Characterization of genetically complex Collaborative Cross mouse strains that model divergent locomotor activating and reinforcing properties of cocaine

Schoenrock, Sarah A.; Kumar, Padam; Gómez-A, Alexander; Dickson, Price E.; Kim, Sam-Moon; Bailey, Lauren S.; Neira, Sofia; Riker, Kyle D.; Farrington, Joseph; Gaines, Christiann H.; Khan, Saad; Wilcox, Troy; Roy, Tyler; Leonardo, Michael; Olson, Ashley; Gagnon, Leona H.; Philip, Vivek M.; Valdar, William; Villena, Fernando Pardo-Manuel de; Jentsch, J. David; Logan, Ryan W.; McClung, Colleen A.; Robinson, Donita L.; Chesler, Elissa J.; Tarantino, Lisa M.

doi:10.1007/s00213-019-05429-3

Cited by 25 publications

(49 citation statements)

References 62 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: 95%

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: 95%

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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“…To determine whether the reported phenotypic differences between CC mouse strains (Schoenrock et al, 2018;Schoenrock et al, 2020) are accompanied by differences in striatal DA levels, we measured DA levels in isolated dorsal striata from the eight inbred founder CC strains ( Supplementary Table S1). In total, dopamine from 102 mice at the age of 3 months was measured by GC-MS. DA levels varied significantly across the founders (one-way ANOVA, p=0.0004, F=4.507), indicating strain-specific differences in DA levels in the nigrostriatal dopaminergic circuit (Figure 1).…”

Section: Differences In Striatal Dopamine Levels Across Collaborativementioning

confidence: 99%

“…Finally, recent studies showed significant effect of the genetic background on locomotor behaviour (Schoenrock et al, 2020) and response to cocaine (Schoenrock et al, 2018) using recombinant inbred intercrosses generated from CC strains, illustrating how the CC strains can serve as useful model for identifying further QTLs and genetic variants that govern structure and function of DAn's.…”

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confidence: 99%

Quantitative trait locus mapping identifies Col4a6 as a novel regulator of striatal dopamine level and axonal branching in mice

Buttini

Thomas

Gui

et al. 2020

Preprint

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The features of dopaminergic neurons (DAns) of nigrostriatal circuitry are orchestrated by a multitude of yet unknown factors, many of them genetic. Genetic variation between individuals at baseline can lead to differential susceptibility to and severity of diseases. As decline of DAns, a characteristic of Parkinson’s disease, heralds a significant decrease in dopamine level, measuring dopamine can reflect the integrity of DAns. To identify novel genetic regulators of the integrity of DAns, we used the Collaborative Cross (CC) mouse strains as model system to search for quantitative trait loci (QTLs) related to dopamine levels in the dorsal striatum. The dopamine levels in dorsal striatum varied greatly in the eight CC founder strains, and the differences were inheritable in 32 derived CC strains. QTL mapping in these CC strains identified a QTL associated with dopamine level on chromosome X containing 393 genes. RNA-seq analysis of the ventral midbrain of two of the founder strains with large striatal dopamine difference (C57BL/6J and A/J) revealed 24 differentially expressed genes within the QTL. The protein-coding gene with the highest expression difference was Col4a6, which exhibited a 9-fold reduction in A/J compared to C57BL/6J, consistent with decreased dopamine levels in A/J. Publicly available single cell RNA-seq data from developing human midbrain suggests that Col4a6 is highly expressed in radial glia-like cells and neuronal progenitors, indicating possible involvement in neurogenesis. Interestingly, the lowered dopamine levels were accompanied by reduced striatal axonal branching of striatal DAns in A/J compared to C57BL/6J. Because Col4a6 is known to control axogenesis in non-mammal model organisms, we hypothesize that different dopamine levels in mouse dorsal striatum are due to differences in axogenesis induced by varying COL4A6 levels during neural development.

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“…While there are few studies directly examining the relationships between period and amplitude, there is evidence that a longer period is usually accompanied by lower amplitude rhythms 39 . Recently, we reported differences between CC strains, which are also derived from the eight founders, where one of the lines displayed a longer period and lower amplitude in both molecular and behavioral rhythms compared to another line 40 . This suggests that circadian amplitude and period may be modulated by common genetic substrates in certain mouse strains and CC lines.…”

Section: Discussionmentioning

confidence: 99%

High-throughput measurement of fibroblast rhythms reveals genetic heritability of circadian phenotypes in diversity outbred mice and their founder strains

Kim

Vadnie

Philip

et al. 2021

Sci Rep

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Circadian variability is driven by genetics and Diversity Outbred (DO) mice is a powerful tool for examining the genetics of complex traits because their high genetic and phenotypic diversity compared to conventional mouse crosses. The DO population combines the genetic diversity of eight founder strains including five common inbred and three wild-derived strains. In DO mice and their founders, we established a high-throughput system to measure cellular rhythms using in vitro preparations of skin fibroblasts. Among the founders, we observed strong heritability for rhythm period, robustness, phase and amplitude. We also found significant sex and strain differences for these rhythms. Extreme differences in period for molecular and behavioral rhythms were found between the inbred A/J strain and the wild-derived CAST/EiJ strain, where A/J had the longest period and CAST/EiJ had the shortest. In addition, we measured cellular rhythms in 329 DO mice, which displayed far greater phenotypic variability than the founders—80% of founders compared to only 25% of DO mice had periods of ~ 24 h. Collectively, our findings demonstrate that genetic diversity contributes to phenotypic variability in circadian rhythms, and high-throughput characterization of fibroblast rhythms in DO mice is a tractable system for examining the genetics of circadian traits.

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Characterization of genetically complex Collaborative Cross mouse strains that model divergent locomotor activating and reinforcing properties of cocaine

Cited by 25 publications

References 62 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

Quantitative trait locus mapping identifies Col4a6 as a novel regulator of striatal dopamine level and axonal branching in mice

High-throughput measurement of fibroblast rhythms reveals genetic heritability of circadian phenotypes in diversity outbred mice and their founder strains

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