Consideration of genetic and sex effects in mice enhances consilience with human addiction studies

Saul, Michael C.; Bagley, Jared R.; Bailey, Lauren S.; Datta, Udita; Dickson, Price E.; Dodd, Rainy; Gagnon, Leona H.; Hugett, Spencer B.; Kimble, Violet M.; Leonardo, Michael; Kim, Sam-Moon; Olson, Ashley; Roy, Tyler; Schoenrock, Sarah A.; Wilcox, Troy; Jentsch, J. David; Logan, Ryan W.; McClung, Colleen A.; Palmer, Rohan; Philip, Vivek; Reinholdt, Laura G.; Rizzo, Stacey J. Sukoff; Tarantino, Lisa M.; Chesler, Elissa J.

doi:10.1101/2020.02.14.949784

Cited by 10 publications

(26 citation statements)

References 65 publications

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“…Although other populations of rats may indeed show a different degree of relatedness between these particular tasks, HS rats in particular would be useful in examining each of these particular traits in isolation of the other. Behavioral heterogeneity has been linked to strain and genetic lineage in rodents for Pavlovian conditioned approach [42][43][44] and locomotor sensitivity to cocaine 45,46 , and thus we suggest HS rats may be a well suited tool for genetic mapping within specific behavioral domains.…”

Section: Discussionmentioning

confidence: 94%

Sensitivity to food and cocaine cues are independent traits in a large sample of heterogeneous stock rats

King

Tripi

Hughson

et al. 2021

Sci Rep

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Sensitivity to cocaine and its associated stimuli (“cues”) are important factors in the development and maintenance of addiction. Rodent studies suggest that this sensitivity is related, in part, to the propensity to attribute incentive salience to food cues, which, in turn, contributes to the maintenance of cocaine self-administration, and cue-induced relapse of drug-seeking. Whereas each of these traits has established links to drug use, the relatedness between the individual traits themselves has not been well characterized in preclinical models. To this end, the propensity to attribute incentive salience to a food cue was first assessed in two distinct cohorts of 2716 outbred heterogeneous stock rats (HS; formerly N:NIH). We then determined whether each cohort was associated with performance in one of two paradigms (cocaine conditioned cue preference and cocaine contextual conditioning). These measure the unconditioned locomotor effects of cocaine, as well as conditioned approach and the locomotor response to a cocaine-paired floor or context. There was large individual variability and sex differences among all traits, but they were largely independent of one another in both males and females. These findings suggest that these traits may contribute to drug-use via independent underlying neuropsychological processes.

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Section: Discussionmentioning

confidence: 94%

Sensitivity to food and cocaine cues are independent traits in a large sample of heterogeneous stock rats

King

Tripi

Hughson

et al. 2021

Sci Rep

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“…These analyses may be more appropriate among genetically diverse strains of mice (e.g. diversity outbred), which have demonstrated robust neuromolecular overlap with human CUD 45 …”

Section: Discussionmentioning

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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“…Some of these efforts have focused on cocaine-induced psychomotor activation; multiple QTL have been associated with cocaine-induced locomotion, with confirmation of some QTL by secondary mapping approaches (Boyle & Gill, 2001, 2009; Gill & Boyle, 2003; Jones et al, 1999; Kumar et al, 2013; Phillips, Huson, & McKinnon, 1998; Tolliver, Belknap, Woods, & Carney, 1994). Additional efforts have characterized measures of cocaine reward and reinforcement with success in mapping QTL and identifying candidate genes and genetic correlations among behavioral and physiological measures (Bagley, Szumlinski, et al, 2019; Bagley, Adams, Bozadjian, Bubalo, & Kippin, 2019; Cervantes et al, 2013; Dickson et al, 2014, 2015; Kippin et al, 2015; Roberts et al, 2018; Saul et al, 2020, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…Cocaine intravenous self-administration (IVSA) is an assay of voluntary cocaine use and is thought to provide a model of cocaine use with predictive, face and construct validity (Belin-Rauscent et al, 2016; O’Connor et al, 2011). Advances in surgical techniques and devices have allowed for improved catheter patency rates that make characterization of large numbers of genetically diverse mice for cocaine IVSA feasible (Cervantes et al, 2013; Dickson et al, 2014, 2015; Roberts et al, 2018; Saul et al, 2020). Application of this assay to advanced mouse populations may enhance understanding of genetic factors unique to voluntary cocaine use.…”

Section: Introductionmentioning

confidence: 99%

“…Application of this assay to advanced mouse populations may enhance understanding of genetic factors unique to voluntary cocaine use. The BXD recombinant inbred strain panel was utilized to map cocaine IVSA QTL and genetic correlations (Dickson et al, 2015), and a similar study is underway using Collaborative Cross and Diversity Outbred mice (CC/DO) (Saul et al, 2020). Application of cocaine IVSA to additional mouse populations may offer additional opportunities to generate replicable and/or reproducible information on the genetics of cocaine use and related traits.…”

Section: Introductionmentioning

confidence: 99%

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Extreme Phenotypic Diversity in Operant Responding for an Intravenous Cocaine or Saline Infusion in the Hybrid Mouse Diversity Panel

Bagley

Smith

et al. 2021

Preprint

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Cocaine self-administration is complexly determined trait, and a substantial proportion of individual differences in cocaine use is determined by genetic variation. Cocaine intravenous self-administration (IVSA) procedures in laboratory animals provide opportunities to prospectively investigate neurogenetic influences on the acquisition of voluntary cocaine use. Large and genetically diverse mouse populations, like the Hybrid Mouse Diversity Panel (HMDP), have been developed for forward genetic approaches that can reveal genetic variants that influence traits like cocaine IVSA. This population enables high resolution and well-powered genome wide association studies, as well as the discovery of genetic correlations. Here, we provide information on cocaine (or saline - as a control) IVSA in 65 strains of the HMDP. We found cocaine IVSA to be substantially heritable in this population, with strain-level intake ranging for near zero to >25 mg/kg/session. Though saline IVSA was also found to be heritable, a very modest genetic correlation between cocaine and saline IVSA indicates that operant responding for the cocaine reinforcer was influenced by a substantial proportion of unique genetic variants. These data indicate that the HMDP is suitable for forward genetic approaches for the analysis of cocaine IVSA, and this project has also led to the discovery of reference strains with extreme cocaine IVSA phenotypes, revealing them as polygenic models of risk and resilience to cocaine reinforcement. This is part of an ongoing effort to characterize genetic and genomic variation that moderates cocaine IVSA, which may, in turn, provide a more comprehensive understanding of cocaine risk genetics and neurobiology.

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Consideration of genetic and sex effects in mice enhances consilience with human addiction studies

Cited by 10 publications

References 65 publications

Sensitivity to food and cocaine cues are independent traits in a large sample of heterogeneous stock rats

Sensitivity to food and cocaine cues are independent traits in a large sample of heterogeneous stock rats

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

Extreme Phenotypic Diversity in Operant Responding for an Intravenous Cocaine or Saline Infusion in the Hybrid Mouse Diversity Panel

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