spatial coding in the HD system of juvenile Fmr1-/y, followed by a degradation in adulthood, providing insights into network-level dysfunctions in FXS and their developmental trajectories. Overall, our work establishes the HD system as a valuable and tractable model for studying neurodevelopmental disorders. | | 1:31a |
Revealing hidden knowledge in amnestic mice
Alzheimers disease (AD) is a form of dementia in which memory and cognitive decline is thought to arise from underlying neurodegeneration. These cognitive impairments, however, are transient when they first appear and can fluctuate across disease progression. Here, we investigate the neural mechanisms underlying fluctuations of performance in amnestic mice. We trained APP/PS1+ mice on an auditory go/no-go task that dissociated learning of task contingencies (knowledge) from its more variable expression under reinforcement (performance). APP/PS1+ exhibited significant performance deficits compared to control mice. Using large-scale two-photon imaging of 6,216 excitatory neurons in 8 mice, we found that auditory cortical networks were more suppressed, less selective to the sensory cues, and exhibited aberrant higher-order encoding of reward prediction compared to control mice. A small sub-population of neurons, however, displayed the opposite phenotype, reflecting a potential compensatory mechanism. Volumetric analysis demonstrated that deficits were concentrated near A{beta} plaques. Strikingly, we found that these cortical deficits were reversed almost instantaneously on probe (non-reinforced) trials when APP/PS1+ performed as well as control mice, providing neural evidence for intact stimulus-action knowledge despite variable ongoing performance. A biologically-plausible reinforcement learning model recapitulated these results and showed that synaptic weights from sensory-to-decision neurons were preserved (i.e. intact stimulus-action knowledge) despite poor performance that was due to inadequate contextual scaling (i.e. impaired performance). Our results suggest that the amnestic phenotype is transient, contextual, and endogenously reversible, with the underlying neural circuits retaining the underlying stimulus-action associations. Thus, memory deficits commonly observed in amnestic mouse models, and potentially at early stages of dementia in humans, relate more to contextual drivers of performance rather than degeneration of the underlying memory traces. | | 9:22a |
Unique transcriptional profiles of adult human immature neurons in healthy aging, Alzheimer's disease, and cognitive resilience
The existence and functional significance of immature neurons in the adult human brain, particularly in the context of neurodegenerative disorders, remain controversial. While rodent studies have highlighted active roles for adult-born immature neurons in the hippocampus under both healthy conditions and in Alzheimer's disease (AD), evidence from the human brain is limited and lacks detailed molecular characterization. To address this gap, we performed single-nucleus RNA sequencing in aged healthy, AD and dementia-resilient human hippocampus to probe immature neuronal signatures and gene expression alterations associated with AD pathology and resilience. Employing a novel experimental and computational pipeline, we identified persistent populations of immature neurons across all donor groups, with transcriptional profiles distinct from both fetal counterparts and adult mature hippocampal neurons. These profiles were associated with 'juvenile' cellular functions, suggesting that the presence of these immature neuronal populations per se may actively contribute to maintaining homeostasis within the aged human hippocampus, a role that may be disrupted in AD. In the resilient brain, immature neurons were involved in transcriptional programs and intercellular interactions associated with anti-inflammatory, neurotrophic, neuroprotective, myelinating, anti-apoptotic and anti-amyloidogenic signaling pathways, suggesting active roles for the immature cells in enhancing cognitive resilience in the presence of AD pathology. Our findings reveal novel, putative physiological roles for immature neurons in the healthy and resilient adult human brain, and offer a resource for probing new strategies with potential functional relevance in AD. | | 10:30a |
Global dissection of the impact of Alzheimer's disease on brain architecture and behavior: High resolution MRH resolves robust regional effects
