Network-Based Discovery of Opioid Use Vulnerability in Rats Using the Bayesian Stochastic Block Model

Allen, Carter; Kuhn, Brittany N; Cannella, Nazzareno; Crow, Ayteria D; Roberts, Analyse T.; Lunerti, Veronica; Ubaldi, Massimo; Hardiman, Gary; Woods, Leah C. Solberg; Ciccocioppo, Roberto; Kalivas, Peter W.; Chung, Dongjun

doi:10.3389/fpsyt.2021.745468

Cited by 6 publications

(8 citation statements)

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“…Behaviors include: escalation of intake: hour 1-12, consumption, break point, extinction burst, extinction day 6, prime reinstatement and cued reinstatement (ST1). The parameters as well as behavioral and neurobiological validation of this model are extensively detailed in prior publications [24, 29]. OUD phenotype cluster composition for top SNP coding variants were assessed with a Chi-square test.…”

Section: Methodsmentioning

confidence: 99%

“…Behavioral clustering: To assess if GWAS results were associated with OUD vulnerability versus resiliency, behavior across the different OUD phases (taking, refraining and seeking) were assessed using a non-linear network-based clustering approach [29] with rats were characterized as OUD vulnerable, intermediate or resilient. Behaviors include: escalation of intake: hour 1-12, consumption, break point, extinction burst, extinction day 6, prime reinstatement and cued reinstatement (ST1).…”

Section: Statistical Analysesmentioning

confidence: 99%

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Genome-wide association study reveals multiple loci for nociception and opioid consumption behaviors associated with heroin vulnerability in outbred rats

Kuhn,

Cannella,

Chitre

et al. 2024

Preprint

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The increased prevalence of opioid use disorder (OUD) world-wide has made it imperative to disentangle the biological mechanisms contributing to OUD propensity. OUD shows strong heritability, however genetic variants contributing toward vulnerability remain under explored. In the current study, genome-wide association (GWAS) analysis on over 850 male and female heterogeneous stock rats were performed to identify genes underlying heroin-taking, refraining and seeking behaviors. By using an animal model of OUD, we were able to identify genetic variants associated with distinct behaviors contributing to OUD, an experimental design not easily achieved in human GWAS analysis, and not performed to date for OUD GWAS studies. Our findings show, akin to the human population, several heritable traits related with OUD. We also identified genetic variants associated with heroin consumption, escalation of intake, motivation to obtain heroin, and basal levels of analgesic threshold prior to heroin experience, which was behaviorally unrelated to the heroin behaviors. Several of the genes identified are known biomarkers of other substance use disorders and mediators of neurobiological mechanisms underlying addiction-related behaviors. These findings emphasize the need to assess the role of these genetic variants in OUD, thereby augmenting our understanding of risk factors and neurobiological processes associated with OUD vulnerability.

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Section: Methodsmentioning

confidence: 99%

Section: Statistical Analysesmentioning

confidence: 99%

Genome-wide association study reveals multiple loci for nociception and opioid consumption behaviors associated with heroin vulnerability in outbred rats

Kuhn,

Cannella,

Chitre

et al. 2024

Preprint

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“…Sexes were then analyzed as independent groups for all subsequent analyses. We previously described a nonlinear network-based clustering analysis (9) and provided an R package 'mlsbm' (5). A rat-rat similarity network was constructed from the standardized data to assess behavioral similarities between rats, and then a Bayesian stochastic block model (SBM) was applied to define clusters within the data set.…”

Section: Statistical Analysesmentioning

confidence: 99%

A multi-symptomatic model of heroin use disorder in rats reveals distinct behavioral profiles and neuronal correlates of heroin vulnerability versus resiliency

