The PACAP signaling pathway as a novel regulator of the neural circuits underlying fear generalization

Project Summary / Abstract Anxiety disorders, such as generalized anxiety disorder (GAD) and posttraumatic stress disorder (PTSD), are the most common mental illnesses in the US, affecting up to 18% of the general population. A defining symptom of these disorders is fear generalization, in which learned fear responses are transferred to similar but novel stimuli. Examining the neural circuits that modulate fear generalization and context discrimination is therefore a critical step to understanding the neural substrates of stress resilience. The neuropeptide pituitary adenylate cyclase-activating peptide (PACAP) is known as a critical regulator of fear responses in the brain and periphery. PACAP acts on several different receptors in the brain, including pituitary adenylate cyclase-activating polypeptide type I receptor (PAC1) and vasoactive intestinal peptide receptor 2 (VPAC2). This Kirschstein-NRSA F31 application presents a program for research and training that will support me on a path towards developing the skills necessary to become an independent research scientist focused on studying PACAP and VPAC2 signaling and their effects on fear generalization using cutting-edge techniques such as whole-brain imaging, and simultaneous optogenetic manipulation and in vivo Ca2+ imaging. In this proposal, I will investigate how whole-brain VPAC2 expression correlates with the behavioral output of fear generalization (Aim 1), and assess the contribution of VPAC2 in altering activity of the neural circuits underlying fear generalization (Aim 2). In Aim 1, mice will be assayed using a contextual fear discrimination (CFD) task. Whole-brain imaging techniques will then be used to visualize and compare brain-wide VPAC2 expression between populations of high- and low-fear generalizing mice. In Aim 2, I will leverage the Inscopix nVoke system for simultaneous in vivo optogenetic and Ca2+ imaging during real-time CFD behavior to investigate how VPAC2 modulates neural activity to affect fear generalization behavior. Successful completion of this study will help elucidate the role of a novel signaling pathway in mediating the neural substrates of fear generalization. Ultimately, this knowledge could contribute to the development of more targeted, specific interventions to better treat and prevent fear and anxiety disorders. These data, along with the research and scientific expertise developed through this F31 award, will support my successful transition into an independent neuroscientist.