Vargas Wanette M, Bengston Lynn, Gilpin Nicholas W, Whitcomb Brian W, Richardson Heather N
Neuroscience and Behavior Program and Department of Psychological and Brain Sciences, University of Massachusetts, Amherst, Massachusetts 01003.
Department of Psychological and Brain Sciences, University of Massachusetts, Amherst, Massachusetts 01003.
J Neurosci. 2014 Oct 29;34(44):14777-82. doi: 10.1523/JNEUROSCI.3189-13.2014.
Teen binge drinking is associated with low frontal white matter integrity and increased risk of alcoholism in adulthood. This neuropathology may result from alcohol exposure or reflect a pre-existing condition in people prone to addiction. Here we used rodent models with documented clinical relevance to adolescent binge drinking and alcoholism in humans to test whether alcohol damages myelinated axons of the prefrontal cortex. In Experiment 1, outbred male Wistar rats self-administered sweetened alcohol or sweetened water intermittently for 2 weeks during early adolescence. In adulthood, drinking behavior was tested under nondependent conditions or after dependence induced by 1 month of alcohol vapor intoxication/withdrawal cycles, and prefrontal myelin was examined 1 month into abstinence. Adolescent binge drinking or adult dependence induction reduced the size of the anterior branches of the corpus callosum, i.e., forceps minor (CCFM), and this neuropathology correlated with higher relapse-like drinking in adulthood. Degraded myelin basic protein in the gray matter medial to the CCFM of binge rats indicated myelin was damaged on axons in the mPFC. In follow-up studies we found that binge drinking reduced myelin density in the mPFC in adolescent rats (Experiment 2) and heavier drinking predicted worse performance on the T-maze working memory task in adulthood (Experiment 3). These findings establish a causal role of voluntary alcohol on myelin and give insight into specific prefrontal axons that are both sensitive to alcohol and could contribute to the behavioral and cognitive impairments associated with early onset drinking and alcoholism.
青少年酗酒与额叶白质完整性降低及成年后患酒精中毒风险增加有关。这种神经病理学现象可能是由酒精暴露导致的，也可能反映了易成瘾人群预先存在的状况。在此，我们使用了与人类青少年酗酒和酒精中毒具有临床相关性记录的啮齿动物模型，来测试酒精是否会损害前额叶皮质的有髓轴突。在实验1中，远交系雄性Wistar大鼠在青春期早期间歇性地自行饮用加甜酒精或加甜水，持续2周。成年后，在非依赖条件下或在经过1个月酒精蒸汽中毒/戒断循环诱导产生依赖后测试饮酒行为，并在禁欲1个月后检查前额叶髓磷脂。青少年酗酒或成年期依赖诱导会减小胼胝体前支，即小钳（CCFM）的尺寸，并且这种神经病理学现象与成年后更高的复发性饮酒相关。酗酒大鼠CCFM内侧灰质中髓鞘碱性蛋白的降解表明，内侧前额叶皮质（mPFC）中的轴突上的髓磷脂受到了损害。在后续研究中，我们发现酗酒会降低青春期大鼠mPFC中的髓磷脂密度（实验2），并且饮酒量越大预示着成年后在T迷宫工作记忆任务中的表现越差（实验3）。这些发现确立了自愿饮酒对髓磷脂的因果作用，并深入了解了对酒精敏感且可能导致与早发性饮酒和酒精中毒相关的行为和认知障碍的特定前额叶轴突。
