PROJECT SUMMARY/ABSTRACT This research project focuses on identifying common neurobiological substrates that confer vulnerability both to addiction and to frequently co-occurring disorders such as post-traumatic stress disorder (PTSD). Pavlovian conditioning procedures will be used to distinguish ?sign-tracking? rats that tend to attribute high levels of motivational significance to discrete predictive cues while largely ignoring context, from ?goal-tracking? rats that make more use of context to appropriately modify their emotional responses. Sign-tracking individuals are more prone to both addiction- and PTSD-like behaviors than goal-trackers. The neurobiological basis of these behavioral traits will be explored by testing for differences between sign- and goal-trackers in dynamic epigenetic histone acetylation, brain-derived neurotrophic factor (BDNF) expression, and functional connectivity within key limbic circuits known to mediate motivated behavior, namely the pathway from ventral hippocampus to medial prefrontal cortex to basolateral amygdala and nucleus accumbens. Epigenetic changes and growth factor expression will also be manipulated using viral vectors to test for a causal influence on conditioned motivational responses to appetitive and aversive cues and contexts, as well as electrophysiological measures of connectivity and synaptic efficiency within the limbic pathway of interest. These experiments will test the hypothesis that decreased histone acetylation in goal-trackers relative to sign- trackers after behavioral conditioning leads to increased transcription of BDNF, which in turn is transported axonally and released onto medial prefrontal cortical targets. The BDNF then causes an increase in synaptic connectivity between the medial prefrontal cortex and its downstream targets, the basolateral amygdala and nucleus accumbens. Thus, goal-trackers are hypothesized to have an increased capacity to use contextual information, derived from hippocampal inputs and relayed through the medial prefrontal cortex, to appropriately modify subcortical responses to cues associated with emotionally salient events. This proposed R01 project is well-aligned with the missions of the NIH and NIDA, as it will help clarify neurobiological pathways to addiction and frequently co-occurring disorders, which is a significant public health priority.