Visualizing Hypothalamic Network Dynamics for Appetitive and Consummatory Behaviors

Jennings, Joshua H.; Ung, Randall L.; Resendez, Shanna L.; Stamatakis, Alice M.; Taylor, Johnathon G.; Huang, Jonathan; Veleta, Katie; Kantak, Pranish A.; Aita, Megumi; Shilling-Scrivo, Kelson; Ramakrishnan, Charu; Deisseroth, Karl; Otte, Stephani; Stuber, Garret D.

doi:10.1016/j.cell.2014.12.026

Cited by 485 publications

(569 citation statements)

References 57 publications

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“…These findings establish the GAD65 LH cells as key players in intra-LH information processing. Together with recent findings on roles of defined LH neurons in eating and arousal (7,36,38), our results substantiate specific LH circuits as orchestrators of key voluntary actions.…”

Section: Discussionsupporting

confidence: 87%

“…Thus, the previous studies of VGAT LH cells (36-39) likely targeted larger and more heterogeneous cell populations than our study, which was selective for GAD65 LH cells. This fact may explain why the VGAT LH cell stimulation drove different behaviors [increased eating and insignificant effect on locomotion (36,39)] than the GAD65 LH cell stimulation (increased locomotion and no significant effect on eating; Fig. 3 and Fig.…”

Section: Discussionmentioning

confidence: 99%

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

Kosse

Schöne

Bracey

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

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

Kosse

Schöne

Bracey

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The lateral hypothalamus (LH) is a critical modulator of feeding (12,13). A previous study by Jennings et al demonstrated that GABAergic (Vgat-expressing) neurons in the LH are responsible for producing appetitive and consummatory behaviors (14). FXS animal models have lowered GABA subunit receptors, synthesis of GABA, GABAergic input to many regions of the brain, and increased catabolism of GABA (15,16).…”

Section: Neurobiology Of Fxs With Pwpmentioning

confidence: 99%

The neurobiology of the Prader-Willi phenotype of fragile X syndrome

Muzar

Lozano

Kolevzon

et al. 2016

IRDR

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“…Historically, direct manipulation of specific cell populations was challenging, but recently developed optogenetic and chemogenetic approaches allow one to achieve this goal. In one recent example, Jennings et al (2015) used a combination of optogenetic, chemogenetic, and neuronal ablation procedures to show that activation of LH GABAergic neurons increased, and inhibition or ablation of GABAergic neurons decreased, appetitive (food-seeking) and consummatory (eating) behaviors.…”

Section: Introductionmentioning

confidence: 99%

Lateral Hypothalamus GABAergic Neurons Modulate Consummatory Behaviors Regardless of the Caloric Content or Biological Relevance of the Consumed Stimuli

Navarro

Olney

Burnham

et al. 2015

Neuropsychopharmacol

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It was recently reported that activation of a subset of lateral hypothalamus (LH) GABAergic neurons induced both appetitive (food-seeking) and consummatory (eating) behaviors in vGat-ires-cre mice, while inhibition or deletion of GABAergic neurons blunted these behaviors. As food and caloric-dense liquid solutions were used, the data reported suggest that these LH GABAergic neurons may modulate behaviors that function to maintain homeostatic caloric balance. Here we report that chemogenetic activation of this GABAergic population in vGat-ires-cre mice increased consummatory behavior directed at any available stimulus, including those entailing calories (food, sucrose, and ethanol), those that do not (saccharin and water), and those lacking biological relevance (wood). Chemogenetic inhibition of these neurons attenuated consummatory behaviors. These data indicate that LH GABAergic neurons modulate consummatory behaviors regardless of the caloric content or biological relevance of the consumed stimuli.

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Visualizing Hypothalamic Network Dynamics for Appetitive and Consummatory Behaviors

Cited by 485 publications

References 57 publications

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

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

The neurobiology of the Prader-Willi phenotype of fragile X syndrome

Lateral Hypothalamus GABAergic Neurons Modulate Consummatory Behaviors Regardless of the Caloric Content or Biological Relevance of the Consumed Stimuli

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