Hypothalamic Circuits Research Articles

Brain receptor dynamics in early and adult life stress: Gateways to maladaptive coping strategies.

Stress plays a significant role in the onset of numerous psychiatric disorders. Depending on individual resilience or stressor's nature, long-term changes to stress in the brain can lead to a wide range of behavioral symptoms, including social withdrawal, feelings of helplessness, and emotional overeating. The brain receptor molecules are key mediators of these processes, translating neuromodulatory signals into neuronal responses or circuit activity changes that ultimately shape behavioral outcomes. Here, I highlight several of my previous studies that reveal the pivotal role of receptor molecules in critical brain regions such as the nucleus accumbens, lateral hypothalamus, and lateral septum. I identified how mGluR5 signaling in the nucleus accumbens promotes stress resilience through pathways involving ΔFosB and SRF, while leptin receptor or glucocorticoid receptor signaling within lateral hypothalamic circuits contributes to stress eating. Additionally, I uncovered the role of dopamine receptor 3 signaling in the lateral septum in mediating the impact of early life stress on social behaviors. These findings underscore the functional relevance of brain receptor molecules in transducing stress-from early life through adulthood-into maladaptive coping behaviors. As druggable targets, these receptor-mediated pathways provide a critical foundation for developing targeted interventions to alleviate stress-related psychiatric symptoms.

The Spiraling Cognitive-Emotional Brain: Combinatorial, Reciprocal, and Reentrant Macro-organization.

This article proposes a framework for understanding the macro-scale organization of anatomical pathways in the mammalian brain. The architecture supports flexible behavioral decisions across a spectrum of spatiotemporal scales. The proposal emphasizes the combinatorial, reciprocal, and reentrant connectivity-called CRR neuroarchitecture-between cortical, BG, thalamic, amygdala, hypothalamic, and brainstem circuits. Thalamic nuclei, especially midline/intralaminar nuclei, are proposed to act as hubs routing the flow of signals between noncortical areas and pFC. The hypothalamus also participates in multiregion circuits via its connections with cortex and thalamus. At slower timescales, long-range behaviors integrate signals across levels of the neuroaxis. At fast timescales, parallel engagement of pathways allows urgent behaviors while retaining flexibility. Overall, the proposed architecture enables context-dependent, adaptive behaviors spanning proximate to distant spatiotemporal scales. The framework promotes an integrative perspective and a distributed, heterarchical view of brain function.

Brain endocannabinoid control of metabolic and non-metabolic feeding behaviors.

The central endocannabinoid (eCB) system in brain shows a crucial role in the regulation of feeding behaviors, influencing both metabolic and non-metabolic mechanisms of appetite control, which has been paid much attention. Although there are already many review articles discussing eCB modulation of feeding behaviors, our paper attempts to summarize the recent advancements through synapses, circuits, and network in brain. Our focus is on the dual role of eCB signalling in regulating metabolic energy balance and hedonic reward-related feeding. In the context of metabolic regulation of feeding behaviors, eCBs affect the hypothalamic circuits that balance hunger and satiety through signal integration related to energy status and nutrient availability. Dysregulation of this system can contribute to metabolic disorders such as obesity and anorexia. In non-metabolic feeding, the eCB system influences the hedonic aspects of eating by modulating reward pathways, including the mesolimbic system and the olfactory bulb, critical for motivating food intake and processing sensory cues. This review also explores therapeutic strategies targeting the eCB system, including cannabinoid receptor antagonists and eCB hydrolase enzyme inhibitors, which hold promise for treating conditions associated with appetite dysregulation and eating disorders. By synthesizing recent findings, we aim to highlight the intricate mechanisms through which the eCB system affects feeding behavior and to propose future directions for research and therapeutic intervention in the realm of appetite control and eating disorders.

Treatment of Hypothalamic Obesity With GLP-1 Analogs.

