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

项目总结(总体) 严重抑郁障碍(MDD)和焦虑症是主要的公共卫生问题，其特征是 钝化的与接近相关的行为和更多的回避，这预示着更糟糕的疾病轨迹， 自杀风险增加，治疗反应差。尽管有这些令人信服的证据，但人们对 在这些障碍中，异常接近-回避行为背后的神经生物学机制 阻碍了治疗的发展。为了解决这一未得到满足的需求，我们提出了一个综合研究计划 通过一个统一的Conte中心，该中心将研究皮质-纹状体-中脑和伤害素回路的作用 在接近-回避行为中。目标将是确定新的治疗目标和标记物 病程。这些目标将通过汇聚一个高度跨学科的团队来实现， 相互补充的专业知识和成功合作的既定记录。这支队伍将攻克关键技术 通过高度协调的方法提出问题，这将涉及许多概念和技术 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 (小鼠、非人灵长类、人类)、方法(非侵入性神经成像、皮质内记录和 人类脑深部刺激；光遗传学、化学遗传学技术和CRISPR-Cas9基因敲除 非人类动物)和分析单位(基因、分子、细胞、电路、生理、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 目标将在三个物种中进行探测。计算建模核心将测试特定的 状态(例如，MDD、焦虑、压力诱导的抑郁表型)或药物操作(例如， 伤害素受体拮抗剂)对不同物种的模型参数有类似的影响，这是意料之中的 以提高翻译成功的可能性。统一的假设是：(1)MDD、焦虑 障碍的特征是在接近/回避行为中存在负面偏见；(2) 接近/回避行为与皮质-纹状体-中脑回路和伤害素功能障碍有关 系统上调；以及(3)伤害素受体拮抗剂与皮质-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 由一个管理核心和一个计算模型支持的四个紧密交织的项目 核心。这一统一的研究计划将为NIMH的三个战略目标做出独特的贡献： (1)更好地了解精神病的病理生理学(NIMH战略目标1.1)；(2) 确定新的治疗目标(战略目标3.1)；和(3)确定标记物 病程(战略目标2.2)。因此，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 影响美国35%人口的疾病，这是迈向更有效治疗的必要一步。

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.