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

描述(申请人提供)：毒瘾是一种慢性复发性疾病，通常会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，这种吸毒和复发循环的一个可能原因可能是认知障碍。长期接触可卡因等滥用药物会扰乱边缘结构中对认知过程至关重要的神经编码，如基底外侧杏仁核(BLA)和BLA投射的目标伏隔核(NAC)，从而对一般学习和执行功能产生有害影响。事实上，众所周知，这一回路对于支持正常(药物)动物的简单和更高层次的认知学习是至关重要的。因此，了解这个回路中正常的神经处理过程以及它是如何被反复的可卡因经验改变的，对于了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是至关重要的。在这里，我假设正常学习的特征是BLA输入到NAC神经元的相互作用，而NAC神经元受到来自腹侧被盖区(VTA)的多巴胺(DA)能输入的调制。在反复接触可卡因后，这一回路将被扰乱，其特征是NAC的BLA输入不足和DA信号贫乏。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，我将使用补充技术彻底探索这一功能电路。首先，我将使用快速扫描循环伏安法(FCSV)描述在执行二阶巴甫洛夫学习任务时有和没有可卡因自我给药史的大鼠的DA信号。接下来，我将学习光遗传技术，并将其应用于TH：：CRE转基因大鼠的转基因品系中，这将允许VTA中DA神经元的特异性靶向。有了这项技术，我将能够操纵VTA-NAC通路特有的DA释放，从而能够观察DA释放的短暂停顿是否足以阻止正常动物的学习，以及DA的短暂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对这个系统的贡献，方法是用体内电生理学的第二级任务的BLA神经编码来表征有可卡因经验或轭控制的大鼠。最后，我将使用该实验的数据来观察选择性地对NAC的BLA传入的光学抑制是否能够改变 在正常动物中学习，但在有可卡因自我给药史的大鼠中恢复功能。综上所述，这项提议将提供反复暴露可卡因后BLA-NAC-VTA神经回路的彻底特征，使用更高阶的学习任务来解析特定的认知缺陷。

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.