光控腺苷A2A受体时空特异性探索皮层纹状体通路突触前膜腺苷A2A受体对认知可塑性的调控作用

Behavior cognitive flexibility is fundamental to human and animal adaptation to the changing environment and controlled by the corticostriatal pathway. Impaired behaviorally cognitive flexibility are observed in many psychiatry diseases and there is no effective medicine and ideal therapeutic target for this deficiency. Our previous work and the data of preliminary experiment found that specific deletion of postsynaptic adenosine A2AR in the whole striatum would significantly improve the behaviorally cognitive flexibility, which indicated A2AR may be one of potential therapeutic targets in treating the deficits of behaviorally cognitive flexibility. But due to the fact that the different and opposite function of corticostriatal presynaptic and postsynaptic A2AR on the controlling dopamine and glutamine signaling and other behaviors and the limitation of available approaches unable to spatialtemporally modulate the presynaptic A2AR ,which severely dampen the research of A2AR as be a potential and efficient therapeutic target.So the goal of this project is, using the opto A2AR approach, to spatialtemporally activate corticostriatal presynaptic A2AR to critically evaluate their effect on the cognitive flexibility, especially in different timing (cue, lever pressing and reward). Meanwhile, we will selectively knockdown the presynaptic A2AR by cre-lopx system to further confirm the results. Eventually, we hope we can provide robust experiment data to support A2AR as an effecient target to improve the cognitive flexibility.

行为认知可塑性是人和动物能良好适应环境的基本能力，受控于皮层纹状体通路，其功能降低是多种精神类疾病的共同表症，但至今缺少有效药物和靶点。基于已发表的文献和本项目预实验结果，我们发现特异性敲除纹状体腺苷A2A受体（A2AR）能明显改善动物的行为认知可塑性。但是由于皮层纹状体通路突触前膜和突触后膜A2AR主要通过调控多巴胺信号和谷氨酸信号而对多种认知行为产生不同甚至相反的作用。而受现有技术的限制，无法在活动动物上时空特异性地调控突触前膜，严重阻碍了A2AR作为药物靶点的研究。因此本项目拟通过光控激活A2AR（opto-A2AR）技术，在不同的时间窗口（Cue 出现时，压杆时，奖赏时），时空特异性激活皮层纹状体突触前膜A2AR，阐明该通路突触前膜A2AR对认知可塑性的调控作用及对谷氨酸信号时相精准调控机制，最后通过cre-loxP技术特异性敲除突触前膜A2AR，进一步验证突触前膜A2AR的功能。

行为认知可塑性是人和动物能良好适应环境的基本能力，其功能降低是多种精神类疾病和药物滥用的共同表症，但至今缺少有效药物和靶点。本项目首先发现特异性敲除伏隔核（NAc）腺苷A2A受体（A2AR）能明显改善动物的行为认知可塑性和目标导向性行为。随后通过光控激活A2AR（opto-A2AR）技术，在奖赏时出现时，瞬时特异性激活NAc 间接通路神经元胞体A2AR（病毒注射及光纤插入位点都在NAc），发现间接通路神经元胞体A2AR主要通过对奖赏（多巴胺）信号的时相精准调控作用，抑制动物目标导向性行为。而将病毒注射在NAc，光纤植入腹侧苍白球（VP）位点， 在奖赏的同时瞬时激活伏隔核腹侧苍白球末梢（突触前膜）的A2AR，发现瞬时激活伏隔核腹侧苍白球突触前膜的A2AR能促进目标导向性行为。同时我们发现给予A2AR的拮抗剂能明显抑制皮层纹状体通路大麻素1型受体过度激活所引起的习惯性行为及星型胶质细胞大麻素1型受体过度激活所引起的工作记忆损伤。我们的结果提示A2AR 有望成为治疗精神类疾病和药物滥用引起的认知障碍的有效靶点之一。