Arbitration Between Goal-directed and Habitual Ethanol Seeking by the Nucleus Accumbens Shell.

伏核壳的目标导向和习惯性乙醇搜寻之间的仲裁。

• 批准号: 9180489
• 负责人: JACQUELINE M BARKER
• 金额: $ 12.31万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-10 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9180489
• 关键词: Agonist; Alcohol consumption; Alcohol dependence; Alcohols; Amygdaloid structure; Arbitration; Award; Behavior; Behavioral; Brain region; Career Mobility; Chronic; Consumption; Corpus striatum structure; Data; Dependence; Development; Ethanol; Food; Generations; Glutamates; Goals; Habits; Hippocampus (Brain); Individual; Investigation; Knowledge; Laboratories; Lead; Literature; Mediating; Mentors; Microinjections; Modeling; Mus; Neurobiology; Neurons; Nucleus Accumbens; Outcome; Performance; Pharmaceutical Preparations; Pharmacogenetics; Phase; Prefrontal Cortex; Prevention strategy; Procedures; Process; Regulation; Relapse; Research Training; Rewards; Rodent Model; Role; Scientist; Stimulus; Structure; Sucrose; Techniques; Testing; Time; Training; Treatment Efficacy; Work; alcohol exposure; alcohol seeking behavior; alcohol use disorder; awake; base; career; career development; cognitive control; design; drinking; drinking behavior; drug seeking behavior; extracellular; flexibility; glutamatergic signaling; insight; metabotropic glutamate receptor 2; multi-electrode arrays; novel; optogenetics; premature; presynaptic; reduced alcohol use; reinforcer; research study; response; skills; treatment strategy

PROJECT SUMMARY The development of alcohol use disorders involves a transition to inflexible habitual drug-seeking behavior, resulting in difficulty regulating or terminating drinking behavior. Ethanol exposure is thought to facilitate the expression of habitual ethanol seeking, and indeed our own data indicate that chronic intermittent ethanol exposure (CIE) promotes the expression of this behavior. A growing body of literature suggests that glutamatergic signaling within corticostriatal circuits is dysregulated across chronic ethanol exposure. In particular, data suggest that CIE increases extracellular glutamate in the nucleus accumbens shell (NAcS), and that this effect may be mediated by the loss of presynaptic mGluR2. Despite strong evidence that glutamate signaling within these circuits mediates behavioral flexibility, little is known regarding how NAcS glutamate signaling changes across the development of inflexible reward seeking, and further, how alterations in NAcS glutamate signaling can regulate the expression of actions versus habits. This K99/R00 proposal contains a comprehensive training and research plan based on the applicant’s preliminary findings that regulation of glutamate signaling within the NAcS can reverse CIE-induced deficits in goal-directed behavior, directly implicating NAcS glutamate signaling in response strategy selection. During the mentored portion of the award, the applicant will receive training in cutting-edge laboratory techniques including multielectrode array (MEA) recording in awake behaving mice, pharmacogenetics and optogenetics. The candidate will use this training to test the novel hypothesis that alterations in NAcS glutamate signaling resulting from CIE exposure impair behavioral flexibility. Aim 1 is designed to confirm the hypothesis that CIE-induced deficits in goal-directed ethanol seeking can be reversed by mGluR2/3 agonism and to confirm the neuroanatomical locus of this effect. In Aim 2 we will use MEA recordings to test the hypothesis that acquisition of habitual behavior is accompanied by changes in neuronal activity in the NAcS, as well as synchrony between the NAcS and structures that send glutamatergic projections to this brain region, including the infralimbic prefrontal cortex (IfL), the basolateral amygdala (BLA) and the ventral hippocampus (VH). Aim 3 is designed to test the hypothesis that pharmacogenetic and optogenetic manipulations of activity within distinct glutamatergic projections to the NAcS – from the IfL, BLA and VH - alter the expression of habitual ethanol seeking. The results of these experiments are expected to provide considerable information on the neurobiology of habitual ethanol seeking and to identify mechanisms through which behavioral flexibility can be restored. We expect that the knowledge gained from these studies will provide significant insight into the development of alcohol use disorders that will ultimately inform the generation of novel prevention and treatment strategies. The training that the candidate receives during the mentored portion of this award is expected to facilitate her career development and transition toward becoming an independent neuroscientist.

项目摘要 酒精使用障碍的发展涉及过渡到僵化的习惯性寻求毒品行为， 导致难以调节或终止饮酒行为。乙醇暴露被认为有助于 习惯性乙醇的表达，甚至我们自己的数据表明慢性间歇性乙醇 暴露（CIE）促进了这种行为的表达。越来越多的文学表明 在慢性乙醇暴露中，皮质纹状体回路中的谷氨酸能信号传导失调。在 特别是，数据表明CIE增加了伏伏壳（NACS）的细胞外谷氨酸，并且 这种作用可能是通过突触前MGLUR2的丧失来介导的。尽管有强烈的证据表明谷氨酸 这些电路中的信号传导介导了行为灵活性，关于NACS谷氨酸如何了解 在整个不灵活的奖励的发展中的信号变化，以及NACS的变化如何 谷氨酸信号传导可以调节作用与习惯的表达。此K99/R00建议包含一个 基于申请人的初步发现，该计划的全面培训和研究计划 NAC中的谷氨酸信号传导可以逆转CIE引起的目标指导行为的缺陷，直接 将NACS谷氨酸信号传导植入响应策略选择。在奖项的指导部分期间， 申请人将接受包括多电极阵列（MEA）在内的尖端实验室技术的培训 记录在行为的小鼠，药物遗传学和光遗传学中记录。候选人将使用此培训来 测试新的假设，即CIE暴露导致NACS谷氨酸信号传导的变化受损 行为灵活性。 AIM 1旨在确认CIE引起的目标定向的缺陷的假设 寻求乙醇可以通过MGLUR2/3激动剂逆转，并确认这种作用的神经解剖学基因座。 在AIM 2中，我们将使用MEA记录来测试习惯行为的获取的假设 通过NACS中神经元活性的变化，以及发送的NAC和结构之间的同步 向该大脑区域的谷氨酸能项目，包括额叶前额叶皮层（IFL），Basolatoral 杏仁核（BLA）和腹海马（VH）。 AIM 3旨在检验以下假设 对NACS的不同谷氨酸能项目中活性的药物遗传学和光学遗传操作 - 来自IFL，BLA和VH-改变寻求习惯乙醇的表达。这些实验的结果 期望提供有关寻求习惯乙醇神经生物学的考虑信息，并确定 可以恢复行为灵活性的机制。我们期望从中获得的知识 这些研究将为酒精使用障碍的发展提供重大洞察力，最终将 告知新型预防和治疗策略的一代。候选人接受的培训 在指导部分期间，该奖项有望促进她的职业发展和过渡 成为独立的神经科学家。