Mechanism and function of presynaptic inhibition in Drosophila proprioceptors

项目摘要/摘要 与外部环境的相互作用是由感官系统实现的，感官系统传递物理的， 将化学或视觉信息转化为大脑可以编码和解释的电信号。一旦换能器 在电信号中，环境刺激要经过过滤以增强或减弱特定的特征和 以防止过度刺激。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是必不可少的。抑制性 神经递质GABA被释放到感觉传入，使轴突终末去极化，并抑制 神经递质释放。尽管突触前抑制的重要性和普遍性尚不清楚 轴突末端的去极化会导致突触抑制。此外，GABA能中间神经元 向传入终末提供突触输入仍然难以捉摸，因此它们的功能和调节 未知。为了了解突触前抑制及其在感觉编码中的作用，我建议使用 以果蝇腿本体感受器为模型系统。从人类到昆虫的动物，本体感受器 位于全身的投射到中枢神经系统，在那里肢体运动等信息 或位置被编码。通过研究果蝇突触前抑制的机制和调节， 我将受益于他们神经系统的相对简化的电路和无与伦比的能力 从基因上定位神经元的亚群。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？2)GABA能 中间神经元对特定本体感受器具有靶向性，以及3)本体感受器是如何动态变化的 在自发和被动运动过程中受到调节吗？为了回答第一个问题，我将使用电压成像 外源性刺激诱导抑制过程中本体感受器膜电压的测定 GABA。然后，我将确定GABA能中间神经元是否混杂，或者它们是否在功能上 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 或运动敏感型本体感受器。通过测量GABA过程中本体感受器的膜电压 应用，主动运动，和被动运动，我希望确定的生物物理机制 突触前抑制，并确定如何动态招募抑制神经元来提供反馈。

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.