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The disruption of hypocretin regulation is known to be associated with depression, however, their exact correlation is remains to be elucidated. Hypocretin\u20101 levels are increased in the plasma and hypothalamus from chronic unpredictable mild stress (CUMS) model mice. Excessive hypocretin\u20101 conducted with hypocretin receptor 1 (HCRTR1) reduced lactate production and brain\u2010derived neurotrophic factor (BDNF) expression by hypoxia\u2010inducible factor\u20101\u03b1 (HIF\u20101\u03b1), thus impairing adult hippocampal neuroplasticity, and cognitive impairment in CUMS model. Subsequently, it is found that HCRTR1 antagonists can reverse these changes. The direct effect of hypocretin\u20101 on hippocampal lactate production and cognitive behavior is further confirmed by intraventricular injection of hypocretin\u20101 and microPET\u2010CT in rats. In addition, these mechanisms are further validated in astrocytes and neurons in vitro. Moreover, these phenotypes and changes in molecules of lactate transport pathway can be duplicated by specifically knockdown of HCRTR1 in hippocampal astrocytes. 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