Structural and functional coupling of epidermis to somatosensory neurons in Drosophila

表皮细胞为感觉刺激提供第一接触点，并受躯体感觉神经支配 神经元（SSN）塑造了我们对世界的体验。SSN和表皮细胞都具有重要的临床意义 相关性; SSN是生理性和病理性疼痛以及某些病理性皮肤病的介质 会导致虚弱的疼痛和瘙痒然而，我们对表皮细胞在 SSN的发育和功能，特别是伤害性感受，除了少数研究之外，仍然有限。 例子.表征这些重要的细胞间相互作用是复杂的异质性， 脊椎动物神经系统的复杂性。果蝇提供了一个有吸引力的系统来弥补我们大脑中的这一差距。 知识，提供了丰富的遗传资源，准备成像访问SSN/表皮与单细胞 分辨率，紧凑的神经系统，以及SSN关键调节因子的进化保守性 发展/功能。在这个项目中，我们将使用一个综合的方法来研究一个进化上保守的 细胞内相互作用，涉及表皮细胞包裹SSN神经突。保护这个 与其他SSN相比，细胞间的相互作用和伤害感受器的优先鞘化表明， 这些鞘可能在伤害感受性SSN的发育和功能中起关键作用。在这里，我们测试 假设SSN的表皮鞘化功能性地将表皮细胞与SSN偶联。我们将测试 这个假设使用了三条实验路线。首先，我们将描述 果蝇表皮细胞，并确定介导表皮反应的表皮感觉通道， 有害刺激其次，我们将测试伤害感受器表皮激活中鞘的要求，定义 表皮门控行为反应的神经元底物，定义了SSN库功能耦合 表皮刺激，并量化的贡献表皮激活的感觉诱发的行为。第三、 我们将确定联系表皮和外周C4da神经元的信号机制，并确定电路， 鞘化的水平效应。鉴于病理性疼痛对生活质量的巨大影响-慢性疼痛 影响更多的美国人比糖尿病，心脏病和癌症的总和-了解表皮如何 细胞调节伤害感受SSN功能对于开发新的疼痛治疗剂具有极大的兴趣 管理该项目的成功完成将使我们深入了解 躯体感觉，代表了一个新的控制点的伤害，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.