5-HT1B Autoreceptors in Animal Models of Stress Disorders

描述(申请人提供)：大脑中的5-羟色胺系统在决定对环境应激源的反应中起着重要作用。然而，压力和5-羟色胺之间的相互作用是复杂的，因为5-羟色胺的急剧增加可能会导致焦虑，而慢性增加实际上可以减少焦虑和抑郁症状，这取决于背景和大脑区域。由于5-HT1B自身受体调节轴突终末5-羟色胺的释放和可能的重摄取，它在调节大脑中介导恐惧、焦虑和应激诱导的抑郁的细胞外5-羟色胺具有战略地位。然而，5-HT1B自身受体的作用研究是具有挑战性的，因为5-HT1B异种受体定位于大脑中其他类型神经元的轴突终末，这就需要使用解剖学上的特定技术。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，过度表达5-HT1B的动物在没有暴露在环境应激源时不那么焦虑，但在压力下更焦虑。我们最近构建了一个基于5-羟色胺转运体启动子的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。我们现在建议从四个方面探讨5-HT1B自身受体在中缝背侧的作用。我们将研究5-HT1B自身受体在吻侧和尾侧背侧中缝对行为的神经解剖学贡献，这两个亚区似乎分别介导焦虑和抑郁。我们将通过检测5-HT1B自身受体对条件性恐惧的获得、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。我们将研究这些自身受体调节细胞外5-羟色胺水平的机制，以及它们是否通过调节5-羟色胺转运体功能来做到这一点。我们将研究5-HT1B自身受体对应激和CRF相关多肽对行为的调节作用。这些问题将使用我们在实验室开发的新的分子、药理学和行为策略的组合来解决，使我们能够分离5-HT1B自身受体在这些应激相关疾病动物模型中的作用。

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.