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

基本信息

批准号：
10490460
负责人：
William A. Carlezon
金额：
$ 54.14万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
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/10490460
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 Cell Nucleus 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 behavioral response 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 response sleep regulation stress resilience stressor tool transcription factor transcriptome sequencing virtual

项目摘要

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.

概括该申请是为了竞争竞争的赠款，该赠款在其20年的课程中阐明了这一方法核内转录因子CREB和KAPPA-阿片受体（Kor）系统的功能伏尊（NAC）通过经验而改变，包括压力暴露，以及其功能的变化如何影响行为。我们已经表明（a）应力上调NAC Creb和Kor信号传导，（b）这些影响足以产生情绪和焦虑症的特征，以及（c）CREB或封锁KOR会产生抗抑郁药和抗焦虑样作用。最近，我们还展示了这些在睡眠和生物学（昼夜）节奏中的系统，这些系统在许多类型的精神科中失调疾病。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，到目前为止表现出巨大的希望。 21 - 25年以来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的压力源的响应，包括一种类型与COVID-19大流行有关的免疫应激，同时优先使用终点改善了与人类使用的对齐方式的一致性。在AIM 1中，我们将检查CREB介导的机制使用新版本的认知控制任务（称为侧翼任务）的抑郁行为，我们开发了使用实际上相同的程序启用测试大鼠和人类。具体来说，我们将确定如何 D1-和/或D2-MEDIUM棘神经元（MSN）中NAC CREB功能的改变会影响任务性能和事件相关电位（ERP） - 在人类抑郁症中已知异常 - 男性和女性老鼠。在AIM 2中，我们将确定产生持久的早期免疫激活（EIA）的方案是否存在小鼠的抑郁样作用会导致NAC CREB和KOR系统的持续变化。具体来说，我们将使用单核RNA测序进行全面检查NAC细胞中EIA诱导的改变种群，包括MSN和小胶质细胞，并比较男性和女性的对比影响。尽管 NAC CREB和KOR系统的上调通常与抑郁表型有关，目的是3-4 我们将研究在压力弹性中的可能作用。对于AIM 3，我们将研究KOR的表达方式调节免疫功能的小胶质细胞会影响对压力的敏感性。具体来说，我们将研究如何消融小胶质细胞的KOR会影响慢性应激破坏睡眠和活动的昼夜节奏和体温。同样，在AIM 4中，我们将表征改变CREB目标功能的影响 DFOSB在D1-或D2-MSN中，在应力诱导的睡眠和昼夜节奏中造成的破坏，而在平行检查中 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）也可以在人类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功能会影响域经常是的机制情绪和焦虑症失调，可能会促进诊断和治疗这些疾病的新方法。