Reciprocal control of obesity and anxiety\u2013depressive disorder via a GABA and serotonin neural circuit

Guobin Xia,Minghao Dang,Richard D Palmiter,Yanlin He,Fantao Meng,Yong Xu,Yong Han,Qi Wu,Dollada Srisai,Monica Farias

doi:10.1038/s41380-021-01053-w

Abstract

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.

Highlights

IntroductionObesity is a growing epidemic and is emerging as one of the leading health concerns over the recent two decades, with
We evaluated the effect of chronic high-fat diet (HFD) on GABAAR α subunits profiles by qPCR, which revealed that Gabra5 mRNA within the MC4RdBNST neurons was greatly reduced after 5 wk of HFD (Fig. 4a)
We found that GABAAR-α5 is expressed in post-synaptic neurons within the dorsal bed nucleus of the stria terminus (dBNST) that were labeled with trans-synaptic wheat germ agglutinin (WGA):ZsGreen tracer virally transduced by AgRP neurons (Fig. 4b–e)

Summary

Introduction

Obesity is a growing epidemic and is emerging as one of the leading health concerns over the recent two decades, with Present address: Pennington Biomedical Research Center, Brain Glycemic and Metabolism Control Department, Louisiana State University, Baton Rouge, LA, USA disorders, the neural circuit mechanism and associated key neurotransmitter pathways are poorly understood [5,6,7,8,9]. AgRP neurons contribute to fasting-induced anxiolytic effects [24] Together, these recent studies support a notion that a unique AgRP neural circuit may integrate peripheral hormonal signals with a category of metabolism-sensitive mental functions

Methods

Results

Conclusion