Identification of a neurocircuit underlying regulation of feeding by stress-related emotional responses

Yuanzhong Xu,Qingchun Tong,Benjamin R Arenkiel,Zhiying Jiang,Xugen Huang,Canjun Zhu,Ryan M Cassidy,Nicholas J Justice,Leandra R Mangieri,Yong Xu,Yungang Lu

doi:10.1038/s41467-019-11399-z

Abstract

Feeding is known to be profoundly affected by stress-related emotional states and eating disorders are comorbid with psychiatric symptoms and altered emotional responses. The neural basis underlying feeding regulation by stress-related emotional changes is poorly understood. Here, we identify a novel projection from the paraventricular hypothalamus (PVH) to the ventral lateral septum (LSv) that shows a scalable regulation on feeding and behavioral changes related to emotion. Weak photostimulation of glutamatergic PVH→LSv terminals elicits stress-related self-grooming and strong photostimulation causes fear-related escape jumping associated with respective weak and strong inhibition on feeding. In contrast, inhibition of glutamatergic inputs to LSv increases feeding with signs of reduced anxiety. LSv-projecting neurons are concentrated in rostral PVH. LSv and LSv-projecting PVH neurons are activated by stressors in vivo, whereas feeding bouts were associated with reduced activity of these neurons. Thus, PVH→LSv neurotransmission underlies dynamic feeding by orchestrating emotional states, providing a novel neural circuit substrate underlying comorbidity between eating abnormalities and psychiatric disorders.

Highlights

Feeding is known to be profoundly affected by stress-related emotional states and eating disorders are comorbid with psychiatric symptoms and altered emotional responses
Four weeks after delivery of Cre-dependent adeno-associated viral (AAV) vectors engineered to express a channelrhodopsin (ChR2)-eGFP fusion protein (AAV-Flex-ChR2-eGFP) to the paraventricular hypothalamus (PVH) of Sim1-Cre::ROSA-lsl-tdTomato mice (Fig. 1a, b), we assayed for ChR2 projections originating from Sim[1] expressing PVH neurons in potential downstream target domains
To determine whether these projections were functional, we recorded LSv neurons for excitatory postsynaptic currents (EPSCs) following photostimulation of ChR2expressing hypothalamic fibers. 12 out of 18 recorded LSv neurons showed strong photo-induced postsynaptic responses, all of which were blocked by the glutamate receptor antagonists (CNQX/APV) (Fig. 1d), and refractory to the GABA-A receptor antagonist (GABAzine) (Fig. 1e) and AP4/TTX (Fig. 1f), suggesting that the PVH provides monosynaptic glutamatergic projections to LSv neurons

Summary

Introduction

Feeding is known to be profoundly affected by stress-related emotional states and eating disorders are comorbid with psychiatric symptoms and altered emotional responses. Chronic eating disorders are accompanied by marked maladaptive changes in emotional state and are known to be associated with altered stress and anxiety[6,7,8,9], whereas food over-consumption is often associated with increased impulsivity and positive reinforcement, similar to drug addiction[10,11] These observations support the idea that regulation of feeding and emotional states involves a common brain neural pathway. We identify a novel neurocircuit in which PVH neurons regulate feeding by orchestrating emotional states by integrating environmental stressors by direct glutamatergic projections to the LSv, providing a candidate neural circuit substrate for comorbidity between eating and psychiatric disorders

Methods

Results

Conclusion