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

项目摘要 情绪失调和多巴胺（DA）功能改变发生在许多精神疾病。一 我们研究计划的中心目标是了解杏仁核，情绪的关键调节器， 在灵长类动物的细胞水平上传入影响DA功能。在上一个融资期，我们发现， 杏仁核-中央延伸杏仁核（CEA）通路靶向主要位于“经典”外的DA亚群。 腹侧被盖区（VTA），下游影响“边缘联合”纹状体。 CEA介导各种应激诱导的行为，并且具有高含量的神经肽， 包括促肾上腺皮质激素释放因子（CRF）。应激诱导的CEA激活和/或CEA的操纵 CEA中的CRF对DA细胞具有下游作用，并促使目标导向的 反应，如药物寻求，社会反应和强迫行为。做的工作很少 在高等灵长类动物中理解这种模型，部分原因是缺乏详细的"中- 解剖学水平。在绘制非人灵长类动物CEA-DA-纹状体通路的图谱时，我们发现CEA具有一个 向臂旁色素核（PBP）和A8神经元（即中线外的DA亚群）的强输入 （“经典”）VTA）。虽然通常不是研究的主题，但这些DA神经元组不成比例地 在人类和非人类灵长类动物中得到了扩展。我们还发现，1）CEA投影是细分特异性的， 2)CRF在CEA-DA传入输入中高度表达，3）CEA-DA传入通路与 特殊的传出路径到纹状体区域以外的'经典'核的脑桥。因此，CRF富集的CEA- DA回路主要投射到“经典（内侧）VTA”（中脑边缘）路径之外，以调节中枢/尾侧 腹内侧（边缘联合）纹状体。 在这个提议中，我们将在更高的分辨率水平上检查CEA-DA-纹状体回路， 了解细胞类型特异性连接，并从关键的DA神经元群体参与， 非人灵长类：PBP和A8亚群。在DA上量化CRF联系人（来自所有来源）后 与非DA细胞（AIM 1a）相比，我们将检查1）谷氨酸，GABA或两者存在于 CEA-DA通路，以及它们与CRF的共表达（AIM 1b），2）CEA靶向DA神经元的程度， 非DA神经元，或两者（AIM 2），3）PBP和A8中的纹状体投射神经元是否接受直接CEA 接触（AIM 3）。

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).