Leptin engages the lateral hypothalamus to ventral tegmental area circuit to modulate sleep-wake behavior Article Swipe
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· 2024
· Open Access
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· DOI: https://doi.org/10.21203/rs.3.rs-3934916/v1
· OA: W4392094116
<title>Abstract</title> Sleep and metabolism are inextricably linked and mutually affect each other. Leptin is a pivotal regulator of metabolic homeostasis, but its effect on sleep-wake regulation remains elusive. Here we demonstrate that leptin acts on a small subset of lateral hypothalamic area (LHA) GABAergic neurons to affect sleep-wake behavior. We found that the selective loss of leptin receptors (LepRs) in the LHA causes sleep fragmentation without altering total sleep time, while severe sleep fragmentation in obese LepR-null mice can be rescued by the selective restoration of LHA<sup>LepR </sup>signaling. <italic>In vivo </italic>Ca<sup>2+</sup> imaging revealed that the vast majority of LHA<sup>LepR+</sup> neurons are REM sleep- and/or wake-active, and chemogenetic activation of LHA<sup>LepR+</sup> neurons lead to sustained wakefulness. Furthermore, optogenetic activation of LHA<sup>LepR+</sup> neuron projections to the ventral tegmental area promotes arousal. Collectively, our results identify an important hypothalamic substrate linking metabolic alterations to aberrant sleep-wake patterns in obesity.
