bioRxiv Subject Collection: Neuroscience's Journal

Human AUTS2 regulates neurodevelopmental pathways via dual DNA/RNA binding.
The AUTS2 gene is implicated in neurodevelopmental and psychiatric disorders, with patient mutations leading to intellectual disability, microcephaly, and autistic behavior. While AUTS2 chromatin- and RNA-related functions are recognized, its direct binding to RNA in human neural progenitors has not been previously demonstrated. Here, we used ChIP-seq and eCLIP-seq in human neural progenitor cells (NPCs) to map AUTS2 chromatin targets and, for the first time, its direct RNA interactome. AUTS2 knockdown in NPCs led to widespread gene expression changes and impaired cell proliferation, migration, and neurite outgrowth. Integrated analysis revealed downregulation of Wnt pathway genes, notably WNT7A, among targets directly bound by AUTS2 at both chromatin and RNA levels. Supplementation with WNT7A rescued cellular phenotypes in AUTS2-deficient NPCs, underscoring the significance of Wnt signaling. These findings highlight AUTS2 central role in human neurodevelopment and provide mechanistic insight into how its disruption may contribute to the pathology of neurodevelopmental disorders.

Biophysical simulations of fMRI responses using realistic microvascular models: insights into distinct hemodynamics in humans and mice
Functional Magnetic Resonance Imaging (fMRI) is broadly used to measure human brain activity, however the hemodynamic changes that comprise the fMRI response to neuronal activity are often interpreted using microscopy data in mice. These microscopy data provide ground-truth observations of how individual blood vessels respond to neuronal activity and thus form the basis of our fundamental understanding of neurovascular coupling. Although these invasive experiments provide invaluable insight, there are striking differences in the vascular architecture of mouse and human brains that may influence the hemodynamic response. Motivated by this, we developed a biophysical modeling framework for realistic hemodynamic simulations in both mouse and human cerebral cortex. For this, we utilized Vascular Anatomical Network (VAN) models that explicitly represent the full microvascular tree as a single connected network, originally based on anatomical reconstructions from a given location of mouse cerebral cortex. We extended the VAN modeling framework using synthetic VAN models representing the microvascular network at a single location of the human cerebral cortex. To account for larger size and complexity of the human VAN models, we developed an efficient computational framework to simulate the full hemodynamic responses in this human model and compared the simulated fMRI responses between mice and humans. Our biophysical simulations are based entirely on first principles (e.g., conservation of mass); model parameter values were fixed across all simulations, not tuned to fit data, as they represent meaningful physical constants taken from previous measurements. Only two simple calibrations were tuned for each simulation, to match baseline perfusion rates (blood flow) and oxygen extraction (OEF). Our results show that differences in microvasculature indeed influenced the hemodynamic response and led to observable differences in timing-e.g., the simulated fMRI response peak in humans was delayed by ~2 s compared to mice, consistent with prior fMRI observations. While there are many known differences in vascular architecture in rodents and humans, we also discovered that, unexpectedly, an asymmetry in the numbers of branches of the penetrating intracortical arterioles and venules appears to be conserved across species. We demonstrate through further simulations that this anatomical property may also be needed for suitable hemodynamic responses. Our framework thus provides a valuable tool for bridging in-vivo microscopy of microvascular dynamics to human fMRI.

Neural Underpinnings of Olfactory Dysfunction across Parkinson's and Alzheimer's Spectra
Olfactory dysfunction is a frequent yet understudied feature of neurodegenerative spectrum disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). To disentangle the neural substrates of hyposmia across disease spectra, we examined 222 participants from the Parkinson's and Alzheimer's Disease Dimensional Neuroimaging Initiative cohort. Participants were classified according to the presence of cognitive disturbance, movement disorder, or both. Olfactory testing disclosed that cognitive disturbance and movement disorder were independently associated with hyposmia, and having both cognitive disturbance and movement disorder was associated with severe hyposmia. Whole-brain voxel-based morphometry revealed that hyposmia was associated with atrophy in the medial temporal lobe (MTL) in individuals with cognitive disturbance, whereas an artificial intelligence-based segmentation model identified olfactory bulb atrophy in those with movement disorder. Regression analysis and structural equation modeling further confirmed that the MTL and olfactory bulb volume contributed to olfactory performance through distinct processes. Individuals with cognitive disturbance and movement disorder had atrophy in both the MTL and olfactory bulb ("double hit"). We identified dual processes underlying hyposmia in the AD and PD spectra: a process linking MTL degeneration to cognitive disturbance and a process linking olfactory bulb degeneration to movement disorder. Our transdiagnostic approach enhances strategy in identifying specific neural correlates underlying hyposmia, lending support to the development of biomarkers for early intervention in AD and PD.

