K Matthew Lattal - US grants

? DESCRIPTION (provided by applicant): There is a fundamental gap between human psychological experiences and how we study them in animal models. Humans typically learn and experience emotions within a variety of social contexts. By contrast, animal models are typically studied within an isolated environment. This discontinuity in social context imposes an obstacle to the development of treatments for psychological disorders. We propose a series of experiments that examine learning within the context of social interaction. The proposed experiments will allow us to develop and characterize new procedures for studying fear conditioning and extinction in the rodent laboratory, resulting in a novel conceptual framework for understanding the environmental, genetic, and molecular mechanisms that underlie learning and memory. To evaluate the interplay between learning and psychosocial experience, we need an environment sufficiently robust to impart translational relevance, yet simple enough to be accessible to multiple laboratories for routine assessments of genetically modified mice. Through a novel integration of readily available experimental tools, our model will focus on how different shared social experiences and non-social stimuli modulate the acquisition and extinction of fearful behaviors. In Aim 1, we propose to determine how two critical features of social interaction, familiarity and social motivation, influence the capacity for vicarious fear learning. In the proposed experimental paradigm, a subject mouse observes an object mouse receive cued fear conditioning, repeated trials in which a tone is paired with a shock. Depending upon the strain of mice tested, C57BL/6J (B6), BALB/cJ (BALB), or FVB/NJ (FVB), the subject mouse then expresses a conditioned fear response to the tone. We ask whether the capacity of a subject mouse to learn from an object mouse is sensitive to its social motivation and its familiarity with the animal undergoing the tone-shock contingency. In Aim 2, we ask how these same social variables, social motivation and familiarity, moderate the ability of a mouse to suppress a fearful memory; how social factors moderate fear extinction. We propose to examine juvenile mice of the B6, BALB, and FVB strains because they show robust fear conditioning yet differ in key social behaviors. B6 mice express greater levels of social interaction, social reward and vicarious fear learning relative to BALB mice. By comparing these three strains, we gain substantial insight to the role of social motivation in learning and extinction. We envision the proposed study will lead to a larger research program that reveals how social mechanisms enhance memory formation and extinction and that it will lead to novel models for a range of disorders that involve memory and social components, including PTSD, addiction, and autism.

Project Summary There is a high comorbidity between substance use disorders (SUDs) and post-traumatic stress disorder (PTSD). A consequence of this comorbidity is that exposure to cues associated with trauma in a patient with PTSD may trigger relapse of drug seeking, even after successful treatment or periods of abstinence. Thus, a major goal of treatment for both PTSD and substance use disorders is to weaken the ability of environmental cues to induce relapse. One way to do this is through extinction techniques, in which the relation between the cue and the drug, or the cue and the traumatic memory, is severed. A major challenge for purely behavioral approaches to substance abuse and PTSD is that successful treatment with extinction often does not persist and relapse occurs with time, changes in context, or exposure to stress. Work in our laboratories has focused on manipulating epigenetic mechanisms to make the learning that occurs during extinction persistent, resulting in long-term weakening of fear responses (in the case of animal approaches to PTSD) and long-term elimination of drug-seeking (in animal approaches to substance abuse). However, our work, and most of the work in the general field of the neuroscience of extinction, comes from preclinical studies of basic mechanisms of extinction within approaches to PTSD (such as fear conditioning) or addiction (such as drug self- administration) in isolation; comparatively little is known about how learned fear and drug seeking interact at behavioral and molecular levels. We have developed a novel model of the comorbidity between PTSD and addiction in rodents that combines behavioral approaches that are well characterized at behavioral, circuit, and molecular levels. In this model, rodents receive exposure to a battery of shocks in one context and are tested for drug-seeking behaviors in a second context. Our preliminary data show that this exposure to a single battery of shocks causes persistent changes (>30 days) in responsivity to a mild stressor and results in increased cue-induced reinstatement of drug-seeking after extensive extinction. Thus, this approach captures a persistent context-independent change in drug-seeking that is not captured in other stress-induced reinstatement procedures and provides a strong basis for investigating, at a basic level, how reward and aversive processes interact across long periods of time and, at a translational level, how a single traumatic experience results in persistent effects on relapse after successful treatment. The three specific aims outlined in this application are designed to (1) elucidate the persistent behavioral and molecular effects of an acute trauma, (2) evaluate the post-trauma effects of pharmacological manipulation of a specific histone deacetylase (HDAC3) in circuits involved in extinction of fear and drug-seeking, and (3) to evaluate the mechanisms through which HDAC3 manipulations alter relapse after trauma. Our focus on epigenetic mechanisms holds significant promise for understanding how persistent changes in behavior are established following trauma, and provides a novel therapeutic avenue.