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.

项目摘要 美国大多数饮酒者的饮酒剂量和频率与 酒精使用障碍(AUD)。越来越多的证据表明，低剂量酒精暴露会影响大脑和 但尽管如此，长期低剂量酒精的行为和神经生物学后果 人们对消费知之甚少。寻求奖励的决定与其价值有直接关系。这个 重新评估和更新奖励价值的能力对于适应性价值导向决策至关重要。美国的财政赤字 适度动机行为的过程可能有助于从随意饮酒过渡 敬澳元。来自我们实验室的数据表明，慢性低剂量乙醇以一种渐进的方式增强了奖励动机 雄性小鼠的比率(PR)任务，而不是雌性小鼠。相比之下，接触乙醇的雌性小鼠对 与酒精天真的女性相比，奖励价值降低，而酒精暴露并不会增加对 雄性的奖赏价值发生了变化。这些变化可能是由于酒精引起的能力失调所致。 使用奖励值信息来指导行为，这可以通过使用 以价值为导向的决策任务。一种潜在的神经生物学底物是介导这一效应的 杏仁基底外侧核(BLA)。BLA是奖赏价值编码的关键神经解剖学底物 参与价值信息的更新，影响价值导向的决策。初步数据来自 我们的实验室提示，长期低剂量酒精暴露降低了BLA中CFOS的表达及其投射 在寻找奖赏后到达伏核(NAC)。这项提议将检验总体假设。 慢性低剂量乙醇改变BLA谷氨酸受体表达，从而导致脑组织损伤 检测并使用奖励价值信息来指导行为。在目标1中，我们将使用价值导向的决策- 让任务来验证我们的假设，即慢性低剂量乙醇损害了更新奖赏变化的能力 自适应行为的价值。在AIM2中，我们将研究慢性低剂量乙醇暴露对血乳酸的影响 和NAC突触后谷氨酸受体以及这些变化与表现之间的关系 价值导向的决策任务。目标3将使用化学发生策略来检验抑制作用 BLA或BLA→NAC电路活动将削弱在以下过程中成功使用奖励值信息的能力 一项价值导向的决策任务。这些实验的结果将扩大我们对 慢性低剂量酒精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，这笔奖学金将使申请者能够在她的基础上再接再厉 在学习和记忆过程方面的专业知识，这些过程可能因酒精使用而失调，通过整合 从概念上理解低剂量乙醇对分子底物、特定电路和行为的影响。 巴克实验室和德雷克塞尔大学丰富的资源和机会将确保 申请人已准备好并有资格从事独立的酒精研究事业。