Congenital and acquired damage to hypothalamic nuclei or neuronal circuits controlling satiety and energy expenditure results in hypothalamic obesity (HO). To date, successful weight loss and satiety has only been achieved in a limited number of affected patients across multiple drug trials. Glucagon-like peptide-1 (GLP-1) acts via central pathways that are independent from the hypothalamus to induce satiety. GLP-1 receptor agonists (GLP-1RAs) may provide an alternative approach to treating HO. We performed a comprehensive search in Medline, Google Scholar, and clinical trials registries (ClinicalTrials.gov; clinicaltrialsregister.eur). This nonsystematic literature review was conducted to identify scientific papers published from January 2005 to February 2024 using the Pubmed and Embase databases. Key words used were GLP-1, GLP-1RA, hypothalamic obesity, suprasellar tumor, and craniopharyngioma. Our search identified 7 case studies, 5 case series, and 2 published clinical trials relating to the use of GLP-1RAs in HO. All case studies demonstrated weight loss and improved metabolic function. In contrast, results from case series were variable, with some showing no weight loss and others demonstrating moderate to significant weight loss and improved metabolic parameters. In the ECHO clinical trial, nearly half the subjects randomized to weekly exenatide showed reduced body mass index (BMI). Paradoxically, BMI reduction was greater in patients with more extensive hypothalamic injuries. GLP-1RAs potentially offer a new approach to treating HO. There is a need to stratify patients who are more likely to respond. Further randomized controlled trials are required to determine their efficacy either in isolation or combined with other therapies.

Early perturbations to fluid homeostasis alter development of hypothalamic feeding circuits with context-specific changes in ingestive behavior.

Drinking and feeding are tightly coordinated homeostatic events and the paraventricular nucleus of the hypothalamus (PVH) represents a possible node of neural integration for signals related to energy and fluid homeostasis. We used TRAP2;Ai14 and Fos labeling to visualize neurons in the PVH and median preoptic nucleus (MEPO) responding to both water deprivation and hunger. Moreover, we determined that structural and functional development of dehydration-sensitive inputs to the PVH from the MEPO precedes those of agouti-related peptide (AgRP) neurons, which convey hunger signals and are known to be developmentally programmed by nutrition. We also determined that osmotic hyperstimulation of neonatal mice led to enhanced AgRP inputs to the PVH in adulthood, as well as disruptions to ingestive behaviors during high-fat diet feeding and dehydration-anorexia. Thus, development of feeding circuits is impacted not only by nutritional signals, but also by early perturbations to fluid homeostasis with context-specific consequences for coordination of ingestive behavior.

A hypothalamic circuit mechanism underlying the impact of stress on memory and sleep.

Stress profoundly affects sleep and memory processes. Stress impairs memory consolidation, and similarly, disruptions in sleep compromise memory functions. Yet, the neural circuits underlying stress-induced sleep and memory disturbances are still not fully understood. Here, we show that activation of CRHPVN neurons, similar to acute restraint stress, decreases sleep and impairs memory in a spatial object recognition task. Conversely, inhibiting CRHPVN neurons during stress reverses stress-induced memory deficits while slightly increasing the amount of sleep. We found that both stress and stimulation of CRHPVN neurons activate neurons in the lateral hypothalamus (LH), and that their projections to the LH are critical for mediating stress-induced memory deficits and sleep disruptions. Our results suggest a pivotal role for CRHPVN neuronal pathways in regulating the adverse effects of stress on memory and sleep, an important step towards improving sleep and ameliorating the cognitive deficits that occur in stress-related disorders.

