Development of synaptic inputs on spinal interneurons

描述(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)高度复杂也就不足为奇了，我们对脊髓INS的种类、性质、连接和分化机制的了解相当不完整。这些信息不仅对了解运动功能至关重要，而且对于了解基因改变、疾病或损伤如何影响成年人和新生儿的这些回路也是至关重要的。几年前，几个典型的胚胎类型的发现推动了一个新的概念框架来理解脊髓INS，这些胚胎类型多样化地形成了大量的成体表型。在之前的研究中，我们证实了神经发生和转录因子(TF)表达的时间控制与V1类中特定的IN表型相关。V1-INS包括介导运动神经元反复抑制的神经元(Renshaw细胞)和许多介导运动神经元与单个关节上的拮抗作用相互抑制的神经元(Ia抑制中间神经元，IaINs)。因此，我们将V1分为早期生成组(包括Renshaw细胞和MafB的表达)和晚期生成组(包括IaIN和Foxp2的表达)。然而，V1的多样性要大得多，V1IN的多样性和功能还没有一个完整的方案，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的信息。这里我们假设，不同出生日期的V1表达不同的TF组合，在定义轴突投射和放电特性方面具有特定的作用。在目标1中，我们将分析V1轴突投射，并将它们与Tf表达和出生时间联系起来。目的2分析Foxp2是否控制轴突长度，从而影响不同V1‘S的吻尾投射范围。目的3分析V1组的放电特性。 它们与特定的电压门控通道的关系以及这些关系是否由特定的TF确定。对我们的假设的验证表明，出生日期和Tf的表达可以区分具有不同联系和激发调制的V1组。这些结果还将提供V1的更完整的图景，这将有助于提高我们对脊髓局部运动回路的理解。

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.