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.

项目摘要 /摘要 感官系统使与外部环境的互动成为可能，这会导致物理， 大脑可以编码和解释的电信号的化学或视觉信息。一旦转导 进入电信号，环境刺激受到过滤以增强或减少特定特征，并且 防止过度刺激。突触前抑制是早期感觉处理的普遍特征，IS 必须调节从感觉神经元到中央神经元的突触输出。抑制性 神经递质GABA被释放到感觉传入，将轴突末端去除并抑制 神经递质释放。尽管突触前抑制的重要性和普遍性，但尚不清楚如何 轴突末端的去极化会导致突触抑制。此外，GABA能中间神经元 向传入终端提供突触输入仍然难以捉摸，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 果蝇的腿部原理作为模型系统。从人到昆虫的跨动物，本体感受器 位于中枢神经系统的整个身体项目中，肢体运动等信息 或位置编码。通过研究果蝇突触前抑制的机制和调节， 我将从他们的神经系统的相对简化电路和无与伦比的能力中受益 遗传靶向神经元的亚群。我将执行实验以解决三个特定问题：1） 在本体受体中突触前抑制的生物物理机制是什么，2）做gabaergic 中间神经元具有针对特定本体感受器的目标特异性，3）如何动态地进行本体感受器 在自发和被动运动期间受到监管？要解决第一个问题，我将使用电压成像 通过用外源性刺激诱导抑制期间本体受体的膜电压 加巴。然后，我将确定gabaergic中间神经元是否是混杂的，或者它们是否具有功能 隔离目标。最后，我将确定哪些GABA能中间神经元被方向敏感激活 或运动敏感的本体受体。通过在GABA期间测量跨跨受体的膜电压 应用，主动运动和被动运动，我希望确定 突触前抑制并确定如何动态募集抑制性神经元以提供反馈。