Social behaviors are dramatically influenced by variations in mating systems that shape sex differences in the neural substrates underlying such displays. In polygamous species, distinct evolutionary pressures on males and females produce pronounced behavioral and anatomical sexual dimorphism, supported by strongly sexually differentiated social behavior and social decision-making networks at levels of brain structure, connectivity, physiology, and gene expression. By contrast, socially monogamous species display more similar or monomorphic social behaviors-such as shared parenting, convergent juvenile play, and selective pair bonding-accompanied by either reduced or more subtle neural dimorphism. Here, we discuss two nonexclusive models: that monomorphic behaviors arise from decreased circuit-level dimorphism, or instead, from conserved sexually dimorphic circuits that are differentially tuned in each sex to yield convergent behavioral outputs. Integrating pharmacological work on oxytocin, vasopressin, and other neuromodulators with modern genetic and circuit-level perturbations, including our recent studies in prairie voles, we highlight hidden molecular and circuit sexual dimorphism within nodes of the social behavior network and extended reward circuitry that support attachment, parenting, aggression, and social valuation. We propose that sex-biased weighting of shared, evolutionarily conserved circuits allows species- and sex-specific optimization of social strategies while preserving robustness in key behaviors like pair bonding and biparental care. Finally, we consider the implications of such masked sex differences for neurodevelopmental and psychiatric disorders marked by impaired social cognition and strong sex biases in incidence and presentation. We suggest that dissecting how dimorphic circuits support ostensibly monomorphic social behaviors may reveal sex-specific vulnerabilities and new targets for interventions.
Neuroscience has long relied on (typically binary) categorisations to manage the complexity of brain organisation. Yet growing anatomical and physiological evidence reveals that these dichotomies artificially partition systems that are inherently continuous and heterogeneous. In the thalamus, neurons display mixed afferent-efferent motifs and graded physiological properties that defy rigid categorisation. In the cerebral cortex, laminar somatic labels obscure the contribution of multilayer active dendritic nonlinearities, such as burst spiking, which radically reshapes modes of neural communication. Here, we propose that heterogeneity is not taxonomic noise, rather it is a key functional resource. Specifically, we argue that corticothalamocortical loops implement a dynamical process algorithmically akin to natural selection. Cortical and thalamic heterogeneity provides variation across neural coalitions; inhibitory competition, particularly within the thalamic reticular nucleus, enacts selection among competing whole-brain signals; and neural amplification, paradigmatically via subcortical projecting bursting promotes inheritance by recruiting selected neural coalitions across time. This perspective emphasises the corticothalamocortical system as a dynamic substrate for neural selection, rather than a static circuit motif. By integrating anatomy, physiology, and dynamical systems theory, we outline a framework that leverages neural heterogeneity for flexible, adaptive behaviour.
Astrocytes regulate hippocampal excitatory transmission by controlling glutamate dynamics, yet the contribution of cholinergic signaling to these processes remains poorly understood. Here, we investigated the role of astrocytic α7 nicotinic acetylcholine receptors (α7-nAChRs) in regulating glutamate homeostasis, synaptic plasticity, and memory flexibility in the hippocampus. Using ultrastructural analyses, functional imaging of glutamate, calcium, and sodium, electrophysiology, and behavioral approaches, we studied α7-nAChR knockout mice (α7KO) and an AAV-based mouse model enabling astrocyte-specific re-expression of α7-nAChRs (α7KI-astro). Electron microscopy revealed abundant α7nAChR expression in astrocytic processes at excitatory synapses in the hippocampal CA1 region. In α7KO mice, astrocytic calcium signaling and glutamate uptake were impaired. These alterations of glutamate dynamics were accompanied by reduced expression and altered localization of the glutamate transporter GLT-1, retraction of perisynaptic astrocytic processes, and deficits in synaptic fatigue, vesicle recycling, long-term depression, and memory flexibility. In α7KI-astro mice, calcium signaling, glutamate dynamics, synaptic plasticity, and memory flexibility were restored. Similarly, pharmacological enhancement of GLT-1 activity with ceftriaxone rescued both synaptic and behavioral deficits. Together, these findings identify astrocytic α7-nAChRs as critical regulators of glutamate homeostasis and hippocampal function, revealing a cholinergic mechanism through which astrocytes influence synaptic plasticity and cognitive flexibility.
