Development of synaptic inputs on spinal interneurons

描述（由申请人提供）：脊髓网络对产生所有行为的运动输出进行编码，因此，脊髓中间神经元（IN）高度复杂并且我们对存在多少类脊髓IN、其性质、连接和分化机制的知识相当不完整并不奇怪。这些信息不仅对于了解运动功能至关重要，而且对于了解遗传改变、疾病或损伤如何影响成人和新生儿的这些回路也至关重要。几年前，一个新的概念框架，以了解脊髓神经元的发现，促使了几个典型的胚胎类，多样化成各种各样的成人表型。通过以前的资助，我们确定了神经发生和转录因子（TF）表达的时间控制与一类称为V1的特定IN表型相关。V1-IN包括介导运动神经元的复发性抑制的那些（Renshaw细胞）和许多介导运动神经元与单个关节上的拮抗剂作用的相互抑制的V1-IN（Ia抑制性中间神经元，IaIN）。因此，我们将V1分为早期生成组（包括Renshaw细胞和MafB表达）和晚期生成组（包括IaIN和Foxp 2表达）。然而，V1的多样性要大得多，还没有一个完整的方案V1 IN的品种和功能，部分原因是缺乏信息的轴突投射，连接和发射方面的输出。在这里，我们假设，V1的不同出生日期表达不同的组合的TF与特定的角色，在定义轴突的预测和发射性能。在目标1中，我们将分析V1轴突投射，并将其与TF表达和出生时间联系起来。目的2将分析Foxp 2是否控制轴突长度，从而控制不同V1的头尾向投射的程度。目的3分析V1群的点火特性， 它们与特定电压门控通道的关系以及这些是否由特定的TF决定。验证我们的假设表明，出生日期和TF表达区分V1组具有不同的连接和放电调制。结果也将提供一个更完整的图片V1，这将有助于提高我们的理解脊髓局部运动回路。

DESCRIPTION (provided by applicant): Spinal networks encode the motor outputs that generate all behaviors, therefore it is not surprising that spinal interneurons (INs) are highly complex and that our knowledge is rather incomplete about how many classes of spinal INs exist, their properties, connections and mechanisms of differentiation. This information is essential not only to understand motor function, but also how genetic alterations, disease or injury affects these circuits in adults and newborns. A few years ago a new conceptual framework to understand spinal INs was prompted by the discovery of a few canonical embryonic classes that diversify into the large variety of adult phenotypes. With previous funding we established that temporal control of neurogenesis and transcription factor (TF) expression correlates with specific IN phenotypes within a class known as V1. V1-INs include those that mediate recurrent inhibition of motoneurons (Renshaw cells) and many that mediate reciprocal inhibition of motoneurons with antagonist actions on a single joint (Ia inhibitory interneurons, IaINs). Thus, we divided V1s in an early generated group (that includes Renshaw cells and expression of MafB) and a late generated group (that includes IaINs and expression of Foxp2). However, V1 diversity is much larger and there is not yet a complete scheme of V1 IN variety and function, in part because lack of information about their output in terms of axon projections, connections and firing. Here we hypothesize that V1s of different birthdates express different combinations of TFs with specific roles in defining axonal projections and firing properties. In aim 1 we will analyze V1 axon projections and relate them to TF expression and time of birth. Aim 2 will analyze whether Foxp2 controls axon length and therefore the extent of rostro-caudal projections of different V1's. Aim 3 will analyze the firing properties of V1 groups, their relation to specific voltage-gated channels and whether these are determined by specific TFs. Validation of our hypotheses would suggest that birth-date and TF expression differentiate V1 groups with distinct connections and firing modulation. The results will also provide a more complete picture of V1s that will contribute to improve our understanding of spinal local motor circuits.