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

基本信息

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
项目类别：
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

项目摘要

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 /摘要吸毒成瘾是一种长期复发的疾病，通常会对上瘾产生毁灭性的后果整个人与社会。新兴证据表明，这种药物周期的可能原因是接受和继电器可能以认知障碍为中心。长期暴露于像可卡因这样的滥用药物可以通过破坏边缘的神经编码，对一般学习和执行功能删除了影响认知过程至关重要的结构，例如基底外侧杏仁核（BLA）和BLA的目标投影，伏隔核（NAC）。确实，同一电路对于支持两者都是至关重要的在正常（不接受药物）动物中简单，更认知的高阶学习。那是理解的该电路中的正常神经处理以及如何通过重复可卡因经验改变它是必不可少的了解成瘾的某些关键组成部分，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输入与由腹侧对段区域引起的多巴胺能（Daergic）输入调节的NAC神经元（VTA）。反复的可卡因暴露后，该电路将被破坏，其特征是BLA输入不良 NAC和贫困的DA信号传导。这种功能障碍将防止与任务相关的正常编码表示并因此损害行为。在物质K99阶段，我将彻底探索该功能电路使用完成技术。首先，我将使用快速扫描来表征DA信令在有或没有可卡因自我管理史的大鼠中，循环伏安法（FCSV）执行二阶Pavlovian学习任务。接下来，我将学习光遗传技术，并将其应用于 Th :: Crece大鼠的转基因线，该线将允许在VTA中特定靶向DA神经元。与此技术，我将能够操纵特定于VTA-NAC途径的DA释放，从而可以看到 DA释放中的短暂暂停是否足以阻止普通动物的学习，以及是否瞬时爆发 DA足以挽救认知功能。在我的独立R00阶段，我将探讨该系统的BLA通过表征BLA神经编码，并用第二次体内电生理学在具有可卡因经验或受体控制史的大鼠中订购任务。最后，我将使用其中的数据实验以查看对NAC选择性的BLA传入的光学抑制是否能够改变学习正常动物，但在具有可卡因自我管理史的大鼠中恢复功能。总的来说，这个提案将在重复可卡因后提供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。