Synaptic and Behavioral Correlates of Adeonsinergic Signaling in the BLA

BLA 中腺苷酸信号传导的突触和行为相关性

• 批准号: 8702978
• 负责人: Andrew Ryan Rau
• 金额: $ 3.67万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-22 至 2015-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8702978
• 关键词: Acute; Adenosine; Adolescent; Agonist; Alcohol consumption; Alcoholism; Amygdaloid structure; Animal Model; Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Attenuated; Behavior; Behavioral; Behavioral Assay; Brain region; Characteristics; Chronic; Clinical; Comorbidity; Complex; Data; Development; Disease; Doctor of Philosophy; Ethanol; Fellowship; Funding; Glutamates; Goals; Health Sciences; Housing; Human; Individual; Investigation; Knowledge; Laboratories; Lead; Life Stress; Link; Literature; Mediating; Modeling; Monkeys; National Research Service Awards; Neuraxis; Neurobiology; Neuromodulator; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Physiological; Physiology; Play; Property; Publishing; Purinergic P1 Receptors; Rattus; Regulation; Research; Research Training; Rodent; Rodent Model; Role; Self Administration; Series; Signal Transduction; Site; Social isolation; Specificity; Synapses; Synaptic Transmission; System; Testing; Therapeutic; Time; Treatment Protocols; Universities; Withdrawal; Work; addiction; adenosine receptor activation; alcohol effect; alcohol exposure; alcohol use disorder; analog; base; catalyst; design; effective therapy; follow-up; forest; insight; interest; neurotransmission; novel; postsynaptic; pre-doctoral; preclinical study; presynaptic; receptor; relating to nervous system; research study; transmission process

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.

描述（由申请人提供）：Andrew R. Rau提交了此露丝L. Kirschstein NRSA的申请。 Wake Forest University Health Sciences的生理学和药理学系Weiner博士实验室的研究重点是阐明负责乙醇和焦虑症相关疾病的复杂突触和行为影响的机制。本应用程序中提出的研究旨在首次表征腺苷的作用 （ADO）调节基底外侧杏仁核（BLA）内的突触传播。 此外，这些研究将进一步理解腺苷在与早期生活压力模型相关的神经生物学基础中的作用，这与焦虑样行为和乙醇消耗的明显增加相关。腺苷通常通过激活抑制谷氨酸释放的突触前A1受体来发挥其抑制作用。为此，如果在BLA中是这种情况，那将是至关重要的治疗益处，因为该区域的过度兴奋性已与啮齿动物，猴子和人类的焦虑般的行为表现直接相关。 因此，该建议概述了一系列实验，旨在表征ADO在BLA中的作用，并研究ADO激动剂和拮抗剂的BLA递送的行为结果。 简而言之，AIM 1将跟进初步发现，以识别介导BLA突触传播的ADO调制的ADO受体亚型。该目的还将检验以下假设：补品腺苷能张力积极调节BLA中的兴奋性传播。这个目标还将检验以下假设：青少年社会隔离后腺苷能语调被破坏，这是一种早期生活压力的模型，这种模型会增加焦虑症行为以及乙醇消耗的增加。在此目标的基础上，AIM 2将使用行为分析来确定ADO直接传递到BLA的能力，以减轻社会隔离带来的类似焦虑般的行为和乙醇消费的增加。 这些研究将大大提高我们对BLA中ADO信号的理解，并可能识别出将早期生活压力和增加焦虑样行为和乙醇饮用的新型神经底物。此外，从这些调查中收集的见解可能揭示了有希望的新靶标，用于开发用于治疗成瘾和焦虑症的新型药物治疗剂。