Modulation of vestibular afferent properties by cholinergic and GABAergic inputs: from neural mechanisms to behavioral outcomes

项目总结 前庭感受器编码有关头部运动的信息，并通过 将前庭神经连接到脑干。反过来，受体和传入细胞接受来自 起源于脑干的胆碱能传出纤维。到目前为止，传出的功能 路径仍然难以捉摸。已有研究表明，传出神经可能在正常大脑中起作用。 前庭反射的发展和损伤后的代偿。特别是传出的主要是 影响具有完全覆盖基底外侧壁的花萼末端的传入神经的活动 前庭毛细胞，提供一种独特的突触形式。此外，除了乙酰胆碱， 前庭周围也发现了伽马氨基丁酸(GABA)的来源， 在支持细胞中，可能也在一些传出纤维中。然而，几乎没有 已知突触属性、受体类型以及胆碱能和胆碱能之间的相互作用 GABA能传入及其对前庭传入反应的影响当前的目标是 建议是研究调节传入反应变化的潜在机制 胆碱能和GABA能输入的特性。我们将使用体外完整的制剂 前庭感觉上皮细胞不同亚型特异性激动剂的作用 小鼠毛细胞和传入终末上的受体。我们还将使用活体小鼠 记录前庭神经传入反应特性的准备及光学 胆碱能纤维/GABA能细胞的刺激及其激动剂和拮抗剂的应用 内耳中的特定受体。最后，我们研究了这些药物对前庭的影响。 通过测量前庭-眼睛反射来提高警觉小鼠的功能。这些研究的结果提供了 将末端器官中单个突触水平上的变化与前庭相关的信息 神经活动和行为反应。这些研究的最终目标是为 用于寻找新的治疗方案，通过在耳朵内局部应用药物来改善 患者的前庭代偿。

PROJECT SUMMARY Vestibular receptors encode information about head movements and send these signals through the vestibular nerve to the brain stem. In turn, receptors and afferents receive bilateral inputs from cholinergic efferent fibers that originate in the brain stem. To date, the function of the efferent pathway has remained elusive. It has been suggested that efferents might play a role in normal development of vestibular reflexes and compensation after lesions. In particular, efferents mainly affect activity of afferents with calyx terminals that completely cover the basolateral walls of vestibular hair cells, providing a unique form of synapse. Furthermore, in addition to acetylcholine, sources for gamma amino butyric acid (GABA) have also been found in the vestibular periphery, in the supporting cells and probably also in some of the efferent fibers. However, there is little known about the synaptic properties, receptor types, and interaction between cholinergic and GABAergic inputs and their effect on responses of vestibular afferents. The goal of the present proposal is to investigate the underlying mechanisms that mediate changes in afferent response properties by cholinergic and GABAergic inputs. We will use an in vitro whole preparation of the vestibular sensory epithelium to study the effect of specific agonists of different subtypes of receptors on hair cells and afferent terminals in mouse. We will also use an in vivo mouse preparation to record response properties of vestibular nerve afferents along with optical stimulation of cholinergic fibers/ GABAergic cells and application of agonists and antagonists of specific receptors in the inner ear. Finally, we investigate the effect of these drugs on vestibular function in alert mice by measuring the vestibulo-ocular reflex. Results of these studies provide the information to correlate changes at the level of single synapses in the end organs, to vestibular nerve activity, and behavioral responses. The ultimate goal of these studies is to pave the way for finding new treatment options through local application of drugs into the ear to improve vestibular compensation in patients.