The Downregulation of the Liver Lipid Metabolism Induced by Hypothyroidism in Male Mice: Metabolic Flexibility Favors Compensatory Mechanisms in White Adipose Tissue

In mammals, the maintenance of energy homeostasis relies on complex mechanisms requiring tight synchronization between peripheral organs and the brain. Thyroid hormones (THs), through their pleiotropic actions, play a central role in these regulations. Hypothyroidism, which is characterized by low circulating TH levels, slows down the metabolism, which leads to a reduction in energy expenditure as well as in lipid and glucose metabolism. The objective of this study was to evaluate whether the metabolic deregulations induced by hypothyroidism could be avoided through regulatory mechanisms involved in metabolic flexibility. To this end, the response to induced hypothyroidism was compared in males from two mouse strains, the wild-derived WSB/EiJ mouse strain characterized by a diet-induced obesity (DIO) resistance due to its high metabolic flexibility phenotype and C57BL/6J mice, which are prone to DIO. The results show that propylthiouracil (PTU)-induced hypothyroidism led to metabolic deregulations, particularly a reduction in hepatic lipid synthesis in both strains. Furthermore, in contrast to the C57BL/6J mice, the WSB/EiJ mice were resistant to the metabolic dysregulations induced by hypothyroidism, mainly through enhanced lipid metabolism in their adipose tissue. Indeed, WSB/EiJ mice compensated for the decrease in hepatic lipid synthesis by mobilizing lipid reserves from white adipose tissue. Gene expression analysis revealed that hypothyroidism stimulated the hypothalamic orexigenic circuit in both strains, but there was unchanged melanocortin 4 receptor (Mc4r) and leptin receptor (LepR) expression in the hypothyroid WSB/EiJ mice strain, which reflects their adaptability to maintain their body weight, in contrast to C57BL/6J mice. Thus, this study showed that WSB/EiJ male mice displayed a resistance to the metabolic dysregulations induced by hypothyroidism through compensatory mechanisms. This highlights the importance of metabolic flexibility in the ability to adapt to disturbed circulating TH levels.

Control of tuberal hypothalamic development and its implications in metabolic disorders.

The tuberal hypothalamus regulates a range of crucial physiological processes, including energy homeostasis and metabolism. In this Review, we explore the intricate molecular mechanisms and signalling pathways that control the development of the tuberal hypothalamus, focusing on aspects that shape metabolic outcomes. Major developmental events are discussed in the context of their effect on the establishment of both functional hypothalamic neuronal circuits and brain-body interfaces that are pivotal to the control of metabolism. Emerging evidence indicates that aberrations in molecular pathways during tuberal hypothalamic development contribute to metabolic dysregulation. Understanding the molecular underpinnings of tuberal hypothalamic development provides a comprehensive view of neurodevelopmental processes and offers a promising avenue for future targeted interventions to prevent and treat metabolic disorders.

Intestinal gluconeogenesis controls the neonatal development of hypothalamic feeding circuits

ObjectiveIntestinal gluconeogenesis (IGN) regulates adult energy homeostasis in part by controlling the same hypothalamic targets as leptin. In neonates, leptin exhibits a neonatal surge controlling axonal outgrowth between the different hypothalamic nuclei involved in feeding circuits and autonomic innervation of peripheral tissues involved in energy and glucose homeostasis. Interestingly, IGN is induced during this specific time-window. We hypothesized that the neonatal pic of IGN also regulates the development of hypothalamic feeding circuits and sympathetic innervation of adipose tissues. MethodsWe genetically induced neonatal IGN by overexpressing G6pc1 the catalytic subunit of glucose-6-phosphatase (the mandatory enzyme of IGN) at birth or at twelve days after birth. The neonatal development of hypothalamic feeding circuits was studied by measuring Agouti-related protein (AgRP) and Pro-opiomelanocortin (POMC) fiber density in hypothalamic nuclei of 20-day-old pups. The effect of the neonatal induction of intestinal G6pc1 on sympathetic innervation of the adipose tissues was studied via tyrosine hydroxylase (TH) quantification. The metabolic consequences of the neonatal induction of intestinal G6pc1 were studied in adult mice challenged with a high-fat/high-sucrose (HFHS) diet for 2 months. ResultsInduction of intestinal G6pc1 at birth caused a neonatal reorganization of AgRP and POMC fiber density in the paraventricular nucleus of the hypothalamus, increased brown adipose tissue tyrosine hydroxylase levels, and protected against high-fat feeding-induced metabolic disorders. In contrast, inducing intestinal G6pc1 12 days after birth did not impact AgRP/POMC fiber densities, adipose tissue innervation or adult metabolism. ConclusionThese findings reveal that IGN at birth but not later during postnatal life controls the development of hypothalamic feeding circuits and sympathetic innervation of adipose tissues, promoting a better management of metabolism in adulthood.

