While attention distraction alleviates pain and negative affect, the underlying neural circuits remain unclear. Here, we show that novelty exposure, a means to attract attention, significantly alleviates acute and chronic pain in mice. Using a Fos-driven viral strategy, we identified a lateral hypothalamus (LH) neuronal ensemble activated during novelty exploration. This novelty ensemble also responds to pain- and anxiety-like stimuli. Activation of this ensemble produces analgesic and anxiolytic effects, whereas its inhibition exacerbates pain and anxiety-like behavior in mouse pain models. The LH ensemble comprises both GABAergic and glutamatergic subpopulations, both contributing to pain and anxiety modulation. However, activating their specific projections to the lateral preoptic area, lateral habenula, ventral tegmental area, and lateral periaqueductal gray regulates pain and anxiety in distinct patterns. Together, we define an LH novelty-activated neuronalsubpopulation mediating the analgesic and anxiolytic benefits of novelty exposure, revealing circuit-specific targets for relieving pain and anxiety.

The hypothalamus is a key structure in the human brain, comprising numerous functionally distinct subnuclei that regulate critical physiological processes such as energy balance, stress response, and circadian rhythms. Due to the complexity and functional diversity of its subregions, precise segmentation is essential for elucidating its operational mechanisms. This review systematically summarizes hypothalamic segmentation methods and their applications in physiological and clinical research. Current approaches are categorized into two complementary types: anatomy-based manual segmentation and deep learning-based fully automated segmentation. The former provides a gold standard for algorithm validation through expert knowledge, enabling accurate identification of key functional subregions; the latter offers an efficient solution for large-scale studies, facilitating in-depth exploration of the hypothalamus's heterogeneous functional architecture. The review also highlights major challenges in the field, including the lack of unified segmentation protocols-which hinders cross-study comparability-and a significant methodological gap in pediatric population studies. Moving forward, it is crucial to establish standardized segmentation workflows, reduce subjective bias, improve reproducibility, and address the technical shortcomings in hypothalamic segmentation for children, thereby laying a foundation for comprehensively understanding the structure and function of this critical brain region.ABBREVIATIONS: ARC＝ arcuate nucleus; PVN＝ paraventricular nucleus; VM＝ ventromedial nucleus; DM＝ dorsomedial hypothalamic nucleus; SCh＝ suprachiasmatic nucleus; LH＝ lateral hypothalamus.

The neurocircuitry changes mediating the development and maintenance of an alcohol use disorder are complex and dynamic. The parasubthalamic nucleus (PSTN), a small nucleus of the posterior lateral hypothalamus best known for suppressing appetite, is interconnected with brain regions disrupted in addiction; yet its potential role in the regulation of alcohol consumption had never been examined. Here we show that the PSTN exerts potent control over alcohol drinking in mice. Remarkably, the influence of endogenous PSTN activity on voluntary alcohol consumption switches from inhibitory to stimulatory upon induction of alcohol dependence. Among PSTN cells, Crh neurons represent a unique subpopulation that promotes alcohol drinking and fires more in dependent mice. Alcohol intake escalation driven by PSTN Crh neurons involves thalamic output and behavioral disinhibition. Based on our results, PSTN Crh neurons could represent a critical node in the brain circuitry overactive in alcohol addiction driven by reward seeking in humans.

Neuropeptide S alleviates neuropathic pain through lateral hypothalamic orexinergic circuit in rats.

Social experience affects patterns of vasopressin receptor 1a expression in a way that differs by sex.

The activity of D2 dopamine receptors of the ventral tegmental area changed the induced- cognitive responses of the lateral hypothalamic cholinergic stimulation following neuropathic pain.

