Declined memory is a hallmark of Alzheimer’s disease (AD). Experiments in rodents and human postmortem studies suggest that serotonin (5-hydroxytryptamine, 5-HT) plays a role in memory, but the underlying mechanisms are unknown. Here, we investigate the role of 5-HT 2C receptor (5-HT _2C R) in regulating memory. Transgenic mice expressing a humanized HTR2C mutation exhibit impaired plasticity of hippocampal ventral CA1 (vCA1) neurons and reduced memory. Further, 5-HT neurons project to and synapse onto vCA1 neurons. Disruption of 5-HT synthesis in vCA1-projecting neurons or deletion of 5-HT _2C Rs in the vCA1 impairs neural plasticity and memory. We show that a selective 5-HT _2C R agonist, lorcaserin, improves synaptic plasticity and memory in an AD mouse model. Cumulatively, we demonstrate that hippocampal 5-HT _2C R signaling regulates memory, which may inform the use of 5-HT _2C R agonists in the treatment of dementia.

Glucose is the basic fuel essential for maintenance of viability and functionality of all cells. However, some neurons — namely, glucose-inhibited (GI) neurons — paradoxically increase their firing activity in low-glucose conditions and decrease that activity in high-glucose conditions. The ionic mechanisms mediating electric responses of GI neurons to glucose fluctuations remain unclear. Here, we showed that currents mediated by the anoctamin 4 (Ano4) channel are only detected in GI neurons in the ventromedial hypothalamic nucleus (VMH) and are functionally required for their activation in response to low glucose. Genetic disruption of the Ano4 gene in VMH neurons reduced blood glucose and impaired counterregulatory responses during hypoglycemia in mice. Activation of VMH^Ano4 neurons increased food intake and blood glucose, while chronic inhibition of VMH^Ano4 neurons ameliorated hyperglycemia in a type 1 diabetic mouse model. Finally, we showed that VMH^Ano4 neurons represent a unique orexigenic VMH population and transmit a positive valence, while stimulation of neurons that do not express Ano4 in the VMH (VMH^non-Ano4) suppress feeding and transmit a negative valence. Together, our results indicate that the Ano4 channel and VMH^Ano4 neurons are potential therapeutic targets for human diseases with abnormal feeding behavior or glucose imbalance.

The major female ovarian hormone, 17β-estradiol (E ₂ ), can alter neuronal excitability within milliseconds to regulate a variety of physiological processes. Estrogen receptor-α (ERα), classically known as a nuclear receptor, exists as a membrane-bound receptor to mediate this rapid action of E ₂ , but the ionic mechanisms remain unclear. Here, we show that a membrane channel protein, chloride intracellular channel protein-1 (Clic1), can physically interact with ERα with a preference to the membrane-bound ERα. Clic1-mediated currents can be enhanced by E ₂ and reduced by its depletion. In addition, Clic1 currents are required to mediate the E ₂ -induced rapid excitations in multiple brain ERα populations. Further, genetic disruption of Clic1 in hypothalamic ERα neurons blunts the regulations of E ₂ on female body weight balance. In conclusion, we identified the Clic1 chloride channel as a key mediator for E ₂ -induced rapid neuronal excitation, which may have a broad impact on multiple neurobiological processes regulated by E ₂ .

Light plays an essential role in a variety of physiological processes, including vision, mood, and glucose homeostasis. However, the intricate relationship between light and an animal's feeding behavior has remained elusive. Here, we found that light exposure suppresses food intake, whereas darkness amplifies it in male mice. Interestingly, this phenomenon extends its reach to diurnal male Nile grass rats and healthy humans. We further show that lateral habenula (LHb) neurons in mice respond to light exposure, which in turn activates 5-HT neurons in the dorsal Raphe nucleus (DRN). Activation of the LHb→5-HT^DRNcircuit in mice blunts darkness-induced hyperphagia, while inhibition of the circuit prevents light-induced anorexia. Together, we discovered a light-responsive neural circuit that relays the environmental light signals to regulate feeding behavior in mice.

The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is increasing, with an incompletely understood pathophysiology involving multiple factors, particularly innate and adaptive immune responses. Given the limited pharmacological treatments available, identification of novel immune metabolic targets is urgently needed. In this study, we aimed to identify hub immune-related genes and potential biomarkers with diagnostic and predictive value for MASH patients. The GSE164760 dataset from the Gene Expression Omnibus was utilized for analysis, and the R package was used to identify differentially expressed genes. Immune-related differentially expressed genes (IR-DEGs) were identified by comparing the overlap of differentially expressed genes with well-known immune-related genes. Furthermore, the biological processes and molecular functions of the IR-DEGs were analyzed. To characterize the hub IR-DEGs, we employed a protein-protein interaction network. The diagnostic and predictive values of these hub IR-DEGs in MASH were confirmed using GSE48452 and GSE63067 datasets. Finally, the significance of the hub IR-DEGs was validated using a mouse model of MASH. A total of 91 IR-DEGs were identified, with 61 upregulated and 30 downregulated genes. Based on the protein-protein interaction network, FN1, RHOA, FOS, PDGFRα, CCND1, PIK3R1, CSF1, and FGF3 were identified as the hub IR-DEGs. Moreover, we found that these hub genes are closely correlated with immune cells. Notably, the validation across two independent cohorts as well as a murine MASH model confirmed their high diagnostic potential. The hub IR-DEGs, such as FN1, RHOA, FOS, PDGFRα, CCND1, PIK3R1, CSF1, and FGF3, may enhance the diagnosis and prognosis of MASH by modulating immune homeostasis.

The serotonin 2C receptor (5-HT_2CR)-melanocortin pathway plays well-established roles in the regulation of feeding behavior and body weight homeostasis. Dysfunctions in this system, such as loss-of-function mutations in the Htr2c gene, can lead to hyperphagia and obesity. In this study, we aimed to investigate the potential therapeutic strategies for ameliorating hyperphagia, hyperglycemia and obesity associated with a loss-of-function mutation in the Htr2c gene (Htr2c^F327L/Y). We demonstrated that re-expressing functional 5-HT_2CR solely in hypothalamic pro-opiomelanocortin (POMC) neurons is sufficient to reduce food intake and body weight in Htr2c^F327L/Y mice subjected to a high-fat diet. In addition, 5-HT_2CR expression restores the responsiveness of POMC neurons to lorcaserin, a selective agonist for 5-HT_2CR. Similarly, administration of melanotan II (MT II), an agonist of the melanocortin receptor 4 (MC4R), effectively suppresses feeding and weight gain in Htr2c^F327L/Y mice. Strikingly, promoting wheel running activity in Htr2c^F327L/Y mice results in a decrease in HFD consumption and improved glucose homeostasis. Together, our findings underscore the crucial role of the melanocortin system in alleviating hyperphagia and obesity related to dysfunctions of the 5-HT_2CR, and further suggest that MC4R agonists and lifestyle interventions might hold promise in counteracting hyperphagia, hyperglycemia and obesity in individuals carrying rare variants in Htr2c gene.