Alzheimers disease (AD) affects brain regions with remarkable heterogeneity, but the precise impact of this disease on hundreds of small cortical, subcortical, and brainstem regions remains poorly defined. Here, as a prelude to testing preclinical models to prevent AD, we systematically quantified effects of human AD mutations in APP and PSEN1 on 231 regions and comprehensively evaluated changes in volume with unprecedented resolution in genetically diverse mice as a function of sex and genetic background. We studied 34 5XFAD F1 hybrids and 23 sibling controls at 14 months, evaluating learning and memory behaviors, followed by ex vivo diffusion tensor images (DTI) at 25 {micro}m resolution. We delineated 231 regions of interest (ROIs) bilaterally with high precision. Remarkably, we found bidirectional changes: marked volume increases (up to 10%) in neocortex, hippocampus, amygdala, and sensory nuclei, contrasted with decreases in striatum, pallidum, thalamus, hypothalamus, and most fiber tracts. These opposing effects are unrelated to amyloid load and are likely to reflect temporal gradients in susceptibility of ROIs. Effects are similar in both sexes but far more prominent in females. Genetic background strongly modulates penetrance of the human mutations with the AD-BXD77 F1 type having the greatest sensitivity. Light sheet microscopy and stereological analysis of NeuN+ neurons and amyloid {beta} aggregates in 22 regions revealed up to 20% loss of cells in CA3 and in anterior and intralaminar parts of the thalamus. Volumetric changes correlated with impaired fear acquisition and memory, with cases and controls often showing opposite relations between performance and regional volumes. These findings reveal unprecedented regional heterogeneity in AD progression and suggest therapeutic efficacy may vary substantially across genetic backgrounds and between sexes. | | 10:30a |
Deficiency of Shank3 in the Nucleus Accumbens Reveals a Loss of Social-Specific Motivation
Deficits in social interaction are a hallmark symptom of autism and other neuropsychiatric disorders. SHANK3 encodes a postsynaptic density scaffold protein and is one of the most common causal genes for autism. SHANK3 protein is highly expressed in the nucleus accumbens (NAc), a critical brain region underlying motivated behavior, including social motivation. We previously reported that global Shank3{Delta}e4-22 deletion mice have decreased motivation for palatable food, increased unilateral social investigation, and show a hypoactive NAc and NAc-connected circuits. We thus developed a new Shank3flox/floxmouse tool to conditionally knockdown SHANK3 in a region-specific manner. We found that knockdown of Shank3 in the NAc decreased social preference in the 3-chamber assay and decreased social motivation in the social conditioned place preference (sCPP) assay. Shank3-NAc deletion did not alter food reward seeking, reciprocal social investigation, or anxiety-like behaviors, that we report in global Shank3{Delta}e4-22 deletion mice. These data establish a novel and specific role of Shank3 in the NAc on social motivation. | | 10:30a |
Rapid "recycling" of logical algorithm representations in fronto-parietal reasoning systems following computer programming instructions
Programming is a cornerstone of modern society, yet its cognitive and neural basis remains poorly understood. In this study, we test the hypothesis that programming "recycles" pre-existing neural mechanisms and representations in fronto-parietal reasoning networks. Using fMRI, we scanned programming-naive undergraduates (n=22) before (PRE) and after (POST) an introductory Python course. During the PRE scan, participants viewed pseudocode (plain English descriptions of algorithms), and during the POST scan, they read Python code. We found that a left-lateralized fronto-parietal network, previously implicated in programming experts, distinguished between "for" loops and "if" conditionals across both pseudocode and Python code. Representational similarity analysis revealed consistent representations of algorithms across formats (code/pseudocode) and learning stages. Furthermore, such representations encode abstract meanings rather than superficial features. Our findings demonstrate that programming not only recycles pre-existing neural resources evolved for logical reasoning, but the recycling takes place rapidly with only a single semester of training. | | 10:30a |
Development of catecholaminergic neurons of Otp-lineage in the medial extended amygdala and other centers of the social behavior network
