Molecular and circuit mechanisms of low dose ethanol preference in Drosophila

项目总结/摘要 酒精醉酒改变大脑，诱导短期生理和病理变化，包括 乙醇耐受性、偏好和奖励。这些改变是乙醇长期效应的基础 包括在面对负面后果时继续饮酒，烦躁不安和复发。分子 急性醉酒所选择的途径似乎很复杂，而且还没有被很好地理解， 乙醇作用的满意模型。低剂量乙醇的分子靶点和神经反应仍然存在 更不好研究。在哺乳动物中，小于10 mM的乙醇内部浓度会影响 许多神经元分子，并导致行为变化，如改善情绪，减少焦虑， 认知功能的改变行为影响的广度意味着类似的广泛参与， 情绪、动机和认知的神经回路 果蝇体内低浓度的乙醇增加了运动活性，诱导 乙醇偏好和乙醇奖励，并在2-选择偏好测定中实现。我们发现了一个 受急性乙醇摄入影响的表观遗传途径，调节突触前关键神经元的可用性 这是乙醇偏好和奖励所必需的。这条通路在 蘑菇体对学习、记忆和分配积极和消极的效价至关重要。我们 假设低剂量乙醇导致果蝇蘑菇体出现适应不良学习 通过分子和神经活动机制的奖励/关联电路，导致从乙醇 厌恶偏好。 我们建议确定低剂量乙醇诱导的功能相关分子变化 特别是在果蝇蘑菇体中，以及低剂量乙醇偏好的发展如何影响 蘑菇体功能电路特性。我们将测试乙醇对电路的影响的关系 糖奖励记忆需要相同的蘑菇体神经元。我们的长期目标是 结合低剂量乙醇分子效应如何影响电路配置以引起持久行为 变化，以及乙醇与同一回路中自然高价刺激的处理有何不同。

Project Summary/Abstract Ethanol inebriation alters the brain, inducing short-term physiological and pathological changes including ethanol tolerance, preference, and reward. These alterations are a foundation for ethanol’s longer-term effects including continued drinking in the face of negative consequences, dysphoria, and relapse. The molecular pathways co-opted by acute inebriation appear complex, and are not understood well enough to construct satisfying models of ethanol’s action. The molecular targets and neural responses for low dose ethanol remain even less well studied. In mammals, less than 10 mM ethanol internal concentration impacts the function of many neuronal molecules, and causes changes in behavior such as improved mood, decreased anxiety, and changes in cognitive functioning. The breadth of behavioral effects implies a similarly broad engagement of neural circuitry for emotion, motivation, and cognition. Low internal concentrations of ethanol in the fruit fly Drosophila increase locomotor activity, induce ethanol preference and ethanol reward, and are achieved in 2-choice preference assays. We discovered an epigenetic pathway impacted by acute ethanol intake that regulates the availability of key presynaptic molecules, and that is required for both ethanol preference and reward. This pathway functions in the mushroom bodies that are critical for learning, memory, and assigning positive and negative valence. We hypothesize that low dose ethanol causes maladaptive learning to occur in the Drosophila mushroom body reward/association circuitry through molecular and neural activity mechanisms, leading to a shift from ethanol aversion to preference. We propose to determine the functionally relevant molecular changes induced by low dose ethanol specifically in the Drosophila mushroom bodies, and how low dose ethanol preference development affects mushroom body functional circuit properties. We will test for the relationship of ethanol’s impact on the circuit with sugar reward memory that requires the same mushroom body neurons. Our long term goals are to integrate how low dose ethanol’s molecular effects impact circuit configuration to cause lasting behavioral change, and how ethanol differs from the processing of natural, high valence stimuli in the same circuit.