Neuroscience

Glutamatergic neuronal synapses in the mouse neocortex mature during the first two months after birth. A key event during synaptic maturation is a change in short-term synaptic plasticity (STP), i.e. a switch from strong synaptic depression to a weaker depression or even facilitation. Glutamatergic pyramidal neurons located in the cortical layers II/III, layer V, and layer VI project axons through the corpus callosum where they release glutamate along their shafts and form glutamatergic synapses with oligodendrocyte precursor cells (OPCs). Here, we used single-cell electrophysiological recordings in brain slices to investigate synaptic plasticity at neuron-OPC synapses along axonal shafts in the white matter, and applied computation approaches to pinpoint the mechanisms of this plasticity. We found that during postnatal development of mice, there is a switch from short-term synaptic depression to short-term synaptic facilitation at glutamatergic neuron-OPC synapses in the corpus callosum. Synaptic delay of phasic neuron-OPC excitatory postsynaptic current shortens, and the amount of asynchronous release at neuron-OPC synapses decrease as animals mature, indicating that glutamate release becomes more synchronized. Our computational modelling suggests that both pre- and postsynaptic changes may contribute to the functional development and changes of plasticity at neuron-OPC synapses in the white matter. Taking together, our findings indicate that synaptic release machineries located at different sites along the same axon (i.e. axonal shaft in the white matter vs synaptic boutons in the grey matter) mature in a very similar fashion, STP occurs at both synaptic sites, and STP dynamics represent an important event during brain maturation.

Reward can enhance motor performance. However, its potential to counteract motor fatigability, a reduction in motor performance during sustained movements, remains underinvestigated. This could be particularly relevant in neurological conditions such as multiple sclerosis, where increased motor fatigability is a prominent symptom. One form of motor fatigability is motor slowing, a decline in movement speed over time evoked by fast, repetitive movements. In this study, we investigated whether the possibility to earn reward attenuates motor slowing, and examined associated changes in muscle activity and pupil size, a putative marker of physical effort. Participants performed a wrist tapping task at maximal voluntary speed with or without the possibility of earning a reward. We found that wrist tapping induced motor slowing and that slowing was significantly reduced by reward. Over time, tapping became more costly as indicated by higher muscle activity and coactivation per tap. This was accompanied by a sustained pupil dilation, which could not solely be explained by tapping speed. These findings suggest that, rather than restoring efficient motor control, reward attenuates motor slowing by allowing participants to access a performance reserve and invest more resources into the task, reflected by increased muscle activation per tap and sustained pupil dilation.

The aim of this study was to improve our understanding of muscle contractions in the arm as a function of hand orientation for grasp. While there have been several reports on arm kinematics for reach and grasp movements, little has been done at the muscular level. To this end, we analyzed the modulation of shoulder, elbow and hand muscles for a reach and grasp task involving a target in either horizontal or vertical orientation. We hypothesized that unlike what has been observed for kinematics, at the muscular level we would see less correlation between the three muscle groups. A decoding approach with Machine Learning revealed adaptation patterns that were not visible using classical methods. Reach-and-grasp has traditionally been treated as being made of two components - the reach and the grasp components. Our dynamic decoding approach revealed a more complex picture with very different dynamics in the shoulder and elbow muscle groups during reach. All muscle groups showed peak capacity for predicting hand orientation before the start of grasp and followed the ubiquitous proximo-distal organization. The patterns of muscular modulation for hand orientation were strongly perturbed by the eyes closed and slow movement conditions, potentially decreasing the available degrees of freedom for adaptation.

