bioRxiv Subject Collection: Neuroscience's Journal

Information transfer from spatial to social distance in rats: implications for the role of the posterior parietal cortex in spatial-social integration
Humans and other social animals can represent and navigate complex networks of social relationships in ways that are suggestive of representation and navigation in space. There is some evidence that cortical regions initially required for processing space have been adapted to include processing of social information. One candidate region for supporting both spatial and social information processing is the posterior parietal cortex (PPC). We examined the hypothesis that rats can transfer or generalize distance information across spatial and social domains and that this phenomenon requires the PPC. In a novel apparatus, rats learned to discriminate two conspecifics positioned at different spatial distances (near vs. far) in a goal-driven paradigm. Following spatial learning, subjects were tested on probe trials in which spatial distance was replaced with social distance (cagemate vs. less familiar conspecific). The PPC was chemogenetically inactivated during a subset of probe sessions. We predicted that, in control probe trials, subjects would select conspecifics whose social distance matched the previously learned spatial distance. That is, if trained on the near distance, the rat would choose the highly familiar cagemate, and if trained on the far distance, the rat would choose the less familiar conspecific. Subjects learned to discriminate conspecifics based on spatial distance in our goal-driven paradigm. Moreover, choice for the appropriate social distance in the first probe session was significantly higher than chance. This result suggests that rats transferred learned spatial information to social contexts. Contrary to our predictions, PPC inactivation did not impair spatial to social information transfer. Possible reasons are discussed. To our knowledge, this is the first study to provide evidence that spatial and social distance are processed by shared cognitive mechanisms in the rat model.

Isolating the effect of beat salience on rhythmic auditory stimulation outcomes
Rhythmic auditory stimulation (RAS) is an intervention for gait-disordered populations that involves synchronizing footsteps to regular auditory cues. Previous research has shown that high- groove music (music that induces the desire to move or dance to it) improves gait relative to low- groove music, but how this effect occurs is unclear. Greater beat salience in high-groove music may improve gait because salient beats are easier to synchronize with. Here, we manipulated beat salience by embedding metronome tones to emphasize beat onsets in both high- and low-groove music. We expected that, if beat salience drives gait improvements to high-groove music, then embedding metronome in low-groove music would elicit similar gait improvements (e.g. increased stride velocity). Here, we quantified gait synchronization in terms of period-matching (overall step rate to the cue pace) and phase-matching (individual step onsets to beat onsets). We tested a sample of healthy younger and older adults, with auditory cues matched to 10% faster than baseline. Low- groove music with embedded metronome, compared to without, elicited better period-matching; there were no differences between metronome conditions in high-groove music. These findings suggest gait improvements to high-groove music could be due to its high beat salience. On the other hand, embedded metronome did not improve phase-matching accuracy, but high-groove music did. This suggests that beat salience may not improve gait via easing step-to-beat synchronization, but rather through an overall increase in movement vigor.

Individual variation in the functional lateralization of human ventral temporal cortex: Local competition and long-range coupling
The ventral temporal cortex (VTC) of the human cerebrum is critically engaged in computations related to high-level vision. One intriguing aspect of this region is its asymmetric organization and functional lateralization. Notably, in the VTC, neural responses to words are stronger in the left hemisphere, whereas neural responses to faces are stronger in the right hemisphere. Converging evidence has suggested that left-lateralized word responses emerge to couple efficiently with left-lateralized frontotemporal language regions, but evidence is more mixed regarding the sources of the right-lateralization for face perception. Here, we use individual differences as a tool to adjudicate between three theories of VTC organization arising from: 1) local competition between words and faces, 2) local competition between faces and other categories, 3) long-range coupling with VTC and frontotemporal areas subject to their own local competition. First, in an in-house functional MRI experiment, we demonstrated that individual differences in laterality are both substantial and reliable within a right-handed population of young adults. We found no (anti-)correlation in the laterality of word and face selectivity relative to object responses, and a positive correlation when using selectivity relative to a fixation baseline, challenging ideas of local competition between words and faces. We next examined broader local competition with faces using the large-scale Human Connectome Project (HCP) dataset. Face and tool laterality were significantly anti-correlated, while face and body laterality were positively correlated, consistent with the idea that generic local representational competition and cooperation may shape face lateralization. Last, we assessed the role of long-range coupling in the development of VTC laterality. Within our in-house experiment, substantial correlation was evident between VTC text laterality and several other nodes of a distributed text-processing circuit. In the HCP data, VTC face laterality was both negatively correlated with frontotemporal language laterality, and positively correlated with social perception laterality in the same areas, consistent with a long-range coupling effect between face and social processing representations, driven by local competition between language and social processing. We conclude that both local and long-range interactions shape the heterogeneous hemispheric specializations in high-level visual cortex.

From movements to words: action monitoring in the medial frontal cortex along a caudal to rostral prediction error gradient
Speech error monitoring recruits the medial frontal cortex (MFC) region in the human brain. Error monitoring-related activity in the MFC has been interpreted both in terms of conflict monitoring and feedback-driven control, but as similar regions of the MFC are implicated in various levels of behavioral control ranging from basic motor movement control to high-level cognitive control functions, a more comprehensive account is needed. Moreover, as speech errors and other actions that involve varying control demands engage a widespread yet partially overlapping set of regions of the MFC, such an account should ideally explain the anatomical distribution of error-related functional activations within the MFC. Here we wanted to assess the hypothesis that the MFC has a similar role in the evaluation of action outcomes for motor and mental actions, operating along a rostral-caudal gradient of higher-lower level control demands involving prediction errors from both sensory and epistemic sources. To this end, we conducted an individual-specific annotation of task-fMRI BOLD activation peaks related to speech errors versus correct productions (i.e. that involve the largest cognitive control demands, Study I and II), tongue movement monitoring (i.e. that involve an intermediate level of cognitive and motor control demands) and tongue movement (i.e. that involve only motor control demands, Study II) in the MFC region. Results revealed overlapping clusters across the three contrasts across the MFC, but importantly both the number of peaks and their relative position along the rostral caudal axis were consistent with a hierarchical rostral caudal processing gradient in the MFC. While tongue movement showed more caudal activation in the MFC, speech errors showed more rostral activation, and tongue movement monitoring patterned in between. Furthermore, the combined results of both studies suggested that activation peaks were located more dorsally for participants that had a paracingulate gyrus, replicating a previously documented effect for movement and further supporting a common functional role of the MFC across very distinct actions.

