Kappa opioid receptor modulation of depression-like behaviors through mTOR signaling

Kappa 阿片受体通过 mTOR 信号传导调节抑郁样行为

基本信息

批准号：
9386396
负责人：
Benjamin Land
金额：
$ 23.25万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9386396
关键词：
Acute Affect Agonist American Anatomy Attenuated Behavior Behavioral Biochemical Markers Brain Chronic Chronic stress Clinical Complement Data Dendrites Dependence Disease Drug Targeting Dynorphins Elements Event Exposure to FRAP1 gene Female Functional disorder GTP-Binding Proteins Genetic Genetic Models Hippocampus (Brain)Individual Ketamine Knockout Mice Knowledge Label Learning Length Link MAP Kinase Gene MAPK14 gene Major Depressive Disorder Measures Mediating Mental Depression Microscopy Molecular Morphology Mus Neuronal Plasticity Neurons Opioid Receptor Outcome Pathway interactions Pharmacology Phosphotransferases Population Pre-Clinical Model Prefrontal Cortex Proteins Quality of life Receptor Activation Receptor Signaling Regulation Resolution Risk Factors Role Series Sex Characteristics Shapes Signal Pathway Signal Transduction Stimulus Stress Swimming Synapses Synapsins Synaptosomes System Testing Therapeutic United States Vertebral column Width combat density depressive behavior depressive symptoms design experimental study human female human male improved inhibitor/antagonist insight kappa opioid receptors male neuromechanism new therapeutic target novel optogenetics public health relevance receptor receptor function response social stress resilience synaptogenesis therapy design tool

项目摘要

Project Summary Stress is a known risk factor for clinical depression, and stress can exacerbate depressive symptoms in vulnerable individuals. By better understanding the molecular mechanisms by which stress can drive pro-depressive behaviors, we will be able to generate novel/tailored therapeutics to combat this prevalent disease. Both the kappa-opioid receptor (KOR) and mammalian target of rapamycin (mTOR) systems have been shown to mediate elements of stress-induced, depression-like behaviors in mice. However, these two systems have never been linked, representing a major gap in our knowledge of a complete pathway from stress to pathophysiology and behavior. Understanding how KOR activity is related to mTOR function will be critical in refining drugs that target these systems. One possible intermediate protein in these pathways is p38 MAPK, which is activated by KOR and whose activity is necessary for stress-induced immobility, aversion, and social avoidance. The proposed experiments will directly test the relationship between KOR, p38 MAPK, and mTOR as a functional signaling pathway mediating depression-like behaviors and neuronal plasticity. Specifically, we propose to first validate preliminary data demonstrating that mTOR levels are modulated by KOR activation. In Aim 1, we will use pharmacological inhibitors/antagonists and genetic models to test whether p38 MAPK is necessary for the changes in mTOR level seen by KOR activation. We will then assess whether mTOR mediates KOR/p38-induced place aversion and changes in swim stress immobility. In aim 2, we will test whether KOR changes markers of neuronal plasticity including dendrite length, spine density/shape, and synaptic proteins. We will use both pharmacological activation of KOR and stress to test dependence of p38 MAPK and mTOR, and finally determine if KOR antagonism is able to attenuate changes in stress-induced plasticity. The proposed studies described here will better define the molecular pathways from stress exposure to depression-like behaviors, and possibly uncover novel targets for therapeutic action that could be used in the clinical population to treat stress-vulnerable individuals.

项目概要压力是临床抑郁症的已知危险因素，压力会加剧抑郁症状在弱势个体中。通过更好地理解压力的分子机制驱动促抑郁行为，我们将能够产生新颖/定制的疗法来对抗这种行为流行病。 κ-阿片受体 (KOR) 和雷帕霉素的哺乳动物靶标 (mTOR) 系统已被证明可以调节压力诱发的抑郁样行为的因素在小鼠中。然而，这两个系统从未连接起来，这代表了我们的一个重大差距了解从压力到病理生理学和行为的完整途径。了解如何 KOR 活性与 mTOR 功能相关，对于精炼针对这些系统的药物至关重要。这些途径中一种可能的中间蛋白是 p38 MAPK，它由 KOR 和其活动对于压力引起的不动、厌恶和社交回避是必要的。这所提出的实验将直接测试 KOR、p38 MAPK 和 mTOR 之间的关系作为介导抑郁样行为和神经元可塑性的功能信号通路。具体来说，我们建议首先验证初步数据，证明 mTOR 水平受 KOR 调节激活。在目标1中，我们将使用药理学抑制剂/拮抗剂和遗传模型来测试 p38 MAPK 是否是 KOR 激活引起的 mTOR 水平变化所必需的。我们随后将评估 mTOR 是否介导 KOR/p38 诱导的地方厌恶和游泳压力的变化不动。在目标 2 中，我们将测试 KOR 是否会改变神经元可塑性的标志物，包括树突长度、脊柱密度/形状和突触蛋白。我们将同时使用药理学激活KOR和应激来测试p38 MAPK和mTOR的依赖性，最后确定是否 KOR 拮抗作用能够减弱应力引起的可塑性变化。拟议的研究这里描述的将更好地定义从压力暴露到抑郁样症状的分子途径行为，并可能发现可用于临床的治疗作用的新目标人群来治疗压力脆弱的个体。