30Sprague Dawley (SD) rats are one of the most commonly used outbred rat strains. Despite 31 this, the genetic characteristics of SD are poorly understood. We collected behavioral data from 32 4,625 SD rats acquired predominantly from two commercial vendors, Charles River Laboratories 33 and Harlan Sprague Dawley Inc. Using double-digest genotyping-by-sequencing (ddGBS), we 34 obtained dense, high-quality genotypes at 234,887 SNPs across 4,061 rats. This genetic data 35 allowed us to characterize the variation present in Charles River vs. Harlan SD rats. We found that 36 the two populations are highly diverged (FST > 0.4). We also used these data to perform a genome-37 wide association study (GWAS) of Pavlovian conditioned approach (PavCA), which assesses the 38 propensity for rats to attribute motivational value to discrete, reward-associated cues. Due to the 39 genetic divergence between rats from Charles River and Harlan, we performed two separate 40 GWAS by fitting a linear mixed model that accounted for within vendor population structure and 41 using meta-analysis to jointly analyze the two studies. We identified 18 independent loci that were 42 significantly associated with one or more metrics used to describe PavCA; we also identified 3 43 loci that were body weight, which was only measured in a subset of the rats. The genetic 44 characterization of SD rats is a valuable resource for the rat community that can be used to inform 45 future study design. 46 AuthorSummary 47 Outbred Sprague Dawley rats are among the most commonly used rats for neuroscience, 48 physiology and pharmacological research. SD rats are sold by several commercial vendors, 49 including Charles River Laboratories and Harlan Sprague Dawley Inc. (now Envigo). Despite their 50wide spread use, little is known about the genetic diversity of SD. We genotyped more than 4,000 51 2 SD rats, which we used to characterize genetic differences between SD rats from Charles River 52 Laboratories and Harlan. Our analysis revealed that the two SD colonies are highly divergent. We 53 also performed a genome-wide association study (GWAS) for Pavlovian conditioned approach 54 (PavCA), which assesses the propensity for rats to attribute motivational value to discrete, reward-55 associated cues. Our results demonstrate that, despite sharing an identical name, SD rats are 56 obtained from different vendors are genetically very different. We conclude that results obtained 57 using SD rats should not be presented without also carefully noting the vendor. 58 Introduction 59Rats are among the most commonly used organisms for experimental psychology and 60 biomedical research. Whereas research using mice makes extensive use of inbred strains, in rats, 61 it is more common to use commercially available outbred populations. Among the commercially 62 available outbred rat populations, the Sprague Dawley strain (SD) is one of the most widely used. 63SD rats are distributed by several vendors. Each vendor has multiple breeding locations, and each 64 breeding locatio...

Sprague Dawley (SD) rats are among the most widely used outbred laboratory rat populations. Despite this, the genetic characteristics of SD rats have not been clearly described, and SD rats are rarely used for experiments aimed at exploring genotype-phenotype relationships. In order to use SD rats to perform a genome-wide association study (GWAS), we collected behavioral data from 4,625 SD rats that were predominantly obtained from two commercial vendors, Charles River Laboratories and Harlan Sprague Dawley Inc. Using double-digest genotyping-by-sequencing (ddGBS), we obtained dense, high-quality genotypes at 291,438 SNPs across 4,061 rats. This genetic data allowed us to characterize the variation present in Charles River vs. Harlan SD rats. We found that the two populations are highly diverged (FST > 0.4). Furthermore, even for rats obtained from the same vendor, there was strong population structure across breeding facilities and even between rooms at the same facility. We performed multiple separate GWAS by fitting a linear mixed model that accounted for population structure and using meta-analysis to jointly analyze all cohorts. Our study examined Pavlovian conditioned approach (PavCA) behavior, which assesses the propensity for rats to attribute incentive salience to reward-associated cues. We identified 46 significant associations for the various metrics used to define PavCA. The surprising degree of population structure among SD rats from different sources has important implications for their use in both genetic and non-genetic studies.

At least ve years of adjuvant endocrine therapy (ET) is recommended for patients with hormone receptor-positive invasive breast cancer to reduce cancer recurrence risk. Up to half of patients prematurely discontinue ET, often due to musculoskeletal pain. Nociplastic pain is abnormal central nervous system pain processing without evidence of tissue or neuronal damage. This study aimed to evaluate the relationship between baseline nociplastic pain and ET discontinuation. MethodsThis was a retrospective, single center, cohort study. Included patients were female, had stage 0-III invasive breast cancer, did not receive neoadjuvant therapy, and completed quality of life questionnaires prior to breast surgery, including Fibromyalgia Survey for nociplastic pain. Clinical data including duration of ET were abstracted from the medical record. Patient characteristics were analyzed with t-tests and chisquared tests, as appropriate. Univariate and multivariable regressions were performed with Cox proportional hazard models. Results681 patients diagnosed between 2012-2019 met inclusion criteria; 480 initiated ET and were included in the analysis. Of these 480 patients, 203 (42.3%) prematurely discontinued initial ET therapy. On univariate analysis, tamoxifen use (hazard ratio [HR] 0.70, p = 0.021) and premenopausal status (HR 0.73, p = 0.04) were inversely associated with ET discontinuation, while Fibromyalgia Score was positively associated (HR 1.04, p = 0.043). On multivariable analysis, baseline Fibromyalgia Score remained associated with ET discontinuation. ConclusionNociplastic pain present prior to surgery was associated with premature ET discontinuation. Fibromyalgia Score screening may be useful for evaluating ET discontinuation risk. Treatments targeting nociplastic pain may be more effective for treating ET-emergent pain.

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Purpose At least five years of adjuvant endocrine therapy (ET) is recommended for patients with hormone receptor-positive invasive breast cancer to reduce cancer recurrence risk. Up to half of patients prematurely discontinue ET, often due to musculoskeletal pain. Nociplastic pain is abnormal central nervous system pain processing without evidence of tissue or neuronal damage. This study aimed to evaluate the relationship between baseline nociplastic pain and ET discontinuation. Methods This was a retrospective, single center, cohort study. Included patients were female, had stage 0-III invasive breast cancer, did not receive neoadjuvant therapy, and completed quality of life questionnaires prior to breast surgery, including Fibromyalgia Survey for nociplastic pain. Clinical data including duration of ET were abstracted from the medical record. Patient characteristics were analyzed with t-tests and chi-squared tests, as appropriate. Univariate and multivariable regressions were performed with Cox proportional hazard models. Results 681 patients diagnosed between 2012–2019 met inclusion criteria; 480 initiated ET and were included in the analysis. Of these 480 patients, 203 (42.3%) prematurely discontinued initial ET therapy. On univariate analysis, tamoxifen use (hazard ratio [HR] 0.70, p = 0.021) and premenopausal status (HR 0.73, p = 0.04) were inversely associated with ET discontinuation, while Fibromyalgia Score was positively associated (HR 1.04, p = 0.043). On multivariable analysis, baseline Fibromyalgia Score remained associated with ET discontinuation. Conclusion Nociplastic pain present prior to surgery was associated with premature ET discontinuation. Fibromyalgia Score screening may be useful for evaluating ET discontinuation risk. Treatments targeting nociplastic pain may be more effective for treating ET-emergent pain.