Investigating the role of neuropsychological processes in stress induced negative affective states and assocaited behaviour

Stress-related disorders are a major issue in western society contributing to both social and economic loss. Stress is strongly associated with development of psychiatric disorders with more than 20% of the population directly affected by either anxiety or depression. Stress is also associated with other conditions including psychosomatic disturbances (lower back pain, gastrointestinal diseases such as irritable bowl syndrome), addiction and obesity.

Although drugs to treat stress-related conditions, such as depression, were discovered in the 1950s, scientists have found it difficult to explain how they act in the brain to treat the symptoms of the disease and why it takes several weeks before the patient starts to feel better. Studying the brain and how it controls our behaviour, including our emotional behaviour, is complicated and psychiatric disorders represent one of the biggest challenges. Whilst studies in patients use questionnaires, interviews, brain imaging techniques and psychology, experiments in animals are important to unlock the specific parts of the brain and brain chemistry involved. Animal tests are also very important for the development of new treatments and are essential to establishing whether a drug is likely to be effective in a patient and therefore suitable for clinical trials.

In this project, we aim to bring together two aspects of stress-related biology and test a novel hypothesis. The two areas we are interested in are:
1. Stress-related changes in brain structure
2. Stress-related changes in behaviour e.g. reduced motivation, reduced experience of pleasure, apathy and social withdrawal.

Until very recently, studies in animals have largely concentrated on stress-related changes in brain structure with the behavioural tests available revealing little about how these relate to the human conditions. Whilst research into the basic biology of stress-related conditions has focused on the more molecular and cellular aspects, clinical research has recently looked toward psychological processes to try to provide a better explanation for the symptoms observed in patients. We have now developed a new method to study emotional behaviour in animals which taps into similar psychological processes. We are now in the unique position to carryout studies to directly assess how stress impacts on both behavioural and structural changes in the brain. We predict that our studies will reveal that cognitive affective processes are the key mechanisms influencing behaviour rather than arising as a consequence of structural adaptation. We also predict that the symptoms of stress-related disorders, such as reduced motivation, reduced experience of pleasure, apathy and social withdrawal, in fact cause the structural changes in the brain.

Our research has the potential to reveal an important causal relationship between neuropsychological processes implicated in stress-induced negative emotional behaviour and structural changes in the brain. If we are successful in achieving this, the results of this work will have a major impact on how we target stress-related conditions in man in the future. It will also provide new insights into the impact of different types of stress, their duration and their long term impact on vulnerability to future stress and emotional disorders. Because our work is in animals, it will also impact on how we consider stress in the context of animal welfare.

The overarching aim of this research is to test a novel hypothesis about the biological relationship between stress and the neurotrophic changes in the brain. Molecular and cellular studies have demonstrated opposing roles of stress and antidepressant drugs however, demonstrating a direct link with behavioural symptoms of emotional disorders has been more challenging. Clinical research, and recently our own pre-clinical research, suggests that the behavioural outcomes of stress may involve neuropsychological mechanisms, including negative cognitive affective biases. Here we propose a series of experiments to test the idea that the structural changes associated with deleterious effects of stress are consequential of these negative cognitive affective biases influencing behaviour. Rather than neurotrophic changes causing the behavioural symptoms observed in stress-related disorders, we propose that stress affects cognitive affective behaviour which in turn causes the behavioural symptoms of reduced motivation, anhedonia, apathy, decreased social and environmental interaction and, it is these behavioural changes, which result in brain atrophy.

The first part of the project will focus on advancing our understanding of how stress impacts on cognitive affective biases using our novel translational task. We will look at different types of physiological and psychological stressors and vulnerability associated with stress-induced negative affective states and early life adversity. The second component of the project is a longitudinal study designed to assess whether the acute negative affective biases we have observed in our assay will translate to a more general effects on behaviour as predicted by our hypothesis. This will use complex analyses of social and environmental interactions in combination with molecular and cellular studies to correlate the time course of behavioural adaptation with neurotrophic changes.

There are a number of beneficiaries for whom this research could be helpful in the longer term:

1. Academia
2. Patients suffering from emotional disorders
3. Family and friends of such patients
4. The economy
5. The government and the National Health Service
6. Laboratory and farm animal welfare

1. International academia in the fields of preclinical and clinical stress research. The major impact of the proposed work will be to influence the direction of research into stress-related emotional dysfunction. Unlocking the relationship between cause (stress) and effect (emotional and behavioural dysfunction) would be a major breakthrough. We have already made a major step forward by demonstrating stress-induced negative cognitive affective behaviour in animals (Stuart et al., 2013, Neuropsychopharmacology). The work outlined in this project aims to link these acute negative biases with more long term effects on behavior and potentially a consequential link with neurotrophic changes. (See also 'Academic Beneficiaries').

2. Patients suffering from stress-related disorders. Stress-related disorders are widespread in western society and extend beyond psychiatric disorders. The main reason for the lack of adequate treatments is that the underlying neurobiology of these disorders is still unknown. This means that patients suffering from these conditions often do not achieve adequate control of their symptoms with major impacts on the patient's health, well-being and ability to contribute to society both economically and socially. It is also likely that there are sub-clincial effects of stress on health such as increasing vulnerability to infectious diseases and stress is strongly linked to psychosomatic disturbances, addiction and obesity.

3. Family and friends of such patients. Stress-related disorders can be very disruptive for someone's social life often leading to divorce and social isolation affective their partners, children and friends. Thus, the social environment of the patient and their family would benefit greatly from a better understanding of how stress causes these maladaptive behaviours and symptoms.

4. The economy. Depression alone is thought to cost the UK economy 8.6 billion pounds (prescriptions alone costing ~265 million pounds). If the stress-related conditions are looked at as a whole, this estimate could readily be more than tripled. In a knowledge-based economy such as that of the UK, stress-related impacts on productivity are particularly detrimental. Stress is linked to cognitive impairments and deficits in executive function which can lead to problems with concentration and poor decision-making. Research has shown that stress leads to the loss of over 15 million work days per year and many billions of pounds in economic damages. A better understanding of the factors which influence cognitive and emotional changes associated with stress could lead to social strategies to reduce risk and improve treatment. The pharmaceutical industry would benefit as this research could spark new avenues in drug development.

5. The government and the National Health Service (NHS). It is logical that the social, economic and health problems of such patients are a great burden for the government and the NHS. Clearly, an improved treatment of these patients would alleviate this burden significantly. Better insight into the effects of stress on animals could be beneficial to improve legislation for a better treatment of laboratory, farm and our animals.

6. Laboratory and farm animal welfare. We will be able to use the results obtained from our planned experiments to quantify the relative impact of different types of stressors on emotional behaviour in animals and inform on strategies to reduce stress-related induction of negative affective states in laboratory and farm animals. Aspects of these outcomes may also be relevant to behavioural disorders in companion animals.