Cross-species molecular dissection across alcohol behavioral domains

Farris, Sean P.; Riley, Brien P.; Williams, Robert W.; Mulligan, Megan K.; Miles, Michael F.; López, Marcelo F.; Hitzemann, Robert; Iancu, Ovidiu D.; Colville, Alexander; Walter, Nicole A.R.; Darakjian, Priscila; Oberbeck, Denesa; Daunais, James B.; Zheng, Christina; Searles, Robert P.; McWeeney, Shannon K.; Grant, Kathleen A.; Mayfield, R. Dayne

doi:10.1016/j.alcohol.2017.11.036

Cited by 12 publications

(10 citation statements)

References 119 publications

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“…Human postmortem brain studies have produced useful information regarding the molecular hallmarks associated with the “end point” of psychiatric disorders 8 . While useful, these studies have many inherent limitations (for review see Reference 9).…”

Section: Introductionmentioning

confidence: 99%

Do gene expression findings from mouse models of cocaine use recapitulate human cocaine use disorder in reward circuitry?

Huggett

Bubier

Chesler

et al. 2020

Genes Brain and Behavior

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Animal models of drug use have investigated possible mechanisms governing human substance use traits for over 100 years. Most cross‐species research on drug use/addiction examines behavioral overlap, but studies assessing neuromolecular (e.g. RNA) correspondence are lacking. Our study utilized transcriptome‐wide data from the hippocampus and ventral tegmental area (VTA)/midbrain from a total of 35 human males with cocaine use disorder/controls and 49 male C57BL/6J cocaine/saline administering/exposed mice. We hypothesized differential expressed genes and systems of co‐expressed genes (gene networks) would show appreciable overlap across mouse cocaine self‐administration and human cocaine use disorder. We found modest, but significant relationships between differentially expressed genes associated with cocaine self‐administration (short access) and cocaine use disorder within reward circuitry. Differentially expressed genes underlying models of acute cocaine exposure (cocaine), context re‐exposure and cocaine + context re‐exposure were not consistently associated with human CUD across brain regions. Investigating systems of co‐expressed genes, we found several validated gene networks with weak to moderate conservation between cocaine/saline self‐administering mice and disordered cocaine users/controls. The most conserved hippocampal and VTA gene networks demonstrated substantial overlap (2029 common genes) and included both novel and previously implicated targets for cocaine use/addiction. Lastly, we conducted (expression‐based) phenome‐wide association studies of the nine common hub genes across conserved gene networks. Common hub genes were associated with dopamine/serotonin function, cocaine self‐administration and other relevant mouse traits. Overall, our study pinpointed and characterized conserved brain‐related RNA patterns across mouse cocaine self‐administration and human cocaine use disorder. We offer recommendations for future research and add to the dialogue surrounding pre‐clinical animal research for human disease.

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Section: Introductionmentioning

confidence: 99%

Do gene expression findings from mouse models of cocaine use recapitulate human cocaine use disorder in reward circuitry?

Huggett

Bubier

Chesler

et al. 2020

Genes Brain and Behavior

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show abstract

“…Human post-mortem brain studies have produced useful information 63 regarding the molecular hallmarks associated with the "end point" of psychiatric 64 disorders 8 . While useful, these studies have many inherent limitations (for review 65 see 9 ).…”

Section: Introduction 37mentioning

confidence: 99%

Meso-limbic Gene Expression Findings from Mouse Cocaine Self-Administration Recapitulate Human Cocaine Use Disorder

