Prenatal Ethanol Exposure and Postnatal Environmental Intervention Alter Dopaminergic Neuron and Microglia Morphology in the Ventral Tegmental Area During Adulthood
Prenatal Ethanol Exposure and Postnatal Environmental Intervention Alter Dopaminergic Neuron and Microglia Morphology in the Ventral Tegmental Area During Adulthood
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DOI：
10.1111/acer.14275
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发表时间：
2020-01-25
影响因子：
3.2
通讯作者：
Shen, Roh-Yu
中科院分区：
文献类型：
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作者：
Aghaie, Claudia, I;Hausknecht, Kathryn A.;Shen, Roh-Yu
背景产前酒精暴露（PE）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，通常见于胎儿酒精谱系障碍患者。目前，PE诱导的缺陷的潜在机制尚不清楚。PE可通过激活在突触功能中起重要作用的小胶质细胞而导致神经炎症。在本研究中，我们研究了PE对腹侧被盖区（VTA）小胶质细胞活化和DA神经元密度和形态的影响。由于出生后的环境丰富，可以减少神经炎症和改善几个PE诱导的行为缺陷，我们研究了如果出生后的环境干预策略，新生儿处理和断奶后复杂的住房可以扭转PE对腹侧被盖区DA神经元和小胶质细胞的影响。方法孕鼠于妊娠第8 ~ 20天分别灌胃乙醇0或6 g/kg/d，共2次。出生后，大鼠在标准实验室或富集条件下饲养。雄性成年大鼠（8至12周龄）用于免疫细胞化学。结果PE可使标准饲养大鼠腹侧被盖区DA能神经元胞体缩小。此外，PE大鼠VTA小胶质细胞分支和连接的数量显著减少，表明小胶质细胞的形态学活化和可能的神经炎症。PE对小胶质细胞的影响通过出生后的环境干预而正常化，这也减少了对照动物中小胶质细胞分支和连接的数量，可能是通过减少压力。结论PE诱导的小胶质细胞形态学激活与腹侧被盖区DA能神经元形态学受损有关。重要的是，出生后的环境干预挽救了可能的PE诱导的小胶质细胞活化。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，如注意力缺陷和成瘾风险增加。
Background 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. Methods 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. Results 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. Conclusions 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.