Investigation of genetic and life events on hippocampal-dependent structure and function

Rationale
It is well established that the formation of new memories is critically dependent on the hippocampus and its neural circuitry. This circuitry is assembled during embryonic development from neural precursor cells that proliferate, differentiate, migrate and synapse with other neurons in the hippocampus, and defects in these processes have been implicated in neurodevelopmental disorders such as autism.
Yet this circuitry is not fixed, since the hippocampus is one of only two regions in the CNS were neurogenesis continues throughout life and is required for the formation of new memories (1). Defects in hippocampal neurogenesis have been implicated in the pathogenesis of epilepsy, dementia, and mental illness (2). Moreover, rates of neurogenesis in the hippocampus are altered by lifestyle factors, such as exercise, diet, social isolation, stress and medications (3-6). This means that hippocampal circuitry and memory performance is influenced by both inherited and lifestyle factors.

Aims & objectives
Aims:
Identify genetic and lifestyle factors that influence hippocampal structure and function during healthy ageing and in disease
Objectives:
1. Calculate heritability estimates using genome-wide complex trait analyses (GCTA)
2. Perform genome-wide association analyses to identify associated genetic variants
3. Analyse the effects of exercise, diet and early psychosocial exposures
4. Identify causal relationships for observed associations using Mendelian randomization methods

Methods
The student will learn a range of skills (as above) to investigate genetic and lifestyle factors influencing hippocampal-dependent structure and function. Hippocampal structure will be measured by analysis of magnetic resonance imaging (MRI) and hippocampal function from the results of neuropsychological tests, in two large population cohorts:
1. The Avon Longitudinal Study of Parents and Children (ALSPAC).
2. The UK Biobank of 500,000 adults aged 40-69.
Data from lifestyle questionnaires as well as genetic, epigenetic, neuropsychological and MRI studies are available for subsets of participants in both cohorts.
The student will learn multiple skills in cleaning, categorizing and analyzing complex genetic and phenotypic traits. They will have the opportunity to perform causal analyses, including Mendelian randomization (8), using these instruments and phenotypes in UK Biobank, then follow up interesting associations with more detailed analyses.