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: 10018474
• 负责人: Lylah Deady
• 金额: $ 6.16万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2022-03-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018474
• 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

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.

感官系统使与外部环境的相互作用成为可能，这些感觉系统将物理，化学或视觉信息转换为大脑可以编码和解释的电信号。一旦传输到电信号中，环境刺激就会受到过滤以增强或减少特定特征并防止过度刺激。突触前抑制是早期感觉处理的无处不在特征，对于从感觉神经元到中枢神经元调节突触输出至关重要。抑制性神经递质GABA被释放到感觉传入，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流行率，但尚不清楚轴突末端的去极化如何导致突触抑制作用。此外，向传入终端提供突触输入的GABA能中神经元仍然难以捉摸，因此其功能和调节尚不清楚。为了理解突触前抑制及其在感觉编码中的作用，我建议将果蝇腿部前置受体作为模型系统。从人类到昆虫的动物，整个身体项目到中枢神经系统的跨植物受体，肢体运动或位置等信息被编码。通过研究果蝇中突触前抑制的机制和调节，我将受益于他们的神经系统的相对简化电路以及无与伦比的靶向神经元亚群的无与伦比的能力。我将进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，而2）GABA能中神经元是否具有针对特定原理接受者的目标特异性，而3）3）在自发和被动运动期间如何动态调节前的受体受体？为了解决第一个问题，我将使用电压成像来测量通过用外源性GABA刺激诱导抑制过程中本体受体的膜电压。然后，我将确定GABA能中神经元是否是混杂的，或者它们是否具有功能隔离的靶标。最后，我将确定哪些GABA能中间神经元被方向敏感或对运动敏感的前置受体激活。通过在GABA应用过程中测量跨本体受体，主动运动和被动运动的膜电压，我希望确定突触前抑制的生物物理机制，并确定如何在动态上募集抑制性神经元以提供反馈。