Cell-type brain-region specific changes in prefrontal cortex of a mouse model of alcohol dependence

The prefrontal cortex is a crucial regulator of alcohol drinking, and dependence, and other behavioral phenotypes associated with AUD. Comprehensive identification of cell-type specific transcriptomic changes in alcohol dependence will improve our understanding of mechanisms underlying the excessive...

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Vydané v:Neurobiology of disease Ročník 190; s. 106361
Hlavní autori: Salem, Nihal A., Manzano, Lawrence, Keist, Michael W., Ponomareva, Olga, Roberts, Amanda J., Roberto, Marisa, Mayfield, R. Dayne
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States Elsevier Inc 01.01.2024
Elsevier
Predmet:
Alcohol dependence
Alcohol dependence cell-type specific responses
Alcoholism - genetics
Animals
Brain - metabolism
Chronic intermittent ethanol exposure
Ethanol - toxicity
Gene co-expression networks
Mice
Mice, Inbred C57BL
Multimodal data integration
Neuroinflammatory Diseases
Prefrontal Cortex - metabolism
Single nucleus RNA sequencing
Spatial transcriptomics
Single nucleus RNA sequencing
Chronic intermittent ethanol exposure
Spatial transcriptomics
Gene co-expression networks
Alcohol dependence cell-type specific responses
Alcohol dependence
Multimodal data integration
ISSN:0969-9961, 1095-953X, 1095-953X
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Shrnutí:The prefrontal cortex is a crucial regulator of alcohol drinking, and dependence, and other behavioral phenotypes associated with AUD. Comprehensive identification of cell-type specific transcriptomic changes in alcohol dependence will improve our understanding of mechanisms underlying the excessive alcohol use associated with alcohol dependence and will refine targets for therapeutic development. We performed single nucleus RNA sequencing (snRNA-seq) and Visium spatial gene expression profiling on the medial prefrontal cortex (mPFC) obtained from C57BL/6 J mice exposed to the two-bottle choice-chronic intermittent ethanol (CIE) vapor exposure (2BC-CIE, defined as dependent group) paradigm which models phenotypes of alcohol dependence including escalation of alcohol drinking. Gene co-expression network analysis and differential expression analysis identified highly dysregulated co-expression networks in multiple cell types. Dysregulated modules and their hub genes suggest novel understudied targets for studying molecular mechanisms contributing to the alcohol dependence state. A subtype of inhibitory neurons was the most alcohol-sensitive cell type and contained a downregulated gene co-expression module; the hub gene for this module is Cpa6, a gene previously identified by GWAS to be associated with excessive alcohol consumption. We identified an astrocytic Gpc5 module significantly upregulated in the alcohol-dependent group. To our knowledge, there are no studies linking Cpa6 and Gpc5 to the alcohol-dependent phenotype. We also identified neuroinflammation related gene expression changes in multiple cell types, specifically enriched in microglia, further implicating neuroinflammation in the escalation of alcohol drinking. Here, we present a comprehensive atlas of cell-type specific alcohol dependence mediated gene expression changes in the mPFC and identify novel cell type-specific targets implicated in alcohol dependence. •We provide a snRNA-seq atlas in a mouse model of alcohol dependence.•Oligodendrocytes & inhibitory neurons subtypes are the most affected in dependence.•Multimodal integration identified spatial specificity of neuronal cell subtypes.•Neuroinflammation genes are enriched in dependence-dysregulated microglial module.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:0969-9961
1095-953X
1095-953X
DOI:10.1016/j.nbd.2023.106361