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Sex differences in the ventral tegmental area and nucleus accumbens proteome at baseline and following nicotine exposure

ABSTRACT: Sex differences in behaviors relevant to nicotine addiction have been observed in rodent models and human subjects. Behavioral, imaging and epidemiological studies also suggest underlying sex differences in mesolimbic dopamine signaling pathways. In this study we evaluated the proteome in the ventral tegmental area (VTA) and nucleus accumbens (NAc) shell in male and female mice. Experimental groups included two mouse strains (C3H/HeJ and C57BL/6J) at baseline, a sub-chronic, rewarding regimen of nicotine in C3H/HeJ mice, and chronic nicotine administration and withdrawal in C57BL/6J mice. Isobaric labeling with a TMT 10-plex system, sample fractionation, and tandem mass spectrometry were used to quantify changes in protein abundance. Similar or greater numbers of differentially regulated proteins were found between sexes at baseline in C3H/HeJ or C57BL/6J mice than within sexes following their respective regimen of nicotine administration. Despite differences by sex, strain, and nicotine exposure parameters, glial fibrillary acidic protein (GFAP) and dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32, Ppp1r1b) were repeatedly identified as significantly altered proteins, especially in the VTA. Further, network analyses showed sex- and nicotine-dependent regulation of a number of signaling pathways, including dopaminergic signaling. Sub-chronic nicotine exposure in female mice increased proteins related to dopaminergic signaling in the NAc shell but decreased them in the VTA, whereas the opposite pattern was observed in male mice. In contrast, dopaminergic signaling pathways were similarly upregulated in both male and female VTA after chronic nicotine and withdrawal. Overall, this study identifies significant sex differences in the proteome of the mesolimbic system, at baseline and after nicotine reward or withdrawal, which may help explain differential trajectories and susceptibility to nicotine addiction in males and females.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Mohammad Shahid Mansuri

LAB HEAD: Angus Nairn

PROVIDER: PXD023859 | Pride | 2021-06-28

REPOSITORIES: Pride

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Project description:Tobacco cigarette smoking, with nicotine (NIC) as the addictive component, is a large risk factor for human mortality. In animals, repeated NIC exposure leads to sensitization (SST) and enhances self-administration (SA) of NIC. However, the molecular basis of SST and SA and their genetic relevance to smoking behavior are poorly understood. Using F1 progeny of inbred Envigo rats (F344/BN), we carried out a transcriptional profiling of NIC SST and SA in ventral tegmental area (VTA), nucleus accumbens core (Nac) and shell (Nash). We observed male-specific NIC SST and a parental effect of NIC with SA only present in paternal F344 crosses. Gene differential expression (DE) analysis revealed sex and brain region-specific transcriptomic signatures of SST and SA, with genes downregulated in male VTA associated with both SST and SA, while genes upregulated in male Nac were associated with SA. DE genes associated with SST and SA are enriched for those related to synaptic processes, myelin sheath, and tobacco use disorder or chemdependency. Interestingly, we found that for SST the downregulated genes in the male VTA tended to be upregulated in female VTA, and the overlapping genes were strongly enriched for smoking genome-wide association study (GWAS) risk variants, which may thus explain male-specific SST. To gain mechanistic insight on the observed parental effect of SA, we analyzed the allelic imbalance of expression (AIE) in reciprocally crossed F1 rats that exhibited differential tendency of SA and found widespread region-specific AIE. For the SA-inclined rats, the genes showing AIE bias towards paternal F344 alleles in Nac were strongly enriched for genes upregulated in Nac DE—the gene set most relevant to NIC SA—and also for GWAS risk variants of smoking initiation. These findings show a prominent role for sex and region-specific gene expression and imprinting in NIC SST and SA, and suggest a mechanistic link between genes underlying these processes and human NIC addiction. This study provides a resource for understanding the biology underlying the genetic findings on human smoking phenotypes.

			Action	DRS
	NAc_Chronic.txt	Txt
	NAc_Subchronic.txt	Txt
	OTF19-0126_VTA_Set1_A_MS3.raw	Raw
	OTF19-0132_VTA_Set1_B_MS3.raw	Raw
	OTF19-0138_VTA_Set1_C_MS3.raw	Raw

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Sex differences in the ventral tegmental area and nucleus accumbens proteome at baseline and following nicotine exposure

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