5-HT1B Autoreceptors in Animal Models of Stress Disorders

描述（由申请人提供）：大脑中的血清素系统在决定对环境压力源的反应中起着重要作用。然而，压力和血清素之间的相互作用是复杂的，因为血清素的急性增加可能会引起焦虑，而慢性增加实际上可以减少焦虑和抑郁症状，这取决于环境和大脑区域。由于5-HT1B自身受体调节轴突末端5-HT的释放和可能的再摄取，因此它被战略性地置于调节介导恐惧、焦虑和应激性抑郁的脑区细胞外5-HT的位置。然而，研究5-HT1B自身受体的作用具有挑战性，因为5-HT1B异受体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异性技术。在此之前，我们开发了一种病毒介导的基因转移策略来操纵中缝背核的5-HT1B自受体，并选择性地增加5-HT1B自受体的表达。我们发现过表达5-HT1B的动物在不暴露于环境压力源时焦虑程度较低，但在有压力时焦虑程度较高。我们最近构建了一种基于5-羟色胺转运启动子的5-羟色胺选择性病毒载体，仅在5-羟色胺能神经元中增加5-HT1B受体的表达。我们现在提出从四种途径探索5-HT1B自受体在中背的功能。我们将研究5-HT1B自受体在鼻侧和尾侧背中叶行为中的神经解剖学贡献，这两个亚区似乎分别介导焦虑和抑郁。我们将通过检查5-HT1B自身受体对条件恐惧的习得、表达和消退的影响来研究它们在调节恐惧学习中的时间作用。我们将研究这些自受体调节细胞外5-羟色胺水平的机制，以及它们是否通过调节血清素转运体功能来调节细胞外5-羟色胺水平。我们将研究应激和CRF相关肽对5-HT1B自身受体对行为的调节作用。这些问题将使用我们在实验室开发的新型分子，药理学和行为策略的组合来解决，使我们能够在这些动物模型中分离出5-HT1B自身受体在压力相关疾病中的作用。

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.