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The high comorbidity between obesity and mental disorders, such as depression and anxiety, often exacerbates metabolic and neurological symptoms significantly. However, neural mechanisms that underlie reciprocal control of feeding and mental states are largely elusive. Here we report that melanocortin 4 receptor (MC4R) neurons located in the dorsal bed nucleus of the stria terminus (dBNST) engage in the regulation of mentally associated weight gain by receiving GABAergic projections from hypothalamic AgRP neurons onto α5-containing GABAA receptors and serotonergic afferents onto 5-HT3 receptors. Chronic treatment with a high-fat diet (HFD) significantly blunts the hyperexcitability of AgRP neurons in response to not only hunger but also anxiety and depression-like stimuli. Such HFD-mediated desensitization reduces GABAergic outputs from AgRP neurons to downstream MC4RdBNST neurons, resulting in severe mental dysregulation. Genetic enhancement of the GABAAR-α5 or suppression of the 5-HT3R within the MC4RdBNST neurons not only abolishes HFD-induced anxiety and depression but also robustly reduces body weight by suppression of food intake. To gain further translational insights, we revealed that combined treatment of zonisamide (enhancing the GABAAR-α5 signaling) and granisetron (a selective 5-HT3R antagonist) alleviates mental dysfunction and yields a robust reversal of diet-induced obesity by reducing total calorie intake and altering food preference towards a healthy low-fat diet. Our results unveil a neural mechanism for reciprocal control of appetite and mental states, which culminates in a novel zonisamide-granisetron cocktail therapy for potential tackling the psychosis-obesity comorbidity.

In this paper, we propose a novel shape-sensing method based on deep learning with a multi-core optical fiber for the accurate shape-sensing of catheters and guidewires. Firstly, we designed a catheter with embedded multi-core fiber containing three sensing outer cores and one temperature compensation middle core. Then, we analyzed the relationship between the central wavelength shift, the curvature of the multi-core Fiber Bragg Grating (FBG), and temperature compensation methods to establish a Particle Swarm Optimization (PSO) BP neural network-based catheter shape sensing method. Finally, experiments were conducted in both constant and variable temperature environments to validate the method. The average and maximum distance errors of the PSO-BP neural network were 0.57 and 1.33 mm, respectively, under constant temperature conditions, and 0.36 and 0.96 mm, respectively, under variable temperature conditions. This well-sensed catheter shape demonstrates the effectiveness of the shape-sensing method proposed in this paper and its potential applications in real surgical catheters and guidewire.

Homeotherms maintain a stable internal body temperature despite changing environments. During energy deficiency, some species can cease to defend their body temperature and enter a hypothermic and hypometabolic state known as torpor. Recent advances have revealed the medial preoptic area (MPA) as a key site for the regulation of torpor in mice. The MPA is estrogen-sensitive and estrogens also have potent effects on both temperature and metabolism. Here, we demonstrate that estrogen-sensitive neurons in the MPA can coordinate hypothermia and hypometabolism in mice. Selectively activating estrogen-sensitive MPA neurons was sufficient to drive a coordinated depression of metabolic rate and body temperature similar to torpor, as measured by body temperature, physical activity, indirect calorimetry, heart rate, and brain activity. Inducing torpor with a prolonged fast revealed larger and more variable calcium transients from estrogen-sensitive MPA neurons during bouts of hypothermia. Finally, whereas selective ablation of estrogen-sensitive MPA neurons demonstrated that these neurons are required for the full expression of fasting-induced torpor in both female and male mice, their effects on thermoregulation and torpor bout initiation exhibit differences across sex. Together, these findings suggest a role for estrogen-sensitive MPA neurons in directing the thermoregulatory and metabolic responses to energy deficiency. Torpor is a state of reduced metabolism and body temperature that conserves energy when food is scarce. Here the authors show that estrogen-sensitive neurons in the hypothalamus regulate torpor in mice, maintaining torpor in both sexes but initiating torpor and regulating core temperature differentially across sex.

