Emotional dysregulation and altered dopamine (DA) function occur in many psychiatric disorders. A central goal of our research program has been to understand how the amygdala, a key regulator of emotion, afferently influences DA function at the cellular level in primates. In the previous funding period, we found that amygdala-central extended amygdala (CEA) paths target DA subpopulations that lie mainly outside the ?classic ventral tegmental area (VTA)?, with downstream effects on ?limbic-associative? striatum. The CEA mediates various stress-induced behaviors, and has a high content of neuropeptides, including corticotropin releasing factor (CRF). Stress-induced activation of the CEA and/or manipulation of CRF in the CEA, has downstream effects on DA cells, and precipitates lasting changes in goal-directed responses such as drug seeking, social responses, and compulsive behavior. Very little work has been done on understanding this model in higher primates, in part because of lack of a detailed circuit map at the ?meso- anatomic? level. In mapping the CEA-DA-striatal path in nonhuman primates we found that the CEA has a strong input to parabrachial pigmented nucleus (PBP) and A8 neurons (i.e. DA subgroups outside midline (?classic?) VTA). While usually not a subject of research, these DA neuronal groups are disproportionately expanded in human and nonhuman primates. We also found that 1) the CEA projection is subdivision-specific, 2) CRF is highly expressed in CEA-DA afferent inputs, and, 3) CEA-DA afferent paths are associated with specific efferent paths to striatal regions outside the ?classic? nucleus accumbens. Thus, a CRF-enriched CEA- DA circuit projects largely outside the ?classic (medial) VTA? (mesolimbic) path, to modulate central/caudal ventromedial (?limbic-associative?) striatum. In this proposal, we will examine the on CEA-DA-striatal circuit at a more ?high resolution? level to understand cell-type specific connections to and from the key DA neuronal populations that are involved in the nonhuman primate: the PBP and A8 subgroups. After quanitifying CRF contacts (from all sources) on DA versus non-DA cells (AIM 1a), we will examine 1) the extent to which glutamate, GABA, or both exist in the CEA-DA path, and their co-expression with CRF (AIM 1b), 2) the extent to which the CEA targets DA neurons, non-DA neurons, or both (AIM 2), 3) whether striatal-projecting neurons in the PBP and A8 receive direct CEA contacts (AIM 3).
In humans, dysregulation of the dopamine neurons is associated with stressful life events, and progression to symptoms such as psychosis and substance dependence in vulnerable people. This proposal will examine how information on emotional cues reaches specific dopamine neurons, and act as a substrate for abnormal dopamine signaling in situations of prolonged or overwhelming stress.
