A new approach to the role of prefrontal-limbic circuits in anxiety disorders

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Project summary Dysfunction within the circuits connecting the prefrontal cortex (PFC) and limbic system is the cause of nearly every psychiatric condition, including anxiety disorders. Determining how individual pathways within these circuits function to drive specific aspects of cognition and affect would revolutionize our understanding of the biological bases of psychiatric disorders and provide the critical foundation for pathway-specific treatments in humans. In order to establish the function of these circuits, we must be able to characterize and manipulate the activity of distinct neural pathways that connect the prefrontal and limbic system. The ability to do this in monkeys would be a major advance in basic neuroscience research and would also have significant translational impact. This is because the macaque PFC is more similar, in both its cytoarchitecture and its connections, to the human PFC than that of any other available animal model. What we discover in macaques can be directly translated to humans and have the greatest possible bearing on the understanding and treatment of psychiatric disorders. Our goal here is to develop the use of pathway specific manipulations of neural activity in monkeys and to combine them with recordings of single neurons to answer a fundamental question relating to the pathophysiology of anxiety disorders. Neuroimaging studies of people with anxiety disorders have observed dysfunction between the ventrolateral PFC and amygdala, but little is know about the specific contribution of this circuit to behavior and the role of specific pathways within this circuit. We hypothesize that the ventrolateral PFC-amygdala circuit is vital for encoding the probability that an event will occur. Furthermore, we theorize that dysfunction within the specific pathway from amygdala to ventrolateral PFC heightens anxiety related to the likelihood that a negative outcome will occur. To test our hypothesis we will use an innovative combination of single-neuron recordings, field potential recordings, and pathway specific chemogenetic silencing, analyzing the timing of reward-related neural responses (Aim1) and the LFP synchrony (Aim 2) within this circuit under normal physiological conditions and when neurons in the amygdala that specifically project to the ventrolateral prefrontal cortex are transiently inhibited (Aim 3). Completing the aims of this project will fundamentally advance our understanding of the neural pathways and mechanisms involved in representing uncertainty as well as providing a pathway specific understanding of how amygdala influences outcome probability representations. In addition, achieving the aims of this project will not only provide unique insights into the pathophysiology of anxiety disorders, but it will also lay the foundation for pathway specific manipulations of neural activity in the monkey brain. Given the close correspondence between the human and monkey brains, these experiments in monkeys are a necessary first step to refining and evaluating the potential use of these techniques to treat humans with anxiety disorders.