bioRxiv Subject Collection: Neuroscience's Journal

Platelets from early-stage Alzheimer patients show enhanced amyloid binding, an elevated open canalicular system and sex-specific differences in their activation profile
Introduction: Alzheimers disease (AD) is associated with neurodegeneration and dementia. The clinical parameters include the deposition of amyloid-beta into senile plaques in the brain parenchyma and in cerebral vessels known as cerebral amyloid angiopathy (CAA). Currently, beta-amyloid-antibodies are emerging as possible therapy for AD. Several biomarkers, such as beta-Amyloid and tau-protein have gained significant value for diagnosing early AD. However, these biomarkers require cerebrospinal fluid. Blood tests for screening of AD are urgently needed. Methods: Patients diagnosed with early AD were analyzed for extracellular amyloid-beta binding to platelets, platelet morphology and platelet activation and compared to age-matched controls. Results: Beside unaltered platelet number and size, we detected increased binding of amyloid-beta to activated platelets isolated from AD patients. Electron microscopy revealed an altered platelet morphology in AD patients including the number of dense granules and the area of the open canalicular system (OCS) as compared to controls. While only minor differences in platelet activation were detected between patients and controls, a significant reduction of integrin alphaIIbbeta3 (fibrinogen receptor) activation was evident in platelets from female compared to male AD patients as determined by flow cytometry. Conclusion: The here presented results emphasize the importance to increase our understanding how platelets contribute to AD pathology in patients in a sex-specific manner. Furthermore, platelet parameters might serve as an ideal biomarker for a first prognosis of AD because platelets can be easily accessed by blood samples. These parameters might include a sex-specific platelet activation profile, the capability to bind Abeta to the platelet surface and the dimension of the OCS by electron microscopy.

The UAP56 mRNA Export Factor is Required for Dendrite and Synapse Pruning via Actin Regulation in Drosophila
Neurite and synapse pruning are conserved mechanisms that adapt neuronal circuitry to different developmental stages. Drosophila sensory c4da neurons prune their larval dendrites and their presynaptic terminals during metamorphosis using a gene expression programme that is induced by the steroid hormone ecdysone and involves posttranscriptional regulation pathways. Here we show that loss of the helicase UAP56, an important mediator of nuclear mRNA export, causes strong dendrite and presynapse pruning defects. Loss of UAP56 is linked to actin regulation, as it causes defects in the expression of the actin severing enzyme Mical during dendrite pruning, and actin accumulation at presynapses, where cofilin is required for pruning. Our findings suggest specificity in mRNA export pathways and identify a role for actin disassembly during presynapse pruning.

Prediction and updating abilities in motor imagery during the Timed Up and Go task in young and older adults
Aging is associated with declines in sensorimotor and cognitive functions that affect internal motor models, thought to mediate the risk of falls. Motor imagery, an experimental window into internal models, has been studied in aging, but it remains unclear whether age differentially impacts their predictive versus updating components. In this study, younger and older adults completed the Timed Up and Go task along with imagined trials before and after execution, enabling separate assessment of prediction and update accuracy. It was found that older adults exhibited similar or better accuracy during prediction and update, but the accuracy measures were linked with distinct cognitive and sensorimotor factors in the two age groups. These findings suggest that while internal model function is preserved in healthy aging, at least for every-day tasks, it is shaped by different compensatory mechanisms across the lifespan.

Gαq/11 signaling counteracts endothelial dysfunction in the brain and protects cognition in aged mice
Cognitive impairment is a major medical problem in the aging population. The risk of developing cognitive impairment is higher in several systemic conditions like hypertension, diabetes, and obesity. While a vascular contribution to cognitive impairment in these pathologies is well established, the underlying mechanisms are not fully understood. Endothelial dysfunction, which frequently accompanies the abovementioned conditions and increases with age, might be a key causal and mechanistic factor in cognitive deficits associated with systemic conditions. In this study, we demonstrate that the inducible deletion of the Gq/11 signaling pathway in brain endothelial cells leads to an impaired reactivity of the brain vasculature to vasodilating stimuli such as neuronal activity, representing an isolated cerebral endothelial dysfunction. These mice develop mild cognitive impairment with aging that could be explained by increased tau phosphorylation, decreased myelination, and capillary rarefaction, suggesting that endothelial cell-driven processes protect cognition in aging and providing a mechanistic explanation for how endothelial dysfunction can lead to cognitive impairment in cerebral small vessel disease.

