Genetic risk factors involved in brain circuit changes caused by early life adversity

Supervisors: Prof Mellor, University of Bristol & Prof Hall, Cardiff University, Dr Robinson, University of Bristol & Prof Wilkinson, Cardiff University

The early life experiences and genetic background of children are key determinants in their future mental health. Early life adversity including trauma or disruption of the mother-infant relationship and genetic risk factors are highly significant in determining a child’s future susceptibility to a range of psychiatric disorders including anxiety, depression and psychosis.

Early life adversity causes stress and raises cortisol levels but we know relatively little about the changes in brain circuit development caused by early life adversity and stress and what genetic factors influence their emergence. The circuits controlling positive and negative affect (or emotions) and those that regulate the stress response to emotional situations are known to involve the amygdala and hippocampus. In particular, positive and negative affective behaviour is thought to be significantly controlled by the strength of synaptic inputs to genetically and anatomically defined subsets of neurons in the hippocampus and amygdala. Thus we propose that adverse early life events will lead to altered synaptic strengths in these hippocampal and amygdala circuits compared to normal early life experiences. Genetic mutations that affect the process of synaptic plasticity may modulate the susceptibility of these circuits to early life stress. Ultimately, reversing these changes in synaptic strength could ameliorate the behavioural effects of early life adversity in adults.

This project will test this hypothesis using rodent models of early life stress and behavioural tests of positive versus negative affective behaviour developed by the Hall and Robinson groups. The primary objective will be to determine how these early life effects on developing circuits impact on adult behaviour, particularly affective behaviour and decision-making. By making electrophysiological measurements of synaptic transmission coupled with genetic and anatomical identification of neuronal subtypes developed in the Mellor group we will investigate how these circuits are altered by early life adversity. We also have the potential to determine how these early life stress factors differentially impact on transgenic animals bearing mutations in synaptic genes associated with psychiatric illness. The ultimate goal will be to find out if manipulating synapses within the circuits underlying behaviour using pharmacological or optogenetic tools is capable of changing the balance of positive and negative affect in adult animals.

The student will be trained in animal behavioural paradigms developed in Cardiff and Bristol, in vitro and in vivo electrophysiology and genetic manipulation of neuronal subtypes and related molecular techniques. In addition, through a longstanding collaboration with Krasimira Tsaneva-Atanasova in Exeter the project can also be extended to use computational models to predict the likely outcome of synaptic modifications on behaviour.