Input-specific Regulation of Transmission by Alpha2A Adrenergic Receptors

描述（由申请人提供）：成瘾是一种使人衰弱，慢性复发的疾病，其特征是持续使用药物，尽管有负面后果。在临床环境中，成瘾尤其难以治疗，因为即使在长时间的戒断后，复发的可能性也很高。暴露于与药物有关的线索或先前与药物使用有关的环境刺激后，复发的风险增加。然而，药物寻求行为复发风险最显著的增加发生在暴露于压力下。以往的研究表明终纹床核（BNST）与应激诱导的药物寻求行为恢复有关。特别是，通过BNST中¿2-肾上腺素能受体（¿2 -ARs）的去甲肾上腺素信号传导已被证明可以调节应激诱导的药物寻求行为的恢复。局部给药的2 -AR激动剂可减弱应力诱导的恢复行为。了解¿2-AR激动剂阻断应激诱导恢复的机制可能会导致发现新的药物治疗方法，用于预防应激诱导的药物寻求行为复发。先前的研究表明，2A -AR激动剂胍法辛可抑制BNST中的兴奋性神经元传递。然而，最近的研究表明，¿2 - ar能够差异调节特定的兴奋输入到杏仁核中央核（CeA），这是一个与BNST密切相关的大脑结构。因此，我们将使用光遗传学技术来测试这一假设，即¿2A-ARs对来自岛叶皮质、基底外侧杏仁核和臂旁核的BNST的兴奋性输入进行差异调节。此外，最近的研究已经证明了¿2A -ARs在增强BNST兴奋性传递方面的潜在作用。因此，我们将测试BNST中一群神经元被¿2A -ARs激活的假设，我们将努力探索这群神经元的特性。我们希望更好地了解¿2A-ARs如何调节BNST的兴奋性输入，以及这些输入的调节如何影响BNST中的神经元激活。这样的理解可能有助于阐明BNST中¿2-ARs调节应激诱导的药物寻求行为恢复的机制，并可能导致确定新的药物治疗方法，以防止应激诱导的药物寻求复发。本项目的主要导师，丹尼·温德博士，在压力和成瘾研究方面有多年的经验，在脑切片制备的电生理技术方面也有多年的经验。我将接受脑切片制备电生理技术的培训，并将在导师的直接指导下为实验室建立光遗传学方法。我还将通过教学课程、每周研讨会、期刊俱乐部和实验室会议来学习实验技能和技术。在我的研究生训练中获得的技能对我未来的职业目标是无价的，作为一名研究压力和成瘾相互作用的神经机制的内科科学家。

DESCRIPTION (provided by applicant): Addiction is a debilitating, chronically relapsing disorder, characterized by continued use of drugs, despite negative consequences. Addiction is particularly difficult to treat in the clinical setting due to the high probability of relapse evenafter prolonged periods of abstinence. Risk of relapse increases after exposure to drug-related cues or to environmental stimuli previously associated with drug-use. However, the most substantial increase in risk for relapse to drug-seeking behavior occurs with exposure to stress. Previous studies have implicated the bed nucleus of the stria terminalis (BNST) in stress-induced reinstatement of drug-seeking behavior. In particular, norepinephrine signaling through ¿2-adrenergic receptors (¿2 -ARs) in the BNST has been shown to modulate stress-induced reinstatement of drug-seeking behavior. ¿2 -AR agonists locally administered into the BNST attenuate stress-induced reinstatement behavior. Understanding the mechanism by which ¿2-AR agonists block stress-induced reinstatement may lead to the identification of new pharmacological therapies to be used for the prevention of stress-induced relapse to drug-seeking behavior. Previous work has shown that the ¿2A -AR agonist, guanfacine, depresses excitatory neuronal transmission in the BNST. However, recent studies have shown that ¿2 -ARs are capable of differentially modulating specific excitatory inputs to the central nucleus of the amygdala (CeA) which is a brain structure closely related to the BNST. Therefore, we will be testing the hypothesis that ¿2A-ARs differentially modulate excitatory inputs to the BNST from the insular cortex, the basolateral amygdala, and the parabrachial nucleus using optogenetic techniques. In addition, recent studies have demonstrated a potential role for ¿2A -ARs in enhancing excitatory transmission in the BNST. Therefore, we will be testing the hypothesis that a population of neurons in the BNST is activated by ¿2A -ARs, and we will work to explore properties of this neuronal population. We hope to gain a better understanding of how ¿2A-ARs modulate excitatory inputs to the BNST, and how modulation of these inputs affects neuronal activation in the BNST. Such an understanding may help to elucidate mechanisms by which ¿2-ARs in the BNST can modulate stress-induced reinstatement of drug-seeking behavior, and may lead to the identification of new pharmacological therapies for preventing stress-induced relapse to drug-seeking. The primary mentor of this project, Dr. Danny Winder, has many years of experience in stress and addiction research, and in electrophysiological techniques in brain slice preparations. I will be trained in electrophysiological techniques in brain slice preparation, and will work under direct supervision of my advisor to establish optogenetic methodologies for the lab. I will also learn experimental skills and techniques through didactic coursework, and through weekly seminars, journal clubs, and lab meetings. The skills gained during my graduate training will be invaluable to my future career goals as a physician-scientist studying the neural mechanisms underlying the interaction of stress and addiction.