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).

项目总结(项目1，项目负责人：麦克莱恩医院Pizzagalli) 重新提交P50的前提是严重抑郁障碍(MDD)和焦虑症 由于(1)皮质内的调节失调，在接近-回避行为中具有负面偏见的特征 纹状体-中脑回路和(2)伤害素/孤儿FQ肽和伤害素受体(NOPR)。项目 1将通过在未服用药物的情况下使用功能磁共振成像(FMRI)直接为实现这一目标做出贡献 患有当前MDD或焦虑症的个人或有既往MDD的个人执行接近-回避决定- 完成我们从非人灵长类动物改编的任务(项目3)。在研究1.1中，56名未服用药物的人患有 目前的MDD或焦虑症和56名人口统计学上匹配的健康对照将执行该方法- 接受安慰剂或NOPR拮抗剂(这会增加与接近相关的行为)后的回避fMRI任务 在初步研究中对老鼠和人类都是如此)。在研究1.2中，48名有既往病史的未服用药物的缓解者 MDD和48名健康对照将在心理社会实验前后执行接近-回避任务 压力源。目标1将检验这样的假设，即相对于对照组，患者将表现出与任务相关的异常 前扣带回皮质、背外侧前额叶皮质和纹状体的激活 异常会对动态计算决策参数产生不同的影响。在《目标2》中，我们预计， 相对于安慰剂，NOPR拮抗剂将显著增加与入路相关的纹状体激活和 皮质纹状体连接和正常化与回避相关的pACC激活。目标3将检验这一假设， 从应激前到应激后，缓解的MDD患者与入路相关的纹状体显著减少 激活与皮质纹状体功能连接和异常回避相关的pACC激活相关 到控制程序。在目标4中，预计pACC、DLPFC和NAC异常激活将预测抑郁症的变化， 日常生活中的快感缺乏、焦虑和自杀以及接近回避行为(使用 生态瞬时评估)。使用尸检，Aim 5将检验NOPR的假设 在MDD中，它与多巴胺能系统的相互作用在皮质-纹状体-中脑回路中发生了变化。 对中心整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和焦虑症表现出皮质-纹状体-中脑回路内的失调，这将 在项目2-4(目标1)中使用录音、刺激和化学生成方法作为靶点；(2)伤害素 受体拮抗将使MDD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)心理社会应激源将 诱导既往MDD缓解患者的行为和神经转向更多的回避(目标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记 行为将在12个月后预测疾病进程(目标4)；以及(5)MDD将以NOP/NOPR为特征 将在项目2-4(目标5)中进行因果测试的皮质-纹状体-中脑区内的干扰。