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Ethanol withdrawal-induced adaptations in prefrontal corticotropin releasing factor receptor1-expressing neurons regulate anxiety and conditioned rewarding effects of ethanol

ABSTRACT: Ethanol withdrawal-induced adaptations in prefrontal corticotropin releasing factor receptor1-expressing neurons regulate anxiety and conditioned rewarding effects of ethanol

PROVIDER: PRJNA837796 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19200912.fastq.gz	Fastqsanger.gz
	SRR19200913.fastq.gz	Fastqsanger.gz
	SRR19200914.fastq.gz	Fastqsanger.gz
	SRR19200915.fastq.gz	Fastqsanger.gz
	SRR19200916.fastq.gz	Fastqsanger.gz

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Project description:While women are more vulnerable than men to many of the medical consequences of alcohol abuse, the role of sex in the response to ethanol is controversial. Neuroadaptive responses that result in the hyperexcitability associated with withdrawal from chronic ethanol likely reflect gene expression changes. We have examined both genders for the effects of withdrawal on brain gene expression using mice with divergent withdrawal severity that have been selectively bred from a genetically heterogeneous population. A total of 295 genes were identified as ethanol regulated from each gender of each selected line by microarray analyses. Hierarchical cluster analysis of the arrays revealed that the transcriptional response correlated with sex rather than with the selected withdrawal phenotype. Consistent with this, gene ontology category over-representation analysis identified cell death and DNA/RNA binding as targeted classes of genes in females, while in males, protein degradation, and calcium ion binding pathways weremore altered by alcohol. Examination of ethanol regulated genes and these distinct signaling pathways suggested enhanced neurotoxicity in females. Histopathological analysis of brain damage following ethanol withdrawal confirmed elevated cell death in female but not male mice. The sexually dimorphic response was observed irrespective of withdrawal phenotype. Combined, these results indicate a fundamentally distinct neuroadaptive response in females compared to males during chronic ethanol withdrawal and are consistent with observations that female alcoholics may be more vulnerable than males to ethanol-induced brain damage associated with alcohol abuse. A total of 32 microarrays were run with 4 biological replicates per treatment, line, and sex. Selection replicates (i.e. WSP-1 and WSP-2) for each treatment, line, and sex were collapsed to improve statistical power (n=4) and to facilitate in the identification of phenotype related effects and exclude selection artifacts. For comparisons, EtOH regulation was determined by comparing 4 arrays from (for example) Male WSR EtOH treated versus 4 arrays from Male WSR Air treated arrays.

Project description:Purpose: Genetic factors significantly affect alcohol consumption and vulnerability to withdrawal. Some genetic models that show predisposition to severe withdrawal are also predisposed to low ethanol consumption and vice versa, even when tested independently in naïve animals. The study was undertaken to understand gene and network differences between mice selectively bred for high withdrawal/low withdrawal or low withdrawal/high consumption. Methods: Beginning with a C57BL/6J×DBA/2J F2 intercross founder population, animals were simultaneously selectively bred for both high alcohol consumption and low acute withdrawal (SOT line), or vice versa (NOT line). Using randomly chosen fourth selected generation (S4) mice (N= 18-22/sex/line), RNA-Seq was employed to assess genome-wide gene expression in the ventral striatum. The Mega-MUGA array was used to detect genome-wide genotypic differences. Differential gene expression and the weighted gene co-expression network analysis (WGCNA) were implemented. Results: The new selection of the SOT and NOT lines was similar to that reported previously (Metten et al. 2014). One thousand eight hundred and fifteen transcripts were detected as being differentially expressed between the lines. For the genes overexpressed in the SOT line there was enrichment in genes associated with cell adhesion, synapse organization and post-synaptic membrane. The genes with a cell adhesion annotation included 23 protocadherins, Mpdz & Dlg2. Genes with a postsynaptic membrane annotation included Gabrb3, Gphn, Grid1, Grin2b, Grin2c & Grm3. The genes overexpressed in the NOT line were enriched in a network module (red) with annotations associated with mitochondrial function. Several of these genes were module hub nodes and these included Nedd8, Guk1, Elof1, Ndufa8, & Atp6v1f. Conclusions: Marked effects of selection on gene expression were detected. The NOT line was characterized by the increased expression of hub nodes associated with mitochondrial function. Genes overexpressed in the SOT aligned with previous findings e.g. Colville et al. (2017) that high ethanol preference and consumption is associated with effects on cell adhesion and glutamate synaptic plasticity.

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Ethanol withdrawal-induced adaptations in prefrontal corticotropin releasing factor receptor1-expressing neurons regulate anxiety and conditioned rewarding effects of ethanol

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