Dissecting the Role of Amygdala Circuits in the Control of Fear Extinction and Alcohol Drinking

Substance use disorders and mood disorders exhibit high co-morbidity suggesting that these conditions may result from changes in common neurocircuits. Here we examine how outputs to and from the amygdala are altered in models of excessive alcohol use and Post-Traumatic Stress Disorder (PTSD). In the first set of experiments, we used extinction of Pavlovian conditioned fear to understand the type of learning that is impaired in patients with PTSD. Using retrograde anatomical tract tracing, we found that distinct sets of neurons in the Prefrontal Cortex (PFC) project to the Basolateral Amygdala (BLA) and Nucleus Accumbens (NAc). Next, we demonstrated that fear extinction results in output-specific changes in excitability wherein PFC projections to the BLA showed increased excitability after extinction training whereas the excitability of NAc outputs were unaltered. Finally, we found that the PFC to BLA pathway is required for extinction recall in vivo as pathway-specific chemogenetic inhibition impaired the recall of a previously acquired extinction memory. These experiments refine our understanding of the role of PFC in mediating fear extinction, and suggest that projections to the amygdala may be a potential therapeutic target in treating PTSD. In the second set of experiments, we examine the contribution of the endogenous opioid system in the Central Amygdala (CeA) to regulating excessive alcohol drinking. We find that the Kappa Opioid Receptor (KOR) is expressed on largely separate sets of neurons in the CeA than its endogenous ligand Dynorphin (PDYN). Knockout of KOR results in reductions in alcohol drinking in male, but not female animals whereas knockout of PDYN results in reduced alcohol intake in both sexes. These changes were observed without alterations in consummatory or anxiety-like behavior. There were also sex-specific alterations in CeA physiology as chronic alcohol decreased the excitability decreased the excitability of PDYN neurons in female, but not male animals. These findings highlight the potential utility of KOR antagonists in treating Alcohol Use Disorders and demonstrate the need to systematically investigate sex differences in the endogenous opioid system. Taken together these experiments support using genetic and anatomical specificity to understand the role of brain region and cell type in this behavior. These approaches will ultimately lead to a more thorough understanding of the alterations in neural circuits that underlie psychiatric conditions.Doctor of Philosoph