RTFED, an open-source versatile tool for home-cage monitoring of behaviour and fibre photometry recording in mice
Background: Conventional approaches for studying feeding and reward-driven behaviours require frequent animal handling or relocation of animals to specialized chambers, inducing stress, confounding behavioural outcomes, and limiting continuous (24/7) data collection. In recent years, the Feeding Experimentation Device (FED3) has emerged as a major advance, offering programmable modes of operation, affordable costs, and flexibility for investigating a range of feeding and operant behaviours. However, certain limitations prevent researchers from fully harnessing the FED3's capabilities in a user-friendly manner. New method: Here, we present the Realtime and Remote FED3 (RTFED) developed for continuous and online home-cage monitoring of mice. Operating on both Raspberry Pi and Windows, RTFED integrates with FED3 to log and transmit feeding events and operant behaviours in real-time. It also incorporates event-triggered video capture through USB cameras, providing additional observational depth. Moreover, RTFED can send TTL signals to external devices (e.g., fibre photometry systems) for precise behaviour-neural synchronization. A key strength of RTFED is its customizable open-source architecture, enabling researchers to tailor both software and hardware configurations to meet specific experimental objectives. Comparison with existing methods: This flexibility, together with features such as remote data logging and email notifications that allow timely adjustments and animal welfare monitoring based on behavioural observations, substantially reduces animal disturbance and researcher intervention and labour. Conclusion: By offering a cost-effective and modifiable alternative to proprietary commercial solutions, RTFED broadens accessibility, heightens reproducibility, and deepens investigations into feeding and reward-driven behaviours in home-cage settings, ultimately improving the quality and translational relevance of behavioural research.

Divergent Roles of Nucleus Accumbens D1- and D2-MSNs in Regulating Hedonic Feeding
The nucleus accumbens (NAc) is a critical node in the neural circuitry underlying reward and motivated behavior, including hedonic feeding, and its dysfunction is implicated in maladaptive behaviors in numerous psychiatric disorders. Medium spiny neurons (MSNs) in the NAc are predominantly categorized into dopamine 1 receptor-expressing (D1-MSNs) and dopamine 2 receptor-expressing (D2-MSNs) subtypes, which are thought to exert distinct and sometimes opposing roles in reward-related processes. Here, we used optogenetic, chemogenetic, and fiber photometry approaches in Cre-driver mouse lines to dissect the causal contributions of D1- and D2-MSNs to the consumption of a high-fat diet in sated animals. Activation of D1-MSNs via optogenetics or DREADDs significantly suppressed high-fat intake, whereas inhibition of these neurons increased consumption. Conversely, activation of D2-MSNs enhanced high-fat food intake, while their inhibition reduced intake. Fiber photometry revealed dynamic shifts in D2-MSN activity over repeated high-fat exposures, with increasing activity correlating with escalating intake. These results highlight opposing contributions of D1- and D2-MSN populations in regulating hedonic feeding and support a model in which motivational salience and consumption are modulated by MSN subtype-specific activity in the NAc. Understanding this circuitry has implications for the development of targeted treatments for obesity and other disorders of compulsive consumption.

