Neurocircuitry Plasticity After Cocaine Seeking

寻找可卡因后的神经回路可塑性

• 批准号: 8293292
• 负责人: Brian Robert Lee
• 金额: $ 4.22万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8293292
• 关键词: Active Learning; Addictive Behavior; Address; Amygdaloid structure; Animal Model; Behavior; Behavioral Model; Biological Assay; Brain; Clinical; Cocaine; Cocaine Dependence; Development; Doctor of Philosophy; Drug Addiction; Excitatory Synapse; Future; Gene Expression; Gene Transfer; Generations; Glutamates; Goals; Hippocampus (Brain); Impulsive Behavior; Intervention; Learning; Limbic System; Measures; Mediating; Memory; Modeling; Modification; Molecular; Neurons; Outcome; Pharmaceutical Preparations; Play; Prefrontal Cortex; Public Health; Research; Rewards; Rhodopsin; Role; Self Administration; Short-Term Memory; Solid; Staging; Synapses; Synaptic plasticity; Testing; Viral; Work; addiction; base; clinically relevant; cocaine exposure; cocaine use; design; drug reward; experience; innovation; neural circuit; novel; premature; research study; synaptogenesis; treatment strategy

Our long-term goal is to understand the mechanistic details that underlie the formation of nascent synapses after repeated cocaine exposure. The objective of this application is to use cocaine self- administration, viral-mediated gene transfer and electrophysiological assays to begin to elucidate the formation of these synapses. Within the limbic system, three major glutamatergic afferents that synapse onto NAc neurons originate from the prefrontal cortex (PFC), hippocampus, and the amygdala. Given that these three afferents play distinct roles in addictive behaviors, identifying the specific afferents that undergo cocaine-induced generation of nascent synapses and thus circuitry reorganization will provide a circuitry- based understanding of different aspects of the addictive state. The central hypothesis of the application is that self-administration of cocaine increases the number of silent synapses in NAc neurons among the PFC afferent and that this increase is correlated with an enhancement in the ability to learn about drug reward; thus, forming an apparent pathological memory. We plan to test our hypotheses by pursuing the following two aims: 1) Determine the effect of the contingency of cocaine administration on silent synapses development; and, 2) Establish the glutamatergic afferent to the NAc that express cocaine-generated silent synapses. The proposed work is innovative because it will further our understanding of the cellular and molecular changes that accompany cocaine exposure. Silent synapses have been shown to be crucial in the development of synapses and circuitry in the developing brain. If we can understand the development of addiction from this novel angle, more accurate pharmacological manipulations can be designed for future clinical interventions to block and/or reverse pro-addiction cellular adaptations.

我们的长期目标是了解反复接触可卡因后新生突触形成的机制细节。本申请的目的是利用可卡因自我施用、病毒介导的基因转移和电生理学测定来开始阐明这些突触的形成。在边缘系统内，突触到 NAc 神经元的三个主要谷氨酸传入神经源自前额皮质 (PFC)、海马和杏仁核。鉴于这三种传入神经在成瘾行为中发挥着不同的作用，识别经历可卡因诱导的新生突触生成的特定传入神经以及电路重组将提供对成瘾状态不同方面的基于电路的理解。该申请的中心假设是，自我施用可卡因会增加 PFC 传入神经元中 NAc 神经元的沉默突触数量，并且这种增加与了解药物奖励能力的增强相关；从而形成明显的病态记忆。我们计划通过追求以下两个目标来检验我们的假设：1）确定可卡因管理的意外事件对沉默突触发育的影响； 2) 建立表达可卡因产生的沉默突触的 NAc 的谷氨酸传入神经。 拟议的工作具有创新性，因为它将进一步加深我们对可卡因暴露引起的细胞和分子变化的理解。沉默突触已被证明对于发育中的大脑的突触和电路的发育至关重要。如果我们能够从这个新的角度理解成瘾的发展，就可以为未来的临床干预设计更准确的药理学操作，以阻止和/或逆转促成瘾的细胞适应。