Primary Cilia: A Novel Signaling Gateway To Neural Circuit Modulation

项目摘要 初级纤毛是一种以微管为基础的触角样细胞器，存在于每一个皮层 神经元，并且当有缺陷时，导致纤毛病。的一个显著特点 睫状体病是有缺陷的神经回路的形成和功能。施工中断 和神经回路的功能导致诸如自闭症的疾病， 智力障碍，情绪障碍，肥胖症和癫痫，从而暗示了 初级纤毛在神经元功能和电路动力学。初级纤毛信号可能 作为一种非突触性信号传导机制，通过这种机制，环境信号可以 塑造和完善健康和疾病中的神经元回路。尽管如此，初级纤毛 信号塑造神经元回路动力学和初级纤毛是否可以被增选 作为一种治疗管道来修复神经回路故障仍然是个谜。我们的目标 为了解决这一挑战，定义了 初级纤毛，使适当的神经元功能所必需的出现， 维持大脑中的功能性神经回路。我们将使这一目标得以实现 通过利用光遗传学和化学遗传学研究的最新进展， 初级纤毛发出的信号，神经元纤毛受体组定位，分析 人类大脑皮层回路中的纤毛连接体，纤毛驱动的实时成像 活体神经回路可塑性过程中神经元活性和转录的变化 动物，并在脑类器官中模拟人类纤毛病变，目的是拯救 电路故障使用初级纤毛作为工具。总的来说，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， 必须成功地利用这一洞察力， 改善神经回路紊乱这些成果将提供一个变革性的 有机会定义神经回路形成和功能的新细胞原理 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.