NEURONAL SUBSTRATES OF ETHANOL MEDIATED BEHAVIOR

长期睡眠（LS）和短期睡眠（SS）小鼠在酒精暴露后表现出明显不同的行为反应。在这些不同的反应中，最明显的是动物在摄入一定剂量的乙醇后无法自我纠正的时间长度（“睡眠时间”）。在摄入相同剂量的乙醇后，长时间睡眠的老鼠通常需要比短时间睡眠的老鼠多6到20倍的时间来恢复它们的翻正反射。虽然已经发现这种反应是由中枢神经系统介导的，但介导这种差异的神经解剖结构尚不清楚。该项目的目标是测试候选神经元群，并找到可能介导LS和SS小鼠恢复反应丧失差异的其他候选神经元群。实验小鼠嵌合体将在长睡眠小鼠和短睡眠小鼠的胚胎之间进行。该系统的独特之处在于每个神经元群由不同百分比的每种基因型细胞组成。这使得对乙醇的反应时间与每个神经元群中长睡眠基因型细胞的百分比相关。几个候选群体将被检查包括小脑浦肯野细胞，海马锥体细胞和下丘脑神经元。新的候选区域将通过检查嵌合小鼠中表型和基因型不匹配的其他候选区域来确定。在神经元基因型和“睡眠时间”之间表现出最强相关性的区域是乙醇暴露后这种行为效应的神经解剖学基础的一个很好的候选区域。这一数据将有助于深入了解大脑中对乙醇具有遗传易感性的区域。这一数据对于理解酒精中毒的原因可能很重要，因为研究表明，酒精中毒的倾向可能是由对酒精敏感性的神经差异介导的（Schuckit, 1994）。

Long-sleep (LS) and short-sleep (SS) mice have been shown to exhibit significantly different behavioral responses following ethanol exposure. The most evident of these differential responses is the length of time that an animal is unable to right itself ("sleep time") following a dose of ethanol. Long-sleep mice typically require 6 to 20 times longer than short-sleep mice to regain their righting reflex after the same dose of ethanol. While this response has been found to be mediated by the CNS, the neuroanatomical structures that mediate this difference are unknown. The goal of this project is to test candidate neuronal populations and to find other candidate neuronal populations that may mediate the diffences in loss of righting response in LS and SS mice. Experimental murine chimeras will be made between embryos from long-sleep mice and short-sleep mice. The uniqueness of this system is that each neuronal population is composed of different percentages of cells of each genotype. This allows for the response time to ethanol to be correlated with the percentage of cells of the long-sleep genotype in each neuronal populations. Several candidate populations will be examined including cerebellar Purkinje cells, hippocampal pyramidal cells and hypothalamic neurons. New candidate regions will be determined through the examination of chimeric mice in which phenotype and genotype are unmatched in the other candidate regions. The region(s) that exhibit(s) the strongest correlation between neuronal genotype and "sleep time" is a good candidate for the neuroanatomical substrate(s) of this behavioral effect following ethanol exposure. This data will provide insights into the region of the brain that underlies genetic susceptibility to ethanol. This data may be important in understanding the causes of alcoholism, as studies have suggested that the tendency for alcoholism may be mediated by neural differences in sensitivity to alcohol (Schuckit, 1994).