Structural and functional coupling of epidermis to somatosensory neurons in Drosophila

表皮细胞是感觉刺激的第一个接触点，由躯体感觉支配。 神经元(SSN)塑造了我们对世界的体验。SSN和表皮细胞都有很好的临床应用价值 相关性：SSN是生理性和病理性疼痛以及某些病理性皮肤状况的媒介 与衰弱的疼痛和瘙痒有关。然而，我们对表皮细胞在其中扮演的角色的理解 SSN的发展和功能，特别是伤害性感受，除了几个研究得很好的之外，仍然是有限的 举个例子。表征这些重要的细胞间相互作用是复杂的异质性和 脊椎动物神经系统的复杂性。果蝇提供了一个吸引人的系统来弥合我们的 知识，提供丰富的遗传资源，准备好单细胞SSN/表皮的成像通道 分辨率、紧凑的神经系统和SSN关键调控因子的进化保守 开发/功能。在这个项目中，我们将使用一种综合的方法来研究进化上保守的 细胞内相互作用，包括由表皮细胞包裹SSN神经突起。这一点的保护 与其他SSN相比，伤害性感受器的细胞间相互作用和优先包膜表明 这些鞘可能在伤害性SSN的发育和功能中发挥关键作用。在这里，我们测试 假设SSN的表皮被功能性地将表皮细胞连接到SSN。我们将测试 这一假设使用了三条线的实验。首先，我们将描述以下响应特性 果蝇表皮细胞和鉴定介导表皮反应的表皮感觉通道 有害的刺激。其次，我们将测试伤害性感受器表皮中鞘的激活要求，定义 表皮门控行为反应的神经元底物，定义功能耦合的SSN谱系 对表皮刺激，并量化表皮激活对感觉诱发行为的贡献。第三, 我们将确定连接表皮和外周C4da神经元的信号机制，并确定电路- 鞘的水平效应。鉴于病理性疼痛对生活质量的巨大影响--慢性疼痛 影响美国人的人数超过糖尿病、心脏病和癌症的总和--了解表皮如何 细胞调控伤害性SSN功能对疼痛新疗法的开发具有重要意义 管理层。该项目的成功完成将使我们能够深入了解 躯体感觉，代表了一种新的伤害感控制点，可以定义一个新的切入点 疼痛管理。

Epidermal cells provide the first point of contact for sensory stimuli and are innervated by somatosensory neurons (SSNs) that shape our experience of the world. Both SSNs and epidermal cells are of great clinical relevance; SSNs are mediators of physiological and pathological pain, and some pathological skin conditions are associated with debilitating pain and itch. However, our understanding of roles that epidermal cells play in SSN development and function, particularly nociception, remain limited aside from a few well-studied examples. Characterizing these important intercellular interactions is complicated by the heterogeneity and complexity of vertebrate nervous systems. Drosophila provides an appealing system to close this gap in our knowledge, offering a wealth of genetic resources, ready imaging access of SSNs/epidermis with single cell resolution, a compact nervous system, and evolutionary conservation of key regulators of SSN development/function. In this project we will use an integrated approach to study an evolutionarily conserved intracellular interaction that involves the wrapping of SSN neurites by epidermal cells. The conservation of this intercellular interaction and the preferential ensheathment of nociceptors compared to other SSNs suggest that these sheaths may play key roles in development and function of nociceptive SSNs. Here, we test the hypothesis that epidermal ensheathment of SSNs functionally couples epidermal cells to SSNs. We will test this hypothesis using three lines of experimentation. First, we will characterize the response properties of Drosophila epidermal cells and identify epidermal sensory channels that mediate epidermal responses to noxious stimuli. Second, we will test requirements for sheaths in epidermal activation of nociceptors, define the neuronal substrates for epidermally-gated behavior responses, define the SSN repertoire functionally coupled to epidermal stimulation, and quantify contributions of epidermal activation to sensory-evoked behaviors. Third, we will identify signaling mechanisms linking epidermis and C4da neurons in the periphery and identify circuit- level effects of ensheathment. Given the enormous impact of pathological pain on quality of life – chronic pain affects more Americans than diabetes, heart disease, and cancer combined – understanding how epidermal cells modulate nociceptive SSN function is of great interest for development of novel therapeutics for pain management. Successful completion of this project will provide insight into a fundamental component of somatosensation that represents a novel control point for nociception that could define a new entry point for pain management.