Genetics of novelty seeking and propensity for drug abuse in outbred rats

近交系大鼠寻求新奇事物的遗传学和药物滥用倾向

• 批准号: 10669951
• 负责人: HUDA AKIL
• 金额: $ 82.09万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669951
• 关键词: ATAC-seq; Addictive Behavior; Address; Affect; American; Anatomy; Animal Model; Animals; Anxiety; Area; Behavior; Behavioral; Biological Assay; Biology; Brain; Brain region; Breeding; CCRL2 gene; Candidate Disease Gene; Cell Nucleus; Cells; Characteristics; Chromatin; Chronic; Cocaine; Cue-induced relapse; DNA; Disease; Drug Addiction; Drug Experimentation; Drug abuse; Emotional; Environment; Environmental Risk Factor; Esthesia; Exhibits; Female; Fluorescent in Situ Hybridization; Funding; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genomics; Genotype; Goals; Heritability; High-Throughput Nucleotide Sequencing; Hippocampus; Human; Impulsivity; Individual; Individual Differences; Intervention; Learning; Link; Locomotion; Mental Depression; Microglia; Modeling; Molecular; Neurobiology; Neurons; Neurosciences; Nucleus Accumbens; Pathway interactions; Personality Traits; Persons; Pharmaceutical Preparations; Phase; Phenotype; Play; Population; Predisposition; Psychosocial Stress; Quantitative Trait Loci; Rattus; Reaction; Recommendation; Regulation; Relapse; Research; Role; Selection Criteria; Shapes; Societies; Specificity; Sprague-Dawley Rats; Stress; Substance Use Disorder; Substance abuse problem; Techniques; Technology; Temperament; Text; Transcript; Transposase; Variant; Vulnerable Populations; addiction; anxious behavior; brain metabolism; causal variant; cell type; clinically relevant; cocaine seeking; cocaine self-administration; depressive behavior; drug of abuse; drug seeking behavior; epigenetic regulation; genetic architecture; genetic selection; genome sequencing; genome-wide; insight; male; multiple omics; neural; neural circuit; neural patterning; new technology; novel; personalized approach; pharmacologic; psychostimulant; response; stimulant abuse; stimulant use; stress reactivity; substance abuse prevention; tool; trait; transcriptome sequencing; transcriptomics; whole genome

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Substance abuse disorders (SUDs) are a major challenge to individuals and society and are caused by the interplay between genetic factors that shape vulnerability to drug addiction and environmental variables that can trigger and affect the course of these disorders. The goal of this project is to uncover the genetic and genomic mechanisms underlying the propensity for drug seeking and drug addiction. Evidence shows that the vast inter-individual differences in vulnerability to SUDs are strongly related to temperamental traits. We therefore established a unique animal model of temperament that is highly genetic and highly predictive of drug-related behaviors. We selectively bred two lines of rats based on differences in their propensity for exploratory locomotion (EL) in a mildly stressful novel environment. The bred High Responders (bHRs) and bred Low Responders (bLRs) show contrasting spectra of heritable behaviors. Compared to bLRs, bHRs exhibit higher sensation seeking and impulsivity, a greater propensity to sensitize to psychostimulants, and lower thresholds for drug- and cue-induced relapse, reminiscent of human “externalizing disorders”. The bLRs are more prone to anxious and depressive behaviors, more responsive to stress, which triggers drug-seeking behavior. Thus, the two lines model sensation seeking and high reactivity to stress as two paths to SUD. Our working hypothesis is that functional DNA variants, derived from outbred Sprague Dawley founders, account for the current neural and behavioral divergence of the two lines and are relevant to drug addiction. During the past funding period, we have identified quantitative trait loci (QTL) for EL and anxiety behaviors and have uncovered several genes and genetic pathways associated with differences in temperament. Our current goal is to increase our understanding of the genetic architecture of our two selectively bred lines and to focus on specific genes likely to shape the differential propensity for cocaine-seeking. Our Specific Aims (SA) are: SA1: Deepen our understanding of the genomic and transcriptional neural activity of the bHR-bLR lines using new technologies to characterize structural variations, chromatin accessibility and single nuclei multiomics. SA2: Characterize the differential impact of cocaine acquisition on the brains of bHRs vs. bLRs and relate the findings to genetic and genomic differences between them. Use chromatin accessibility/gene expression at the single cell level and spatial transcriptomics to define the neural impact of cocaine with cellular granularity. SA3: Identify target genes that play a key role in temperamental differences and/or the response to psychostimulants using stringent convergent criteria. We will characterize their expression and regulation by cocaine in specific cell types and brain areas implicated in addiction. This will lay the groundwork for mechanistic studies that establish their causal role in addiction and will enable future pharmacological interventions. Our discoveries will illuminate the genetic and neurobiological links between sensation seeking and psychostimulant abuse in humans and inform precision approaches to the treatment and prevention of SUDs.

