儿茶酚胺类递质调控认知功能的前额叶皮层机制研究

Cognitive functions associated with prefrontal cortex (PFC) are strongly influenced by catecholamine [dopamine (DA) and norepinephrine (NE). Traditionally, the impact of these transmitter systems on cognitive functions or post-synaptic cellular physiology is often characterized one at a time, i.e. the impact of DA or the impact of NE on specific parameters of neuronal or circuit functions. Under physiological state, these two transmitters exert powerful regulation on neuron and neuronal circuitry activities underling cognitive functions via activation of a number of membrane-bound receptors and their complicated downstream pathways in the PFC. Therefore, a critical step in addressing the issue of neuromodulator influences on cognitive functions would be to consider the whole effects of these two transmitters. Ritalin, a nervous stimulant, can raise the levels of DA and NE in the brain, and can excerts powerful regulation on cognitive functions. Probed by Ritalin to improve behavioral cognitive function, this project integrates a variety of behavioral, electrophysiological and molecular methods, to clarify the following scientific questions: 1. Behavioral beneficial dose of Ritalin in different behavior cognitive-related tasks. 2. The correlation between cognitive improvement and dynamic expression of NMDA and AMPA receptor. 3. The correlation between dynamic expression of NMDA and AMPA receptor, and the increase in neuronal circuitry activity underlying prefrontal cognitive functions. Our primary results revealed that the cognitive-effective doses of Ritalin are matched well to the typical “inverted U type” feature of catecholamine neurotransmitters. And the cognitive-improvement effect of Ritalin is associated with the enhancement in the expression and function of membrane NMDAR in the PFC. In this project, we aim to identify the downstream signaling mechanism underlying NMDAR expression up-regulation, and sought to explore the correlation between NMDAR function potentiation and cognitive improvement, as well as and the increase in neuronal circuitry activity underlying prefrontal cognitive functions. These results supported the proposal of this project. The accomplishment of this project will elucidate the molecular mechanism and neural circuits underlying cognitive function, and will provide experimental evidence for neuropsychiatry disease and their clinical treatment strategies.

儿茶酚胺类递质多巴胺（DA）和去甲肾上腺素（NE）分别通过不同的受体和信号通路影响前额叶神经元和神经回路功能，对前额叶皮层认知功能实施复杂的调控。以往研究往往针对单一递质，但在生理状态下，DA和NE的共同作用调控认知功能的机制尚不清楚。神经兴奋剂利他林（Ritalin）可以同时提高脑内DA和NE浓度，对认知功能产生调控作用。本项目从整体、细胞和分子水平，以利他林为工具药，拟阐明：行为学上利他林的认知功能改善效应，1）与前额叶皮层NMDA受体表达量的相关性, 揭示NMDA受体的动态表达以及胞内分子调控机制；2）对认知功能相关神经回路产生的影响。前期结果显示：利他林对工作记忆的影响与递质浓度的“倒U”型特征有相似性，对工作记忆的改善与NMDA受体的动态表达呈正相关，提示本项目的研究目标可行性强。本项目的完成，将为阐明认知功能的分子和环路机制提供实验证据，为相关神经精神疾病的治疗策略提供思路。

儿茶酚胺类递质多巴胺（DA）和去甲肾上腺素（NE）分别通过不同的受体和信号通路影响前额叶神经元和神经回路功能，对前额叶皮层认知功能实施复杂的调控。以往研究往往针对单一递质，但在生理状态下，DA和NE的共同作用调控认知功能的机制尚不清楚。神经兴奋剂利他林（Ritalin）可以同时提高脑内DA和NE浓度，对认知功能产生调控作用。我们综合行为学、脑片膜片钳电生理和免疫印迹技术，从整体、细胞和分子水平研究利他林调控认知功能的前额叶皮层机制。主要研究结果：（1）利他林对认知功能的调控与前额叶皮层NMDA受体表达和功能呈正相关。改善工作记忆剂量的利他林上调前额叶NMDA受体的表达和功能，反之，损害认知功能剂量的利他林降低前额叶NMDA受体表达和功能；（2）利他林上调NMDA受体的胞内机制。cAMP-PKA和PLC-PKC通路均参与利他林对NMDA受体GluN2B亚基表达的上调，但是只有PLC-PKC通路参与利他林对GluN2B亚基在突触上表达的上调。（3）利他林对前额叶NMDA和AMPA受体表达的上调具有不同的时程效应。利他林可以使NMDA受体表达呈快速一过性上调，而AMPA受体表达和功能上调效应出现较慢，持续时间较长。而且，AMPA受体表达的上调依赖于NMDA受体表达的上调。（4）利他林改善工作记忆的效应是通过上调前额叶NMDA受体GluN2B亚基（不是AMPA受体）的表达和功能实现的；利他林对行为抑制的改善是通过上调前额叶AMPA受体表达和功能实现的。本项目的实施阐明了生理状态下前额叶DA和NE调控认知功能的细胞和分子机制，为探寻相关神经精神疾病发病机制和寻找治疗策略提供了神经生物学证据。