Catecholaminergic (CA) neurons of the medial extended amygdala, preoptic region and adjacent alar hypothalamus have been involved in different aspects of social behavior. Previous data suggested that at least some CA neurons of the medial extended amygdala could originate in a hypothalamic embryonic domain that expresses the transcription factor Otp. To investigate this, we used Otp-eGFP mice to analyze coexpression of GFP and tyrosine hydroxylase (TH) throughout ontogenesis by way of double immunofluorescence. Our results showed that some TH cells coexpress GFP in the medial extended amygdala preoptic region, and alar and basal hypothalamus. However, the presence of TH/GFP double-labeled cells in the extended amygdala is transient, as they are not seen in adults. Based on previous data, the Otp-related CA cells of the medial extended amygdala might derive from the telencephalon-opto-hypothalamic domain, and those of the central paraventricular and supraoptic hypothalamic nuclei likely derive from the supraopto-paraventricular hypothalamic core domain. Taken together, these data provide new evidence for several Otp-related CA subpopulations in centers of the social brain network. The results open interesting questions about the role of these catecholaminergic subpopulations during the development and in different aspects of social behavior. | | 10:30a |
Replay builds an efficient cognitive map offline to avoid computation online
How do humans integrate fragmented experiences into a coherent structure for novel inferences? Although offline replay is proposed to reorganize memories, whether it constructs an integrated cognitive map remains unclear. Using magnetoencephalography, we tracked neural activity as participants learned one-dimensional, pairwise rank relationships that together formed a two-dimensional (2D) conceptual map, and then inferred unobserved relationships. Offline replay during rest integrated piecemeal memories into a 2D representation, predicting future inference accuracy. This offline replay and fast on-task replay during inference correlated with grid-cell-like code, representing a generalizable schema that minimized effortful online computations. In contrast, slow on-task replay focusing on trial-specific details, negatively correlated with grid-like codes and inference performance. Together, replay builds an efficient cognitive map offline, reducing reliance on deliberate computations online. | | 10:30a |
Predictive acoustical processing in human cortical layers
In our dynamic environments, predictive processing is vital for auditory perception and its associated behaviors. Predictive coding formalizes inferential processes by implementing them as information exchange across cortical layers and areas. With laminar-specific blood oxygenation level dependent we measured responses to a cascading oddball paradigm, to ground predictive auditory processes on the mesoscopic human cortical architecture. We show that the violation of predictions are potentially hierarchically organized and associated with responses in superficial layers of the planum polare and middle layers of the lateral temporal cortex. Moreover, we relate the updating of the brains internal model to changes in deep layers. Using a modeling approach, we derive putative changes in neural dynamics while accounting for draining effects. Our results support the role of temporal cortical architecture in the implementation of predictive coding and highlight the ability of laminar fMRI to investigate mesoscopic processes in a large extent of temporal areas. | | 10:30a |
Impaired Myelination in Multiple Sclerosis Organoids: p21 Links Oligodendrocyte Dysfunction to Disease Subtype
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system. The cause of the disease is unknown but both genetic and environmental factors are strongly implicated in its pathogenesis. We derived cerebral and spinal cord organoids from induced pluripotent stem cells (iPSC) from healthy controls as well as from primary progressive MS (PPMS), secondary progressive MS (SPMS) and relapsing-remitting MS (RRMS) patients to investigate and compare oligodendrocyte differentiation and myelination capacity in healthy subjects and MS subtypes. In MS organoids, particularly in PPMS, we observed a decrease in p21 expression associated with a dysregulation of PAK1 and E2F1 expression. In parallel, a decrease in oligodendrocyte maturation was detected in long-term cultured cerebral and spinal cord organoids, especially in PPMS, leading to a reduced myelination capacity. Disruption of astrocyte and neuronal populations was also observed. Our findings demonstrate that in MS, inherent deficits in the p21 pathway may alter glial and neuronal cell populations and may contribute to the disease pathogenesis by reducing the capacity for myelin repair.