Attention networks engage the default mode network related to policy precision under uncertainty
In decision-making, choices impact the present and cascade into future decisions, highlighting the importance of confidence when making a decision. Here, we investigated the meta-network level neural correlates of this confidence by estimating the instantaneous changes in precision in selecting actions and comparing them with brain state trajectories. To confirm the relationship between behavioral and neural signals, we leveraged inter subject correlation to determine how similar the group shared components of time-series of precision-triggered meta-network occurrences are across participants and how this similarity changes during decision-making. We found that policy precision is a proper behavioral signal to explain the meta-network level neural dynamics. It positively correlated with the default mode network (DMN) dominant state, the occurrence of which is mutually exclusive with the dorsal attentional network-(DAN) and frontoparietal network (FPN)-dominant state, the activation of which is speculated to be associated with a highly uncertain state and arises from increased integration between the DAN, FPN, and DMN. Therefore, supporting the novel perspective that the DMN may reflect internal beliefs, these findings indicate that their integration promotes the DAN and FPN to exert attention to decrease uncertainty.

ZMYND11 Functions in Bimodal Regulation of Latent Genes and Brain-like Splicing to Safeguard Corticogenesis
Despite the litany of pathogenic variants linked to neurodevelopmental disorders (NDD) including autism (ASD) and intellectual disability, our understanding of the underlying mechanisms caused by risk genes remain unclear. Here, we leveraged a human pluripotent stem cell model to uncover the neurodevelopmental consequences of mutations in ZMYND11, a newly implicated risk gene. ZMYND11, known for its tumor suppressor function, encodes a histone-reader that recognizes sites of transcriptional elongation and acts as a co-repressor. Our findings reveal that ZMYND11-deficient cortical neural stem cells showed upregulation of latent developmental pathways, impairing progenitor and neuron production. In addition to its role on histones, ZMYND11 controls a brain-specific isoform switch involving the splicing regulator RBFOX2. Extending our findings to other chromatin-related ASD risk factors revealed similar developmental pathway activation and splicing dysregulation, partially rescuable through ZMYND11's regulatory functions.

Disrupted Hippocampal-Prefrontal Networks In A Rat Model Of Fragile X Syndrome: A Study Linking Neural Dynamics To Autism-Like Behavioral Impairments
Fragile X Syndrome (FXS) is associated with autism spectrum symptoms that are associated with cognitive, learning, and behavioral challenges. We investigated how known molecular disruptions in the Fmr1 knockout (FMR-KO) rat model of FXS negatively impact hippocampal-prefrontal cortex (H-PFC) neural network activity and consequent behavior. Methods: FMR-KO and control rats underwent a battery of behavioral tests assessing sociability, memory, and anxiety. Single-unit electrophysiology recordings were then conducted to measure patterns of neural activity in H-PFC circuit. Advanced mathematical models were used to characterize the patterns that were then compared between groups using generalized linear mixed models. Results: FMR-KO rats demonstrated significant behavioral deficits in sociability, spatial learning, and anxiety, aligning with symptoms of ASD. At the neural level, these rats exhibited abnormal firing patterns in the H-PFC circuit that is critical for learning, memory, and social behavior. The neural networks in FMR-KO rats were also less densely connected and more fragmented, particularly in hippocampal-PFC correlated firing. These findings suggest that disruptions in neural network dynamics underlie the observed behavioral impairments in FMR-KO rats. Conclusion: FMR-KO significantly disrupts several characteristics of action potential firing in the H-PFC network, leading to deficits in social behavior, memory, and anxiety, as seen in FXS. This disruption is characterized by less organized and less resilient hippocampal-PFC networks. These findings suggest that therapeutic strategies aimed at normalizing neural dynamics, such as with brain stimulation, could potentially improve behavior and cognitive functions in autistic individuals.

Diversification of Dentate Gyrus Granule Cell Subtypes is Regulated by Neuregulin1 Nuclear Back Signaling.
Neuronal heterogeneity is a defining feature of the developing mammalian brain, but the mechanisms regulating the diversification of closely related cell types remain elusive. In this study, we investigated the heterogeneity of dentate gyrus (DG) granule cells (GCs) and the influence of a psychosis associated V321L mutation in Neuregulin1 (Nrg1) on GC subtype composition. Using morpho-electric characterization, single-nucleus gene expression, and chromatin accessibility profiling, we identified distinct morphological and molecular features of typical GCs and a rare subtype known as semilunar granule cells (SGCs). The V321L mutation disrupts Nrg1 nuclear back-signaling, resulting in an overabundance of SGC-like cells. We discovered pseudotime gene expression trajectories suggesting the potential for GC-to-SGC transitions, supported by the accessibility of SGC-specific genes in other GCs. Intriguingly, we found an increase in SGC-marker expression over the adolescence to adulthood transition window in wild-type mice, coinciding with a decline in Nrg1 nuclear back-signaling capacity. This suggests that intact Nrg1 signaling suppresses SGC-like fate acquisition, and that its natural downregulation may underlie the emergence of SGC-like cells during postnatal development. Similarly, a pathological block of nuclear back signaling by the V321L mutation in Nrg1, may result in acquisition of the SGC-like fate due to loss of the repressive mechanisms maintained by intact nuclear back signaling. Our findings reveal a novel role for Nrg1 in maintaining DG cell-type composition and suggest that disrupted subtype regulation may contribute to disease-associated changes in DG GC morphology and function. Understanding these mechanisms provides new insights into mechanisms of cell-type diversity and its potential role in psychiatric pathology.