在此输入文本，它是您的应用程序的新摘要信息。此部分不得超过30行文本。 物质滥用障碍(SODS)是对个人和社会的重大挑战，是由形成药物成瘾脆弱性的遗传因素和可能引发和影响这些疾病过程的环境变量之间的相互作用造成的。这个项目的目标是揭示毒品寻觅和毒瘾倾向背后的遗传和基因组机制。有证据表明，易患肥皂泡的个体间的巨大差异与气质特征密切相关。因此，我们建立了一种独特的动物气质模型，该模型高度遗传，对药物相关行为具有高度预测性。我们选择性地培育了两个品系的大鼠，基于它们在温和应激的新环境中进行探索性运动(EL)倾向的不同。繁育的高响应者(BHRS)和繁育的低响应者(BLR)表现出遗传行为的不同光谱。与bLR相比，bhr表现出更高的感觉寻求和冲动，对精神刺激物更敏感的倾向，以及更低的药物和线索诱导的复发阈值，这让人想起人类的“外化障碍”。BLRs更倾向于焦虑和抑郁的行为，对压力更敏感，这会引发寻求毒品的行为。因此，这两条线将感觉寻求和对应激的高反应性建模为通向SUD的两条途径。我们的工作假设是，源自远缘繁殖的SpragueDawley创始人的功能性DNA变体解释了这两个品系目前的神经和行为差异，并与药物成瘾有关。在过去的资助期间，我们已经确定了与情绪障碍和焦虑行为有关的数量性状基因座(QTL)，并发现了几个与气质差异有关的基因和遗传途径。我们目前的目标是增加我们对我们两个选择性培育的品系的遗传结构的理解，并专注于可能形成不同的可卡因寻求倾向的特定基因。我们的具体目标(SA)是： SA1：利用新技术表征结构变异、染色质可及性和单核多组学，加深我们对BHR-BLR系基因组和转录神经活性的理解。 SA2：描述可卡因获取对BHRS和bLR大脑的不同影响，并将这些发现与它们之间的遗传和基因组差异联系起来。使用染色质可及性/基因在单细胞水平的表达和空间转录来定义可卡因对细胞粒度的神经影响。 SA3：使用严格的趋同标准确定在气质差异和/或对精神刺激的反应中起关键作用的目标基因。我们将描述它们在特定细胞类型和与成瘾有关的脑区的可卡因表达和调节的特征。这将为建立它们在成瘾中的因果作用的机制研究奠定基础，并将使未来的药理学干预成为可能。 我们的发现将阐明人类感觉寻求和精神刺激剂滥用之间的遗传和神经生物学联系，并为肥皂症的治疗和预防提供精确的方法。

项目成果

Genomic modules and intramodular network concordance in susceptible and resilient male mice across models of stress.

• DOI: 10.1038/s41386-021-01219-8
• 发表时间: 2022-04
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: Caradonna SG;Zhang TY;O'Toole N;Shen MJ;Khalil H;Einhorn NR;Wen X;Parent C;Lee FS;Akil H;Meaney MJ;McEwen BS;Marrocco J
• 通讯作者: Marrocco J

Adolescent cocaine differentially impacts psychomotor sensitization and epigenetic profiles in adult male rats with divergent affective phenotypes.

• DOI: 10.3389/fpsyt.2022.1024617
• 发表时间: 2022
• 期刊: FRONTIERS IN PSYCHIATRY
• 影响因子: 4.7
• 作者: Parsegian, Aram;Garcia-Fuster, M. Julia;Hebda-Bauer, Elaine;Watson, Stanley. J. J.;Flagel, Shelly. B. B.;Akil, Huda
• 通讯作者: Akil, Huda

Genome-wide association study in a rat model of temperament identifies multiple loci for exploratory locomotion and anxiety-like traits.

• DOI: 10.3389/fgene.2022.1003074
• 发表时间: 2022
• 期刊: Frontiers in genetics
• 影响因子: 3.7

Exploratory locomotion, a predictor of addiction vulnerability, is oligogenic in rats selected for this phenotype.

探索性运动是成瘾脆弱性的预测因子，在选择这种表型的大鼠中是寡基因的。

• DOI: 10.1073/pnas.1820410116
• 发表时间: 2019
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Zhou,Zhifeng;Blandino,Peter;Yuan,Qiaoping;Shen,Pei-Hong;Hodgkinson,ColinA;Virkkunen,Matti;Watson,StanleyJ;Akil,Huda;Goldman,David
• 通讯作者: Goldman,David

Differences in microglia morphological profiles reflect divergent emotional temperaments: insights from a selective breeding model.

• DOI: 10.1038/s41398-022-01821-4
• 发表时间: 2022-03-15
• 期刊: Translational psychiatry
• 影响因子: 6.8
• 作者: Maras PM;Hebda-Bauer EK;Hagenauer MH;Hilde KL;Blandino P Jr;Watson SJ Jr;Akil H
• 通讯作者: Akil H