Brain glucose-sensing neurons detect glucose fluctuations and prevent severe hypoglycemia, but mechanisms mediating functions of these glucose-sensing neurons are unclear. Here we report that estrogen receptor-α (ERα)-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH) can sense glucose fluctuations, being glucose-inhibited neurons (GI-ERα vlVMH ) or glucose-excited neurons (GE-ERα vlVMH ). Hypoglycemia activates GI-ERα vlVMH neurons via the anoctamin 4 channel, and inhibits GE-ERα vlVMH neurons through opening the ATP-sensitive potassium channel. Further, we show that GI-ERα vlVMH neurons preferentially project to the medioposterior arcuate nucleus of the hypothalamus (mpARH) and GE-ERα vlVMH neurons preferentially project to the dorsal Raphe nuclei (DRN). Activation of ERα vlVMH to mpARH circuit and inhibition of ERα vlVMH to DRN circuit both increase blood glucose. Thus, our results indicate that ERα vlVMH neurons detect glucose fluctuations and prevent severe hypoglycemia in mice. Glucose-sensing neurons are found in the ventromedial hypothalamic nucleus (VMH). Here the authors identify the role of estrogen receptor-α expressing neurons in the ventrolateral subdivision of the VMH in sensing hypoglycemia.

To investigate the duration of humoral immune response in convalescent coronavirus disease 2019 (COVID-19) patients, we conduct a 12-month longitudinal study through collecting a total of 1,782 plasma samples from 869 convalescent plasma donors in Wuhan, China and test specific antibody responses. The results show that positive rate of IgG antibody against receptor-binding domain of spike protein (RBD-IgG) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the COVID-19 convalescent plasma donors exceeded 70% for 12 months post diagnosis. The level of RBD-IgG decreases with time, with the titer stabilizing at 35.7% of the initial level by the 9th month. Moreover, male plasma donors produce more RBD-IgG than female, and age of the patients positively correlates with the RBD-IgG titer. A strong positive correlation between RBD-IgG and neutralizing antibody titers is also identified. These results facilitate our understanding of SARS-CoV-2-induced immune memory to promote vaccine and therapy development. COVID-19 pandemic is a global health risk, but our understanding on the induced durable immunity remains scarce. Here the authors assess antibody responses in 869 convalescent COVID-19 patients to find that specific antibody titers reduce with time, and the RBD-IgG positive rate exceed 70% at 12 month post diagnosis, with male and older patients showing stronger responses.

Chronic stress causes dysregulations of mood and energy homeostasis, but the neurocircuitry underlying these alterations remain to be fully elucidated. Here we demonstrate that chronic restraint stress in mice results in hyperactivity of pro-opiomelanocortin neurons in the arcuate nucleus of the hypothalamus (POMCARH neurons) associated with decreased neural activities of dopamine neurons in the ventral tegmental area (DAVTA neurons). We further revealed that POMCARH neurons project to the VTA and provide an inhibitory tone to DAVTA neurons via both direct and indirect neurotransmissions. Finally, we show that photoinhibition of the POMCARH→VTA circuit in mice increases body weight and food intake, and reduces depression-like behaviors and anhedonia in mice exposed to chronic restraint stress. Thus, our results identified a novel neurocircuitry regulating feeding and mood in response to stress.

Asprosin, a recently identified secreted hormone from adipose tissue, acts centrally to promote food intake. Asprosin is a recently discovered fasting-induced hormone that promotes hepatic glucose production. Here we demonstrate that asprosin in the circulation crosses the blood–brain barrier and directly activates orexigenic AgRP + neurons via a cAMP-dependent pathway. This signaling results in inhibition of downstream anorexigenic proopiomelanocortin (POMC)-positive neurons in a GABA-dependent manner, which then leads to appetite stimulation and a drive to accumulate adiposity and body weight. In humans, a genetic deficiency in asprosin causes a syndrome characterized by low appetite and extreme leanness; this is phenocopied by mice carrying similar mutations and can be fully rescued by asprosin. Furthermore, we found that obese humans and mice had pathologically elevated concentrations of circulating asprosin, and neutralization of asprosin in the blood with a monoclonal antibody reduced appetite and body weight in obese mice, in addition to improving their glycemic profile. Thus, in addition to performing a glucogenic function, asprosin is a centrally acting orexigenic hormone that is a potential therapeutic target in the treatment of both obesity and diabetes.

