Lateral hypothalamic neurotensin neurons promote arousal and hyperthermia

Sleep and wakefulness are greatly influenced by various physiological and psychological factors, but the neuronal elements responsible for organizing sleep-wake behavior in response to these factors are largely unknown. In this study, we report that a subset of neurons in the lateral hypothalamic area (LH) expressing the neuropeptide neurotensin (Nts) is critical for orchestrating sleep-wake responses to acute psychological and physiological challenges or stressors. We show that selective activation of Nts(LH) neurons with chemogenetic or optogenetic methods elicits rapid transitions from non-rapid eye movement (NREM) sleep to wakefulness and produces sustained arousal, higher locomotor activity (LMA), and hyperthermia, which are commonly observed after acute stress exposure. On the other hand, selective chemogenetic inhibition of Nts(LH) neurons attenuates the arousal, LMA, and body temperature (Tb) responses to a psychological stress (a novel environment) and augments the responses to a physiological stress (fasting). Author summary Adjusting sleep-wake behavior in response to environmental and physiological challenges may not only be of protective value, but can also be vital for the survival of the organism. For example, while it is crucial to increase wake to explore a novel environment to search for potential threats and food sources, it is also necessary to decrease wake and reduce energy expenditure during prolonged absence of food. In this study, we report that a subset of neurons in the lateral hypothalamic area (LH) expressing the neuropeptide neurotensin (Nts) is critical for orchestrating sleep-wake responses to such challenges. We show that brief activation of Nts(LH) neurons in mice evokes immediate arousals from sleep, while their sustained activation increases wake, locomotor activity, and body temperature for several hours. In contrast, when Nts(LH) neurons are inhibited, mice are neither able to sustain wake in a novel environment nor able to reduce wake during food deprivation. These data suggest that Nts(LH) neurons may be necessary for generating appropriate sleep-wake responses to a wide variety of environmental and physiological challenges.