Input-specific Regulation of Transmission by Alpha2A Adrenergic Receptors

描述(申请人提供)：上瘾是一种衰弱的，长期复发的障碍，特征是继续使用药物，尽管有负面后果。成瘾在临床环境中尤其难以治疗，因为即使在长期戒断之后，复发的可能性也很高。在接触到与药物有关的线索或以前与药物使用有关的环境刺激后，复发的风险会增加。然而，重蹈覆辙的风险最大的增加发生在压力之下。以前的研究表明，终纹床核(BNST)与应激诱导的药物寻找行为的恢复有关。特别是，BNST中的去甲肾上腺素信号通过2-肾上腺素能受体(2-ARs)被证明调节应激诱导的药物寻找行为的恢复。BNST内局部注射2-AR激动剂可减弱应激诱导的恢复行为。了解2-AR激动剂阻断应激诱导的恢复的机制可能有助于确定新的药物治疗方法，用于防止应激诱导的复发寻求药物的行为。以前的工作表明，2A-AR激动剂，鸟嘌呤，抑制了BNST中的兴奋性神经元传递。然而，最近的研究表明，2-AR能够不同地调节杏仁中央核(CEA)的特定兴奋性输入，CEA是一种与BNST密切相关的大脑结构。因此，我们将使用光遗传学技术来检验这一假设，即2A-Ars差异化地调制从岛叶皮质、杏仁基底外侧核和臂旁核到BNST的兴奋性输入。此外，最近的研究表明，2A-ARs在增强BNST的兴奋性传递方面具有潜在的作用。因此，我们将检验BNST中的一组神经元被2A-ARs激活的假设，并将致力于探索这一神经元组的特性。我们希望更好地了解2A-ARs如何调制BNST的兴奋性输入，以及这些输入的调制如何影响BNST中的神经元激活。这样的理解可能有助于阐明BNST中的2-ARs调节应激诱导的药物寻找行为恢复的机制，并可能导致发现防止应激诱导的复发药物寻找的新的药物疗法。该项目的主要导师丹尼·温德博士在压力和成瘾研究以及脑片准备的电生理技术方面拥有多年经验。我将接受脑片制备方面的电生理技术培训，并将在我的导师的直接监督下工作，为实验室建立光遗传学方法。我还将通过教学课程、每周的研讨会、杂志俱乐部和实验室会议来学习实验技能和技巧。我在研究生培训期间获得的技能对我未来的职业目标将是无价的，我是一名内科科学家，研究压力和成瘾相互作用的神经机制。

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.