Dopamine (DA) neurons of the midbrain project throughout the striatum, including the nucleus accumbens core (NAc) and are thought to co-release ATP with DA from vesicles. The mechanisms of evoked NAc ATP release and clearance and their relationship to exocytotic DA transmission are largely unexplored and the focus of the present work. Using fast scan cyclic voltammetry (FSCV), we measured simultaneous ATP and DA transmission in response to pharmacological manipulations of release and reuptake cellular machinery. ATP transmission is tightly coupled to that of DA, though ATP release concentrations are typically smaller. Manipulations that increase DA transmission (increased release via 4-aminopyridine Kv channel blockade or decreased uptake via cocaine) also increase ATP transmission, though to a smaller extent. Blocking DA vesicular packaging (reserpine) or action potentials (lidocaine), results in attenuated DA and ATP release. Interestingly, reserpine or lidocaine can result in completely abolished DA release, but not a complete prevention in ATP release, suggesting a secondary source for ATP transmission thats not dependent on DA terminals. Both transmitters were reduced to a similar extent following nAChR blockade, demonstrating that nAChR activation regulates ATP in addition to DA. Surprisingly, cocaine inhibition of DATs reduced clearance for both ATP and DA, which correlated with one another when cocaine concentration was highest. There was also a strong relationship between the effect of cocaine on release of ATP and DA. As the first FSCV study to examine evoked NAc ATP release, this paper bridges prior work to confirm the strong association between ATP and DA in the mesolimbic circuit and identifies unexpected overlap in mechanisms regulating their transmission. Our results contribute novel evidence of both vesicular and non-vesicular ATP release in the NAc and demonstrate that extracellular ATP is a modulator of DA terminal function.

Oligodendrocyte precursor cells (OPCs) are unique glial cells that communicate bidirectionally with neurons. Neuronal inputs drive various OPC behaviors, including proliferation and differentiation, immunomodulation, blood brain barrier regulation, synapse engulfment and axonal remodeling. OPCs are implicated in numerous stress and pain conditions, where their involvement is likely driven by neuronal activity (ie. neurotransmitter and neuropeptide signaling). One neuropeptide causally involved in chronic pain and stress conditions is calcitonin gene-related peptide (CGRP). Here, we tested the hypothesis that OPCs receive direct inputs from CGRP-containing neurons in the adult brain. Using RNAscope, immunofluorescence and analysis of single-cell datasets, we find that OPCs express receptors for CGRP and we identify close spatial contacts between CGRP and OPCs, with nearly half of CGRP puncta occurring within 1 {micro}m of an OPC. Some of these contacts appear to be synaptic, with CGRP-OPC contacts colocalizing with the presynaptic protein Bassoon and the postsynaptic protein PSD-95. This work suggests the presence of both diffuse and more direct forms of CGRP signaling to OPCs, raising the importance of future experiments to identify both the mode of CGRP release onto OPCs and the functional effects of these different contact types.

BackgroundTourette Syndrome (TS) is a neurodevelopmental movement disorder involving involuntary motor and vocal tics believed to be characterised by disordered neural inhibition. Cortical representations have previously been manipulated by disruptions in the inhibitory neurotransmitter {gamma}-aminobutyric acid (GABA). However, while facial tics are the most reported motor tic, it is unclear if facial sensorimotor representations differ in TS. MethodsSixteen individuals with Tourette Syndrome (TS) or chronic tic disorder and twenty typically developing (TD) control participants underwent 3-Tesla functional magnetic resonance imaging (fMRI). Blood-oxygenation level-dependent (BOLD) responses were measured during a block-design task comprising cued facial movements of common facial tics (blinking, grimacing and jaw clenching). Activations in bilateral pre- and post-central cortices and supplementary motor areas (SMA) were examined. Conjunction analyses identified voxels commonly and uniquely activated across movements within each group. ResultsBoth groups showed significant activations in the bilateral sensorimotor cortices and SMA in response to blink, grimace and jaw clench movements, with no significant between-group differences. Between-group similarities were lowest for unique blink maps. Common voxel maps also revealed low between-group similarity, with reduced sensorimotor activation and no shared SMA activation across movements in the TS group. ConclusionVoluntary facial sensorimotor representations do not differ between groups. However, low similarities between group unique blink maps may reflect greater prevalence of blinking tics in TS. Additionally, reduced overlap in sensorimotor activation and absent common SMA engagement across cued movements in the TS group may indicate altered motor integration or action initiation.