Fast and robust visual object recognition in young children
By adulthood, humans rapidly identify objects from sparse visual displays and across significant disruptions to their appearance. What are the minimal conditions needed to achieve robust recognition abilities and when might these abilities develop? To test this question, we investigated the upper-limits of children's object recognition abilities. We found that children as young as 3-years-of-age successfully identified objects at speeds of 100 ms (both forward and backward masked) under sparse and disrupted viewing conditions. By contrast, a range computational models implemented with biologically plausible properties or optimized for visual recognition did not reach child-level performance. Models only matched children if they were trained with more data than children are capable of experiencing. These findings highlight the robustness of the human visual system in the absence of extensive experience and identify important developmental constraints for building biologically plausible machines.

Cell-extrinsic controls over neocortical neuron fate and diversity
Cellular diversity in the neocortex emerges gradually during prenatal and postnatal development. While environmental interactions occur during this extended maturation period, the impact of extrinsic cues on determining the fate of distinct neuron types remains unknown. To address this question, we exposed developing neocortical cells to various environmental conditions and examined how this affects cell fate and diversity. Our developmental analyses reveal a hierarchical molecular program in which cell class-distinguishing features emerge [fi]rst, followed by subclass- and type-related characteristics, with distinct developmental paces among cell populations. Environmental contribution was assessed in vivo, using genetically modi[fi]ed mice models in which position or innervation are altered, and in vitro using two-dimensional cultures. Acquisition of cellular identity and diversity remained stable across in vivo models. In contrast, in vitro glutamatergic neurons showed decreased expression of identity-de[fi]ning genes, reduced diversity and alterations in canonical cortical connectivity. Cellular identity and diversity were restored towards in vivo values in organotypic slice cultures. These [fi]ndings reveal cell population-speci[fi]c responses to environmental conditions and highlight the role of extracellular context in shaping cell diversity in the maturing neocortex.

Enhancing cortico-motoneuronal projections for vocalization in mice
Several hypotheses have been proposed on the anatomical brain differences that endow some species with the rare ability of vocal learning, a critical component of spoken language. One long-standing thus far untested hypothesis is that a robust direct projection from motor cortex layer 5 neurons to brainstem vocal motor neurons enables fine motor control of vocal laryngeal musculature in vocal learners. This connection has been proposed to form from specialized expression of axon guidance genes in human speech layer 5 neurons and the equivalent songbird neurons of the robust nucleus of the arcopallium. Here we generated mice with conditional knock-down of an axon-guidance receptor PLXNA1 in motor cortex layer 5 neurons, to recapitulate the human and songbird brain expression patterns. These mice showed enhanced layer 5 cortical projections to brainstem vocal motor neurons, increased functional connectivity to phonatory muscles, and displayed a wider range of vocal abilities depending on developmental and social contexts. Our findings are consistent with the theory that direct vocal cortico-motoneuronal projections influence vocal behaviors.

Optical profiling of NMDA receptor molecular diversity at synaptic and extrasynaptic sites
NMDA receptors (NMDARs) are glutamate-gated ion channels that play essential roles in brain development and function. NMDARs exist as multiple subtypes that differ in their subunit composition, distribution and signaling properties, with GluN1/GluN2A (GluN2A diheteromers), GluN1/GluN2B (GluN2B diheteromers) and GluN1/2A/2B (GluN2A/2B triheteromers) receptors prevailing. Studying these subtypes separately has proved difficult due to the limited specificity of available pharmacological and genetic approaches. Here, we designed a photoswitchable tool (Opto2B) enabling specific and reversible modulation of GluN2B diheteromers (while other receptor subtypes remain unaffected). Using Opto2B, we were able to establish the differential contribution of GluN2B diheteromers relative to GluN2A-receptors (GluN2A diheteromers and GluN2A/2B triheteromers) to synaptic and extrasynaptic NMDAR pools. In young postnatal CA1 hippocampal pyramidal cells, extrasynaptic NMDARs are exclusively composed of GluN2B diheteromers, whereas GluN2A subunits already populate synaptic sites. In adult CA1 cells, GluN2A-receptors predominate at both sites, with no preferential contribution of GluN2B diheteromers to extrasynaptic currents. Our study clarifies decades of controversial research and paves the way for interrogating NMDAR signaling diversity with unprecedented molecular and spatio-temporal resolution.

A top-down insular cortex circuit crucial for non-nociceptive fear learning
Understanding how threats in environments drive fear memory formation is crucial to understanding how organisms adapt to changing environments and treat threat-related disorders such as PTSD. Despite decades of pioneering work using the Pavlovian conditioning model, our understanding has been limited because only one type (an electric shock) among diverse threats has been exclusively used. We developed a threat conditioning paradigm by utilizing a looming visual threat as an unconditioned stimulus (US) in mice and identified a distinct threat conditioning circuit. Parabrachial CGRP neurons were required for conditioning and memory retrieval. Their upstream neurons in the posterior insular cortex (pIC) responded to looming stimuli and projections of these neurons to the parabrachial nucleus induced aversive affective states and drove conditioning. But the pIC to PBN pathway was dispensable for foot-shock conditioning. Our findings provide insights into how a simple pattern of non-nociceptive visual stimuli can induce aversive states and drive fear memory formation.

