Mechanisms of Higher-Order Learning in the NAc Impaired by Cocaine Exposure

可卡因暴露损害 NAC 的高阶学习机制

• 批准号: 8866716
• 负责人: Michael Saddoris
• 金额: $ 24.89万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8866716
• 关键词: Abstinence; Affect; Amygdaloid structure; Animals; Behavior; Brain; Cell Nucleus; Chronic; Cocaine; Cognitive; Cognitive deficits; Cues; Data; Decision Making; Development; Disease; Dopamine; Drug Addiction; Drug usage; Educational process of instructing; Electrophysiology (science); Exposure to; Food; Foundations; Functional disorder; Future; Goals; Grant; Halorhodopsins; Impaired cognition; Impairment; Individual; Learning; Lesion; Light; Lighting; Measures; Mentors; Neurons; Nucleus Accumbens; Optics; Outcome; Pathway interactions; Persons; Pharmaceutical Preparations; Phase; Physiology; Process; Rattus; Recording of previous events; Reinforcement Schedule; Relapse; Research; Rewards; Risk-Taking; Role; Saline; Scanning; Self Administration; Signal Transduction; Slice; Societies; Structure; System; Techniques; Testing; Therapeutic; Training; Transgenic Organisms; Ventral Tegmental Area; Work; abstracting; addiction; behavioral impairment; classical conditioning; cocaine exposure; cocaine use; cognitive function; conditioning; dopaminergic neuron; drug addict; drug of abuse; executive function; experience; functional restoration; in vivo; insight; neural circuit; neuroadaptation; neurobiological mechanism; neuromechanism; neuronal cell body; novel therapeutics; optogenetics; prevent; relating to nervous system; research study; skills; tool

Project Summary / Abstract Drug addiction is a chronically relapsing disorder that often has devastating consequences for the addicted person and society as a whole. Emerging evidence suggests that one possible reason for this cycle of drug taking and relapse may center on cognitive impairments. Chronic exposure to drugs of abuse like cocaine can have deleterious effects on general learning and executive functions by disrupting neural encoding in limbic structures critical for cognitive processes such as the basolateral amygdala (BLA) and a target of BLA projections, the nucleus accumbens (NAc). Indeed, this same circuit is known to be critical for supporting both simple and more cognitive higher-order learning in normal (drug-naïve) animals. Thus, understanding the normal neural processing in this circuit and how it is altered by repeated cocaine experience will be essential for understanding some of the critical components of addiction and provide potential therapeutic avenues for possible treatments. Here, I hypothesize that normal learning is characterized by the interaction of BLA input to NAc neurons which are modulated by dopaminergic (DAergic) inputs arising from the ventral tegmental area (VTA). Following repeated cocaine exposure, this circuit will be disrupted, characterized by poor BLA input to NAc and impoverished DA signaling. This dysfunction will prevent the normal encoding of task-relevant representations and consequently impair behavior. During the mentored K99 phase, I will thoroughly explore this functional circuit using complementary techniques. First, I will characterize DA signaling using fast-scan cyclic voltammetry (FCSV) in rats with and without a prior history of cocaine self-administration while performing a second-order Pavlovian learning task. Next, I will learn optogenetic techniques and apply them in a transgenic line of TH::Cre rats which will allow for specific targeting of DA neurons in VTA. With this technique, I will be able to manipulate DA release specific to the VTA-NAc pathway, allowing the ability to see whether brief pauses in DA release are sufficient to block learning in normal animals, and if transient bursts of DA are sufficient to rescue cognitive function. In my independent R00 phase, I will explore the contributions of the BLA to this system by characterizing BLA neural encoding with in vivo electrophysiology of the second- order task in rats with a history of cocaine experience or yoked controls. Finally, I will use data from that experiment to see whether optical inhibition of BLA afferents selective to the NAc is able to alter learning in normal animals, but restore function in rats with a history of cocaine self-administration. Taken together, this proposal will provide a thorough characterization of the BLA-NAc-VTA neural circuit after repeated cocaine exposure, using a higher-order learning task to parse specific cognitive deficits.

项目摘要/摘要 毒瘾是一种慢性复发性疾病，通常会对成瘾者造成毁灭性的后果。 个人和社会作为一个整体。新出现的证据表明，这种药物循环的一个可能原因 吸毒和复发可能集中在认知障碍上。长期接触可卡因等滥用药物可能会 通过扰乱边缘的神经编码而对一般学习和执行功能产生有害影响 对认知过程至关重要的结构，如杏仁基底外侧核(BLA)和BLA的靶点 伏隔核(NAC)的投射。事实上，众所周知，这条线路对于支持这两条线路都至关重要 在正常(药物天真的)动物中，简单且更具认知性的高级学习。因此，理解 这个回路的正常神经处理以及它如何被反复的可卡因经验改变将是必不可少的。 了解成瘾的一些关键成分，并提供潜在的治疗途径 可能的治疗方法。在这里，我假设正常学习的特征是BLA输入到 受腹侧被盖区多巴胺能(DA能)传入调制的NAC神经元 (VTA)。在反复接触可卡因后，这一回路将被中断，其特征是血乳酸输入不良 NAC和贫乏的DA信令。这种功能障碍将阻碍任务相关的正常编码 表达，并因此损害行为。在指导K99阶段，我将深入探索 此功能电路采用互补技术。首先，我将使用快速扫描来表征DA信令 有和无可卡因自身给药史大鼠的循环伏安法(FCSV) 执行二阶巴甫洛夫学习任务。接下来，我将学习光遗传技术，并将它们应用于 TH：：CRE大鼠的转基因品系，将允许对VTA中的DA神经元进行特异性靶向。有了这个 技术，我将能够操纵VTA-NAC通路特有的DA释放，从而能够看到 DA释放的短暂停顿是否足以阻止正常动物的学习，以及如果短暂的 DA足以挽救认知功能。在我独立的R00阶段，我将探讨 通过表征BLA神经编码与体内第二电生理学的第二- 在有可卡因经验的大鼠或有颈项控制的大鼠中进行排序任务。最后，我将使用其中的数据 光学抑制对NAC选择性的BLA传入是否能够改变大鼠的学习能力 正常动物，但在有可卡因自我给药史的大鼠中恢复功能。总而言之，这是 该提案将提供反复吸食可卡因后BLA-NAC-VTA神经回路的彻底特征 暴露，使用更高级别的学习任务来解析特定的认知缺陷。