Reconstruction of the ascending neural circuit from the spiral ganglion

项目摘要 螺旋神经节神经元(SGN)置换是治疗感音神经性耳聋的关键。 基于干细胞(SC)的策略。然而，如果神经连接，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。这项提案将调查这一假说 外周植入的神经元可以形成上升突起，并与耳蜗区进行突触接触 核团(CN)。 这一假说得到了之前的观察结果的支持，即胚胎干细胞(ESC)来源的神经元可以入侵 大脑切片并与脑神经元形成突触。我们实验室最近的一项研究发现，NTS刺激了轴突 耳蜗-前庭神经节-神经干细胞来源神经元(CVG-NSC-神经元)的体外生长 体内移植的CVG-NSC神经元沿着脑神经VIII束向外延伸轴突 中央情报局。这些发现表明，SGN区和CN之间的神经回路重建是 有可能。 这项提议的中心目标是制定策略，刺激外源性神经元 在治疗后，沿着VIII神经产生与CN神经元形成突触的神经突起 和新台币。为实现这一目标，我们提出了以下具体目标： (1)确定NTS是否诱导CVG-NSCs向谷氨酸能神经元分化。 (2)探讨NTS是否刺激外源性神经元将突起向CN延伸，并使 使用耳蜗-VIII神经-CN外植体模型进行突触样接触。 (3)评估外源性神经元向中枢神经突起延伸并形成突触样接触的能力 在活体模型中。 这项提议将探索外源性神经元与宿主中枢听觉系统的整合，这是一个关键的 以SC为基础的听力再生的步骤。这些结果将为重建提升层提供洞察力。 从外周内耳到中枢神经的神经通路。动物模型的发展将导致 对人类潜在应用的研究。这些发现可能被用来改善 依靠SGN刺激将听觉信息传递给大脑的人工耳蜗术。 1

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