Synaptic targets and cellular sources of CB1 cannabinoid receptor and vesicular glutamate transporter-3 expressing nerve terminals in relation to GABAergic neurons in the human cerebral cortex
Cannabinoid receptor 1 (CB1) regulates synaptic transmission through presynaptic receptors in nerve terminals, and its physiological roles are of clinical relevance. The cellular sources and synaptic targets of CB1-expressing terminals in the human cerebral cortex are undefined. We demonstrate a variable laminar pattern of CB1-immunorective axons and electron microscopically show that CB1-positive GABAergic terminals make type-2 synapses innervating dendritic shafts (69%), dendritic spines (20%) and somata (11%) in neocortical layers 2-3. Of the CB1-immunopositive GABAergic terminals, 25% were vesicular-glutamate-transporter-3 (VGLUT3)-immunoreactive, suggesting GABAergic/glutamatergic co-transmission on dendritic shafts. In vitro recorded and labelled VGLUT3 or CB1-positive GABAergic interneurons expressed cholecystokinin, vasoactive-intestinal-polypeptide and calretinin, had diverse firing, axons and dendrites, and included rosehip, neurogliaform and basket cells, but not double bouquet or axo-axonic cells. CB1-positive interneurons innervated pyramidal cells and GABAergic interneurons. Most glutamatergic synaptic terminals formed type-1 synapses and some were positive for CB1 receptor concentrated in the presynaptic active zone, unlike in GABAergic terminals. From the sampled VGLUT3-positive terminals, 60% formed type-1 synapses with dendritic spines (80%) or shafts (20%) and 52% were also positive for VGLUT1, suggesting intracortical origin. Some VGLUT3-positive terminals were immunopositive for vesicular-monoamine-transporter-2, suggesting 5-HT/glutamate co-transmission. Overall, the results show that CB1 regulates GABA release mainly to dendritic shafts of both pyramidal cells and interneurons, and predict CB1-regulated co-release of GABA and glutamate from single cortical interneurons. We also demonstrate the co-existence of multiple vesicular glutamate transporters in a select population of terminals probably originating from cortical neurons and innervating dendritic spines in the human cerebral cortex.

Diversity of ancestral brainstem noradrenergic neurons across species and multiple biological factors
The brainstem region, locus coeruleus (LC), has been remarkably conserved across vertebrates. Evolution has woven the LC into wide-ranging neural circuits that influence functions as broad as autonomic systems, the stress response, nociception, sleep, and high-level cognition among others. Given this conservation, there is a strong possibility that LC activity is inherently similar across species, and furthermore that age, sex, and brain state influence LC activity similarly across species. The degree to which LC activity is homogenous across these factors, however, has never been assessed due to the small sample size of individual studies. Here, we pool data from 20 laboratories (1,855 neurons) and show diversity across both intrinsic and extrinsic factors such as species, age, sex and brain state. We use a negative binomial regression model to compare activity from male monkeys, and rats and mice of both sexes that were recorded across brain states from brain slices ex vivo or under different anesthetics or during wakefulness in vivo. LC activity differed due to complex interactions of species, sex, and brain state. The LC became more active during aging, independent of sex. Finally, in contrast to the foundational principle that all species express two distinct LC firing modes ("tonic" or "phasic"), we discovered great diversity within spontaneous LC firing patterns. Different factors were associated with higher incidence of some firing modes. We conclude that the activity of the evolutionarily-ancient LC is not conserved. Inherent differences due to age and species-sex-brain state interactions have implications for understanding the role of LC in species-specific naturalistic behavior, as well as in psychiatric disorders, cardiovascular disease, immunology, and metabolic disorders.

Reward-driven adaptation of movements requires strong recurrent basal ganglia-cortical loops
The basal ganglia (BG), a set of subcortical nuclei involved in motor control, sensorimotor integration, and procedural learning, modulate movement through tonic inhibition of thalamo-cortical networks. While essential for sensorimotor integration and learning, the BG are not necessary for executing well-learned movements. During skill learning, they guide behavioral corrections via dopamine-dependent cortico-striatal plasticity, but these corrections become BG-independent as modifications occur in the motor cortex. Existing models of BG function often overlook the feedback dynamics of cortico-BG-thalamo-cortical loops, and do not address the relative role of cortex and the BG in the generation and adaptation of movement. In this work, we develop a theoretical model of this multiregional network, integrating anatomical, physiological, and behavioral evidence to explore how its dynamics shape movement execution and reward-based adaptation. We show that the BG-thalamo-cortical network influences motor output through three key factors: (i) the rich dynamics of its closed-loop architecture, (ii) attractor dynamics from recurrent cortical connections, and (iii) classical reinforcement learning via dopamine-dependent cortico-striatal plasticity. Our study highlights that efficient visuomotor adaptation requires strong feedback from the BG to the cortex. Finally, we propose a mechanism for initial movement learning through motor babbling. This model suggests the BG-cortical network shapes motor output through its intricate closed-loop dynamics and cortico-striatal dopamine-dependent plasticity.

Differential contribution of P73+ Cajal-Retzius cells and Reelin to cortical morphogenesis
Cajal-Retzius cells (CRs) are a peculiar neuronal type within the developing mammalian cerebral cortex. One of their best documented feature is the robust secretion of Reln, a glycoprotein essential for the establishment of cortical layers through the control of radial migration of glutamatergic neurons. We previously identified Gmnc as a critical fate determinant for P73+ CRs subtypes from the hem, septum and thalamic eminence. In Gmnc-/- mutants, P73+ CRs are initially produced, cover the telencephalic vesicle but undergo massive apoptosis resulting in their complete depletion at mid-corticogenesis. Here we investigated the consequence of such a CRs depletion on dorsal cortex lamination and hippocampal morphogenesis. We found preplate splitting occurs normally in Gmnc-/- mutants but is followed by defective radial migration arrest in the dorsal cortex, altered cellular organization in the lateral cortex, aberrant hippocampal progenitor proliferation resulting in abnormal CA1 folding and lack of vasculature development in the hippocampal fissure. We then performed conditional Reln deletion in P73+ CRs to evaluate its relative contribution and found that only radial migration defects were recapitulated. We concluded that at mid-corticogenesis, CRs-derived Reln is required for radial migration arrest and additionally identified Reln-independent functions for CRs in the control of hippocampal progenitor proliferation and vessel remodelling.

