Theme: Mechanisms

Project Description

Bipolar disorder (BD) is characterised by recurring episodes of mania and depression, with sleep disturbances being a central feature throughout its course. Sleep problems emerge in childhood, precede diagnosis, and can trigger relapse, yet the biological mechanisms underlying these disturbances remain poorly understood. Current treatments are limited to behavioural interventions or medications with potential risks such as dependence.

This PhD project proposes that instability in “sleep pressure”, the biological drive to sleep that accumulates during wakefulness, may be a key mechanism linking sleep disturbances and BD. In mania, individuals feel little need for sleep, while in depression they often experience persistent lethargy. Research from animal models suggests that sleep pressure is regulated by processes involving mitochondrial activity and polyunsaturated fatty acids (PUFAs).

Importantly, the strongest genetic risk factor identified for BD is the FADS gene cluster, which controls PUFA synthesis. Evidence indicates that lower PUFA levels are associated with sleep problems and shorter sleep duration, while PUFA supplementation may improve sleep. Thus, PUFAs may be a mechanistic “smoking gun” linking genetic risk for BD and sleep, pointing towards a modifiable target early in life.

This is a PhD studentship focused on multi-omic and clinical data with three objectives. The student will:

1. Identify developmental periods when PUFAs influence sleep problems and emerging BD using longitudinal cohorts (ALSPAC and ABCD). 
2. Determine whether sleep pressure is a core mechanism in BD by examining overlap between BD genetic risk and brain gene-expression signatures for sleep pressure derived from animal models. 
3. Identify existing drugs and compounds that target sleep-pressure pathways using genomic drug-repositioning approaches.

Ultimately, the project aims to establish novel therapeutic targets and inform future clinical trials for bipolar disorder.