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）：社会失败压力导致持续的社会回避行为和其他抑郁症情绪障碍的表现。用Kappa阿片类受体拮抗剂进行预处理或Dynorphin的遗传破坏/？ - 奥opire受体系统（DYN/KOR）有效地防止了这些不良反应。以前已经发现，压力诱导的DYN/KOR系统的激活编码压力的烦躁和焦虑作用（如厌恶和升高的迷宫行为所测量的操作）；但是，尚未定义这些反应的基础的细胞机制和神经元电路。在拟议的研究中，请求对理查德·古斯汀博士的博士后奖学金支持，我们问：1）在反复的社交失败压力后，社会回避会导致社交互动行为持续下降，而长期行动，非竞争性的kor antagonist，norbinaltorphimine，norbinaltorphimine（norbni（Norbni）随后的KOR抑制作用可以逆转，这可以逆转。 2）哪些大脑区域是Dyn/Kor作用的必要目标，导致社会回避和类似焦虑行为的行为将取决于局部抑制背侧raphe核，伏隔核和基底外侧杏仁核的局部抑制？ 3）最后，哪些大脑区域足以引起这些行为，将通过局部注射编码KOR的慢病毒的注射来确定，从而选择性地恢复了Kor缺乏（敲除）小鼠中的受体表达？获得的结果将有助于定义KOR激活如何调节社会失败压力后的社会回避和类似焦虑的行为，并有助于确定特定的压力引起的行为如何在大脑中编码。该提议将使对压力如何产生烦躁和焦虑般的行为有更深入的了解，并可能有助于定义Kor拮抗剂在治疗压力引起的抑郁症和相关情绪障碍方面的治疗潜力。解决这些问题将为人类疾病动物模型的发展提供研究培训，为行为药理分析提供其他培训，并提高分子遗传学方法的研究技能。本应用程序中概述的培训计划还将提供专业发展的机会，增强演示和写作技巧，并为未来的学术研究职业创造强大的基础。公共卫生相关性：暴露于压力源可能会使人衰弱，并导致临床抑郁症，焦虑症的表现，并且会加剧许多其他精神病。我们旨在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，我们的锅有潜力鉴定出可能扭转压力诱发抑郁和焦虑的影响的新型治疗剂。