Alternative polyadenylation (APA) is a common posttranscriptional mechanism to regulate gene expression. APA generates mRNAs with varying lengths of 3' UTRs or transcripts that encode distinct protein carboxy-terminal ends. APA is especially important in neurons, where different mRNA variants are often asymmetrically localized to dendrites and axons, and can be locally translated into proteins. Local protein synthesis is crucial for axon guidance, synaptic plasticity, and learning and memory, key processes associated with the development of alcohol use disorder (AUD). We investigated the role of APA in AUD using a mouse model of alcohol dependence characterized by increased voluntary drinking after chronic intermittent ethanol (CIE) exposure. We examined APA during protracted withdrawal from alcohol in three brain regions of male and female mice. Our analyses revealed hundreds of genes undergoing APA in males, but substantially fewer in females, suggesting sex-specific effects of CIE on APA. Notably, male and female mice displayed distinct APA signatures. APA genes were different from differentially expressed genes (DEGs), suggesting that these molecular processes are regulated independently. We also determined that the expression of APA genes was associated with neurons, while DEGs were associated with non-neuronal cells. Many of the APA genes were involved in synaptic integrity, neuroplasticity, and neuronal maintenance, which was consistent with their enrichment in neurons. Our study suggests that APA is a crucial sex- and cell type-specific mechanism in AUD with the potential to influence localized neuronal protein expression during protracted withdrawal and to modify alcohol consumption behavior. HIGHLIGHTSO_LIChronic ethanol exposure in mice results in profound changes of APA genes in brain. C_LIO_LICommonly regulated cleavage and polyadenylation sites and genes were identified in male but not in female mice. C_LIO_LIThere was a minimal overlap between APA and differentially expressed genes (DEGs). C_LIO_LIAPA genes were primarily associated with neurons, whereas DEGs were associated with non-neuronal cells. C_LI

Cognitive flexibility, switching behaviour responses to changing task demands, is classically attributed to the prefrontal cortex. Yet thalamocortical circuits involving the mediodorsal thalamus (MD) and thalamic nucleus reuniens (Re) are dysfunctional across a range of neurological conditions with cognitive flexibility deficits. Interventions involving thalamocortical interactions may offer therapeutic benefits. Here we examined the effects of MD or Re bilateral glutamatergic neurotoxic damage in rats on cognitive flexibility using the attentional set-shifting task. Rats must attend to a sensory dimension that reliably predicts reward (intradimensional shift, ID) followed by a shift in attention to a previously irrelevant sensory dimension when contingencies change (extradimensional shift, ED). We found MD rats required more trials to criterion in the ED, while Re rats showed significant impairments on the first of three ID subtasks (ID1) only. Both MD and Re rats required more trials to criterion to complete each subtask than Sham controls. Intraperitoneal noradrenaline (atipamezole 1mg/kg), given 30 minutes prior to the task reduced trials to criterion across all rats, improving cognitive flexibility even after thalamic damage. These findings demonstrate the influence MD and Re contribute to cognitive flexibility and support noradrenergic regulation of thalamocortical circuits as potential therapeutic targets for cognitive flexibility dysfunction.

Stroke impairs dexterous hand use in daily activities, which may be due to compromised coordination complexity and diminished task-appropriate and individually-distinctive coordination (expressiveness). This loss of complexity and expressiveness, however, has not been elucidated, especially in spatiotemporal coordination. Here, we characterized spatiotemporal coordination in able-bodied and post-stroke hands during finger individuation. We quantified coordination complexity and expressiveness using principal component analysis (PCA) and linear discriminant analysis of 3D isometric forces from all five fingers. Paretic fingers showed reduced complexity (number of PCs) and expressiveness (task-, individual-, and group-specificity), which was associated with greater intrusion of flexor bias in the paretic hand. Higher-variance PCs were characteristic of tasks and groups, while both higher- and lower-variance PCs were characteristic of individual-specific coordination. These findings advance understanding of how stroke affects finger coordination complexity and expressiveness, and may inform the development of targeted therapies to improve task-relevant and individually distinctive coordination post-stroke.

