Reconstruction of the ascending neural circuit from the spiral ganglion

从螺旋神经节重建上行神经回路

• 批准号: 8230074
• 负责人: Zhengqing Hu
• 金额: $ 15.2万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230074
• 关键词: Acoustic Nerve; Adopted; Adult; Area; Auditory; Auditory system; Axon; Brain; Brain-Derived Neurotrophic Factor; Cells; Cochlea; Cochlear Implants; Cochlear nucleus; Disease; Electrophysiology (science); Embryo; Future; Genes; Glutamates; Goals; Hearing; Human; Implant; In Vitro; Invaded; Laboratories; Labyrinth; Lead; Modeling; Molecular; Mus; Mutation; Natural regeneration; Nerve; Neural Pathways; Neurites; Neurodegenerative Disorders; Neuronal Differentiation; Neurons; Neurotransmitters; Neurotrophin 3; Peripheral; Phenotype; Proteins; Research; Risk; Sensorineural Hearing Loss; Slice; Stem cells; Synapses; Tinnitus; Transfection; Vestibular ganglion; Virus; Work; animal model development; auditory pathway; base; brain cell; cell type; deafness; embryonic stem cell; hair cell regeneration; hearing impairment; improved; in vivo; in vivo Model; insight; nerve stem cell; nerve supply; neural circuit; neurodevelopment; neurotrophic factor; novel strategies; novel therapeutic intervention; receptor; reconstruction; relating to nervous system; repaired; self-renewal; spiral ganglion; success; synaptogenesis; tumor; young adult

DESCRIPTION (provided by applicant): Spiral ganglion neurons (SGN) replacement is critical for the treatment of sensorineural hearing loss using a stem cell (SC)-based strategy. However, this repair strategy is unlikely to restore hearing if neural connections are not established between the implanted cells and the brain. This proposal will investigate the hypothesis that peripherally implanted neurons can form ascending neurites and make synaptic contacts with cochlear nucleus (CN). This hypothesis is supported by previous observations that embryonic SC (ESC)-derived neurons can invade brain slices and form synapses with brain neurons. A recent study in our lab found that NTs stimulated neurite outgrowth from cochlear-vestibular ganglion-neural SC-derived neurons (CVG-NSC-neurons) in vitro and that in vivo-implanted CVG-NSC-neurons extended neurites along the cranial nerve VIII (VIII nerve) tract toward the CN. These findings suggest that the reconstruction of neural circuitry between the SGN area and CN is possible. The central objective of this proposal is to develop strategies to stimulate exogenous neurons to generate neurites along the VIII nerve that form synaptic contacts with CN neurons following treatment with NT. To achieve this goal, we propose the following specific aims: (1) Determine whether NTs induce glutamatergic neuronal differentiation of CVG-NSCs. (2) Explore whether NTs stimulate exogenous neurons to extend neurite outgrowth toward the CN and make synapse-like contacts using a cochlea-VIII nerve-CN explant model. (3) Assess the ability of exogenous neurons to extend neurites toward the CN and form synapse-like contacts in an in vivo model. This proposal will explore the integration of exogenous neurons into the host central auditory system, a critical step in SC-based hearing regeneration. The results will provide insights into reconstructing the ascending neural pathway from the peripheral inner ear to the CN. The development of an animal model will lead to research toward potential applications in humans. These findings may be used to improve the efficacy of cochlear implants, which rely on SGN stimulation to communicate auditory information to the brain. 1 PUBLIC HEALTH RELEVANCE: A stem cell-based replacement has been proposed to substitute damaged spiral ganglion neurons in hearing loss. This proposal investigates whether exogenous neurons can rebuild the neural circuits from the peripheral auditory system to the central auditory system. The development of an animal model will lead to research toward potential applications in humans. The success of this proposal will provide insights into the ascending auditory pathway reconstruction in the replacement studies for hearing loss, tinnitus, vestibular disorders, and other neurodegenerative diseases.

描述（由申请人提供）：螺旋神经神经元（SGN）替代对于使用基于干细胞（SC）的策略治疗感觉性听力损失至关重要。但是，如果未在植入细胞和大脑之间建立神经连接，这种修复策略不可能恢复听力。该建议将研究以下假设：外周植入神经元可以形成升高的神经突并与耳蜗核（CN）建立突触接触。以前的观察结果支持了这一假设，即胚胎SC（ESC）衍生的神经元可以侵入脑切片并用脑神经元形成突触。 A recent study in our lab found that NTs stimulated neurite outgrowth from cochlear-vestibular ganglion-neural SC-derived neurons (CVG-NSC-neurons) in vitro and that in vivo-implanted CVG-NSC-neurons extended neurites along the cranial nerve VIII (VIII nerve) tract toward the CN.这些发现表明，可以在SGN区域和CN之间重建神经回路。该提案的核心目的是制定刺激外源神经元的策略，以沿着VIII神经产生神经突，并在NT治疗后与CN神经元形成突触接触。为了实现这一目标，我们提出以下特定目标：（1）确定NTS是否诱导CVG-NSC的谷氨酸能神经元分化。 （2）探索NTS是否刺激外源性神经元向CN延伸神经突的生长，并使用耳蜗VIII神经-CN epplant模型进行类似突触的接触。 （3）评估外源神经元在体内模型中延伸神经突向CN并形成突触样接触的能力。该建议将探索外源性神经元进入主机中央听觉系统的整合，这是基于SC的听力再生的关键一步。结果将为重建从周围内耳到CN的上升神经途径的洞察力提供见解。动物模型的发展将导致对人类潜在应用的研究。这些发现可用于提高人工耳蜗的功效，这些植入物依赖于SGN刺激将听觉信息传达给大脑。 1 公共卫生相关性：已提出了一种基于干细胞的替代品来替代受损的螺旋神经神经元的听力损失。该提案调查了外源神经元是否可以重建从外围听觉系统到中央听觉系统的神经回路。动物模型的发展将导致对人类潜在应用的研究。该提案的成功将为听力损失，耳鸣，前庭疾病和其他神经退行性疾病的替代研究中的上升听觉途径重建提供见解。