Oxytocin shortens spreading depolarization-induced periorbital allodynia

BackgroundMigraine is among the most prevalent and burdensome neurological disorders in the United States based on disability-adjusted life years. Cortical spreading depolarization (SD) is the most likely electrophysiological cause of migraine aura and may be linked to trigeminal nociception. We previously demonstrated, using a minimally invasive optogenetic approach of SD induction (opto-SD), that opto-SD triggers acute periorbital mechanical allodynia that is reversed by 5HT1B/1D receptor agonists, supporting SD-induced activation of migraine-relevant trigeminal pain pathways in mice. Recent data highlight hypothalamic neural circuits in migraine, and SD may activate hypothalamic neurons. Furthermore, neuroanatomical, electrophysiological, and behavioral data suggest a homeostatic analgesic function of hypothalamic neuropeptide hormone, oxytocin. We, therefore, examined the role of hypothalamic paraventricular nucleus (PVN) and oxytocinergic (OXT) signaling in opto-SD-induced trigeminal pain behavior.MethodsWe induced a single opto-SD in adult male and female Thy1-ChR2-YFP transgenic mice and quantified fos immunolabeling in the PVN and supraoptic nucleus (SON) compared with sham controls. Oxytocin expression was also measured in fos-positive neurons in the PVN. Periorbital mechanical allodynia was tested after treatment with selective OXT receptor antagonist L-368,899 (5 to 25 mg/kg i.p.) or vehicle at 1, 2, and 4 h after opto-SD or sham stimulation using von Frey monofilaments.ResultsOpto-SD significantly increased the number of fos immunoreactive cells in the PVN and SON as compared to sham stimulation (p < 0.001, p = 0.018, respectively). A subpopulation of fos-positive neurons also stained positive for oxytocin. Opto-SD evoked periorbital mechanical allodynia 1 h after SD (p = 0.001 vs. sham), which recovered quickly within 2 h (p = 0.638). OXT receptor antagonist L-368,899 dose-dependently prolonged SD-induced periorbital allodynia (p < 0.001). L-368,899 did not affect mechanical thresholds in the absence of opto-SD.ConclusionsThese data support an SD-induced activation of PVN neurons and a role for endogenous OXT in alleviating acute SD-induced trigeminal allodynia by shortening its duration.

Microglia in physiological conditions and the importance of understanding their homeostatic functions in the arcuate nucleus.

Microglia are highly dynamic cells that have been mainly studied under pathological conditions. The present review discusses the possible implication of microglia as modulators of neuronal electrical responses in physiological conditions and hypothesizes how these cells might modulate hypothalamic circuits in health and during obesity. Microglial cells studied under physiological conditions are highly diverse, depending on the developmental stage and brain region. The evidence also suggests that neuronal electrical activity modulates microglial motility to control neuronal excitability. Additionally, we show that the expression of genes associated with neuron-microglia interaction is down-regulated in obese mice compared to control-fed mice, suggesting an alteration in the contact-dependent mechanisms that sustain hypothalamic arcuate-median eminence neuronal function. We also discuss the possible implication of microglial-derived signals for the excitability of hypothalamic neurons during homeostasis and obesity. This review emphasizes the importance of studying the physiological interplay between microglia and neurons to maintain proper neuronal circuit function. It aims to elucidate how disruptions in the normal activities of microglia can adversely affect neuronal health.

