Lateral hypothalamic neuronal ensembles regulate pre-sleep nest-building behavior

• Published in: Current biology 2022-02, Vol.32 (4), p.806-822.e7
• Main Authors: Sotelo, Maria I., Tyan, Jean, Markunas, Chelsea, Sulaman, Bibi A., Horwitz, Lorraine, Lee, Hankyu, Morrow, Joshua G., Rothschild, Gideon, Duan, Bo, Eban-Rothschild, Ada
• Format: Article
• Language: English
• Subjects: Animals; Brain - physiology; chemogenetics; grooming; Hypothalamic Area, Lateral - physiology; lateral hypothalamus; Mice; nest-building; nesting; neuronal ensembles; Neurons - physiology; pre-sleep; sleep; Sleep - physiology; TRAP; wakefulness; Wakefulness - physiology
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2021.12.053

The transition from wakefulness to sleep requires striking alterations in brain activity, physiology, and behavior, yet the precise neuronal circuit elements facilitating this transition remain unclear. Prior to sleep onset, many animal species display characteristic behaviors, including finding a safe location, performing hygiene-related behaviors, and preparing a space for sleep. It has been proposed that the pre-sleep period is a transitional phase in which engaging in a specific behavioral repertoire de-arouses the brain and facilitates the wake-to-sleep transition, yet both causal evidence for this premise and an understanding of the neuronal circuit elements involved are lacking. Here, we combine detailed behavioral observations, EEG-EMG recordings, selective targeting, and activity modulation of pre-sleep-active neurons to reveal the behaviors preceding sleep initiation and their underlying neurobiological mechanisms. We show that mice engage in temporally structured behaviors with stereotypic EEG signatures prior to sleep and that nest-building and grooming become significantly more prevalent with sleep proximity. We next demonstrate that the ability to build a nest promotes the initiation and consolidation of sleep and that the lack of nesting material chronically fragments sleep. Lastly, we identify broadly projecting and predominantly glutamatergic neuronal ensembles in the lateral hypothalamus that regulate the motivation to engage in pre-sleep nest-building behavior and gate sleep initiation and intensity. Our study provides causal evidence for the facilitatory role of pre-sleep behaviors in sleep initiation and consolidation and a functional characterization of the neuronal underpinnings regulating a sleep-related and goal-directed complex behavior. [Display omitted] •Prior to falling asleep, mice mainly engage in nesting and grooming•The capacity to nest prior to sleep promotes sleep initiation and consolidation•Lateral hypothalamus glutamatergic ensembles regulate the motivation to engage in pre-sleep nesting•Lateral hypothalamus glutamatergic ensembles gate sleep initiation and intensity Sotelo et al. demonstrate that mice have a temporally structured pre-sleep phase dominated by nesting and grooming. They show that the capacity to build and sleep in a nest promotes sleep initiation and consolidation and that pre-sleep nesting is controlled by non-hypocretin glutamatergic LH ensembles that also gate sleep initiation and intensity.