Impact of Neonatal Infection on the Development of Hippocampal-Dependent Learning

 描述(申请人提供)：发育障碍是干扰儿童正常发育的几种障碍之一。这些障碍可能只影响一个或几个不同的发展领域，包括语言、运动、社交和学习技能。尤其是学习障碍是最常见的发育障碍形式之一，通常在儿童早期被诊断出来。值得注意的是，一般来说，男孩比女孩更容易被诊断为学习障碍和发育障碍，至少部分被认为是大脑发育早期免疫激活的结果。尽管有这些理论，但许多发育障碍的潜在病因还没有被很好地理解，特别是在外周免疫功能、小胶质功能和性别方面。拟议中的实验的目的有两个。首先，我们将试图了解正常海马区小胶质细胞的发育和突触可塑性分子在幼年雄性和雌性大鼠海马依赖情景恐惧学习开始期间的发育性表达。其次，我们将研究男性和女性发育中的免疫系统的激活如何导致随后的小胶质细胞发育延迟，突触可塑性分子在海马区的表达，以及以性别依赖的方式在海马区依赖学习的发育延迟。这些实验的结果将大大增加我们对内在因素(如性别)和环境因素(如免疫激活)之间相互作用的理解，这些因素从青少年时期到成年，扰乱了大脑和行为的正常发展。此外，这些实验将确定神经元和神经胶质相互作用的新分子靶点，这些靶点可能会因早期免疫激活而在整个发育过程中受到干扰，为未来的治疗干预提供潜在的靶点。

 DESCRIPTION (provided by applicant): Developmental disorders are one of several disorders that interrupt normal development in childhood. These disorders may affect only one or several different areas of development, including language, motor, social and learning skills. Learning disabilities in particular are one of the most common forms of developmental disorders and are typically diagnosed early in children. Notably, learning disabilities and developmental disorders, in general, are more often diagnosed in boys than in girls and it is thought, at least in part, to e the result of immune activation during early brain development. Despite these theories, the underlying etiologies of many developmental disorders are not well understood, particularly in the context of peripheral immune function, microglial function, and sex. The purpose of the proposed experiments is two-fold. First, we will seek to understand normal hippocampal development of microglia and the developmental expression of synaptic plasticity molecules during the onset of hippocampal dependent contextual fear learning in juvenile male and female rats. Second, we will examine how activation of the developing immune system in males and females may result in subsequent delays in microglial development, the expression of synaptic plasticity molecules in the hippocampus, and developmental delays in hippocampal dependent learning in a sex-dependent manner. The results of these experiments will significantly increase our understanding of the interactions between intrinsic factors (such as sex) and environmental factors (such as immune activation) that perturb the normal development of brain and behavior from the juvenile period and into adulthood. In addition, these experiments will identify new molecular targets of neuronal and glial interactions that are likely disrupted throughout development as a result of early-life immune activation, providing potential targets for future therapeutic interventions.