ENA0000GenomicsMultiomicsKristine Wiren, Behavioral Neuroscience, Oregon Health & Science University; Portland VA Research Servicehttps://www.ebi.ac.uk/ena/browser/view/PRJNA242779Mus musculusEthanol is the most common substance of abuse in the US, and abuse can lead to physical dependence, addiction, brain damage and premature death. The cycle of alcohol addiction has been described as a composite consisting of three stages: intoxication, withdrawal and craving/abstinence. As a complex brain disorder, there is evidence for both a genetic contribution to risk and sexually-dimorphic responses in alcoholism, but an overall understanding of the biological contributions and the neuroadaptive underpinnings of alcohol addiction is limited. Utilizing novel genetic animal models with highly divergent withdrawal severity, Withdrawal Seizure-Resistant (WSR) and Withdrawal Seizure-Prone (WSP) selected lines of mice and by examining both sexes, the distinct or common contributions of response to alcohol genotype/phenotype and of sex to addiction stages over time were characterized. Transcriptional profiling was performed to identify neuroadaptive changes as a consequence of chronic intoxication in the medial prefrontal cortex (mPFC). Significant expression differences were identified for each line and tracked over a behaviorally-relevant time course that covered each stage of alcohol addiction; i.e., after chronic intoxication, during peak withdrawal, and after a defined period of abstinence. Females were more responsive to ethanol with higher fold expression differences. Data structure was analyzed by bioinformatics, which showed a strong effect of sex with high similarity of male vs. female expression profiles during chronic intoxication and at peak withdrawal irrespective of genetic background. However, during abstinence, striking differences were observed instead between the lines/phenotypes irrespective of sex. Because sex was the strongest influence on neuroadaptive changes overall, confirmation analysis compared males vs. females. Notably, results revealed distinct inflammatory signaling between males and females at peak withdrawal, with a pro-inflammatory inflammotoxic phenotype in females but in contrast overall suppression of immune signaling in males. Thus, the early response to chronic intoxication is strongly influenced by sex while pathways that are altered during a period of abstinence are dependent on genotype. Combined, these results suggest that each stage of the addiction cycle is influenced differentially by sex vs. genetic background and support the development of distinct translational targets for stage- and sex-specific therapies for the treatment of alcohol withdrawal and the maintenance of sobriety. Overall design: 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.ENA3.4.22.-, Anterior Prefrontal, Brodmann Area 47, Lateral Orbitofrontal, Grain Alcohol, Anterior, Frontal Sulcus, Rectus, Brodmann's Area 47, Medial, Ventromedial, Laboratory, Frontalis Superior, Pars Orbitalis, Mus domesticus, etanol, Subcallosal Areas, Gene, mini-ICE, CASP-14, slow time, 1-hydroxyethane, House Mouse, Gyrus, alcohol, Aethylalkohol, Ethanol, Marginal, Subcallosal, prefrontal association complex, Inferior Frontal Gyrus, House, Lateral Orbitofrontal Cortices, Alkohol, Mus musculus domesticus, Frontal Convolution, Gyrus Rectus, Olfactory Sulci, Prefrontal Cortices, Pars, Frontal, (2Z)-but-2-enedioate, Ventromedial Prefrontal Cortex, Mice, Convolutions, Gyrus Orbitalis, Anterior Prefrontal Cortices, male, Brodmanns Area 47, spiritus vini., Grain, Gyrus Frontalis Superior, Gene Expressions, Subcallosal Area, Orbital Areas, prefrontal association cortex, Swiss, Absolute, ethanol, Ethyl, Orbital Area, Olfactory Sulcus, Swiss Mice, Orbitofrontal Region, Aethanol, Orbital Gyrus, Expressions, [CH2Me(OH)], C2H5OH, Dehydrated ethanol, Orbitofrontal Cortex, Area 47, Superior Frontal Gyrus, Chronic, Expression, Orbitofrontal Gyri, Orbital Gyri, Ventral Medial Prefrontal Cortex, Straight, Orbitofrontal, Brodmann's, Straight Gyrus, Gyrus Frontalis, Rectal, Alcohol, female human body, Males, Anterior Prefrontal Cortex, mouse, frontal association cortex, Sulcus, Orbital Cortex, Ethyl alcohol, Ventromedial Prefrontal, increased time, female, chronic, Absolute Alcohol, Brodmann Area 10, Brodmann Area 12, Brodmann Area 11, Cortex, Mus, increased period, Brodmann, Superior Frontal Convolution, Mini-ICE, high time, alcool ethylique, Area, Lateral Orbitofrontal Cortex, Rectal Gyrus, prolonged period, Region, ETHANOL, [OEtH], Ethyl Alcohol, Brodmanns Area 12, Medial Frontal, Brodmanns Area 11, Mus musculus, Brodmanns Area 10, Cortices, Gyrus Frontalis Inferior, Caspase-14 subunit p10, EtOH, Area 11, Frontal Gyrus, Area 10, maleate, Area 12, mice, Superior, Swiss Mouse, Superior Frontal Convolutions, Convolution, House Mice, Caspase-14 subunit p19, MICE, Rectus Gyrus, alcohol etilico, Methylcarbinol, Superior Frontal, Laboratory Mice, domesticus, male human body, Orbitofrontal Regions, hydroxyethane, Prefrontal, Lateral, Marginal Gyrus, Ventromedial Prefrontal Cortices, Brodmann's Area 10, Inferior, Brodmann's Area 12, Brodmann's Area 11, Medial Frontal Gyrus, Orbital Cortices, Inferior Frontal, Prefrontal Cortex, Orbitofrontal Cortices, Mouse, Orbitalis, Orbitofrontal Gyrus, Laboratory Mouse, Females, Orbitalmouse, mouse <Mus musculus>, house mouse.0.00.00.00.00.00falseMus musculusPrefrontal cortex gene expression in WSP and WSR male and female mice following 72h of chronic ethanol vapor exposure2022-05-122014-09-19PRJNA242779GSE562472519479110090