Kappa-opioid Receptor Modulation of the Stress Response

Kappa-阿片受体对应激反应的调节

基本信息

批准号：
8313257
负责人：
Richard M GUSTIN
金额：
$ 1.6万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2012-07-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8313257
关键词：
Address Adverse effects Affect Amygdaloid structure Animal Model Animals Anxiety Behavior Behavioral Benign Biological Brain Brain region C57BL/6 Mouse Child Comorbidity Complex Development Dynorphins Endogenous depression Exposure to Fellowship Foundations Future Genetic Individual Infection Injection of therapeutic agent Knockout Mice Lead Long-Term Depression Measures Mediating Mental Depression Mental disorders Microinjections Molecular Genetics Mood Disorders Moods Mus Neurodegenerative Disorders Neurons Neuropeptides Nucleus Accumbens Opioid Receptor Perception Phenotype Proteins Receptor Inhibition Reporting Research Research Training Risk Factors Role School-Age Population Social Interaction Specificity Stress Subfamily lentivirinae System Testing Therapeutic Training Training Programs Viral Virus Writing animal model development avoidance behavior biological adaptation to stress bullying career depressive symptoms design disability disease phenotype dorsal raphe nucleus gustin human disease kappa opioid receptors neuronal circuitry norbinaltorphimine novel therapeutics prevent receptor expression recombinase research study response selective expression skills social social stress stressor tool transcription factor young adult

项目摘要

DESCRIPTION (provided by applicant): Social defeat stress results in sustained social avoidance behaviors and other manifestations of depression- like mood disorders. Pretreatment with kappa opioid receptor antagonists or genetic disruption of the dynorphin/? -opioid receptor system (Dyn/KOR) effectively prevents these adverse effects. Stress-induced activation of the Dyn/KOR system has previously been found to encode the dysphoric and anxiogenic effects of stress (as operationally measured by aversion and elevated plus maze behaviors); however, the cellular mechanisms and neuronal circuitry underlying these responses have not yet been defined. In the proposed studies, requesting postdoctoral fellowship support for Dr. Richard Gustin, we ask: 1) Does Social Avoidance following repeated social defeat stress lead to a sustained decrease in social interaction behaviors that can be reversed by subsequent KOR inhibition by the long-acting, non-competitive KOR antagonist, norbinaltorphimine (norBNI)? 2) Which brain regions are necessary targets of Dyn/KOR action that result in the social avoidance and anxiety-like behaviors will be determined by local inhibition of KOR in the dorsal raphe nucleus, nucleus accumbens, and basolateral amygdala? 3) Finally, which brain regions are sufficient to elicit these behaviors will be determined by local injection of lentivirus encoding KOR, selectively restoring receptor expression in the KOR deficient (knockout) mice? Results obtained would help define how KOR activation regulates social avoidance and anxiety-like behaviors following social defeat stress and will help to identify how specific stress-induced behaviors are encoded in the brain. This proposal will lead to a deeper understanding of how stress can produce dysphoric- and anxiety-like behaviors and may help define the therapeutic potential of KOR antagonists in treating the progression of stress-induced depression and related mood disorders. Addressing these questions will provide research training in the development of animal models of human disease, provide additional training in behavioral pharmacological analysis, and enhance research skills in molecular genetic approaches to behavior. The training program outlined in this application would also provide professional development opportunities, enhance presentation and writing skills, and create a strong foundation for a future academic research career. PUBLIC HEALTH RELEVANCE: Exposure to stressors can be extremely debilitating and lead to the manifestation of clinical depression, anxiety, and can exacerbate a number of other psychiatric diseases. We aim to identify how the brain encodes different forms of stress, and how these different stressors can alter brain functions leading to disability. Additionally, our wok has the potential to identify novel therapeutics that may reverse the affects of stress- induced depression and anxiety.

描述（由申请人提供）：社交失败压力会导致持续的社交回避行为和抑郁样情绪障碍的其他表现。使用 kappa 阿片受体拮抗剂或强啡肽基因破坏进行预处理？ -阿片受体系统（Dyn/KOR）有效预防这些不良反应。先前已发现压力诱导的 Dyn/KOR 系统激活可以编码压力的烦躁和焦虑效应（通过厌恶和高架十字迷宫行为进行操作测量）；然而，这些反应背后的细胞机制和神经元回路尚未明确。在拟议的研究中，为理查德·古斯汀博士请求博士后奖学金支持，我们提出以下问题：1）反复社交失败压力后的社交回避是否会导致社交互动行为持续减少，而这种减少可以通过长效药物随后的 KOR 抑制来逆转，非竞争性 KOR 拮抗剂，去甲吗托菲明 (norBNI)？ 2）哪些大脑区域是Dyn/KOR作用的必要目标，导致社交回避和焦虑样行为将由中缝背核、伏隔核和基底外侧杏仁核中KOR的局部抑制决定？ 3）最后，哪些大脑区域足以引发这些行为将通过局部注射编码KOR的慢病毒来确定，选择性地恢复KOR缺陷（敲除）小鼠中的受体表达？获得的结果将有助于确定 KOR 激活如何调节社交失败压力后的社交回避和类焦虑行为，并将有助于确定特定的压力诱发行为是如何在大脑中编码的。该提议将导致人们更深入地了解压力如何产生烦躁和焦虑样行为，并可能有助于确定 KOR 拮抗剂在治疗压力引起的抑郁症和相关情绪障碍进展方面的治疗潜力。解决这些问题将为开发人类疾病动物模型提供研究培训，提供行为药理学分析方面的额外培训，并增强行为分子遗传学方法的研究技能。本申请中概述的培训计划还将提供专业发展机会，提高演示和写作技能，并为未来的学术研究生涯奠定坚实的基础。公共卫生相关性：暴露于压力源可能会导致极度虚弱，并导致临床抑郁、焦虑的表现，并可能加剧许多其他精神疾病。我们的目标是确定大脑如何编码不同形式的压力，以及这些不同的压力源如何改变大脑功能，导致残疾。此外，我们的工作有可能发现新的疗法，可以逆转压力引起的抑郁和焦虑的影响。