Synaptic and Behavioral Correlates of Adeonsinergic Signaling in the BLA

描述(由申请人提供)：此申请Ruth L.Kirschstein NRSA个人博士前奖学金是由Andrew R.Rau提交的，目的是在维克森林大学健康科学系生理学和药理学博士Jeff L.Weiner的指导下为研究培训寻求资金。韦纳博士实验室的研究重点是揭开酒精和焦虑相关障碍对突触和行为产生复杂影响的机制。在本申请中提出的研究旨在首次表征腺苷的作用。 (ADO)调节杏仁基底外侧核(BLA)内的突触传递。此外，这些研究将进一步加深我们对腺苷在神经生物学基础上的作用的理解，该神经生物学基础与早期生活应激模型有关，该模型与焦虑样行为和酒精消费的显著增加有关。腺苷一般通过激活突触前A1受体来发挥抑制作用，A1受体抑制谷氨酸的释放。为此，如果在BLA中是这样的话，这将是至关重要的治疗益处，因为该区域的过度兴奋直接与啮齿动物、猴子和人类的焦虑行为的表现有关。因此，这项建议概述了一系列实验，旨在描述ADO在BLA中的作用，并调查ADO激动剂和拮抗剂在BLA内传递的行为结果。简而言之，Aim 1将跟进初步发现，以确定介导ADO调节BLA突触传递的ADO受体亚型。这一目标也将检验这样一种假设，即强直性腺苷能主动调节BLA中的兴奋性传递。这一目标还将检验以下假设：在青少年社交孤立之后，腺苷能紧张会被扰乱，这是一种早期生活压力的模型，会导致焦虑样行为的增加以及酒精摄入量的增加。在这一目标的基础上，Aim 2将使用行为分析来确定ADO的能力，将其直接输送到BLA中，以减轻因社交孤立而导致的焦虑样行为和酒精消耗的增加。这些研究将极大地促进我们对BLA中ADO信号的理解，并可能发现新的神经底物，将早期生活应激与焦虑样行为增加和饮酒联系在一起。此外，从这些研究中收集的见解可能会揭示出开发治疗成瘾和焦虑症的新药物疗法的有希望的新目标。

DESCRIPTION (provided by applicant): This application for a Ruth L. Kirschstein NRSA for Individual Predoctoral Fellowship is submitted by Andrew R. Rau in order to seek funding for research training under the guidance of Jeff L. Weiner, Ph.D. in the Department of Physiology and Pharmacology at Wake Forest University Health Sciences. Research in the laboratory of Dr. Weiner is focused on unraveling the mechanisms responsible for the complex synaptic and behavioral effects of ethanol and anxiety related disorders. The research studies proposed in this application are intended to, for the first time characterize the role of adenosine (ADO) in regulating synaptic transmission within the basolateral amygdala (BLA). Moreover, these studies will further our understanding of adenosine's role in the neurobiological underpinnings associated with a model of early life stress that is associated with marked increases in anxiety-like behavior and ethanol consumption. Adenosine generally exerts its inhibitory effects by activating presynaptic A1 receptors which inhibit glutamate release. To that end, it would be of critical therapeutic benefit if this was the case in the BLA, as excessive excitability in this region has been directly linked to the manifestation of anxiety-like behaviorsin rodents, monkeys, and humans. Therefore this proposal outlines a series of experiments designed to characterize ADO's actions in the BLA and to investigate the behavioral outcomes of intra-BLA delivery of ADO agonists and antagonists. Briefly, Aim 1 will follow up on preliminary findings to identify the ADO receptor subtypes that mediate ADO modulation of BLA synaptic transmission. This aim will also test the hypothesis that tonic adenosinergic tone actively regulates excitatory transmission in the BLA. This aim will also test the hypothesis that adenosinergic tone is disrupted following adolescent social isolation, a model of early life stress that engenders increases in anxiety-like behavior as well as increases in ethanol consumption. Building upon this aim, Aim 2 will use behavioral assays to determine the ability of ADO, delivered directly into the BLA, to attenuate the increases in anxiety-like behavior and ethanol consumption brought on by social isolation. These studies will significantly advance our understanding of ADO signaling in the BLA and possibly identify novel neural substrates linking early life stress and increased anxiety-like behaviors and ethanol drinking. Moreover, insights gathered from these investigations may reveal promising new targets for development of novel pharmacotherapeutics for treating addiction and anxiety disorders.