基底前脑对听觉稳态反应的影响及其在精神分裂症听觉功能异常中的作用

Under the stimulation of acoustic signals with a specific rhyme(30-60Hz),auditory cortex neurons generally show electoral responses synchronizing to the rhyme of stimulation. This phenomenon is called as auditory steady state response (ASSR). The patients of schizophrenia often have a deficit of ASSR. However, the mechanism of ASSR abnormality remains unclear. Basal forebrain (BF) contains cholinergic，glutamatergic and GABAergic neural projection systems，regulating the excitability and coherence of cortical neurons. Therefore, BF may play an important role in the mechanism of ASSR. Because the tree types of neuons mixed in BF, we donot know the detailed effects of each neuron type on ASSR. In the present study, we, for the first time, apply optogenetic techniques to selectively activate or inhibit the cholinergic，glutamatergic and GABAergic neurons, while recording the action potentials and local field potential of auditory cortex. We will systemically analyze the roles of BF neuronal activity in the ASSR. Furthermore, we will use the animal models of schizophrenia to investigate the effects of BF on the abnormality of ASSR,in order to find a way to rescue the dysfunction of ASSR and provide a new strategy for the treatment of schizophrenia.

正常大脑听皮层在特定节律的声音刺激（30-60Hz）下会出现与刺激节律一致的同步化神经电反应，称为听觉稳态反应（ASSR）。大量临床研究已发现精神分裂症患者常出现ASSR异常。但目前有关ASSR的产生机制和异常原因尚不清楚。基底前脑（BF）包含胆碱能，谷氨酸能和GABA能神经元等多种上行投射系统，负责调节大脑皮层神经元的兴奋性，因而BF在ASSR形成过程中可能发挥重要作用。由于BF内胆碱能神经元与其它神经元混合在一起，我们还不清楚它们各自对ASSR有何具体作用。本项目将首次利用光遗传学技术分别单独控制BF内三种神经元的活动，同时记录听皮层内神经元动作电位和局部场电位信号，全面系统地分析ASSR的形成机制和BF的调控作用。进一步我们还将在精神分裂症模型动物上，检验BF对ASSR异常有何影响，力图找到缓解ASSR异常的方法，为精神分裂症的治疗提供新途径.

在本项目执行期间，我们应用在体多通道神经电生理记录技术，系统研究了清醒大鼠和小鼠大脑听皮层(AC)，前额皮层（PFC）,海马（HP）, 杏仁核（AMY）和内侧膝状体（MGB）等区域听觉稳态反应（ASSR）的特征。证实了从MGB到AC颗粒细胞层的听觉传导路可能是形成皮层ASSR的主要来源。通过采用麻醉药，足底电刺激和头部固定等处置手段，诱导实验动物分别处于意识丧失，情绪激惹或自发运动的状态，探讨了各种行为状态下ASSR的变化，证实皮层ASSR是一种较为可靠的评价脑神经系统兴奋性活动的指标。我们还将光遗传技术和电生理记录相结合，证实了基底前脑（BF）胆碱能和谷氨酸能神经元对AC的ASSR具有正向调控的作用，而GABA能神经元具有负向调控的作用。我们还系统研究了精神分裂症动物模型中ASSR异常的特征，并发现MGB-AC传导路中NMDAr受体低功可能是ASSR降低的原因，而激活BF胆碱能或谷氨酸能神经元可以纠正ASSR异常。这些研究成果有力地推进了我们对大脑感觉神经中枢工作机理的了解，为寻找防治脑认知障碍的新策略提供了理论依据。截止本报告撰写时，本项目共发表SCI论文10篇,另有两篇已经投稿。