AgRP neurons trigger long-term potentiation and facilitate food seeking

Chunmei Wang,Yong Xu,Qi Wu,Julia Wang,Qingchun Tong,Yongjie Yang,Tiffany Yang,Pingwen Xu,Xing Cai,Tingting Yang,Yanlin He,Hailan Liu,Makoto Fukuda,Chen Liang,Zheng Sun,Wenjun Zhou,Yang He,Meng Yu,Hesong Liu

doi:10.1038/s41398-020-01161-1

Abstract

Sufficient feeding is essential for animals’ survival, which requires a cognitive capability to facilitate food seeking, but the neurobiological processes regulating food seeking are not fully understood. Here we show that stimulation of agouti-related peptide-expressing (AgRP) neurons triggers a long-term depression (LTD) of spontaneous excitatory post-synaptic current (sEPSC) in adjacent pro-opiomelanocortin (POMC) neurons and in most of their distant synaptic targets, including neurons in the paraventricular nucleus of the thalamus (PVT). The AgRP-induced sEPCS LTD can be enhanced by fasting but blunted by satiety signals, e.g. leptin and insulin. Mice subjected to food-seeking tasks develop similar neural plasticity in AgRP-innervated PVT neurons. Further, ablation of the majority of AgRP neurons, or only a subset of AgRP neurons that project to the PVT, impairs animals’ ability to associate spatial and contextual cues with food availability during food seeking. A similar impairment can be also induced by optogenetic inhibition of the AgRP→PVT projections. Together, these results indicate that the AgRP→PVT circuit is necessary for food seeking.

Highlights

Brain slices containing the arcuate nucleus of the hypothalamus (ARH) were prepared from these mice (9 weeks, fed ad libitum), and double-patch whole-cell recordings were made in a pair of a randomly selected agouti-related peptide-expressing (AgRP) neuron and an adjacent POMC neuron, respectively (Fig. S1A)
We further examined the contributions of GABA, AgRP, and neuropeptide Y (NPY) to the spontaneous excitatory post-synaptic current (sEPSC) long-term depression (LTD) in paraventricular nucleus of the thalamus (PVT) neurons, and found that only AgRP and NPY actions are required but GABA signals play a minimal role in the formation of the sEPSC LTD in AgRP-innervated PVT neurons (Fig. S3M, N)
One was the instant activation of POMC neuron upon AgRP neuron inhibition; the other was the time-locked IPSCs in the POMC neuron evoked by activation of the AgRP neuron, a response that was blocked by bicuculline but not by 4-AP + TTX

Summary

Introduction

Neurons that co-release agouti-related peptide (AgRP), neuropeptide Y (NPY), and GABA are located in the arcuate nucleus of the hypothalamus (ARH)[1,2]. These AgRP neurons play essential roles in promoting feeding behavior and ensure survival. AgRP neurons project to a number of longdistant targets throughout the brain[7,11,12,13] These include the paraventricular nucleus of the hypothalamus (PVH), the paraventricular nucleus of the thalamus (PVT), the parabrachial nucleus (PBN), the bed nucleus of stria terminalis (BNST), the central amygdala (CeA), and the medial amygdala (MeA).

Methods

Results

Conclusion