The Neural Basis of Quantity Discrimination in Mice
Quantity discrimination is an ability of identifying preferable sizes or amounts of subjects, yet its mechanisms remain elusive. Here, we report that mice exhibit an innate quantity discrimination behavior for food amounts, consistent with the Weber-Fechner law. Inhibition of the Posterior Parietal Cortex (PPC), but not other cortex regions, disrupts this behavior. Two-photon analysis reveals that selected neurons with preferential activities or Number Neurons are detected at a given time; however, these neurons are not correlated with quantity discrimination behavior and alter their preferential identities over time. Furthermore, inhibition of other cortex regions with Number Neurons does not affect quantity discrimination. Conversely, the PPC neuronal population changes synchronous firing levels, which correlates with quantity discrimination behavior and could be explained by a Neural Entropy model. Together, our study identifies a central role of the PPC in quantity discrimination, providing a neuronal population model of synchronous firing for quantity discrimination coding.

Representational drift without synaptic plasticity
Neural computations support stable behavior despite relying on many dynamically changing biological processes. One such process is representational drift (RD), in which neurons' responses change over the timescale of minutes to weeks, while perception and behavior remain unchanged. Generally, RD is believed to be caused by changes in synaptic weights, which alter individual neurons' tuning properties. Since these changes alter the population readout, they require adaptation of downstream areas to maintain stable function, a costly and non-local problem. Here we propose that much of the observed drift phenomena can be explained by a simpler mechanism: changes in the excitability of cells without changes in synaptic weights. We show that such excitability changes can change the apparent tuning of neurons without requiring adaptation of population readouts in downstream areas. We use spike coding networks (SCN) to show that the extent of these tuning shifts matches experimentally observed changes. Moreover, specific decoders trained on one excitability setting perform poorly on others, while a general decoder can perform close to optimal across excitability changes if trained across many days. Our work proposes a simple mechanism without synaptic plasticity that explains experimentally observed RD, while downstream decoding and, by extension, behavior remain stable.

Characterizing a hallmark of glymphatic insufficiency: Wasteosomes accumulate in periventricular white matter hyperintensities and exhibit complex relationships with mixed pathology, sclerotic index and perivascular space
The glymphatic system is a recently elucidated waste clearance system in the brain, thought to be critical for the maintenance of homeostasis. Corpora amylacea or wasteosomes, are discontinuous lipid labyrinth structures that are polyglucosan rich, retain cellular waste and are thought to be of astrocytic origin. Wasteosomes have been proposed as a hallmark of glymphatic insufficiency predominantly due to: 1) their spatial localization around glymphatic drainage points including periventricular (PV) regions, perivascular spaces (PVS), and sub-pial regions; and, 2) their correlation with aging, vascular disorders, neurodegenerative diseases, and conditions that impair sleep. White matter hyperintensities (WMHs) are diffuse hyperintense areas seen on T2-weighted or fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) scans that represent damage to white matter. PV WMHs and are known predictors of mild cognitive impairment, stroke, dementia and death. The relationship between wasteosome accumulation, PV WMHs, vascular pathology and PVS is currently unknown. For the first time, in a mixed diagnostic cohort of pathologically diagnosed: Alzheimers disease (AD), cerebrovascular disease (CVD), mixed AD/CVD, and control tissue with no pathological diagnosis, we connected the histopathological wasteosome profile in periventricular brain sections in relation to 7T FLAIR-MRI confirmed PV WMHs, vascular stenosis and PVS. Our results reveal wasteosomes accumulate in PV WMHs, are increased in proximity to large PV venules, and exhibit complex relationships with WMH severity, mixed pathology, sclerotic index and PVS. These findings suggest wasteosomes may serve as histological markers of impaired glymphatic drainage and provide new insights into the pathophysiology underlying white matter injury.

