Project Summary Traumatic experiences, such as combat exposure or sexual/physical abuse can lead to the development of post-traumatic stress disorder (PTSD). Patients with PTSD often show generalized fear to non-dangerous or “safe” stimuli, and have difficulty learning that a previously threatening stimulus is now safe. Although impaired safety learning is a suggested biomarker of PTSD, the precise mechanisms that underlie this impairment are unclear. Notably, human imaging studies have revealed hypoactivity of the ventromedial prefrontal cortex (vmPFC) and retrosplenial cortex (RSC) in patients with PTSD (Hayes et al., 2012; Pissiota et al., 2002) suggesting the possibility that vmPFC – RSC dysfunction might underlie impairments in safety learning observed in patients with PTSD. Consistent with a role for the RSC in safety learning, a recent study from our lab found that permanent damage of the RSC specifically impairs safety learning (Todd et al., 2016a; see also Gabriel, Sparenborg, & Stolar, 1987). Nevertheless, although the RSC has a putative role in processing safety cues, little is known about how cell populations within the RSC encode safety, or the nature of RSC – vmPFC interaction during safety learning. In this project, large-scale single unit ensemble recording and analysis, and local field recordings and analysis, will be combined with chemogentics and learning-theory based behavioral analysis to investigate vmPFC – RSC circuitry in the control of safety learning and behavior. The proposed experiments will therefore establish how cortical ensembles encode safety, and explore interaction between the vmPFC and RSC during two forms of safety learning. Thus, the proposed research is significant in that it will yield a detailed understanding of the mechanisms underlying safety learning, ultimately informing the link between cortical dysfunction and mental illness, including PTSD. In addition to its significance, the current project will provide the trainee with an excellent opportunity to master in vivo electrophysiological recordings and analysis in freely behaving rats. The trainee intends to use this technique, combined with chemogenetic manipulation of neural activity to establish an independent line of research probing the neural circuits underlying learning, memory, and behavior. In addition, the proposed award will ensure the trainee acquires the professional skill necessary to reach his career goals. This training will take place at Dartmouth College, an exceptional research and teaching intuition, under the guidance of an established team of mentors as well as an external advisory committee comprised of luminaries in the fields of behavioral neuroscience and PTSD research. This proposal is well-designed to provide Dr. Todd with the continued career development necessary to establish himself as an independent investigator and leader in the field.