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

项目总结 情绪失调和多巴胺(DA)功能改变在许多精神障碍中都会发生。一个 我们研究项目的中心目标是了解杏仁核--情绪的关键调节器--是如何 在细胞水平上影响灵长类动物的多巴胺功能。在上一个资助期，我们发现 杏仁核-中央扩展杏仁核(CEA)通路针对的是主要位于经典杏仁核外的DA亚群 腹侧被盖区(VTA)，其下游作用于“边缘-联合”纹状体。 CEA介导各种应激诱导行为，神经肽含量高， 包括促肾上腺皮质激素释放因子(CRF)。应激诱导CEA的激活和/或操纵 CEA中的CRF对DA细胞有下游影响，并促使目标导向的持久变化 如寻求毒品、社交反应和强迫行为等反应。几乎没有做过什么工作 在高等灵长类动物中理解这一模型，部分原因是缺乏详细的中-中层电路图。 解剖水平。在绘制非人灵长类的CEA-DA-纹状体通路图时，我们发现CEA有一个 臂旁核(PBP)和A8神经元(即中线外DA亚群)的强传入 (‘经典’)VTA)。虽然通常不是研究的对象，但这些DA神经元群不成比例 在人类和非人类灵长类动物中扩展。我们还发现，1)CEA投影是特定于细分的， 2)CRF在CEA-DA传入输入中高表达；3)CEA-DA传入通路与 通向伏隔核外的纹状体区域的特定传出路径。因此，富含CRF的CEA- DA回路主要投射在经典(内侧)VTA(中边缘)通路之外，以调节中枢/尾侧。 腹内侧(边缘-联合)纹状体。 在这项提案中，我们将在更高分辨率的水平上研究CEA-DA-纹状体回路，以 了解细胞类型与关键DA神经元群之间的特定联系，这些神经元群参与 非人灵长类：PBP和A8亚群。在对DA上的CRF联系人(来自所有来源)进行资格审核后 对照非DA细胞(AIM 1a)，我们将检查1)谷氨酸、GABA或两者同时存在于 CEA-DA通路，以及它们与CRF(AIM 1b)的共表达，2)CEA靶向DA神经元的程度， 非DA神经元，或两者兼而有之(AIM 2)，3)PBP和A8的纹状体投射神经元是否接受直接CEA 联系人(目标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).