Novel, small molecules targeting the 5-HT4R receptor protect against stress-induced maladapative behavior with efficacy across age
BACKGROUND: Stress is a risk factor for developing psychiatric disorders, including major depressive disorder (MDD). Compounds targeting the serotonin type 4 receptor (5-HT4R) hold promise as novel rapid-acting treatments of mood disorders. However, a lack of selectivity and numerous side effects have been limiting factors for their clinical use. Here, we developed and characterized novel-composition 5-HT4R compounds in mouse models of stress. METHODS: Three 5-HT4R-targeting compounds were designed and synthesized based on PF-04995274, a high-affinity 5-HT4R ligand reported to be a partial agonist. G-protein assays were utilized to characterize molecular activity. Saline, PF-04995274, or a novel compound were administered before or after stress in male and female mice. Drug effects were assayed using behavioral paradigms. Patch clamp electrophysiology was used to determine the effect of drug on glutamatergic activity in hippocampal Cornu Ammonis 3 (CA3). RESULTS: Prophylactic administration of DL5, DL7, or DL8 was effective at reducing stress-induced maladaptive behaviors in male and female mice; DL7 and DL8 were effective when administered after stress. When administered following learned helplessness (LH), DL7 reduced behavioral despair and increased c-Fos in the dentate gyrus (DG) and CA3. All novel compounds attenuated large-amplitude AMPA receptor mediated bursts in ventral CA3 (vCA3). In aged male mice, prophylactic DL7 reduced behavioral despair. CONCLUSIONS: These results characterize novel 5-HT4R-targeting compounds for stress-induced psychiatric disease with the potential to address unmet needs in adult and aged patients with stress-induced psychiatric illness. Future work will characterize their mechanism of action with the goal of clinical development.

Developmental Reorganization of Whole-Body Muscle Synergies During Overarm Throwing in Children
Overarm throwing is a uniquely human skill that requires precise whole-body coordination. Although throwing behavior emerges early in childhood, the neuromuscular mechanisms that support its development remain poorly characterized. Here, we provide novel evidence for the developmental reorganization of whole-body muscle synergies during maximum-effort throwing in preschool-aged (PS) and school-aged (SA) children. Electromyography was recorded from 16 muscles, and non-negative matrix factorization was applied to extract low-dimensional coordination modules (muscle synergies). We compared ball speed, number of synergies, synergy structure, and temporal consistency between groups. Ball speed was significantly higher in SA than PS (33.6 {+/-} 10.2 vs. 21.4 {+/-} 6.2 km/h, p < 0.05), reflecting improved performance. Yet, the number of synergies did not differ (PS: 6.0 {+/-} 1.1; SA: 6.4 {+/-} 1.3, p > 0.05), suggesting that the dimensionality of coordination is largely established by the preschool years. Instead, developmental improvements were driven by structural and temporal reorganization: trunk- and upper-limb synergies merged into a single module in SA, reflecting improved postural integration, while a bilateral soleus-dominant synergy fractionated into lateralized modules, reflecting increased lower-limb specialization. Moreover, the temporal variability of synergy activation was reduced in SA (p < 0.01), indicating that movement sequences became more precise and stable with development. These findings reveal that early gains in throwing arise not from expanding synergy number but from reorganizing their structure and sharpening temporal coordination, offering mechanistic insight into how complex whole-body skills are refined during childhood.

