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Reciprocal lateral hypothalamic and raphe GABAergic projections promote wakefulness

Gazea, Mary, Furdan, Szabina, Sere, Péter, Oesch, Lukas, Molnár, Benedek, Di Giovanni, Giuseppe, Fenno, Lief E., Ramakrishnan, Charu, Mattis, Joanna, Deisseroth, Karl, Dymecki, Susan M., Adamantidis, Antoine R. and L?rincz, Magor L. 2021. Reciprocal lateral hypothalamic and raphe GABAergic projections promote wakefulness. Journal of Neuroscience 41 (22) , pp. 4840-4849. 10.1523/JNEUROSCI.2850-20.2021

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The lateral hypothalamus (LH), together with multiple neuromodulatory systems of the brain, such as the dorsal raphe nucleus (DR), is implicated in arousal, yet interactions between these systems are just beginning to be explored. Using a combination of viral tracing, circuit mapping, electrophysiological recordings from identified neurons, and combinatorial optogenetics in mice, we show that GABAergic neurons in the LH selectively inhibit GABAergic neurons in the DR, resulting in increased firing of a substantial fraction of its neurons that ultimately promotes arousal. These DRGABA neurons are wake active and project to multiple brain areas involved in the control of arousal, including the LH, where their specific activation potently influences local network activity leading to arousal from sleep. Our results show how mutual inhibitory projections between the LH and the DR promote wakefulness and suggest a complex arousal control by intimate interactions between long-range connections and local circuit dynamics. SIGNIFICANCE STATEMENT: Multiple brain systems including the lateral hypothalamus and raphe serotonergic system are involved in the regulation of the sleep/wake cycle, yet the interaction between these systems have remained elusive. Here we show that mutual disinhibition mediated by long range inhibitory projections between these brain areas can promote wakefulness. The main importance of this work relies in revealing the interaction between a brain area involved in autonomic regulation and another in controlling higher brain functions including reward, patience, mood and sensory coding.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Society for Neuroscience
ISSN: 0270-6474
Date of First Compliant Deposit: 18 January 2022
Date of Acceptance: 28 February 2021
Last Modified: 08 May 2023 09:55

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