Psychological, pharmacological and developmental insights into the prefrontal circuits underlying threat regulation and negative bias in marmosets

As individuals we are faced with situations that provoke fear and anxiety on a daily basis, whether they be relatively mild, e.g. giving a talk to a group of people, or more serious, e.g. the prospect of losing one's job. Mild fear and anxiety are associated with changes in our behaviour and accompanying changes in our physiology, including increased heart rate, muscle tension and stress hormone levels. Such emotional responses allow us to adapt to a given situation and either prepare us for, or help us to avoid, a negative event. However, if unregulated and in excess, these responses lead to clinical anxiety, which is a core symptom of anxiety disorders (which have a lifetime prevalence of 16%) but can also be a prominent symptom of many other disorders, including Depression, Obsessive Compulsive disorder and Schizophrenia. Unfortunately, the range of potential treatments is relatively restricted and the level of treatment success, highly variable. For example, selective serotonin reuptake inhibitors (SSRIs) work for some people, while for others, they need to be combined with noradrenaline re-uptake inhibitors (SNRIs) to be beneficial and for still others, neither treatment is effective. One reason for this variability is that there are likely varied causes underlying why someone may show clinical anxiety that are dependent upon alterations in the activity of distinct brain circuits. In support of this, we have recently shown in animals that increases or decreases in the activity of functionally distinct areas within a region of the brain called the prefrontal cortex, similar to those seen in patients with clinical anxiety, can lead to enhanced anxiety-like behaviour and cardiovascular responses e.g. racing heart.
One major aim of this research proposal therefore is to differentiate the psychological deficits that underlie the enhanced anxiety-like state induced by dysregulation of these distinct regions of prefrontal cortex. We achieve this by training animals on a variety of behavioural tests that critically, can also be studied in humans, ensuring our findings can be translated into the clinic. We will use a methodology that will allow us to temporarily inactivate or activate a given brain region for a short time period (approx. 30 minutes) and investigate its effects in a variety of threat-eliciting contexts. This will help provide better diagnosis if we can differentiate the distinct underlying causes of anxiety in different people.
A second aim is to determine the effects of distinct classes of drugs that may be used to treat anxiety in humans e.g. SSRIs, on the anxiety-like behaviour in our animals induced by activations or inactivations of distinct regions of the prefrontal cortex. This will allow us to determine whether distinct classes are more or less effective in ameliorating these separable anxiety-like states. The results from these studies will help to pave the way for developing patient specific treatment strategies.
Finally, if we are to fully understand clinical anxiety, we need to understand how brain circuits develop and how they are affected by stress, since anxiety disorders often emerge in adolescence, with stress in early childhood among the most significant risk factors. There is little understanding of how complex brain circuits involved in regulating our anxiety develop and so by using animals, in which the developmental period is far shorter than humans, we can image the brain of individuals at key stages across development, including childhood and early and late adolescence. Using a variety of sophisticated imaging techniques we aim to identify when these brain circuits become integrated across development and how individual differences in integration relate to individual differences in anxiety-like traits in adulthood. Together, this will inform our understanding of when the circuits that give rise to anxiety may be at their most vulnerable to stress.

Dysregulation of negative emotions is a prominent symptom of neuropsychiatric disorders. Unfortunately, the range of treatments is restricted and the level of treatment success highly variable; due in part to the diverse set of cognitive control processes and underlying brain circuits that regulate responses to negative events and when dysregulated, induce clinical anxiety. Clinical anxiety is associated with altered activity across prefrontal and cingulate cortex but a fundamental understanding of these regions' distinct contributions is lacking. We have shown that heightened threat reactivity is induced by both ventromedial prefrontal overactivation or orbitofrontal inactivation. By focussing on the negative biases in decision making that are a common symptom of anxiety disorders we will differentiate these regions' unique cognitive contributions to such biases; applying computational modelling to identify the distinct underlying psychological constructs. We will also determine the contribution of dorsolateral prefrontal cortex which has been little studied with respect to threat reactivity and negative biases. These studies will provide insight into the multi-determined nature of clinical anxiety and inform diagnoses. By differentiating the effectiveness of different classes of anxiolytics to ameliorate the anxiety-like phenotypes induced by distinct prefrontal manipulations, we will provide insight into the variable success of current anxiolytics and guide future individualised treatment strategies. Since clinical anxiety emerges during adolescence, neuroimaging of prefronto-cingulate cortex across development will identify the discrete developmental stages in which the different regions integrate into structural and resting state networks. This will reveal those stages likely to be most vulnerable to environmental stress, a risk factor for clinical anxiety and how individual differences in developmental trajectories relate to anxiety-like traits in adulthood.