Low dose ethanol effects on reward learning and motivation

项目摘要 在美国，超过一半的频繁饮酒者的饮酒水平不符合诊断标准。 酒精使用障碍的标准这种慢性饮酒，即使在亚诊断水平，仍然可以 对神经生物学和行为产生了深远的影响。临床研究表明，低水平的急性 学习后一小时内饮用酒精可以增强任务巩固和记忆回忆。与此相反， 学习前喝酒会削弱记忆力。尽管频繁使用低剂量乙醇 消耗量，重复训练后乙醇对学习的影响和神经生物学后果 这一水平和接触频率在很大程度上仍然未知。此外，尚不清楚这些 影响是在蛋白质合成依赖性记忆巩固期间暴露于乙醇的结果 具体地说，或者说，是训练后乙醇暴露的一般结果。我们的初步数据显示， 行为训练后慢性低剂量乙醇暴露增加了蔗糖奖励寻求行为， 只有在蛋白质合成依赖性巩固过程中乙醇暴露才能增强蔗糖奖励 动机腹侧海马（vHPC）是记忆巩固和再巩固的关键结构。 它对乙醇引起的破坏特别敏感，使其成为乙醇的可能贡献者。 暴露对奖励学习的影响这可能是由vHPC投射到丘脑核介导的 外壳（NAcS），因为该电路在跟踪奖励值和奖励相关上下文方面至关重要。因此，本提案 将测试总体假设，即行为训练后慢性低剂量乙醇暴露会影响 奖励寻求和动机，并调节vHPC → NAcS回路参与。AIM 1将联合收割机 GCaMP6光度法与行为评估，以检验慢性低剂量乙醇 暴露增强了奖励寻求和动机，这伴随着vHPC → NAcS的改变 活动目的2将利用化学遗传学策略来验证抑制vHPC → NAcS活性 在奖励过程中，学习可以减弱寻求奖励行为和动机的升级，而与奖励无关 乙醇对这条线路的影响。这些实验的结果将扩大我们对 长期低剂量乙醇暴露对行为和神经生物学的影响，这是一个仍然存在的领域。 酒精使用领域的研究严重不足。此外，该奖学金将使申请人能够在她的基础上 通过整合对低剂量酒精的概念性理解， 乙醇对行为和技术训练在体神经元钙成像的影响。的丰度 巴克实验室和德雷克塞尔大学的资源和机会将确保申请人 准备好并有资格从事长期的科学事业。

Project Summary More than half of frequent alcohol drinkers in the United States do so at a level that does not meet diagnostic criteria for an alcohol use disorder. This chronic alcohol drinking, even at sub-diagnostic levels, can still produce profound impacts on neurobiology and behavior. Clinical studies have shown that low levels of acute ethanol drinking within an hour after learning can enhance task consolidation and memory recall. In contrast, drinking before learning attenuates memory recall. Despite the prevalence of frequent, low-dose ethanol consumption, the effects of repeated post-training ethanol on learning and the neurobiological consequences of this level and frequency of exposure remain largely unknown. Furthermore, it is unclear whether these effects are a result of ethanol exposure during the period of protein synthesis-dependent memory consolidation specifically or, rather, a general outcome of post-training ethanol exposure. Our preliminary data suggest that chronic, low-dose ethanol exposure after behavioral training increases sucrose reward-seeking behavior, while only ethanol exposure specifically during protein synthesis-dependent consolidation enhances sucrose reward motivation. The ventral hippocampus (vHPC) is a key structure for memory consolidation and reconsolidation. It is further particularly sensitive to ethanol-induced disruptions, making it a likely contributor to ethanol exposure effects on reward learning. This may be mediated by vHPC projections to the nucleus accumbens shell (NAcS) as this circuit is critical in tracking reward value and reward-related contexts. Thus, this proposal will test the overarching hypothesis that chronic, low-dose ethanol exposure after behavioral training impacts reward seeking and motivation and modulates vHPC → NAcS circuit engagement. Aim 1 will combine GCaMP6 photometry with behavioral assessment in order to test the hypothesis that chronic, low-dose ethanol exposure enhances reward seeking and motivation, which are accompanied by alterations in vHPC → NAcS activity. Aim 2 will use chemogenetic strategies to test the hypothesis that inhibiting vHPC → NAcS activity during reward learning can attenuate escalations in reward-seeking behavior and motivation independent of ethanol impacts on this circuit. The results from these experiments will expand our understanding of the impacts of long-term low dose ethanol exposure on behavior and neurobiology, which is an area that remains severely understudied in the alcohol use field. Further, this fellowship will enable the applicant to build on her expertise in neural circuit regulation of alcohol use by integrating a conceptual understanding of low-dose ethanol effects on behavior and technical training in in vivo calcium imaging in neurons. The abundance of resources and opportunities available in the Barker lab and at Drexel University will ensure that the applicant is prepared and qualified for a long-term career in science.