Electrophysiological effects of psilocybin co-administered with midazolam
The serotonergic psychedelic psilocybin induces glutamatergic neural plasticity and profoundly alters consciousness. Midazolam, a benzodiazepine and positive allosteric modulator of GABAA receptors, blunts neural plasticity and induces conscious amnesia. In our recent open label pilot study, we co-administered psilocybin (25 mg) with intravenous midazolam, targeting midazolam doses that allowed maintained subjective experience (mild to moderate sedation) while blocking memory encoding. We reported preliminary results from high density scalp electroencephalography (EEG) recorded during dosing session. Here, we used linear mixed effects models to examine changes in EEG band power (delta, theta, alpha, beta, gamma), normalized Lempel Ziv complexity (LZCn), and spectral exponent (SE) as a function of time during the dosing session, and relate these changes to the subjective effects of the drugs measured with the Observer's Assessment of Arousal and Sedation (OAA/S) and the Altered States of Consciousness (ASC) questionnaire. We found that SE, LZCn, and power in all frequency bands changed during drug administration, with an early (15-30 mins) increase in beta power and decrease in SE followed by increases in LZCn and SE and broadband decreases in power over the next 6 hours. OAA/S improved model fits for alpha power while ASC improved the model fits for SE and LZCn. These data are further evidence that the effects of psilocybin are maintained in the presence of midazolam, and that aspects of the subjective experience are captured by EEG measures.

Physical exercise and motor learning: A scoping review
Physical exercise, as an adjunct to motor task practice, can enhance motor learning by inducing neurophysiological changes known to facilitate this process. This preregistered scoping review mapped current knowledge on physical exercise effect on motor learning. The search strategy used indexed terms and keywords across several databases: MEDLINE, EMBASE, SPORTDiscus, Web of Science, PsycINFO, CINAHL Complete, ERIC and Dissertations & Theses Global (ProQuest). A total of 66 sources were included, comprising 62 experimental studies and 4 review articles. Most studies involved healthy populations (83%), while fewer focused on clinical populations (17%). Aerobic exercise was the predominant type used, with lower-limb cycling the most common approach (73%). Among various intensity levels, high-intensity exercise was most frequently investigated; however, in some studies, reported exercise intensity did not accurately reflect the method prescribed (6%). In contrast, resistance exercise was rarely examined (0.6%), highlighting a notable gap in existing literature. While some studies assessed both motor skill acquisition and a retention test (55%), others only employed a retention test (45%). Motor learning was measured at different time points including short-term or long-term delayed retention tests, or both. This underscores the need for consistent inclusion of long-term delayed retention tests to better capture lasting effects of physical exercise on motor learning. This review highlights gaps in the literature, including underrepresentation of clinical populations, inaccurate reporting of exercise intensity, scarce research on resistance exercise, and limited assessment of long-term retention tests, all of which may affect interpretation of the effect of physical exercise on motor learning.

Mapping neural activity during naturalistic visual and memory search
In everyday life, individuals often search for one of several items stored in memory. This cognitive process, known as hybrid search, is critical for tasks like navigating using landmarks. While the behavioral aspects of hybrid search have been extensively studied, the underlying neural mechanisms remain less understood. In this study, we combined concurrent magnetoencephalography (MEG) and eye movement recordings to investigate the oscillatory and evoked neural dynamics supporting hybrid search in naturalistic settings. Twenty-one participants (12 males, 9 females) performed a free-viewing task involving visual search for targets embedded in memory (hybrid search) across naturalistic scenes. Time-Frequency analyses revealed specific neural signatures during memory encoding, retention, and visual search. During encoding and retention, posterior alpha-band power decreased with memory load, reflecting heightened perceptual and mnemonic demands. During visual search, frontoparietal beta-band activity scaled with memory load, suggesting increased cognitive control. By aligning MEG signals to eye movement events and applying source reconstruction, we identified an early visually evoked lambda response, localized to V1, followed by a distributed P3m component, with maximum activation in the right inferior parietal lobe, that discriminated target from distractor fixations. Together, these findings demonstrate how oscillatory and evoked responses dynamically support hybrid search in naturalistic settings, revealing how memory, attention, and visual processing interact during active vision.

