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

胆碱能和 GABA 能输入对前庭传入特性的调节：从神经机制到行为结果

• 批准号: 10365156
• 负责人: Soroush Sadeghi Ghandehari
• 金额: $ 34.8万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-10 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10365156
• 关键词: Acetylcholine; Address; Affect; Agonist; Behavioral; Bilateral; Brain Stem; Butyric Acids; Cells; Cessation of life; Cholinergic Fibers; Code; Crista ampullaris; Development; Disease; Drug usage; Ear; Efferent Pathways; Elderly; Electrophysiology (science); Epithelial; Equilibrium; Feedback; Fiber; Financial compensation; Frequencies; Functional disorder; Goals; Hair Cells; Head Movements; In Vitro; Injections; Knowledge; Laboratories; Labyrinth; Learning; Lesion; Link; Measures; Mediating; Membrane; Methods; Mus; Muscarinic Acetylcholine Receptor; Neurotransmitters; Optics; Organ; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Play; Positioning Attribute; Preparation; Property; Research; Role; Rotation; Sensory; Signal Transduction; Source; Supporting Cell; Synapses; System; Testing; United States; Vestibular Hair Cells; Vestibular Nerve; afferent nerve; antagonist; base; behavioral outcome; behavioral response; cell type; cholinergic; exercise rehabilitation; extracellular; falls; improved; improved functioning; in vivo; macula; multisensory; nerve supply; neuromechanism; optogenetics; patch clamp; posture instability; receptor; response; sensor; tool; transmission process; vestibular pathway; vestibular reflex; vestibulo-ocular reflex

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.

项目摘要 前庭感受器编码头部运动的信息，并将这些信号通过 前庭神经到脑干反过来，受体和传入神经接受来自 起源于脑干的胆碱能传出纤维。到目前为止，传出神经的功能 路径仍然难以捉摸。有人认为，传出神经可能在正常的 损伤后前庭反射和代偿的发展。特别是，传出神经主要 影响活动的传入与萼终端完全覆盖基底外侧壁 前庭毛细胞，提供了一种独特的突触形式。此外，除了乙酰胆碱， 在前庭周围也发现了γ-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 已知的突触特性，受体类型，以及胆碱能和 GABA能输入及其对前庭传入反应的影响。目前的目标是 一个提议是调查介导传入反应变化的潜在机制 胆碱能和GABA能输入的性质。我们将使用一种体外全制剂， 前庭感觉上皮，以研究不同亚型的特异性激动剂的作用。 小鼠毛细胞和传入终末上的受体。我们还将使用体内小鼠 记录前庭神经传入沿着的响应特性的制备 胆碱能纤维/GABA能细胞的刺激以及胆碱能纤维/GABA能细胞的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功能的影响。 通过测量前庭眼反射来观察警觉小鼠的功能。这些研究结果提供了 在终末器官中单个突触水平上的变化与前庭神经元的变化之间的相关性的信息。 神经活动和行为反应这些研究的最终目的是为 寻找新的治疗方案，通过局部应用药物到耳朵，以改善 患者的前庭代偿。