Mechanism and function of presynaptic inhibition in Drosophila proprioceptors

与外部环境的互动是通过感觉系统实现的，它将物理、化学或视觉信息转化为大脑可以编码和解释的电信号。环境刺激一旦转化为电信号，就会经过过滤，以增强或减弱特定的特征，防止过度刺激。突触前抑制是早期感觉加工的普遍特征，是调节从感觉神经元到中枢神经元的突触输出的必要条件。抑制性神经递质GABA被释放到感觉传入，使轴突末端去极化，抑制神经递质释放。尽管突触前抑制的重要性和普遍性，轴突末端去极化如何导致突触抑制尚不清楚。此外，为传入终端提供突触输入的gaba能中间神经元仍然难以捉摸，因此它们的功能和调控尚不清楚。为了理解突触前抑制及其在感觉编码中的作用，我建议使用果蝇腿本体感受器作为模型系统。从人类到昆虫，遍布全身的本体感受器投射到中枢神经系统，在中枢神经系统中，肢体运动或位置等信息被编码。通过研究果蝇突触前抑制的机制和调控，我将受益于果蝇神经系统相对简化的回路和无与伦比的基因靶向神经元亚群的能力。我将通过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是否具有靶特异性；3)在自发和被动运动中，本体感受器是如何动态调节的？为了解决第一个问题，我将使用电压成像来测量外源性GABA刺激诱导抑制过程中本体感受器的膜电压。然后，我将确定gaba能中间神经元是否混杂，或者它们是否有功能分离的目标。最后，我将确定哪些gaba能中间神经元是由方向敏感或运动敏感本体感受器激活的。通过测量在GABA应用、主动运动和被动运动期间本体感受器的膜电压，我希望确定突触前抑制的生物物理机制，并确定抑制神经元是如何动态募集以提供反馈的。

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.