Low dose ethanol effects on reward learning and motivation

项目摘要 在美国，超过一半的经常饮酒者的饮酒量不符合诊断标准 酒精使用障碍的标准。这种长期饮酒，即使处于亚诊断水平，仍然可以 对神经生物学和行为产生深远的影响。临床研究表明，低水平的急性 学习后一小时内饮酒可以增强任务巩固和记忆回忆。相比之下， 在学习之前饮酒会削弱记忆回忆。尽管频繁的、低剂量的乙醇盛行 训练后反复饮酒对学习的影响及其神经生物学后果 这种接触的程度和频率在很大程度上仍不清楚。此外，目前还不清楚这些是否 影响是在蛋白质合成依赖的记忆巩固期间酒精暴露的结果 具体地说，或者更确切地说，是训练后酒精暴露的一般结果。我们的初步数据表明 行为训练后长期低剂量酒精暴露会增加蔗糖寻求奖励的行为，而 只有在依赖蛋白质合成的巩固过程中酒精暴露才能增强蔗糖奖励 动力。腹侧海马区(VHPC)是记忆巩固和再巩固的关键结构。 此外，它对乙醇引起的干扰特别敏感，使其可能成为乙醇的贡献者 暴露对奖赏学习的影响。这可能是通过vHPC投射到伏隔核来实现的。 壳牌(NACS)作为这一电路，在跟踪奖励价值和与奖励相关的背景方面至关重要。因此，这项提议 将测试行为训练后长期、低剂量酒精暴露会影响 奖赏寻求和动机，并调节vHPC→nacs电路参与。目标1将结合 GCaMP6光度测定法和行为评估，以验证慢性、低剂量乙醇的假设 暴露增强了奖赏寻求和动机，并伴随着vHPC→NAC的变化 活动。目标2将使用化学发生策略来验证抑制vHPC→nacs活性的假设 在奖励过程中，学习可以减弱寻求奖励行为和动机的升级，独立于 乙醇对这条线路的影响。这些实验的结果将扩大我们对 长期低剂量酒精暴露对行为和神经生物学的影响，这是一个有待研究的领域 在酒精使用领域的研究严重不足。此外，这笔奖学金将使申请者能够在她的基础上再接再厉 通过整合对低剂量的概念性理解，在酒精使用的神经回路调节方面的专业知识 酒精对神经元体内钙成像的行为和技术训练的影响。丰富的…… 巴克实验室和德雷克塞尔大学提供的资源和机会将确保申请者 做好了长期从事科学工作的准备和资格。

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.