Primary Cilia: A Novel Signaling Gateway To Neural Circuit Modulation

项目总结 初级纤毛是一种以微管为基础的触角状细胞器，存在于每个皮质中。 神经元，当有缺陷时，会导致纤毛疾病。的一个显著特点 纤毛病变是神经回路形成和功能缺陷。施工中断 纤毛疾病中神经回路的功能会导致自闭症等疾病， 智力障碍、情绪障碍、肥胖和癫痫，因此暗示了 初级纤毛的神经功能和电路动力学。初级纤毛信号可以 作为一种非突触信号机制，环境信号可以通过它 塑造和提炼健康和疾病中的神经元电路。尽管如此，初级纤毛如何 信号塑造神经元电路动力学和初级纤毛是否可以被增选 作为修复神经回路故障的治疗通道，它仍然是个谜。我们的目标是 要解决这一挑战，请定义由 初级纤毛能够使适当的神经元功能出现和 维持大脑中的功能神经回路。我们将使这一目标成为可能。 通过利用光遗传学和化学遗传学方面的最新进展 初级纤毛发出的信号，绘制神经元纤毛感受器组图，剖析 人脑皮质回路中的纤毛连接体，活体成像纤毛驱动 生活中神经回路可塑性过程中的神经元活动和转录变化 动物，并在脑器官中模拟人类纤毛病，目的是拯救 使用初级纤毛作为工具的电路故障。总而言之，这项工作将揭示如何 初级纤毛活动转化为神经元回路功能的变化 必须成功地利用这种洞察力来服务于 改善神经回路障碍。这些结果将提供一个变革性的 定义神经回路形成和功能的新细胞原理的机会 并将为神经回路矫正开辟新的治疗途径。

PROJECT SUMMARY Primary cilium, a microtubule based antennae-like organelle, is present in every cortical neuron, and when defective, leads to ciliopathies. A distinguishing feature of ciliopathies is defective neural circuit formation and function. Disrupted construction and function of neural circuits in ciliopathies lead to disorders such as autism, intellectual disabilities, mood disorders, obesity, and epilepsy, thus implying a role for primary cilia in neuronal function and circuit dynamics. Primary cilia signaling may serve as a non­synaptic signaling mechanism through which environmental signals can shape and refine neuronal circuits in health and disease. Nonetheless, how primary cilia signaling sculpts neuronal circuit dynamics and whether primary cilia can be co-opted as a therapeutic conduit to mend neural circuit malfunctions remain enigmatic. We aim to resolve this challenge by defining the signaling mechanisms that are utilized by primary cilia to enable appropriate neuronal functions necessary for the emergence and maintenance of functional neural circuits in the brain. We will make this goal attainable by leveraging the latest advances in optogenetic and chemogenetic interrogation of signaling emanating from primary cilia, mapping neuronal ciliary receptome, profiling ciliary connectome within human cerebral cortical circuitry, live imaging cilia driven neuronal activity and transcriptional changes during neural circuit plasticity in living animals, and modeling human ciliopathies in brain organoids with the aim of rescuing circuit malfunctions using primary cilia as a tool. Collectively, this work will reveal how primary cilia activity is transformed into changes in neuronal circuit function and the pathways that must be successfully engaged to harness this insight in the service of ameliorating neural circuit disorders. These outcomes will offer a transformative opportunity to define new cellular principles of neural circuit formation and function and will open up new therapeutic avenues of neural circuit correction.