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：
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
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

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

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.

在此输入您的申请的新摘要信息的文本。此部分的文本长度不得超过 30 行。药物滥用障碍 (SUD) 是对个人和社会的重大挑战，是由导致药物成瘾脆弱性的遗传因素与可能引发和影响这些疾病进程的环境变量之间的相互作用引起的。该项目的目标是。揭示药物寻求和药物成瘾倾向的遗传和基因组机制有证据表明，个体间对 SUD 的脆弱性与气质特征有关，因此我们建立了一种具有高度遗传性和高度遗传性的独特气质动物模型。预测性的我们根据两只老鼠在轻度压力的新环境中探索性运动（EL）倾向的差异，选择性地培育它们，培育出的高反应者（bHR）和低反应者（bLR）表现出对比的谱系。与 bLR 相比，bHR 表现出更高的感觉寻求和冲动性，对精神兴奋剂更敏感，并且对药物的阈值更低。和提示诱发的复发，让人想起人类的“外化障碍”，bLR 更容易出现焦虑和抑郁行为，对压力更敏感，从而引发寻求药物的行为，因此，这两条线模拟了感觉寻求和对压力的高反应性。作为通向 SUD 的两条途径，我们的工作假设是，来自远亲繁殖的 Sprague Dawley 创始人的功能性 DNA 变异解释了这两条线路目前的神经和行为差异，并且与药物成瘾有关。已经确定了 EL 和焦虑行为的数量性状位点 (QTL)，并发现了与气质差异相关的几个基因和遗传途径。我们当前的目标是增加我们对两个选择性育种品系的遗传结构的理解，并专注于特定的遗传结构。可能影响可卡因寻求差异倾向的基因是： SA1：使用新技术来表征结构变异、染色质可及性和单核多组学，加深我们对 bHR-bLR 系的基因组和转录神经活性的理解。 SA2：描述可卡因获取对 bHR 与 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。使用单细胞水平的染色质可及性/基因表达和空间转录组学来定义可卡因的神经影响。具有细胞粒度。 SA3：使用严格的趋同标准来识别在气质差异和/或对精神兴奋剂的反应中发挥关键作用的目标基因，我们将表征可卡因在与成瘾有关的特定细胞类型和大脑区域中的表达和调节。进行机制研究，确定其在成瘾中的因果作用，并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与精神兴奋剂滥用之间的遗传和神经生物学联系，并为治疗和预防 SUD 的精确方法提供信息。

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）

Forebrain Glucocorticoid Receptor Overexpression Alters Behavioral Encoding of Hippocampal CA1 Pyramidal Cells in Mice.

前脑糖皮质激素受体过度表达改变小鼠海马 CA1 锥体细胞的行为编码。

DOI：
发表时间：
2022-11
期刊：
影响因子：
3.4
作者：
Gavade S;Wei Q;Johnston C;Kounelis-Wuillaume S;Laborc K;Baranwal S;Akil H;Spencer-Segal JL
通讯作者：
Spencer-Segal JL

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

青少年可卡因对具有不同情感表型的成年雄性大鼠的精神运动敏化和表观遗传特征有不同的影响。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Parsegian, Aram;García;Hebda;Watson, Stanley J;Flagel, Shelly B;Akil, Huda
通讯作者：
Akil, Huda

Corticosteroid Treatment During Sepsis Alters Hippocampal Function in Male and Female Survivors.

脓毒症期间的皮质类固醇治疗会改变男性和女性幸存者的海马功能。

DOI：
发表时间：
2024-01
期刊：
影响因子：
0
作者：
Hill, Alice;Khalil, Huzefa;Laborc, Klaudia;Kounelis;Gavade, Swapnil;Johnston, Colin;Singer, Benjamin H;Spencer
通讯作者：
Spencer

Neural cell adhesion molecule peptide mimetics modulate emotionality: pharmacokinetic and behavioral studies in rats and non-human primates.

神经细胞粘附分子肽模拟物调节情绪：大鼠和非人类灵长类动物的药代动力学和行为研究。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Turner, Cortney A;Lyons, David M;Buckmaster, Christine L;Aurbach, Elyse L;Watson, Stanley J;Schatzberg, Alan F;Akil, Huda
通讯作者：
Akil, Huda

Extended regions of suspected mis-assembly in the rat reference genome.

大鼠参考基因组中疑似错误组装的扩展区域。

DOI：
发表时间：
2019
期刊：
影响因子：
9.8
作者：
Ramdas, Shweta;Ozel, Ayse Bilge;Treutelaar, Mary K;Holl, Katie;Mandel, Myrna;Woods, Leah C Solberg;Li, Jun Z
通讯作者：
Li, Jun Z