Gursky Zachary H, Klintsova Anna Y
Department of Psychological & Brain Sciences, University of Delaware, Newark, DE 19716, USA.
Alcohol Alcohol. 2022 Jul 9;57(4):413-420. doi: 10.1093/alcalc/agac008.
Recent studies have recognized that thalamic nucleus reuniens (Re) undergoes substantial neuron loss following alcohol exposure (AE) during the brain growth spurt (BGS). As all previous studies have utilized high-dose AE paradigms, we tested whether moderate-dose AE is capable of damaging Re to a similar degree as high-dose AE.
We used a rat model of third-trimester binge AE (relative to human pregnancy) to administer ethanol to rat pups at either a high (5.25 g/kg/day) or moderate (3.00 g/kg/day) dose during the BGS (postnatal days [PD] 4-9) via intragastric intubation. In adulthood (i.e. PD72), we quantified the volume of Re as well as the total number of neurons and non-neuronal cells in the nucleus (which were further divided into microglia versus 'other' non-neurons), using unbiased stereological estimation of cells identified with immunofluorescent markers (i.e. nuclear label Hoechst, neuron-specific protein NeuN, and microglia-specific protein Iba1). Data were analyzed both between-treatment and correlated with peak blood alcohol concentration (BAC).
We observed significant neuronal and non-neuronal cell loss in both the high-dose and moderate-dose AE groups (relative to both procedural control and typically-developing control groups), which mediated reductions in Re volume. Outcomes did not correlate with peak BAC, further supporting that Re is vulnerable to AE-induced neurodegeneration at lower doses than previously suspected. Given the role that Re has in coordinating prefrontal cortex and hippocampus, the current study highlights the role that thalamic damage may play in the range of behavioral alterations observed in Fetal Alcohol Spectrum Disorders.
最近的研究已经认识到，在脑发育加速期（BGS），酒精暴露（AE）后丘脑连合核（Re）会出现大量神经元丢失。由于之前所有的研究都采用了高剂量AE范式，我们测试了中等剂量AE是否能像高剂量AE一样对Re造成相似程度的损害。
我们使用了一个妊娠晚期暴饮AE的大鼠模型（相对于人类怀孕），在BGS期间（出生后第[PD]4 - 9天）通过胃内插管给幼鼠施用高剂量（5.25克/千克/天）或中等剂量（3.00克/千克/天）的乙醇。在成年期（即PD72），我们使用对用免疫荧光标记物识别的细胞（即核标记物Hoechst、神经元特异性蛋白NeuN和小胶质细胞特异性蛋白Iba1）进行无偏立体学估计，来量化Re的体积以及核内神经元和非神经元细胞的总数（非神经元细胞进一步分为小胶质细胞和“其他”非神经元）。对数据进行组间分析，并与峰值血酒精浓度（BAC）进行相关性分析。
我们在高剂量和中等剂量AE组中均观察到显著的神经元和非神经元细胞丢失（相对于程序对照组和正常发育对照组），这介导了Re体积的减小。结果与峰值BAC不相关，进一步支持了Re在比之前怀疑的更低剂量下就易受AE诱导的神经退行性变影响的观点。鉴于Re在协调前额叶皮层和海马体方面的作用，本研究强调了丘脑损伤可能在胎儿酒精谱系障碍所观察到的一系列行为改变中所起的作用。
