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

低剂量乙醇对奖励价值决策和基底外侧杏仁核的影响

• 批准号: 10825973
• 负责人: Christina Curran-Alfaro
• 金额: $ 4.77万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10825973
• 关键词: AMPA Receptors; Abstinence; Adaptive Behaviors; Alcohol consumption; Alcohols; Amygdaloid structure; Anxiety; Area; Atrophic; Behavior; Behavioral; Biological; Brain; Chronic; Coupled; Data; Decision Making; Dependence; Detection; Development; Diagnostic; Dissociation; Dose; Ensure; Equilibrium; Ethanol; Exhibits; Exposure to; Fellowship; Female; Frequencies; Genetic; Glutamate Receptor; Impairment; Individual; Learning; Mediating; Mental Depression; Molecular; Motivation; Mus; N-Methyl-D-Aspartate Receptors; Neuroanatomy; Neurobiology; Nucleus Accumbens; Outcome; Performance; Population; Prevention strategy; Process; Qualifying; Recording of previous events; Regulation; Research; Resources; Rewards; Synapses; Testing; Training; Universities; Update; Western Blotting; alcohol effect; alcohol exposure; alcohol research; alcohol risk; alcohol use disorder; career; designer receptors exclusively activated by designer drugs; executive function; experimental study; flexibility; genetic approach; genetic manipulation; male; memory process; motivated behavior; neural; neurobehavioral; neurotransmission; postsynaptic; receptor; receptor expression; relapse risk; response; willingness

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.

项目概要 美国大多数饮酒者的饮酒剂量和频率与实际情况不一致。 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和健康。 但尽管如此，长期低剂量酒精的行为和神经生物学后果 人们对寻求奖励的决定与其价值有直接关系。 重新评估和更新奖励价值的能力对于适应性价值引导的决策制定至关重要。 调节动机行为的过程可能有助于从随意饮酒的转变 我们实验室的数据表明，长期低剂量乙醇可以增强渐进的奖励动机。 雄性小鼠而非雌性小鼠的比率（PR）任务相反，暴露于乙醇的雌性小鼠对这一任务更敏感。 与未接触过乙醇的女性相比，奖励值降低，而乙醇暴露并没有增加对乙醇的敏感性 男性奖励值的变化这些变化可能是由乙醇引起的能力失调引起的。 使用奖励值信息来指导行为，可以通过使用 介导这种效应的一个潜在的神经生物学基础是价值引导的决策任务。 基底外侧杏仁核 (BLA) 是奖励值编码的关键神经解剖学基础。 参与更新价值信息并影响价值导向的决策。 我们的实验室表明，长期接触低剂量乙醇会降低 BLA 中的 cFos 表达及其预测 该提案将测试总体假设。 长期低剂量乙醇会改变 BLA 谷氨酸受体表达，从而导致 检测并使用奖励价值信息来指导行为 在目标 1 中，我们将使用价值引导的决策 - 制定任务来检验我们的假设，即长期低剂量乙醇会损害更新奖励变化的能力 在 Aim2 中，我们将研究长期低剂量乙醇暴露对 BLA 的影响。 和 NAc 突触后谷氨酸受体以及这些变化与表现之间的关系 目标 3 将使用化学遗传学策略来检验抑制的假设。 BLA 或 BLA → NAc 电路活动将损害在期间成功使用奖励值信息的能力 这些实验的结果将扩展我们对价值引导的决策任务的理解。 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 此外，该奖学金将使申请人能够在酒精使用领域进一步发展。 通过整合学习和记忆过程的专业知识，这些过程可能会因饮酒而失调 对低剂量乙醇对分子底物、特定电路和行为影响的概念性理解。 巴克实验室和德雷克塞尔大学提供的丰富资源和机会将确保 申请人已准备好并有资格从事独立的酒精研究职业。