As you read this sentence, you integrate meanings of individual words into complex, higher-order representations. In addition to the core language network (LN), this dynamic process recruits other domain-general networks such as the default mode network (DMN), with which it partially overlaps anatomically but segregates from functionally. To evaluate interactions between LN and DMN, we extracted instantaneous frequency, power, and phase (4-30 Hz) from intracranial electrodes in 32 participants who read sentences and wordlists. We isolated a complex low-frequency modulation, most reliably measured as a ramping of instantaneous frequency in the alpha band throughout sentences, greater than wordlists, occurring robustly across both the LN and DMN. Granger causal networks demonstrate this coincided with ramping increases in alpha-band connectivity between and within DMN and LN. We suggest that alpha-band modulations index dynamic interactions between core LN and broader domain-general networks and may be crucial for higher order semantic integration and the derivation of crossmodal knowledge from the language domain.
The whole-brain connectivity of thalamic reticular nucleus (TRN) parvalbumin-positive (PV+) neurons has been characterized at the population level, yet their single-cell projectome diversity and the corresponding electrophysiological heterogeneity remain incompletely understood. In this study, we systematically characterized the three-dimensional whole-brain projection patterns and electrophysiological properties of TRNPV neurons in PV-Cre mice via neural circuit tracing, high-definition fluorescence micro-optical sectioning tomography, and whole-cell patch-clamp recordings. Our findings revealed that these neurons receive extensive cortical inputs, primarily projecting to the dorsal thalamus with region-specific distribution patterns. Notably, ventral TRNPV neurons preferentially target first-order thalamic nuclei and display higher intrinsic excitability, while dorsal TRNPV neurons project to higher-order thalamic nuclei with lower excitability - a dorsoventral functional gradient that extends the PV+/SOM+ projection dichotomy to a continuous spatial axis within the PV+ population at single-cell resolution. These findings establish a topographically organized cortex-TRN-thalamus regulatory framework and provide a mechanistic basis for understanding sensory gating and thalamocortical dysregulation in neuropsychiatric disorders.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and restricted repetitive behaviors. Genetic studies have implicated chromosomal microdeletions in the 8p23.2-pter region in ASD and related disorders, highlighting FBXO25 as a candidate gene. FBXO25 encodes an F-box protein component of the SCF E3 ubiquitin ligase complex, which is involved in protein degradation through the ubiquitin-proteasome system. To investigate the impact of FBXO25 deletion, we generated Fbxo25-deficient mice and conducted behavioral, structural, molecular, transcriptomic, and proteomic analyses. Homozygous Fbxo25 mutant mice exhibited excessive self-grooming, a core ASD-related repetitive behavior. In contrast, both heterozygous and homozygous mice displayed impaired recognition memory in the novel object recognition test. However, social behaviors, anxiety-like responses, and spatial memory were preserved. Golgi staining revealed reduced dendritic complexity in hippocampal dentate gyrus granule cells of both heterozygous and homozygous mice. Western blotting revealed altered protein expression, including decreased PSD95 and CaMKII alpha, and elevated Arc in homozygous mice. Transcriptomic and proteomic analyses identified 17 differentially expressed proteins (DEPs) shared between heterozygous and homozygous mutants, supporting a model of FBXO25 haploinsufficiency. Many DEPs are involved in focal adhesion, cytoskeletal organization, synaptic transmission and signaling, oxidative stress, and protein degradation. These findings suggest that FBXO25 deletion impairs ubiquitin-mediated degradation, leading to synaptic dysfunction and ASD-relevant phenotypes. Our study establishes a novel mouse model of FBXO25 deficiency. It provides mechanistic insight into how disrupted protein degradation may contribute to ASD pathogenesis, highlighting protein degradation as a potential therapeutic target.