Morphometric Interpretation of Postganglionic Sympathetic Neurons that Innervate Myocardium
Background and Aims: The sympathetic nervous system modulates cardiac functions through neurotransmitters such as neuropeptide-Y and galanin released by postganglionic neurons. Hence, we hypothesize that dendritic and axonal morphological architecture of cardiac-innervating neurons might reflect the communicating input and output signals either within the postsynaptic neurons or to the adjacent myocardial cells. Methods: In the current study, we carried-out morphometric analyses of cardiac-innervating neurons, measuring dendritic size, shape, and neuronal-polarity. We used retrograde tracers (adeno-associated virus conjugate to fluorophores) injected either from left-ventricular myocardial tissue or fore-limb skin tissue-beds. Stellate ganglia were harvested from the mice for imaging and morphometric analysis. Results: Our findings revealed that cardiac-projecting neurons exhibit a multipolar structure and are significantly larger in cross-sectional area and volume compared to forelimb skin-pad-innervating neurons. Interpretation: These morphological characteristics may offer valuable insights into the neural architecture underlying cardiac remodeling, although further investigation is needed. This study focuses solely on the structural, not functional, features of cardiac-innervating neurons to better understand their specialization within the autonomic nervous system.

Functional specialisation across the first five years of life: a longitudinal characterisation of social perception with fNIRS
Research in typically developing infants has shown robust and consistent brain activation to social versus non-social visual and auditory stimuli in a network of brain regions, including the inferior frontal, anterior temporal and posterior superior temporal cortex. However, large-scale, longitudinal neuroimaging studies across early childhood, particularly in low- and middle-income countries are rare, yet important, given that they offer a powerful means of capturing within-person changes in neurodevelopment and identifying targets for intervention and support. Here we investigated brain responses to social perception across the first 2000 days of life (conception to five years of age) with functional near-infrared spectroscopy (fNIRS) longitudinally with participants in The Gambia within the Brain Imaging for Global Health (BRIGHT) Project. We found that social visual stimuli elicited a specialised right posterior temporal response across all six age points studied here (5, 8, 12, 18, 24 months and 3-5 years of age), with concurrent specialised left responses at four of the six time points (5, 8, 18 months and 3-5 years of age). Inferior frontal regions showed age-related changes in brain activation, with the youngest (5 months) and oldest (24 months to 3-5 years) time points evidencing more widespread frontal social visual responses. In contrast, social auditory stimuli elicited a significantly stronger and more prolonged response than non-social auditory stimuli across all six age points from 5 months to 3-5 years across a range of frontal and temporal areas. Furthermore, from individual infant trajectories of brain activation, we identified different profiles of age-dependent specialisation to social auditory stimuli, with some specialising earlier than others. Finally, in studying the hemodynamic responses, we showed that their different characteristics were influenced by age and stimulus type, highlighting the limitations of comparing fNIRS signal amplitudes across ages, and the importance of incorporating the timing of the fNIRS response to characterise brain activation more comprehensively.

Synaptic density and relative connectivity conservation maintain circuit stability across development
As bodies grow during postembryonic and postnatal development, nervous systems must expand to preserve circuit integrity. To investigate how circuits retain stable wiring and function throughout development, we combined synaptic-level resolution electron microscopy (EM) with computational modeling in the Drosophila larval nociceptive system. Based on EM data, we generated the contactome-the set of synaptic membrane contacts-of this circuit across development to evaluate how different mechanisms contribute to wiring stability. Specifically, we investigated three mechanisms: correlation-based plasticity and synaptic scaling, which modify synaptic strength, and structural plasticity, which preserves synaptic density. We found that synaptic sizes remain largely stable across development, and synapses between the same pre- and postsynaptic neurons do not correlate in size, suggesting that synaptic scaling and correlation-based plasticity play a limited role in shaping connectivity. In contrast, dendritic synaptic density remains invariant despite a previously reported fivefold increase in neuron size and synapse number. This conservation requires increased axonal presynaptic density to compensate for unequal axonal and dendritic growth. As neurons grow, this adjustment is necessary to maintain the relative synaptic input associated with each presynaptic partner across development. Our EM analysis and modeling show that conserving relative connectivity and synaptic density is sufficient to maintain consistent postsynaptic responses across development, highlighting these conserved structural features as key contributors to circuit stability during growth.