Serotonin is one of the main neuromodulators in the brain, involved in regulating mood, complex behaviors and sensory input. Serotonin reaches primary somatosensory cortex (S1) via axons of neurons located in the dorsal raphe nucleus (DRN). DRN neurons can be modulated, amongst others, by reward, sensory stimulation, or movement but the activity pattern of serotonergic neurons targeting S1 is not known. Therefore, it is unclear under which circumstances serotonin is released in S1. Here, we expressed GCaMP8 in serotonergic neurons of the DRN to analyze the activity of their axons in S1 using two-photon Ca2+-imaging. Cluster analysis of axonal activities suggests that one to four functional groups of serotonergic axon segments project to a 0.3 mm2 horizontal plane of S1. We show that activity in serotonergic axons is strongly driven by reward and weakly by sensory stimulation of the whiskers. Movement, however, is preceded by a modulation, up and down, of the serotonergic signal seconds before the running onset. In summary, rewards and sensory stimulation lead to activity in serotonergic axons which is likely to adjust signal processing in S1 upon these events. The serotonergic signal changes seconds before movement onset probably preparing the neural network in S1 for the state change that accompanies running.

Mental fatigue is known to impair cognitive and motor performance, but its impact on motor learning remains unclear. This study examined how mental fatigue affects skill acquisition in a sequential finger-tapping task. Twenty-eight participants were assigned to either a mental fatigue group, which completed a thirty-minute Stroop task, or a control group, which watched a documentary of equivalent duration. Both groups then trained on the finger-tapping task across multiple practice blocks with brief rest periods. Overall motor skill improved similarly in both groups. However, mental fatigue altered the pattern of acquisition: participants in the fatigue group showed decreased performance during practice blocks, which was compensated by larger gains during inter-block rest periods. A strong negative correlation was observed between online decrements and offline improvements, indicating that greater declines during practice were associated with larger gains during rest. This study highlights the critical role of rest periods in maintaining learning under cognitively demanding conditions and provides insight into how internal states, such as mental fatigue, can selectively influence the expression of performance without compromising overall learning.

Hierarchy in the brain emerges across spatial and temporal scales, enabling transformations from rapid sensory encoding to sustained cognitive control. Hierarchical gradients are well established in sensory systems. In contrast, the hierarchical organization of the primate motor cortex remains debated, partly due to its agranular architecture and the absence of clear laminar input-output projections, that obscures the distinction between feedforward and feedback pathways. In particular, the relative hierarchical position of the dorsal premotor cortex (PMd) and the primary motor cortex (M1) cannot be resolved from anatomy alone. To investigate their relative organization, we here adopted a multimodal approach using intrinsic timescales derived from both single-unit spiking activity (SUA) and local field potentials (LFPs) in macaques performing a delayed-match-to-sample reaching task. We found convergent evidence for inter-areal temporal hierarchy, with longer spiking timescales and smaller LFP aperiodic spectral exponents in M1. Across cortical depth, however, temporal organization depended on signal modality. LFP spectral exponents were significantly smaller in deep than superficial layers in both areas, and LFP-autocorrelation timescales were longer in deep layers in M1. In contrast, spiking activity did not show significant laminar differences in intrinsic timescales. Functionally, neurons with longer timescales exhibited more stable representations of the planned movement direction during motor preparation in PMd and slower temporal evolution of movement encoding during execution in both areas. In conclusion, multimodal temporal measures converge on the same hierarchical organization across these two motor areas, with M1 placed higher than PMd. Our study provides the first characterization of intrinsic spiking timescales across cortical layers in any cortical area and shows that laminar temporal organization depends on the neural signal analyzed. This divergence likely reflects their distinct physiological origins. Spikes capture neuronal output, whereas LFPs primarily reflect synaptic and dendritic population activity, potentially integrating differential contributions from apical and basal dendritic inputs.

