Publications by authors named "Apurva Chitre"

9 Publications

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Integration of Evidence across Human and Model Organism Studies: A Meeting Report.

Genes Brain Behav 2021 Apr 23:e12738. Epub 2021 Apr 23.

The Jackson Laboratory, Bar Harbor, ME, USA.

The National Institute on Drug Abuse and Joint Institute for Biological Sciences at the Oak Ridge National Laboratory hosted a meeting attended by a diverse group of scientists with expertise in substance use disorders (SUDs), computational biology, and FAIR (Findability, Accessibility, Interoperability, and Reusability) data sharing. The meeting's objective was to discuss and evaluate better strategies to integrate genetic, epigenetic, and 'omics data across human and model organisms to achieve deeper mechanistic insight into SUDs. Specific topics were to (a) evaluate the current state of substance use genetics and genomics research and fundamental gaps, (b) identify opportunities and challenges of integration and sharing across species and data types, (c) identify current tools and resources for integration of genetic, epigenetic, and phenotypic data, (d) discuss steps and impediment related to data integration, and (e) outline future steps to support more effective collaboration-particularly between animal model research communities and human genetics and clinical research teams. This review summarizes key facets of this catalytic discussion with a focus on new opportunities and gaps in resources and knowledge on SUDs.
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http://dx.doi.org/10.1111/gbb.12738DOI Listing
April 2021

The cocaine and oxycodone biobanks, two repositories from genetically diverse and behaviorally characterized rats for the study of addiction.

eNeuro 2021 Apr 15. Epub 2021 Apr 15.

Department of Psychiatry, University of California, San Diego, La Jolla CA 92093, USA

Substance use disorders are pervasive in our society and have substantial personal and socio-economical costs. A critical hurdle in identifying biomarkers and novel targets for medication development is the lack of resources for obtaining biological samples with a detailed behavioral characterization of substance use disorder. Moreover, it is nearly impossible to find longitudinal samples. As part of two ongoing large-scale behavioral genetic studies in heterogeneous stock (HS) rats, we have created two preclinical biobanks using well-validated long access models of intravenous cocaine and oxycodone self-administration and comprehensive characterization of addiction-related behaviors. The genetic diversity in HS rats mimics diversity in the human population and includes individuals that are vulnerable or resilient to compulsive-like responding for cocaine or oxycodone. Longitudinal samples are collected throughout the experiment, before exposure to the drug, during intoxication, acute withdrawal, and protracted abstinence, and include naive, age-matched controls. Samples include, but are not limited to, blood plasma, feces and urine, whole brains, brain slices and punches, kidney, liver, spleen, ovary, testis, and adrenal glands. Three preservation methods (fixed in formaldehyde, snap-frozen, or cryopreserved) are used to facilitate diverse downstream applications such as proteomics, metabolomics, transcriptomics, epigenomics, microbiomics, neuroanatomy, biomarker discovery, and other cellular and molecular approaches. To date, >20,000 samples have been collected from over 1000 unique animals and made available free of charge to non-profit institutions through https://www.cocainebiobank.org/ and https://www.oxycodonebiobank.org/The cocaine and oxycodone biobanks offer genetically and behaviorally characterized, longitudinally, and cross-sectionally diverse samples to researchers free of charge. Through this resource, we want to make these valuable samples available to researchers who may not have the equipment or expertise to perform behavioral experiments but can make valuable contributions to the addiction field and facilitate the identification of biomarkers and the development of novel, effective therapies for substance use disorders.
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http://dx.doi.org/10.1523/ENEURO.0033-21.2021DOI Listing
April 2021

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

Sci Rep 2021 Jan 26;11(1):2223. Epub 2021 Jan 26.

Behavioral Neuroscience Program, Department of Psychology, University At Buffalo, Park Hall B72, Buffalo, NY, 14260, USA.

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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http://dx.doi.org/10.1038/s41598-020-80798-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838206PMC
January 2021

Genome-Wide Association Study in 3,173 Outbred Rats Identifies Multiple Loci for Body Weight, Adiposity, and Fasting Glucose.

Obesity (Silver Spring) 2020 10 29;28(10):1964-1973. Epub 2020 Aug 29.

Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

Objective: Obesity is influenced by genetic and environmental factors. Despite the success of human genome-wide association studies, the specific genes that confer obesity remain largely unknown. The objective of this study was to use outbred rats to identify the genetic loci underlying obesity and related morphometric and metabolic traits.

