Chronic Sleep Disruption Increases Activity of Cholinergic Neurons in the Habenula

Post by Sarah Hill

What's the science?

In recent years, sleep has been increasingly recognized as an important regulator of a myriad of biological processes, including memory performance, food valuation, and resting cerebral blood flow (see previous BrainPosts). As it turns out, emotional health may also be regulated by sleep, though the molecular, cellular, and circuit mechanisms responsible have been difficult to pin down. This week in Molecular Psychiatry, Ge and colleagues show that the baseline firing rate of cholinergic neurons (ChNs) within the medial habenula complex (a brain region involved in signalling reward prediction and errors in reward prediction), is increased after chronic sleep disruption.

How did they do it?

To model chronic sleep disruption in mice, the authors carried out a protocol of sleep fragmentation, a procedure designed to specifically disrupt REM sleep in rodents. SF animals were housed in custom-made treadmill boxes for 5 days: while the floor of the animal's cage consisted of a layer of steel mesh, timed rotating of a treadmill belt caused a cylindrical object underneath the mesh layer to roll back-and-forth along the length of the cage, preventing the mouse from sleeping uninterrupted. In a control group of mice, no treadmill was present. Sleeping behavior was monitored for a portion of the animals by surgically implanting EEG/EMG electrodes and decoding neural activity into 3 broad categories: wakefulness, REM sleep, and NREM sleep. Following sacrifice of the animals, electrophysiology was used to record activity of cholinergic neurons (ChNs) in brain slices containing the medial habenula complex; various ion channel- and neurotransmitter receptor-modifying reagents were added to the bath solution to test the resulting effects on ChN activity. Finally, immunohistochemical and in situ hybridization techniques were employed to label cholinergic neurons and TASK-3, a potassium channel important for modulating neuronal activity.            

What did they find?

EEG/EMG recordings showed that animals who experienced sleep fragmentation exhibited significant decreases in average duration of REM sleep episodes during the 5-day protocol, compared to control mice. Electrophysiological recording showed augmented baseline firing rate of ChNs in the medial habenula complex of REM sleep-disrupted animals. This is significant because the activity of medial habenula ChNs has been previously linked to a number of affect-related behaviors, including stress and drug-relapse. Application of various neurotransmitter-modifying reagents failed to produce any changes in baseline ChN activity in both the SF and control groups, indicating that sleep-induced alterations in ChN activity are not mediated by synaptic transmission. However, group differences in baseline ChN activity were observed upon application of a TASK-3 antagonist. First, while depolarization of the resting membrane potential was seen in the control group following addition of the antagonist, no changes in resting membrane potential were recorded in mice who experienced sleep fragmentation. Second, application of the TASK-3 antagonist led to an increase in firing rate in the control group, but not the fragmented sleep  group. Finally, the increase in firing rate observed in the control group was accompanied by a significant increase in firing regularity (measured as the coefficient of variation of firing interval), which was also not observed in the fragmented sleep group. Taken together, these findings suggest that TASK-3 potassium channels are compromised following sleep fragmentation, leading to alterations in baseline ChN activity in the medial habenula.     


What's the impact?

This is the first study to investigate the effects of sleep disruption on medial habenula ChN activity. Though additional studies are needed to determine exactly how TASK-3 potassium channels are targeted by sleep fragmentation, these findings are strongly indicative of a direct mechanism linking sleep and emotion regulation.  

Ge et al. Chronic sleep fragmentation enhances habenula cholinergic neural activity. Molecular Psychiatry (2019). Access the original scientific publication here.