NEUROMODULATION IN THE EXTENDED AMYGDALA SHAPES CONDITIONED FEAR PROCESSES

Fear is a protective behavioral response where an organism forms the associations between a threat and the environmental signals that predict it in. The ability to accurately predict and avoid harm is essential for survival, however excessive fear is detrimental to wellbeing. Excessive and generalized fear is a core symptom of many anxiety disorders, thus understanding the neurobiological basis of fear is critical for improving treatment options. Central to fear circuitry is signaling in the extended amygdala which integrates information about cues relevant to harm, assigns emotional value, and coordinates and drives defensive behaviors to avoid danger. Many neurotransmitter systems play a role in fear by shaping activity in the central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST). Two neuromodulators that are key for the regulation of fear are serotonin (5HT) and corticotropin releasing factor (CRF). The overarching goal of this dissertation is to understand how 5HT signaling in the CeA and CRF signaling in the BNST contribute to pathological fear states, and how this differs in males and females. Using a series of experiments, we first characterize a novel inhibitory pathway for fear from the ventral periaqueductal gray to the CeA, and characterize 5HT signaling dynamics. We find that 5HT potentiates inhibitory transmission during fear conditioning to drive plasticity in the CeA. Next, we identify novel sex differences in BNST CRF signaling that may drive persistent and generalized fear, providing insight for the neural correlates that drive the transition from adaptive to pathological fear differentially in males and females. Collectively, these finding establish a role for 5HT in the CeA and CRF in the BNST in fear and highlight novel sex differences that may contribute to higher incidence of mood disorders in women. These findings provide critical insight for the development of novel and sex-specific treatments for anxiety disorders.