Dysfunction of the Locus coeruleus (LC), a small brainstem nucleus which consists a primary source of norepinephrine, is linked to various neurological and psychiatric disorders. Light exposure influences many non-image-forming (NIF) biological functions including those modulated by LC activity. Yet direct evidence of light-driven modulation of the LC has remained elusive due to the small size of the structure and deep location. Using ultra-high-field (7 Tesla) functional MRI during an emotional task under varying illuminances, we demonstrate that light modulates LC activity in an emotion-dependent manner. We show that increased illuminance dampens LC responses to negative emotional stimuli while enhancing responses to neutral stimuli. Furthermore, we provide tentative evidence that within an emotional context, light may affect LC activity through the basomedial nucleus of the amygdala as well as through a region of the hypothalamus encompassing the lateral hypothalamus. These findings open avenues for the development of targeted, non-pharmacological treatments leveraging light to modulate norepinephrine tone and/or LC activity in several neuropsychiatric disorders.

The hypothalamus is a critical central hub for regulating sleep-wake patterns in organisms, maintaining the balance between daily activity and rest by modulating sleep-wake-related neural circuits. This article reviews research on hypothalamus-mediated neural circuits involved in sleep-wake regulation. Studies demonstrate that activating specific neuronal subtypes in the lateral hypothalamic area (LHA), paraventricular nucleus of the hypothalamus (PVH), supramammillary nucleus (SuM), preoptic area (POA) and its subregions, and dorsomedial hypothalamic nucleus (DMH) can induce sleep or wakefulness through distinct circuit mechanisms. At the same time, the limitations of the traditional sleep-wake flip-flop model are discussed, along with the supplements and hypotheses. Multiple hypothalamic nuclei form extensive connections with other brain regions, collectively establishing a sophisticated neural architecture that drives wakefulness and stabilizes sleep. This finely tuned regulatory system enables precise control of sleep-wake states, offering foundational insights into the neural mechanisms of sleep-wake transitions and informing potential therapeutic strategies for sleep disorders.

Hyperactivity is a persistent and clinically relevant symptom in anorexia nervosa (AN). Hyperactivity is inversely correlated with leptin levels. While systemic leptin administration attenuates hyperactivity in rodent models, the specific brain regions mediating this effect remain unclear. Leptin acts on different brain areas involved in energy expenditure and motivation, including the ventral tegmental area (VTA), substantia nigra (SN) and lateral hypothalamus (LH). The present study aimed to determine through which of these regions leptin mediates its suppressive effects on hyperactivity, reflected in rodent models as compulsive running, in the Activity-Based Anorexia (ABA) model. To identify the neural substrates of leptin's behavioural effects, female Wistar rats were stereotactically cannulated targeting the VTA, SN, or LH. Animals were subjected to the ABA paradigm, and site-specific leptin (300ng) or vehicle infusions were administered just before the onset of compulsive running. Running wheel activity (RWA), food intake, and body weight were assessed. Pooled analyses identified the SN, LH, and VTA as functionally relevant nodes where leptin administration significantly reduced compulsive running. While leptin also attenuated the compensatory increase in food intake across all three regions, the robust suppression of running compared to the more modest effects on feeding suggests a partial functional dissociation within this distributed network. These findings indicate that leptin modulates compulsive running and feeding through a distributed neural network rather than a single discrete locus. The identification of the SN and LH as novel targets for the suppression of compulsive running provides a first mapping of the neural substrates underlying leptin's regulation of hyperactivity.

Internal states including stress and satiety, affect cue-induced feeding behaviors, yet the underlying neural mechanisms remain poorly understood. The nucleus of the solitary tract (NTS), a key hindbrain hub that integrates interoceptive and viscerosensory signals and projects to reward processing nuclei, is anatomically well-positioned to modulate cue-induced feeding behaviors in response to internal state changes. Using behavioral paradigms combined with chemogenetics and fibre photometry, this study investigated the hypothesis that NTS mediates the effects of stress and satiety on cue-induced feeding behaviors via A2 neurons and modulation of ventral tegmental area (VTA) dopamine signaling. We first showed that both foot shock stress and outcome specific satiety (i.e., sucrose prefeed) reduced cue-induced appetitive behavior. Inhibition of NTS neurons only attenuated the suppressive effect of foot shock stress, but not that of outcome specific satiety, indicating that NTS is required for stress-induced suppression of cue-induced appetitive behavior. Further investigation into the contributing neural phenotype revealed that stimulation of NTS A2 neurons reduced conditioned approach and suppressed cue-evoked VTA dopamine neural activity, without any effects on lateral hypothalamus (LH) neuron activity. Together, these findings suggest that NTS neurons mediate the effects of foot shock stress, but not outcome specific satiety, on cue-induced appetitive behavior, in part through activation of NTS A2 neurons and modulation of cue-evoked VTA dopamine neural activity. These results provide an NTS-mediated mechanism through which stress suppresses cue-induced feeding behavior.

