Mechanism and function of presynaptic inhibition in Drosophila proprioceptors

果蝇本体感受器突触前抑制机制及功能

• 批准号: 10380469
• 负责人: Lylah Deady
• 金额: $ 3.43万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-16 至 2022-03-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380469
• 关键词: Action Potentials; Address; Afferent Neurons; American; Animal Model; Animals; Axon; Behavior; Biological Models; Biophysical Process; Brain; Calcium; Chemicals; Chronic; Claw; Disease; Disputes; Drosophila genus; Electrophysiology (science); Environment; Feedback; Felis catus; Genetic; Human; Image; Impairment; Insecta; Interneurons; Lateral; Lead; Leg; Limb structure; Maps; Measures; Mediating; Membrane; Membrane Potentials; Methods; Monitor; Movement; Nervous system structure; Neuraxis; Neurons; Neurotransmitters; Optical Methods; Optics; Organ; Output; Patients; Pattern; Population; Positioning Attribute; Presynaptic Terminals; Prevalence; Proprioceptor; Regulation; Resistance; Role; Sensory; Signal Transduction; Specificity; Stimulus; Synapses; Synaptic Transmission; System; Testing; Touch sensation; Visual; cell type; chronic pain; effective therapy; experience; experimental study; fly; gamma-Aminobutyric Acid; inhibitory neuron; insight; joint mobilization; limb movement; neurotransmitter release; presynaptic; prevent; receptor; recruit; response; sensorimotor system; sensory system; somatosensory; synaptic inhibition; therapy development; tool; two-photon; vibration; visual information; voltage

PROJECT SUMMARY / ABSTRACT Interaction with the external environment is made possible by sensory systems, which transduce physical, chemical, or visual information into electrical signals that the brain can encode and interpret. Once transduced into electrical signals, environmental stimuli are subject to filtering to enhance or diminish specific features and to prevent overstimulation. Presynaptic inhibition is a ubiquitous feature of early sensory processing and is imperative for modulating synaptic output from sensory neurons to central neurons. The inhibitory neurotransmitter GABA is released onto sensory afferents, depolarizes the axon terminal, and suppresses neurotransmitter release. Despite the importance and prevalence of presynaptic inhibition, it is not clear how depolarization of the axon terminal results in synaptic inhibition. In addition, the GABAergic interneurons providing synaptic input to the afferent terminals remain elusive and therefore their function and regulation are unknown. In order to understand presynaptic inhibition and its role in sensory encoding, I propose to use Drosophila leg proprioceptors as a model system. Across animals from humans to insects, proprioceptors located throughout the body project to the central nervous system, where information such as limb movement or position are encoded. By investigating the mechanism and regulation of presynaptic inhibition in Drosophila, I will benefit from the relatively simplified circuitry of their nervous system and the unparalleled ability to genetically target subpopulations of neurons. I will perform experiments to address three specific questions: 1) what is the biophysical mechanism of presynaptic inhibition in proprioceptors and 2) do GABAergic interneurons have target specificity for specific proprioceptors, and 3) how are proprioceptors dynamically regulated during spontaneous and passive movement? To address the first question, I will use voltage imaging to measure membrane voltage of proprioceptors during induced inhibition by stimulating with exogenous GABA. Then, I will determine whether GABAergic interneurons are promiscuous or if they have functionally segregated targets. Lastly, I will determine which GABAergic interneurons are activated by direction-sensitive or movement-sensitive proprioceptors. By measuring membrane voltage across proprioceptors during GABA application, active movements, and passive movements, I hope to identify the biophysical mechanism of presynaptic inhibition and determine how the inhibitory neurons are dynamically recruited to provide feedback.

项目总结/摘要 与外部环境的相互作用是通过感觉系统实现的， 将化学或视觉信息转化为大脑可以编码和解释的电信号。一旦转导 在电信号中，环境刺激经受过滤以增强或减弱特定特征， 防止过度刺激突触前抑制是早期感觉加工的普遍特征， 对于调节从感觉神经元到中枢神经元的突触输出至关重要。的抑制 神经递质GABA被释放到感觉传入神经上，使轴突末端去极化，并抑制 神经递质释放尽管突触前抑制的重要性和普遍性， 轴突末端的去极化导致突触抑制。此外，GABA能中间神经元 向传入末梢提供突触输入仍然是难以捉摸的，因此它们的功能和调节是 未知为了理解突触前抑制及其在感觉编码中的作用，我建议使用 果蝇腿本体感受器作为模型系统。从人类到昆虫，本体感受器 分布在全身的神经元投射到中枢神经系统， 或位置被编码。通过研究果蝇突触前抑制的机制和调控， 我将受益于他们相对简单的神经系统电路和无与伦比的能力， 基因靶向神经元亚群。我将进行实验来解决三个具体问题：1） 本体感受器突触前抑制的生物物理机制是什么？ 中间神经元对特定的本体感受器具有靶特异性，以及3）本体感受器如何动态地 在自发和被动运动中调节？为了解决第一个问题，我将使用电压成像 测量外源性刺激诱导抑制过程中本体感受器的膜电压 GABA然后，我将确定GABA能中间神经元是否是混杂的，或者它们是否在功能上具有 隔离目标最后，我将确定哪些GABA能中间神经元被方向敏感的 或运动敏感的本体感受器。通过测量GABA作用期间本体感受器的膜电压， 应用，主动运动和被动运动，我希望确定生物物理机制， 突触前抑制，并确定如何抑制神经元动态招募提供反馈。