CNS-penetrant NLRP3 inhibitor achieves durable weight loss and reverses hypothalamic inflammation in diet-induced obesity
The NLRP3 inflammasome is a key mediator of innate immunity that integrates inflammatory and metabolic stress signals. Increased and/or chronic activation of this critical pathway has been implicated in obesity, with hypothalamic neuroinflammation linked to dysregulation of energy balance. TN-783 is an investigational, CNS-penetrant, small-molecule NLRP3 inhibitor that potently suppressed inflammasome activation across multiple in vitro assays. In diet-induced obese (DIO) mice, only TN-783, and not the peripherally restricted NLRP3 inhibitor TN-101, produced progressive and sustained weight loss, underscoring the requirement for central target engagement. Weight loss was driven by a persistent reduction in food intake across both acute and chronic phases, without altering energy expenditure. This effect was further characterized by selective reduction of fat mass, with minimal impact on lean tissues. Mechanistically, NLRP3 inhibition attenuated DIO-induced hypothalamic neuroinflammation and partially reversed obesity-associated molecular changes based on transcriptomic and proteomic profiling of the hypothalamus. Beyond monotherapy, TN-783 enhanced the effects of the GLP-1 receptor agonist semaglutide by amplifying weight loss, reinitiating weight loss after semaglutide effect had plateaued, and maintaining the weight loss benefit after semaglutide withdrawal. Discontinuation of TN-783 resulted in reversal of both weight and feeding effects, indicating that its therapeutic activity requires ongoing target engagement rather than permanent remodeling of metabolic pathways. Collectively, these observations support central NLRP3 inhibition as a distinct and promising approach for obesity treatment, offering robust induction and sustained maintenance of weight loss while preserving reversibility.

Molecular and neuropathological determinants of neuronal dysfunction in Alzheimer's disease
The biological basis of neuronal excitatory/inhibitory (E/I) imbalance in Alzheimer's disease (AD) remains unclear. Using a comprehensive cohort with ante-mortem functional neuroimaging and post-mortem molecular data from the same participants, we mapped individual, whole-brain E/I imbalances through biophysical modeling. E/I ratios in regions supporting higher-order cognitive functions were significantly associated with cognitive performance and decline, with mediation by global neuropathological burden. We also observed a significant inverted U-shaped relationship between E/I ratios and neurofibrillary tangle severity, peaking at the limbic stage (Braak III-IV) in 14 brain areas, including the bilateral hippocampus and superior frontal gyrus. In addition, we identified 89 genes and 101 proteins that predict regional E/I ratios, with pathways related to synaptic signaling and immune response overrepresented. The generalizability of these molecular predictors was confirmed in two independent cohorts, achieving good classification performance for neuropathology severity and AD dementia. Lastly, the estimated E/I imbalances in AD aligned with whole-brain distributions of microglia and oligodendrocyte precursor cells, suggesting that spatial cellular organization contributes to vulnerability to neuronal dysfunction. Overall, this study provides critical insights into the cellular, molecular, and neuropathological signatures of circuit-level dysfunction in AD.

Distinct contributions of memorability and object recognition to the representational goals of the macaque inferior temporal cortex
The primate inferior temporal (IT) cortex, at the apex of the ventral visual stream, encodes information that supports diverse representational goals, from recognizing objects to determining which images are likely to be remembered. Specific artificial neural networks (ANNs), that currently serve as the leading computational hypotheses of ventral stream processing, are typically trained exclusively for object recognition. We asked whether incorporating image memorability as an additional optimization objective could improve ANN-brain alignment. Models optimized for memorability explained additional, non-overlapping variance in IT responses beyond that captured by recognition-optimized networks, indicating that memorability and recognition rely on partly independent dimensions of IT representation. Notably, these models also exhibited fewer non-brain-like units, bringing their representational geometry closer to that of IT. Furthermore, networks jointly optimized for both objectives were more predictive of human memorability than memorability-only models, while maintaining their alignment with human object recognition performance patterns. Together, these findings suggest that IT encodes multiple representational goals and that models trained solely for recognition provide an incomplete account of ventral stream computation.

