The Effect of Prenatal Ethanol Exposure and Environmental Enrichment on Midbrain Dopaminergic Neuron and Microglial Organization During Adulthood
Aghaie, Claudia Iyla
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Background: Prenatal ethanol exposure (PE) has been shown to impair midbrain dopaminergic (DA) neuron function, which might contribute to various cognitive and behavioral deficits, including attention deficits and increased addiction risk, observed in children with fetal alcohol spectrum disorders (FASD). Currently, the neuronal mechanisms underlying the PE-induced impairments are not clear. Ethanol is known to cause neuroinflammation mediated by the activation of microglia, which play an important role in the maintenance of synaptic functions. In the present study, we investigate the effects of PE on microglia around DA neurons in the ventral tegmental area (VTA). We also examined possible changes in VTA DA neuron cell number and body size. Since postnatal environmental enrichment can ameliorate PE-induced behavioral problems, we also investigated whether postnatal environmental enrichment can ameliorate PE effects on microglia and VTA DA neurons. Methods: Pregnant rats were administered a daily dose of 0 or 6 g/kg ethanol using intragastric intubation from gestation day 8 through 20. After birth, rats were reared in standard conditions or received pre-weaning handling enrichment and post-weaning housing enrichment. Adult animals were perfused between 7 and 18 weeks of age and midbrain sections were stained for tyrosine hydroxylase (DA neuron marker) and IBA-1 (microglia marker). They were imaged using the Zeiss Axioimager fluorescence microscope with ApoTome technology. FIJI was used to quantify DA neuron and microglia cell size and count, as well as microglia branching patterns. Results: The results showed that PE decreased the cell body size in the anterior and middle VTA DA neurons in standard housed rats. No differences were found in cell count and cell body size for microglia in the same regions. However, there was a significant decrease in the number of branches and branch points in standard housed PE rats, indicating more activated microglia and neuroinflammation. Interestingly, this effect was normalized in PE rats with environmental enrichment, which did not influence microglia in control rats. Conclusions: Our findings show an association in PE-induced microglia activation following PE and impaired VTA DA neuron morphology. Importantly, we showed that postnatal environmental enrichment rescues microglia activation/neuroinflammation in PE rats, which may ultimately lead to normalized synaptic function in VTA DA neurons. This data supports the hypothesis that environmental enrichment can be an effective intervention to lessen the extent of cognitive and behavioral impairments associated with VTA DA neuron dysfunction, such as poor attention span and increased addiction risk.