A high genetic predisposition for neuropsychiatric disorders, such as schizophrenia and autism spectrum disorders (ASDs), is 22q11.2 deletion syndrome (22q11DS), caused by a hemizygous microdeletion in the q-arm of human chromosome 22. The deletion most often spans a 3 Mb region, with variable breakpoints ranging from 1.5 to 3 Mb. Experimental studies on 22q11DS have revealed several aspects of the pathophysiology of neuropsychiatric disorders and also identified various interventional and rescue strategies. Herein, we review these strategies by grouping the studies into three main mechanistic categories: (i) microRNA (miR)-mediated, (ii) mitochondrial, and (iii) neural circuit deficits in polygenic deletion, and also briefly describe a few other monogenic mechanisms implicated. Haploinsufficiency of Dgcr8, a 22q11DS gene involved in miR processing, forms the center of miR-mediated mechanisms and rescuing consequent pathophysiology rely on age-dependent, brain region-specific or global replenishment of miRs or their targets. Seven genes in the 22q11.2 genomic region encode mitochondrial proteins and approaches to mitigate these gene deficiencies concentrate on the respective mitochondrial functions affected. We briefly describe other potential monogenic mechanisms for intervention including transcriptional regulation, synaptic release, catecholamine metabolism, and cell-cell adhesion, represented by Tbx1, Sept5, Comt, Arvcf, and Cldn5. We also give examples of how the multifaceted pathophysiological mechanisms and rescue strategies can have convergent effects at the molecular, synaptic, cellular and circuit levels. Based on the experimental interventions identified in the 22q11DS studies, we inform on the supportive therapies possible now and the future potential of curative interventions.
Sleep remains a complex and only partially understood neurophysiological process, with current theories often fragmented across electrophysiological, metabolic, and phenomenological domains. In this paper, we propose an advanced and integrative framework that conceptualizes rapid eye movement (REM) sleep as a state in which the brain constructs a provisional dummy model of the external world. In this context, non-REM (NREM) sleep serves as a critical phase of synaptic and network reorganization, coupled with glymphatic clearance, during which neural circuits undergo structural updates in response to prior waking experience. REM sleep subsequently provides an internally generated testing ground, wherein the brain simulates reality-including the consequences of internally generated motor commands-to evaluate and refine these updates through iterative cycles. This framework further distinguishes between phasic and tonic REM states, highlighting the involvement of subcortical networks, including the Papez circuit and the claustrum, in orchestrating state transitions. The model incorporates cerebrovascular, metabolic, and glymphatic dynamics, thereby placing sleep within a multiscale systems conceptual framework. A central prediction is that prediction errors generated during REM simulation drive selective synaptic consolidation in the subsequent NREM episode via hippocampal sharp-wave ripple-mediated feedback. A further prediction is that awakening occurs when the global prediction error across the dummy-model network falls below a biological threshold, and that total sleep duration should be proportional to the complexity of novel experience acquired during prior wakefulness. By aligning electrophysiological signatures, single-unit spiking activity data, metabolic processes, and the phenomenology of dreaming, the model seeks to transcend the limitations of domain-specific theories.
Larry Young had a huge impact on the study of neuropeptides and social behavior. Here I give an autobiographical perspective on how Larry and his work influenced the field and my own career.
Neuronal representations of the world are dynamic. A striking example is the rapid remapping of the hippocampal spatial code, which occurs even when the environment and behavior remain unchanged. CA3 input to CA1 has been shown to exert a key role in triggering synaptic plasticity in place-encoding CA1 cells - a phenomenon which could provide the cellular foundations for the remapping of the hippocampal code for space. However, how CA3 input directly contributes to place field formation and remapping of the place code in CA1 remains incompletely understood. By combining longitudinal two-photon calcium imaging of CA1 place cells with optogenetic stimulation of presynaptic CA3 neurons in mice running on a linear treadmill, we demonstrate that CA3 transiently modulates the code for allocentric space in CA1. Activation of CA3 cells both induced a small pool of new CA1 place cells and altered the pre-existing CA1 place code. The latter occurred through an unbiased shift of existing place fields specifically, and not through modifications of place field precision or a loss of place tuning in pre-existing place cells. All CA3-driven changes in the CA1 place code were transient and almost completely disappeared by the next day. Taken together, stimulation of CA3 input to CA1 cells alters CA1encoded spatial representations, leading to a transient deterioration of the spatial map rather than an overrepresentation of the stimulation zone.
Background Preterm birth is a life-changing event, followed by hospitalization in the Neonatal Intensive Care Unit. During this critical period of biological immaturity, preterm infants encounter atypical sensory stimulation and (painful and stressful) medical interventions. Such early environmental factors can alter the development of the hypothalamic-pituitary-adrenal (HPA) axis and the oxytocinergic system, potentially leading to long-term effects on neurodevelopment. The research on these physiological markers in preterm individuals remains inconclusive, partly due to variability in study designs, sample collection, and participant selection. Studies later in life, during childhood or adulthood, are particularly scarce. Methods Oxytocin and cortisol levels, and DNA methylation of the oxytocin receptor gene (OXTR) and the glucocorticoid receptor gene (NR3C1) were assessed in 39 preterm and 38 full-term school-aged children. Salivary samples were collected at two timepoints: one sample after awakening, and two samples at the end of the study visit. Results Preterm children had lower morning oxytocin levels but similar afternoon oxytocin levels compared to full-term children. Both groups showed elevated cortisol levels in the morning compared to the afternoon. Preterm children exhibited a steeper decline in cortisol, with lower afternoon cortisol levels compared to full-term children. DNA methylation of NR3C1 was lower in preterm children, whereas no group differences were observed for OXTR. Conclusion These findings suggest differences in salivary measures of the HPA axis and oxytocinergic system in preterm school-aged children compared to full-term children, highlighting the importance of further research into the long-term impact of preterm birth and early life stressors.