Kuhn,

Cannella,

Crow

et al. 2024

Preprint

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ObjectiveThe behavioral and diagnostic heterogeneity within human opioid use disorder (OUD) diagnosis is not readily captured in current animal models, limiting translational relevance of the mechanistic research that is conducted in experimental animals. We hypothesize that a non-linear clustering of OUD-like behavioral traits will capture population heterogeneity and yield subpopulations of OUD vulnerable rats with distinct behavioral and neurocircuit profiles.MethodsOver 900 male and female heterogeneous stock rats, a line capturing genetic and behavioral heterogeneity present in humans, were assessed for several measures of heroin use and rewarded and non-rewarded seeking behaviors. Using a non-linear stochastic block model clustering analysis, rats were assigned to OUD vulnerable, intermediate and resilient clusters. Additional behavioral tests and circuit analyses using c-fos activation were conducted on the vulnerable and resilient subpopulations.ResultsOUD vulnerable rats exhibited greater heroin taking and seeking behaviors relative to those in the intermediate and resilient clusters. Akin to human OUD diagnosis, further vulnerable rat sub- clustering revealed subpopulations with different combinations of behavioral traits, including sex differences. Lastly, heroin cue-induced neuronal patterns of circuit activation differed between resilient and vulnerable phenotypes. Behavioral sex differences were recapitulated in patterns of circuitry activation, including males preferentially engaging extended amygdala stress circuitry, and females cortico-striatal drug cue-seeking circuitry.ConclusionUsing a non-linear clustering approach in rats, we captured behavioral diagnostic heterogeneity reflective of human OUD diagnosis. OUD vulnerability and resiliency were associated with distinct neuronal activation patterns, posing this approach as a translational tool in assessing neurobiological mechanisms underpinning OUD.

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“…Combining hundreds of animals’ genetic data can thus feed a subsequent GWAS to identify gene variants contributing to a phenotype of interest. Moreover, using a new multidimensional data clustering strategy of large-scale data sets across different study sites can now be used to identify specific behavioral domains for disease vulnerability or resilience in rats ( Allen et al, 2021 ). Therefore, it is recommended to use HS rats in confirmatory preclinical multi-site studies to mimic the human situation and provide additional genetic information under well-controlled environmental conditions.…”

Section: What Can Be Done To Improve Reproducibility In Animal Experi...mentioning

confidence: 99%

Ten Points to Improve Reproducibility and Translation of Animal Research

Spanagel

2022

Front. Behav. Neurosci.

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Findings from animal experiments are often difficult to transfer to humans. In this perspective article I discuss two questions. First, why are the results of animal experiments often so difficult to transfer to humans? And second, what can be done to improve translation from animal experiments to humans? Translation failures are often the result of poor methodology. It is not merely the fact that low statistical power of basic and preclinical studies undermine a “real effect,” but the accuracy with which data from animal studies are collected and described, and the resulting robustness of the data is generally very low and often does not allow translation to a much more heterogeneous human condition. Equally important is the fact that the vast majority of publications in the biomedical field in the last few decades have reported positive findings and have thus generated a knowledge bias. Further contributions to reproducibility and translation failures are discussed in this paper, and 10 points of recommendation to improve reproducibility and translation are outlined. These recommendations are: (i) prior to planning an actual study, a systematic review or potential preclinical meta-analysis should be considered. (ii) An a priori power calculation should be carried out. (iii) The experimental study protocol should be pre-registered. (iv) The execution of the study should be in accordance with the most recent ARRIVE guidelines. (v) When planning the study, the generalizability of the data to be collected should also be considered (e.g., sex or age differences). (vi) “Method-hopping” should be avoided, meaning that it is not necessary to use the most advanced technology but rather to have the applied methodology under control. (vii) National or international networks should be considered to carry out multicenter preclinical studies or to obtain convergent evidence. (viii) Animal models that capture DSM-5 or ICD-11 criteria should be considered in the context of research on psychiatric disorders. (ix) Raw data of publication should be made publicly available and should be in accordance with the FAIR Guiding Principles for scientific data management. (x) Finally, negative findings should be published to counteract publication bias. The application of these 10 points of recommendation, especially for preclinical confirmatory studies but also to some degree for exploratory studies, will ultimately improve the reproducibility and translation of animal research.

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Network-Based Discovery of Opioid Use Vulnerability in Rats Using the Bayesian Stochastic Block Model

Cited by 6 publications

References 27 publications

Genome-wide association study reveals multiple loci for nociception and opioid consumption behaviors associated with heroin vulnerability in outbred rats

Genome-wide association study reveals multiple loci for nociception and opioid consumption behaviors associated with heroin vulnerability in outbred rats

A multi-symptomatic model of heroin use disorder in rats reveals distinct behavioral profiles and neuronal correlates of heroin vulnerability versus resiliency

Ten Points to Improve Reproducibility and Translation of Animal Research

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