Long-term consequences of extinction enhancements

About This Grant

PROJECT SUMMARY One of the challenges in treating post-traumatic stress disorder (PTSD) is its high comorbidity with other disorders, especially those involving reward and motivation. Treatment interventions for PTSD often consistent of cognitive-behavioral therapy, which involves learning coping strategies for the mental re-experiencing of traumatic memories. Preclinical work has attempted to model aspects of this treatment by focusing on extinction – a process that involves retrieving a traumatic memory and learning that the cues that evoke that memory are now safe. The challenge with extinction is that the learning that occurs during extinction is fragile; extinguished behavior returns with time, changes in context, or reminders of the original event. Pairing this extinction experience with pharmacological compounds that enhance memory may create a form of extinction that is persistent and resists relapse. We have found that drugs (histone deacetylase (HDAC) inhibitors) that promote histone acetylation may be especially powerful in creating a persistent memory for extinction. Although prior research on HDACs and extinction has been rigorous, the field has become stagnant at the behavioral level, with a major gap being that all of the focus has been on changes within an aversive or an appetitive system. That is, there is little to no understanding of how enhanced extinction effects operate in a model of PTSD comorbidities, where a traumatic experience results in persistent changes in appetitive behaviors. This is a major gap in the literature that our work attempts to fill by asking how potentiating extinction in a model of stress results in long-term changes in expression of appetitive behaviors that are persistently altered by that stressor. The two aims of our approach take the field of HDAC inhibition and extinction in novel and innovative directions. In Aim 1, we evaluate the persistent effects of acute systemic HDAC3 inhibition during extinction of a traumatic memory and in Aim 2, we evaluate the persistent effects of chronic site-specific HDAC3 inhibition within the infralimbic cortex during extinction of a traumatic memory. We evaluate these effects behaviorally, focusing on the reversibility of persistent changes that we have found to be induced by trauma – hyperresponsivity to mild stressors and alterations in appetitive motivation. We also evaluate the extinction effects at a molecular level, evaluating how HDAC3 inhibition alters specific loci within an extinction circuit. This work will have broad implications for pharmacological treatment strategies in preclinical models of PTSD.