The influence of complex gut microbiota on central nervous system development and adult cognition and behavior

项目摘要 情绪和焦虑症等神经精神疾病在儿童中越来越多地被诊断出来， 比较同卵双胞胎和异卵双胞胎发病率的研究表明，环境因素起到了一定作用 就像基因对疾病风险的影响一样。最近几项使用动物模型的研究表明， 存在于胃肠道(即肠道微生物区系，GM)中的细菌种群具有很强的影响 关于宿主行为，包括焦虑和压力相关行为，以及抑郁行为。此外，研究 比较无菌小鼠和GM基因正常的小鼠，发现了这些不同的 行为特征和几种神经递质和其他神经活性分子的产生 中枢神经系统(CNS)。值得注意的是，神经发育最活跃的时期，突触 各种神经活性分子的形成和产生在新生儿大脑中上调，发生在 与转基因作物的初始播种和成熟时间相同。尽管如此，人们对此了解甚少 早期生活对GM的影响以及随后对焦虑相关行为或焦虑症的易感性。 同样，尽管对无菌小鼠的研究清楚地表明了转基因对宿主的影响 神经发育和行为，关于受影响的和不同的GM的了解很少 具有不同复杂的、自然发生的转基因特征的未受影响的个人。因此，我们的长期目标 是识别和表征早期生命转基因所通过的主要途径和机制 在不同的背景下，影响宿主对焦虑相关行为和基因表达的易感性 自然发生的转基因。要做到这一点，我们的具体目标是1)表征基因表达模式 在小鼠中枢神经系统的整个发育过程中，小鼠的两种GM图谱中的一种与 对焦虑相关行为的易感性或抵抗力，使用全局基因表达和靶向(基因 具体的)方法，以及2)在整个过程中表征微生物组成和基因表达 在生命的头几周，使用类似的全球和有针对性的方法。产水坝是主要的 定植于新生儿和她的GM的细菌来源也与子宫内发育的胎儿有关，因为它们 共享一条血液。因此，为了确定出生前和出生后接触转基因的相对贡献，也 作为产后治疗操作的易损性窗口，将在母坝之间交叉养育猫砂 在出生后24小时内或7日龄内存在易感或保护性的GM特征。而当 这些项目的直接目标是确定特定的微生物功能和相关的宿主途径 随着生活后期焦虑相关行为的发展，相同的GM特征被开发和保持 在我们的实验室里有超过20代人在小鼠身上表现出类似的对临床症状的保护或易感性 自闭症模型，在拟议的项目中产生的数据将产生深远的影响，包括 通过益生菌补充剂为孕妇或新生儿制定可能的预防措施。

Project Summary Neuropsychiatric conditions such as mood and anxiety disorders are increasingly diagnosed in children, and studies comparing the incidence in identical and fraternal twins suggest that environmental factors contribute as much as genetics to disease risk. Several recent studies using animal models have revealed that the bacterial populations present in the gastrointestinal tract (i.e., the gut microbiota, GM) have a strong influence on host behavior including anxiety- and stress-related behavior, and depressive behavior. Moreover, studies comparing germ-free mice and those with a normal GM have revealed associations between these different behavioral profiles and the production of several neurotransmitters and other neuroactive molecules in the central nervous system (CNS). Notably, the most active periods of neurodevelopment, wherein synapse formation and production of various neuroactive molecules are upregulated in the neonatal brain, occur at the same time as the initial seeding and maturation of the GM. Despite this, very little is known regarding the influence of the early life GM and subsequent susceptibility to anxiety-related behavior or anxiety disorders. Similarly, while studies of germ-free mice have clearly shown the influence of the GM on host neurodevelopment and behavior, very little is known regarding the differences in the GM of affected and unaffected individuals with different complex, naturally occurring GM profiles. Thus, our long-term objectives are to identify and characterize the primary pathways and mechanisms through which the early life GM influences host susceptibility to anxiety-related behavior and gene expression, in the context of different naturally occurring GM. To do so, our Specific Aims are 1) to characterize the gene expression patterns throughout development in the CNS of mice colonized with one of two GM profiles associated with either susceptibility or resistance to anxiety-related behavior, using both global gene expression and targeted (gene specific) approaches, and 2) to characterize the microbial composition and gene expression throughout the first several weeks of life, using similar global and targeted approaches. The birth dam serves as the primary source of bacteria colonizing the newborn and her GM is also relevant to the developing fetus in utero as they share a bloodstream. Thus, to determine the relative contribution of pre- and post-natal GM exposures, as well as windows of vulnerability to post-natal therapeutic manipulation, litters will be cross-fostered between dams harboring the susceptible or protective GM profiles within 24 hours of birth or at 7 days of age. While the immediate goal of these projects is to identify the specific microbial functions and host pathways associated with the development of anxiety-related behavior later in life, the same GM profiles developed and maintained in our lab for over 20 generations have shown similar protection or susceptibility to clinical signs in a mouse model of autism, and the data generated in the proposed project will have far-reaching implications, including the development of possible preventive measures for pregnant women or neonates via probiotic supplements.