State-dependent functions of the cholinergic system in the brain
Supervisors:
Dr Shuzo Sakata, Strathclyde Institute of Pharmacy and Biomedical Sciences (University of Strathclyde)
Prof Andrew Tobin, School of Molecular Biosciences, (University of Glasgow)
Summary:
Sleep is a fundamental biological function across the animal kingdom. Sleep abnormalities are closely linked to various brain disorders. Despite its significance, the regulatory mechanism and function of sleep is incompletely understood.
Acetylcholine (ACh) is a key neuromodulator for arousal, anxiety, learning and memory. Interestingly, although ACh facilitates learning and memory during wakefulness, ACh diminishes memory consolidation during slow-wave sleep. However, we know little about the underlying circuit mechanism.
To address this issue, we will employ a multidisciplinary approach in mice. Combining in vivo electrophysiology, imaging, optogenetics, pharmacology and behavioural analysis, we will test the hypothesis that cholinergic functions are state-dependent.
By focusing on M1 muscarinic acetylcholine receptors (M1Rs), we aim to (1) map M1R-positive neuronal activity across sleep-wake cycles and brain regions, (2) investigate state-dependent responses of these neurons to M1R positive allosteric modulator (PAM), (3) determine the state-dependent impact of M1R PAM on memory, and (4) optimize M1R modulation through time-resolved cholinergic manipulation.
Under the guidance of a world-leading molecular pharmacologist and systems neuroscientist, a student undertaking this project will acquire cutting-edge experimental and computational skills as well as developing essential research competencies, preparing them for successful research careers.