Mitochondrial morphology varies by neuronal cell type and subcellular compartment; however, the functional significance of these differences is unclear. Hippocampal CA2 neurons are enriched for genes encoding mitochondrial proteins compared to CA1, suggesting a difference in metabolic demand across hippocampal circuits. However, whether CA2 neuron mitochondria are structurally or functionally distinct to support circuit-specific energy demands is unknown. Here we compared mitochondrial morphology, protein expression, and calcium levels across CA1 and CA2 circuits. We found that CA2 dendritic mitochondria were larger than in CA1. However, both subregions harbored larger mitochondria in the entorhinal cortex (EC)-contacting distal dendrites compared to CA3-contacting proximal dendrites. Together, these data demonstrate cell type- and input-specific regulation of mitochondrial morphology that likely influences the function of these distinct circuits. To determine whether differences in mitochondrial fission or fusion account for cell and/or layer specific differences in morphology, we immunostained for MFF and OPA1, which showed a general enrichment in distal relative to proximal dendrites, and an unexpected increase in CA1 distal dendrites compared to CA2 distal dendrites. To show whether these morphological differences result in functionally distinct mitochondria, we measured mitochondrial calcium levels in live slices. We found a striking enrichment of mitochondrial calcium levels in CA2 distal dendrites relative to proximal dendrites, and this layer-specific effect was significantly different from that in CA1 at baseline and after activity. Collectively, these findings reveal discrete morphological and functional differences in mitochondria across hippocampal subregions and dendritic layers, which likely confer unique circuit properties and/or vulnerability to disease.
Every neuron in the supraoptic nucleus projects to the neurohypophysis and secretes vasopressin or oxytocin. This simple fact has massively facilitated the study of how oxytocin and vasopressin are made, packaged into neurosecretory vesicles and transported down the axons to the neurohypophysis, and how their secretion is regulated by action potentials. When researchers began using electrophysiology to study the oxytocin and vasopressin cells it was not clear what this could add to the knowledge that came from endocrine studies, but being able to record the electrical activity of identified neuroendocrine neurons during defined physiological challenges made it possible to relate mechanistic understanding to physiological function. Here we study the influence of electrophysiological studies, building a citation network to help explore how our present understanding has been constructed. Our purpose is to try to show what progress is like, and by doing so to talk about impact in a meaningful sense. We focus on fundamental insights attributable to electrophysiological approaches, rather than on electrophysiological features of the neuroendocrine neurons per se, or on findings that have merely confirmed what was known from measurements of hormone secretion.
Oxytocin is synthesized primarily by neurons in the hypothalamus, and it exerts diverse central and peripheral effects through activation of its receptor, the oxytocin receptor (OXTR). A sexually dimorphic population of OXTR-expressing neurons was identified in the anteroventral periventricular nucleus (AVPV) in the preoptic area of female mice. The expression of OXTR in the AVPV is estrogen-dependent and becomes further upregulated during the postpartum period. Functional inactivation of these neurons in dams disrupts specific components of maternal behavior, including pup retrieval and nest building, indicating that their activity is essential for normal maternal behavior. Furthermore, approximately 30% of these AVPV-OXTR neurons are immunoreactive to tyrosine hydroxylase (TH⁺). Because these neurons also express DOPA decarboxylase, the enzyme that converts L-DOPA to dopamine, they are considered dopaminergic. TH⁺ AVPV-OXTR neurons generate intrinsic pacemaker-like short-burst activity, and OXTR activation elevates burst frequency, supporting the idea that these neurons regulate dopaminergic levels in their projection sites and that oxytocin can enhance dopamine output. Moreover, oxytocin neurons are near these OXTR neurons within the AVPV-so close that conventional axonal release is unlikely to account for their interaction. Given that both dopamine and oxytocin signaling in the preoptic area are required for the heightened maternal motivation observed during the postpartum period, the presence of both oxytocin and OXTR-expressing neurons in the AVPV points to previously unrecognized mechanisms contributing to this enhancement. This review discusses the potential role of oxytocin signaling in the AVPV in the regulation of maternal motivation, integrating molecular, morphological, and electrophysiological evidence.
