Sleep is under homeostatic control: After prolonged wakefulness, animals engage in persistent, consolidated, and deep sleep. Over the course of the past century, a great deal of research has been done on the homeostatic regulation of sleep; however, the biological foundations of this process remain a mystery. Progress is being made delineating molecular pathways that mediate sleep homeostasis. By contrast, the identity of neural circuits that sense and/or transmit homeostatic sleep signals is unclear.

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Sleep can be divided into rapid eye movement (REM) and non-REM (NREM) sleep, which is considered the deeper, more restorative form of sleep. To date, many NREM-promoting neural circuits have been identified. However, it is still unknown which specific neuronal clusters are necessary for the development of sleep need, and the objective of this study was to locate such a neural circuit. RESULTS
From a circuit screen in mice, a group of excitatory neurons in the thalamic nucleus reuniens (RE) was identified that projected to multiple downstream NREM-promoting clusters. Brief optogenetic activation of RE neurons led to an unusual phenotype—persistent, consolidated, and deep NREM sleep after a delay. Notably, during this delay period before falling asleep, the animals engaged in sleep-preparatory behaviors, which included grooming and nesting. Because the persistent, consolidated, and deep sleep phenotype resembled the homeostatic recovery sleep seen after sleep deprivation, we sought to investigate whether RE neurons participate in the homeostatic regulation of sleep. Most NREM-promoting neurons exhibit increased activity during NREM sleep. During recovery sleep and sleep deprivation, chronic Neuropixels recordings were made to measure the in vivo activity of RE neurons. These recordings revealed that RE activity was greater during sleep deprivation and/or wakefulness and reduced during recovery sleep. The next question we asked was whether the accumulation of sleep need required this increased RE activity during sleep deprivation. Chemogenetic inhibition of RE neurons during sleep deprivation reduced the quantity, consolidation, and depth of subsequent homeostatic recovery sleep. RE neurons promote NREM sleep by signaling to a previously identified NREM-promoting cluster in the zona incerta (ZI). Unexpectedly, sleep deprivation induced neural plastic changes of the RE-ZI connection. The degree of this RE-ZI plasticity correlated with the amount of subsequent homeostatic recovery sleep. Additionally, the morphological and functional connectivity between the RE and ZI neuronal clusters was improved by this synaptic plasticity. Calcium- and calmodulin-dependent protein kinase II (CaMKII) is well described to regulate synaptic plasticity and has been implicated in the homeostatic regulation of sleep. Inhibition of CaMKII activity in RE neurons reduced the RE-ZI plasticity and subsequent homeostatic recovery sleep triggered by sleep deprivation.
CONCLUSION
Our findings suggest that RE neurons are required for the accrual of sleep need and are able to generate persistent, deep sleep, similar to homeostatic recovery sleep. Sleep deprivation induces plasticity of the RE-ZI circuit, strengthening the connectivity of this sleep-promoting module. The degree of this plasticity correlates with the amount of homeostatic sleep rebound, which suggests that RE-ZI plasticity serves as a molecular readout for sleep need. These findings reveal a mechanism by which sleep loss transforms the functional coupling of a sleep circuit to promote persistent, deep sleep.

By Loknath

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