Cannabis Use and Glutamate across the Psychosis Spectrum: In Vivo Evidence from 7T Proton Magnetic Resonance Spectroscopy
Cannabis use is linked to elevated psychosis risk, yet the neurobiological mechanisms that couple use to symptom expression remain unclear. Because glutamatergic dysregulation has been implicated in both cannabis effects and psychosis vulnerability, we examined whether brain glutamate relates to dimensional symptoms as a function of cannabis use across the psychosis spectrum. Seventy-nine participants--typically developing controls, clinical high-risk individuals, and patients with psychosis--completed dimensional clinical assessments, detailed cannabis surveys, urine toxicology, and ultra-high-field 7T 1HMRS quantification of anterior cingulate cortex (ACC) glutamate levels. Linear models assessed the main and interactive effects of ACC glutamate and cannabis use on positive and negative symptoms. Self-reported cannabis use showed strong concordance with urine toxicology. Cannabis use was associated with higher positive and negative symptoms. Independently, higher ACC glutamate predicted greater positive and negative symptoms. Notably, lower glutamate levels were associated with higher positive symptoms in cannabis users. Exploratory analyses suggested interactions for depressive and manic symptoms, indicating that glutamatergic abnormalities may amplify the overall severity of cannabis-related symptoms. Sensitivity analyses revealed lower ACC glutamate in psychosis patients--especially cannabis users--highlighting diagnostic group differences and reinforcing the link between cannabis exposure and glutamatergic dysfunction. These findings implicate ACC glutamatergic dysfunction as a transdiagnostic correlate of symptom burden, particularly in those with psychosis who are cannabis users. Glutamate-targeted interventions and longitudinal designs will be needed to examine causal pathways linking cannabis exposure to psychosis-relevant outcomes.

A Quest for a Histaminergic or Orexinergic Biomarker for Sudden Infant Death Syndrome
Background: This study investigated the role of the Hypocretin/Orexin (Ox) and Histamine (HA) systems-two key regulators of wakefulness-in sudden infant death syndrome (SIDS), a condition characterized by impaired arousal responses during sleep. Methods: Cerebrospinal fluid (CSF) Ox levels were measured in 61 healthy controls, 70 Sudden Unexpected Death Infants (38 SIDS, 32 explained deaths). HA and its metabolite tele-methylhistamine (t-MeHA) were analysed in an additional 46 SUDI (34 SIDS, 12 ED) and 42 controls. Immunocytochemistry was performed on hypothalamic tissue from 11 SIDS and 8 ED cases to assess the number of Ox and HA neurons. Results: CSF Ox levels did not differ globally but were relatively higher in deceased infants aged 2-6 months. HA and t-MeHA levels were significantly elevated in both SIDS and ED cases, likely due to postmortem release. Immunohistochemistry showed increased Ox neurons in SIDS compared to EDs, while HA neurons did not differ. Conclusions: Findings suggest increased Ox activity in SIDS especially within the 2-6 month risk window, potentially reflecting repeated stress or hypoxia prior to death, while HA neurons do not appear involved.

Amelioration of symptomatic Alzheimer's Disease after selective impairment of p75NTR function in adult forebrainexcitatory neurons
The p75 neurotrophin receptor (p75NTR) contributes to the development of Alzheimer's Disease (AD) pathology by enhancing amyloid precursor protein (APP) cleavage and amyloid plaque formation. However, the cell type-specific and temporal roles of p75NTR in AD progression remain unclear. Here, we report that conditional knock-in of functionally impaired p75NTR variants lacking the death domain ({Delta}DD) or transmembrane Cys259 (C259A) specifically in forebrain excitatory neurons of 5xFAD mice significantly attenuated multiple AD-associated pathologies, including amyloid plaque accumulation, gliosis, neurite dystrophy, as well as learning and memory deficits. Hippocampal amyloid plaque burden was reduced to levels comparable to those in whole-body knock-in mice. Strikingly, delaying introduction of p75NTR variants until advanced disease stages produced comparable beneficial effects, and rescued behavior performance in cognitively impaired animals. These findings suggest that blunting p75NTR function can have beneficial effects even during symptomatic stages of AD, offering a potential therapeutic approach complementary to passive vaccination.

