The role of the central amygdala kappa opioid receptor and dopamine in discriminatory fear learning and anxiety

Abstract

Collectively, anxiety disorders are the most common mental illness in the U.S., with about 30% of Americans experiencing this disorder in their lifetime. There are a variety of anxiety disorders, including phobias, obsessive compulsive disorders, generalized anxiety, and post-traumatic stress disorder (PTSD), which display heterogeneous symptoms. Many of these disorders are based in aberrant information processing of fear-inducing stimuli. To develop new treatment options, it is necessary to identify new therapeutic targets that mediate normal and dysfunctional fear learning. While discriminative fear can be adaptive, high intensity non-discriminative generalized fear is often maladaptive and can result in fear disorders, such as post traumatic stress disorder (PTSD). Within the amygdala, the central amygdala (CeA) is highly heterogeneous, dynamic population which is critical for the acquisition, consolidation, and expression of cued fear. The CeA acts as a hub of threat discrimination information. This complex discrimination calculation is dependent on a variety of signaling molecules and neural circuits. We have previously demonstrated that CeA corticotrophin releasing hormone (CRH) expression and its local action on CRH receptor 1 (CRHR1) are necessary for the acquisition of low-threat-intensity, discriminative fear. We have also identified the critical role of VTA dopamine projections to the CeA for maintaining cue-specific, non-generalized fear. Now, we have characterized the coexpression and localization of a variety of stress-associated neuropeptides in the CeA and identified an additional CeA signaling system that regulates anxiety and fear discrimination. I investigated the role of kappa opioid receptor (KOR) in the CeA for regulation of conditioned threat discrimination and anxiety-like behavior in mice. We demonstrated that reduced KOR expression in the CeA, through genetic inactivation of the KOR-encoding gene (Oprk1) results in increased anxiety and impaired conditioned threat discrimination. KOR’s endogenous ligand, dynorphin (Pdyn) is expressed locally in the CeA. Local Pdyn+ cells densely innervate the CeA, but reduction of CeA Pdyn through genetic inactivation of the Pdyn-encoding gene (Pdyn) in the CeA had no effect on anxiety or conditioned threat discrimination. However, the CeA also receives distal Pdyn+ inputs from throughout the brain. When we inactivated all sources of dynorphin to the CeA we were able to recapitulate the anxiety and fear discrimination phenotypes of CeA KOR inactivation. These findings suggest that Pdyn inputs to the CeA signal through KOR to promote threat discrimination and reduce anxiety. We believe that a better understanding of this pathway and how it interacts with other stress-associated signaling molecules could aid in the discovery of new drug targets for the treatment of fear and anxiety disorders.