Project 1_Pizzagalli : Pharmaco-Neuroimaging Studies of Approach/Avoidance Behaviors and Post-Mortem Studies

项目 1_Pizzagalli：接近/回避行为的药物神经影像研究和尸检研究

• 批准号: 10383685
• 负责人: Diego A Pizzagalli
• 金额: $ 80.56万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10383685
• 关键词: Acute; Anatomy; Anhedonia; Anterior; Anxiety; Anxiety Disorders; Automobile Driving; Autopsy; Behavior; Behavioral; Behavioral Model; Biological Assay; Biological Markers; Cell Nucleus; Chronic stress; Clinical; Corpus striatum structure; Data; Decision Making; Disease; Dopamine; Dose; Double-Blind Method; Ecological momentary assessment; Exposure to; Functional Magnetic Resonance Imaging; Goals; Grant; Hospitals; Human; Individual; Investigation; Life; Link; Major Depressive Disorder; Mental Depression; Midbrain structure; Mood Disorders; Mus; Neurobiology; Neurons; Nucleus Accumbens; ORL1 receptor; Pathway interactions; Patients; Peptides; Pharmacology; Phenotype; Placebo Control; Placebos; Plasma; Play; Prefrontal Cortex; Process; Psychiatry; Psychosocial Stress; Rattus; Relapse; Rodent; Sampling; Signal Pathway; Stress; Suicide; System; Testing; Tyrosine 3-Monooxygenase; Ventral Striatum; antagonist; approach avoidance behavior; approach behavior; base; cingulate cortex; design; dopamine transporter; dopaminergic neuron; follow-up; human study; neural correlate; neuroimaging; nociceptin; nonhuman primate; novel; prospective; psychosocial stressors; receptor expression; relating to nervous system; stressor; striosome; therapy development; treatment response

PROJECT SUMMARY (PROJECT 1, Project Leader: Pizzagalli, McLean Hospital) The premise of this P50 resubmission is that major depressive disorder (MDD) and anxiety disorders are characterized by negative biases in approach-avoidance behaviors due to dysregulation within (1) cortico- striatal-midbrain circuitry and (2) nociceptin/orphanin FQ peptide and the nociceptin receptor (NOPR). Project 1 will directly contribute to this goal by using functional magnetic resonance imaging (fMRI) while unmedicated individuals with current MDD or anxiety or individuals with past MDD perform an approach-avoidance decision- making task we adapted from non-human primates (Project 3). In Study 1.1, 56 unmedicated individuals with current MDD or anxiety disorders and 56 demographically matched healthy controls will perform the approach- avoidance fMRI task after receiving placebo or a NOPR antagonist (which increased approach-related behaviors in both rats and humans in preliminary studies). In Study 1.2, 48 unmedicated, remitted individuals with past MDD and 48 healthy controls will perform the approach-avoidance task both before and after a psychosocial stressor. Aim 1 will test the hypothesis that, relative to controls, patients will show aberrant task-related activations in the anterior cingulate cortex, dorsolateral prefrontal cortex and striatum, and that these abnormalities will differentially impact dynamic computational decision parameters. In Aim 2, we expect that, relative to placebo, NOPR antagonism will significantly increase approach-related striatal activation and corticostriatal connectivity and normalize avoidance-related pACC activation. Aim 3 will test the hypothesis that, from pre- to post-stress, remitted MDD individuals will show significantly decreased approach-related striatal activation and corticostriatal functional connectivity and dysregulated avoidance-related pACC activation relative to controls. In Aim 4, expect that abnormal pACC, DLPFC and NAc activation will predict changes in depression, anhedonia, anxiety, and suicidality as well as approach-avoidance behaviors in daily life (assessed using ecological momentary assessments). Using post-mortem assays, Aim 5 will test the hypothesis that the NOPR and its interactions with the dopaminergic system is altered in MDD within cortico-striatal-midbrain circuitry. Contribution to Overall Center Goals and Interactions with Other Center Components. Project 1 will test the hypotheses that (1) MDD and anxiety show dysregulation within a cortico-striatal-midbrain circuitry that will be targeted using recordings, stimulation and chemogenetic approaches in Projects 2-4 (Aim 1); (2) nociceptin receptor antagonism will normalize approach/avoidance behavior in MDD and anxiety (Aim 2), similar to non- human primate findings in Project 3 and rodent findings from Projects 3-4; (3) a psychosocial stressor will induce behavioral and neural shifts toward increased avoidance in remitted individuals with past MDD (Aim 3), similar to rodent and NHP findings in Projects 3-4; (4) behavioral and neural markers of approach/avoidance behaviors will predict disease course 12 months later (Aim 4); and (5) MDD will be characterized by NOP/NOPR disruptions within cortico-striatal-midbrain regions that will be causally tested in Projects 2-4 (Aim 5).