Concurrent category-selective neural activity across the ventral occipito-temporal cortex supports a non-hierarchical view of human visual recognition
Visual recognition is a fundamental human brain function, supported by a network of regions in the ventral occipito-temporal cortex (VOTC). This network is thought to be organized hierarchically, with definite processing stages increasing in invariance and time-course from posterior to anterior cortical regions. Here we provide a stringent test of this view by measuring category-selective neural activity to natural images of faces across the VOTC with electrophysiological intracerebral recordings in a large human sample (N=140; >11000 recording sites). Face-selective high frequency broadband (30-160 Hz) neural activity is distributed across the VOTC, with right-hemispheric dominance and regional peaks of activity. Crucially, while a progressive increase in degree of category-selectivity is found along the postero-anterior axis, neural activity occurs largely concurrently (~100ms onset and ~450ms offset) across all VOTC regions. These observations challenge the standard hierarchical view of neural organization of visual object recognition in the human association cortex, calling for alternative models of this key brain function.

Extracting Value Coding Features from Individual Serotonin Neurons
Adaptive behaviour requires animals to continually re-evaluate the appetitive or aversive quality of their surroundings. Dorsal raphe serotonin neurons, the main source of serotonergic input to the forebrain, have been implicated in both signaling the quality of an animal's environment and regulating reward-seeking and punishment-avoiding behaviour, but the precise quantity signaled by these neurons has remained unclear, as well as how these neurons relate with behaviour. Using open-access recordings of serotonergic neurons of the dorsal raphe nucleus while animals perform a dynamic Pavlovian task, we compare firing rate and behavioral data with a model that considers reward history accumulated over a tunable timescale. Our Bayesian parameter estimation supports that serotonergic neurons are consistent with reward history being estimated over about a hundred trials on average, with a heterogeneity across individual neurons spanning 30 to 300 trials. Anticipatory licking also correlated with reward history at multiple timescale, but could not be dissociated from that of a time/thirst nuisance variable and otherwise mostly on a timescale faster than seen in serotonergic cells. These results provide a more precise picture of the dynamics of serotonergic cells under a dynamic Pavlovian task.

Compositionality of social gaze in the prefrontal-amygdala circuits
Each social gaze can be deconstructed into primitive components, including gaze content, social state, and gaze duration. To reduce dimensionality and facilitate generalization, the brain needs to represent primitive components in an abstract format. We examined the compositional aspects of social gaze primitives in the brain when macaques were engaged in real-life social gaze interaction. Interactive social gaze behavior was determined by how primitives were combined, rather than by their independent sums, providing evidence for behavioral compositionality. The amygdala and the anterior cingulate cortex represented content and state in an abstract format and orthogonally to one another, whereas the dorsomedial prefrontal and orbitofrontal cortices exhibited limited generalization. Linear mixed selective neurons facilitated the abstraction underlying generalization. The content and state information had distinct communicative patterns across the prefrontal-amygdala circuits to minimize interference, which was mediated by linear mixed selectivity neurons. Our findings provide the neural grammar supporting the compositionality of social gaze.

Spectral decomposition of local field potentials uncovers frequency-tuned gain modulation of working memory in primate visual system
Working memory has been shown to modulate visual processing in a variety of ways, including changes in visual response gain, oscillatory power, spike timing, and phase coding of information1-3. Here we probe working memorys influence on various oscillatory components within visual areas, using the Maximal Overlap Discrete Wavelet Transform (MODWT) technique to decompose the local field potential(LFP)4; this method allows single-trial quantification of the properties of various oscillatory components. We examine the impact of spatial working memory on visual processing within the extrastriate middle temporal (MT) visual area of rhesus macaque monkeys, comparing the responses in MT when remembering a location inside or outside the receptive fields of the neurons being recorded. Using traditional bandpass filtering, we replicate previous reports that working memory enhances visual responses, low-frequency oscillatory power, spike-phase locking, and phase coding of visual information. Applying the MODWT method, we find that working memory modulates both oscillatory power and the precise frequency of oscillations within a general frequency band. The precise frequency of several lower frequency components (alpha, theta, and beta frequencies, but not gamma or high gamma) correlates with visually-evoked firing rates of MT neurons on a trial-by-trial basis. This relationship between firing rate and oscillatory component frequency is maintained across memory conditions, indicating a close link between the neural mechanisms driving oscillatory frequency and firing rates.

