Neural circuit dysfunction in a mouse model of 22q11.2 deletion syndrome. PhD in Medical Studies (MRC GW4 BioMed DTP)

Supervisory team:
Dr Michael Craig, Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter
Prof Emma Robinson, Faculty of Life Sciences, University of Bristol
Prof Andrew Randall, College of Medicine and Health, University of Exeter

This project will study the neural circuitry of mice with a chromosomal microdeletion that, in humans, greatly increases the risk of developing schizophrenia or ASD. The project will employ a combination of electrophysiology, optogenetics and behaviour to determine how impaired neural circuit function leads to impaired cognition.

Research into discovering changes in neural circuit function that underlies the pathophysiology of disorders such as schizophrenia and autistic spectrum disorder (ASD) is limited due to a poor understanding of the causes of these disorders in humans. However, recent studies into rare buy highly-penetrant mutations have discovered that copy number variations (CNVs), small de novo mutations on chromosomes, underlie many neurological and psychiatric disorders. One such CNV, a microdeletion on chromosome 22q11.2, hugely increases an individual’s risk of developing schizophrenia or ASD. 22q11.2 deletion syndrome (DS) typically affects around 20 genes, many of which are involved in CNS function. Chromosome 16 in mice is syntenic with human chromosome 22, allowing mouse models of 22q11.2DS to closely resemble the human condition, and this project will use one such model, Df16A mice.

Preliminary findings from our group have found that Df16A mice show impaired motivation in behavioural experiments that involve learning that is reinforced using food rewards. This impaired learning is associated with reduced activity in dopaminergic brain regions including the dorsal striatum and ventral tegmental area. The aim of this PhD project is to study the neural circuitry that underpins this impaired motivation, as this has the potential to generate key insights both into the neural circuitry underlying motivation in healthy individuals, and pathological changes that may be associated with some of the negative symptoms of schizophrenia. Specific aims of the project are as follows:

Aim 1: determine whether regions linked with motivation show impaired synaptic connectivity with brain regions involved in learning and memory, such as PFC and hippocampus in Df16A mice. Aim 2: Investigate the specific deficits which underlie the observed impairments in reward motivation using behavioural assays designed to distinguish between changes in reward sensitivity, motivation and learning. Aim 3: determine whether perturbing specific projections between reward centres and cortical / hippocampal regions in wildtype mice can replicate deficits seen in Df16A mice.

This project will use a combination of viral-assisted circuit mapping and patch-clamp electrophysiology to determine which inputs and outputs from the brain’s reward centres are affected in 22q11.2DS. The project will also use behavioural tests combined with an intersectional virus strategy, using a combination of retrograde and anterograde transduction, to allow inactivation of specific projections between regions involved in reward (e.g. striatum) and those involved in learning and decision-making (e.g. hippocampus and PFC).

This interdisciplinary project will enable the student to gain expertise in cutting-edge genetic manipulations of neural circuit function, as well learning electrophysiological and behavioural methods, both of which are currently very much in-demand skills.

To apply for this project, please complete the application form at https://cardiff.onlinesurveys.ac.uk/gw4-biomed-mrc-doctoral-training-partnership-student-appl by 5pm Friday 25 November 2019.