Microbiota and Neural Circuits controlling Social Behavior

 描述（由申请人提供）：最近的突破性研究表明，生活在消化道中的微生物群落（肠道微生物群）在以情绪和社会反应紊乱为特征的精神疾病中起着关键作用。在理解焦虑和社会行为的神经控制方面也取得了加速进展，特别是关于“社会神经肽”、加压素和催产素的作用。到目前为止，还没有人把这两个令人兴奋的领域联系起来。两个拥有互补专业领域的成熟实验室联手承担这项任务：一个专注于大脑中的性别差异和社会行为的神经基础，另一个专注于微生物组与肠道健康之间关系的分子途径。这些实验室将共同开发小鼠模型，以测试肠道微生物群在生命早期起作用的整体假设。 永久性地编程加压素和催产素系统以及由这些系统控制的焦虑相关和社会行为。在第一个实验中，大脑和行为将在无菌小鼠的发育过程中和成年期进行比较，这些小鼠在出生时被来自两种小鼠品系中的任何一种的肠道微生物群定殖，这两种小鼠品系在社会和焦虑相关行为以及微生物组的组成方面存在显着差异。第二个实验利用了两个参与实验室之一最近的一项发现，即常用的食品添加剂，乳化剂，具有令人惊讶的强大效果 通过作用于微生物群组成及其与宿主的相互作用对生理学产生影响。初步数据表明，这些影响延伸到大脑和行为，这将在当前的项目中进行测试。总之，该项目将解决我们对肠脑轴的理解及其在焦虑相关和社会行为发展中的作用的关键差距，使用生理学相关的方法。这些发现将使随后识别影响焦虑相关和社会行为的特定微生物群以及相关的信号通路成为可能。此外，研究微生物群对加压素和催产素表达的影响的回报将超越理解微生物群对行为的影响，包括微生物群对自主神经功能，代谢综合征和疼痛的影响，所有这些都受到微生物群的影响并受到这些肽的调节。

 DESCRIPTION (provided by applicant): Groundbreaking recent studies indicate that the community of microorganisms living in the digestive tract (the gut microbiota) plays a key role in psychiatric illnesses characterized by disordered emotional and social responses. Accelerated progress has also been made in understanding neural control of anxiety and social behavior, especially with regard to the roles of the `social neuropeptides,' vasopressin and oxytocin. To date nobody has linked these two exciting fields. Two established laboratories with complementary areas of expertise have joined forces to take on this task: one focused on sex differences in the brain and the neural basis of social behavior, the other on molecular pathways underlying the relationship between the microbiome and gut health. Together, these laboratories will develop mouse models to test the overall hypothesis that the gut microbiota acts early in life to permanently program vasopressin and oxytocin systems as well as anxiety- related and social behaviors controlled by these systems. In the first experiment, brain and behavior will be compared during development and in adulthood of germ-free mice after they have been colonized at birth by gut microbiota derived from either of two strains of mice that differ significantly in social and anxiety-related behaviors as well as composition of the microbiome. The second experiment takes advantage of a recent discovery in one of the two participating laboratories that commonly used food additives, i.e., emulsifiers, have surprisingly strong effects on physiology by acting on microbiota composition and its interaction with the host. Preliminary data suggest that these effects extend to the brain and behavior, which will be tested in the current project. Together, this project will address a crucial gap in our understanding of the gut-brain axis and its role in the development of anxiety-related and social behaviors, using physiologically relevant approaches. The findings will make possible subsequent identification of the specific microbiota affecting anxiety-related and social behaviors, and the signaling pathways involved. In addition, the payoff for studying effects of the microbiota on vasopressin and oxytocin expression will go beyond understanding microbiota effects on behavior, to include effects of the microbiota on autonomic functions, metabolic syndrome, and pain, all of which are affected by microbiota and modulated by these peptides.