Contrasting to the established role of the hypothalamic agouti-related protein (AgRP) neurons in feeding regulation, the neural circuit and signaling mechanisms by which they control energy expenditure remains unclear. Here, we report that energy expenditure is regulated by a subgroup of AgRP neurons that send non-collateral projections to neurons within the dorsal lateral part of dorsal raphe nucleus (dlDRN) expressing the melanocortin 4 receptor (MC4R), which in turn innervate nearby serotonergic (5-HT) neurons. Genetic manipulations reveal a bi-directional control of energy expenditure by this circuit without affecting food intake. Fiber photometry and electrophysiological results indicate that the thermo-sensing MC4R dlDRN neurons integrate pre-synaptic AgRP signaling, thereby modulating the post-synaptic serotonergic pathway. Specifically, the MC4R dlDRN signaling elicits profound, bi-directional, regulation of body weight mainly through sympathetic outflow that reprograms mitochondrial bioenergetics within brown and beige fat while feeding remains intact. Together, we suggest that this AgRP neural circuit plays a unique role in persistent control of energy expenditure and body weight, hinting next-generation therapeutic approaches for obesity and metabolic disorders. Neuronal signaling has an important role in the regulation of energy expenditure and body weight, however, the underlying mechanisms are incompletely understood. Here, the authors report a AgRP-MC4R-serotonin expressing neuronal circuit that regulate energy expenditure without affecting feeding.

Nuclear receptor corepressor 1 (NCOR1) and NCOR2 (also known as SMRT) regulate gene expression by activating histone deacetylase 3 through their deacetylase activation domain (DAD). We show that mice with DAD knock-in mutations have memory deficits, reduced anxiety levels, and reduced social interactions. Mice with NCOR1 and NORC2 depletion specifically in GABAergic neurons (NS-V mice) recapitulated the memory deficits and had reduced GABAA receptor subunit α2 (GABRA2) expression in lateral hypothalamus GABAergic (LHGABA) neurons. This was associated with LHGABA neuron hyperexcitability and impaired hippocampal long-term potentiation, through a monosynaptic LHGABA to CA3GABA projection. Optogenetic activation of this projection caused memory deficits, whereas targeted manipulation of LHGABA or CA3GABA neuron activity reversed memory deficits in NS-V mice. We describe de novo variants in NCOR1, NCOR2 or HDAC3 in patients with intellectual disability or neurodevelopmental disorders. These findings identify a hypothalamus–hippocampus projection that may link endocrine signals with synaptic plasticity through NCOR-mediated regulation of GABA signaling.Zhou et al. show that NCORs regulate memory and synaptic plasticity through a GABAergic hypothalamus–hippocampus projection in mice, and that variants in NCOR1 and NCOR2 are linked to intellectual disability and neurodevelopmental defects in humans.

Purpose of ReviewObesity and diabetes have already become the second largest risk factor for cardiovascular disease. During the last decade, remarkable advances have been made in understanding the human genome’s contribution to glucose homeostasis disorders and obesity. A few studies on rare mutations of candidate genes provide potential genetic targets for the treatment of diabetes and obesity. In this review, we discussed the detailed findings of these studies and the possible causalities between specific genetic variations and dysfunctions in energy or glucose homeostasis. We are optimistic that novel therapeutic strategies targeting these specific mutants for treating and preventing diabetes and obesity will be developed in the near future.Recent FindingsStudies on rare genetic mutation-caused obesity or diabetes have identified potential genetic targets to decrease body weight or reduce the risk of diabetes.SummaryRare mutations observed in lipodystrophy, obese, or diabetic human patients are promising targets in the treatment of diabetes and obesity.