Mechanisms of sensory neuron morphological diversification, signaling, and functional plasticity

项目总结 我实验室由NIGMS资助的研究的总体目标是通过 哪些单独的感觉神经元类型获得其独特的形态和功能，并探索如何 这些特性进一步取决于动物的经验和环境。在一个领域，我们调查 线虫中的感觉神经元如何精心设计细胞类型特定的纤毛，即容纳感觉信号的细胞器 分子。在第二个领域，我们描述了线虫表现出高度敏感的机制 以及对环境温度的经验依赖性反应，这是一种关键但知之甚少的感觉 情态。这些问题是相互依存的；神经元解剖学支配着神经元的功能，反过来， 神经元活动塑造了神经元的形态。整合这些项目不仅使我们能够继续我们的 正在进行的成功的研究战略，但也将使我们能够启动新的调查途径。第一次 未来几年的主要目标是发展对遗传途径的详细理解，通过 实现了纤毛形态多样性。结构上独特的纤毛对于特定的功能至关重要 多种物种的感觉神经元类型。虽然纤毛形成的机制现在已经被很好地描述了，但如何 纤毛结构的多样性产生的原因尚不清楚。我们计划分析纤毛的产生机制 线虫的形态多样性，并将我们的分析扩展到哺乳动物细胞。第二个主要目标 是剖析一类新的但保守的热敏分子的性质，我们最近 描述，并探索这些蛋白质如何有助于非凡的体验依赖 感觉神经元型的温度敏感性。我们还将研究转录和翻译的变化 在单个温度感觉神经元中，神经元类型对状态和经验依赖的可塑性有贡献 改变热敏行为的电路属性。一个特别创新的目标是将我们在 神经细胞生物学和刺激诱发感觉反应的分析，以系统地描述 感觉活动调节纤毛蛋白质组成和神经元功能，反之，探索纤毛如何 体系结构决定了感觉神经元的反应轮廓。根据这一合并奖励，我们将能够聘用 我们的多方面实验方法拓宽和深化了我们对神经元形态和功能的分析， 融合概念和实验创新，建立新的研究方向，并提供更多 综合研究培训经验。纤毛结构和功能缺陷以及神经元改变 信号和可塑性是众多神经疾病的基础。考虑到广泛的保护 哺乳动物和线虫之间的纤毛形成和神经元通路，我们完全期待从 这项工作将影响和指导其他生物在发育和疾病方面的相关研究。

PROJECT SUMMARY The overall goal of NIGMS-funded research in my lab is to describe the molecular and cellular mechanisms by which individual sensory neuron types acquire their distinctive morphologies and functions, and explore how these properties are further shaped by the animal's experience and environment. In one area, we investigate how sensory neurons in C. elegans elaborate cell type-specific cilia, organelles that house sensory signaling molecules. In a second area, we characterize the mechanisms by which C. elegans exhibits highly sensitive and experience-dependent responses to environmental temperature, a critical but poorly understood sensory modality. These issues are interdependent; neuronal anatomy governs neuronal function, and conversely, neuronal activity shapes neuronal morphology. Integrating these projects will not only allow us to continue our ongoing successful research strategies, but will also enable us to initiate novel avenues of investigation. A first major goal for the next several years is to develop a detailed understanding of the genetic pathways by which ciliary morphological diversity is achieved. Structurally unique cilia are critical for the functions of specific sensory neuron types in multiple species. Although ciliogenic mechanisms are now well-described, how diversity in ciliary structures is generated is unclear. We plan to analyze mechanisms generating ciliary morphological diversity in C. elegans, and also expand our analysis to mammalian cells. A second major goal is to dissect the properties of a class of novel but conserved thermosensory molecules that we recently described, and to explore how these proteins contribute to the extraordinary experience-dependent thermosensitivity of a sensory neuron type. We will also examine how transcriptional and translational changes in single thermosensory neuron types contribute to state- and experience-dependent plasticity in neuronal and circuit properties to alter thermosensory behaviors. A particularly innovative goal is to combine our expertise in neuronal cell biology and analysis of stimulus-evoked sensory responses to systematically describe how sensory activity modulates cilia protein composition and neuronal function, and conversely, explore how cilia architecture dictates sensory neuron response profiles. Under this combined award, we will be able to employ our multifaceted experimental approach to broaden and deepen our analysis of neuronal form and function, incorporate conceptual and experimental innovations to establish new research directions, and provide a more integrative research training experience. Defects in cilia structure and function, as well as altered neuronal signaling and plasticity, underlie a plethora of neurological disorders. Given the extensive conservation of ciliogenic as well as neuronal pathways between mammals and C. elegans, we fully expect that findings from this work will influence and guide related investigations in other organisms in both development and disease.