正常及延长觉醒条件下组胺系统对内嗅皮层III层锥体神经元功能活动及其空间信息处理的影响

The encoding, acquisition and retrieval of the spatial learning and memory depends on a good arousal state, which is primarily maintained by the arousal-promoting systems including histaminergic system. As the gateway of the hippocampus, entohinal cortex plays a crucial role in the spatial learning and memory. Our previous study found that the histamine system is involved in the spatial reference memory by the regulating the layer II stellate neurons in the entorhiral cortex. However, the effects of histaminergic system on the layer III pyramidal neurons-related spatial working memory remain unclear. Hence, the present project will firstly use whole-cell patch-clamp recording and two-photon calcium imaging methods to investigate the effects of the histamine on the layer III pyramidal neuron excitability and the underlying receptor, intracellular signaling pathway and ionic channel mechanisms. On this basis, we will explore the influence of the histaminergic system on the spatial memory-related neural network oscillatory activity in the layer III of the entorhinal cortex. Finally, the present project, combining with clinical practice, will explore the changes in the spatial information processing, as well as the alterations in histaminergic modulation of the layer III of the entorhinal cortex under prolonged wakefulness condition. The aims of the present project is to reveal the neural mechanisms underlying the histaminergic modulation of spatial working memory in the entorhinal cortex during normal wakefulness, and the neural mechanisms of the impairment in the spatial cognition during extended wakefulness condition.

空间学习记忆编码，获得及提取依赖于良好的觉醒状态。而觉醒状态的维持依赖于组胺等促觉醒系统的调控。内嗅皮层作为海马的“门户”，在空间学习记忆过程中具有重要的作用。前期本研究室发现组胺通过调控内嗅皮层II层星状神经元参与空间参考记忆，而组胺觉醒系统对内嗅皮层III层锥体神经元相关的空间工作记忆调控及其神经机制还不清楚。为此,本项目拟先采用膜片钳和双光子成像技术,观测组胺对内嗅皮层III层锥体神经元兴奋性的影响及相应的受体，胞内信号通路及离子通道机制。在此基础上，进一步采用多通道记录和光遗传技术，观察组胺系统对空间记忆相关的内嗅皮层III层神经网络振荡活动的影响。最后，本项目结合临床实际，探讨延长觉醒条件下，内嗅皮层III层神经元神经网络处理空间信息的特征及组胺对其调控的变化。以期在神经网络水平上，揭示在正常觉醒下组胺觉醒系统关联空间工作记忆及延长觉醒条件下空间认知功能受损的在体神经电生理机制。

空间学习记忆的获得及提取依赖于良好的觉醒状态。而觉醒状态的维持依赖于组胺等促觉醒系统的调控。内嗅皮层作为海马的“门户”，在空间学习记忆过程中具有重要的作用。本项目采用多通道记录技术和神经药理学技术,观测组胺对内嗅皮层浅层谷氨酸能神经元的兴奋性、网络振荡的影响以及相应的受体机制。组胺剂量依赖地增加内嗅皮层浅层神经元放电频率，并能增加内嗅皮层浅层局部theta和gamma振荡的能量、神经元的放电-theta相位锁定以及gamma-theta的耦合。组胺的这种调控作用是通过激活H1R和H3R实现的。在此基础上，我们进一步探讨了组胺对内嗅皮层浅层空间编码相关功能神经元的影响。内嗅皮层浅层局部给予组胺不影响空间编码相关的网格细胞和边界细胞的功能特性。我们也发现给予组胺后可增加内嗅皮层浅层c-fos表达，表明组胺可增加内嗅皮层浅层神经元的兴奋性。最后，采用行为学检测技术，我们探讨组胺觉醒系统对内嗅皮层浅层相关的空间学习记忆的影响。内嗅皮层浅层局部给予H1R阻断剂可显著损害大鼠空间学习记忆。综上，本项目研究揭示组胺能促觉醒系统调控内嗅皮层浅层信息编码，进而参对空间认知功能。该研究为觉醒关联学习记忆提供了理论依据，并为临床改善认知功能障碍提供了方向。