VESTIBULAR SIGNAL PROCESSING CARRIED OUT BY THE CEREBELLAR NODULUS AND UVULA

描述（申请人提供）：结节和小舌（NU）是小脑皮层中前庭处理和空间导航所必需的区域。它们处理来自前庭传入（耳石和半规管）的运动信号，并将输出信号发送到小脑和脑干前庭核。该项目的长期目标是了解NU在空间导航和前庭处理中的作用。最近有研究表明，NU浦肯野细胞（小脑皮层的唯一输出）通过将耳石信号与来自半圆形管道的转换信号相结合，专门编码惯性运动（平移选择性浦肯野细胞）和重力（倾斜选择性浦肯野细胞）。然而，平移和重力信号是在NU中计算的，还是已经被发送到那里（例如从前庭核），这仍然是未知的。本基金提案旨在通过研究局部gaba能抑制在浦肯野细胞和颗粒层中间神经元的神经元反应特性中的作用，并表征苔藓纤维的反应，来解决这个问题。我们将验证在NU浦肯野细胞附近（Aim 1）和颗粒层（Aim 2） GABAergic抑制参与计算惯性运动和重力所需的前庭传入信号转换的假设。我们将描述翻译和倾斜选择性NU浦肯野细胞（Aim 1a, b）和颗粒层中间神经元（Aim 2b）对使用和不使用GABA-A和GABA-B受体拮抗剂的前庭刺激的反应特性。这些药物将通过小电流注射（50-100nAmp）离子透送，仅影响位于记录部位附近的受体。该项目重点研究阻断GABA-A和GABA-B受体的效果，因为它们是小脑皮层中最常见的抑制性受体。我们将测试这些受体是否属于执行不同计算的途径，或者它们是否相互补充以计算平移和倾斜。我们还将学习前庭信息的类型

DESCRIPTION (provided by applicant): The Nodulus and Uvula (NU) are regions of the cerebellar cortex essential for vestibular processing and spatial navigation. They process motion signals arriving from vestibular afferents (otoliths and semicircular canals), and send outputs to cerebellar and brainstem vestibular nuclei. The long-term goal of this project is to understand the role of the NU in spatial navigation and vestibular processing. Recently it has been shown that NU Purkinje cells (the sole output of the cerebellar cortex) exclusively encode inertial motion (translation- selective Purkinje cells) and gravity (tilt-selective Purkinje cell) by combinng otolith signals with a transformed signal from the semicircular canals. It is still unknown however, whether translation and gravity signals are computed in NU or they are sent there already computed (e.g. from the vestibular nuclei). This grant proposal is designed to tackle this question through investigating the role of local GABAergic inhibition in the neuronal response properties of Purkinje cells and granular layer interneurons, and characterizing the response of mossy fibers. We will test the hypothesis that GABAergic inhibition near NU Purkinje cells (Aim 1) and in the Granular Layer (Aim 2) participate in vestibular afferent signal transformations necessary to compute inertial motion and gravity. We will characterize the response properties of translation- and tilt-selective NU Purkinje cells (Aim 1a, b) and Granule Layer Interneurons (Aim 2b) to vestibular stimulation with and without application of GABA-A and GABA-B receptor antagonists. These drugs will be delivered iontophoretically using small current injections (50-100nAmp) to affect only receptors located near the recording site. The project focuses on studying the effect of blocking GABA-A and GABA-B receptors because they are the most commonly found inhibitory receptors in the cerebellar cortex. We will test if these receptors belong to pathways performing different computations, or if they work to complement each other in order to compute translation and tilt. We will also study what type of vestibular information is send by mossy fibers to NU by recording mossy fiber responses to vestibular stimulation. The proposed experiments are designed to complement each other and strengthen the power of interpretation. Based on preliminary data, blockage of GABAergic inhibition will remove the ability of NU Purkinje cells to estimate translational and gravitational acceleration, and will change the vestibular driven responses of GLI. Together, these experiments will elucidate the role of inhibitory interneurons in the signal transformations carried out by NU. Indeed, they have the potential of unveiling general rules of cerebellar function. Our preliminary data together with data collected by a precedent R03 (see progress report) are the strongest evidence available today that some of the computations necessary to form an internal estimation of tilt and translation take place in NU.