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: 10681203
• 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/10681203
• 关键词: Accidents; Acetylcholine; Affect; Agonist; Behavioral; Bilateral; Brain Stem; Butyric Acids; Cells; Cessation of life; Cholinergic Fibers; Code; Compensation; Crista ampullaris; Development; Disease; Drug usage; Ear; Efferent Pathways; Elderly; Electrophysiology (science); Epithelium; Equilibrium; Feedback; Fiber; 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; Nicotinic Receptors; Optics; Organ; Patients; Peripheral; Pharmaceutical Preparations; Positioning Attribute; Preparation; Probability; Property; Research; Role; Rotation; Sensory; Signal Transduction; Source; Supporting Cell; Synapses; System; Testing; United States; Vestibular Hair Cells; Vestibular Nerve; afferent nerve; antagonist; behavioral outcome; behavioral response; cholinergic; exercise rehabilitation; extracellular; falls; functional improvement; improved; in vivo; macula; multisensory; nerve supply; neuromechanism; optogenetics; patch clamp; pharmacologic; posture instability; receptor; response; sensor; tool; transmission process; vestibular pathway; vestibular reflex; vestibulo-ocular reflex; Accidents; Acetylcholine; Affect; Agonist; Behavioral; Bilateral; Brain Stem; Butyric Acids; Cells; Cessation of life; Cholinergic Fibers; Code; Compensation; Crista ampullaris; Development; Disease; Drug usage; Ear; Efferent Pathways; Elderly; Electrophysiology (science); Epithelium; Equilibrium; Feedback; Fiber; 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; Nicotinic Receptors; Optics; Organ; Patients; Peripheral; Pharmaceutical Preparations; Positioning Attribute; Preparation; Probability; Property; Research; Role; Rotation; Sensory; Signal Transduction; Source; Supporting Cell; Synapses; System; Testing; United States; Vestibular Hair Cells; Vestibular Nerve; afferent nerve; antagonist; behavioral outcome; behavioral response; cholinergic; exercise rehabilitation; extracellular; falls; functional improvement; improved; in vivo; macula; multisensory; nerve supply; neuromechanism; optogenetics; patch clamp; pharmacologic; 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 前庭受体编码有关头部运动的信息，并通过 前庭神经到脑干。反过来，受体和传入从 起源于脑干的胆碱能传出纤维。迄今为止，传出的功能 途径仍然难以捉摸。有人建议传出可能在正常中发挥作用 病变后的前庭反射和补偿。特别是，主要是 用花萼末端的传入的活动，完全覆盖了基底外侧壁 前庭毛细胞，提供独特的突触形式。此外，除了乙酰胆碱外， 在前庭外围也发现了伽马氨基丁酸（GABA）的来源， 在支持细胞中，也可能在某些传出纤维中。但是，几乎没有 有关突触特性，受体类型以及胆碱能和相互作用的了解 GABA能输入及其对前庭传入反应的影响。现在的目标 建议是研究介导传入反应变化的基本机制 胆碱能和GABA能输入的特性。我们将使用整体准备 前庭感觉上皮研究不同亚型的特定激动剂的作用 毛细胞上的受体和小鼠传入的末端。我们还将使用体内鼠标 准备记录前庭神经传入的响应特性以及光学 刺激胆碱能纤维/ GABA能细胞以及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 - 眼反射来在警报小鼠中起作用。这些研究的结果提供了 在末端器官中的单个突触级别上关联变化的信息与前庭 神经活动和行为反应。这些研究的最终目标是铺平道路 通过将药物在耳朵中局部应用以改进的新治疗选择 患者的前庭补偿。