Methods: This study measured obesity-relevant traits, including body weight, body length, BMI, fasting glucose, and retroperitoneal, epididymal, and parametrial fat pad weight in 3,173 male and female adult N/NIH heterogeneous stock (HS) rats across three institutions, providing data for the largest rat genome-wide association study to date. Genetic loci were identified using a linear mixed model to account for the complex family relationships of the HS and using covariates to account for differences among the three phenotyping centers.

Results: This study identified 32 independent loci, several of which contained only a single gene (e.g., Epha5, Nrg1, Klhl14) or obvious candidate genes (e.g., Adcy3, Prlhr). There were strong phenotypic and genetic correlations among obesity-related traits, and there was extensive pleiotropy at individual loci.

Conclusions: This study demonstrates the utility of HS rats for investigating the genetics of obesity-related traits across institutions and identify several candidate genes for future functional testing.
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http://dx.doi.org/10.1002/oby.22927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511439PMC
October 2020

Sex-dependent associations between addiction-related behaviors and the microbiome in outbred rats.

EBioMedicine 2020 May 8;55:102769. Epub 2020 May 8.

APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Room 2.33, 2nd Floor, Western Gateway Building, Cork, Ireland. Electronic address:

Background: Multiple factors contribute to the etiology of addiction, including genetics, sex, and a number of addiction-related behavioral traits. One behavioral trait where individuals assign incentive salience to food stimuli ("sign-trackers", ST) are more impulsive compared to those that do not ("goal-trackers", GT), as well as more sensitive to drugs and drug stimuli. Furthermore, this GT/ST phenotype predicts differences in other behavioral measures. Recent studies have implicated the gut microbiota as a key regulator of brain and behavior, and have shown that many microbiota-associated changes occur in a sex-dependent manner. However, few studies have examined how the microbiome might influence addiction-related behaviors. To this end, we sought to determine if gut microbiome composition was correlated with addiction-related behaviors determined by the GT/ST phenotype.

Methods: Outbred male (N=101) and female (N=101) heterogeneous stock rats underwent a series of behavioral tests measuring impulsivity, attention, reward-learning, incentive salience, and locomotor response. Cecal microbiome composition was estimated using 16S rRNA gene amplicon sequencing. Behavior and microbiome were characterized and correlated with behavioral phenotypes. Robust sex differences were observed in both behavior and microbiome; further analyses were conducted within sex using the pre-established goal/sign-tracking (GT/ST) phenotype and partial least squares differential analysis (PLS-DA) clustered behavioral phenotype.

Results: Overall microbiome composition was not associated to the GT/ST phenotype. However, microbial alpha diversity was significantly decreased in female STs. On the other hand, a measure of impulsivity had many significant correlations to microbiome in both males and females. Several measures of impulsivity were correlated with the genus Barnesiella in females. Female STs had notable correlations between microbiome and attentional deficient. In both males and females, many measures were correlated with the bacterial families Ruminocococcaceae and Lachnospiraceae.

Conclusions: These data demonstrate correlations between several addiction-related behaviors and the microbiome specific to sex.
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http://dx.doi.org/10.1016/j.ebiom.2020.102769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218262PMC
May 2020

Adapting Genotyping-by-Sequencing and Variant Calling for Heterogeneous Stock Rats.

G3 (Bethesda) 2020 07 7;10(7):2195-2205. Epub 2020 Jul 7.

Department of Psychiatry,

The heterogeneous stock (HS) is an outbred rat population derived from eight inbred rat strains. HS rats are ideally suited for genome wide association studies; however, only a few genotyping microarrays have ever been designed for rats and none of them are currently in production. To address the need for an efficient and cost effective method of genotyping HS rats, we have adapted genotype-by-sequencing (GBS) to obtain genotype information at large numbers of single nucleotide polymorphisms (SNPs). In this paper, we have outlined the laboratory and computational steps we took to optimize double digest genotype-by-sequencing (ddGBS) for use in rats. We evaluated multiple existing computational tools and explain the workflow we have used to call and impute over 3.7 million SNPs. We have also compared various rat genetic maps, which are necessary for imputation, including a recently developed map specific to the HS. Using our approach, we obtained concordance rates of 99% with data obtained using data from a genotyping array. The principles and computational pipeline that we describe could easily be adapted for use in other species for which reliable reference genome sets are available.
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http://dx.doi.org/10.1534/g3.120.401325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341140PMC
July 2020

Genome-Wide Association Study in Two Cohorts from a Multi-generational Mouse Advanced Intercross Line Highlights the Difficulty of Replication Due to Study-Specific Heterogeneity.

G3 (Bethesda) 2020 03 5;10(3):951-965. Epub 2020 Mar 5.

