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

项目总结（项目1，项目负责人：Pizzagalli，McLean Hospital） 这种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- 纹状体-中脑回路和（2）FQ肽和痛敏素受体（NOPR）中的痛敏素/痛敏素。项目 1将直接有助于这一目标的使用功能性磁共振成像（fMRI），而不用药 当前患有MDD或焦虑症的个体或过去患有MDD的个体执行接近-回避决策- 我们从非人类灵长类动物中改编的任务（项目3）。在研究1.1中，56名未经药物治疗的个体， 目前的抑郁症或焦虑症和56个人口统计学匹配的健康对照将执行该方法- 接受安慰剂或NOPR拮抗剂（增加接近相关行为）后的回避fMRI任务 在大鼠和人类的初步研究中）。在研究1.2中，48名未经药物治疗的缓解个体， MDD和48名健康对照者将在心理社会学之前和之后执行接近-回避任务。 压力源目的1将检验以下假设：相对于对照组，患者将表现出异常的任务相关性。 激活前扣带皮层，背外侧前额叶皮层和纹状体，这些 异常将不同地影响动态计算决策参数。在目标2中，我们期望， 相对于安慰剂，NOPR拮抗作用将显著增加接近相关的纹状体激活， 皮质纹状体连接和正常化回避相关的pACC激活。目标3将检验以下假设： 从应激前到应激后，缓解的MDD个体将显示与接近相关的纹状体神经元数量显著减少， 激活和皮质纹状体功能连接和失调的回避相关的pACC激活相对 控制。在目标4中，预期异常的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接近-回避行为（使用 生态环境评估（ecological momentum assessments）目标5将使用尸检分析来检验NOPR 并且其与多巴胺能系统的相互作用在皮质-纹状体-中脑回路内的MDD中改变。 对中心总体目标的贡献以及与其他中心组件的互动。项目1将测试 假设（1）MDD和焦虑显示皮质-纹状体-中脑回路内的失调， 在项目2 - 4（目标1）中使用记录、刺激和化学发生方法进行靶向;（2）伤害感受素 受体拮抗剂将使MDD和焦虑中的接近/回避行为正常化（目的2），类似于非- 项目3中的人类灵长类动物研究结果和项目3 - 4中的啮齿类动物研究结果;（3）心理社会压力源将 诱导行为和神经向增加回避过去MDD缓解个体转变（目的3）， 与项目3 - 4中的啮齿动物和NHP结果相似;（4）接近/回避的行为和神经标志物 行为将预测12个月后的疾病进程（目的4）;（5）MDD将以NOP/NOPR为特征 皮质-纹状体-中脑区域内的干扰，将在项目2 - 4（目标5）中进行因果检验。

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).