Roles of nuleus accumbens CREB and Kappa function in depression

伏隔核 CREB ​​和 Kappa 功能在抑郁症中的作用

• 批准号: 10687178
• 负责人: William A. Carlezon
• 金额: $ 51.29万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687178
• 关键词: Ablation; Address; Affect; Animal Model; Anti-Anxiety Agents; Antidepressive Agents; Anxiety Disorders; Behavior; Behavioral; Biological; Body Temperature; Brain; COVID-19 impact; COVID-19 pandemic; CREB1 gene; Cells; Characteristics; Chronic stress; Clinical Trials; Cognition; Cognitive; Complex; Data; Development; Diagnosis; Diurnal Rhythm; Dynorphins; Electroencephalography; Equilibrium; Etiology; Event-Related Potentials; Female; Foundations; Genetic Transcription; Goals; Grant; Human; Immune; Immune response; Immune system; Inflammation; Intervention; Life; Ligands; Longevity; Measurement; Mediating; Mental Depression; Mental disorders; Microglia; Modeling; Molecular; Mood Disorders; Motivation; Mus; Neuroglia; Neurons; Nucleus Accumbens; Opioid Antagonist; Performance; Phenotype; Play; Population; Predictive Value; Predisposition; Procedures; Process; Psychiatry; Psychopathology; Rattus; Receptor Signaling; Regimen; Regulation; Research; Rodent; Role; Sleep; Sleep Architecture; Sleep disturbances; Stress; Symptoms; System; Task Performances; Testing; Therapeutic Effect; Up-Regulation; Work; cell type; cognitive control; depressive behavior; depressive symptoms; early life stress; experience; human tissue; immune activation; immune function; improved; in vivo; innovation; insight; kappa opioid receptors; male; novel; programs; receptor expression; receptor function; resilience; resilience factor; response; single nucleus RNA-sequencing; sleep regulation; stress resilience; stressor; tool; transcription factor; virtual

SUMMARY This application is for competitive renewal of a grant that over its 20-year course has elucidated the ways in which the function of the transcription factor CREB and kappa-opioid receptor (KOR) systems within the nucleus accumbens (NAc) are changed by experience, including stress exposure, and how alterations in their function affect behavior. We have shown that (a) stress upregulates NAc CREB and KOR signaling, (b) these effects are sufficient to produce characteristic features of mood and anxiety disorders, and (c) disruption of CREB or blockade of KORs produces antidepressant- and anxiolytic-like effects. Recently we have also shown a role for these systems in sleep and biological (diurnal) rhythms, which are dysregulated across many types of psychiatric illness. Our work has provided a basis for clinical trials of KOR antagonists to treat depression, which thus far show great promise. Major goals for Years 21-25 are to further characterize the ways in which NAc CREB and KOR systems regulate complex behavior and responses to different forms of stressors, including a type of immune stress relevant to the COVID-19 pandemic, while prioritizing the use of endpoints in rodents with improved alignment to those used in humans. In Aim 1, we will examine the mechanisms of CREB-mediated depressive behavior using a new version of a cognitive control task (called the Flanker task) that we developed to enable testing rats and humans using virtually identical procedures. Specifically, we will determine how alterations in NAc CREB function in D1- and/or D2-medium spiny neurons (MSNs) affect task performance and event-related potentials (ERPs)—endpoints known to be aberrant in human depression—in male and female rats. In Aim 2, we will determine if a regimen of early immune activation (EIA) that produces long-lasting depressive-like effects in mice causes persistent alterations in NAc CREB and KOR systems. Specifically, we will use single-nucleus RNA sequencing to comprehensively examine EIA-induced alterations in NAc cell populations, including MSNs and microglia, and compare and contrast effects in males and females. While upregulation of NAc CREB and KOR systems is commonly associated with depressive phenotypes, in Aims 3-4 we will examine possible roles in stress resilience. For Aim 3, we will examine how KORs expressed on microglia, which regulate immune function, affect sensitivity to stress. Specifically, we will examine how ablation of KORs from microglia affects the ability of chronic stress to disrupt sleep and diurnal rhythms of activity and body temperature. Similarly, in Aim 4 we will characterize the effects of altering the function of the CREB target DFosB in D1- or D2-MSNs on stress-induced disruption of sleep and diurnal rhythms, while in parallel examining effects on CREB, DYN, and KOR expression in NAc MSNs and microglia. All of these studies involve endpoints (behavioral, molecular) that can also be studied in humans or human tissues. This work will improve our understanding of the mechanisms by which NAc CREB and KOR function affect domains that are frequently dysregulated in mood and anxiety disorders, and may enable new ways to diagnose and treat these conditions.

