Development of neural circuits for simple reflex behavior

描述：从简单的感觉反射和运动反应到更复杂的认知功能，神经元组装成功能性神经网络是行为各个方面的基础。在发育中的脊椎动物中枢神经系统中，也许最简单的神经回路是协调感觉输入和运动输出——脊髓的单突触拉伸反射回路。该回路的功能依赖于三种主要神经元的选择性相互连接：运动神经元、初级感觉神经元和一组调节运动神经元输出的腹侧中间神经元。理解这个简单的回路是如何在发育过程中产生的，首先取决于确定这些特定神经元亚型的独特身份是如何获得的。因为正是这种亚型身份的早期获得为神经元提供了与特定神经目标形成选择性连接的能力。因此，该项目的主要目的是确定控制运动神经元和中间神经元分化的分子机制，这些神经元是发育中的脊髓运动回路形成和功能的基础。该项目将特别关注转录因子在腹侧脊髓神经元亚型识别规范中的关键作用。我们之前的研究已经开始提供证据，证明编码两类同源结构域蛋白的基因，Pax和Nhr基因在决定运动神经元和腹侧中间神经元的身份和最终它们的连接中起着关键作用。目前的建议将试图在分子细节上定义这些转录因子在指导发育中的哺乳动物脊髓神经元亚型的身份和组装中的功能。因此，这些研究应该为理解神经元回路形成的分子基础及其对简单运动行为的控制提供了第一步。我们建议定义不同类别的运动神经元和中间神经元产生的机制。为此，我们建议进行三组具体的实验。1. 确定Pax6在Shh信号和腹侧模式中的功能。Nkx基因在Shh信号传导和腹侧模式中的作用。复合Nkx2.2和Nkx2.9、Pax6、Nkx2.2和Pax6 x Nkx2.9突变体腹侧图案缺陷分析

DESCRIPTION: The assembly of neurons into functional neural networks underlies all aspects of behavior-from simple sensory reflexes and motor responses to more complex cognitive functions. Within the developing vertebrate central nervous system, perhaps the simplest neural circuit is that coordinating sensory input with motor output-the monosynaptic stretch reflex circuit of the spinal cord. The function of this circuit depends on the selective interconnections of three major classes of neurons: motor neurons, primary sensory neurons, and a set of ventral interneurons that regulates the output of motor neurons. Understanding how this simple circuit is generated during development depends first on defining how the distinct identities of these specific neuronal subtypes if acquired. For it is the early acquisition of such subtype identities that provides neurons with the ability to form selective connections with specific neural targets. The major aim of this project is therefore to define the molecular mechanism that controls the differentiation of motor neurons and interneurons that underlie the formation and function of motor circuits in the developing spinal cord. The project will focus in particular on the key role of transcription factors in the specification of neuronal subtype identity in the ventral spinal cord. Our previous studies have begun to provide evidence that genes encoding two classes of homeodomain proteins, the Pax and Nhr genes have critical roles in defining motor neuron and ventral interneuron identity and eventually their connectivity. The present proposal will attempt to define in molecular detail the function of these transcription factors in directing the identity and assembly of neuronal subtypes in the developing mammalian spinal cord. These studies should therefore provide a first step towards the understanding of the molecular basis of neuronal circuit formation and its control of a simple motor behavior. We propose to define the mechanisms whereby distinct classes of motor neurons and interneurons are generated. To this end, we propose to carry out three specific sets of experiments. 1. Defining Pax6 Functions in Shh Signaling and Ventral Patterning. 2. Defining the Role of Nkx Genes in Shh Signaling and Ventral Patterning. 3. Analysis of Ventral Patterning Defects in Compound Nkx2.2 and Nkx2.9, Pax6, NKx2.2, and Pax6 x Nkx2.9 Mutants.