Information about eye movements is necessary for linking auditory and visual information across space. Recent work has suggested that such signals are incorporated into processing at the level of the ear itself (Gruters, Murphy et al. 2018). Here we report confirmation that the eye movement signals that reach the ear can produce perceptual consequences, via a case report of an unusual participant with tensor tympani myoclonus who hears sounds when she moves her eyes. The sounds she hears could be recorded with a microphone in the ear in which she hears them (left), and occurred for large leftward eye movements to extreme orbital positions of the eyes. The sounds elicited by this participants eye movements were reminiscent of eye movement-related eardrum oscillations (EMREOs, (Gruters, Murphy et al. 2018, Brohl and Kayser 2023, King, Lovich et al. 2023, Lovich, King et al. 2023, Lovich, King et al. 2023, Abbasi, King et al. 2025, Sotero Silva, Kayser et al. 2025, King and Groh 2026, Leon, Ramos et al. 2026, Sotero Silva, Brohl et al. 2026)), but were larger and longer lasting than classical EMREOs, helping to explain why they were audible to her. Overall, the observations from this patient help establish that (a) eye movement-related signals specifically reach the tensor tympani muscle and that (b) when there is an abnormality involving that muscle, such signals can lead to actual audible percepts. Given that the tensor tympani contributes to the regulation of sound transmission in the middle ear, these findings support that eye movement signals reaching the ear have functional consequences for auditory perception. The findings also expand the types of medical conditions that produce gaze-evoked tinnitus, to date most commonly observed in connection with acoustic neuromas.

The rat vestibular system plays a critical role in anti-gravity responses such as the tail-lift reflex and the air-righting reflex. In a previous study in male rats, we obtained evidence that these two reflexes depend on the function of non-identical populations of vestibular sensory hair cells (HC). Here, we caused graded lesions in the vestibular system of female rats by exposing the animals to several different doses of an ototoxic chemical, 3,3-iminodipropionitrile (IDPN). After exposure, we assessed the anti-gravity responses of the rats and then assessed the loss of type I HC (HCI) and type II HC (HCII) in the central and peripheral regions of the crista, utricle and saccule. As expected, we recorded a dose-dependent loss of vestibular function and loss of HCs. The relationship between hair cell loss and functional loss was examined using non-linear models fitted by orthogonal distance regression. The results indicated that both the tail-lift reflex and the air-righting reflexes mostly depend on HCI function. However, a different dependency was found on the epithelium triggering the reflex: while the tail-lift response is sensitive to loss of crista and/or utricle HCIs, the air-righting response rather depends on utricular and/or saccular integrity.

Clarifying the mechanisms underlying the emergence of consciousness remains a fundamental challenge in modern neuroscience. Integrated Information Theory (IIT) provides a mathematical framework derived from the phenomenological properties of consciousness as its axioms. IIT proposes that consciousness is identical to a systems intrinsic cause-effect information structure, quantified by integrated information {Phi}. While IIT predicts that the {Phi} of a neuronal system should decrease during the loss of consciousness, this hypothesis has remained untested at the neural circuit level. The present study provides empirical support for this IIT prediction. It was found that {Phi} within local circuits decreases during non-rapid-eye-movement (NREM) sleep compared to wakefulness and REM sleep, independent of cortical laminar structure or firing rates or regions. The reduction in {Phi} was particularly pronounced during off-periods, when neural activity is collectively suppressed. These results imply that consciousness is an information structure that cannot be reduced to the properties of individual system elements (such as firing rates), and that its collapse is fundamentally linked to the loss of consciousness. The findings provide critical empirical support for IIT as a mathematical theory aiming to explain conscious experiences. Significance StatementThis study bridges the gap between abstract mathematical theories of consciousness and high-resolution neurophysiology. According to Integrated Information Theory (IIT), conscious existence depends on a systems intrinsic cause-effect structure. By analyzing neural population activity, this study demonstrates that the transition from wakefulness to NREM sleep is characterized by a reduction in integrated information ({Phi}) within local circuits. This reduction is most pronounced during NREM off-periods, where causal integration is effectively severed, leading to a breakdown of the systems intrinsic information structure. These findings provide a neural foundation for IIT and suggest that consciousness is underpinned by specific, irreducible cause-effect structures within the brain.

