Extinction is an experience-dependent process by which a previously learned behavioral response is reduced. It is currently in use as a form of behavioral therapy for human disorders including posttraumatic stress and anxiety disorders. Drugs that enhance extinction have been shown to be effective at enhancing extinction-based behavioral therapy in clinical trials. Extinction has been studied extensively at the behavioral level, but its molecular mechanisms have been investigated only recently. Based on what is known about original associative learning and its similarity to extinction, it is possible that transcription, which is necessary for original associative learning, is also necessary for extinction learning. Recently, it has become clear that regulation of gene transcription necessary for long-term memory formation involves the concerted action of multiple transcription factors and cofactors that interact with chromatin, a protein complex that packages DNA. Chromatin modification via histone acetylation (a form of epigenetic gene regulation) is emerging as a major molecular pathway involved in the transcriptional regulation of gene expression required for synaptic plasticity and memory storage. The primary goal of this proposal incorporates behavioral, pharmacological, and molecular approaches to examine the role of histone acetylating/deacetyling enzymes that may underlie extinction processes. The first aim of this research proposal is to determine the role of CREB-binding protein (CBP), a histone acetyltransferase known to be involved in associative learning, in the acquisition of extinction. The second aim is to determine the effects of histone deacetylase inhibitors, which increase histone acetylation and have been shown to enhance associative learning, on the acquisition and persistence of extinction. The focus of the third aim is to determine how chromatin modifying enzymes (HDACs and CBP) regulate transcription of Nr4a genes during extinction. My research plan focuses on two important aspects of extinction: development and persistence. By understanding the molecular and epigenetic mechanisms of extinction, we can recommend techniques to reduce the duration of human extinction therapy for disorders such as post-traumatic stress disorder, phobias and anxiety disorders, which has the potential to greatly impact the people who complete a treatment program. By examining the persistence of extinction, we can determine whether these treatments cause lasting changes, thus reducing relapse. Furthermore, histone deacetylase inhibitors are FDA approved drugs, which significantly increases the potential translational value of this research.
NIH ExPorter
NIH ExPorter