Extracellular amyloid plaques formed from aggregated Amyloid-β (Aβ), a specific cleavage product of Amyloid Precursor Protein (APP), and intracellular tau-containing neurofibrillary tangles are the two key histopathological hallmarks of Alzheimer's Disease (AD). However, increasing evidence suggests that the trigger for neurodegeneration in AD involves intraneuronal defects in endolysosomes, which might be induced by both Aβ and tau. Recent high-resolution analysis of trafficking inside neuronal and non-neuronal cells suggests such defects may arise through aberrant compartmental maturation events during regulated secretion. These events bring together APP, secretory and endosomal compartments, and also the proteolytic secretases that generate Aβ. They may be initiated by the accumulation of Aβ and/or C-terminal fragments of APP, which interfere with endolysosomal trafficking and potentially induce tau pathology. They also lead to secretion of proteins from these Aβ-containing compartments, which can trigger endolysosomal phenotypes in other cells that endocytose them. By implicating regulated secretion in the initiation of AD, this new model highlights novel intracellular mechanisms that might drive neurodegeneration. Identifying suppressors of these pathways could suggest entry points for the development of novel therapies that target the earliest stages of AD pathology.
Objective Somatic mutations in mechanistic target of rapamycin (mTOR) pathway genes produce focal brain malformations that can lead to epilepsy. Malformations show a high degree of mosaicism, sometimes with less than 1% of neurons carrying the mutation. Seizures are hypothesized to be driven by mutation-carrying dysmorphic excitatory neurons, but lesions in patients and animal models also show loss of interneurons. Here, we queried whether interneuron loss could act as a second hit, releasing the brake on excitatory dysmorphic neurons and increasing epilepsy severity. Methods To test this hypothesis, we developed a two-hit mouse model in which we combined loss of the mTOR pathway inhibitor phosphatase and tensin homologue (Pten) from excitatory hippocampal dentate granule cells with ablation of local parvalbumin or somatostatin interneurons. Pten was deleted from roughly 3% of granule cells, a level which is subthreshold for producing frequent generalized seizures, thus facilitating assessment for synergistic effects. Results Pten loss alone produced occasional seizures, while interneuron ablation alone initiated frequent seizures lasting for about one week, followed by a significant decline in seizure incidence in subsequent weeks. The combination of Pten deletion and interneuron ablation did not produce a synergistic increase in seizure incidence over ablation alone. Interpretation Findings confirm the potential for interneuron loss to drive epileptogenesis, but do not support the hypothesis that rapid disinhibition of Pten knockout granule cells enhances their ictogenic potential. Results provide new insights into the role of GABAergic inhibitory input in regulating the activity of mTOR hyperactive neurons.
Chronic pain remains a major unmet medical challenge, yet the metabolic checkpoints that govern its persistence are poorly defined. Astrocytes are increasingly recognized as chemically programmable hubs that tune neuronal excitability through metabolic circuits. Building on reports that astrocyte-neuron lactate shuttling (ANLS) in the anterior cingulate cortex (ACC) supports chronic pain, we asked how astrocytic metabolic states evolve over the course of pain chronification. Using untargeted metabolomics of the ACC combined with GFAP-RiboTag-based astrocyte-specific transcriptomics, we provide a time-resolved map of astrocytic metabolism across the transition from acute nociception to chronic neuropathic pain. This analysis reveals a biphasic glycogen program-an acute glycogenolysis-triggered glycogen supercompensation-that culminates in the emergence of a Warburg-like metabolic signature associated with late astrocyte-enriched glycolytic and lactate-related changes and persistent circuit activation. Using glycogen phosphorylase inhibitors (GPI-1, GPI-2) as pharmacological probes, we show that early glycogenolysis blockade attenuates this Warburg-like shift, partially normalizes ACC metabolic signatures, and reduces long-lasting mechanical hypersensitivity, without impairing acute nociceptive sensitization. These findings identify astrocytic metabolic reprogramming as a pharmacologically tractable circuit-level process and nominate glycogenolysis as an upstream biochemical gate and potential therapeutic control point in neuropathic pain.
