Cell-based approach for increasing central auditory inhibition

项目总结/摘要 多种证据表明，声学过度暴露导致耳蜗损伤， 听觉中枢抑制，导致时间处理缺陷、耳鸣和听觉过敏。先前 纠正这种过度兴奋状态的尝试集中在增加GABA能抑制张力 系统地，在提供耳鸣缓解方面取得了一些成功。然而，这些药物的副作用 对剂量、持续时间和使用安全性施加限制。一种更精确的治疗方法， 听觉核团的抑制可以潜在地治疗潜在的病理，同时最小化脱靶侧， 方面的影响.下丘（IC）是中枢听觉通路的一个重要皮层下整合中心，是一个重要的听觉中枢。 特别容易的目标，以探索抑制的局部增加的影响，因为它在 介导一些声学行为（如间隙检测和前脉冲抑制），并表现出超 听觉过度刺激后的兴奋性反应特性。一种潜在的增加抑制的方法 在IC局部是通过移植来自内侧神经节隆起（MGE）的细胞， 最终皮层抑制性中间神经元。虽然MGE本来是要进入大脑皮层的， 细胞已经被证明可以存活，整合，并增加非皮质细胞中抑制事件的数量。 电路，如脊髓。作为了解当地增加的潜在作用的第一步， 抑制可能在减轻声暴露的影响，我建议测试的假设， 移植的MGE细胞将在功能上整合到成年CBA/CaJ小鼠的IC电路中， 在噪声暴露的受试者中观察到抑制。提出了三个具体目标：1）描述迁移， 移植到幼稚和噪声暴露小鼠IC中的MGE细胞的分化。2)确定如何 MGE细胞移植影响成年CBA/CaJ小鼠的听觉行为。3)确定MGE的影响 细胞移植对IC神经元自发性和声诱发反应的影响。这些实验 代表了MGE细胞移植的一种新应用，并将提高我们对MGE细胞移植的认识。 病理性抑制，可能是耳鸣等听觉病理形成和持续的基础 和听觉过敏，从长远来看，可能会导致新的治疗策略的发展。

Project Summary/Abstract Multiple lines of evidence suggest that acoustic overexposure results in cochlear damage and decreased inhibition in auditory centers, contributing to deficits in temporal processing, tinnitus, and hyperacusis. Previous attempts to correct this hyper-excitable state have focused on increasing GABAergic inhibitory tone systemically, with some success in providing tinnitus relief. However, the side effect profile of these drugs impose constraints on the dose, duration, and safety of use. A more precise treatment that locally increases inhibition in auditory nuclei could potentially treat the underlying pathology while minimizing off-target side effects. The inferior colliculus (IC), a major subcortical integration center of the central auditory pathway, is a particularly apt target to explore the effects of local increases in inhibition, as it plays an important role in mediating some acoustic behaviors (such as gap detection and pre-pulse inhibition) and demonstrates hyper- excitable response properties following acoustic overexposure. A potential approach to increase inhibition locally in the IC is through transplantation of cells from the medial ganglionic eminence (MGE), the birthplace of eventual cortical inhibitory interneurons. While naturally destined for the cerebral cortex, transplanted MGE cells have been shown to survive, integrate, and increase the number of inhibitory events in non-cortical circuits, such as the spinal cord. As a first step toward understanding the potential role local increases in inhibition may have in mitigating the effects of acoustic exposure, I propose to test the hypothesis that transplanted MGE cells will functionally integrate into IC circuits in adult CBA/CaJ mice, mitigating the reduced inhibition seen in noise exposed subjects. Three specific aims are proposed: 1) Characterize the migration and differentiation of MGE cells transplanted into the IC of naïve and noise exposed mice. 2) Determine how transplantation of MGE cells affects auditory behavior in adult CBA/CaJ mice. 3) Determine the effects of MGE cell transplantation on spontaneous and sound-evoked responses of IC neurons in vivo. These experiments represent a novel application of MGE cell transplantation and will improve our understanding of the pathological inhibition that might underlie the formation and persistence of auditory pathologies such as tinnitus and hyperacusis, and in the long run may lead to the development of novel treatment strategies.