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

项目总结/摘要 药物成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 人和整个社会。新出现的证据表明，这种药物循环的一个可能原因是， 服用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， 通过扰乱边缘系统的神经编码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，如基底外侧杏仁核（BLA）和BLA的靶点 投射，即延髓核（NAc）。事实上，已知同一电路对于支持 在正常（未用药）动物中进行简单和更认知的高阶学习。因此，理解 这个回路中的正常神经处理以及它如何被重复的可卡因经验所改变将是至关重要的 了解成瘾的一些关键组成部分，并提供潜在的治疗途径， 可能的治疗。在这里，我假设正常学习的特点是BLA输入的相互作用， 由腹侧被盖区产生的多巴胺能（DA能）输入调制的NAc神经元 （VTA）。在反复接触可卡因后，该回路将被破坏，其特征是BLA输入不足， NAc和贫乏的DA信号传导。这种功能障碍将阻止任务相关的正常编码， 行为，从而影响行为。在辅导K99阶段，我将彻底探索 该功能电路使用互补技术。首先，我将使用快速扫描来表征DA信号 循环伏安法（FCSV）在有和没有可卡因自我给药既往史的大鼠中进行， 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大鼠的转基因品系，其将允许VTA中的DA神经元的特异性靶向。与此 技术，我将能够操纵DA释放特定的VTA-NAc途径，使能够看到 多巴胺释放的短暂停顿是否足以阻止正常动物的学习，以及是否短暂的多巴胺释放的突然爆发。 DA足以挽救认知功能。在我的独立R 00阶段，我将探索 BLA到这个系统通过表征BLA神经编码与体内电生理学的第二- 在有可卡因使用史的大鼠或对照组中进行订单任务。最后，我将使用这些数据 实验，看看是否光学抑制BLA传入选择性的NAc能够改变学习， 正常动物，但恢复功能的历史，可卡因自我管理的大鼠。总的来说，这 该提案将提供重复可卡因后BLA-NAc-VTA神经回路的彻底表征 暴露，使用高阶学习任务来解析特定的认知缺陷。

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.