Abstract
The Mediodorsal (MD) thalamus that represents a fundamental subcortical relay has been underrepresented in the studies focusing on the molecular changes in the brains of subjects with alcohol use disorder (AUD). In the current study, MD thalamic regions from AUD subjects and controls were analyzed with Affymetrix Clariom S human microarray. Long-term alcohol use induced a significant (FDR ≤ 0.05) upregulation of 2802 transcripts and downregulation of 1893 genes in the MD thalamus of AUD subjects. A significant upregulation of GRIN1 (glutamate receptor NMDA type 1) and FTO (alpha-ketoglutarate dependent dioxygenase) was confirmed in western blot analysis. Immunohistochemical staining revealed similar heterogenous distribution of GRIN1 in the thalamic nuclei of both AUD and control subjects. The most prevalent functional categories of upregulated genes were related to glutamatergic and GABAergic neurotransmission, cellular metabolism, and neurodevelopment. The prevalent gene cluster among down-regulated genes was immune system mediators. Forty-two differentially expressed genes, including FTO, ADH1B, DRD2, CADM2, TCF4, GCKR, DPP6, MAPT and CHRH1, have been shown to have strong associations (FDR p < 10−8) with AUD or/and alcohol use phenotypes in recent GWA studies. Despite a small number of subjects, we were able to detect robust molecular changes in the mediodorsal thalamus caused by alcohol emphasizing the importance of deeper brain structures such as diencephalon, in the development of AUD-related dysregulation of neurocircuitry.
Highlights
IntroductionExcessive alcohol use is associated with deleterious neurobehavioral consequences to the drinker and causes significant burden to the family members and for the society as a whole [1]
Alcohol is the most widely used addictive substance worldwide
We detected detected strong strong alteralterations in the well-known direct targets of ethanol [42], such as gene clusters related to the GABAergic, glutamatergic, dopaminergic, endocannabinoid-mediated and corticotropin releasing factor (CRF)-related neurotransmission, and provided evidence about the extended profile of alterations in addition to well characterized molecular targets, many of them overlapped with the significant findings from recent genome wide association studies (GWAS) studies for alcoations in the well-known direct targets of ethanol [42], such as gene clusters related to the GABAergic, glutamatergic, dopaminergic, endocannabinoid-mediated and corticotropin releasing factor (CRF)-related neurotransmission, and provided evidence about the extended profile of alterations in addition to well characterized molecular targets, many of them overlapped with the significant findings from recent GWAS studies for alcohol dependence or related phenotypes
Summary
Excessive alcohol use is associated with deleterious neurobehavioral consequences to the drinker and causes significant burden to the family members and for the society as a whole [1]. This burden results from the increased health risks associated with alcohol use disorder (AUD), as well as from the social harms caused by alcohol. For the past few years, genome wide association studies (GWAS) of AUD and related traits such as alcohol consumption measurements, have been conducted by using the sample sizes exceeding hundreds of thousands of cases and controls [4,5,6,7,8,9]
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