听觉感知是人和动物获取外界信息的重要渠道之一。哺乳动物中，听觉感知依赖丘系和非丘系这两条并行且交叉的信息传递和处理通路而完成。丘系通路中的初级听觉皮层（A1）通过跟随声音幅度包络进行反应来实现对声音中包络尺度时域信息的处理。然而，A1中声音时域信息处理能力发育的突触机制还不清楚。此外，非丘系通路中的听觉丘脑与多种高级听觉认知功能紧密相关。然而，在小鼠中，非丘系听觉丘脑在环路层面的解剖连接和功能作用机制尚未解析清楚。本研究中首先采用在体膜片钳记录，对大鼠A1神经元时域信息处理能力发育的突触机制进行探究。实验结果表明，A1神经元时域信息处理能力的发育轨迹呈现出细胞特异性。皮层主要丘脑输入层中椎体神经元的时域信息处理能力在发育过程中得到显著提升。全细胞记录结果显示，幼年动物中很强且缓慢衰减的抑制性输入是限制椎体神经元声音反应跟随能力的主要因素。其次，听觉发育关键期中简短的快速声音刺激暴露，可以显著而持久地加快抑制性输入的衰减速度，从而提高神经元对声音的反应跟随能力。药理学实验进一步证明，在声音暴露和发育过程中抑制性输入发生的变化主要由GABAB受体介导并且依赖NMDA受体的激活。以上结果揭示了抑制性输入在A1椎体神经元发育过程中扮演的关键角色，也强调了感觉经验在听觉系统声音时域信息处理能力发育过程中的重要作用。紧接着，结合转基因小鼠、病毒追踪、光遗传、清醒小鼠多通道胞外电生理和皮层局部场电位（LFP）记录等方式，在解剖连接和功能两个层面探究非丘系丘脑的环路机制。结果表明，非丘系听觉丘脑中不同亚区具有截然不同的全脑连接模式。清醒小鼠的胞外电生理记录结果显示，非丘系较丘系丘脑在声音编码特征的多个方面呈现出显著差异。其次，病毒追踪和电生理结果都提示，非丘系丘脑中神经元对声音的反应会受到众多因素的调控，如其他感觉信息的输入以及动物本身的行为状态。最后通过光遗传和LFP记录证明了非丘系丘脑对皮层中γ振荡的重要贡献作用。本研究的重要意义在于完善了听觉系统时域信息处理在A1中神经元突触输入的发育机制和非丘系听觉通路中丘脑的环路机制。加深了对听觉系统中时域信息处理机制的理解，为非丘系听觉丘脑的进一步功能研究奠定了基础。
Auditory perception is one of the most important sensations for animals and human to acquire information from the surroundings. In mammals, auditory perception is largely depended on two parallel and interconnected pathways-lemniscal and nonlemniscal-to transform and process ascending sound information. Primary auditory cortex (A1) in lemniscal pathway plays a vital role in fulfilling temporal information processing by representing the sound envelops faithfully. However, the synaptic mechanism of developmental cortical temporal processing in A1 remains poorly understood. Besides, thalamus in the nonlemniscal auditory pathway is proved to be involved in a variety of high-level auditory cognitive functions. However, the circuit mechanisms of its anatomical and functional connection in mice are still unclear.In this dissertation, in vivo patch clamp recording on rats was firstly applied to shed light on the synaptic mechanism of developmental cortical temporal processing in A1. The results showed that the developmental trajectory of temporal processing ability in developing A1 was cell type-specific rather than universal. Pyramidal neurons in thalamic recipient layer demonstrated significantly enhanced temporal processing ability during development. Whole-cell recording revealed a strong and long-lasting inhibitory input to single pyramidal neuron in A1 of rat pups, which was proved to be the main factor that restrained temporal processing capacity of pyramidal neurons. Furthermore, brief exposure to sounds at high repetition rate produced significant and long-lasting shortening of inhibition duration, resulting in strongly improved stimulus-following ability of pyramidal neurons. Additional pharmacological experiments suggested that the accelerated inhibition decay during sound exposure and development was mainly mediated by GABAB receptor and relied on the activation of NMDA receptor. These results uncover a critical role of inhibition in temporal processing maturation in A1 and emphasize the importance of sensory experience for development of temporal processing ability in auditory system. Next, Cre-transgenic mice, virus mediated retrograde and anterograde tracing, optogenetics, multichannel extracellular recording for head-fixed awake mice and LFP recording were combined to explore the circuit mechanisms of nonlemniscal auditory thalamus at anatomical and functional levels. Results showed that different divisions of nonlemniscal auditory thalamus formed distinct anatomical connectivity patterns across the whole brain. Multichannel extracellular recording in awake mice further demonstrated significant different properties of sound responses in nonlemniscal auditory thalamus compared with lemniscal part. Moreover, results from both anatomical and electrophysiological experiments suggested that neuronal responses to sound in nonlemniscal auditory thalamus were potentially modulated by many factors, such as multisensory integration and behavioral state of animals. Finally, optogenetic stimulation and local field potential recording proved the contribution of nonlemniscal auditory thalamus to γ oscillation in auditory cortex. The significance of this study lies in revealing synaptic mechanisms underlying the temporal processing ability in auditory system for developing A1, and circuit mechanisms for nonlemniscal auditory thalamus. These findings will greatly promote our understanding on the mechanisms of temporal processing ability in auditory system and lay a solid foundation for further functional exploration of nonlemniscal auditory thalamus.
