Orexin-driven GAD65 network of the lateral hypothalamus sets physical activity in mice

Christin Kosse,Cornelia Schöne,Edward Bracey,Denis Burdakov

doi:10.1073/pnas.1619700114

Abstract

Damage to the lateral hypothalamus (LH) causes profound physical inactivity in mammals. Several molecularly distinct types of LH neurons have been identified, including orexin cells and glutamic acid decarboxylase 65 (GAD65) cells, but their interplay in orchestrating physical activity is not fully understood. Here, using optogenetic circuit analysis and cell type-specific deep-brain recordings in behaving mice, we show that orexin cell activation rapidly recruits GAD65LH neurons. We demonstrate that internally initiated GAD65LH cell bursts precede and accompany spontaneous running bouts, that selective chemogenetic silencing of natural GAD65LH cell activity depresses voluntary locomotion, and that GAD65LH cell overactivation leads to hyperlocomotion. These results thus identify a molecularly distinct, orexin-activated LH submodule that governs physical activity in mice.

Highlights

Damage to the lateral hypothalamus (LH) causes profound physical inactivity in mammals
We examined resulting optically induced postsynaptic responses in GAD65LH neurons (Fig. 1A; group data and/or statistics for findings illustrated as figures are described in the figure legends)
To determine if orexin peptide signaling drives the GAD65LH network, we investigated the effect of applying exogenous orexin peptide

Summary

Introduction

Damage to the lateral hypothalamus (LH) causes profound physical inactivity in mammals. Several molecularly distinct types of LH neurons have been identified, including orexin cells and glutamic acid decarboxylase 65 (GAD65) cells, but their interplay in orchestrating physical activity is not fully understood. We demonstrate that internally initiated GAD65LH cell bursts precede and accompany spontaneous running bouts, that selective chemogenetic silencing of natural GAD65LH cell activity depresses voluntary locomotion, and that GAD65LH cell overactivation leads to hyperlocomotion These results identify a molecularly distinct, orexin-activated LH submodule that governs physical activity in mice. It was recently found that LH neurons expressing glutamic acid decarboxylase 65 (GAD65) are distinct from orexin and MCH neurons [21] We hypothesized that these cells may be a source of natural LH signals underlying normal levels of physical activity. We find that GAD65LH cells operate as a stress- and orexin-activated LH module whose physiological activity is essential for normal locomotion, and whose hyperactivity causes hyperlocomotion

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Results

Conclusion