Burst firing and dysrhythmia of thalamocortical (TC) neurons are involved in central pain. In neuropathic pain, peripheral nerve damage can trigger abnormal firing of distant TC neurons. Here, in the mouse whisker somatosensory thalamus, we aimed to identify the regulatory mechanisms for TC firing induced by an infraorbital nerve cut (IONC). IONC hyperpolarized resting membrane potentials and reduced input resistances of TC neurons. These changes are related to accelerated burst firing and increased spike-frequency adaptation during depolarization. In addition, IONC decreased hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity by attenuating hyperpolarization-induced voltage sag and shifting the activation potential towards more hyperpolarized potentials. Consistently, IONC reduced the number of rebound spikes after hyperpolarization. We previously reported that IONC-induced neuronal and glial changes in thalamic and brainstem whisker regions are necessary for the development of mechanical hypersensitivity: increased thalamic tonic inhibition via extrasynaptic GABAA receptors and aggregated microglia in the brainstem projecting to the thalamus. We found that genetic ablation of extrasynaptic GABAA receptors in TC neurons prevented IONC-induced changes in membrane properties, and that brain-wide microglial ablation exhibited the same tendency. Whereas brainstem local microglial ablation prevented IONC-induced enhancement of tonic inhibition, thalamic local microglial ablation failed to cause the same phenomenon. Thus, our results suggest that IONC alters distant TC firing via microglial and tonic inhibitory interactions along the ascending pathway. By using these remote mechanisms, peripheral nerve injury may cause central sensitization of neuropathic pain.
Our brains support at least two major spatial representations: an egocentric, short-horizon representation of peripersonal space (PPS), and an allocentric, longer-horizon cognitive map system. Here, we speculate on their relationship from an evolutionary perspective. We argue that an ancient proto-PPS system for contact prediction likely emerged early in vertebrate evolution as a fight-or-flight mechanism for managing imminent threats, supported by evolutionarily conserved midbrain circuits such as the optic tectum (superior colliculus in mammals). The subsequent transition of many species from aquatic to terrestrial environments dramatically expanded sensory ranges and environmental complexity, arguably creating selective pressures for longer-horizon navigation, prediction, and planning. These pressures likely contributed to the emergence of hippocampal and entorhinal systems supporting allocentric spatial representations. Next, as navigation and foraging behaviors became more sophisticated and required dexterous multi-joint movements, it is possible that a cortical PPS system emerged within neocortical networks, including posterior parietal and ventral premotor cortices. Rather than mediating coarse fight-or-flight responses, we suggest this cortical PPS system now supports fine-grained hierarchical sensorimotor control, reference-frame transformations, tool use, and social interactions. In parallel, the allocentric mapping systems seemingly expanded beyond spatial navigation to support relational, conceptual, and abstract cognitive structures. We suggest that PPS and cognitive maps instantiate shared computational principles operating at different spatial and temporal scales and in different reference frames; a view supported by recent reinforcement-learning frameworks linking body-centered and allocentric predictive value. Together, this perspective points to a putative scaffolded evolutionary trajectory in which cognition may have expanded from near-body safety to a multiscale predictive architecture supporting flexible, goal-directed behavior across space and time.
The subthalamic nucleus (STN) is a core component of the basal ganglia circuitry, traditionally viewed as a "brake" that suppresses motor output via the indirect and hyperdirect pathways. While this model explains certain aspects of motor control, it fails to account for the complex involvement of the STN in dynamic, value-based behaviors. Movement-related increases in STN neuronal activity have been well documented across species, but the functional organization of these responses during value-based decisions has remained unclear. Here, we recorded 187 STN neurons from macaque monkeys performing a value-based sequential choice task. Data-driven clustering identified three functionally distinct populations. Two populations (comprising approximately 89% of task-responsive neurons) exhibited facilitative activity modulated by learned object value. Temporal alignment analysis revealed that the majority of these neurons were target-locked, suggesting a predominantly stimulus-driven evaluation signal rather than a strictly movement-locked command. A third, smaller population encoded a negative value signal upon presentation of unrewarded objects, independent of subsequent motor strategy. Response latencies of the facilitative STN populations systematically preceded those of functionally analogous populations in the GPe recorded during the same task paradigm, supporting an STN-GPe facilitative pathway for value-based action selection. These findings reveal a functional organization within the ventral STN in which evaluation of stimulus target value, beyond the traditional motor suppressive model, is the predominant mode of processing.
