Project No. 2407

STANDARD PROJECT

Primary Supervisor

Dr Emily Brookes – University of Southampton

Co-Supervisor(s)

Prof Jerome Swinny – University of Portsmouth

Summary

Early life adversity (ELA), including child abuse and deprivation, increases the risk of neuropsychiatric disorders developing after later stressful events.

The importance of ELA to lifelong health is underscored by its association with ~30% adult-onset mental health disorders, including depression, anxiety, and schizophrenia. Understanding the molecular underpinnings of ELA will enable more successful identification and counteraction of ELA-linked neurological vulnerability, mitigating long-term consequences.

Epigenetic changes are a key mechanism of environmental influence on physiology. There are profound changes across the epigenome after ELA, but the functional impact is unclear. A recent study identified ‘ELA-primed genes’ which show expression changes only after ELA is combined with adult stress, with no change after ELA or adult stress alone; these are candidates to underpin brain dysfunction linked to neurological sensitivity. The contribution of genome architecture, including looping to distal regulatory elements, and location within the 3D nucleus, to gene priming in the context of neurological vulnerability has not been explored. Moreover, the importance of looking at neurons across brain stress circuits has been emphasised by recent reports on the wide distribution of fear memory engrams in adult mice, but has not been applied to the study of ELA.

In this project, using adult brains of male and female mice subjected to the limited bedding and nesting model of ELA, we will examine the regulation of candidate ELA-primed genes in neurons composing brain stress circuits.

The project will assess:

i) changes in the amount and location of target mRNAs and protein using single molecule RNA-FISH and immunohistochemistry.

ii) the location of genes with respect to nuclear landmarks including the repressive nuclear lamina using immunoDNA-FISH.

iii) genome looping to distal enhancers using DNA-FISH.

Candidates with a strong interest in epigenetics, imaging, and mental health research are encouraged to apply.