Negative feedback control of hypothalamic feeding circuits by the taste of food

The rewarding taste of food is critical for motivating animals to eat, but whether taste has a parallel function in promoting meal termination is not well understood. Here, we show that hunger-promoting agouti-related peptide (AgRP) neurons are rapidly inhibited during each bout of ingestion by a signal linked to the taste of food. Blocking these transient dips in activity via closed-loop optogenetic stimulation increases food intake by selectively delaying the onset of satiety. We show that upstream leptin-receptor-expressing neurons in the dorsomedial hypothalamus (DMHLepR) are tuned to respond to sweet or fatty tastes and exhibit time-locked activation during feeding that is the mirror image of downstream AgRP cells. These findings reveal an unexpected role for taste in the negative feedback control of ingestion. They also reveal a mechanism by which AgRP neurons, which are the primary cells that drive hunger, are able to influence the moment-by-moment dynamics of food consumption.

Microglia are Required for Developmental Specification of AgRP Innervation in the Hypothalamus of Offspring Exposed to Maternal High Fat Diet During Lactation.

Nutritional fluctuations that occur early in life dictate metabolic adaptations that will affect susceptibility to weight gain and obesity later in life. The postnatal period in mice represents a time of dynamic changes in hypothalamic development and maternal consumption of a high fat diet during the lactation period (MHFD) changes the composition of milk and leads to enhanced susceptibility to obesity in offspring. Agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus (ARH) react to changes in multiple metabolic signals and distribute neuroendocrine information to other brain regions, such as the paraventricular hypothalamic nucleus (PVH), which is known to integrate a variety of signals that regulate body weight. Development of neural projections from AgRP neurons to the PVH occurs during the lactation period and these projections are reduced in MHFD offspring, but underlying developmental mechanisms remain largely unknown. Microglia are the resident immune cells of the central nervous system and are involved in refinement of neural connections and modulation of synaptic transmission. Because high fat diet exposure causes activation of microglia in adults, a similar activation may occur in offspring exposed to MHFD and play a role in sculpting hypothalamic feeding circuitry. Genetically targeted axonal labeling and immunohistochemistry were used to visualize AgRP axons and microglia in postnatal mice derived from MHFD dams and morphological changes quantified. The results demonstrate regionally localized changes to microglial morphology in the PVH of MHFD offspring that suggest enhanced surveillance activity and are temporally restricted to the period when AgRP neurons innervate the PVH. In addition, axon labeling experiments confirm a significant decrease in AgRP innervation of the PVH in MHFD offspring and provide direct evidence of synaptic pruning of AgRP inputs to the PVH. Microglial depletion with the Colony-stimulating factor 1 receptor inhibitor PLX5622 determined that the decrease in AgRP innervation observed in MHFD offspring is dependent on microglia, and that microglia are required for weight gain that emerges as early as weaning in offspring of MHFD dams. However, these changes do not appear to be dependent on the degree of microglial mediated synaptic pruning. Together, these findings suggest that microglia are activated by exposure to MHFD and interact directly with AgRP axons during development to permanently alter their density, with implications for developmental programming of metabolic phenotype.

Central Role of Hypothalamic Circuits for Acupuncture's Anti-Parkinsonian Effects.

Despite clinical data stretching over millennia, the neurobiological basis of the effectiveness of acupuncture in treating diseases of the central nervous system has remained elusive. Here, using an established model of acupuncture treatment in Parkinson's disease (PD) model mice, we show that peripheral acupuncture stimulation activates hypothalamic melanin-concentrating hormone (MCH) neurons via nerve conduction. We further identify two separate neural pathways originating from anatomically and electrophysiologically distinct MCH neuronal subpopulations, projecting to the substantia nigra and hippocampus, respectively. Through chemogenetic manipulation specifically targeting these MCH projections, their respective roles in mediating the acupuncture-induced motor recovery and memory improvements following PD onset are demonstrated, as well as the underlying mechanisms mediating recovery from dopaminergic neurodegeneration, reactive gliosis, and impaired hippocampal synaptic plasticity. Collectively, these MCH neurons constitute not only a circuit-based explanation for the therapeutic effectiveness of traditional acupuncture, but also a potential cellular target for treating both motor and non-motor PD symptoms.

