Specificity of neuronal Connections in the Zebrafish Lateral Line

斑马鱼侧线神经元连接的特异性

• 批准号: 8046336
• 负责人: Aaron Nagiel
• 金额: $ 1.45万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046336
• 关键词: Acceleration; Address; Afferent Neurons; Autistic Disorder; Brain; Cations; Cell Polarity; Cells; Complement; Detection; Development; Developmental Process; Epilepsy; Genetic; Hair; Hair Cells; Human; Imaging Techniques; Individual; Injury; Light; Location; Logic; Maps; Mechanics; Mental disorders; Nerve Fibers; Nervous system structure; Neurons; Optical Methods; Organ; Pattern; Positioning Attribute; Process; Recovery; Research; Role; Schizophrenia; Sensory; Specific qualifier value; Specificity; Stereotyping; Stimulus; Stroke; Structure; Synapses; Synaptic Transmission; System; Testing; Time; Transgenic Organisms; Water; Zebrafish; afferent nerve; base; in vivo; insight; inward rectifier potassium channel; lateral line; light gated; mutant; nervous system disorder; neural circuit; neuromast; neuronal patterning; optical imaging; pressure; sensory system

DESCRIPTION (provided by applicant): The proper wiring of the vertebrate brain represents an extraordinary developmental challenge, with over 100 billion neurons forming an estimated quadrillion synapses in humans. An essential but poorly understood feature of this process is the specificity of neuronal connections. Individual neurons must make synaptic contacts with a specific set of target cells in order for neural circuits to be functional. Owing to the stunning complexity of the human brain, simple vertebrate systems must be employed in order to comprehend synaptic specificity in mechanistic detail. The lateral-line organ of larval zebrafish is a sensory system composed of superficial hair cells that transform water-borne mechanical stimuli into electrical activity in afferent nerve fibers. In order to generate real-time estimates of water current velocity and acceleration, the larval brain keeps track of hair-cell location and directional sensitivity with respect to the bodily axes. This function requires that afferent neurons make distinctions based on these two parameters when innervating hair cells. The specific aims of this research are to understand how individual afferent neurons selectively synapse with particular hair cells according to their location and directional sensitivity and to decipher the logic by which these hair-cell parameters are represented in the brain. These experimental aims will be addressed through a combination of genetic and optical imaging techniques. Transgenic approaches that either silence synaptic activity in hair cells or allow for remote control of synaptic activity using channelrhodopsin-2 will provide a means of assessing the role of synaptic activity in specifying appropriate synaptic targets. Analysis of synaptic wiring in a mutant zebrafish lacking the stereotyped pattern of hair-cell polarity will complement these studies. Finally, genetic and optical methods will be developed to map the neural circuits that represent lateral-line stimuli in the brain. The studies proposed here have the potential to shed light upon the establishment of synaptic specificity in a vertebrate sensory system in vivo. Because these specific patterns of neuronal connectivity form the basis for normal brain function, abnormalities in this wiring can cause neurological and psychiatric disease. A detailed understanding of the mechanisms that promote the proper wiring of the nervous system will bolster our understanding and treatment of mental illnesses such as autism, epilepsy, and schizophrenia, as well as our capacity to harness normal developmental processes toward the recovery of brain function following stroke and traumatic injury.

描述(由申请人提供)： 脊椎动物大脑的正确连接是一个非同寻常的发育挑战，在人类中，超过1000亿个神经元形成了大约1万亿个突触。这一过程的一个基本但鲜为人知的特征是神经元连接的特异性。单个神经元必须与一组特定的靶细胞进行突触接触，才能使神经回路发挥作用。由于人脑的惊人复杂性，必须使用简单的脊椎动物系统来理解突触的机械细节。斑马鱼幼体的侧线器官是由浅层毛细胞组成的感觉系统，它将水中的机械刺激转化为传入神经纤维中的电活动。为了实时估计水流速度和加速度，幼虫的大脑跟踪毛细胞的位置和相对于体轴的方向敏感度。这一功能要求传入神经元在支配毛细胞时根据这两个参数进行区分。这项研究的具体目的是了解单个传入神经元如何根据它们的位置和方向敏感性选择性地与特定的毛细胞突触，并破译这些毛细胞参数在大脑中表示的逻辑。这些实验目标将通过基因和光学成像技术的组合来实现。转基因方法要么沉默毛细胞中的突触活动，要么允许使用通道视紫红质-2远程控制突触活动，这将提供一种评估突触活动在指定适当突触靶点方面的作用的方法。对缺乏毛细胞极性定型模式的突变斑马鱼的突触连接的分析将补充这些研究。最后，将开发遗传和光学方法来绘制大脑中代表侧线刺激的神经回路。本文提出的研究有可能阐明在活体脊椎动物感觉系统中建立突触特异性的可能性。因为这些特定的神经元连接模式构成了正常大脑功能的基础，这种连接的异常可能会导致神经和精神疾病。对促进神经系统正确连接的机制的详细了解将增强我们对自闭症、癫痫和精神分裂症等精神疾病的理解和治疗，以及我们利用正常发育过程恢复中风和创伤后大脑功能的能力。