Ventral hippocampal control of behavioural flexibility, and its disruption by adolescent social isolation

Long periods of stress during adolescence can result in profound differences in behaviour in adulthood. For example, long term stress during adolescence can impair what is termed flexible behaviour - the ability to alter what actions you take in response to a particular situation.

This is a problem as these changes in behaviour are thought to increase susceptibility to almost all of the most common mental health disorders such as addiction, depression and schizophrenia. This results in almost 80 % of young adults that report significant early life stress subsequently being diagnosed with one of these disorders.

Despite this remarkable prevalence, exactly how chronic stress early in life results in these behavioural deficits is not well understood. One of the only consistent findings in both humans, and also preclinical models such as mice, is that a part of the brain called the hippocampus is dramatically reduced in size and function after long lasting stress, for example after long periods of social isolation during adolescence. However, how and if this dramatic change in hippocampal circuitry results in these behavioural impairments later in life is unknown.

In this project we propose to answer this problem directly for the first time. We will train mice to perform versions of the same tasks used to study stress-induced behaviour in humans. We will then use computational modelling to understand exactly how the mice are carrying out these tasks. By using this modelling approach, this will allow us to directly relate our work in mice to work in humans.

We will then take advantage of the large range of state-of-the-art techniques available in mice to study detailed neuronal circuitry and investigate exactly which hippocampal neurons are affected by early life stress, and exactly how they are altered.

Finally, we will use this new knowledge to directly investigate how these alterations in hippocampal neurons result in changes to behaviour. To do this we will use genetics to carry out manipulations that 'fix' the changes to the circuit induced by chronic stress. We can then look to see how 'fixed' mice carry out our behavioural tasks to see if repairing the deficits to the hippocampus can repair problems with behaviour.

Overall our aim with this research is to understand exactly what neurons are altered by adolescent stress, and how these alterations result in changes to behaviour. In the future we hope to use this knowledge to develop more specific treatments for these disorders.

The aim of this project is to understand how adolescent isolation induced circuit alterations in the ventral hippocampus directly contribute to deficits in behavioural flexibility.

Our overarching hypotheses are:
i) Isolation-induced behavioural inflexibility results from a combination of alterations affecting different reinforcement learning processes;
ii) Each of these processes is impaired by changes to a unique population of projection neurons in the ventral hippocampus.

To address these questions we aim to:

1) Apply detailed computational models of behaviour developed through human research, based on state-of-the-art reinforcement learning techniques, to identify the precise cognitive processes that drive the observed alterations to flexible behaviour induced by social isolation, and investigate how these are supported by unique populations of projection neurons in the ventral hippocampus;

2) Use intersectional anatomical, genetic and viral techniques to investigate how chronic social isolation alters the intrinsic electrophysiological properties, synaptic function and genetic makeup of each unique neuronal population in the ventral hippocampus;

3) Combine the findings from these two aims and use optogenetic and molecular manipulations of each projection population to ask whether restoring specific adolescent isolation induced circuit alterations can rescue maladaptive changes in behavioural flexibility.

Achieving these aims will provide a quantitative, computationally-informed understanding of how hippocampal circuitry is altered by chronic adolescent social isolation, as well as detailed mechanistic insight into why dysfunction in this circuitry results in cognitive inflexibility: a hallmark of the progression to mental illness.