Novel Treatment Targets For Affective Disorders Through Cross-Species Investigation of Approach/Avoidance Decision Making

项目概要（总体） 重度抑郁症（MDD）和焦虑症是主要的公共卫生问题， 迟钝的接近相关行为和增加的回避，这预示着更糟糕的疾病轨迹， 自杀风险增加，治疗效果差。尽管有这些令人信服的证据，但人们对 神经生物学机制潜在的异常接近回避行为在这些疾病中， 阻碍了治疗的发展。为了解决这一未满足的需求，我们提出了一个综合研究计划， 通过一个统一的康特中心，将调查皮质-纹状体-中脑和伤害感受素回路的作用， 接近-回避行为。目标是确定新的治疗靶点和标记物， 病程。这些目标将通过汇集一个高度跨学科的团队来实现 互补的专业知识和成功合作的既定记录。该团队将解决关键问题， 通过高度协调的方法解决问题，这将需要大量的概念和技术 创新。在大量初步数据的指导下，所提出的方法跨越了不同的物种 (mice、非人类灵长类动物、人类）、方法（非侵入性神经成像、皮质内记录和 人类的深部脑刺激;光遗传学，化学遗传学技术和CRISPR-cas9敲除， 非人类动物）和分析单元（基因、分子、细胞、电路、生理学、行为、自我报告）。 重要的是，为了增加翻译影响，将使用功能相同的任务和相同的分子标记。 将在三个物种中探测目标。计算建模核心将测试特定的 状态（例如，MDD、焦虑、应激诱导的抑郁表型）或药物操作（例如， 伤害感受素受体拮抗剂）对跨物种的模型参数具有类似的影响，这是预期的。 提高翻译成功的可能性。统一的假设是：（1）MDD，焦虑 障碍的特征是接近/回避行为的负偏差;（2）接近/回避行为的负偏差 接近/回避行为与皮质-纹状体-中脑回路和伤害感受素功能障碍有关 伤害感受素受体拮抗剂和皮质-纹状体-中脑的调节 电路将使接近/回避行为正常化。这些创新的假设将通过 四个紧密交织的项目，由管理核心和计算建模支持 核心这个统一的研究计划将对NIMH的三个战略目标做出独特的贡献： (1)更好地了解精神疾病的病理生理学（NIMH战略目标1.1）;（2） 确定新的治疗靶点（战略目标3.1）;以及（3）确定映射 战略目标（2.2）。因此，由知识产生的意义和影响， 该中心将是实质性的，因为我们的目标是改变我们对两种疾病的病理生理学的理解， 这些疾病影响超过35%的美国人口，这是迈向更有效治疗的必要步骤。

PROJECT SUMMARY (Overall) Major depressive disorder (MDD) and anxiety disorders are major public health problems characterized by blunted approach-related behaviors and increased avoidance, which predict worse disease trajectories, increased suicide risk, and poor treatment response. Despite this compelling evidence, little is known about the neurobiological mechanisms underlying abnormal approach-avoidance behavior in these disorders, which has hampered treatment development. To address this unmet need, we propose an integrated research program through a unified Conte Center that will investigate the role of cortico-striatal-midbrain and nociceptin circuitry in approach-avoidance behaviors. The goals will be to identify novel treatment targets and markers that map disease course. These goals will be achieved by bringing together a highly interdisciplinary team with complementary expertise and an established record of successful collaboration. The team will tackle pivotal questions through a highly coordinated approach that will entail numerous conceptual and technological innovations. Guided by a large amount of preliminary data, the proposed approach spans different species (mice, non-human primates, humans), approaches (non-invasive neuroimaging, intracortical recordings and deep brain stimulation in humans; optogenetics, chemogenetics techniques, and CRISPR-cas9 knockdown in non-human animals), and units of analyses (genes, molecules, cells, circuits, physiology, behavior, self-report). Critically, to increase translational impact, functionally identical tasks will be used and identical molecular targets will be probed across three species. The Computational Modeling Core will test whether specific states (e.g., MDD, anxiety, stress-induced depressive phenotypes) or pharmacological manipulations (e.g., nociceptin receptor antagonists) have similar effects on model parameters across species, which is expected to improve the likelihood of successful translation. The unifying hypotheses are that: (1) MDD, anxiety disorders are characterized by negative biases in approach/avoidance behaviors; (2) Negative biases in approach/avoidance behaviors are linked to dysfunction in cortico-striatal-midbrain circuitry and nociceptin system upregulation; and (3) nociceptin receptor antagonists and modulation of cortico-striatal-midbrain circuitry will normalize approach/avoidance behaviors. These innovative hypotheses will be pursued through four closely intertwined Projects supported by an Administrative Core and a Computational Modeling Core. This unified research program will make unique contributions towards three NIMH Strategic Objectives: (1) A better understanding of the pathophysiology of mental illness (NIMH Strategic Objective 1.1); (2) Identification of novel treatment targets (Strategic Objective 3.1); and (3) Identification of markers that map disease course (Strategic Objective 2.2). Thus, the significance and impact of the knowledge generated by the Center will be substantial, as we aim to transform our understanding of the pathophysiology of two disorders that affect >35% of the US population, which is a necessary step towards more effective treatments.