Cell-based approach for increasing central auditory inhibition

项目摘要/摘要 多条证据表明，过多的声学暴露会导致耳蜗损伤并减少 听觉中枢抑制，导致时间处理障碍、耳鸣和听力亢进。上一首 纠正这种过度兴奋状态的尝试主要集中在增加GABA能抑制音 系统性地，在提供耳鸣缓解方面取得了一些成功。然而，这些药物的副作用概况 对使用的剂量、持续时间和安全性施加限制。更精确的治疗，在当地增加 抑制听觉核团可以潜在地治疗潜在的病理，同时最大限度地减少偏离靶点的侧面 效果。下丘(IC)是中枢听觉通路的主要皮质下整合中枢。 尤其适合于探索局部增加抑制的影响，因为它在 调节某些声学行为(如间隙检测和预脉冲抑制)，并显示超 声学过度暴露后的兴奋性反应特性。一种潜在的增加抑制的方法 在IC的局部是通过移植来自内侧神经节隆起(MGE)的细胞，即发源地 最终的皮质抑制性中间神经元。虽然天生注定要进入大脑皮层，但移植的MGE 细胞已经被证明在非皮质中存活、整合并增加抑制事件的数量。 环路，如脊髓。作为理解地方增加的潜在作用的第一步 抑制可能在减轻声暴露的影响方面起作用，我建议检验以下假设 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，减轻 在噪声暴露的受试者中出现抑制。提出了三个具体目标：1)描述迁徙和 MGE细胞移植到幼稚和噪声暴露小鼠IC内的分化。2)确定如何 MGE细胞移植对成年CBA/CAJ小鼠听觉行为的影响3)确定MGE的效果 细胞移植对在体IC神经元自发和声诱发反应的影响。这些实验 代表了MGE细胞移植的新应用，将提高我们对MGE细胞移植的认识 可能是耳鸣等听觉病理形成和持续的基础的病理抑制 和听觉过敏症，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.