RECOVERY OF VESTIBULAR FUNCTION DURING REGENERATION

描述(申请人提供)：头部运动中的凝视稳定是一种复杂的行为反应，高度依赖于功能正常的前庭系统。事实上，对前庭的侮辱往往会导致平衡和凝视障碍。值得注意的是，鸟类在受损后表现出深刻的自发前庭感受器再生。然而，最近的发现表明，与损伤前相比，再生后组成凝视的前庭介导的眼睛和头部成分的反应明显不同。这些发现表明，在再生过程中，对运动做出反应的凝视控制潜在的前庭神经机制已经被修改。为了了解损伤后前庭功能是如何恢复的，拟议的项目将检查初级前庭传入神经元和辅助凝视的中央核神经元的生理学。实验旨在扩大我们对前庭感受器的形态再生发育的广泛知识。例如，已知的受体传入再生是一个三阶段的时间序列，其中bouton纤维首先恢复，然后是变态，然后是花萼传入。完成后，再生的神经传入的大部分局部组织复制了正常形态发生表型的组织。然而，再生的神经支配模式与正常纤维明显不同，正常纤维的神经支配结构不那么复杂。然后提出了关于这些形态差异如何影响运动信息的神经处理的问题。在具体目标1中，将在感受器再生的三个独特阶段获得前庭对运动的传入反应的神经生理学记录。在这些研究中，我们将考察传入反应在其再发展过程中的空间和时间特性。此外，我们将检查空间分辨阈值，以细化运动方向上的差异。《特定目标2》将研究特定控制凝视行为的眼睛和头部成分的中央前庭神经元。神经生理学记录将在识别的神经元上进行，这些神经元要么投射到脊髓，要么在再生的三个阶段与眼球运动有关。基于先前的行为凝视研究，我们预计前庭脊髓神经元将较早地恢复对运动的反应，以稳定头部。稍后，眼球运动相关的神经元将恢复对运动的反应。具体目标3将根据两类传入的放电规律性处理两类传入的贡献的相关问题。以前的研究表明，规则的放电传入主要涉及眼球运动的控制，而不规则的放电传入更多地涉及头部稳定。利用一种可逆的不规则放电传入电流沉默的方法，研究规则纤维和不规则纤维对凝视的相对贡献。 公共卫生相关性：虽然前庭眼球反射(VOR)是大脑中最被了解的神经系统之一，但关于VOR、前庭结肠反射(VCR)和颈结肠反射(CCR)反应是否能充分控制凝视行为，人们知之甚少。此外，我们对前庭感受器损伤后凝视代偿的神经底物的功能恢复仍然缺乏了解。目前的项目旨在增加我们对前庭传入神经元、中央前庭神经元和凝视行为反应恢复过程的基本了解，这是实现更有效的前庭系统障碍治疗之前必不可少的。

DESCRIPTION (provided by applicant): Gaze stabilization during head motion is a complex behavioral response that is highly dependent upon a functioning vestibular system. In fact, vestibular insult often results in balance and gaze disorders. Remarkably, birds demonstrate profound spontaneous vestibular receptor regeneration following damage. However, recent findings have demonstrated that the vestibular mediated eye and head component responses that comprise gaze differ significantly following regeneration as compared to pre-lesion conditions. These findings suggest that the vestibular neural mechanisms underlying gaze control in response to motion have been modified during regeneration. In an effort to understand how vestibular functions recover following damage, the proposed project will examine the physiology of primary vestibular afferents and central nuclei neurons that sub-serve gaze. Experiments are designed to expand upon our extensive knowledge of the regarding the morphological regenerative development of vestibular receptors. For example, it is known that a tri-staged temporal sequence of receptor afferent regeneration occurs, in which bouton fibers recover first, followed by dimorph, then calyx afferents late. When complete, much of the topographic organization of regenerated afferents reproduced that of the normal morphogenetic phenotype. However, the regenerated innervation patterns differed significantly from normal fibers having less complex innervation structures. The question is then raised as to how these morphologic differences affect neural processing of motion information. In Specific Aim 1, neurophysiological recordings of vestibular afferent responses to motion will be obtained during the three unique stages of receptor regeneration. In these studies, we will examine the spatial and temporal properties of afferent responses during their re-development. In addition, we will examine spatial discrimination thresholds to fine differences in motion direction. Specific Aim 2 will examine the central vestibular neurons that specifically control the eye and head components of gaze behavior. Neurophysiological recordings will be performed on identified neurons that project either to the spinal cord or are eye movement related during the three stages of regeneration. Based upon previous behavioral gaze studies, we expect that vestibulospinal neurons will regain their response to motion early in order to stabilize the head. Later, eye movement related neurons will regain their response to motion. Specific Aim 3 will address a related issue of the contribution of two classes of afferents based upon their discharge regularity. Previous studies have suggested that regular firing afferents are primarily involved in control of eye movements while irregular firing afferents are more involved in head stabilization. By utilizing a reversible method of galvanic silencing of irregular firing afferents, the relative contributions of regular and irregular fibers toward gaze will be examined. PUBLIC HEALTH RELEVANCE: Although the vestibuloocular reflex (VOR) is one of the most well understood neural systems in the brain, much less is known regarding the complimentary function of VOR, vestibulocollic reflex (VCR), and cervicocollic reflex (CCR) responses to adequately control gaze behavior. In addition our knowledge regarding the functional recovery of the neural substrates underlying the gaze compensation following vestibular receptor damage remains lacking. The current project seeks to Increase our fundamental understanding of the afferent, central vestibular neuron, and gaze behavior response recovery process, which is essential, before more effective treatments of vestibular system disorders can be realized.