Synchrony dynamics underlie irregular neocortical spiking
Cortical neurons are characterized by their variable spiking patterns. We challenge prevalent theories for the origin of spiking variability. We examine the specific hypothesis that cortical synchrony drives spiking variability in vivo. Using dynamic clamp, we demonstrate that intrinsic neuronal properties do not contribute substantially to spiking variability, but rather spiking variability emerges from weakly synchronous network drive. With large-scale electrophysiology we quantify the degree of synchrony and its time scale in cortical networks in vivo. We demonstrate that physiological levels of synchrony are sufficient to generate irregular responses found in vivo. Further, this synchrony shifts over timescales ranging from 25 to 200 ms, depending on the presence of external sensory input. Such shifts occur when the network moves from spontaneous to driven modes, leading naturally to a decline in response variability as observed across cortical areas. Finally, while individual neurons exhibit reliable responses to physiological drive, different neurons respond in a distinct fashion according to their intrinsic properties, contributing to stable synchrony across the neural network.

Glymphatic system health in early Alzheimer's disease and its relationship to sleep, cognition and CSF biomarkers.
BACKGROUND: The glymphatic system is thought to facilitate waste clearance from the brain during sleep. Impairment in this system may underpin the elevated deposition of pathological proteins in neurodegenerative conditions like Alzheimer's disease (AD). Putative glymphatic system activity has been measured with contrast-enhanced, serial MRI, revealing slower clearance in people who are sleep deprived. It is important that these methods are used to understand changes to glymphatic function in people with early-stage AD. METHODS: Twenty-four individuals with mild cognitive impairment were recruited. N=20 had CSF biomarker data, with 16 meeting criteria for AD positivity (AD+). Participants underwent polysomnography, cognitive testing and serial T1 MRI with intravenous gadolinium-based contrast agent, diffusion tensor imaging along the perivascular space (DTI-ALPS index), and core AD CSF biomarkers collection. Rate (over 24hrs) and efficiency (the amount of tracer cleared after 28hrs relative to uptake after 4hrs) of GCBA clearance were measured. RESULTS: Faster/more efficient GBCA clearance was associated with shorter sleep latency. In AD+ participants faster 24hr clearance of GBCA was associated with a lower ratio of AB1-42/AB1-40 in the CSF. In addition, better clearance efficiency was associated with greater levels of AB-40, lower levels of AB1-42, and a smaller ratio of AB-142/AB1-40 in the CSF. Higher DTI-ALPS indicated better cognitive performance and, unexpectedly, higher tau levels. However, it was not associated with GCBA clearance. CONCLUSIONS: We show, for the first time in humans, that glymphatic system function is associated with AD-related changes to sleep, cognition and core AD biomarker concentrations in CSF. However, for AD biomaker concentrations, these relationships are not in the expected direction: higher concentrations and lower AB1-42/AB1-40 ratio were associated with faster or more efficient clearance of GCBA. We suggest that increased neurodegeneration in those with elevated levels of tau and AB1-40 may paradoxically increase glymphatic activity locally to brain regions with more atrophy relative to less, but not in a way that improves sleep or cognition. In fact, larger extracellular spaces may exacerbate the spread of tau via the glymphatic system and therefore accelerate the progression of AD.

A Cortical Site that Encodes Vocal Expression and Reception
Socially effective vocal communication requires brain regions that encode expressive and receptive aspects of vocal communication in a social context-dependent manner. Here, we combined a novel behavioral assay with microendoscopy to interrogate neuronal activity in the posterior insula (pIns) in socially interacting mice as they switched rapidly between states of vocal expression and reception. We found that distinct but spatially intermingled subsets of pIns neurons were active during vocal expression and reception. Notably, pIns activity during vocal expression increased prior to vocal onset and was also detected in congenitally deaf mice, pointing to a motor signal. Furthermore, receptive pIns activity depended strongly on social cues, including female odorants. Lastly, tracing experiments reveal that deep layer neurons in the pIns directly bridge the auditory thalamus to a midbrain vocal gating region. Therefore, the pIns is a site that encodes vocal expression and reception in a manner that depends on social context.

Deficient Memory, Long-Term Potentiation and Hippocampal Synaptic Plasticity in Galectin-4-KO Mice.
Intestinal infections trigger inflammation and can contribute to degenerative and cognitive brain pathologies through the microbiota-gut-brain axis. Galectin-4 is an intestinal lectin key in the control of pathogenic bacterial infections. Here we report that galectin-4 deficient mice (Lgals4-KO) show an altered intestinal commensal microbiota in the absence of pathogens, defining a new role of galectin-4 in the modulation of commensal bacteria. Strikingly, Lgals4-KO mice present a deficient memory formation, and impaired hippocampal long-term potentiation (LTP) in vivo and ex vivo. Furthermore, Lgals4-KO neurons show a reduced activation of the AMPA receptor and of the CaMKII upon chemically induced LTP in vitro. These mice also display significantly lower dendritic spine density and shorter spine length in hippocampal dendrites, as well as an increased area of the postsynaptic densities, all coherent with an alteration of the synaptic function. In all, our results demonstrate that the absence of galectin-4 induces synaptic dysfunctions and memory impairment, along with changes in gut microbial composition, suggesting that variations in endogenous intestinal microbiota may cause or contribute to such neurological pathologies.

