5-HT1B Autoreceptors Animal Models of Stress Disorders

5-HT1B 自身受体应激障碍动物模型

• 批准号: 7049118
• 负责人: John F Neumaier
• 金额: $ 31.04万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-09 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7049118
• 关键词: anxiety; anxiety disorders; axon; behavior test; behavioral /social science research tag; brain mapping; conditioning; corticotropin releasing factor; depression; disease /disorder model; dorsal raphe nucleus; environmental stressor; fear; laboratory rat; psychopathology; psychosomatic disorders; receptor expression; serotonin; serotonin receptor; serotonin transporter; stress; transfection /expression vector

DESCRIPTION (provided by applicant): The serotonin system in the brain plays an important role in determining the responses to environmental stressors. The interaction between stress and serotonin is complex, however, since acute increases in serotonin can be anxiogenic, while chronic increases can actually reduce anxiety and depressive symptoms, depending on the context and the brain region. Since the 5-HT1B autoreceptor regulates the release and possibly the reuptake of 5-HT at axon terminals, it is strategically placed to modulate extracellular 5-HT in brain regions that mediate fear, anxiety, and stress-induced depression. The effects of 5-HT1B autoreceptors are challenging to study, though, because 5-HT1B heteroreceptors are localized in axon terminals of other neuron types throughout the brain, necessitating the use of anatomically specific techniques. Previously we developed a viral mediated gene transfer strategy to manipulate 5-HT1B autoreceptors in dorsal raphe nucleus and increase the expression of 5-HT1B autoreceptors selectively. We have found that 5-HT1B- overexpressing animals are less anxious when not exposed to environmental stressors, but more anxious when stressed. We have recently constructed a serotonin selective viral vector based on the serotonin transporter promoter to increase expression of 5-HT1B receptors only in serotonergic neurons. We now propose to pursue the function of 5-HT1B autoreceptors in dorsal raphe in four ways. We will examine the neuroanatomical contribution of 5-HT1B autoreceptors to behavior in rostral vs. caudal dorsal raphe, subregions that appear to mediate anxiety and depression, respectively. We will investigate the temporal role of 5-HT1B autoreceptors in modulating fear learning by examining their effects on acquisition, expression, and extinction of conditioned fear. We will study the mechanism by which these autoreceptors regulate extracellular 5-HT levels, and whether they do so by modulating serotonin transporter function. We will examine the modulation of 5-HT1B autoreceptor effects on behavior by stress and the CRF related peptides. These questions will be addressed using a combination of novel molecular, pharmacological, and behavioral strategies that we have developed in our lab, allowing us to isolate the role of 5-HT1B autoreceptors in these animal models of stress-associated illnesses.

描述（由申请人提供）：大脑中的5-羟色胺系统在确定对环境压力源的反应中起着重要作用。但是，压力与5-羟色胺之间的相互作用很复杂，但是，由于5-羟色胺的急性增加可能是焦虑的，而慢性增加实际上可以减轻焦虑和抑郁症状，具体取决于上下文和大脑区域。由于5-HT1b自身受体可以调节轴突终端处的释放，并可能在轴突终端重新摄取5-HT，因此在策略上放置了调节细胞外5-HT的大脑区域，以介导恐惧，焦虑和压力诱导的抑郁症。但是，5-HT1b自身受体的影响很难研究，因为5-HT1B杂感位定位于整个大脑中其他神经元类型的轴突末端，因此需要使用解剖学特定的技术。以前，我们开发了一种病毒介导的基因转移策略，以操纵背侧raphe核中的5-HT1B自身受体，并选择性地增加5-HT1B自身受体的表达。我们发现，当不暴露于环境压力源时，5-HT1B过表达的动物不那么焦虑，而是在压力时更加焦虑。我们最近基于5-羟色胺转运蛋白启动子构建了5-羟色胺选择性病毒载体，以增加5-HT1B受体的表达，仅在5-羟色胺能神经元中。现在，我们建议通过四种方式在背raphe中追求5-HT1B自身受体的功能。我们将研究5-HT1B自感受器对尾部背侧raphe中的行为的神经解剖学贡献，似乎分别介导了焦虑和抑郁的子区域。我们将研究5-HT1b自感受器在调查恐惧学习中对有条件恐惧的收购，表达和灭绝的影响，从而调节恐惧学习的时间作用。我们将研究这些自身受体调节细胞外5-HT水平的机制，以及它们是否通过调节5-羟色胺转运蛋白的功能来调节。我们将检查5-HT1B自身受体对压力和CRF相关肽对行为的影响。这些问题将使用我们在实验室中开发的新分子，药理学和行为策略的结合来解决，从而使我们能够隔离5-HT1B自身受体的作用在这些与压力相关疾病的动物模型中。