Sexual dimorphism in the complete connectome of the Drosophila male central nervous system
Sex differences in behaviour exist across the animal kingdom, typically under strong genetic regulation. In Drosophila, previous work has shown that fruitless and doublesex transcription factors identify neurons driving sexually dimorphic behaviour. However, the organisation of dimorphic neurons into functional circuits remains unclear. We now present the connectome of the entire Drosophila male central nervous system. This contains 166,696 neurons spanning the brain and ventral nerve cord, fully proofread and comprehensively annotated including fruitless and doublesex expression and 11,691 cell types. By comparison with a previous female brain connectome, we provide the first comprehensive description of the differences between male and female brains to synaptic resolution. Of 7,319 cross-matched cell types in the central brain, 114 are dimorphic with an additional 262 male- and 69 female-specific (totalling 3.8% of neurons in males and 1.9% in females). This resource enables analysis of full sensory-to-motor circuits underlying complex behaviours as well as the impact of dimorphic elements. Sex-specific and dimorphic neurons are concentrated in higher brain centres while the sensory and motor periphery are largely isomorphic. Within higher centres, male-specific connections are organised into hotspots defined by male-specific neurons or the presence of male-specific arbours on neurons that are otherwise similar between sexes. Numerous circuit switches reroute sensory information to form conserved, antagonistic circuits controlling opposing behaviours.

Cortical Microstructural Variations Explain Individual Differences in Gamified Exploration-Exploitation Behaviours
The exploration-exploitation trade-off is ubiquitous in our everyday lives, and individuals display considerable variability in their preferred decision-making strategies. Most previous work pertaining to neural signatures of exploration is restricted to functional pathways. However, the specific contributions of cortical microarchitectures to high-level cognitive processes such as decision-making are as yet unknown. Here, we investigated the neuroanatomical foundations of inter-individual variability in decision-making strategies. To this end, 122 healthy participants completed a gamified multi-armed bandit paradigm aimed at teasing apart distinct exploration-exploitation decision strategies. We also collected whole-brain quantitative MRI maps indexing microstructural features of cortical myelination and iron content. Through computational modelling, we disentangled individual-specific exploration strategies, including value-free random exploration. Whole-brain regression analyses identified significant associations between value-free exploration and increased cortical myelination in right frontal brain areas with reported links to impulsivity. By elucidating the brain microstructural correlates of distinct exploration-exploitation strategies, we aimed to further our understanding of why individuals differ in their decision-making capabilities, and how decision-making may become aberrant in mental health conditions.

Mechanical stretch disrupts calcium dynamics and redistributes Piezo1 in human astrocytes
Astrocytes regulate the activity of nearby neurons so disruption of astrocyte calcium dynamics by traumatic brain injury (TBI) could have profound consequences for neural network activity in the brain. In this study, human induced pluripotent stem cell (hiPSC)-derived astrocytes were used in a two-dimensional (2D) in vitro stretch injury model to evaluate the effect of trauma on calcium dynamics, mitochondrial function, and the mechanosensitive ion channel Piezo1. Outcomes were assessed using live imaging, immunostaining, and RNA sequencing. Cell viability, mitochondrial membrane potential, and spontaneous calcium transients declined as injury severity increased. At moderate injury severity, the decreases in mitochondrial membrane potential and calcium dynamics were temporary. The spatial distribution of Piezo1 also changed temporarily after injury. RNA sequencing identified 196 genes that changed expression after injury, including downregulation of mitochondrial and oxidative metabolic processes and upregulation of cortical thinning pathways. These findings establish this model as a platform for investigating the cellular mechanisms of TBI and its influence on neurodegeneration. Keywords: Traumatic brain injury, hiPSC-derived astrocytes, calcium dynamics, mitochondrial dysfunction, Piezo1, RNA sequencing

