下丘内部抑制性调控网络在优先效应中的作用机制

The precedence effect (PE) occurs when identical paired sounds in rapid succession are presented to the listener and the first arriving sound interferes with the auditory perception induced by the second sound. This auditory phenomenon is thought to resolve the competition between the initial sound and its reflections in an echoic environment and to make the listener accurately localize sound to achieve perfect speech intelligibility. Previous studies on the PE in the central auditory systems of a variety of species have demonstrated neuronal correlates in which the leading sound suppresses the responses of neurons that are spatially sensitive to lagging sounds; however, the underlying mechanisms remain unknown. Although some previous researches have recommended that the inhibitory processes contribute to the suppression of the lagging sound in the central auditory system, the direct evidences are insufficient and the neural mechanism of the PE is still unclearly. The inferior colliculus (IC) is a strategic relay station in the ascending and descending auditory system pathways，in which neurons demonstrate a sophisticated level of processing for complex sound signals. The object of this project is to investigate the mechanism of suppressive circuit within subdivisions in the inferior colliculus of awake guinea pig in PE. Under standard PE sound stimulus, multi-channel in vivo recording would be performed to record neuronal activity of central nucleus of IC from the anaesthetized and awake guinea pigs. According to the connections within the central nucleus, dorsal cortex and external cortex of IC, electrical stimulation or electrolytic lesions would be applied to the commissure of the IC, the dorsal cortex and external cortex ipsilaterally to the recording central nucleus through electrode array. We also investigate the affect on the electrical activity recorded in the central nucleus by the stimulation of the commissure, dorsal cortex and external cortex of IC with the whole-cell patch clamp in vitro. Through these studies, the effect of subdivisions in PE will be observed, and the details of suppressive circuit within subdivisions of IC will be investigated which will be helpful in revealing the the mechanism of suppressive circuit within subdivisions of IC in PE.

听觉优先效应是确保听者在具有回声的复杂声环境中准确定位原始声源的重要生理机制。本项目主要研究豚鼠下丘内部抑制性调控网络在优先效应中的作用及机制。通过在体多通道细胞外记录技术观察麻醉及清醒状态下豚鼠下丘中央核神经元对标准优先效应刺激声的反应；此外，根据下丘不同亚区间的纤维联系，在下丘间联合及同侧下丘外侧和背侧皮质进行电刺激后，进一步电解毁损该区域，观察其对下丘中央核神经元优先效应反应的变化。在动物离体脑片上，电刺激下丘间联合及同侧下丘外侧和背侧皮质，观察下丘中央核放电及突触后电流、突触后电位的变化。通过此研究，可观察下丘不同亚区在优先效应中的作用，探明下丘内部抑制性调控网络的投射方向及递质情况，有利于进一步明确下丘内部抑制性调控网络在优先效应中的作用机制。

良好的声源定位能力是识别言语、获得有意义声信号的重要前提，听觉优先效应是声源定位的一种特殊机制，存在于我们日常生活中的各个场景中，可以帮助我们在复杂声学环境中排除干扰、准确定位目标声源。下丘在优先效应的机制研究中至关重要，明确其内的抑制性投射网络对优先效应形成的影响，有助于我们更好地理解听者在复杂声环境下如何准确进行声源定位，为进一步增强辅听患者声源定位能力进而提高其言语识别能力奠定理论基础｡本项目主要通过神经电生理技术，从离体和在体两方面研究上述问题。关于离体实验方面，我们主要是通过全细胞膜片钳技术结合western blot实验技术明确了：①同侧及对侧下丘背侧皮质对中央核存在GABA能的抑制性投射。②同侧及对侧下丘外侧皮质对中央核不存在抑制性投射。③下丘间联合对中央核存在GABA能和GLY能的抑制性投射。关于在体实验方面，我们主要通过多通道在体细胞外记录技术，发现：损毁下丘背侧皮质之后，中央核神经元在ISD 4ms时滞后声标准化反应明显增加（P<0.05），表明损毁下丘背侧皮质减弱了滞后声压制反应，提示下丘背侧皮质参与了优先效应在下丘中央核的形成。此外，在完成计划研究任务的基础上，根据研究结果对项目内容进行了延伸，通过改变一侧兴奋性上行性输入来观察对下丘抑制性调控网络的影响，目前已得出部分结论：即明确了单侧耳聋之后，由于耳蜗核缺乏一侧的兴奋性输入，导致上橄榄外侧核的兴奋性及抑制性受体表达改变，且聋侧的神经元兴奋性代偿性增强而健侧的神经元抑制性减弱这种兴奋与抑制不平衡的偏侧化改变，进一步造成下丘内的兴奋性与抑制性神经递质及受体表达发生不对称性改变，表明改变一侧兴奋性上行性输入对下丘的抑制性投射网络产生影响。综上，本项目对下丘内部抑制性调控网络及下丘背侧皮质参与优先效应在下丘的形成机制进行了探究，进一步完善了优先效应在下丘的神经生理机制。