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The comparative contributions of basolateral amygdala and ventral subiculum inputs to the nucleus accumbens in a novel rodent model of maladaptive alcohol self-administration

在适应不良的酒精自我管理的新型啮齿动物模型中，基底外侧杏仁核和腹侧下托输入对伏隔核的比较贡献

基本信息

批准号：
10454129
负责人：
Hannah Carlson
金额：
$ 4.68万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2024-02-28
项目状态：
已结题

项目摘要

PROJECT SUMMARY The progression of recreational drinking to alcohol use disorder is characterized by loss of control over seeking, which involves continued use of alcohol despite a variety of negative consequences. However, due to a paucity of translational models for this aspect of alcohol use disorder, little is known about the circuitry underlying maladaptive alcohol seeking, which precludes the discovery of therapeutic targets. The present study proposes a novel maladaptive alcohol self-administration task (MAST), which will be used to assess the role that two distinct neural circuits might play in inhibitory control. Preliminary findings from our lab demonstrate that chemogenetic inhibition of projections from the basolateral amygdala to the nucleus accumbens core (BLA-NAcC) or from the ventral subiculum of the hippocampus to the nucleus accumbens shell (vSub-NAcSh) produces a uniform reduction in appetitive seeking for alcohol with minimal effects on consumption. Both our lab and others have additionally shown that chronic intermittent ethanol (CIE) not only produces heightened excitability in the BLA and vSub, but also a behavioral phenotype characterized by escalation of seeking and intake. Though alcohol seeking is a common and important metric of animal models, there have been few efforts to parse this construct into more specific facets of motivated behavior. Increased seeking might result from disinhibition, in which the distinction between appropriate and inappropriate behavior is known but overridden, or discrimination failure, in which the distinction between when it is appropriate or inappropriate to drink becomes unclear. Therefore, the proposed studies will employ a multidisciplinary experimental strategy to test the hypothesis that CIE exposure produces a loss of control over alcohol seeking and that hyperexcitation of the BLA-NAcC contributes to a behavioral disinhibition phenotype, while hyperexcitation of the vSub-NAcSh results in discrimination failure. Aim 1 will employ a chemogenetic technique to selectively activate either the BLA-NAcC or vSub-NAcSh during the MAST. In Aim 2, we will use CIE as a model of alcohol dependence. Behavioral changes will be assessed using the MAST and alterations in neural activity in the target accumbens-projecting BLA and vSub populations will be measured by in vivo fiber photometry. These studies may identify a novel behavioral mechanism through which these circuits exert control over alcohol drinking-related behaviors, with the potential to provide further evidence that targeting these circuits may have therapeutic value in treating a key behavioral symptom of alcohol use disorder.

项目总结