Thalamic Coordination of Prefrontal-Hippocampal Interactions Underlying the Retrieval of Fear Extinction Memories

Abstract

Associative learning and memory are key to survival in animals as it allows for adaptive responses to imminent threat. However, memories of traumatic events often become pathological leading to psychiatric disease, such as posttraumatic disorder (PTSD). Commonly used cognitive behavioral therapies, such as exposure therapy, aim to extinguish fear and anxiety by re-exposing individuals to reminder cues in safe and controlled settings. Unfortunately, extinction-based therapies often fail in individuals with PTSD, and moreover, there is currently only one FDA approved drug for PTSD. This necessitates a need to uncover the neural circuitry involved in fear regulation for the advancement of both cognitive behavioral therapies and targets for therapeutic agents. In this dissertation, I report a series of experiments interrogating the neural circuits underlying adaptive aversive learning and memory in rodent models using Pavlovian fear conditioning and extinction. This work focuses on the role of the thalamic nucleus reuniens in coordinating interactions between the hippocampus and prefrontal cortex in aversive learning and memory processes. In Chapter 1, I review the current landscape of the role for oscillatory activity in neural circuits in aversively motivated behavior. In Chapter 2, I show that the nucleus reuniens has a key function in fear suppression through the retrieval of “safe” extinction memories and suggest that it achieves this function by synchronizing activity between the medial prefrontal cortex and hippocampus. In Chapter 3, I report an experiment using fiber photometric calcium recordings of the nucleus reuniens during fear conditioning and extinction that reveals a specific role for the reuniens in saliency processing and fear suppression. Finally, in Chapter 4, I integrate these findings with the current literature and provide a general discussion of pertinent open questions regarding nucleus reuniens functions in fear regulation.