Cellular mechanisms underlying kappa opioid regulation of stress responses

卡帕阿片类药物调节应激反应的细胞机制

基本信息

批准号：
7947587
负责人：
Julia C Lemos
金额：
$ 3.14万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-16 至 2011-09-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7947587
关键词：
Acute Adult Affect Agonist Animal Model Animals Antidepressive Agents Anxiety Behavior Behavioral Brain Brain region Cells Chronic stress Cocaine Coping Behavior Corticotropin-Releasing Hormone Data Depressed mood Disease Dynorphins Electrophysiology (science)Ensure Event Exhibits Face Goals Heart Diseases Human Immunohistochemistry Individual Injection of therapeutic agent Irritable Bowel Syndrome Knock-out Lead Learned Helplessness Literature Measures Mediating Mental Depression Mentors Modeling Molecular Mus Nervous system structure Neuronal Plasticity Neurons Neuropeptides Opioid Opioid Receptor Organism Pathology Peripheral Nervous System Play Preparation Procedures Process Prosencephalon Protocols documentation Receptor Activation Regulation Research Role Scanning Selective Serotonin Reuptake Inhibitor Serotonin Signal Transduction Signaling Molecule Slice Specificity Stress Swimming Synapses System Testing Tryptophan 5-monooxygenase addiction biological adaptation to stress coping depressive symptoms dorsal raphe nucleus environmental stressor extracellular immunoreactivity kappa opioid receptors male neuroregulation neurotransmission preference receptor research study response sample fixation stressor voltage clamp

项目摘要

DESCRIPTION (provided by applicant): Stress responses are vital to an organism's survival and as such these responses are tightly regulated by a host of signaling molecules within the central and peripheral nervous system. There is a large body of evidence to suggest that severe and chronic stress lead to dysregulation of the normal stress-related electrochemical signaling in the nervous system, which in turn predispose the individual to disease. There is a broad spectrum of stress related diseases ranging from pathologies such as irritable bowel syndrome to cardiac disease to depression. Using animal models, recent studies have posited a role for the dynorphin- kappa opioid receptor (KOR) neuropeptide system in mediating the aversive and pro-depressive components of repeated stress. Stress-induced dynorphin release and subsequent KOR activation occurs in various forebrain limbic brain regions, one of which is the serotonergic dorsal raphe nucleus (DRN). There is a well-established literature implicating the DRN-serotonin projection system in mediating stress responses and stress-related pathology. The DRN receives numerous excitatory and inhibitory inputs and is tonically controlled by serotonergic autoinhibition; all of these inputs control DRN net excitability and ultimately serotonin release into the forebrain. Despite evidence that KORs are present in the DRN, the functional role of KORs in modulating excitability of this region is poorly understood. Using a combination of electrophysiology and fast scan cyclic voltammetry in an acute brain slice preparation, the first aim of this proposal assesses the neuromodulatory role of KORs on excitatory and inhibitory inputs in DRN. Very little is known about how the functioning of the kappa opioid or serotonin system is altered when an organism is exposed to repeated stress, let alone how the interaction between these two systems is altered. Thus, using an established behavioral animal model of repeated stress, the second aim of this application will examine stress-induced cellular alterations in KOR neuromodulation in DRN. In order to advance therapies for stress related diseases it is critical to understand the molecular, cellular and systems level changes that occur in the brain following repeated stress. This line of research further elucidates the cellular mechanisms underlying maladaptive stress responses that make individuals vulnerable to disease.

描述（由申请人提供）：应激反应对于生物体的生存至关重要，因此这些反应受到中枢和周围神经系统内许多信号分子的严格调节。大量证据表明，严重和慢性压力会导致神经系统中与压力相关的正常电化学信号失调，进而使个体容易患病。与压力相关的疾病种类繁多，从肠易激综合症、心脏病到抑郁症等病症。最近的研究利用动物模型，提出了强啡肽阿片受体（KOR）神经肽系统在调节重复压力的厌恶和促抑郁成分中的作用。压力诱导的强啡肽释放和随后的 KOR 激活发生在各个前脑边缘脑区域，其中之一是血清素能中缝背核 (DRN)。有一篇成熟的文献表明 DRN-5-羟色胺投射系统可以调节应激反应和应激相关的病理学。 DRN 接收大量的兴奋性和抑制性输入，并受到血清素能自动抑制的调节；所有这些输入控制 DRN 网络兴奋性并最终控制前脑中的血清素释放。尽管有证据表明 KOR 存在于 DRN 中，但人们对 KOR 在调节该区域兴奋性方面的功能作用知之甚少。该提案的第一个目的是在急性脑切片制备中结合使用电生理学和快速扫描循环伏安法，评估 KOR 对 DRN 中兴奋性和抑制性输入的神经调节作用。当生物体反复受到压力时，我们对卡帕阿片类药物或血清素系统的功能如何改变知之甚少，更不用说这两个系统之间的相互作用如何改变。因此，利用已建立的重复应激行为动物模型，本申请的第二个目标将检查 DRN 中 KOR 神经调节中应激诱导的细胞变化。为了推进压力相关疾病的治疗，了解重复压力后大脑中发生的分子、细胞和系统水平的变化至关重要。这一系列研究进一步阐明了导致个体容易患病的适应不良应激反应的细胞机制。