Beyond the classic VTA: extended amygdala influence on DA subcircuits in primate

University Of Rochester, Rochester NY

Investigators

Linked publications & trials

Abstract

PROJECT SUMMARY 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).