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

基本信息

  • 批准号:
    10669951
  • 负责人:
  • 金额:
    $ 82.09万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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

期刊论文数量(19)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Genomic modules and intramodular network concordance in susceptible and resilient male mice across models of stress.
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:
  • 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
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。
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:
  • 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.
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HUDA AKIL其他文献

HUDA AKIL的其他文献

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{{ truncateString('HUDA AKIL', 18)}}的其他基金

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:
    9234690
  • 财政年份:
    2017
  • 资助金额:
    $ 82.09万
  • 项目类别:
Investigating the role of Bmp4 in glial subtype specification and temperament
研究 Bmp4 在神经胶质亚型规格和气质中的作用
  • 批准号:
    10318440
  • 财政年份:
    2017
  • 资助金额:
    $ 82.09万
  • 项目类别:
Can Affective Resilience be Enhanced? A Developmental and Epigenetic Approach
情感弹性可以增强吗?
  • 批准号:
    8748818
  • 财政年份:
    2014
  • 资助金额:
    $ 82.09万
  • 项目类别:
Can Affective Resilience be Enhanced? A Developmental and Epigenetic Approach
情感弹性可以增强吗?
  • 批准号:
    9249678
  • 财政年份:
    2014
  • 资助金额:
    $ 82.09万
  • 项目类别:
ANIMAL CORE
动物核心
  • 批准号:
    7389838
  • 财政年份:
    2007
  • 资助金额:
    $ 82.09万
  • 项目类别:
Antecedents & Consequences of Drug Abuse: Heritability, Stress & Neurplasticity
来路
  • 批准号:
    7347765
  • 财政年份:
    2007
  • 资助金额:
    $ 82.09万
  • 项目类别:
Antecedents & Consequences of Drug Abuse: Heritability, Stress & Neurplasticity
来路
  • 批准号:
    7881576
  • 财政年份:
    2007
  • 资助金额:
    $ 82.09万
  • 项目类别:
FOREBRAIN OVEREXPRESSION OF A STRESS-RELATED GENE
前脑中与压力相关的基因过度表达
  • 批准号:
    7389843
  • 财政年份:
    2007
  • 资助金额:
    $ 82.09万
  • 项目类别:
ADMINISTRATIVE CORE
行政核心
  • 批准号:
    7389837
  • 财政年份:
    2007
  • 资助金额:
    $ 82.09万
  • 项目类别:
Antecedents & Consequences of Drug Abuse: Heritability, Stress & Neurplasticity
来路
  • 批准号:
    7651276
  • 财政年份:
    2007
  • 资助金额:
    $ 82.09万
  • 项目类别:

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成瘾行为中谷氨酸稳态的神经元调节
  • 批准号:
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β-抑制素对 Ghrelin 信号传导在调节成瘾行为中的调节
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  • 财政年份:
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    $ 82.09万
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食欲素和瘦素对 VTA 中进食和成瘾行为的调节
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  • 财政年份:
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  • 资助金额:
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食欲素和瘦素对 VTA 中进食和成瘾行为的调节
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  • 财政年份:
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CBP 乙酰转移酶在成瘾行为中的作用
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  • 资助金额:
    $ 82.09万
  • 项目类别:
CBP Acetyltransferase Function in Addictive Behavior
CBP 乙酰转移酶在成瘾行为中的作用
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    7290942
  • 财政年份:
    2006
  • 资助金额:
    $ 82.09万
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