Antagonistic interplay between hypocretin and leptin in the lateral hypothalamus regulates stress responses

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis functions to coordinate behavioral and physiological responses to stress in a manner that depends on the behavioral state of the organism. However, the mechanisms through which arousal and metabolic states influence the HPA-axis are poorly understood. Here, using optogenetic approaches in mice, we show that neurons that produce hypocretin/orexin (Hcrt) in the lateral hypothalamic area (LHA) regulate corticosterone release and a variety of behaviors and physiological hallmarks of the stress response. Interestingly, we found that Hcrt neuronal activity and Hcrt-mediated stress responses were inhibited by the satiety hormone leptin, which acts, in part, through a network of leptin-sensitive neurons in the LHA. These data demonstrate how peripheral metabolic signals interact with hypothalamic neurons to coordinate stress and arousal and suggest one mechanism through which hyperarousal or altered metabolic states may be linked with abnormal stress responses.

Principal cell types of sleep–wake regulatory circuits

“…Acting in part upon GABA and Glu effector neurons, neuromodulatory systems, including importantly ACh, NA, Orx and MCH neurons, each constitute one principal functional cell type and accordingly selectively promote different states with their EEG and EMG correlated activities. With increasingly specific genetic tagging of cell types according to both neurotransmitter and receptor [57] and calcium imaging [58] along with photo manipulation of the tagged cells, it is possible that future studies will reveal the full image of the differential distributions and activities of constituent cells of the principal functional cell types along with their interactions to further our understanding of sleep-wake regulatory circuits and the generation of sleep-wake states.…”

Euglycemia Restoration by Central Leptin in Type 1 Diabetes Requires STAT3 Signaling but Not Fast-Acting Neurotransmitter Release

“…The increased mTOR expression is also correlated with the fact that central leptin action increased p-S6 levels. Given the recent finding of a role for hypocretin neurons in activating the HPA axis (49), it is surprising that hypocretin levels were reduced by STZ and reversed by leptin. This result suggests that the enhanced HPA axis in STZ-induced T1D may not be mediated by hypocretin neurons.…”

Neural Circuitry of Wakefulness and Sleep

“…Orexin signaling also helps maintain arousal when animals are stressed, seeking rewards, or responding to homeostatic challenges (Bonnavion et al, 2015; Mahler et al, 2014). For example, food deprivation markedly increases wake in wild type mice, probably to encourage foraging, but mice lacking the orexin neurons show very little arousal with hunger (Yamanaka et al, 2003), and, in contrast to wild type mice, food deprivation has little antidepressant-like effect in mice lacking orexins (Lutter et al, 2008).…”