Summary StatementUsing cerebral and spinal cord organoids derived from multiple sclerosis patients, we found an innate disruption of oligodendrocyte differentiation and myelination capacity as well as excitotoxicity, associated with PAK1 and E2F1-induced p21 dysregulation. | | 10:30a |
C12ORF57: a novel principal regulator of synaptic AMPA currents and excitatory neuronal homeostasis
Biallelic recurrent loss of function mutations in C12ORF57, a novel open reading frame, underlie Temtamy syndrome (TS)--a neurodevelopmental disorder characterized by dysgenesis of the corpus callosum, epilepsy, and severe intellectual disability. To study the heretofore unknown function of this gene, we used a knockout (KO) mouse model of its murine ortholog, Grcc10. Grcc10 KO mice exhibit the characteristic phenotypic features seen in human TS patients, including increased epileptiform activity. Consistent with this propensity for seizures, hippocampal neurons in these mice show significantly increased AMPA receptor expression levels and higher amplitude of miniature excitatory postsynaptic currents (mEPSCs). We also find that GRCC10/C12ORF57 modulates the activity of calcium/calmodulin dependent kinase 4 (CAMK4) and regulates the expression of CREB and ARC, which are involved in synaptic scaling of AMPA receptors. Through multiple lines of inquiry, we establish that C12ORF57/GRCC10 plays a central modulatory role in synaptic homeostasis and uncover a novel mechanism for neuronal excitatory tuning. | | 4:15p |
Mechanical impact on neural stem cell lineage decisions in human brain organoids
During neurodevelopment neural stem cells give rise to a spatially patterned tissue in which a regionally differentially regulated balance between proliferation and differentiation produces the fine-tuned number of neurons and macroglia necessary for a functional central nervous system. The cells driving these highly intricated developmental processes of patterning, growth and differentiation are constantly exposed to a mechanical environment that is however variable between different brain regions and along differentiation trajectories. Here we demonstrate that both, acute mechanical manipulations as well as a persistent change in the mechanical environment provided to human brain organoids, instruct neural stem cell lineage decisions. Furthermore, we dissect the underlying changes in the molecular program of organoid-resident cells by bulk- and single cell RNA-sequencing and reveal that mechanical manipulations impact on molecular programs governing early patterning events as well as cell-type specifically alter cellular metabolism. Thus, our results unravel a regulatory network linking mechanics and neural stem cell lineage decisions. | | 5:34p |
Variance spectrum scaling analysis for high-dimensional coordination in human movement
Coordinated movement has been essential to our evolution as a species but its study has been limited by ideas largely developed for one-dimensional data. The field is poised for a change by high-density recording tools and the popularity of data sharing. New ideas are needed to revive classical theoretical questions such as the organization of the highly redundant biomechanical degrees of freedom and the optimal distribution of variability for efficiency and adaptiveness. Methods have been focused on increasing dimensions: making inferences from one or few measured dimensions about the properties of a higher dimensional system. The opposite problem is to record 100+ kinematic degrees of freedom and make inferences about properties of the embedded manifold. We present an approach to quantify the smoothness and degree to which the manifold is distributed among embedding dimensions. The principal components of embedding dimensions are rank ordered by variance. The power-law scaling exponent of this variance spectrum is a function of the smoothness and dimensionality of the embedded manifold. It defines a threshold value beyond which the manifold becomes non differentiable. We verified this approach by showing that the Kuramoto model close to global synchronization in the upper critical end of the coupling parameter obeys the threshold. Next, we tested if the scaling exponent was sensitive to participants' gait impairment in a full-body motion capture dataset containing short gait trials. Variance scaling was highest in the healthy individuals, followed by osteoarthritis patients after hip-replacement, and lastly, the same patients pre-surgery. Thinking about manifold dimensionality, smoothness, and scaling could inform classic problems in movement science and exploration of the biomechanics of full-body action. | | 5:34p |