A Hypothalamic Circuit that Modulates Feeding and Parenting Behaviors.

Across mammalian species, new mothers undergo considerable behavioral changes to nurture their offspring and meet the caloric demands of milk production1-5. While many neural circuits underlying feeding and parenting behaviors are well characterized6-9, it is unclear how these different circuits interact and adapt during lactation. Here, we characterized the transcriptomic changes in the arcuate nucleus (ARC) and the medial preoptic area (MPOA) of the mouse hypothalamus in response to lactation and hunger. Furthermore, we showed that heightened appetite in lactating mice was accompanied by increased activity of hunger-promoting agouti-related peptide (AgRP) neurons in the ARC. To assess the strength of hunger versus maternal drives, we designed a conflict assay where female mice chose between a food source or a chamber containing pups and nesting material. Although food-deprived lactating mothers prioritized parenting over feeding, hunger reduced the duration and disrupted the sequences of parenting behaviors in both lactating and virgin females. We discovered that ARCAgRP neurons directly inhibit bombesin receptor subtype-3 (BRS3) neurons in the MPOA, a population that governs both parenting and satiety. Selective activation of this ARCAgRP to MPOABRS3 circuit shifted behaviors from parenting to food-seeking. Thus, hypothalamic networks are modulated by physiological states and work antagonistically during the prioritization of competing motivated behaviors.

A hypothalamic circuit for circadian regulation of corticosterone secretion.

The secretion of cortisol in humans and corticosterone (Cort) in rodents follows a daily rhythm which is important in readying the individual for the daily active cycle and is impaired in chronic depression. This rhythm is orchestrated by the suprachiasmatic nucleus (SCN) which governs the activity of neurons in the paraventricular nucleus of the hypothalamus that produce the corticotropin-releasing hormone (PVHCRH neurons). The dorsomedial nucleus of the hypothalamus (DMH) serves as a crucial intermediary, being innervated by the SCN both directly and via relays in the subparaventricular zone, and projecting axons to the PVH, thereby exerting influence over the cortisol/corticosterone rhythm. However, the role and synaptic mechanisms by which DMH neurons regulate the daily rhythm of Cort secretion has not been explored. We found that either ablating or acutely inhibiting the DMH glutamatergic (DMHVglut2) neurons resulted in a 40-70% reduction in the daily peak of Cort. Deletion of the Vglut2 gene within the DMH produced a similar effect, highlighting the indispensable role of glutamatergic signaling. Chemogenetic stimulation of DMHVglut2 neurons led to an increase of Cort levels, and optogenetic activation of their terminals in the PVH in hypothalamic slices directly activated PVHCRH neurons through glutamate release (the DMHVglut2 → PVHCRH pathway). Similarly, ablating, inhibiting, or disrupting GABA transmission by DMH GABAergic (DMHVgat) neurons diminished the circadian peak of Cort, particularly under constant darkness conditions. Chemogenetic stimulation of DMHVgat neurons increased Cort, although with a lower magnitude compared to DMHVglut2 neuron stimulation, suggesting a role in disinhibiting PVHCRH neurons. Supporting this hypothesis, we found that rostral DMHVgat neurons project directly to GABAergic neurons in the caudal ventral part of the PVH and adjacent peri-PVH area (cvPVH), which directly inhibit PVHCRH neurons, and that activating the DMHVgat terminals in the cvPVH in brain slices reduced GABAergic afferent input onto the PVHCRH neurons. Finally, ablation of cvPVHVgat neurons resulted in increased Cort release at the onset of the active phase, affirming the pivotal role of the DMHVgat → cvPVHVgat → PVHCRH pathway in Cort secretion. In summary, our study delineates two parallel pathways transmitting temporal information to PVHCRH neurons, collectively orchestrating the daily surge in Cort in anticipation of the active phase. These findings are crucial to understand the neural circuits regulating Cort secretion, shedding light on the mechanisms governing this physiological process and the coordinated interplay between SCN, DMH, and PVH.

