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

The hypothalamic–pituitary–adrenal (HPA) axis functions to coordinate behavioural and physiological responses to stress in a manner that depends on the behavioural 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 (​Hcrt)/​orexin in the lateral hypothalamic area (LHA) regulate ​corticosterone release and a variety of behaviours 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.

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