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Chromosome substitution strains: a powerful tool to study the stress response in mouse

Final Activity Report Summary - CSS-OMICS (Chromosome substitution strains: a powerful tool to study the stress response in mouse)

Depression is a common, severely debilitating mental illness but we still know little about what causes depression, which genes and biological systems are involved and how to successfully treat this illness. Depression is closely related to stressful life events and some people are much more vulnerable to stress and adverse life events than others but we do not understand what makes one person susceptible and another not. Exciting, recent research has found that our genes can interact with environment, with some genes protecting us and other genes making us vulnerable to adverse events. Stressful events associated with loss of social support have been linked with depression, whereas social support has been found to be beneficial for people suffering from depression.

To understand how environment can influence our mental health, we need to study environment either under controlled conditions or manipulate the environment and observe the consequences. We clearly cannot do this with human subjects so it is vital scientists develop model systems. Mice are excellent model organisms as we can influence their genes and alter their environments in many ways. In this project, a model of social support was used to study the effects of manipulating social stress at the level of the brain (behaviour) and body (physiology). For the model of social support, mice were either housed alone or in small social groups from when they are weaned from their mother until adulthood. This model of social support was combined with a powerful genetic model. A special population of mice were used that had been bred in a way that allows researchers to identify specific genetic regions containing genes (chromosomes) within the complete set of mouse genes (genome). Researchers can use this genetic reference population of mice, called a chromosome substitution (CSS) panel, to hunt for specific genes. (The particular CSS panel used in this project had been generated by Joseph Nadeau and colleagues in 2004).

By combining the model of environment (social support) with the genetic model, my aim was to look for genes that are responsible for conferring either resilience or susceptibility to social stress that may relate to depression. There were three key results arising from this project. Firstly, specific interactions between the environment and genes were found in this study at the level of the brain (behaviour). One set of mice (CS-line F) from the CSS panel that were singly housed (social stress) were hyperactive and anxious compared to mice that were socially housed.

There was another set of mice (CS-line H) from the panel that appeared to be resilient to the effects of social stress as they did not have any increase in their activity. This suggests that there are specific genes that confer either susceptibility (in CS-line F mice) or resilience (in CS-line H mice) to social stress. Secondly, a set of mice (line A/J mice) had a bigger physiological response to stress, as measured by levels of a stress hormone (corticosterone) when singly housed compared to socially housed, providing evidence for an interaction between genes and environment at the level of the stress response system. I also looked at the activity of genes (gene expression) to see how useful a measure this would be for the social support model. The third finding from this study was that differences in gene activity can be detected in a related set of mice and that gene expression would be a useful measure of the interaction between genes and environment.

The most important scientific achievement made in this work is the demonstration that gene by environment interactions occurring in response to stress can be identified by combining mouse models of genes and environment. Specific genetic regions underlying these interactions were found - the first step towards identifying specific genes that either put people at risk, or protect against, developing depression.