Microglia mediate the early-life programming of adult glucose control.

Mammalian glucose homeostasis is, in part, nutritionally programmed during early neonatal life, a critical window for the formation of synapses between hypothalamic glucoregulatory centers. Although microglia are known to prune synapses throughout the brain, their specific role in refining hypothalamic glucoregulatory circuits remains unknown. Here, we show that microglia in the mediobasal hypothalamus (MBH) of mice actively engage in synaptic pruning during early life. Microglial phagocytic activity is induced following birth, regresses upon weaning from maternal milk, and is exacerbated by feeding dams a high-fat diet while lactating. In particular, we show that microglia refine perineuronal nets (PNNs) within the neonatal MBH. Indeed, transiently depleting microglia before weaning (P6-16), but not afterward (P21-31), remarkably increased PNN abundance in the MBH. Furthermore, mice lacking microglia only from P6-16 had glucose intolerance due to impaired glucose-responsive pancreatic insulin secretion in adulthood, a phenotype not seen if microglial depletion occurred after weaning. Viral retrograde tracing revealed that this impairment is linked to a reduction in the number of neurons in specific hypothalamic glucoregulatory centers that synaptically connect to the pancreatic β-cell compartment. These findings show that microglia facilitate synaptic plasticity in the MBH during early life through a process that includes PNN refinement, to establish hypothalamic circuits that regulate adult glucose homeostasis.

Loss of transient receptor potential channel 5 causes obesity and postpartum depression

Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, the fight/flight response, socialization, and maternal care. Here, we identified microdeletions on chromosome Xq23 disrupting the brain-expressed transient receptor potential (TRP) channel 5 (TRPC5). This family of channels detects sensory stimuli and converts them into electrical signals interpretable by the brain. Male TRPC5 deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in knockin male mice harboring a human loss-of-function TRPC5 mutation. Women carrying TRPC5 deletions had severe postpartum depression. As mothers, female knockin mice exhibited anhedonia and depression-like behavior with impaired care of offspring. Deletion of Trpc5 from oxytocin neurons in the hypothalamic paraventricular nucleus caused obesity in both sexes and postpartum depressive behavior in females, while Trpc5 overexpression in oxytocin neurons in knock-in mice reversed these phenotypes. We demonstrate that TRPC5 plays a pivotal role in mediating innate human behaviors fundamental to survival, including food seeking and maternal care.

Neuroethology: Fear outside the box

Behavioral neuroscience has successfully and in great detail deconstructed circuit mechanisms underlying fear behaviors using reductionist approaches. Recent research in more naturalistic settings now reveals additional higher-level organization, where hypothalamic circuits multiplex threat detection and fear memory updating to safely navigate complex environments.

GLP-1 increases preingestive satiation via hypothalamic circuits in mice and humans.

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are effective antiobesity drugs. However, the precise central mechanisms of GLP-1RAs remain elusive. We administered GLP-1RAs to patients with obesity and observed a heightened sense of preingestive satiation. Analysis of human and mouse brain samples pinpointed GLP-1 receptor (GLP-1R) neurons in the dorsomedial hypothalamus (DMH) as candidates for encoding preingestive satiation. Optogenetic manipulation of DMHGLP-1R neurons caused satiation. Calcium imaging demonstrated that these neurons are actively involved in encoding preingestive satiation. GLP-1RA administration increased the activity of DMHGLP-1R neurons selectively during eating behavior. We further identified that an intricate interplay between DMHGLP-1R neurons and neuropeptide Y/agouti-related peptide neurons of the arcuate nucleus (ARCNPY/AgRP neurons) occurs to regulate food intake. Our findings reveal a hypothalamic mechanism through which GLP-1RAs control preingestive satiation, offering previously unexplored neural targets for obesity and metabolic diseases.