Huggett

Bubier

Chesler

et al. 2020

Preprint

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Animal models of drug use have been employed for over 100 years to facilitate the 10 identification of mechanisms governing human substance use and addiction. Most 11 cross-species research on drug use/addiction examines behavioral overlap, but 12 studies assessing neuro-molecular correspondence are lacking. Our study utilized 13 transcriptome-wide data from the hippocampus and ventral tegmental area 14 (VTA)/midbrain from a total of 35 human males with cocaine use disorder/controls 15 and 49 male C57BL/6J cocaine/saline administering/exposed mice. We 16hypothesized that individual genes (differential expression) and systems of co-17 expressed genes (gene networks) would demonstrate appreciable overlap across 18 mouse cocaine self-administration and human cocaine use disorder. We found 19modest, but significant associations between differentially expressed genes 20 associated with cocaine self-administration (short access) and cocaine use disorder 21 within meso-limbic circuitry, but non-robust associations with mouse models of 22 acute cocaine exposure, (cocaine) context re-exposure and cocaine + context re-23 exposure. Investigating systems of co-expressed genes, we also found several 24 validated gene networks with weak to moderate conservation between 25 cocaine/saline self-administering mice and disordered cocaine users/controls. The 26 most conserved hippocampal and VTA gene networks demonstrated substantial 27 overlap (2,029 common genes) and included novel and previously implicated 28 targets of cocaine use/addiction. Lastly, we conducted expression-based phenome-29 wide association studies of the nine common hub genes across conserved gene 30 networks and found that they were associated with dopamine/serotonin function, 31cocaine self-administration and other relevant mouse traits. Overall, our study 32 identified and characterized homologous transcriptional effects between mouse 33 models of cocaine self-administration and human cocaine use disorder that may 34 serve as a benchmark for future research. 35 36

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“…Identifying the genetic effects of AUD is important to advance prevention and treatment options in the human population. Beginning with Lewohl and colleagues (), there are more than 100 studies using genome‐wide profiling to examine the brain transcriptional features associated with excessive ethanol (EtOH) consumption (see, e.g., Contet, ; Farris et al, ; Mulligan et al, ). These studies have focused on factors associated with risk, individual variation, dependence, and/or chronic consumption.…”

mentioning

confidence: 99%

Chronic Voluntary Ethanol Drinking in Cynomolgus Macaques Elicits Gene Expression Changes in Prefrontal Cortical Area 46

Walter

Zheng

Searles

et al. 2020

Alcoholism Clin & Exp Res

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Background: Genome-wide profiling to examine brain transcriptional features associated with excessive ethanol (EtOH) consumption has been applied to a variety of species including rodents, nonhuman primates (NHPs), and humans. However, these data were obtained from cross-sectional samples which are particularly vulnerable to individual variation when obtained from small outbred populations typical of human and NHP studies. In the current study, a novel within-subject design was used to examine the effects of voluntary EtOH consumption on prefrontal cortex (PFC) gene expression in a NHP model.Methods: Two cohorts of cynomolgus macaques (n = 23) underwent a schedule-induced polydipsia procedure to establish EtOH self-administration followed by 6 months of daily open access to EtOH (4% w/v) and water. Individual daily EtOH intakes ranged from an average of 0.7 to 3.7 g/kg/d. Dorsal lateral PFC area 46 (A46) brain biopsies were collected in EtOH-na€ ıve and control monkeys; contralateral A46 biopsies were collected from the same monkeys following the 6 months of fluid consumption. Gene expression changes were assessed using RNA-Seq paired analysis, which allowed for correction of individual baseline differences in gene expression.Results: A total of 675 genes were significantly down-regulated following EtOH consumption; these were functionally enriched for immune response, cell adhesion, plasma membrane, and extracellular matrix. A total of 567 genes that were up-regulated following EtOH consumption were enriched in microRNA target sites and included target sites associated with Toll-like receptor pathways. The differentially expressed genes were also significantly enriched in transcription factor binding sites.Conclusions: The data presented here are the first to use a longitudinal biopsy strategy to examine how chronic EtOH consumption affects gene expression in the primate PFC. Prominent effects were seen in both cell adhesion and neuroimmune pathways; the latter contained both pro-and antiinflammatory genes. The data also indicate that changes in miRNAs and transcription factors may be important epigenetic regulators of EtOH consumption.

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Cross-species molecular dissection across alcohol behavioral domains

Cited by 12 publications

References 119 publications

Do gene expression findings from mouse models of cocaine use recapitulate human cocaine use disorder in reward circuitry?

Do gene expression findings from mouse models of cocaine use recapitulate human cocaine use disorder in reward circuitry?

Meso-limbic Gene Expression Findings from Mouse Cocaine Self-Administration Recapitulate Human Cocaine Use Disorder

Chronic Voluntary Ethanol Drinking in Cynomolgus Macaques Elicits Gene Expression Changes in Prefrontal Cortical Area 46

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