Reciprocal control of obesity and anxiety–depressive disorder via a GABA and serotonin neural circuit

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.

Regulation of Neurotransmitters by the Gut Microbiota and Effects on Cognition in Neurological Disorders

“…The deregulation of serotonin, GABA, dopamine, and glutamate levels in the central nervous system is associated with the pathogenesis of mental health disorders like anxiety [ 111 , 112 , 113 ]. Moreover, recent studies provide evidence that the gut microbiota affects anxiety symptoms.…”

Tapping into 5-HT3 Receptors to Modify Metabolic and Immune Responses

“…Body weight and energy expenditure are modified through sympathetic regulation of brown adipose tissue that is directed through neurons in the dorsal raphe nucleus expressing melanocortin 4 receptors that in turn innervate 5-HT neurons [ 305 ]. A high fat diet is also associated with anxiety and depression that correlates with desensitization of GABAergic AgRP neurons projecting onto melanocortin 4 receptor neurons in the dorsal bed of nucleus of the stria terminus containing α5-GABA A receptors and afferent serotonergic neurons with 5-HT 3 receptors [ 306 ]. Pharmacologically or genetically subduing 5-HT 3 receptors or enhancing α5-GABA A receptors suppressed food intake and removed the high fat diet induced anxiety or depression [ 306 ].…”

“…A high fat diet is also associated with anxiety and depression that correlates with desensitization of GABAergic AgRP neurons projecting onto melanocortin 4 receptor neurons in the dorsal bed of nucleus of the stria terminus containing α5-GABA A receptors and afferent serotonergic neurons with 5-HT 3 receptors [ 306 ]. Pharmacologically or genetically subduing 5-HT 3 receptors or enhancing α5-GABA A receptors suppressed food intake and removed the high fat diet induced anxiety or depression [ 306 ]. In fact, altered food intake preferences favoring a low fat diet were seen in combined pharmacotherapies of granisetron and zonisamide [ 306 ].…”

“…Pharmacologically or genetically subduing 5-HT 3 receptors or enhancing α5-GABA A receptors suppressed food intake and removed the high fat diet induced anxiety or depression [ 306 ]. In fact, altered food intake preferences favoring a low fat diet were seen in combined pharmacotherapies of granisetron and zonisamide [ 306 ]. Zonisamide is a sulfonamide anticonvulsant that has been considered as a clinical treatment for obesity [ 307 , 308 ] but not in combination with 5-HT 3 receptor antagonists.…”

Reversal of obesogenic feeding and hypometabolism by a bifurcating GABAergic neural circuit

“…AgRP neurons play fundamental roles in regulating feeding behavior and body weight by releasing inhibitory NPY, AgRP and GABA transmitters into broad downstream brain areas [28][29][30] . The neural circuits comprised of AgRP neurons, the neural and hormonal signaling afferent to AgRP neurons, and their postsynaptic targets have been identified…”