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

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 GAD65 LH neurons. We demonstrate that internally initiated GAD65 LH cell bursts precede and accompany spontaneous running bouts, that selective chemogenetic silencing of natural GAD65 LH cell activity depresses voluntary locomotion, and that GAD65 LH cell overactivation leads to hyperlocomotion. These results thus identify a molecularly distinct, orexin-activated LH submodule that governs physical activity in mice.T he lateral hypothalamus (LH) is thought to provide an essential drive for diverse vital behaviors, including locomotion. Peri-LH lesions in mammals disrupt context-appropriate physical activity, and are associated with the human disorder encephalitis lethargica, which has been noted to make humans "sit motionless. . .all day" (1-6). The LH is not a homogeneous entity, but contains many molecularly distinct classes of neurons that are thought to have different physiological roles (7). However, the interrelations of distinct LH cell classes in computing and driving context-appropriate physical activity are not fully understood.For example, LH neurons expressing orexins/hypocretins (8, 9) become activated in diverse stressful contexts, including acute auditory stimulation, hypoglycemia, hypercapnia, and physical capture (3, 9-13). Orexin LH cell activity may thus represent an important input variable for computing context-appropriate locomotor outputs (3,14), and orexin peptides have been proposed to increase arousal and locomotion by actions on extrahypothalamic projections to areas such as the locus coeruleus (15, 16). However, hypoactivity phenotypes caused by orexin LH cell deletion are milder than the hypoactivity phenotypes caused by broader LH lesions (1-3, 5, 12, 13, 17-19), whereas melanin-concentrating hormone LH (MCH LH ) cell deletion causes hyperactivity, implying that MCH LH cells suppress locomotion (20). These findings suggest that additional drivers of physical activity may exist in the LH.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. Here, we investigate this hypothesis by using a combination of cell type-specific manipulation and recording techniques. We find that GAD65 LH cells operate as a stress-and orexin-activated LH module whose physiological activity is essential for normal locomotion, and whose hyperactivity causes hyperlocomotion. ResultsOrexin and Stress Rapidly Recruit GAD65 LH Neurons. To examine whether orex...

Spontaneous Physical Activity Defends Against Obesity

“…A recent study however, indicates that orexin may be acting through glutamic acid decarboxylase 65 (GAD65) neurons. In this study, Kosse et al [95] demonstrated that a network of neurons expressing glutamic acid decarboxylase 65 are located within the LH, separate from MCH and orexin neurons, and may be responsible for facilitating changes in locomotor activity. Specifically, they showed that GAD65 neurons are necessary for carrying out orexin-mediated changes in locomotor activity [95].…”

“…In this study, Kosse et al [95] demonstrated that a network of neurons expressing glutamic acid decarboxylase 65 are located within the LH, separate from MCH and orexin neurons, and may be responsible for facilitating changes in locomotor activity. Specifically, they showed that GAD65 neurons are necessary for carrying out orexin-mediated changes in locomotor activity [95]. Therefore, it is possible that the changes in SPA observed in our studies are facilitated by changes in GAD-65 produced by orexin neuron activation.…”

Dysfunction of ventral tegmental area GABA neurons causes mania-like behavior

“…In rats, repeated delivery of subthreshold stimuli (kindling) to the LH induces manialike behavior 45 . Indeed, the LH promotes physical activity and motivated behavior 46 ; LH lesions in rodents and people produce a state of wakefulness with no motion 47 . The LH contains orexin/glutamate neurons that promote arousal, motivation and energy expenditure 48 , and GABAergic neurons whose activation induces wakefulness and locomotion 46,49,50 .…”

“…Indeed, the LH promotes physical activity and motivated behavior 46 ; LH lesions in rodents and people produce a state of wakefulness with no motion 47 . The LH contains orexin/glutamate neurons that promote arousal, motivation and energy expenditure 48 , and GABAergic neurons whose activation induces wakefulness and locomotion 46,49,50 . It is likely that the VTA Vgat neurons inhibit both the orexin neurons and/or the arousal/locomotorpromoting GABA neurons in the LH 26 .…”

Neuromodulation of orexin neurons reduces diet-induced adiposity

“…For example, a recent study by Kosse et al 2017 demonstrated that a network of neurons expressing glutamic acid decarboxylase 65 are located within the LH, separate from MCH and orexin neurons, and may be responsible for facilitating changes in locomotor activity. Specifically, they showed that GAD65 neurons are necessary for carrying out orexin-mediated changes in locomotor activity (28). Therefore it is possible that the changes in SPA observed in the present study were facilitated by changes in GAD-65 produced by orexin neuron activation.…”