Department of Pathology and Anatomical Sciences, University at Buffalo, Buffalo, New York.
Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York.
Alcohol Clin Exp Res. 2020 Feb;44(2):435-444. doi: 10.1111/acer.14275. Epub 2020 Jan 25.
Prenatal ethanol exposure (PE) impairs midbrain dopaminergic (DA) neuron function, which might contribute to various cognitive and behavioral deficits, including attention deficits and increased addiction risk, often observed in individuals with fetal alcohol spectrum disorders. Currently, the underlying mechanisms for PE-induced deficits are unclear. PE could lead to neuroinflammation by activating microglia, which play an important role in synaptic function. In the present study, we investigated PE effects on microglial activation and DA neuron density and morphology in the ventral tegmental area (VTA). Since postnatal environmental enrichment can reduce neuroinflammation and ameliorate several PE-induced behavioral deficits, we examined if a postnatal environmental intervention strategy using neonatal handling and postweaning complex housing could reverse PE effects on VTA DA neurons and microglia.
Pregnant rats received 0 or 6 g/kg/d ethanol by 2 intragastric intubations on gestation days 8 to 20. After birth, rats were reared in the standard laboratory or enriched condition. Male adult rats (8 to 12 weeks old) were used for immunocytochemistry.
The results showed that PE decreased VTA DA neuron body size in standardly housed rats. Moreover, there was a significant decrease in numbers of VTA microglial branches and junctions in PE rats, suggesting morphological activation of microglia and possible neuroinflammation. The PE effects on microglia were normalized by postnatal environmental intervention, which also decreased the numbers of microglial branches and junctions in control animals, possibly via reduced stress.
Our findings show an association between PE-induced morphological activation of microglia and impaired DA neuron morphology in the VTA. Importantly, postnatal environmental intervention rescues possible PE-induced microglial activation. These data support that environmental intervention can be effective in ameliorating cognitive and behavioral deficits associated with VTA DA neuron dysfunctions, such as attention deficits and increased addiction risk.
产前乙醇暴露 (PE) 会损害中脑多巴胺能 (DA) 神经元功能，这可能导致各种认知和行为缺陷，包括注意力缺陷和成瘾风险增加，这些缺陷通常在胎儿酒精谱系障碍患者中观察到。目前，PE 引起的缺陷的潜在机制尚不清楚。PE 可通过激活小胶质细胞引起神经炎症，小胶质细胞在突触功能中起重要作用。在本研究中，我们研究了 PE 对腹侧被盖区 (VTA) 中小胶质细胞激活和 DA 神经元密度和形态的影响。由于产后环境丰富可以减少神经炎症并改善几种 PE 引起的行为缺陷，我们检查了使用新生儿处理和断奶后复杂饲养的产后环境干预策略是否可以逆转 PE 对 VTA DA 神经元和小胶质细胞的影响。
妊娠大鼠在妊娠第 8 至 20 天通过 2 次胃内插管接受 0 或 6 g/kg/d 乙醇。出生后，大鼠在标准实验室或丰富的环境中饲养。雄性成年大鼠（8 至 12 周龄）用于免疫细胞化学。
结果表明，PE 降低了标准饲养大鼠 VTA DA 神经元的体大小。此外，PE 大鼠 VTA 小胶质细胞分支和节数显著减少，提示小胶质细胞形态激活和可能的神经炎症。产后环境干预使 PE 对小胶质细胞的影响正常化，这也降低了对照动物小胶质细胞分支和节数，可能是通过减少应激。
我们的研究结果表明，PE 诱导的小胶质细胞形态激活与 VTA 中 DA 神经元形态受损之间存在关联。重要的是，产后环境干预可挽救可能由 PE 引起的小胶质细胞激活。这些数据支持环境干预可以有效改善与 VTA DA 神经元功能障碍相关的认知和行为缺陷，例如注意力缺陷和成瘾风险增加。