概括 本申请旨在竞争性更新一项拨款，该拨款在其 20 年的历程中已经阐明了 核内转录因子 CREB ​​和 kappa 阿片受体 (KOR) 系统的功能 伏隔核 (NAc) 会因经验而改变，包括压力暴露及其功能的改变 影响行为。我们已经证明 (a) 压力上调 NAc CREB ​​和 KOR 信号传导，(b) 这些影响 足以产生情绪和焦虑障碍的特征，以及（c）CREB ​​的破坏或 阻断 KOR 会产生抗抑郁和抗焦虑样作用。最近我们还展示了一个角色 这些系统在睡眠和生物（昼夜）节律中存在失调，这些系统在许多类型的精神疾病中都失调 疾病。我们的工作为 KOR 拮抗剂治疗抑郁症的临床试验提供了基础，迄今为止 展现出伟大的希望。 21-25 年的主要目标是进一步描述 NAc CREB ​​和 KOR 系统调节复杂的行为和对不同形式压力源的反应，包括一种类型的压力源 与 COVID-19 大流行相关的免疫应激，同时优先考虑在啮齿类动物中使用终点 改进了与人类使用的一致性。在目标 1 中，我们将研究 CREB ​​介导的机制 使用我们开发的新版本认知控制任务（称为侧卫任务）的抑郁行为 能够使用几乎相同的程序来测试老鼠和人类。具体来说，我们将确定如何 D1 和/或 D2 中型多棘神经元 (MSN) 中 NAc CREB ​​功能的改变会影响任务表现和 事件相关电位 (ERP)——已知人类抑郁症异常的终点——男性和女性 老鼠。在目标 2 中，我们将确定早期免疫激活 (EIA) 方案是否能够产生持久的效果 小鼠体内的抑郁样作用会导致 NAc CREB ​​和 KOR 系统持续改变。具体来说，我们 将使用单核 RNA 测序来全面检查 EIA 诱导的 NAc 细胞变化 人群，包括 MSN 和小胶质细胞，并比较和对比男性和女性的效果。尽管 NAc CREB ​​和 KOR 系统的上调通常与抑郁表型相关（目标 3-4） 我们将研究在抗压能力方面可能发挥的作用。对于目标 3，我们将研究 KOR 如何在 小胶质细胞调节免疫功能，影响对压力的敏感性。具体来说，我们将研究消融如何 来自小胶质细胞的 KOR 会影响慢性压力扰乱睡眠和昼夜活动节律的能力， 体温。同样，在目标 4 中，我们将描述改变 CREB ​​靶点功能的影响 D1-或 D2-MSN 中的 DFosB 对压力引起的睡眠和昼夜节律破坏，同时进行平行检查 对 NAc MSN 和小胶质细胞中 CREB、DYN 和 KOR 表达的影响。所有这些研究都涉及终点 （行为、分子）也可以在人体或人体组织中进行研究。这项工作将改善我们的 了解 NAc CREB ​​和 KOR 功能影响经常出现的域的机制 情绪和焦虑症失调，可能会带来诊断和治疗这些疾病的新方法。