Slow wave stimulation using a smartwatch improves sleep quality
Poor sleep affects millions, increasing long-term health risks. Slow wave entrainment (SWE) is a promising method for improving sleep. While typically lab-based, we developed a smartwatch app to perform SWE and tested it with 93 participants at home. We found our app significantly increased slow wave and delta power amplitude, consistent with lab-based SWE protocols. This stimulation also reduced sleep fragmentation. Furthermore, we found that the increased slow wave amplitude was linked to improvements in mood and cognition measures, indicating the induced slow waves were functional. SWE produced the largest benefits in mood for participants who reported higher levels of pre-existing sleep problems. Our results demonstrate the potential for individuals to improve their sleep and cognition using a health smartwatch that performs SWE, offering an accessible tool for millions to enhance their sleep quality and health.

Multi-omic analyses identify molecular targets of Chd7 that mediate CHARGE syndrome model phenotypes
CHARGE syndrome is a developmental disorder that affects 1 in 10,000 births, and patients exhibit both physical and behavioral characteristics. De novo mutations in chd7 (chromodomain helicase DNA binding protein 7) cause 67% of CHARGE syndrome cases. Chd7 is a DNA-binding chromatin remodeler with thousands of predicted binding sites in the genome, making it challenging to define molecular pathways linking loss of chd7 to CHARGE phenotypes. To address this problem, here we used a previously characterized zebrafish CHARGE model to generate transcriptomic and proteomic datasets from larval zebrafish head tissue at two developmental time points. By integrating these datasets with differential expression, pathway, and upstream regulator analyses, we identified multiple consistently dysregulated pathways and defined a set of candidate genes that link loss of chd7 with disease-related phenotypes. Finally, to functionally validate the roles of these genes, CRISPR/Cas9-mediated knockdown of capgb, nefla, or rdh5 phenocopies behavioral defects seen in chd7 mutants. Our data provide a resource for further investigation of molecular mediators of chd7 and a template to reveal functionally relevant therapeutic targets to alleviate specific aspects of CHARGE syndrome.

Evidence from Formal Logical Reasoning Reveals that the Language of Thought is not Natural Language
Humans are endowed with a powerful capacity for both inductive and deductive logical thought: we easily form generalizations based on a few examples and draw conclusions from known premises. Humans also arguably have the most sophisticated communication system in the animal kingdom: natural language allows us to express complex and structured meanings. Some have therefore argued for a tight relationship between complex thought and language, postulating that reasoning, including logical reasoning, relies on linguistic representations. We systematically investigated the relationship between logical reasoning and language using two complementary approaches. First, we used non-invasive brain imaging (fMRI) to examine neural activity as healthy adults engaged in inductive and deductive logical reasoning tasks. And second, we behaviorally evaluated logical abilities in individuals with extensive lesions to the language brain areas and consequent severe linguistic impairment. Our findings reveal that the language system is not engaged during logical reasoning, and patients with severe aphasia exhibit intact performance on logic tasks. Instead, inductive reasoning recruits the domain-general multiple demand system implicated broadly in goal-directed behaviors, whereas deductive reasoning draws on brain regions that are distinct from both the language and the multiple demand systems. Together, these results indicate that linguistic representations are neither utilized nor required for inductive or deductive logical reasoning.

