Chronic chemogenetic slow-wave-sleep enhancement in mice

Area of Science:

• Neuroscience
• Sleep Science
• Pharmacology

Background:

• Epidemiological studies suggest sleep impacts human disease, but causal links and mechanisms require further investigation.
• Previous work established an acute SWS enhancement mouse model via chemogenetics targeting pontine parafacial zone GABAergic neurons (PZ^GABA).
• The feasibility of chronic SWS enhancement in this model remained unaddressed.

Purpose of the Study:

• To establish and validate a mouse model for chronic slow-wave sleep (SWS) enhancement.
• To investigate the long-term effects of chemogenetic SWS enhancement on sleep phenotypes.
• To provide a tool for mechanistic studies on SWS's physiological and disease-preventing roles.

Main Methods:

• Mice expressing the hM3Dq chemogenetic receptor in PZ^GABA neurons were used.
• Daily administration of chemogenetic ligands (CNO, DCZ, C21) was employed.
• Sleep-wake phenotypes were analyzed using electroencephalogram (EEG) and electromyogram (EMG).

Main Results:

• Chronic SWS enhancement was achieved, with increased SWS duration for up to six months.
• This enhancement was accompanied by a sustained increase in slow wave activity (SWA).
• Elevated SWA persisted for over a week after the six-month dosing period concluded.

Conclusions:

• A robust mouse model for chronic SWS enhancement has been validated.
• This model facilitates mechanistic investigations into SWS's role in physiological functions and disease prevention.
• A rotating ligand schedule offers a potentially broad application in chronic chemogenetic studies.