Eye movement-related eardrum oscillations (EMREOs) appear to consist of a pulse of oscillation occurring in conjunction with saccades. However, this apparent pulse could occur either because there is an increase in energy at that frequency at the time of saccades (a true pulse), or because there is saccade-related phase resetting of ongoing energy at that frequency band, thus appearing like a pulse when averaged in the time domain across many trials. Here we conducted a spectral analysis at the individual trial level in humans performing a visually guided saccade task to determine whether the power at the EMREO frequency (30-45 Hz) is higher during saccades than during steady fixation. We found both an increase in sound power in the EMREO frequency band associated with saccades, i.e. sound pulses at the individual trial level, as well as, phase resetting at saccade onset/offset. While both factors contribute to the apparently pulse-like EMREO signal, phase resetting appears to be more prevalent across participants. The prevalence of phase resetting has implications for the underlying mechanism(s) producing EMREOs as well as functional consequences for how the ear might respond to incoming sound in an eye-position dependent fashion.

The advent and widespread uptake of combination antiretroviral therapy dramatically changed the epidemiological features of human immunodeficiency virus type 1 (HIV-1), whereby older individuals (>50 years of age) account for approximately 50% of HIV-1 seropositive individuals in the United States. Nevertheless, to date, there is no extant in vivo biological system to model the unique age-related neurocognitive impairments observed in HIV-1 seropositive individuals. Herein, the utility of the HIV-1 transgenic (Tg) rat as a biological system to model age-related neurocognitive impairments and neuroanatomical alterations was evaluated. Older adult HIV-1 Tg rodents (i.e., >12 months of age upon testing initiation), relative to their control counterparts, exhibited profound neurocognitive alterations characterized by impairments in stimulus-reinforcement learning, sustained attention, and selective attention; neurocognitive deficits which support a fundamental distortion of temporal processing. Neuronal dysfunction in older adult HIV-1 Tg animals was characterized by structural alterations in pyramidal neurons, and their associated dendritic spines, in the medial prefrontal cortex and abnormal accumulation of amyloid beta (A{beta}). Interestingly, the abnormal accumulation of A{beta} mechanistically underlies, at least in part, the profound dendritic spine dysmorphology in male, but not female, HIV-1 Tg rats. More critically, however, neuronal dysfunction mechanistically underlies neurocognitive impairments in both male and female HIV-1 Tg rodents, whereby neuronal dysfunction accounts for 65.4% and 60.8% of the variance in neurocognitive function, respectively. Establishing the utility of the HIV-1 Tg rat for age-related neurocognitive impairments is fundamental to disentangling the role of HIV-1 viral proteins and comorbidities in neurocognitive function.