The Alzheimer's disease risk gene SORL1 is a regulator of excitatory neuronal function
Background: Synaptic dysfunction is an early feature of Alzheimer's disease (AD) and a significant contributor to cognitive decline and neurodegeneration. Proper localization of proteins involved in pre-and post-synaptic composition is dependent on endosomal recycling and trafficking. Alterations in trafficking complexes, such as retromer, have been shown to impair neuronal synaptic function. The SORL1 gene has been strongly implicated in AD pathogenesis and its protein product, SORLA, is an endosomal receptor that works in conjunction with retromer to regulate endosomal recycling. Methods: We utilized our established human induced pluripotent stem cell (hiPSC) derived excitatory cortical neuron model to examine SORL1's role in synaptic protein composition and neuronal function. We used Quantitative Multiplex co-Immunoprecipitation (QMI), a mesoscale. proteomics assay to measure synaptic protein interactions, immunocytochemistry to assay synapses and AMPA receptor subunits, and multi-electrode arrays (MEAs) to measure neuronal function of SORL1 KO and isogenic control hiPSC derived neurons. Results: We show that loss of SORL1 expression significantly changes many synaptic protein-protein interactions and patterns of expression. We demonstrate that SORL1 deficient neurons are hyperactive and that the increased activity is driven by glutamatergic neurotransmission. Hyperexcitability has been seen in other models of AD with familial AD variants in amyloid precursor protein and presenilin genes, due to the increases in amyloid beta (Ab) peptides. In the case of SORL1 deficiency, the hyperexcitability we observe is primarily due to mis-trafficking of synaptic proteins, rather than an overall increase in Ab. Finally, we find that SORL1 deficient neurons have impaired synaptic plasticity. Conclusions: These findings further support a growing body of literature implicating early endosomal recycling defects as drivers of AD pathogenesis. Furthermore, our work supports further emphasis on exploring the SORL1-retromer pathway for therapeutic development in AD.

Mature interneuron subtypes arise from distinct spatial and temporal subdomains within the caudal ganglionic eminence
Forebrain inhibitory interneurons are born from transient structures during embryogenesis known as the medial and caudal ganglionic eminences (MGE and CGE, respectively). The MGE and CGE generate distinct, non-overlapping cohorts of interneurons that can be defined by their transcriptomic, morphological, and electrophysiological characteristics. In the MGE, somatostatin-expressing (SST+) cells arise predominantly from the dorsal-posterior MGE from E12-E16 whereas parvalbumin-expressing (PV+) cells are born in the ventral-anterior MGE throughout embryogenesis. This relationship between spatiotemporal origin and mature interneuron subtypes has led to genetic insights regarding fate and maturation of these MGE-derived cells. A similar organization has never been explored in the CGE, despite the significant increase in CGE-derived interneurons in primates compared to rodents. Here we harvested fluorescent cells from distinct CGE subdomains at E13.5 and E15.5 and grafted them into WT neonatal mice cortices. One month post-transplantation, brains were immunostained for interneuron markers to relate mature CGE-derived interneurons with spatiotemporal origins within the CGE. Our results indicate that there are significant spatial biases in the CGE, with specific interneuron subtypes preferentially arising from distinct CGE subdomains. These biases are relatively stable over time, implying a minimal relationship between temporal birthdate and interneuron subtype. In the future, combining these insights with spatial transcriptome profiles will generate critical insights into gene regulation of CGE-derived interneurons.

A sensitivity-consistency trade-off in memory formation regulated by dentate gyrus inhibition
A core computational challenge for memory systems is the need to balance two opposing demands: (1) sensitivity to subtle input differences for flexible encoding, and (2) consistency to preserve stable, interference-resistant representations. How the brain dynamically regulates this trade-off remains unclear. Here, we show that modulating parvalbumin-expressing (PV+) interneurons in the dentate gyrus regulates this balance by shifting hippocampal computation between sensitivity and consistency regimes. Combining cell-type-specific pharmacogenetics, behavioral assays, and computational modeling, we found that reducing PV+-mediated inhibition during encoding enhanced the subsequent discrimination of similar inputs but it increased vulnerability to interference. In contrast, increased inhibition stabilized memory representations at the cost of discriminability. Together, the results establish PV+ interneurons as key modulators of hippocampal memory processing, enabling the system to prioritize either flexible updating or robust retention based on inhibitory tone at the time of encoding. This sensitivity-consistency continuum may reflect a fundamental organizing principle of memory computation.