Comparison between dopaminergic and non-dopaminergic neurons in the VTA following chronic nicotine exposure during pregnancy

Renee F Keller,Andrei Dragomir,Yasemin M Akay,Tina Kazemi,Metin Akay

doi:10.1038/s41598-018-37098-1

Abstract

Exposure to nicotine during pregnancy through maternal smoking or nicotine replacement therapy is associated with adverse birth outcomes as well as several cognitive and neurobehavioral deficits. Several studies have shown that nicotine produces long-lasting effects on gene expression within many brain regions, including the ventral tegmental area (VTA), which is the origin of dopaminergic neurons and the dopamine reward pathway. Using a well-established rat model for perinatal nicotine exposure, we sought to investigate altered biological pathways using mRNA and miRNA expression profiles of dopaminergic (DA) and non-dopaminergic (non-DA) neurons in this highly-valuable area. Putative miRNA-gene target interactions were assessed as well as miRNA-pathway interactions. Our results indicate that extracellular matrix (ECM) receptor interactions were significantly altered in DA and non-DA neurons due to chronic nicotine exposure during pregnancy. They also show that the PI3K/AKT signaling pathway was enriched in DA neurons with multiple significant miRNA-gene targets, but the same changes were not seen in non-DA neurons. We speculate that nicotine exposure during pregnancy could differentially affect the gene expression of DA and non-DA neurons in the VTA.

Highlights

Maternal smoking during pregnancy is associated with adverse birth outcomes including cognitive and neurobehavioral deficits[1,2,3]
The ventral tegmental area (VTA) was isolated from the offspring and separated into DA and non-DA neuron groups based on expression of TH and NeuN using fluorescent-activated cell sorting (FACs) (Fig. 1)
We analyzed the differential expression of mRNA and miRNA from VTA neurons in order to compare the function enrichment analyses of DA and non-DA neurons from the VTA with respect to perinatal nicotine treatment

Summary

Introduction

Maternal smoking during pregnancy is associated with adverse birth outcomes including cognitive and neurobehavioral deficits[1,2,3]. MicroRNAs (miRNAs) are short, non-coding RNA sequencing spanning about 22 nucleotides that act to regulate the expression of mRNAs by binding to the 3′ untranslated region (3′UTR) which results in translational inhibition or transcriptional repression[17,21] They are of particular interest because a single miRNA can regulate many factors affecting gene regulatory networks, affecting a large downstream response[21,22]. We investigated RNA expression profiles of DA and non-DA neurons in the VTA following perinatal nicotine exposure due to the importance of the VTA in the mesocorticolimbic DA reward pathway as well as the changes in miRNA and mRNA expression that are modulated by nicotine.

Methods

Results

Conclusion