Investigating the role of Bmp4 in glial subtype specification and temperament

物质使用障碍(SODS)是一种衰弱的疾病，具有严重的个人和 社会影响。预防和治疗策略都需要更好地理解 容易吸毒和上瘾的神经生物学和行为特征。 我们实验室已经有选择地饲养了60多代大鼠，以选择特定的 行为特征，最终产生一个强大的情绪反应和行为模型 上瘾的责任。繁殖的高反应动物(BHR)和繁殖的低反应动物(BHR)代表 情绪反应的极端目的：BHR动物代表一种外化的表型， 低行为抑制和高水平的冲动和寻求毒品的行为。BLR动物 代表内化表型，行为受抑，高度焦虑--和 有类似抑郁的行为，但不太容易吸毒和复发。重要的是 行为特征跨世代的重复性允许预测模型和 对影响成人行为的发育机制的研究。 家长奖(U01)的一个主要目标是了解气质的遗传基础。 容易导致上瘾行为的倾向。近年来，我们的实验室已经将 早期出现的遗传变异以及海马区基因表达的变化 BHR/BLR模式的发展，并强烈区分不同的线路。一件上衣 正在开发的候选基因是骨形态发生蛋白4(Bmp4)，它具有良好的生物学特性。 在发育中的神经系统，神经发生，以及重要的， 在发育过程中星形胶质细胞和少突胶质细胞的数量。它目前是 尚不清楚神经胶质细胞的规格和出生后Bmp4的表达是否对造型重要 性情和行为。 在这一应用中，我们建议研究Bmp4在神经胶质亚型规范和 BHR/BLR模型中的行为反应。我们假设Bmp4中的差异 出现在发育早期，并有助于分化的神经胶质表型，其中世代 少突胶质细胞和星形胶质细胞的差异是修饰的，而细胞类型的差异，反过来， 导致性情不同的原因。这一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。这部作品有可能揭示出一部小说 发育中的海马体在出生后早期窗口形成图案的机制， 并指出了神经胶质亚型在形成成瘾和情绪性易感性方面的新作用 精神错乱。

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.