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：
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
项目类别：
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

项目摘要

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（由适用提供）：吸毒成瘾是一种长期复发的疾病，通常对增加的人和整个社会产生毁灭性的后果。新兴证据表明，这种吸毒周期和继电器周期的可能原因可能是认知障碍。长期暴露于诸如可卡因之类的滥用药物的药物可以通过破坏对认知过程至关重要的边缘结构中的神经编码来对一般学习和执行功能产生有害影响，例如基础型杏仁核（BLA）和BLA项目的目标，即核心Accumbens（NAC）。实际上，已知该电路对于支持正常（药物）动物中简单和更具认知高阶学习至关重要。这是，了解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对于理解成瘾的某些关键组成部分至关重要，并为可能的治疗提供了潜在的治疗途径。在这里，我假设正常学习的特征在于BLA输入与NAC神经元的相互作用，而NAC神经元是由腹侧偏段区域（VTA）引起的多巴胺能（DAERIGIC）输入调节的。反复暴露可卡因后，该电路将被破坏，其特征是对NAC的BLA输入不良和贫困的DA信号传导。这种功能障碍将防止与任务相关表示形式的正常编码，从而损害行为。在此问题期间，我将使用完整的技术彻底探索该功能电路。首先，我将使用有或没有先前的可卡因自我管理病史的大鼠中使用快速扫描环状伏安法（FCSV）来表征DA信号传导，同时执行二阶Pavlovian学习任务。接下来，我将学习光遗传技术，并将其应用于TH :: CRE大鼠的转基因线，这将允许在VTA中特定靶向DA神经元。通过这种技术，我将能够操纵特定于VTA-NAC途径的DA释放，从而可以查看DA释放中的短暂停顿是否足以阻止正常动物的学习，并且如果DA的短暂性爆发足以挽救认知功能。在我的独立R00阶段，我将通过表征具有可卡因经验或Yoked对照史的大鼠的二阶任务的体内电生理学来探讨BLA对该系统的贡献。最后，我将使用该实验中的数据来查看对NAC选择性选择性的光学抑制是否能够改变在普通动物中学习，但在具有可卡因自我管理史的大鼠中恢复功能。综上所述，该提案将在重复可卡因暴露后对BLA-NAC-VTA神经回路进行彻底的表征，并使用高阶学习任务来解析特定的认知缺陷。