BACKGROUND: Glutamatergic neurons in the medial septum (MS) are identified to promote emergence from sevoflurane general anesthesia (GA), with the potential downstream neural circuit remaining to be explored. METHODS: Rabies virus (RV)-mediated monosynaptic retrograde tracing and anterograde tracing were first used to identify the projection from glutamatergic MS neurons (MS Glu ) to glutamatergic neurons in the lateral hypothalamus (LH, LH Glu ). In vivo fiber photometry, optogenetic bidirectionally manipulations, electroencephalogram/electromyogram (EEG/EMG), and behavioral tests were further employed to investigate the role of the circuit from MS Glu neurons to the LH (MS Glu -LH circuit) in regulating states of consciousness under two different states of sevoflurane GA: continuous, steady-state general anesthesia (CSSGA) and burst-suppression (BS) oscillations. RESULTS: The retrogradely labeled upstream neurons of LH Glu neurons were extensively detected in the MS, and most RV-infected neurons in the MS were co-labeled by Vesicular glutamate transporter 2 (Vglut2, mean ± standard error of the mean [SEM], 86.3% ± 1.5%, n = 4 mice). And the MS Glu -LH Glu circuit constitutes the highest proportion among the three downstream LH neuronal populations (presynaptic boutons co-localized ratio: glutamatergic, 77.0% ± 2.2%; γ-aminobutyric acid-ergic, 59.6% ± 0.9%; orexinergic, 28.5% ± 2.0%; n = 4 mice). The calcium activity of the MS Glu -LH circuit was inhibited concurrently as the process of loss of consciousness during 2.4% sevoflurane induction. Optogenetic activation of the MS Glu -LH circuit promoted behavioral arousal and increased β power of EEG (stimulation vs pre-stimulation, 16.8% ± 2.3% vs 9.7% ± 1.7%, P =.0065; n = 8 mice) during CSSGA. In contrast, during CSSGA, optogenetic inhibition of the MS Glu -LH projection deepened cortical inhibition, characterized by increased δ power and decreased power of β and γ (inhibition vs pre-inhibition, δ: 62.4% ± 4.5% vs 55.3% ± 4.2%, P =.0404; β: 6.7% ± 0.8% vs 9.4% ± 1.3%, P =.0069; γ: 3.3% ± 0.6% vs 4.8% ± 0.8%, P =.0076; n = 8 mice). Optogenetic bidirectionally manipulations of the MS Glu -LH circuit induced similar effects during BS: activation of this projection resulted in cortical activation with decreased burst-suppression ratio (BSR; median [25%–75% percentiles], stim vs pre, 59.0% [43.8%–64.5%] vs 77.5% [74.0%–84.3%], P =.0121; n = 8 mice), while inhibition of this projection led to cortical inhibition with increased BSR (inhib vs pre, 76.1% ± 7.0% vs 64.5% ± 8.4%, P =.0382; n = 8 mice). CONCLUSIONS: This study reveals that activation of the glutamatergic MS-LH circuit promotes emergence from sevoflurane GA.