Paroxysmal Slow Wave Events as a diagnostic and predictive biomarker for post-traumatic epilepsy
Traumatic brain injury (TBI) is a major global health concern, affecting more than 40 million people annually. While most cases are mild and present with light symptoms, repeated mild injuries can result in delayed brain pathologies, including cognitive decline, neuropsychiatric complications, and post-traumatic epilepsy (PTE). PTE refers to recurring, unprovoked seizures occurring at least one week after TBI. While the link between moderate to severe TBI and PTE is well established, the epileptogenesis after repetitive mild TBI (rmTBI) is seldom studied. Currently, there are no biomarkers to identify those at risk of developing PTE, and its diagnosis is challenging. Here, we used a rat model to study PTE following rmTBI and assessed human EEG data to identify potential biomarkers for PTE. We employed a closed head TBI model to induce rmTBI, and recorded brain activity using electrocorticography (ECoG) between 2- and 6-months post-injury. Behavioral assessments and post-mortem analysis were also conducted. In humans, we analyzed EEG recordings from the Temple University database to investigate the potential of EEG-derived features for diagnosing PTE. At 6 months post injury, 70% of rmTBI animals developed PTE, compared to 22% in the control group (P=0.01). While neurological assessments following injury did not predict PTE, paroxysmal slow wave events (PSWEs) were found to be a reliable biomarker for PTE prediction. In humans, the percentage time in PSWEs was significantly elevated in PTE patients with epileptiform activity. In conclusion, we suggest PSWEs as a non-invasive, cost-effective biomarker for PTE in rodents and human patients.

Network mechanisms in rapid-onset dystonia-parkinsonism
Background: Rapid-onset dystonia-parkinsonism (RDP) is a rare neurological disorder caused by mutations in the ATP1A3 gene. Symptoms are characterized by a dystonia-parkinsonism. Recently, experimental studies have shown that the pathophysiology of the disease is based on a combined dysfunction of the cerebellum (CB) and basal ganglia (BG) and that blocking their interaction can alleviate the symptoms. The underlying network mechanisms have not been studied so far. Objective: Our aim was to characterize neuronal network activity in the BG and CB and motor cortex in the ouabain model of RDP by site-specific infusion of ouabain. Methods: Rats were chronically infused with ouabain either in the CB, striatum (STR) or at both places simultaneously. Motor behavior was scored using published rating systems. Parallel in vivo recordings of local field potentials (LFP) from M1, deep cerebellar nuclei (DCN) and substantia nigra reticulata (SNr) were performed. Data were compared to untreated controls. Results: Ouabain infusion into the cerebellum produced severe dystonia that was associated with increased high-frequency gamma oscillations in the DCNs, which were subsequently transmitted to the BG and M1. Striatal infusion led to parkinsonism and elevated beta-oscillations in SNr that were transmitted to the CB and M1. The simultaneous application of STRs and CB with ouabain resulted in dystonia-parkinsonism and increased beta oscillations in BG, CB, and M1. Conclusion: We demonstrate that symptom-specific beta and gamma oscillations can be transmitted between the BG and CB, which is likely to be very important for the understanding of disease mechanisms.

Treadmill step training promotes corticospinal tract plasticity after incomplete spinal cord injury
Spinal cord injury (SCI) often impairs motor functions such as voluntary movement and fine motor control, with the corticospinal tract (CST) being a crucial pathway affected. While CST-targeted rehabilitation, such as treadmill training, supports motor recovery, gaps remain in understanding the topographical changes within the CST and how they correlate with behavioral outcomes. In this study, we utilized a custom Emx1Cre;LSL-SynGFP mouse line to quantify CST plasticity following moderate contusion SCI, both with and without exercise (treadmill) training. Fluorescent labeling of cortical synapses allowed for detailed visualization of descending CST rewiring, and we assessed its relationship to behavioral outcomes, including kinematics analysis and motivational state. Mice were stratified by motivational state using the Progressive Ratio Assay, and locomotor recovery was evaluated through the Basso Mouse Scale (BMS), joint/limb kinematics, and Motion Sequencing (MoSeq) analysis. Our findings indicate that treadmill training enhances CST rewiring, especially in highly motivated animals, leading to increased synaptic density in the ventral horn and improved BMS subscores. Motivation further influenced specific kinematic parameters, such as toe clearance, while treadmill training significantly improved speed by reducing the stance phase. Results suggest that while treadmill training induces broad beneficial outcomes, motivation may fine-tune recovery, influencing neural circuit and behavioral changes. This suggests multiple mechanisms converge to promote recovery - those we cannot control and those we can. These results underscore the combined role of task-specific training and also perhaps motivation in driving CST plasticity and functional recovery after SCI.

Telomere length and cognitive function among middle-aged and older participants from communities underrepresented in aging research: A preliminary study
Objective: Accelerated biological aging is a plausible and modifiable determinant of dementia burden facing minoritized communities, but is not well-studied in these historically underrepresented populations. Our objective was to preliminarily characterize relationships between telomere length and cognitive health among American Indian/Alaska Native (AI/AN) and Black/African American (B/AA) middle-aged and older adults. Methods: This study included data on telomere length and neuropsychological test performance from 187 participants, enrolled in one of two community-based cognitive aging cohorts and who identified their primary race as AI/AN or B/AA. Results: Nested multivariable regression models revealed preliminary evidence for associations between telomere length and cognitive performance, and these associations were partially independent of chronological age. Discussion: Small sample size limited estimate precision, however, findings suggest future work on telomere length and cognitive health in underrepresented populations at high risk for dementia is feasible and valuable as a foundation for social and behavioral intervention research.

