Project description:Background: Epidemiological research indicates that iron deficiency (ID) in infancy correlates with long-term cognitive impairment and behavioral disturbances, despite therapy. However, the mechanisms underlying these effects are unknown. Objective: We investigated how ID affected postweaning behavior and monoamine concentration in rat brains to determine whether ID during the juvenile period affected gene expression and synapse formation in the prefrontal cortex (PFC) and nucleus accumbens (NAcc). Methods: Fischer344/Jcl male rats aged 21–39 days were fed low-iron diets (0.35 mg/kg iron; ID group) or standard AIN-93 G diets (3.5 mg/kg iron; control group). The locomotor activity of male offspring was evaluated by the open field and elevated plus maze tests at ages 8 and 12 weeks. Monoamine concentrations in the PFC, NAcc, caudate-putamen, ventral midbrain, dorsal midbrain, and pons were analyzed. Comprehensive gene expression analysis was performed in the PFC and NAcc at age 13 weeks. Finally, we investigated synaptic density in the PFC and NAcc by synaptophysin immunostaining. Results: Behavioral tests revealed significant interactions between age and iron consumption for the total distance traveled and the distance traveled in the peripheral area (p < 0.05), indicating that ID during the juvenile period affected hyperactivity and that this persisted to adulthood. At age 13 weeks, the ID group had increased levels of both dopamine and the metabolites of dopamine and serotonin in the NAcc. Comprehensive gene expression analysis and immunostaining showed decreased Reelin gene expression (adjusted p < 0.01) and significantly increased spine density in the NAcc in the ID group compared with the control group (p < 0.01). Conclusions: ID during the postweaning juvenile period led to long-term hyperactivity, monoamine disturbance in the brain, and downregulation of Reelin expression in the NAcc despite complete iron repletion. Epigenetic modification of Reelin genes may be involved in synaptic plasticity in the NAcc.

Project description:Background: Iron deficiency (ID) during the fetal-neonatal period results in long-term neurodevelopmental impairments associated with pervasive hippocampal gene dysregulation. Prenatal choline supplementation partially normalizes these effects, suggesting an interaction between iron and choline in hippocampal transcriptome regulation. To understand the regulatory mechanisms, we investigated epigenetic marks of genes that are poised to be activated (ATAC-seq) or repressed (H3K9me3 ChIP-seq) in iron-repleted adult rats having experienced fetal-neonatal ID exposure with or without prenatal choline supplementation. Results: Fetal-neonatal ID was induced by limiting maternal iron intake from gestational day (G) 2 through postnatal day (P) 7. Half of the pregnant dams were given supplemental choline (5.0 g/kg) from G11-18. This resulted in 4 groups at P65 (Iron-sufficient [IS], Formerly Iron-deficient [FID], IS with choline [ISch], and FID with choline [FIDch]). Hippocampi were collected from P65 iron-repleted male offspring and analyzed for chromatin accessibility and H3K9me3 enrichment. 22% and 24% of differentially transcribed genes in FID- and FIDch-groups, respectively, exhibited significant differences in chromatin accessibility, whereas 1.7% and 13% exhibited significant differences in H3K9me3 enrichment. These changes mapped onto gene networks regulating synaptic plasticity, neuroinflammation, and reward circuits. Motif analysis of differentially modified genomic sites revealed significantly stronger choline effects than early-life ID and identified multiple epigenetically modified transcription factor binding sites. Conclusions: This study reveals genome-wide, stable epigenetic changes and epigenetically modifiable gene networks associated with specific chromatin marks in the hippocampus, and lays a foundation to further elucidate iron-dependent epigenetic mechanisms that underlie the long-term effects of fetal-neonatal ID, choline, and their interactions.

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Intranasal Insulin Treatment Alters Gene Expression Profile in the Hippocampus of Rats with Perinatal Iron Deficiency

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