New Brain Circuit Helps Recover Lost Sleep

Forgoing sleep to watch one more episode of the latest show, to read one more chapter of a thrilling book, or even to pull an all-nighter, is not uncommon. But sleep deprivation can catch up to people, leading to an accumulated “sleep debt,” and all debts must be paid. To make up for this lost sleep, people typically sleep deeper and longer, restoring sleep homeostasis. However, the neuronal mechanisms that trigger this recovery sleep remain poorly understood.

Now, researchers led by neuroscientist Mark Wu at Johns Hopkins University identified a subgroup of neurons in the thalamus of the mouse brain are crucial for the homeostatic regulation of sleep, providing insights into how animals recover from lost sleep.¹ The researchers published their findings today in Science.

Mammalian sleep can be divided into rapid eye movement (REM) and non-REM (NREM) sleep. Many neuronal clusters promote NREM sleep with switch-like activity: Stimulating these neurons induces sleep in mice while deactivating them prompts the mice to wake up.

Curious to learn more about the neurons that regulate sleep, the researchers first mapped neural circuits upstream of known sleep-promoting brain regions in mice. After identifying 11 candidate regions, they injected mice with clozapine N-oxide, a synthetic molecule, to see if chemical activation of the excitatory neurons in those areas promoted sleep. Of these, the activation of a subset of excitatory neurons in the medial thalamic nucleus reuniens (mRE) led to the greatest increase in NREM sleep.

To further characterize these mRE neurons, the researchers employed chemogenetic and optogenetic tools. Using either method, they found that stimulated neurons led to mice that exhibited deeper and more prolonged NREM sleep several hours later. This suggested that these neurons do not directly induce sleep but instead regulate sleep homeostasis. The researchers also saw that when they activated mRE neurons with light, the mice engaged in enhanced typical pre-sleep behaviors, such as preparing a spot to sleep (nesting) or self-grooming.

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To determine whether mRE activity regulates sleep-wake cycles or plays a more prominent role in restoring sleep homeostasis after sleep deprivation, the researchers recorded neuronal activity during extended wakefulness (ranging from 1–12 hours). The researchers kept mice awake by lightly touching their bedding and tails. They found that mRE neurons fired more frequently while the mice were awake and subsided in subsequent recovery sleep. This pattern contrasts with conventional sleep-promoting neurons, which are typically most active during sleep itself. This further supports the idea that mRE neurons within this circuit are dedicated to reestablishing sleep homeostasis, rather than just regulating sleep-wake cycles.

To examine the downstream effects of mRE neuron activation, the researchers tracked mRE neurons projecting to multiple NREM-promoting clusters of neurons. Of these, they found that mRE neurons act on zona incerta (ZI) cells, which lie in a small region beneath the thalamus, to generate persistent, consolidated, and deep NREM sleep. Not only that, but the researchers also noticed that the density of mRE neurons exhibited weak connections to ZI neurons at baseline sleep. However, sleep deprivation enhanced mRE-ZI interactions.

Lastly, to explore the molecular mechanisms behind this plasticity, the researchers turned to calcium- and calmodulin-dependent protein kinase II (CaMKII), a well-known regulator of synaptic plasticity and a promoter of NREM sleep.^2,3 Inhibiting CAMKII in mRE neurons led to a reduction in NREM sleep, suggesting that CaMKII signaling is required for mRE plasticity and NREM recovery sleep after sleep loss.

Overall, these findings provide insight into a neural circuit where prolonged wakefulness leads to a cascade of events: increased mRE neuronal activity, CaMKII activation, and enhanced neuronal plasticity with ZI neurons to promote deep NREM recovery sleep. In addition, a better understanding of these neural circuits could provide valuable insights into neurological and psychiatric disorders linked to sleep deprivation or abnormal sleep patterns.