Differential kinematic control and co-ordination among redundant joints during whole arm reaching movements
Normative upper limb movements are produced by multiple redundant joints. While the reaching task is specified at the endpoint, such task objectives become implicit at the level of joints. A fundamental question is whether planning and control of joints is solely in the service of the endpoint or whether they also include joint trajectories. Using Spearmans correlation and zero crossings, we found differential kinematic signatures of control between shoulder and elbow joints in contrast to the wrist joint. However, the extent of control among joints was substantially diminished compared to the endpoint. Further, when such control measures were compared to the subspaces of inter-trial joint exploration, we found that online control at proximal joints, such as the shoulder and elbow, were significantly associated in regulating the task space, while control at the wrist (distal) joint was associated in regulating joint redundancy in null space. These results suggest that null space is not entirely uncontrolled as per the uncontrolled manifold hypothesis but selectively controlled by some distal joints. Additionally, across different directions, either the shoulder or the elbow contributed dominantly towards the movement of the endpoint while the other joint was lagging and that this strategy reflected in our kinematic measures of online and trajectory control. Taken together, this study shows how the selective implementation of a leading joint in task space and a lagging joint in null space can enable the control of multi-jointed movements and attenuate the problem of joint redundancy.

Distinct contributions of anterior and posterior orbitofrontal cortex to outcome-guided behavior
The lateral orbitofrontal cortex (OFC) is critical for flexibly adjusting choices when outcome values change. Anterior and posterior parts of the human lateral OFC differ in cytoarchitecture and connectivity, but whether these subregions make differential contributions to outcome-guided (i.e., goal-directed) behavior remains unclear. Outcome-guided behavior requires (a) representations of stimulus-outcome associations and (b) inferring the current value of options when making decisions. Here, we test whether these two functions are differentially supported by the posterior (pOFC) and anterior (aOFC) parts of the lateral OFC, using transcranial magnetic stimulation (TMS) to selectively disrupt activity in functional networks centered on the pOFC and aOFC during a two-day outcome devaluation task. Participants (n = 48) received pOFC or aOFC network-targeted TMS either on day 1 before learning associations between visual stimuli and sweet or savory food odors, or on day 2 before a meal that selectively devalued one of these outcomes, followed by a choice test. TMS targeting pOFC, but not aOFC, before the meal on day 2 disrupted outcome-guided behavior, as measured by choices of stimuli predicting non-sated rewards in the post-meal choice test. In contrast, TMS targeting aOFC, but not pOFC, before learning on day 1 similarly impaired behavior in the post-meal choice test on day 2. These findings demonstrate that anterior and posterior parts of the lateral OFC make distinct contributions to outcome-guided behavior by supporting learning of stimulus-outcome associations and inferring the current value of options, respectively.

Nckx30c, a Drosophila K+-dependent Na+/Ca2+ exchanger, regulates temperature-sensitive convulsions and age-related neurodegeneration
Calcium (Ca2+) homeostasis is fundamental to neuronal physiology, including in the regulation of membrane excitability and synaptic transmission. Disruptions in the ion transporters regulating Ca2+ influx and efflux are clearly linked to seizure disorders and age-related neurodegenerative disease. Yet, the specific contributions of variants in genes encoding these transporters to neurological disease remain to be fully understood. Drosophila melanogaster has proven to be a powerful genetic model for uncovering such mechanisms, particularly through studies of mutants that display temperature-sensitive (TS) behavioral phenotypes. In a forward genetic screen, we identified a mutant line that exhibited TS convulsions along with progressive, age-dependent neurodegeneration. We mapped the mutation to Nckx30c, specifically within the transmembrane ion-binding region of this K+-dependent Na+/Ca2+ exchanger. Characterization of this mutant, together with a second Nckx30c allele, revealed TS convulsions, impaired locomotion, a markedly shortened lifespan, neurodegeneration with age, along with structural defects at larval and adult neuromuscular junctions (NMJs). Gene expression analysis confirmed that Nckx30c levels were reduced in heads of Nckx30c loss-of-function mutants. Tissue-specific manipulation revealed that knockdown of Nckx30c in neurons recapitulated the TS convulsions, locomotor defects, and shortened lifespan phenotypes. Drosophila Nckx30c is highly conserved and shares homology with mammalian SLC24A2, a solute carrier family 24 member whose neurological role is not yet fully elucidated. Our work establishes Nckx30c as an essential regulator of neuronal health and provides an in vivo framework for investigating the contribution of SLC24A2 to neuronal Ca2+ homeostasis, seizures and age-related neurodegeneration.