Pubertal development is associated with changes in hypothalamic-pituitary-adrenal (HPA) axis reactivity, which may contribute to the increase in stress-related vulnerabilities observed during adolescence. In particular, prepubertal rats show significantly protracted stress-induced HPA responses compared to adults. However, the neuroendocrine mechanisms responsible for this developmental change are unclear. In adults, the orexigenic neuropeptide orexin-A has been shown to be a potent modulator of HPA reactivity, and activation of orexin-A neurons aligns with the magnitude of the hormonal stress response. However, it is currently unknown whether pubertal differences in HPA reactivity are associated with changes in orexin-A neurons. We examined the hormonal stress response and the number of activated orexin-A neurons in the lateral hypothalamus by co-labeling with c-Fos, a marker of cellular activation, before, during, or after stress exposure in prepubertal (30d) and adult (70d) male and female rats. The number of immunoreactive orexin-A neurons was also quantified in prepubertal (30d), mid-pubertal (45d) and adult (70d) males and females. We found significantly prolonged stress-induced hormonal responses in prepubertal males and females compared to their adult counterparts. However, we found no developmental differences in either the number of orexin-A cells or their stress-induced activation in either sex. These data suggest minimal association between stress-induced activity of orexin-A neurons and pubertal-related differences in hormonal stress reactivity. However, these data indicate that the number of orexin-A cells is relatively stable throughout adolescent development, and that orexin-A neurons are sensitive to stressors prior to pubertal maturation.

Hypoxia can be classified into two types based on its temporal characteristics: acute hypoxia and chronic hypoxia, posing a severe threat to the physiological homeostasis of the body. Hypoxia stimulates peripheral chemoreceptors and activates compensatory responses in the autonomic nervous system and cardiopulmonary functions. These responses rely on coordinated regulation by the carotid body and multiple nuclei in the central nervous system. Through specific neural pathways and molecular mechanisms, the body adapts to hypoxia and sustains survival. However, severe hypoxia may lead to irreversible damage or asphyxiation. In this review, we discuss recent research on central neural circuits and molecular changes in nuclei induced by hypoxia. It focuses on key regions associated with hypoxia, including the nucleus of the solitary tract, retrotrapezoid nucleus, rostral ventral lateral medulla, parabrachial nucleus, and hypothalamic paraventricular nucleus. From a neuroscience perspective, it elaborates on the effects of hypoxia on respiratory, cardiovascular, and other bodily functions. This understanding may help guide the treatment of hypoxia-related clinical diseases. JOURNAL/mgres/04.03/01612956-990000000-00093/figure1/v/2026-04-11T111231Z/r/image-tiff.

Visual attention enables filtering of irrelevant stimuli and focus on information that is most pertinent to survival. While the locus coeruleus-noradrenaline (LC-NA) system is recognized as crucial in this process, the role of temporally structured NA signaling in visual attentional performance remains unsettled. Here, by using the genetically encoded NA sensor GRABNE2h together with fiber photometry in mice, we identify sub-second NA release signatures in the medial prefrontal cortex (mPFC) that correlate with visual attention accuracy in the rodent Continuous Performance Test (rCPT). The dual-peak release signatures were time-locked to correct, rewarded responses, preceded by a ramp-up after stimulus presentation and followed by a decline at reward collection. No such signatures accompanied misses, correct rejections and mistakes. Similar, albeit less pronounced, patterns were observed in the lateral hypothalamus (LH). Activation of the Gq-coupled DREADD (Designer Receptors Exclusively Activated by Designer Drugs) hM3DGq expressed in LC neurons dose-dependently increased tonic NA levels in both mPFC and LH, while simultaneously distorting phasic NA signatures and impairing rCPT performance without affecting locomotor activity. Summarized our data suggest that NA enhances alertness to reward-associated stimuli through precise, dynamic release patterns underscoring its role in modulating attentional performance beyond tonic signaling.

