Friday, November 22, 2024
11/22/2024
PROJECT SUMMARY Therapeutic interventions, such as exposure therapy, reduce pathological fear in patients with anxiety disorders. Extinction is a fundamental form of learning that underlies these therapies. A major challenge to extinction-based therapies is that the fear reduction is often transient and bound to the place or context in which therapy occurs. For example, when patients confront phobic objects or reminders of trauma outside of the clinic, their fear often relapses. This reveals that extinction learning does not erase fear memory, but yields a context-dependent “safety” memory that inhibits the expression of fear in the place where it is learned. Accordingly, the long-term goal of this project is to understand the neural substrates of fear extinction and relapse, particularly the specific brain circuits involved in the contextual control of extinction. Work in the current funding period of this project has focused on renewal, a relapse of extinguished fear outside the extinction context. Importantly, it was found that the hippocampus (HPC) mediates renewal by inhibiting retrieval of extinction memories encoded by the infralimbic (IL) cortex. In the extinction context, the suppression of conditioned fear is thought to involve IL inhibition of amygdala neurons encoding fear memory. However, recent data challenge this notion—silencing prefrontal-amygdala projections does not impair extinction retrieval. Hence, the precise mechanism for suppressing fear after extinction is still unknown. Recent work on this project suggests a novel alternative: the mPFC may suppress the reactivation of hippocampus-dependent fear memories to facilitate context-dependent extinction memory retrieval. The mPFC projects to the HPC via the thalamic nucleus reuniens (RE), and RE inactivation or chemogenetic silencing of mPFCgRE projections impairs the expression of extinction. Based on this work, it is hypothesized that the RE mediates mPFC-HPC interactions required for context-dependent retrieval of extinction memories. This hypothesis will be tested in three specific aims. The first aim explores whether the mPFC, particularly IL, suppresses the retrieval of extinguished fear memories via RE projections to the HPC. The second aim examines whether the activity of HPC ensembles representing fear and extinction memories are regulated by the RE. The third aim determines whether the RE coordinates oscillatory synchrony in HPC and mPFC during extinction retrieval. The proposed work will elucidate the specific neural circuits mediating the expression of extinction and has important clinical implications for developing therapeutic interventions that target these neural circuits to promote fear suppression and oppose relapse.
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