Investigating the neural circuits and molecular mechanisms which regulate emotional behaviour and cognitive affective bias

The role of emotions in cognitive function is an important area of neuroscience but one where our understanding is limited. Observations of animals and humans have shown that emotions can modify behaviour. In animals, these types of behaviours are classically studied by looking at fear behaviours such as freezing or escape, or reward behaviours such as reward learning. How emotions affect behaviour is much more complex than this and recent developments in the methods used to study emotional behaviour in animals suggest complex and subtle effects of both positive and negative emotional states on cognition. Studies in humans have shown that the emotional state can influence the way they experience their environment and also the decisions they make. These are often referred to as cognitive affective biases. These biases have been shown to influence attention, learning and memory, recall, interpretation and decision-making and dysfunction in these process are linked to emotional disorders. Recently, methods have been developed which have enabled researchers to show that similar cognitive affective biases are found in animals and that emotional state (often referred to as affective state in animals) can induce optimistic or pessimistic cognitive behaviours in animals as diverse as honey bees, mice, rats, sheep, dogs and primates.

Our research project takes forward the advances in methods to study emotional behaviour using animals and focusses on one aspect of cognitive affective bias: the impact of emotions on decision-making. Our research group has been one of leaders in the development of the judgement bias task for rodents. In this task animals are trained to associated specific cues with an emotional outcome, either positive or negative. Once these reference cues are learnt, cognitive affective biases are tested by presenting the animal with an intermediate ambiguous cue and observing how the animal responds. Optimistic animals make more responses in anticipation of the positive event whilst pessimistic animals make more responses in anticipation of the negative event. We can then manipulate the animal's emotional state and observe how the bias in this task changes. We have already shown that this type of methodology relates well to behaviour in humans as we have tested an almost identical task in human participants. We have also made an exciting discovery when looking at antidepressant drugs in this task and found that the effectiveness, and rate of onset of action of the treatments used in people, is mirrored closely in this test. For example, the delayed onset antidepressant fluoxetine does not immediately make rats more optimistic but does if the dosing is given daily for more than a week. This, and the recent discovery that the rapid onset antidepressant, ketamine, can make rats immediately more optimistic in this task forms the basis for the proposed studies in this application.

Our aim is to take forward these discoveries and build towards a better understanding of the brain mechanisms which cause these optimistic versus pessimistic behaviours. Our proposed experiments will use different drug treatments and direct manipulations of small regions of the brain to try to understand the brain circuits which regulate emotional behaviour. We will also be able to utilise the expertise and additional resources provided by our industrial collaborator to undertake a much more sophisticated analysis of specific pathways and neuronal sub-populations in key regions of interest. These studies will combine genetic manipulations with gene sequencing studies and are anticipated to yield a detailed insight into the molecular and neural circuits. These will help identify novel drug targets to take forward for further validation and potentially into a drug development programme.

A major hurdle to the advance in our understanding of emotional behaviour has been limitations associated with methods to quantify their underlying neurobiology using non-human species. In our laboratory, we have developed and validated assays to study how emotions impact on cognitive process to induce cognitive affective biases in rodents. We have established methods to study how affective states (positive or negative) lead to biases in either learning and memory (the affective bias test, ABT, Stuart et al., 2013, 15) or decision-making (judgement bias task, Hales et al., CFS; Anderson et al., 2013). We are now in a unique position where we can undertake novel studies into the neurobiology of emotional behaviour. This specific project will utilise the judgement bias task and will investigate the neurochemical, neural and molecular processes which modulate how emotions affect decision-making. We have chosen to focus on this task because it is specifically designed to test behaviours in terms of either positive (optimistic) or negative (pessimistic) biases in rodents. We have also recently shown that this task can dissociate between delayed and rapid onset antidepressant treatments. The proposed programme of work will provide a detailed analysis of neurobiological processes which regulate these decisions and the way that emotional-state can bias the behavioural outcome. The work will use a number of different techniques so that we can work from a system level analysis down to targeting specific neuronal subpopulations. Our primary focus is to understand how drugs such as ketamine, which rapidly alter mood in humans, function at a neural and molecular level. Using optogenetic, we also aim to isolate specific neuronal populations to study both behaviour and gene expression so we can elucidate molecular mechanisms and identify potential new targets for drug development.

1. International academic and industrial research in psychiatry
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 academic and industrial research in psychiatry. The major impact of the proposed work will be to influence the direction of research into emotional dysfunction and disorders such as depression and anxiety. Unlocking the neural mechanisms and molecular targets associated with emotional regulation would be a major breakthrough. We have already made a major step forward by demonstrating cognitive affective biases in animals associated with learning and memory and how these may be linked to neuropsychological processes in depression (Stuart et al., 2013, 2015). The work outlined in this project aims to build on this and investigate how decision-making is modulate in normal animals and whether distinct processes are involved in the emotional effects of monoaminergic drugs versus NMDA antagonists. This impact will specifically benefit from our industry collaboration.

2. Patients suffering from emotional disorders. Emotional dysfunction and associated disorders are widespread in 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-clinical effects of emotional dysfunction and its impact on cognition which are reflected in people's health and wellbeing e.g. increasing vulnerability addiction and obesity and impaired cognition.

3. Family and friends of such patients. Emotional dysfunction can be very disruptive for someone's social life often leading to divorce and social isolation affecting their partners, children and friends. Thus, treatment of the patient and benefits to their family would benefit greatly from a better understanding the neurobiology of normal cognitive affective behaviour and how this may contribute to maladaptive behaviours and psychiatric symptoms.

4. The economy. Depression alone is thought to cost the UK ~£11 billion and across Europe ~£77 billion. According to a House of Commons report, costs to the UK economy extend beyond direct costs to the NHS (~£520 million) and include people unable to work because of depression (~£8.97bn of potential earnings per year) and loss of earnings from people who commit suicide (~£1.47bn). If the emotion-related symptoms in diseases as a whole are considered, this estimate could readily be more than doubled. In a knowledge-based economy such as that of the UK, the effects of emotional dysfunction on cognitive processes, particular decision-making, have a much greater impact on productivity. Research has shown that stress, which is strongly linked to emotional disorders, 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 normal cognitive and emotional function could also spark new avenues for 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.

6. Laboratory and farm animal welfare. Better insight into the emotional capacity of animals, achieved through the improved validation of these cognitive affective bias tasks, could improve approaches for the treatment and management, including through legislation, of our companion and farmed animals.