Experience-dependent development of neural circuits in the Xenopus visual system

描述(由申请人提供)：了解大脑中的神经回路如何使我们对环境形成感知并引发行为反应一直是神经科学的长期目标。在我们能够弄清中枢神经系统中哪些细胞相互连接之前，我们不可能理解这些复杂的过程。传统的绘制神经回路的工具有局限性，这减缓了了解哪些细胞相互连接的进展；因此，我们对神经回路的发展相对知之甚少，特别是神经元回路连接如何随着感觉体验或突触输入活动的差异而变化。应用嗜神经性病毒来绘制神经回路图谱将对我们理解神经回路的发育做出重大贡献。这项研究项目的总体目标是通过将伪型狂犬病病毒介导的追踪应用到一个独特的适合体内发育研究的模型系统，来了解神经回路是如何发展的，并阐明活动在这一过程中的作用。此外，我们可以使用假型狂犬病病毒介导的跟踪来绘制分子定义的神经元类型的电路，例如GABA能神经元。GABA能神经元在中枢神经系统中所占的比例相对较小，但它们巧妙地平衡了数量多得多的兴奋性神经元产生的兴奋。中枢神经系统兴奋与抑制平衡的紊乱被认为是自闭症和精神分裂症等神经发育障碍的基础。这项建议的具体目的是：(1)使伪型狂犬病病毒跨突触追踪方法适用于非洲爪哇蝌蚪；(2)利用伪型狂犬病病毒的逆行追踪来识别视顶盖神经元的突触前伙伴，并测试视觉经验是否影响顶盖细胞连接图；以及(3)利用伪型狂犬病病毒跨突触追踪来测试谷氨酸或GABA能突触输入是否影响顶盖细胞连接图的开发。这些实验将使我们既可以确定尚未确定的顶盖神经元的突触前伙伴，也可以直接测试视觉体验或突触传输是否会改变顶盖神经元的突触前伙伴的数量和类型。这些实验将有助于阐明调节神经回路发育的机制，这种对大脑发育的基本理解对于开发治疗大脑疾病和损伤的新方法至关重要。此外，这些实验将扩大我们对GABA能回路发育的知识，并可能对自闭症和精神分裂症等神经发育障碍产生重要影响。 公共卫生相关性：了解大脑中哪些细胞相互连接对于了解大脑功能以及治疗脑部疾病和损伤至关重要。这项提议中的实验将扩大我们对神经元连接的知识，并对我们理解和治疗自闭症和精神分裂症等神经发育障碍具有重要意义。

DESCRIPTION (provided by applicant): Understanding how neural circuits in the brain allow us to form a percept of our environment and elicit a behavioral response has been a long-standing goal in Neuroscience. An understanding of these complex processes will not be possible until we can elucidate which cells connect to one another in the central nervous system. Conventional tools to map neural circuits have limitations that have slowed progress in understanding which cells connect to one another; thus, we know relatively little about the development of neural circuits, particularly how neuronal circuit connections change in response to differences in sensory experience or synaptic input activity. Application of neurotropic viruses to map neural circuits will make a significant contribution to our understanding of neural circuit development. The overall goal of this research project is to understand how neural circuits develop and to elucidate the role of activity in this process by applying pseudotyped rabies virus-mediated tracing to a model system uniquely amenable to in vivo developmental studies. Furthermore, we can use pseudotyped rabies virus-mediated tracing to map the circuitry of a molecularly-defined neuron type, such as GABAergic neurons. GABAergic neurons comprise a relatively small proportion of neurons in the central nervous system, but they exquisitely balance out the excitation produced by the far more numerous excitatory neurons. Perturbation in this balance of excitation to inhibition in the central nervous system is thought to underlie neurodevelopmental disorders like autism and schizophrenia. The specific aims of this proposal are to: (1) adapt the pseudotyped rabies virus trans-synaptic tracing method to Xenopus tadpoles, (2) to identify the presynaptic partners of optic tectal neurons using retrograde tracing with pseudotyped rabies virus and to test whether visual experience affects tectal cell connectivity maps, and (3) to test whether glutamatergic or GABAergic synaptic inputs affect the development of tectal cell connectivity maps using pseudotyped rabies virus trans-synaptic tracing. These experiments will allow us to both determine as yet unidentified presynaptic partners of tectal neurons, and also to test directly whether visual experience or synaptic transmission alters the number and type of presynaptic partners that a tectal neuron has. These experiments will help to elucidate the mechanisms regulating the development of neural circuits and this basic understanding of brain development is critical to developing new ways to treat brain illness and injury. Furthermore, these experiments will expand our knowledge of GABAergic circuit development and can have important implications for neurodevelopmental disorders like autism and schizophrenia. PUBLIC HEALTH RELEVANCE: An understanding of which cells in the brain connect to one another is critical to understanding brain function and to treating brain illness and injury. The experiments in this proposal will expand our knowledge of neuronal connectivity and can have important implications for our understanding and treatment of neurodevelopmental disorders such as autism and schizophrenia.