学习诱导的下丘神经元听觉感受域可塑性的神经机制研究

Learning is an important function of the brain. The auditory system can undergo structural and functional alteration through learning. Brain cholinergic modulation has been proved essential for the receptive field remodeling of sensory neurons arising from learning and experience. Previous studies mainly focus on the cholinergic nucleus basalis (NB) in the basal forebrain. However, it cannot account for all the plastic changes induced by learning and experience. The cholinergic pedunculopotine tegmental nucleus (PPTg) in the brainstem shows enhanced activity during learning, but has received little attention from investigators. My recent finding indicates that the PPTg is another important cholinergic nucleus other than the NB, and it's highly possible that the inferior colliculus (IC) is one of the main targets of PPTg modulation. IC is an important relay centre along the auditory pathway and it receives cholinergic innervations from the PPTg. Thus, by using mouse as a model and methods of electrophysiology, neuropharmacology and histochemistry, the present study is going to investigate the auditory plasticity in IC as induced by activation of PPTg paired with a tone. Despite the cholinergic contribution, sound processing underlying learning-induced auditory plasticity involves a core circuit consisting of IC, thalamus and auditory cortex as well. We are also interested in how the cholinergic PPTg work with the core circuit to create the learning-induced auditory plasticity in IC. Results of this study could lead to better understanding of the mechanism of learning-induced auditory plasticity. It could also shed light on the mechanism of language processing and recovery from damage of auditory system in human brain.

学习是脑的重要功能之一，听觉中枢系统可根据学习的需要可塑性地改变其功能结构以适应声环境。大量研究证实脑的学习功能依赖于胆碱能系统的调控。在这方面针对前脑基核（NB）胆碱能神经元做了较多的研究，但NB核团的作用仅仅是脑内胆碱能调控参与学习的一部分，因此，探求胆碱能调控对学习作用的全貌已成为一个关键的科学问题。申请者最近研究工作显示，脑干的PPTg核团是另外一个重要的胆碱能核团，而下丘极可能也是其主要调控目标之一。因此，本项目拟采用电生理、神经药理学以及组织化学染色等方法，探讨PPTg核团诱导产生下丘神经元听觉感受域可塑性的特点及神经机制。研究结果将有助于完善我们对于学习过程中胆碱能调控机制的理解，提高对学习神经机制的认识，而且对许多精神疾病的识别障碍及神经损伤后的功能恢复的认识富有启示作用。

学习是脑的重要功能之一，听觉中枢系统可根据学习的需要可塑性地改变其功能结构以适应声环境。大量研究证实脑的学习功能依赖于胆碱能系统的调控。我们在当年的项目申请中提出，脑干的PPTg核团是一个重要的胆碱能核团，而下丘极有可能是其主要调控目标之一。因此，本项目对PPTg核团诱导下丘神经元产生听觉感受域可塑性的特点及神经机制进行了深入研究。经过近3年的研究，我们得到了以下的主要成果：. 1. 如项目申请中所假设的，在体研究表明，配对电刺激PPTg核团和特定频率的纯音刺激，可以诱导IC神经元产生频率特异性的听觉感受域可塑性。具体表现为，IC神经元的最佳频率朝着配对刺激的纯音频率偏移。在一些神经元中，IC神经元的最佳频率直接偏移到配对纯音刺激的频率。当IC神经元的最佳频率和配对纯音刺激的频率相同时，IC神经元的最小阈值降低，表现为对声音的敏感性增强。进一步的药理学研究表明，激活PPTg核团导致ACh在IC中释放，ACh作用于配对声刺激反应IC神经元的mACh受体，引起了神经元对该特定频率声的表征增强。mACh受体阻断剂可以完全阻断该感受域可塑性的产生（Luo and Yan, 2015）。. 2. 比较IC神经元与MGB和听皮质神经元感受域可塑性。结果表明，可塑性可以沿着IC-MGB-听皮质中枢听觉通路传递，并且通过听皮质离皮质调控机制得到增强。. 3. 为了研究激活mACh受体条件下频率感受域可塑性的细胞机制，本项目采用膜片钳技术手段深入研究了IC神经元的细胞内特性（刘玲等，2015），以及mACh受体激活下对IC神经元的影响。结果表明，模拟在体条件，激活IC神经元mACh受体并同时注入去极化正电流条件下，可诱导IC神经元产生持续性放电现象（Liu et al., in preparation）。该结果为以上的在体研究提供了坚实的细胞理论依据。. 以上研究结果将有助于完善我们对于听觉学习过程中胆碱能调控机制的理解，提高对学习神经机制的认识，并为进一步的细胞水平的突触调控研究打下坚实的基础。.