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: 10570671
• 负责人: Orkun Akin
• 金额: $ 2.89万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10570671
• 关键词: Adult; Affect; Attenuated; Award; Behavior; Brain; Cations; Detection; Development; Disease; Drosophila genus; Genetic; Goals; Individual; Knowledge; Lead; Learning; Memory; Motion; Neurobiology; Neurons; Parents; Pattern; Periodicity; Phase; Process; Research; Retina; Sensory; Signal Transduction; Source; Specific qualifier value; Specificity; Stereotyping; Stimulus; Synapses; Testing; Visual system structure; Work; brain cell; career; cell type; connectome; defined contribution; fly; insight; mutant; neural circuit; overexpression; preference; programs; relating to nervous system; response; spatiotemporal

Research and Career Plan Summary of Parent Award 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 ~2,000 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 strengths 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.

研究和职业规划 家长奖摘要 突触连接决定神经回路如何处理信息。了解力量是如何 而这些联系的特异性已经确立是神经生物学的一个中心挑战。在美国的许多地方 发育中的哺乳动物大脑，刺激非依赖性神经元活动的刻板模式先于感觉- 受驱动的响应。这种发育活动是否以及如何在已定义的水平上引导突触组装 细胞类型和电路还没有被很好地理解。在这里，很大一部分挑战是由于 哺乳动物的大脑本身：即使在视网膜，那里的发育活动是最具特点的，技术上 追问突触水平问题的障碍是很大的。我们最近发现了类似的图案， 在发育中的果蝇大脑中，刺激非依赖性神经活动(PSINA，发音为“see-nah”)。与 随着对其神经生物学知识的不断增长，从连接体到行为，苍蝇在其 承诺进行细胞类型和电路水平的研究。PSINA与全脑范围的周期性活动进行全球协调 和静默阶段。在视觉系统中，每种细胞类型都以不同和刻板的空间模式参与PSINA。 活动的时间模式。这些发育活动模式在成对神经元之间是相关的 已知是成人的突触伙伴。我们的长期目标是测试特定细胞类型的假设 PSINA的活动模式细化了新出现的连接体，以产生野生型突触强度和 专一性。在这里，我们将通过利用PSINA上的一个新的遗传句柄来实现这一目标：Trpγ，一种阳离子 野生型PSINA需要对钙离子有微弱偏好的通道。在Trpγ突变体中，活性的幅度 在整个大脑中减少了50%，特定细胞类型的活动模式和突触数量 被更改了。Trpγ在大脑中1.5%的神经元中表达。值得注意的是，仅通过以下方式使这些神经元沉默 过度表达超极化通道会使PSINA衰减90%。这表明这其中的一部分或全部 不同种类的~2,000个Trpγ表达的神经元(即Trpγ+)在发育过程中对协调PSINA至关重要 大脑。我们假设Trpγ+神经元是特定细胞类型活动模式的来源。在目标1中，我们 将识别支配视觉系统的单个Trpγ+神经元，并测试这些神经元是否指定活动 它们的突触后伙伴的模式。确定这些图案的来源将使我们能够问，它们是否 是突触和回路成熟的原因或结果。在目标2中，我们将专注于一个特定的神经元 这是经过充分研究的运动检测电路的一部分，并询问其突触后接触的强度是否 在Trpγ突变体中发生改变。确定活动模式的细胞来源并了解PSINA的作用 将允许我们可逆地沉默、改变或可能重新编程PSINA。有了这个 知识，我们将能够定义发展活动对结构和功能的贡献 突触和回路的成熟，到感觉处理，到学习、记忆和行为。