Differential effects of dopamine and serotonin on reward and punishment processes in humans: A systematic review and meta-analysis
Importance: To support treatment assignment, mechanistic biomarkers should be selectively sensitive to specific interventions. Here, we examine whether different components of reinforcement learning in humans satisfy this necessary precondition. We focus on pharmacological manipulations of dopamine and serotonin that form the backbone of first-line management of common mental illnesses such as depression and anxiety. Objective: To perform a meta-analysis of pharmacological manipulations of dopamine and serotonin and examine whether they show distinct causal effects on reinforcement learning components in healthy humans. Data Sources: Ovid MEDLINE/PubMed, Embase, and PsycInfo databases were searched for studies published between January 1, 1946 and January 19, 2023 (repeated April 9, 2024, and October 15, 2024) investigating dopaminergic or serotonergic effects on reward/punishment processes in healthy humans. Study Selection: Studies reporting randomized, placebo-controlled, dopaminergic or serotonergic manipulations on a behavioral outcome from a reward/punishment processing task in healthy humans were included. Data Extraction and Synthesis: Standardized mean difference (SMD) scores were calculated for the comparison between each drug (dopamine/serotonin) and placebo on a behavioral reward or punishment outcome and quantified in random-effects models for overall reward/punishment processes and four main subcategories. Study quality, moderators, heterogeneity, and publication bias were also assessed. Main Outcome(s) and Measure(s): Performance on reward/punishment processing tasks. Results: In total, 68 dopamine and 39 serotonin studies in healthy volunteers were included (Ndopamine=2452, Nplacebo=2432; Nserotonin=1364, Nplacebo=1393 participants). Dopamine increased overall reward (SMD=0.21; 95%CI [0.12 0.30]) but not punishment function (SMD=-0.09; 95%CI [-0.27,0.10]). Serotonin did not meaningfully affect overall punishment (SMD=0.22; 95%CI [-0.04,0.49]) or reward (SMD=0.01; 95%CI [-0.33,0.35]). Importantly, dopaminergic and serotonergic manipulations had distinct and selective effects on subcomponents. Dopamine affected reward learning/sensitivity (SMD=0.25; 95%CI [0.10,0.40]), reward discounting (SMD=-0.08; 95%CI [-0.14,-0.01]) and reward vigor (SMD=0.32; 95%CI [0.11,0.54]). By contrast, serotonin shaped punishment learning/sensitivity (SMD=0.32; 95%CI [0.05,0.59]), reward discounting (SMD=-0.35; 95%CI [-0.67,-0.02]), and aversive Pavlovian processes (within-subject studies only; SMD=0.36; 95%CI [0.20,0.53]). Conclusions and Relevance: Pharmacological manipulations of both dopamine and serotonin have measurable effects on reinforcement learning in humans. The selective effects on different components suggests that reinforcement learning tasks could form the basis of selective, mechanistically interpretable biomarkers to support treatment assignment. | | 5:34p |
Alpha and beta desynchronization during consolidation of newly learned words
While a growing body of literature exists on initial word-to-meaning mapping and retrieval of fully lexicalized words, our understanding on the learning of semantic knowledge that occurs between these two stages remains limited. The current study investigated the neural correlates of retrieving newly learned word meanings using oscillatory brain dynamics. Participants learned to associate new words with unknown objects and performed overt and covert naming tasks during the first and last days of a five-day training period. Behavioral results showed improved overt naming on Day 5 compared to Day 1. Selecting only words that were successfully produced in the overt naming task, we examined alpha (8-12 Hz) and beta (13-25 Hz) band oscillatory activity associated with lexical-semantic retrieval while participants produced new words covertly, both pre- (Day 1) and post (Day 5) lexicalization. The results showed a robust alpha and lower beta power decrease during covert naming after learning. We hypothesize that this alpha-beta power decrease indexes successful word retrieval following lexical-semantic integration and consolidation. | | 10:32p |
EPISeg: Automated segmentation of the spinal cord on echo planar images using open-access multi-center data
