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: 8631079
• 负责人: Michael Saddoris
• 金额: $ 10.82万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8631079
• 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; 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; public health relevance; relating to nervous system; research study; skills; tool

DESCRIPTION (provided by applicant): 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-na¿ve) 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.

描述（由申请人提供）：吸毒成瘾是一种慢性复发的疾病，经常对成瘾者和整个社会造成毁灭性的后果。新出现的证据表明，这种药物服用和复发循环的一个可能原因可能集中在认知障碍上。长期接触可卡因等滥用药物会对一般的学习和执行功能产生有害影响，因为它会破坏对认知过程至关重要的边缘结构的神经编码，比如基底外侧杏仁核（BLA）和BLA投射的目标伏隔核（NAc）。事实上，在正常（没有药物的）动物中，同样的回路对于支持简单和更认知的高阶学习至关重要。因此，了解这一回路中的正常神经处理过程，以及它是如何被反复的可卡因体验所改变的，对于理解成瘾的一些关键成分，并为可能的治疗提供潜在的治疗途径至关重要。在这里，我假设正常学习的特点是BLA输入到NAc神经元的相互作用，而NAc神经元由腹侧被盖区（VTA）产生的多巴胺能（DAergic）输入调节。在反复接触可卡因后，该回路将被破坏，其特征是BLA输入NAc和DA信号传递不足。这种功能障碍会阻碍任务相关表征的正常编码，从而损害行为。在指导的K99阶段，我将使用互补技术彻底探索这个功能电路。首先，我将使用快速扫描循环伏安法（FCSV）在有或没有可卡因自我给药史的大鼠中表征DA信号，同时执行二阶巴甫洛夫学习任务。接下来，我将学习光遗传学技术，并将其应用于TH::Cre大鼠的转基因系，这将允许特异性靶向VTA中的DA神经元。有了这项技术，我将能够操纵特定于VTA-NAc通路的DA释放，从而能够观察正常动物的DA释放的短暂停顿是否足以阻碍学习，以及短暂的DA爆发是否足以挽救认知功能。在我独立的R00阶段，我将探索BLA对这一系统的贡献，通过在有可卡因经验的大鼠或负对照的大鼠体内电生理来表征BLA神经编码的二级任务。最后，我将使用该实验的数据来查看选择性的NAc的BLA传入的光学抑制是否能够改变