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

项目摘要 酒精使用障碍的发展涉及到向不灵活的习惯性药物寻求行为的转变， 导致难以调节或终止饮酒行为。酒精暴露被认为有助于 习惯性乙醇寻求的表达，事实上，我们自己的数据表明，慢性间歇性乙醇 曝光（CIE）促进了这种行为的表达。越来越多的文献表明， 在慢性乙醇暴露中，皮质纹状体回路内的多巴胺能信号转导失调。在 特别地，数据表明CIE增加了核壳（NAcS）中的细胞外谷氨酸，并且 这种效应可能是由突触前mGluR 2的缺失介导的。尽管有强有力的证据表明谷氨酸 这些回路中的信号传导介导了行为的灵活性，关于NAcS谷氨酸是如何 在不灵活的奖励寻求的发展过程中发出变化的信号，以及NAcS的改变如何影响 谷氨酸信号可以调节行为与习惯的表达。本K99/R 00建议书包含 根据申请人的初步调查结果，制定全面的培训和研究计划， NAcS内的谷氨酸信号传导可以直接逆转CIE诱导的目标导向行为的缺陷， 暗示NAcS谷氨酸信号传导在响应策略选择中。在奖励的指导部分， 申请人将接受尖端实验室技术的培训，包括多电极阵列（MEA） 记录清醒行为的小鼠，药物遗传学和光遗传学。候选人将利用此次培训， 测试新的假设，即CIE暴露导致的NAcS谷氨酸信号转导的改变损害了 行为灵活性目的1旨在证实CIE诱导的目标导向缺陷的假设， 乙醇寻求可以通过mGluR 2/3激动逆转，并证实这种作用的神经解剖学位点。 在目标2中，我们将使用MEA记录来检验以下假设： 通过NAcS中神经元活动的变化，以及NAcS和发送信号的结构之间的同步， 脑神经投射到这个大脑区域，包括边缘下前额叶皮层（IfL），基底外侧皮层（BFL）， 杏仁核（BLA）和腹侧海马（VH）。目标3旨在检验以下假设： 药物遗传学和光遗传学对NAcS的不同谷氨酸能投射内活性的操纵 - 从IfL，BLA和VH -改变习惯性乙醇寻求的表达。这些实验的结果 有望提供大量关于习惯性乙醇寻求的神经生物学信息， 通过这些机制可以恢复行为的灵活性。我们希望从 这些研究将为酒精使用障碍的发展提供重要的见解， 为制定新的预防和治疗策略提供信息。候选人接受的培训 在这个奖项的指导部分，预计将促进她的职业发展和过渡到 成为一名独立的神经科学家

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.