Functional magnetic resonance imaging (fMRI) of the spinal cord is relevant for studying sensation, movement, and autonomic function. Preprocessing of spinal cord fMRI data involves segmentation of the spinal cord on gradient-echo echo planar imaging (EPI) images. Current automated segmentation methods do not work well on these data, due to the low spatial resolution, susceptibility artifacts causing distortions and signal drop-out, ghosting, and motion-related artifacts. Consequently, this segmentation task demands a considerable amount of manual effort which takes time and is prone to user bias. In this work, we (i) gathered a multi-center dataset of spinal cord gradient-echo EPI with ground-truth segmentations and shared it on OpenNeuro [ https://openneuro.org/datasets/ds005143/versions/1.3.0], and (ii) developed a deep learning-based model, EPISeg, for the automatic segmentation of the spinal cord on gradient-echo EPI data. We observe a significant improvement in terms of segmentation quality compared to other available spinal cord segmentation models. Our model is resilient to different acquisition protocols as well as commonly observed artifacts in fMRI data. The training code is available at [ https://github.com/sct-pipeline/fmri-segmentation/], and the model has been integrated into the Spinal Cord Toolbox as a command-line tool. | | 11:46p |
Compensation of Hyperexcitability with Simulation-Based Inference
The activity of healthy neuronal networks is tightly regulated, and a shift towards hyperexcitability can cause various problems, such as epilepsies, memory deficits, and motor disorders. Numerous cellular, synaptic, and intrinsic mechanisms of hyperexcitability and compensatory mechanisms to restore healthy activity have been proposed. However, quantifying multiple compensatory mechanisms and their dependence on specific pathophysiological mechanisms has proven challenging, even in computational models. We use simulation-based inference to quantify the interactions of compensatory mechanisms in a spiking neuronal network model. Various parameters of the model can compensate for changes in other parameters to maintain baseline activity, and we rank them by their compensatory potential. Furthermore, specific causes of hyperexcitability - interneuron loss, excitatory recurrent synapses, and principal cell depolarization - have distinct compensatory mechanisms that can restore normal excitability. Our results show that spiking neuronal network simulators could provide the quantitative foundation for targeting pathophysiological network mechanisms with precise interventions. | | 11:46p |
Exosomes derived from highly scalable and regenerative human progenitor cells promote functional improvement in a rat model of ischemic stroke
Globally, there are 15 million stroke patients each year who have significant neurological deficits. Today, there are no treatments that directly address these deficits. With demographics shifting to an older population, the problem is worsening. Therefore, it is crucial to develop feasible therapeutic treatments for stroke. In this study, we tested exosomes derived from embryonic endothelial progenitor cells (eEPC) to assess their therapeutic efficacy in a rat model of ischemic stroke. Importantly, we have developed purification methods aimed at producing robust and scalable exosomes suitable for manufacturing clinical grade therapeutic exosomes. We characterized exosome cargos including RNA-seq, miRNAs targets, and proteomic mass spectrometry analysis, and we found that eEPC-exosomes were enhanced with angiogenic miRNAs (i.e., miR-126), anti-inflammatory miRNA (i.e., miR-146), and anti-apoptotic miRNAs (i.e., miR-21). The angiogenic activity of diverse eEPC-exosomes sourced from a panel of eEPC production lines was assessed in vitro by live-cell vascular tube formation and scratch wound assays, showing that several eEPC-exosomes promoted the proliferation, tube formation, and migration in endothelial cells. We further applied the exosomes systemically in a rat middle cerebral artery occlusion (MCAO) model of stroke and tested for neurological recovery (mNSS) after injury in ischemic animals. The mNSS scores revealed that recovery of sensorimotor functioning in ischemic MCAO rats increased significantly after intravenous administration of eEPC-exosomes and outpaced recovery obtained through treatment with umbilical cord stem cells. Finally, we investigated the potential mechanism of eEPC-exosomes in mitigating ischemic stroke injury and inflammation by the expression of neuronal, endothelial, and inflammatory markers. Taken together, these data support the finding that eEPCs provide a valuable source of exosomes for developing scalable therapeutic products and therapies for stroke and other ischemic diseases. |
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