Anxiety disorders are a leading cause of disability, afflicting 5-10% of individuals worldwide with no existing cure. Fear generalization, in which conditioned fear responses occur in an altered, unconditioned context, is a primary symptom in many anxiety disorders such as phobia, panic disorder, and post-traumatic stress disorder (PTSD). Patients and animal models of PTSD consistently show altered activity in brain circuits such as the prefrontal cortex (PFC) and hippocampus, but precise circuit mechanisms and their causal role in fear generalization remain largely unclear. Furthermore, very little is known about the genetic factors that predispose individuals to PTSD. We have already shown that increased activity in the PFC to hippocampus circuits is sufficient to cause fear memory retrieval in an unconditioned context (fear memory generalization). Here, I propose to further dissect the role of circuit and genetic mechanisms of fear generalization behavior. The central hypothesis of this study is that dissection of the PFC to hippocampus circuit, as well as local hippocampal circuit dynamics, in genetic mouse models of fear generalization will provide significant insight into brain mechanisms of PTSD.
Aim 1 and 2 will be focused on the generation of accurate and reproducible mouse models of fear generalization, which will then be used in Aim 3 to determine whether the local hippocampal network dynamics have ensemble features that are associated with increased fear generalization behavior. This project will yield novel insights regarding the important circuit level mechanisms of PTSD, while in the future, providing potential circuit-level handles for manipulation of neural activity toward therapeutic value.
It is thought that dysfunctions in the communication of two brain regions named the prefrontal cortex and the hippocampus underlie symptoms in human post-traumatic stress disorder (PTSD). I have directly demonstrated for the first time that increased activation of the prefrontal cortex to hippocampus projection indeed leads to increased fear memory generalization, a critical feature of PTSD. I now propose a multilevel mapping of these long-range and local circuits, along with the underlying genetic factors, that together will provide crucial insights for our understanding of PTSD. The long-term goal is to enable the detection of at-risk individuals, with potential for prevention or early intervention an therapy.
