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

项目摘要 螺旋神经节神经元（SGN）替代对于使用神经刺激治疗感音神经性听力损失至关重要。 干细胞（SC）为基础的战略。然而，这种修复策略不太可能恢复听力， 在植入的细胞和大脑之间没有建立。这份提案将调查这一假设 外周植入的神经元可以形成上行神经突，并与耳蜗形成突触接触， 核（CN）。 这一假设得到了先前观察结果的支持，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NTs刺激神经突 耳蜗-前庭神经节-神经SC-衍生神经元（CVG-NSC-神经元）的体外生长， 体内植入的CVG-NSC神经元沿着脑神经VIII（VIII神经）束延伸神经突，朝向 CN。这些结果表明，SGN区和CN之间的神经回路重建是可能的。 可能 这项提议的中心目标是开发刺激外源性神经元的策略， 沿着VIII神经产生神经突，其在处理后与CN神经元形成突触接触 在NT为实现这一目标，我们提出以下具体目标： (1)确定NT是否诱导CVG-NSC的多巴胺能神经元分化。 (2)探索NT是否刺激外源性神经元向CN延伸轴突生长， 使用耳蜗-VIII神经-CN外植体模型的突触样接触。 (3)评估外源性神经元向CN延伸神经突并形成突触样接触的能力 在体内模型中。 这项提议将探索外源性神经元整合到宿主中枢听觉系统中，这是一个关键的 基于SC的听力再生的步骤。这些结果将为重建提升者提供洞见 从周围内耳到CN的神经通路。动物模型的发展将导致 研究在人类中的潜在应用。这些发现可用于提高 耳蜗植入物，其依赖于SGN刺激来将听觉信息传达给大脑。 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