The effects of low-dose ethanol on reward-value decision making and the basolateral amygdala

项目摘要 在美国，大多数酒精使用者饮酒的剂量和频率与美国人不一致。 酒精使用障碍（AUD）越来越多的证据表明，低剂量的乙醇暴露会影响大脑， 但尽管如此，慢性低剂量酒精的行为和神经生物学后果 消费者知之甚少。寻求奖励的决定与其价值有直接关系。的 重新评估和更新奖励价值的能力对于自适应价值导向决策至关重要。赤字 适度的动机行为可能有助于从偶尔饮酒转变为 为AUD。来自我们实验室的数据表明，慢性低剂量乙醇增强了渐进式奖励动机。 比率（PR）任务，但不是雌性，小鼠。相比之下，乙醇暴露的雌性小鼠对 降低奖励价值比乙醇naïve女性，而乙醇暴露并没有增加敏感性， 男性奖励价值的变化。这些变化可能是由于乙醇诱导的能力失调引起的 使用奖励值信息来指导行为，这可以通过使用 价值导向的决策任务。介导这种效应的一种潜在的神经生物学底物是 基底外侧杏仁核（BLA）。BLA是奖励价值编码的关键神经解剖学基底， 参与更新价值信息并影响价值导向的决策。的初步数据 我们的实验室表明，慢性低剂量乙醇暴露降低了BLA中cFos的表达及其预测， [001 pdf 1st-31 files]在寻求奖赏之后，进入了丘脑核（NAc）。这一提议将检验总体假设 慢性低剂量乙醇改变BLA谷氨酸受体的表达，从而导致 检测并使用奖励值信息来指导行为。在目标1中，我们将使用价值导向决策- 做任务来检验我们的假设，慢性低剂量乙醇损害更新奖励变化的能力 适应行为的价值。在目标2中，我们将研究慢性低剂量乙醇暴露对BLA的影响。 和NAc突触后谷氨酸受体以及这些变化与运动成绩的关系 价值导向的决策任务。目的3将使用化学遗传学策略来检验抑制 BLA或BLA → NAc回路活动将损害成功使用奖励价值信息的能力， 价值导向的决策任务。这些实验的结果将扩大我们对 慢性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， 在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 学习和记忆过程的专业知识，这可能是由酒精使用失调， 低剂量乙醇对分子基质、特定电路和行为的影响的概念性理解。 巴克实验室和德雷克塞尔大学丰富的资源和机会将确保 申请人准备并有资格从事独立的酒精研究职业。

Project Summary The majority of alcohol users in the US consume alcohol at doses and frequencies that are not consistent with alcohol use disorder (AUD). There is growing evidence that low-dose ethanol exposure impacts the brain and behavior but despite this, the behavioral and neurobiological consequences of chronic low-dose alcohol consumption are poorly understood. The decision to seek a reward has a direct relationship with its value. The ability to reassess and update reward value is critical for adaptive value-guided decision making. Deficits in the processes that moderate motivated behavior may contribute to the transition from casual alcohol consumption to AUD. Data from our lab indicate that chronic low-dose ethanol enhances reward motivation in a progressive ratio (PR) task in male, but not female, mice. In contrast, ethanol-exposed female mice are more sensitive to reduced reward value than ethanol-naïve females, whereas ethanol exposure did not increase sensitivity to change in reward value in males. These changes may result from an ethanol-induced dysregulation in the ability to use reward value information to guide behavior, which can be determined experimentally through the use of a value-guided decision making task. One potential neurobiological substrate mediating this effect is the basolateral amygdala (BLA). The BLA is a key neuroanatomical substrate of reward value encoding and participates in updating value information and influencing value-guided decision making. Preliminary data from our lab suggest that chronic low-dose ethanol exposure decreases cFos expression in BLA and its projections to the nucleus accumbens (NAc) following reward seeking. This proposal will test the overarching hypothesis that chronic-low-dose ethanol alters BLA glutamate receptor expression, thus contributing to impairments in detecting and using reward value information to guide behavior. In Aim 1, we will use a value-guided decision- making task to test our hypothesis that chronic low-dose ethanol impairs the ability to update changes in reward value for adaptive behavior. In Aim2, we will investigate the impact of chronic low-dose ethanol exposure on BLA and NAc postsynaptic glutamate receptors and the relationship between these changes and performance on the value-guided decision-making task. Aim 3 will use chemogenetic strategies to test the hypothesis that inhibiting the BLA or BLA → NAc circuit activity will impair the ability to successfully use reward value information during a value-guided decision-making task. The results from these experiments will expand our understanding of the impacts of chronic 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 learning and memory processes which may be dysregulated by alcohol use by integrating a conceptual understanding of low-dose ethanol effects on molecular substrates, specific circuits, and behavior. 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 an independent alcohol research career.