项目摘要（项目 1，项目负责人：Pizzagalli，麦克莱恩医院） 这次P50重新提交的前提是重度抑郁症（MDD）和焦虑症是 其特征是由于（1）皮质内部的失调而导致接近回避行为的负面偏差 纹状体-中脑回路和 (2) 伤害感受肽/孤啡肽 FQ 肽和伤害感受肽受体 (NOPR)。项目 1 将在不接受药物治疗的情况下使用功能性磁共振成像 (fMRI) 直接为这一目标做出贡献 当前患有 MDD 或焦虑症的个体或过去患有 MDD 的个体会做出接近-回避决策- 我们改编自非人类灵长类动物的任务（项目 3）。在研究 1.1 中，56 名未接受药物治疗的个体患有 当前的 MDD 或焦虑症和 56 名人口统计匹配的健康对照将执行该方法 - 接受安慰剂或 NOPR 拮抗剂后回避功能磁共振成像任务（这会增加与接近相关的行为） 在大鼠和人类的初步研究中）。在研究 1.2 中，48 名未接受药物治疗、有既往病史的缓解者 MDD 和 48 名健康对照组将在心理社会之前和之后执行回避任务 压力源。目标 1 将检验以下假设：相对于对照，患者将表现出异常的任务相关性 前扣带皮层、背外侧前额叶皮层和纹状体的激活，并且这些 异常会对动态计算决策参数产生不同的影响。在目标 2 中，我们期望， 相对于安慰剂，NOPR 拮抗剂将显着增加与接近相关的纹状体激活 皮质纹状体连接并使回避相关的 pACC 激活正常化。目标 3 将检验以下假设： 从压力前到压力后，缓解的MDD个体将表现出与接近相关的纹状体显着下降 激活和皮质纹状体功能连接以及失调回避相关的 pACC 激活相关 来控制。在目标 4 中，预计异常的 pACC、DLPFC 和 NAc 激活将预测抑郁症的变化， 快感缺乏、焦虑、自杀以及日常生活中的回避行为（使用 生态瞬时评估）。使用事后分析，目标 5 将检验 NOPR 的假设 在重度抑郁症中，其与多巴胺能系统的相互作用在皮质-纹状体-中脑回路内发生改变。 对中心总体目标的贡献以及与中心其他组成部分的互动。项目1将测试 假设 (1) MDD 和焦虑表现出皮质-纹状体-中脑回路的失调， 在项目 2-4 中使用记录、刺激和化学遗传学方法作为目标（目标 1）； (2)伤害感受肽 受体拮抗作用将使重度抑郁症和焦虑症患者的接近/回避行为正常化（目标 2），类似于非 项目 3 中的人类灵长类动物发现和项目 3-4 中的啮齿动物发现； (3)社会心理压力源 诱导过去患有重度抑郁症（MDD）的缓解个体的行为和神经转向增加回避（目标 3）， 与项目 3-4 中啮齿动物和 NHP 的发现类似； (4) 接近/回避的行为和神经标记 行为将预测 12 个月后的病程（目标 4）； (5) MDD 的特点是 NOP/NOPR 皮质-纹状体-中脑区域内的干扰将在项目 2-4（目标 5）中进行因果测试。