Reconstruction of the ascending neural circuit from the spiral ganglion

描述（由申请人提供）：螺旋神经节神经元（SGN）替代对于使用基于干细胞（SC）的策略治疗感音神经性听力损失至关重要。然而，如果植入细胞和大脑之间没有建立神经连接，这种修复策略不太可能恢复听力。本研究将探讨外周植入神经元可形成上行神经突并与耳蜗核（CN）发生突触接触的假说。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，NTs在体外刺激耳蜗-前庭神经节-神经干细胞来源的神经元（cvg - nsc -神经元）的神经突生长，并且在体内植入的cvg - nsc -神经元沿脑神经VIII束向CN延伸神经突。这些发现表明，在SGN区域和CN之间重建神经回路是可能的。本提案的中心目标是制定策略，刺激外源神经元沿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，我们提出以下具体目标：(1)确定NTs是否诱导cgm - nscs的谷氨酸能神经元分化。(2)利用耳蜗- viii神经-CN外植体模型，探讨NTs是否刺激外源神经元将神经突向CN延伸并形成突触样接触。(3)在体内模型中评估外源神经元向中枢神经网络延伸神经突并形成突触样接触的能力。本研究将探索外源神经元与宿主中枢听觉系统的整合，这是sc听力再生的关键步骤。该结果将为重建从内耳周围到CN的上行神经通路提供见解。动物模型的发展将导致对人类潜在应用的研究。这些发现可能用于提高人工耳蜗的疗效，人工耳蜗依靠SGN刺激将听觉信息传递给大脑。1

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.