Abstract

BackgroundClinical and animal studies show that alcohol consumption during pregnancy produces lasting behavioral disturbances in offspring, including increased alcohol drinking, which are linked to inflammation in the brain and disturbances in neurochemical systems that promote these behaviors. These include the neuropeptide, melanin-concentrating hormone (MCH), which is mostly expressed in the lateral hypothalamus (LH). Maternal ethanol administration at low-to-moderate doses, while stimulating MCH neurons without affecting apoptosis or gliogenesis, increases in LH the density of neurons expressing the inflammatory chemokine C-C motif ligand 2 (CCL2) and its receptor CCR2 and their colocalization with MCH. These neural effects associated with behavioral changes are reproduced by maternal CCL2 administration, reversed by a CCR2 antagonist, and consistently stronger in females than males. The present study investigates in the embryo the developmental origins of this CCL2/CCR2-mediated stimulatory effect of maternal ethanol exposure on MCH neurons.MethodsPregnant rats from embryonic day 10 (E10) to E15 during peak neurogenesis were orally administered ethanol at a moderate dose (2 g/kg/day) or peripherally injected with CCL2 or CCR2 antagonist to test this neuroimmune system’s role in ethanol’s actions. Using real-time quantitative PCR, immunofluorescence histochemistry, in situ hybridization, and confocal microscopy, we examined in embryos at E19 the CCL2/CCR2 system and MCH neurons in relation to radial glia progenitor cells in the hypothalamic neuroepithelium where neurons are born and radial glia processes projecting laterally through the medial hypothalamus that provide scaffolds for neuronal migration into LH.ResultsWe demonstrate that maternal ethanol increases radial glia cell density and their processes while stimulating the CCL2/CCR2 system and these effects are mimicked by maternal administration of CCL2 and blocked by a CCR2 antagonist. While stimulating CCL2 colocalization with radial glia and neurons but not microglia, ethanol increases MCH neuronal number near radial glia cells and making contact along their processes projecting into LH. Further tests identify the CCL2/CCR2 system in NEP as a primary source of ethanol’s sexually dimorphic actions.ConclusionsThese findings provide new evidence for how an inflammatory chemokine pathway functions within neuroprogenitor cells to mediate ethanol’s long-lasting, stimulatory effects on peptide neurons linked to adolescent drinking behavior.

Highlights

  • Clinical and animal studies show that alcohol consumption during pregnancy produces lasting behavioral disturbances in offspring, including increased alcohol drinking, which are linked to inflammation in the brain and disturbances in neurochemical systems that promote these behaviors

  • We demonstrate that maternal ethanol increases radial glia cell density and their processes while stimulating the C-C motif ligand 2 (CCL2)/CCL2 receptor (CCR2) system and these effects are mimicked by maternal administration of CCL2 and blocked by a CCR2 antagonist

  • Of particular note is that these effects of ethanol in the lateral hypothalamus (LH) of adolescent offspring are detected in the embryo, where maternal ethanol exposure increases the density of CCL2 and CCR2 cells and their colocalization in melanin-concentrating hormone (MCH) neurons more consistently in females and these effects are blocked by maternal administration of a CCL2 antibody and CCR2 receptor antagonist, suggesting an important role for this neuroimmune system in the early development of MCH neurons in the LH [12]

Read more

Summary

Introduction

Clinical and animal studies show that alcohol consumption during pregnancy produces lasting behavioral disturbances in offspring, including increased alcohol drinking, which are linked to inflammation in the brain and disturbances in neurochemical systems that promote these behaviors. Maternal intraoral administration of ethanol in rat, at low-to-moderate doses from embryonic day 10 (E10) to E15 during peak hypothalamic neurogenesis, increases in the offspring the density of neurons in the lateral hypothalamus (LH) that express the orexigenic neuropeptide, melaninconcentrating hormone (MCH) [11, 12], which is known to have a role in reward and motivated behavior [13, 14] This stimulatory effect on MCH is accompanied by behavioral changes, including increased alcohol consumption [11, 15], which are induced in rats by central injection of MCH itself [16,17,18]. Of particular note is that these effects of ethanol in the LH of adolescent offspring are detected in the embryo, where maternal ethanol exposure increases the density of CCL2 and CCR2 cells and their colocalization in MCH neurons more consistently in females and these effects are blocked by maternal administration of a CCL2 antibody and CCR2 receptor antagonist, suggesting an important role for this neuroimmune system in the early development of MCH neurons in the LH [12]

Objectives
Methods
Results
Discussion
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call