Although a differential vulnerability of dopaminergic neurons to degeneration based on their specific location within the dorsal and ventral tiers of the substantia nigra pars compacta (SNcD and SNcV, respectively) has long been postulated, the underlying mechanisms sustaining these tier-specific differences remain poorly understood. Here, upon inducing a viral-mediated enhancement of neuromelanin (NMel) accumulation within dopaminergic neurons in non-human primates, the distribution of Lewy body-like inclusions (LBs) was analyzed within identified SNcD and SNcV neurons, together with their intracellular NMel levels. Results showed that the vast majority of intracytoplasmic inclusions were found in SNcV neurons, and indeed correlated to higher pigmentation levels. By contrast, only very few LBs were found in calbindin-positive neurons of the SNcD, which in parallel exhibited very low levels of NMel accumulation. These results postulate an additive effect made of a tier-specific location of LB burden together with high pigmentation levels as synergistic drivers sustaining the preferential vulnerability of SNcV dopaminergic neurons. Moreover, the evidence obtained here supported that NMel accumulation beyond a given threshold triggers the aggregation of endogenous -Syn in the form of LBs; therefore, approaches intended to reduce pigmentation levels in SNcV neurons would likely induce a neuroprotective effect by preventing the subsequent aggregation of -Syn.

Neuromuscular reflexes elicited by sensory nerve stimulation provide valuable insights into neural motor control pathways. Analysis at the level of individual motor units (MUs) is feasible via electromyographic decomposition, but the factors shaping MU-specific reflex responses remain poorly understood. We investigated long-latency responses to cutaneous electrical stimulation in a large population of tibialis anterior MUs from nine healthy subjects during isometric ankle dorsiflexion at 10-30% of maximum voluntary contraction. Individual MU reflex responses differed markedly. Using 1000 stimulation pulses per trial, substantially more than the 150-300 typically reported in previous studies, provided more reliable estimates of cutaneous reflex characteristics. Across the motor pool, reflex magnitude increased with force level (p < 0.001) while excitation probability correlated significantly with MU recruitment threshold in 78% of subjects (p = 0.012). Furthermore, excitation probability increased systematically with contraction intensity (p < 0.001) for individually tracked MUs. Post-excitatory depression (PED) magnitude correlated significantly with excitation probability (r = 0.50, p < 0.001) of individual MUs. A targeted reflex-removal analysis, validated by MU simulations incorporating realistic excitation probabilities into ordinary firing patterns, reduced the PED by 84.2% in simulated data but only by 34.7% in recorded units. These findings suggest that the PED is a complex, hybrid phenomenon, resulting from synchronization-induced discharge resetting and additional independent inhibitory components. These findings demonstrate that MU-level reflex excitability to somatosensory input is influenced by state- and identity-dependent motor neuron characteristics, underscoring the importance of using sufficient stimulation pulses for reliable reflex measures and MU population analysis.

Identifying the neural circuits engaged and reshaped by chronic stress is critical for understanding how adaptive responses shift to maladaptive behaviors that contribute to stress-related disorders. Our previous work demonstrates that chronic unpredictable stress (CUS) induces a persistent increase in the firing activity of proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC). This hyperactivity is due, in part, to a reduction in GABAergic synaptic transmission onto POMC neurons, indicating a disruption in inhibitory control. However, the sources of GABAergic inputs responsible for this effect of chronic stress are unknown. Although AgRP neurons provide local GABAergic input onto POMC neurons and are suppressed by chronic stress, chemogenetic activation of AgRP neurons during stress exposure failed to reduce POMC neuron hyperactivity. GABAergic projections originating from the dorsomedial hypothalamus (DMH) represent another source of inhibitory input to POMC neurons. We found that CUS decreased the firing activity of DMH GABAergic neurons with sex differences, with females exhibiting greater vulnerability to stress-induced suppression. Chemogenetic activation of these neurons during chronic stress markedly attenuated POMC neuron hyperactivity in both sexes, indicating that DMH GABAergic neurons function as a critical upstream regulator of POMC neuron activity under chronic stress. These findings suggest that reduced inhibitory input from DMH GABAergic neurons, rather than local GABAergic AgRP neurons, drives POMC neuron hyperactivity. The weakening of the DMHGABA[-&gt;]ARCPOMC circuit activity may represent a novel mechanism underlying maladaptive stress responses and a potential therapeutic target for stress-related disorders.