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.

在这里输入文本，即应用程序的新抽象信息。这部分的文本不能超过30行。

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

Neurotransmission-related gene expression in the frontal pole is altered in subjects with bipolar disorder and schizophrenia.

• DOI: 10.1038/s41398-023-02418-1
• 发表时间: 2023-04-08
• 期刊: TRANSLATIONAL PSYCHIATRY
• 影响因子: 6.8
• 作者: Medina, Adriana M.;Hagenauer, Megan Hastings;Krolewski, David M.;Hughes, Evan;Forrester, Liam Cannon Thew;Walsh, David M.;Waselus, Maria;Richardson, Evelyn;Turner, Cortney A.;Sequeira, P. Adolfo;Cartagena, Preston M.;Thompson, Robert C.;Vawter, Marquis P.;Bunney, Blynn G.;Myers, Richard M.;Barchas, Jack D.;Lee, Francis S.;Schatzberg, Alan F.;Bunney, William E.;Akil, Huda;Watson, Stanley J., Jr.
• 通讯作者: Watson, Stanley J., Jr.