Home range is not constrained by number of hippocampal neurons across mammals
Numbers of hippocampal neurons vary by over three orders of magnitude across mammalian species. What evolutionary pressures shape this diversity? Given the role of the hippocampus in spatial mapping, the greater spatial navigation demands of larger home ranges may drive selection for more hippocampal neuron. Using data from 342 species, we crossed home range and population density data with cortical and hippocampal neuron counts predicted from clade-specific brain scaling laws to examine whether home range scales universally with estimated hippocampal neuron numbers across mammals. We confirm that home range scales universally with the inverse of population density across species and increases with body mass and metabolic rate. However, home range does not scale universally with hippocampal or cortical neuron numbers. Rather, scaling relationships differ by clade, such that carnivorans and cetartiodactyls traverse home ranges over 1,000-fold larger than primates with equivalent hippocampal neuron numbers. These findings persist across data subsets controlling for study method, duration, and temporal scope. Numbers of hippocampal neurons are thus not limiting to spatial navigation in the wild, calling into question adaptationist explanations for the evolution of more hippocampal neurons based on a supposed need for increased spatial processing capacity. We propose that home range is determined primarily by population density, mediated by field metabolic rate and diet. The diversity in hippocampal neuron numbers across mammals, in turn, arises as a byproduct of clade-specific scaling of numbers of cortical neurons which we suggest is contingent on energetic opportunity, not on navigational or other cognitive demands.

Transformer Networks Enable Robust Generalization of Source Localization for EEG Measurements
An electroencephalogram (EEG) is an electrical measurement of brain activity using electrodes placed on the scalp surface. After EEG measurements are collected, numerical methods and algorithms can be employed to analyze these measurements and attempt to identify the source locations of brain activity. These traditional techniques often fail for measured data that are prone to noise. Recent techniques have employed neural network models to solve the localization problem for various use cases and data setups. These approaches, however, make underlying assumptions that make it difficult generalize the results past their original training setups. In this work, we present a transformer-based model for single- and multi-source localization that is specifically designed to deal with difficulties that arise in EEG data. Hundreds of thousands of simulated EEG measurement data are generated from known brain locations to train this machine learning model. We establish a training and evaluation framework for analyzing the effectiveness of the transformer model by explicitly considering the source region density, noise levels, drop out of electrodes, and other factors. Across these vast scenarios, the localization error of the transformer model is consistently lower than the other classical and machine learning approaches. Additionally, we perform a thorough ablation study on the network configuration and training pipeline. The code and data used in this work will be made publicly available upon publication.

A dual information seeking strategy improves imprecise human inferences outside the explore-exploit tradeoff
Everyday decisions require not just earning rewards but also learning about the world. We asked how people gather information when sampling is reward free, and compared this with reward seeking under identical outcome distributions. In a large study (N = 420), people employed two dissociable information seeking strategies. They often began by testing one option several times before switching, building early certainty, a sampling rule we call streaking. They also showed a global tendency to sample where uncertainty is greatest. Computational modeling shows that both strategies independently improve decision accuracy under noisy belief updating. Artificial neural networks trained to optimize performance acquired uncertainty-directed sampling but not early streaking, highlighting a feature of human sampling not spontaneously acquired by networks trained on these objectives. These results reveal a dual architecture of information seeking that links traits, sampling policies, and performance.

The GLP-1R Agonist Semaglutide Reduces Motivated Running and Alters Dopamine Dynamics in the Nucleus Accumbens
Glucagon-like peptide-1 receptor (GLP-1R) agonists have recently emerged as powerful tools for the treatment of obesity through their ability to suppress food intake. However, their effects on non-ingestive motivated behaviors remain incompletely understood. Here, we show that the long-acting GLP-1R agonist semaglutide (SG) suppresses voluntary wheel running in both lean and diet-induced obese mice. Importantly, this suppression of activity was not caused by hypophagia and was accompanied by decreased motivation, with SG-treated mice displaying reduced effort for wheel access in a progressive ratio task. Real-time measurements of dopamine via fiber photometry revealed specific dopamine changes in the nucleus accumbens at both the beginning and end of running bouts, with SG-treated animals showing amplified dopamine dynamics at these key behavioral timepoints. Collectively, these data reveal important non-ingestive behavioral effects of GLP-1R agonism and suggest a role for dopamine circuits in mediating reductions of volitional activity following SG treatment.

