Cellular mechanisms underlying kappa opioid regulation of stress responses

描述（由申请人提供）：应激反应对生物体的生存至关重要，因此这些反应受到中枢和外周神经系统内大量信号分子的严格调节。有大量的证据表明，严重和慢性压力导致神经系统中正常压力相关电化学信号的失调，这反过来又使个体易患疾病。与压力相关的疾病有很多种，从肠易激综合征到心脏病再到抑郁症。使用动物模型，最近的研究已经假定了强啡肽-κ阿片受体（KOR）神经肽系统在介导重复压力的厌恶和抑郁成分中的作用。应激诱导的强啡肽释放和随后的KOR激活发生在各种前脑边缘脑区域，其中之一是多巴胺能中缝背核（DRN）。有一个完善的文献涉及DRN-5-羟色胺投射系统介导的应激反应和应激相关的病理。DRN接受许多兴奋性和抑制性输入，并由多巴胺能自抑制进行紧张性控制;所有这些输入控制DRN的净兴奋性，并最终将5-羟色胺释放到前脑。尽管有证据表明KORs存在于DRN中，但KORs在调节该区域兴奋性中的功能作用知之甚少。使用电生理学和快速扫描循环伏安法在急性脑切片制备的组合，本建议的第一个目的是评估的兴奋性和抑制性输入在DRN的KORs的神经调节作用。当一个生物体暴露于反复的压力下时，对κ阿片或5-羟色胺系统的功能是如何改变的知之甚少，更不用说这两个系统之间的相互作用是如何改变的了。因此，使用已建立的重复应激的行为动物模型，本申请的第二个目的将检查DRN中KOR神经调节的应激诱导的细胞改变。为了推进应激相关疾病的治疗，了解反复应激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适应不良应激反应的细胞机制，使个体容易受到疾病的影响。

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.