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

基本信息

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
项目类别：
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

项目摘要

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，对个人和身体造成重大影响。社会影响。预防和治疗策略都需要更好地了解容易吸毒以及成瘾风险的神经生物学和行为特征。我们的实验室已经选择性地饲养了60多代的老鼠，以选择特定的老鼠。行为特征，最终生成一个强大的情绪反应行为模型成瘾责任。繁殖的高反应（bHR）和繁殖的低反应（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药物行为。 bLR动物代表一种内化表型，行为受到抑制，具有高度的焦虑和类似抑郁的行为，但不太容易寻求药物和复发。重要的是跨代行为特征的可重复性允许预测模型和研究有助于成人行为的发育机制。家长奖（U01）的一个主要目标是了解气质的遗传基础容易产生成瘾行为的倾向。近年来，我们实验室的特点是早期出现的遗传变异以及海马基因表达变化 bHR/bLR 模型的发展和线之间的强烈区分。一件上衣正在发育的候选基因是骨形态发生蛋白 4 (Bmp4)，它具有良好的在神经系统发育、神经发生的模式中确立了作用，而且重要的是，发育过程中星形胶质细胞和少突胶质细胞数量的规范。目前是未知胶质细胞规范和出生后 Bmp4 表达是否对塑造很重要气质和行为。在本申请中，我们建议研究 Bmp4 在神经胶质亚型规范中的作用和 bHR/bLR 模型中的行为反应。我们假设 Bmp4 的差异在发育早期出现并导致不同的神经胶质表型，其中一代少突胶质细胞和星形胶质细胞的结构被改变，细胞类型的差异反过来，造成气质上的差异。该假设将使用以下组合进行检验组织学、病毒和行为方法。这部作品有可能揭示一部小说发育中的海马体在产后早期形成模式的机制，并指出神经胶质亚型在塑造成瘾和情感脆弱性方面的新作用失调。