Vedder Lindsey C, Hall Joseph M, Jabrouin Kimberly R, Savage Lisa M
Department of Psychology, Behavioral Neuroscience Program, Binghamton University, State University of New York, Binghamton, New York.
Alcohol Clin Exp Res. 2015 Nov;39(11):2143-53. doi: 10.1111/acer.12859. Epub 2015 Sep 30.
Many alcoholics display moderate to severe cognitive dysfunction accompanied by brain pathology. A factor confounded with prolonged heavy alcohol consumption is poor nutrition, and many alcoholics are thiamine deficient. Thus, thiamine deficiency (TD) has emerged as a key factor underlying alcohol-related brain damage (ARBD). TD in humans can lead to Wernicke Encephalitis that can progress into Wernicke-Korsakoff syndrome and these disorders have a high prevalence among alcoholics. Animal models are critical for determining the exact contributions of ethanol (EtOH)- and TD-induced neurotoxicity, as well as the interactions of those factors to brain and cognitive dysfunction.
Adult rats were randomly assigned to 1 of 6 treatment conditions: chronic EtOH treatment (CET) where rats consumed a 20% v/v solution of EtOH over 6 months; severe pyrithiamine-induced TD (PTD-moderate acute stage); moderate PTD (PTD-early acute stage); moderate PTD followed by CET (PTD-CET); moderate PTD during CET (CET-PTD); and pair-fed (PF) control. After recovery from treatment, all rats were tested on spontaneous alternation and attentional set-shifting. After behavioral testing, brains were harvested for determination of mature brain-derived neurotrophic factor (BDNF) and thalamic pathology.
Moderate TD combined with CET, regardless of treatment order, produced significant impairments in spatial memory, cognitive flexibility, and reductions in brain plasticity as measured by BDNF levels in the frontal cortex and hippocampus. These alterations are greater than those seen in moderate TD alone, and the synergistic effects of moderate TD with CET lead to a unique cognitive profile. However, CET did not exacerbate thalamic pathology seen after moderate TD.
These data support the emerging theory that subclinical TD during chronic heavy alcohol consumption is critical for the development of significant cognitive impairment associated with ARBD.
许多酗酒者表现出中度至重度认知功能障碍，并伴有脑部病变。与长期大量饮酒相混淆的一个因素是营养状况差，许多酗酒者缺乏硫胺素。因此，硫胺素缺乏（TD）已成为酒精相关脑损伤（ARBD）的一个关键因素。人类的TD可导致韦尼克脑病，进而发展为韦尼克-科尔萨科夫综合征，这些疾病在酗酒者中具有很高的患病率。动物模型对于确定乙醇（EtOH）和TD诱导的神经毒性的确切作用，以及这些因素与脑和认知功能障碍之间的相互作用至关重要。
成年大鼠被随机分配到6种治疗条件中的1种：慢性EtOH治疗（CET），大鼠在6个月内饮用20% v/v的EtOH溶液；严重的吡硫胺诱导的TD（PTD-中度急性期）；中度PTD（PTD-早期急性期）；中度PTD后进行CET（PTD-CET）；CET期间中度PTD（CET-PTD）；以及配对喂养（PF）对照。治疗恢复后，所有大鼠进行自发交替和注意力转换测试。行为测试后，采集大脑以测定成熟脑源性神经营养因子（BDNF）和丘脑病理学。
中度TD与CET相结合，无论治疗顺序如何，都会导致空间记忆、认知灵活性显著受损，以及额叶皮质和海马体中BDNF水平所衡量的脑可塑性降低。这些改变比单独中度TD所见的改变更大，中度TD与CET的协同作用导致独特的认知特征。然而，CET并没有加重中度TD后所见的丘脑病理学改变。
这些数据支持了一种新出现的理论，即慢性大量饮酒期间的亚临床TD对于与ARBD相关的严重认知障碍的发展至关重要。
