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

基本信息

批准号：
10601128
负责人：
Diego A Pizzagalli
金额：
$ 80.55万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
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/10601128
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 Diagnostic Disease Disease remission 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 Peptide Receptor Peptides Phenotype Placebo Control Placebos Plasma Play Prefrontal Cortex Process Psychiatry Psychosocial Stress Rattus Relapse Rodent Sampling Signal Pathway Stress System Testing Tyrosine 3-Monooxygenase Ventral Striatum antagonist approach avoidance behavior approach behavior avoidance behavior cingulate cortex design diagnostic strategy dopamine transporter dopaminergic neuron follow-up genetic approach human study neural neural correlate neuroimaging nociceptin nonhuman primate novel pharmacologic prospective psychosocial stressors receptor expression stressor striosome suicidal suicide rate therapy development treatment response

项目摘要

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）此P50重新提交的前提是重度抑郁症（MDD）和焦虑症是以（1）皮质中的失调引起的失调引起的避免进近行为的负偏见的特征纹状体中脑电路和（2）诺西特蛋白/孤立蛋白FQ肽和nocteptin受体（NOPR）。项目 1将通过使用功能磁共振成像（fMRI）直接促进此目标患有当前MDD或焦虑或过去MDD的个体执行避免进近的决策 - 使我们改编自非人类灵长类动物（项目3）。在研究1.1中，有56名未经监测的人当前的MDD或焦虑症以及56个人口统计学匹配的健康对照将执行该方法 - 避免接受安慰剂或NOPR拮抗剂后的fMRI任务（这增加了与进近相关的行为在大鼠和人类的初步研究中）。在研究1.2中，有48个未经监测的，有过去的人 MDD和48个健康对照将在社会心理之前和之后执行避免接近的任务压力源。 AIM 1将检验以下假设：相对于对照组，患者将显示与任务相关的异常前扣带回皮层，背外侧前额叶皮层和纹状体的激活，这些异常将差异影响动态计算决策参数。在AIM 2中，我们期望相对于安慰剂，NOPR拮抗作用将显着增加与进近相关的纹状体激活和皮质纹状体连通性并标准化与回避相关的PACC激活。 AIM 3将检验以下假设：从预压后，汇出的MDD个体将显示出明显降低与入路相关的纹状体激活和皮质纹状体功能连接性和失调的回避相关PACC激活相对进行控件。在AIM 4中，预期异常PACC，DLPFC和NAC激活将预测抑郁症的变化， Anhedonia，焦虑和自杀以及日常生活中的避免进近行为（使用生态瞬间评估）。使用验尸后测定，AIM 5将检验NOPR的假设并且其与多巴胺能系统的相互作用在Cortico-ripriatal-中间回路中的MDD中发生了变化。对整体中心目标以及与其他中心组件的互动的贡献。项目1将测试假设（1）MDD和焦虑表明在皮质 - 纹状体中间电路中的失调在项目2-4中使用记录，刺激和化学遗传学方法来靶向（AIM 1）；（2）nocteptin 受体拮抗剂将在MDD和焦虑中标准化方法/回避行为（AIM 2），类似于非 - 项目3和项目3-4的啮齿动物调查结果中的人类灵长类动物发现；（3）心理压力源诱导行为和神经转移，以增加过去MDD的汇出个人（AIM 3），类似于项目3-4中的啮齿动物和NHP调查结果；（4）方法/避免的行为和神经标记行为将在12个月后预测疾病病程（AIM 4）；（5）MDD将以NOP/NOP的特征在项目2-4（AIM 5）中将在因果测试的Cortico-Striatal-Midbrain区域内的破坏（AIM 5）。