Project 3_Graybiel : Circuit-Specific Disruption, Pharmacological, and Neurophysiological Studies of Approach/Avoidance Behaviors in Mice and Non-Human Primates

项目总结（项目3，项目负责人：Graybiel，马萨诸塞州理工学院） 我们的目标是确定神经回路的机制，潜在的抑郁症（MDD）和焦虑症 疾病，以推进治疗性治疗。项目3的目标与其他项目的目标相协调，将 利用我们对前扣带皮层（ACC）的生理学和功能的发现， 抑郁症和焦虑症，及其与纹状体专门神经化学成分的联系 叫做纹状体纹状体与神经调节多巴胺系统密切相关， 影响动机状态，在功能障碍中，影响神经精神疾病。我们培育了一种非人类灵长类动物 (NHP)在人类中用于研究焦虑和抑郁的接近-回避（Ap-Av）任务的版本，以及 作为啮齿动物模型，允许ACC-纹状体回路的操纵。我们发现对这个回路的操作 深刻地偏见Ap-Av决定，增加回避行为，这种影响可以通过慢性 应激，在NHP中被抗焦虑药剂量依赖性逆转，并由ACC-纹状体回路操纵诱导 在啮齿类动物中。我们现在建议确定伤害感受素受体（NOPR）对这个回路的影响。 全身给予NOPR的拮抗剂增加纹状体多巴胺流出，并且这种治疗减少了多巴胺的释放。 抑郁和焦虑相关的措施在啮齿动物模型，并已显示出初步的有希望的发现，在MDD。 值得注意的是，我们最近与项目4一起发现，伤害感受素肽，伤害感受素/FQ中的N/OFQ， 选择性地在纹状体神经元中表达，我们最近证明的神经元直接投射到黑质 多巴胺神经元因此，我们假设NOPR拮抗剂在一定程度上阻断了纹状体N/OFQ信号传导， 多巴胺神经元调节纹状体多巴胺释放，并在个体 面临成本效益权衡。目的1检验NOPR拮抗剂可以使Ap-Av的变化正常化的假设 行为以及神经纹状体和多巴胺信号诱导的小鼠由先前的慢性应激。Aim 2测试 NOPR拮抗剂是否改变了Ap-Av的决策边界和神经活动， 拮抗剂在不存在纹状体N/OFQ、黑质NOPR或两者的情况下仍然有效。目标3，重要的是， 在Ap-Av决策过程中，通过记录和微刺激ACC来协调测试NHP中的NOPR效应。 对中心总体目标的贡献以及与其他中心组件的互动。这些目标将 为设计治疗MDD和焦虑症的方法提供基本的基础设施， 目标直接关系到其他项目和NIMH的使命，以了解，预防和治疗精神疾病。 我们将建立一个关键的行为桥梁连接小鼠，NHP和人类行为研究，包括 广泛使用的小鼠行为测定的快感缺失和无意志（项目4），NHP Ap-Av行为（我们的项目 3)和人类Ap-Av行为（项目1和2），与计算核心协调，以确定 在物种的翻译小组中保守的行为和神经特征。

PROJECT SUMMARY (PROJECT 3, Project Leader: Graybiel, Massachusetts Institute of Technology) Our goal is to identify neural circuit mechanisms underlying major depressive disorder (MDD) and anxiety disorders to advance therapeutic treatments. Project 3’s Aims, coordinated with those of the other Projects, will capitalize on our findings on the physiology and function of the anterior cingulate cortex (ACC), strongly linked to MDD and anxiety disorders, and its connections with specialized neurochemical compartments of the striatum called striosomes. Striosomes are richly interconnected with the neuromodulatory dopamine system, a key site influencing motivational states and, in dysfunction, neuropsychiatric illness. We developed a non-human primate (NHP) version of the approach-avoidance (Ap-Av) task used in humans to study anxiety and depression, as well as rodent models allowing manipulation of the ACC-striatal circuit. We found that manipulation of this circuit can profoundly bias Ap-Av decisions, increasing avoidance behavior, and such effects can be mimicked by chronic stress, dose-dependently reversed by anxiolytics in NHPs, and induced by ACC-striosomal circuit manipulations in rodents. We now propose to determine the influence of nociceptin receptors (NOPR) on this circuit. Antagonists of NOPR given systemically increase striatal dopamine efflux, and this treatment reduces depression- and anxiety-related measures in rodent models and has shown initial promising findings in MDD. Notably, we recently found together with Project 4 that the nociceptin peptide, nociceptin/orphanin FQ (N/OFQ) is expressed selectively in striosomal neurons, neurons we recently demonstrated project directly to nigral dopamine neurons. Thus, we hypothesize that NOPR antagonists interrupt striosomal N/OFQ signaling at dopamine neurons modulating striatal dopamine release and biasing Ap-Av decision-making when individuals face cost-benefit tradeoffs. Aim 1 tests the hypothesis that NOPR antagonists can normalize a shift in Ap-Av behavior as well as neural striosomal and dopamine signals induced in mice by prior chronic stress. Aim 2 tests whether NOPR antagonists shift Ap-Av decision boundaries and neural activity by asking whether NOPR antagonists remain effective in the absence of striosomal N/OFQ, nigral NOPRs or both. Aim 3, importantly, will coordinately test NOPR effects in NHPs with recordings and microstimulation in the ACC during Ap-Av decisions. Contribution to Overall Center Goals and Interactions with Other Center Components. These Aims will provide a fundamental infrastructure for designing approaches to the treatment of MDD and anxiety disorders, a goal directly related to the other projects and the NIMH mission to understand, prevent and cure mental illness. We will establish a crucial behavioral bridge connecting mouse, NHP and human behavioral studies, including widely used mouse behavioral assays of anhedonia and avolition (Project 4), NHP Ap-Av behavior (our Project 3) and human Ap-Av behavior (Projects 1 and 2), in coordination with the Computational Core, to identify conserved behavioral and neural features across a translational panel of species.