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
• 负责人: HUDA AKIL
• 金额: $ 8.84万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318440
• 关键词: Addictive Behavior; Address; Adult; Affect; American; Animals; Anxiety; Astrocytes; Award; Behavior; Behavioral; Behavioral Model; Behavioral inhibition; Biology; Brain; Breeding; Candidate Disease Gene; Cell Lineage; Chronic; Cocaine; Complex; Corpus Callosum; Development; Disease; Drug usage; Emotional; Equilibrium; Event; Female; Follow-Up Studies; Future; Gene Expression; Generations; Genes; Genetic; Goals; Healthcare Systems; Heroin; Hippocampus (Brain); Histologic; Human; Impulsivity; Inherited; Investigation; Laboratories; Life; Literature; Locomotion; Longevity; Maps; Mediating; Methamphetamine; Modeling; Mood Disorders; Motivation; Nervous system structure; Neurobiology; Neurosciences; Novelty-Seeking Behaviors; Oligodendroglia; Parents; Pattern; Persons; Pharmaceutical Preparations; Phenotype; Prevention strategy; Psychosocial Stress; Rattus; Relapse; Reproducibility; Research Project Grants; Rewards; Risk; Rodent Model; Role; Scientist; Self Administration; Shapes; Simplexvirus; Substance Use Disorder; Substance abuse problem; Talents; Techniques; Temperament; Testing; Viral; Work; addiction; alcohol response; behavioral phenotyping; behavioral response; bone morphogenetic protein 4; cell type; clinically relevant; cost; depressive behavior; depressive symptoms; differential expression; drug of abuse; drug relapse; drug seeking behavior; experimental study; family burden; gene environment interaction; genetic manipulation; genetic variant; indexing; innovation; insight; interest; male; nervous system development; neurogenesis; neuromechanism; novel; oligodendrocyte lineage; oligodendrocyte precursor; overexpression; postnatal; precursor cell; predictive modeling; psychostimulant; response; social stress; training opportunity; trait; treatment strategy

Substance use disorders (SUDs) are debilitating disorders that have a major personal and societal impact. Both prevention and treatment strategies require a better understanding of neurobiological and behavioral traits that predispose for drug taking as well as risk of addiction. Our laboratory has selectively bred rats for over 60 generations in order to select for particular behavioral traits, ultimately generating a robust behavioral model of emotional reactivity and addiction liability. Bred high responder (bHR) and bred low responder (bLR) animals represent extreme ends of emotional reactivity: bHR animals represent an externalizing phenotype, with low behavioral inhibition and high levels of impulsivity and drug-seeking behavior. bLR animals represent an internalizing phenotype, are behaviorally inhibited, with a high level of anxiety- and depressive-like behaviors, but less prone to drug seeking and relapse. Importantly the reproducibility of behavioral traits across generations allows for a predictive model and the investigation of developmental mechanisms that contribute to adult behavior. A major goal of the parent award (U01) is to understand the genetic basis of temperamental tendencies that predispose for addictive behaviors. In recent years, our lab has characterized genetic variants as well as hippocampal gene expression changes that arise early in development in the bHR/bLR model and strongly discriminate between the lines. A top candidate gene in development is the Bone Morphogenetic Protein 4 (Bmp4), which has well- established roles in patterning the developing nervous system, neurogenesis, and importantly, in specification of astrocytes and oligodendrocyte number during development. It is currently unknown whether glial specification and postnatal Bmp4 expression are important for shaping temperament and behavior. In this application we propose to study the role of Bmp4 in glial subtype specification and behavioral responses within the bHR/bLR model. We hypothesize that differences in Bmp4 arise early in development and contribute to a diverging glial phenotype in which the generation of oligodendrocytes and astrocytes is modified, and that differences in cell types, in turn, contribute to differences in temperament. This hypothesis will be tested using a combination of histological, viral, and behavioral approaches. This work has the potential to reveal a novel mechanism by which the developing hippocampus is patterned in the early postnatal window, and point to a new role for glial subtypes in shaping vulnerability to addictive and affective disorders.

物质使用障碍（SUD）是一种使人衰弱的疾病， 社会影响。预防和治疗战略都需要更好地了解 神经生物学和行为特征，使人易于吸毒以及成瘾的风险。 我们的实验室已经选择性饲养了60多代大鼠，以便进行特定的选择 行为特征，最终产生一个强大的情绪反应行为模型， 成瘾倾向繁殖的高应答（bHR）和繁殖的低应答（bLR）动物代表 情绪反应的极端：bHR动物代表一种外化表型， 低行为抑制和高水平的冲动和寻求毒品的行为。bLR动物 代表一种内在化的表型，行为受到抑制，具有高水平的焦虑， 类似抑郁的行为，但不太容易吸毒和复发。重要的是 行为特征在世代间的再现性允许预测模型， 研究对成人行为有贡献的发育机制。 父母奖（U 01）的一个主要目标是了解气质的遗传基础。 容易上瘾的倾向近年来，我们的实验室 遗传变异以及海马基因表达的变化， 在bHR/bLR模型中的发展，并强烈区分线之间。顶部 发育中的候选基因是骨形态发生蛋白4（Bmp 4），它具有良好的 在发育中的神经系统、神经发生的模式化中发挥作用，重要的是， 在发育过程中星形胶质细胞和少突胶质细胞数量的规格。目前 尚不清楚胶质细胞的特化和出生后Bmp 4的表达是否对形成 气质和行为。 在本申请中，我们提出研究Bmp 4在胶质细胞亚型特化中的作用， bHR/bLR模型中的行为反应。我们假设Bmp 4的差异 在发育早期出现，并导致分化的神经胶质表型， 少突胶质细胞和星形胶质细胞的基因被修饰，而细胞类型的差异，反过来， 导致了气质的差异该假设将使用以下组合进行检验： 组织学、病毒学和行为学方法。这项工作有可能揭示一部小说 发育中的海马在出生后早期窗口形成模式的机制， 并指出神经胶质细胞亚型在形成成瘾和情感脆弱性方面的新作用 紊乱