ROLE OF INHIBITION WITHIN THE CEREBELLAR NODULUS/UVULA IN VESTIBULAR PROCESSING

描述(申请人提供)：结节和悬垂(Nu)是小脑皮质的区域，对前庭处理和空间导航至关重要。它们处理来自前庭器官(耳石和半规管)的运动信号，并将输出发送到小脑和脑干前庭核团。这个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 Purkinje细胞(小脑皮质的唯一输出)通过将耳石信号与来自半规管的转换信号相结合来专门编码惯性运动(平移)。然而，尚不清楚翻译是在NU内计算的，还是已经由其输入计算出来的，例如来自前庭核团。这项拨款提案旨在解决这个问题，特别是研究NU内GABA能中间神经元在计算翻译中的作用。本项目的具体目的是验证小脑NU内GABA能中间神经元参与头部中枢性前庭传入信息向惯性运动转化的假说。为此，将在平移、旋转和它们的组合中使用和不使用GABA-A(目标1a)、GABA-B(目标2b)以及联合使用GABA-A和GABA-B(目标1c)受体拮抗剂来表征Nu Purkinje细胞的前庭特性。这些药物将通过小电流注射(50-100nAmp)进行离子电泳法注射，传播范围可能不到100微米，因此只影响记录的浦肯野细胞附近的突触。该项目专注于研究阻断GABA-A和GABA-B受体的效果，因为它们是小脑皮质中最常见的GABA受体形式。拟议的三种实验操作(1a、1b和1c)旨在相辅相成，加强口译能力。例如，研究分别和联合阻断GABA-A和GABA-B受体的效果，可以测试它们属于执行不同计算的通路的可能性，或者它们为了计算翻译而相互补充的可能性。根据初步数据，阻断GABA能抑制将丧失Nu Purkinje细胞区分倾斜和平移的能力，并将影响前庭信号(耳石和管信号)的时间和空间特性。总之，这些实验将阐明抑制性中间神经元在NU进行的信号转换中的作用，并有可能揭示小脑功能的一般规则。此外，更好地了解Nu的功能可能会导致前庭器官或小脑皮质疾病和创伤后康复治疗的发展。 与公共健康相关：我们在我们的环境中轻松地移动，而没有意识到为了正确导航，我们的大脑必须执行高级计算，例如区分我们何时移动，何时相对于重力改变方向。这些计算的一个关键结构是小脑结节和悬垂，这项拨款提案旨在评估这一结构，特别是它的抑制性局部网络在前庭处理中的作用。这项研究的结果将提供对小脑功能的见解，这是开发创伤和前庭感觉器官或中枢神经系统相关结构疾病后康复治疗的必要步骤。

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 the vestibular organs (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) by combining otolith signals with a transformed signal from the semicircular canals. It is still unknown however, whether translation is computed within the NU or it is sent there already computed by its inputs, e.g. from the vestibular nuclei. This grant proposal is designed to tackle this question, specifically to investigate the role of GABAergic interneurons within the NU in computing translation. The specific aim of this project is to test the hypothesis that GABAergic interneurons in the cerebellar NU participate in the transformation of head- centered vestibular afferent information into inertial motion. For this purpose, the vestibular properties of NU Purkinje cells will be characterized with and without application of GABA-A (aim 1a), GABA-B (aim 2b) and combined GABA-A and GABA-B (aim 1c) receptor antagonists during translation, rotation and their combinations. These drugs will be delivered iontophoretically with small current injections (50-100nAmp), and are likely to spread less than 100 microns, thus affecting only synapses near the recorded Purkinje cell. The project focuses on studying the effect of blocking GABA-A and GABA-B receptors because they are the most common forms of GABA receptors in the cerebellar cortex. The three proposed experimental manipulations (1a, 1b and 1c) are designed to complement each other and strengthen the power of interpretation. For instance, studying the effect of blocking GABA-A and GABA-B receptors separately and in combination allows testing the possibility that they belong to pathways performing different computations, or that they work to complement each other in order to compute translation. Based on preliminary data, blockage of GABAergic inhibition will remove the ability of NU Purkinje cells to discriminate tilt from translation, and will affect the temporal and spatial properties of vestibular signals (otolith and canal signals). Together, these experiments will elucidate the role of inhibitory interneurons in the signal transformations carried out by the NU and have the potential of unveiling general rules of cerebellar function. Furthermore, a better understanding NU function could lead to the development of therapies for rehabilitation following disease and trauma of the vestibular organs or the cerebellar cortex. PUBLIC HEALTH RELEVANCE: We move through our environment with ease unaware that for proper navigation our brain must perform high- level computations, such as distinguishing when we move from when we change our orientation with respect to gravity. A key structure for these computations is the cerebellar Nodulus and Uvula, and this grant proposal is designed to evaluate the role of this structure, specifically its inhibitory local network, in vestibular processing. The outcome of this research will provide insights into cerebellar function, which is a necessary step towards developing therapies for rehabilitation after trauma and disease of the vestibular sensory organs or related structures in the central nervous system.