State-dependent brainstem ensemble dynamics and their interactions with hippocampus across sleep states

Abstract

The brainstem plays a crucial role in sleep-wake regulation. However, the ensemble dynamics underlying sleep regulation remain poorly understood. Here, we show slow, state-predictive brainstem ensemble dynamics and state-dependent interactions between the brainstem and the hippocampus in mice. On a timescale of seconds to minutes, brainstem populations can predict pupil dilation and vigilance states and exhibit longer prediction power than hippocampal CA1 neurons. On a timescale of sub-seconds, pontine waves (P-waves) are accompanied by synchronous firing of brainstem neurons during both rapid eye movement (REM) and non-REM (NREM) sleep. Crucially, P-waves functionally interact with CA1 activity in a state-dependent manner: during NREM sleep, hippocampal sharp wave-ripples (SWRs) precede P-waves. On the other hand, P-waves during REM sleep are phase-locked with ongoing theta oscillations and are followed by burst firing of CA1 neurons. This state-dependent global coordination between the brainstem and hippocampus implicates distinct functional roles of sleep.

eLife digest

Though almost all animals sleep, its exact purpose remains an enigma. This is particularly true for the period of sleep where people dream most vividly, which is known as rapid eye movement sleep or REM sleep for short. In addition to the eye movements that give it its name, during this phase of sleep, the pupils of the eyes become smaller, muscles relax and neurons in part of the brain activate in a regular, repeating way known as pontine waves or P-waves.

The brainstem is a key brain region that helps the body determine when it is time to sleep and when it is time to be awake. It is found at the back of the brain, and connects the brain to the spinal cord, serving as a conduit for nerve signals to and from the rest of the body. However, it was not clear how the brainstem’s activity during sleep interacts with other brain regions that are important in the sleep process, such as the hippocampus.

REM sleep is not unique to humans; in fact, it occurs in all mammals. Tsunematsu et al. studied mice to better understand the role of the brainstem during sleep. In the experiments, the brain waves, muscle tone and pupil sizes of the mice were monitored, while a probe inserted into the brainstem of the mice measured the activity of the neurons. Analysis of the probe data could predict changes in pupil size ten seconds beforehand and transitions between wakefulness, REM sleep and non-REM sleep up to sixty seconds in advance. This long timescale suggests that there are a number of complex interactions following brainstem activity that lead to the changes in sleep state.

Tsunematsu et al. were also able to detect P-waves for the first time in mice and found that they are timed with activity from the hippocampus depending on the sleep state. During REM sleep, the P-waves precede the hippocampal activity, while during non-REM sleep, they follow it. These results further imply that the two sleep states serve different purposes. The detection of P-waves in mice shows that they are similar to other mammals that have previously been studied. Further studies in mice could help to provide more insight into the mechanisms of sleep and the purpose of the different stages.