Implied motion guides neither gaze following nor intention attribution
The gaze beam hypothesis (GBH) of gaze following posits that the other's eyes emit imaginary beams of moving energy travelling to the other's object of attention, drawing the observer's attention to the same object. This idea was initially supported by behavioral experiments showing a motion aftereffect (MAE), indicated by longer reaction times in detecting motion direction after viewing a cartoon face looking at an object in the same direction. However, this effect could also be expected if the observer used gaze direction to assume an intentional link between the looker and the object, envisioning directed actions toward the latter. To critically compare the two hypotheses, we tested whether an MAE could be induced by having human subjects detect motion direction after viewing various cue images, designed to differentiate the explanatory power of the two. Cues either suggested a connection between an agent and an object through the agent's gaze or an object-oriented intention by the presence of equipment in the agent's hand, without the agent directly looking at the object. Using Bayesian statistics, our findings provided strong evidence against both hypotheses at the population level, as reaction time modulations did not align with the MAE, leading us to reject motion adaptation as the underlying mechanism for gaze following but also intention attribution. As on an individual level we observed highly diverse effects, with some compatible with one or the other hypothesis, we assume that individual subjects may resort to different perceptual strategies based on different scene interpretations.

Dynamic Multiday Seizure Cycles in a Tetanus Toxin Rat Model of Epilepsy: Evolving Rhythms and Implications for Prediction
Epilepsy is characterized by recurrent, unpredictable seizures that impose significant challenges in daily management and treatment. One emerging area of interest is the identification of seizure cycles, including multiday patterns, which may offer insights into seizure prediction and treatment optimization. This study investigated multiday seizure cycles in a Tetanus Toxin (TT) rat model of epilepsy. Six TT-injected rats were observed over a 40-day period, with continuous EEG monitoring to record seizure events. Wavelet transform analysis revealed significant multiday cycles in seizure occurrences, with periods ranging from 4 to 7 days across different rats. Synchronization Index (SI) analysis demonstrated variable phase locking, with some rats showing strong synchronization of seizures with specific phases of the cycle. Importantly, the study revealed that these seizure cycles are dynamic and evolve over time, with some rats exhibiting shifts in cycle periods during the recording period. This suggests that the underlying neural mechanisms driving these cycles may change as the epileptic state progresses. The identification of stable and evolving multiday rhythms in seizure activity, independent of external factors, highlights a potential intrinsic biological basis for seizure timing. These findings offer promising avenues for improving seizure forecasting and designing personalized, timing-based therapeutic interventions in epilepsy. Future research should explore the underlying neural mechanisms and clinical applications of multiday seizure cycles.

Human Brain-Wide Activation of Sleep Rhythms
During sleep, our brain undergoes highly synchronized activity, orchestrated by distinct neural rhythms. Little is known about the associated brain activation during these sleep rhythms, and even less about their functional implications. In this study, we investigated the brain-wide activation underlying human sleep rhythms by employing simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) in 107 participants during overnight sleep. We identified a significant coupling between slow oscillations (SO) and spindle events during non-rapid eye movement (NREM) sleep, particularly at the UP-state of SOs. This coupling was associated with increased activation in the thalamus and hippocampus, showing a brain-wide activation that resembles episodic memory processing, yet is distinctly dissociated from task-related activation. Moreover, this SO-spindle coupling was linked to a selective increase in functional connectivity from the hippocampus to the thalamus, and from the thalamus to the neocortex, particularly the medial prefrontal cortex. These findings suggest that the thalamus plays a crucial role in coordinating the hippocampal-cortical dialogue during sleep.

Prefoldin 5 is a microtubule-associated protein that suppresses Tau-aggregation and neurotoxicity
Tauopathies represent a major class of neurodegenerative disorders associated with intracellular aggregates of the microtubule-associated protein Tau. To identify molecular modulators of Tau toxicity, we used a genetic screen to identify protein chaperones whose RNAi-mediated knockdown could modulate hTauV337M-induced eye-ommatidial degeneration in Drosophila. This screen identified the Prefoldins Pfdn5 and Pfdn6 as strong modifiers of hTauV337M cytotoxicity. Consistent with the known function of Pfdn as a cotranslational chaperone for tubulin, Pfdn5 mutants showed substantially reduced levels of tubulin monomer. However, additional microtubule-related functions were indicated by the robust unexpected association of Pfdn5 with axonal microtubules in vivo, as well as binding with stabilized microtubules in biochemical assays. Loss of Pfdn5 resulted in neuromuscular junctions (NMJ) defects similar to those previously described in hTau-expressing flies: namely, increased supernumerary boutons and fewer microtubule loops within mature presynaptic boutons. Significantly, synaptic phenotypes caused by hTauV337M overexpression were also strongly enhanced in a Pfdn5 mutant background. Consistent with a role in modulating Tau toxicity, not only did loss of Pfdn5 result in increased accumulations of Tau-aggregates in hTauV337M expressing neurons, but also neuronal overexpression of Prefoldin strikingly ameliorated age-dependent neurodegeneration and memory deficits induced by pathological hTau. Together, these and other observations described herein: (a) provide new insight into Prefoldin-microtubule interactions; (b) point to essential posttranslational roles for Pfdn5 in controlling Tau-toxicity in vivo; and (c) demonstrate that Pfdn5 overexpression is sufficient to restrict Tau-induced neurodegeneration.

