Development of synaptic inputs on spinal interneurons

描述（由申请人提供）：脊髓网络编码产生所有行为的运动输出，因此脊髓中间神经元（INs）非常复杂，我们对存在多少类脊髓中间神经元、它们的性质、连接和分化机制的了解相当不完整，这并不奇怪。这些信息不仅对了解运动功能至关重要，而且对了解基因改变、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，由于发现了几种典型的胚胎类，这些胚胎类可以分化成各种各样的成人表型，因此出现了一种新的概念框架来理解脊髓INs。在之前的资助下，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-INs包括那些介导运动神经元的反复抑制（Renshaw细胞）和许多介导运动神经元在单个关节上具有拮抗剂作用的相互抑制（Ia抑制性中间神经元，IaINs）。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IaINs和Foxp2表达）。然而，V1的多样性要大得多，目前还没有一个完整的V1的多样性和功能方案，部分原因是缺乏关于它们在轴突投射、连接和放电方面的输出信息。在这里，我们假设不同出生日期的V1s表达不同的tf组合，这些tf在定义轴突投射和放电特性方面具有特定的作用。在目的1中，我们将分析V1轴突的投射，并将它们与TF表达和出生时间联系起来。目的2将分析Foxp2是否控制轴突长度，从而控制不同V1的背尾投影的程度。Aim 3将分析V1基团的发射特性，

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.