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: 8518173
• 负责人: Zhengqing Hu
• 金额: $ 14.44万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8518173
• 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

Project Summary 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

项目概要 螺旋神经节神经元 (SGN) 替代对于使用神经元治疗感音神经性听力损失至关重要 基于干细胞（SC）的策略。然而，如果神经连接不正常，这种修复策略不太可能恢复听力 植入的细胞和大脑之间没有建立。该提案将调查假设 外周植入的神经元可以形成上行神经突并与耳蜗进行突触接触 核（CN）。 这一假设得到了先前观察的支持，即胚胎 SC (ESC) 衍生的神经元可以侵入 大脑切片并与大脑神经元形成突触。我们实验室最近的一项研究发现 NT 刺激神经突 体外耳蜗前庭神经节神经 SC 衍生神经元（CVG-NSC-神经元）的生长 体内植入的 CVG-NSC-神经元沿着颅神经 VIII（VIII 神经）束向神经突延伸 CN.这些发现表明 SGN 区和 CN 之间的神经回路的重建是 可能的。 该提案的中心目标是制定刺激外源神经元的策略 沿 VIII 神经生成神经突，治疗后与 CN 神经元形成突触接触 与新台币。为实现这一目标，我们提出以下具体目标： (1)确定NTs是否诱导CVG-NSCs的谷氨酸能神经元分化。 (2)探讨NTs是否刺激外源神经元向CN方向延伸神经突生长并使得 使用耳蜗 VIII 神经 CN 外植体模型进行突触样接触。 (3) 评估外源神经元将神经突向 CN 延伸并形成突触样接触的能力 在体内模型中。 该提案将探索外源神经元与宿主中枢听觉系统的整合，这是一个关键的 基于 SC 的听力再生的一步。结果将为重建上升提供见解 从外周内耳到 CN 的神经通路。动物模型的开发将导致 研究人类的潜在应用。这些发现可用于提高疗效 人工耳蜗，依靠 SGN 刺激向大脑传达听觉信息。 1

项目成果

Sensory epithelial cells acquire features of prosensory cells via epithelial to mesenchymal transition.

感觉上皮细胞通过上皮到间质的转变获得原感觉细胞的特征。

• DOI: 10.1089/scd.2011.0443
• 发表时间: 2012
• 期刊: Stem cells and development
• 影响因子: 4
• 作者: Zhang,Lei;Hu,Zhengqing
• 通讯作者: Hu,Zhengqing

Generation of human inner ear prosensory-like cells via epithelial-to-mesenchymal transition.

通过上皮-间质转化产生人内耳前感觉样细胞。

• DOI: 10.2217/rme.12.53
• 发表时间: 2012
• 期刊: Regenerative medicine
• 影响因子: 2.7
• 作者: Hu,Zhengqing;Luo,Xuemei;Zhang,Lei;Lu,Fengqing;Dong,Fengping;Monsell,Edwin;Jiang,Hui
• 通讯作者: Jiang,Hui

Formation of the peripheral-central transitional zone in the postnatal mouse cochlear nerve.

出生后小鼠耳蜗神经周围-中央过渡区的形成。

• DOI: 10.1177/0194599813489663
• 发表时间: 2013
• 期刊: Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery
• 作者: Hu,Zhengqing

Myelination of the postnatal mouse cochlear nerve at the peripheral-central nervous system transitional zone.

出生后小鼠耳蜗神经在周围-中枢神经系统过渡区的髓鞘形成。

• DOI: 10.3389/fped.2013.00043
• 发表时间: 2013
• 期刊: Frontiers in pediatrics
• 影响因子: 2.6
• 作者: Wang,Jue;Zhang,Baofu;Jiang,Hui;Zhang,Lei;Liu,Danzheng;Xiao,Xiao;Ma,Hannah;Luo,Xuemei;Bojrab2nd,Dennis;Hu,Zhengqing
• 通讯作者: Hu,Zhengqing