Topper Lauren A, Baculis Brian C, Valenzuela C Fernando
Department of Neurosciences, School of Medicine, MSC08 4740, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131-0001, USA.
J Neuroinflammation. 2015 Sep 4;12:160. doi: 10.1186/s12974-015-0382-9.
Fetal alcohol exposure is a leading cause of preventable birth defects, yet drinking during pregnancy remains prevalent worldwide. Studies suggest that activation of the neuroimmune system plays a role in the effects of alcohol exposure during the rodent equivalent to the third trimester of human pregnancy (i.e., first week of neonatal life), particularly by contributing to neuronal loss. Here, we performed a comprehensive study investigating differences in the neuroimmune response in the cerebellum and hippocampus, which are important targets of third trimester-equivalent alcohol exposure.
To model heavy, binge-like alcohol exposure during this period, we exposed rats to alcohol vapor inhalation during postnatal days (P)3-5 (blood alcohol concentration = 0.5 g/dL). The cerebellar vermis and hippocampus of rat pups were analyzed for signs of glial cell activation and neuronal loss by immunohistochemistry at different developmental stages. Cytokine production was measured by reverse transcriptase polymerase chain reaction during peak blood alcohol concentration and withdrawal periods. Additionally, adolescent offspring were assessed for alterations in gait and spatial memory.
We found that this paradigm causes Purkinje cell degeneration in the cerebellar vermis at P6 and P45; however, no signs of neuronal loss were found in the hippocampus. Significant increases in pro-inflammatory cytokines were observed in both brain regions during alcohol withdrawal periods. Although astrocyte activation occurred in both the hippocampus and cerebellar vermis, microglial activation was observed primarily in the latter.
These findings suggest that heavy, binge-like third trimester-equivalent alcohol exposure has time- and brain region-dependent effects on cytokine levels, morphological activation of microglia and astrocytes, and neuronal survival.
胎儿酒精暴露是可预防出生缺陷的主要原因，然而孕期饮酒在全球范围内仍然普遍存在。研究表明，神经免疫系统的激活在啮齿动物相当于人类妊娠晚期（即新生生命的第一周）的酒精暴露影响中起作用，特别是导致神经元损失。在此，我们进行了一项综合研究，调查小脑和海马体中神经免疫反应的差异，这两个部位是相当于妊娠晚期酒精暴露的重要靶点。
为模拟这一时期大量、类似暴饮的酒精暴露，我们在出生后第（P）3 - 5天让大鼠吸入酒精蒸汽（血液酒精浓度 = 0.5 g/dL）。通过免疫组织化学在不同发育阶段分析幼鼠的小脑蚓部和海马体中胶质细胞激活和神经元损失的迹象。在血液酒精浓度峰值和戒断期通过逆转录聚合酶链反应测量细胞因子的产生。此外，对青春期后代的步态和空间记忆改变进行评估。
我们发现这种模式在P6和P45时导致小脑蚓部浦肯野细胞变性；然而，在海马体中未发现神经元损失的迹象。在酒精戒断期，两个脑区的促炎细胞因子均显著增加。虽然海马体和小脑蚓部均发生了星形胶质细胞激活，但小胶质细胞激活主要在后者中观察到。
这些发现表明，大量、类似暴饮的相当于妊娠晚期的酒精暴露对细胞因子水平、小胶质细胞和星形胶质细胞的形态激活以及神经元存活具有时间和脑区依赖性影响。