Arm dominance emerges through asymmetric practice of complex trajectory shapes inherent to tool-use
Limb dominance is a human behavioral characteristic with many cultural, practical, scientific and clinical implications. Yet why the dominant limb performs better across a range of motor skill-requiring tasks remains unanswered. Is it because of an intrinsic hemispheric advantage or instead is it the result of life-long practice with the dominant side? We tested these alternatives using two tasks. The first was 3D reaching with either an inertial challenge or the need to use a stick-like tool. The second required participants to write with their dominant and non-dominant elbows. We applied a novel geometric analysis to quantify movement-trajectory shape. We show that (1) tool-use unmasks markedly inferior control in the non-dominant arm, and this is because it imposes the need to generate unfamiliarly shaped movement trajectories; and (2) there is no general dominant limb motor control advantage, only task-specific experience or practice. These results reframe dominance as predominantly about learned control of kinematics rather than baseline asymmetry in control of dynamics.

TRPM2 is a direct pain transducer
Chronic pain results from maladaptive interaction between the immune and nervous systems. TRPM2 channels in immune cells (immune TRPM2) are believed to facilitate chronic pain by indirectly promoting immune-inflammatory responses. Whereas TRPM2 in sensory neurons (neuronal TRPM2) acts as a warmth sensor critical to sense innocuous warm temperatures. However, neuronal TRPM2 mediates the warmth sensitivity of less than 3.5% of sensory neurons. The functions of the vast majority (42%) of TRPM2+ neurons are unknown. Here we show that neuronal TRPM2 functions as a pain sensor responsible for directly transducing acute and chronic pain independently of immune TRPM2. Both chronic arthritis pain and neuropathic pain were markedly reduced in TRPM2-knockout mice, and the pain deficit was recapitulated by sole deletion of neuronal TRPM2. However, immune and inflammatory responses were largely similar between wild-type and neuronal TRPM2-deficient mice. Moreover, antagonizing joint TRPM2 rapidly reversed chronic arthritis pain without affecting joint inflammation. Mechanistically, TRPM2 is activated by PGE2 and IgG immune complex (IgG-IC) through GalphaoA and FcgRI coupling, respectively, independently of conventional signalling messengers. Consistently, acute pain induced by PGE2 and IgG-IC was abolished in TRPM2 mutant mice. We conclude that neuronal TRPM2 is a convergent direct pain transducer independently of inflammation, representing an appealing target for alleviating chronic pain.

Clinical profile impacts the replicability of multivariate brain-behavioural associations
Recent work suggests that thousands of individuals are required in multivariate brain-behaviour analyses to obtain consistently replicable results. Some believe, however, that smaller sample sizes may be sufficient if specific subpopulations are targeted. We investigated how sample size and cohort composition influence the replicability of Canonical Correlation Analysis (CCA) results using the UK Biobank (N=40,514). We applied CCA to diffusion-weighted magnetic resonance imaging (dMRI) phenotypes and cognitive assessment test scores. We defined four participant cohorts based on clinical profile and found that, across all cohorts, sample sizes of around 500 were needed to obtain replicable canonical correlations and variable loadings. The most targeted cohort required much fewer samples to achieve similar or greater correlations than the other cohorts. Variable loadings were consistent between sample sizes of ~500 to thousands, suggesting that sample sizes in the order of hundreds may be sufficient for obtaining reliable CCA results.

NPS neurons receive extensive input from auditory brainstem nuclei
Neurons that produce NPS send output to brain regions implicated in circadian function and threat responses, but less is known about the afferent control of NPS neurons. In this study, we used a conventional retrograde tracer, cholera toxin beta subunit (CTb), to identify afferents to the rostral-lateral parabrachial region that contains the main concentration of NPS neurons. We then used Cre-dependent rabies retrograde tracing in Nps-2A-Cre mice to identify inputs specifically to NPS neurons. Nps-expressing neurons receive heavy input from auditory brainstem structures, including the inferior colliculus, nucleus of the lateral lemniscus, superior olivary complex, and cochlear nucleus. These findings suggest an unexpected role for auditory information in controlling the activity of NPS neurons.