The lateral hypothalamic area (LHA) is well-known for its conserved role in modulating and driving many forms of innate behaviors, yet the cellular diversity underlying these functions remains incompletely understood. Although neurons expressing the neuropeptide thyrotropin-releasing hormone (TRH) in the hypothalamic paraventricular nucleus have been well-characterized for their hypophysiotropic functions and role in metabolism and feeding behavior, other hypothalamic TRH-expressing neurons, such as those located in the LHA, have received comparatively little attention. Here, using a viral-targeting approach in a Trh-ires-Cre mouse, we probe the anatomical and electrophysiological properties of TRH-expressing neurons in the LHA (LHATRH). We find that LHATRH neurons make both ascending and descending axonal projections throughout the brain, with particularly dense projections to the regions of the dorsal lateral septum, lateral preoptic, basal forebrain, and dorsal premammillary nuclei. We further define the active and passive membrane properties of LHATRH neurons in slices, as well as the morphology of filled neurons. We find that the distinguishing features of LHATRH neurons, in contrast to intermingled hypocretin/orexin-expressing neurons, are capable of anode-break bursting in a majority of neurons and exhibit rhythmic spontaneous bursting in a smaller subset of neurons. We further compare the electrophysiological features of both anode-break bursting and nonbursting LHATRH neurons, as well as determining that anode-break bursting is mediated by T-type calcium channels. Our work defines both the intrinsic membrane properties, morphology and axonal projections of LHATRH neurons, providing a foundation for understanding their roles in physiology and behavior.NEW & NOTEWORTHY This work provides the first characterization of the axonal projections and distinctive electrophysiological properties that define thyrotropin-releasing hormone (TRH)-expressing neurons in the mouse lateral hypothalamic area (LHA) in acute brain slices. We find that a large majority of LHA TRH neurons exhibit robust rebound burst firing, with a smaller subpopulation exhibiting spontaneous rhythmic burst firing. Together, these findings advance our understanding of how LHA TRH neurons may contribute to regulating physiology and behavior.

The intermediolateral column (IML) serves as a crucial hub for sympathetic information processing between the brain and peripheral organs, with its defining hallmark being the presence of cholinergic neurons expressing choline acetyltransferase (ChAT). Specifically, the IML of the lower thoracic cord plays a pivotal role in regulating abdominal metabolic and digestive viscera. However, little is known about the whole-brain neural connectivity targeting these lower thoracic IML cholinergic neurons, necessitating further investigation. Specific retrograde tracing virus was injected into the lower thoracic IML of ChAT-Cre transgenic mice expressing Cre in the cholinergic neurons. After the virus has fully expressed, brain and spinal cord sections were prepared for whole-brain fluorescence imaging and quantitative analysis. We found that virally labeled neurons were detected in 40 brain regions of ChAT-Cre mice, encompassing the telencephalon, diencephalon, and brainstem. Afferents were predominantly concentrated in 25 brainstem regions, with the pons providing the highest total number of afferents and the medulla offering the highest afferent density across both hemispheres. Although a small subset of regions exhibited strictly unilateral inputs or hemispheric preference, the overall projection pattern remained bilateral. Furthermore, our results revealed extensive projections to the IML from regions classically implicated in sympathetic outflow regulation and homeostatic control, including the paraventricular hypothalamic nucleus (PVN), lateral hypothalamic area (LH), and rostroventrolateral reticular nucleus (RVLM). In addition, inputs were also observed from motor-related regions, such as primary and secondary motor cortices (M1, M2), red nucleus (RN), and gigantocellular reticular nucleus (Gi), suggesting a potential anatomical basis for the central coupling of somatic motor and sympathetic functions. Our study provides a comprehensive whole-brain anatomical map of inputs to lower thoracic IML cholinergic neurons. This extensive supraspinal network, integrating classical sympathetic and homeostatic centers with motor-related regions, suggests a potential anatomical basis for the central coordination of somatic motor and autonomic functions.

Antidepressant effect of blue light on depressive phenotype induced by the unfixed light pattern in mice.

Exposure to early life social complexity shapes vasopressin and galanin neural expression in the communal spiny mouse.

Lateral hypothalamus to dorsal raphe nucleus projections modulate intraspecific attack behavior in male mice.

Granular motivational interaction and behavioral choice during feeding.