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：麻省理工学院Graybiel) 我们的目标是确定重度抑郁障碍(MDD)和焦虑的神经回路机制 以推进治疗方法。项目3‘S的目标，与其他项目的目标协调，将 充分利用我们对前扣带回皮质(ACC)的生理和功能的发现，这与我们的研究结果密切相关 MDD和焦虑症及其与纹状体特殊神经化学隔区的联系 称为纹状体。纹状体与神经调节多巴胺系统紧密相连，多巴胺系统是纹状体的一个关键部位。 影响动机状态，在功能障碍的情况下，会导致神经精神疾病。我们开发了一种非人类的灵长类 (NHP)版本的接近-回避(AP-Av)任务，用于人类研究焦虑和抑郁 作为啮齿动物模型，允许操纵ACC-纹状体回路。我们发现操纵这个电路可以 深刻地偏向AP-Av决定，增加回避行为，这种影响可以被慢性 应激，由抗焦虑药物剂量依赖地逆转，并由ACC-纹状体回路操作诱导 在啮齿动物身上。我们现在建议确定伤害素受体(NOPR)对这一回路的影响。 给予NOPR拮抗剂全身性增加纹状体多巴胺外流，这种治疗减少 在啮齿动物模型中与抑郁和焦虑相关的测量，并在MDD中显示了初步的有希望的发现。 值得注意的是，我们最近与项目4一起发现，伤害素多肽，伤害素/孤儿FQ(N/OFQ) 在纹状体神经元中选择性表达，我们最近展示的神经元直接投射到黑质 多巴胺神经元。因此，我们假设NOPR拮抗剂在以下位置中断纹状体N/OFQ信号 多巴胺神经元调节纹状体多巴胺释放和偏向AP-Av决策时 面临成本和收益的权衡。Aim 1验证NOPR拮抗剂可以使AP-Av正常化的假设 先前慢性应激诱导的小鼠行为以及神经纹状体和多巴胺信号。AIM 2测试 NOPR拮抗剂是否通过询问NOPR是否改变AP-Av决策边界和神经活动 在纹状体N/OFQ和/或黑质NOPR缺失的情况下，拮抗剂仍然有效。重要的是，目标3将 在AP-Av决策过程中，在Ap-Av决策期间，通过记录和ACC中的微刺激来协调测试NHP中的NOPR效应。 对中心整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， 目标与其他项目和NIMH了解、预防和治疗精神疾病的使命直接相关。 我们将建立连接小鼠、NHP和人类行为研究的关键行为桥梁，包括 广泛使用的快感缺失和失眠的小鼠行为分析(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留了行为和神经特征。

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.