Patterned, Stimulus-Independent Neuronal Activity In the Developing Drosophila Visual System: Origin and Contribution to Synaptic Maturation

果蝇视觉系统发育中的模式化、刺激独立的神经元活动：起源和对突触成熟的贡献

• 批准号: 10279276
• 负责人: Orkun Akin
• 金额: $ 38.02万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10279276
• 关键词: Adult; Affect; Animals; Appearance; Attenuated; Behavior; Brain; Calcium; Cations; Cells; Complement; Computer software; Data; Detection; Development; Disease; Drosophila genus; Elements; Equilibrium; Future; Gene Expression; Genetic; Goals; Image; Individual; Instruction; Invertebrates; Knowledge; Lead; Learning; Measures; Memory; Modeling; Molecular Genetics; Morphology; Motion; Mutation; Neurobiology; Neurons; Optic Lobe; Pattern; Periodicity; Phase; Play; Process; Protocols documentation; Retina; Role; Rosaniline Dyes; Sensory; Signal Transduction; Site; Source; Specific qualifier value; Specificity; Stereotyping; Stimulus; Structure; Synapses; System; Testing; Vertebrates; Visual; Visual system structure; Work; axon guidance; brain cell; cell type; connectome; defined contribution; fly; genetic approach; insight; mutant; neural circuit; neuron development; optogenetics; overexpression; preference; programs; relating to nervous system; response; spatiotemporal; two-photon

Project Summary/Abstract Synaptic connections determine how neural circuits process information. Understanding how the strength and specificity of these connections is established is a central challenge in neurobiology. In many parts of the developing mammalian brain, stereotyped patterns of stimulus-independent neuronal activity precede sensory- driven responses. Whether and how this developmental activity guides synapse assembly at the level of defined cell types and circuits is not well-understood. Here, much of the challenge is due to the size and complexity of the mammalian brain itself: Even in the retina, where developmental activity is best characterized, the technical barriers to pursuing synapse level questions are significant. We recently discovered analogous patterned, stimulus-independent neural activity (PSINA, pronounced `see-nah') in the developing Drosophila brain. With the ever-growing knowledge of its neurobiology, spanning the connectome to behavior, the fly is unmatched in its promise for cell type- and circuit- level studies. PSINA is globally coordinated with brain-wide, periodic active and silent phases. In the visual system, each cell type participates in PSINA with distinct and stereotyped spatio-temporal patterns of activity. These developmental activity patterns are correlated between pairs of neurons known to be synaptic partners in the adult. Our long term goal is to test the hypothesis that the cell-type-specific activity patterns of PSINA refine the emerging connectome to generate wild-type synaptic strength and specificity. Here, we will work toward this goal by leveraging a new genetic handle on PSINA: Trpγ, a cation channel with a weak preference for Ca2+, is required for wild-type PSINA. In trpγ mutants, the amplitude of activity is reduced by >50% across the whole brain, and cell-type-specific activity patterns and synapse numbers are altered. Trpγ is expressed in <1.5% of the neurons in the brain. Notably, silencing only these neurons by overexpressing a hyperpolarizing channel attenuates PSINA by >90%. This indicates that some or all of this diverse group of ~1,700 Trpγ-expressing (i.e. Trpγ+) neurons are critical to coordinating PSINA in the developing brain. We hypothesize that Trpγ+ neurons are the source of the cell-type-specific activity patterns. In Aim 1, we will identify individual Trpγ+ neurons that innervate the visual system and test if these neurons specify the activity patterns of their post-synaptic partners. Determining the origin of these patterns will allow us to ask whether they are the cause or consequence of synapse and circuit maturation. In Aim 2, we will focus on a specific neuron that is part of the well-studied motion detection circuit and ask if the strength of its post-synaptic contacts are altered in trpγ mutants. Identifying the cellular origin of the activity patterns and understanding the effect of PSINA on synaptic development will allow us to reversibly silence, alter, or possibly re-program PSINA. With this knowledge, we will be able to define the contribution of developmental activity to the structural and functional maturation of synapses and circuits, to sensory processing, to learning, memory, and behavior.

项目总结/摘要 突触连接决定神经回路如何处理信息。了解力量和 建立这些连接的特异性是神经生物学的核心挑战。许多地区 在哺乳动物大脑的发育过程中，非刺激依赖性神经元活动的模式先于感觉神经元活动， 驱动响应。这种发育活动是否以及如何在神经元水平上引导突触组装， 定义的细胞类型和电路还没有被很好地理解。在这里，大部分的挑战是由于规模和 哺乳动物大脑本身的复杂性：即使在视网膜，那里的发育活动是最好的 特征，追求突触水平问题的技术障碍是显著的。我们最近 发现了类似的模式，刺激独立的神经活动（PSINA，发音为“see-nah”）， 正在发育的果蝇大脑随着其神经生物学知识的不断增长， 在行为方面，果蝇在细胞类型和电路水平的研究方面是无与伦比的。PSINA在全球 与全脑周期性的活跃期和沉默期相协调。在视觉系统中，每种细胞类型都参与 在PSINA中具有独特和定型的时空活动模式。这些发展活动 在成年人中，已知是突触伙伴的神经元对之间的模式是相关的。我们的长期 我们的目标是检验PSINA的细胞类型特异性活动模式完善了新出现的 连接体以产生野生型突触强度和特异性。在这里，我们将努力实现这一目标， 需要利用PSINA上的新遗传处理：Trpγ，一种对Ca 2+具有弱偏好的阳离子通道， 对于野生型PSINA。在trpγ突变体中，整个大脑的活动幅度降低>50%， 细胞类型特异性活动模式和突触数目改变。Trpγ的表达率<1.5%， 大脑中的神经元。值得注意的是，通过过度表达超极化通道， 使PSINA衰减> 90%。这表明，一些或所有这一不同的~ 1，700 Trpγ表达组（即， Trpγ+）神经元对于协调发育中的大脑中的PSINA至关重要。我们假设Trpγ+神经元 是细胞类型特异性活动模式的来源。在目标1中，我们将识别单个Trpγ+神经元， 神经支配视觉系统，并测试这些神经元是否指定其突触后的活动模式。 伙伴确定这些模式的起源将使我们能够问他们是否是原因， 突触和回路成熟的结果。在目标2中，我们将重点关注作为神经元一部分的特定神经元 研究运动检测电路，并询问其突触后接触的强度是否在Trpγ中改变 变种人确定活动模式的细胞起源并了解PSINA对 突触发育将允许我们可逆地沉默，改变，或可能重新编程PSINA。与此 知识，我们将能够定义发展活动的结构和功能的贡献， 突触和回路的成熟，感觉处理，学习，记忆和行为。