Behavioral and neural alterations of the ventral tegmental area by Cafeteria diet exposure in rats
The brain reward system is essential for regulating appetitive and consummatory behaviors in response to various incentive stimuli. Junk food, known for its high palatability, is particularly associated with the potential for excessive consumption. While previous studies have shown that excessive junk food intake can impact reward circuitry, the precise mechanisms remain unclear. Additionally, it is unknown whether the functionality of this brain system is similarly altered in response to other natural rewards. In this study, we used fiber photometry combined with a behavioral reward test to investigate how six weeks of excessive cafeteria (CAF) diet consumption affects VTA neural activity and behavioral responses to food and sexual rewards in sexually experienced female rats. For the first time, we demonstrate that prolonged exposure to a CAF diet decreases interest in a food reward, resulting in reduced consumption. These behavioral changes were accompanied by diminished neural activity in the VTA. Similarly, but to a lesser extent, reductions in VTA activity responses were observed in response to a sexual partner, although no significant behavioral differences were detected during sexual interactions. Furthermore, a two-week reversal diet of standard chow was insufficient to restore VTA neural activity in CAF-exposed animals, which continued to show decreased VTA responses to both food rewards and sexual partners. Our findings suggest that prolonged junk food exposure leads to desensitization of the VTA, a key node in the brain's reward circuitry, resulting in reduced responsiveness to natural rewards.

Trade-off between search costs and accuracy in oculomotor and manual search tasks
Humans must weigh various factors when choosing between competing courses of action. In case of eye movements, for example, a recent study demonstrated that the human oculomotor system trades off the temporal costs of eye movements against their perceptual benefits, when choosing between competing visual search targets. Here, we compared such trade-offs between different effectors. Participants were shown search displays with targets and distractors from two stimulus sets. In each trial, they chose which target to search for, and, after finding it, discriminated a target feature. Targets differed in their search costs (how many target-similar distractors were shown) and discrimination difficulty. Participants were rewarded or penalized based on whether the target's feature was discriminated correctly. Additionally, participants were given limited time to complete trials. Critically, they inspected search items either by eye movements only or by manual actions (tapping a stylus on a tablet). Results show that participants traded off search costs and discrimination difficulty of competing targets for both effectors, allowing them to perform close to the predictions of an ideal observer model. However, behavioral analysis and computational modelling revealed that oculomotor search performance was more strongly constrained by decision-noise (what target to choose) and sampling-noise (what information to sample during search) than manual search. We conclude that the trade-off between search costs and discrimination accuracy constitutes a general mechanism to optimize decision-making, regardless of the effector used. However, slow-paced manual actions are more robust against the detrimental influence of noise, compared to fast-paced eye movements.

ATP-gated P2x7 receptor is a major channel type at type II auditory nerves and required for hearing sensitivity efferent controlling and noise protection
Hearing sensitivity and noise protection are mediated and determined by negative feedback of the cochlear efferent system. Type II auditory nerves (ANs) innervate outer hair cells (OHCs) in the cochlea and provide an input to this efferent control. However, little is known about underlying channel information. Here, we report that ATP-gated P2x7 receptor had a predominant expression at type II ANs and the synaptic areas under inner hair cells and OHCs with lateral and medial olivocochlear efferent nerves. Knockout (KO) of P2x7 increased hearing sensitivity with enhanced acoustic startle response (ASR), auditory brainstem response (ABR), and cochlear microphonics (CM) by increasing OHC electromotility, an active cochlear amplifier in mammals. P2x7 KO also increased susceptibility to noise. Middle level noise exposure could impair active cochlear mechanics resulting in permanent hearing loss in P2x7 KO mice. These data demonstrate that P2x7 receptors have a critical role in type II AN function and the cochlear efferent system to control hearing sensitivity; deficiency of P2x7 receptors can impair the cochlear efferent suppression leading to hearing oversensitivity and susceptibility to noise.

Dissociation of movement and outcome representations in metacognition of agency
We studied the role of movement and outcome information in forming metacognitive representations of agency. Participants completed a goal-oriented task, a virtual version of a ball-throwing game. In two conditions, we manipulated either the visual representation of the throwing movement or its distal outcome (the resulting ball flight/trajectory). We measured participants' accuracy in a discrimination agency task, as well as confidence in their responses and tested for differences in the electrophysiological (EEG) signal using linear mixed effect models. We found no mean differences between participants' metacognitive efficiency between conditions, but we also found that metacognitive sensitivity did not correlate between the two conditions, suggesting a dissociation in their underlying mechanisms. Furthermore, exploratory analyses pointed toward a difference in the EEG signal between the two conditions. Taken together, our results suggest that while movement and outcome information contribute equally to participants sense of agency, they may do so through distinct underlying processes.

Enhanced Hippocampal Spare Capacity in Q175DN Mice Despite Elevated mHTT Aggregation
Background: Huntington's disease (HD) is a neurodegenerative disorder causing severe motor, cognitive, and psychiatric impairments, primarily affecting the striatum, which is crucial for movement and cognition. However, the role of the hippocampus in HD-related learning and memory deficits remains unclear. Objective: This study investigates the association between mHTT aggregation and neuropathology in the striatum and hippocampus of two HD mouse models. Methods: We performed a comparative analysis of neuropathology between zQ175 and in-house generated Q175DN mice, focusing on HTT aggregation, neuronal and glial pathology, chaperone expression, and synaptic density in both brain regions. Results: Q175DN mice exhibited increased mHTT aggregation in both the striatum and hippocampus compared to zQ175. Striatal neurons showed greater vulnerability to mHTT accumulation than hippocampal neurons in Q175DN, despite high mHTT levels in both regions. Interestingly, the Q175DN hippocampus displayed increased synaptic density, reduced Iba1+ microglia density, and elevated HSF1 levels in specific hippocampal subregions compared to zQ175 and neuropathology did not correlate with HTT aggregation. Conclusions: Q175DN mice are instrumental in elucidating the varying susceptibilities of striatal and other neuronal types to mHTT toxicity. The high spare capacity of the HD hippocampus suggests that cognitive deficits in HD may stem from striatal dysfunction or other brain regions involved in cognition, rather than from hippocampal degeneration.