Department of Psychiatry,

There has been extensive discussion of the "Replication Crisis" in many fields, including genome-wide association studies (). We explored replication in a mouse model using an advanced intercross line (), which is a multigenerational intercross between two inbred strains. We re-genotyped a previously published cohort of LG/J x SM/J AIL mice (F; n = 428) using a denser marker set and genotyped a new cohort of AIL mice (F; n = 600) for the first time. We identified 36 novel genome-wide significant loci in the F and 25 novel loci in the F cohort. The subset of traits that were measured in both cohorts (locomotor activity, body weight, and coat color) showed high genetic correlations, although the SNP heritabilities were slightly lower in the F cohort. For this subset of traits, we attempted to replicate loci identified in either F or F in the other cohort. Coat color was robustly replicated; locomotor activity and body weight were only partially replicated, which was inconsistent with our power simulations. We used a random effects model to show that the partial replications could not be explained by Winner's Curse but could be explained by study-specific heterogeneity. Despite this heterogeneity, we performed a mega-analysis by combining F and F cohorts (n = 1,028), which identified four novel loci associated with locomotor activity and body weight. These results illustrate that even with the high degree of genetic and environmental control possible in our experimental system, replication was hindered by study-specific heterogeneity, which has broad implications for ongoing concerns about reproducibility.
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http://dx.doi.org/10.1534/g3.119.400763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056977PMC
March 2020

Social and anxiety-like behaviors contribute to nicotine self-administration in adolescent outbred rats.

Sci Rep 2018 12 24;8(1):18069. Epub 2018 Dec 24.

Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN, 38103, USA.

Both emotional and social traits interact with genetic factors to influence smoking behavior. We previously established a socially acquired nicotine intravenous self-administration model where social learning of a nicotine-associated odor cue reversed conditioned flavor aversion and promoted nicotine intake. In this study, we first phenotyped ~800 adolescent heterogeneous stock rats in open field, novel object interaction, social interaction, elevated plus maze, and marble burying behaviors. These rats were then phenotyped on socially acquired nicotine self-administration. We found 243 significant correlations between different behavioral tests. Principal component regression analysis found that ~10-20% of the variance in nicotine-related measures, such as intake during the first or the last three fixed-ratio sessions, the progressive ratio session, and reinstatement behavior, can be explained by variations in behavioral traits. Factors corresponding to social behavior and anxiety were among the strongest predictors of nicotine intake and reinstatement of nicotine-seeking behavior. We also found many sex differences in behavioral measures. These data indicated that the genetic diversity of this population, in combination with social behaviour and anxiety, are significant contributors to the divergent nicotine self-administration behavior and indicated a high probability of discovering sex-specific genetic mechanisms for nicotine intake in future genome-wide association studies.
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http://dx.doi.org/10.1038/s41598-018-36263-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305389PMC
December 2018

Clear cell papillary renal cell carcinoma: micro-RNA expression profiling and comparison with clear cell renal cell carcinoma and papillary renal cell carcinoma.

Hum Pathol 2014 Jun 31;45(6):1130-8. Epub 2014 Jan 31.

Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Urology, Johns Hopkins University, Baltimore, MD 21287, USA. Electronic address:

Clear cell papillary renal cell carcinoma (CCPRCC) is a low-grade renal neoplasm with morphological characteristics mimicking both clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma (PRCC). However, despite some overlapping features, their morphological, immunohistochemical, and molecular profiles are distinct. Micro-RNAs (miRNAs) are small noncoding RNAs that play a crucial role in regulating gene expression and are involved in various biological processes, including cancer development. To better understand the biology of this tumor, we aimed to analyze the miRNA expression profile of a set of CCPRCC using microarray and quantitative reverse transcription-polymerase chain reaction. A total of 15 cases diagnosed as CCPRCC were used in this study. Among the most differentially expressed miRNA in CCPRCC, we found miR-210, miR-122, miR-34a, miR-21, miR-34b*, and miR-489 to be up-regulated, whereas miR-4284, miR-1202, miR-135a, miR-1973, and miR-204 were down-regulated compared with normal renal parenchyma. To identify consensus of differentially regulated miRNA between CCPRCC, CCRCC, and PRCC, we additionally determined differential miRNA expression using 2 publically available microarray data sets from the NCBI Gene Expression Omnibus database (GSE41282 and GSE3798). This comparison revealed that the miRNA expression profile of CCPRCC shows some overlapping characteristics between CCRCC and PRCC. Moreover, CCPRCC lacks dysregulation of important miRNAs typically associated with aggressive behavior. In summary, we describe the miRNA expression profile of a relatively infrequent type of renal cancer. Our results may help in understanding the molecular underpinning of this newly recognized entity.
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http://dx.doi.org/10.1016/j.humpath.2014.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4332813PMC
June 2014