纹状体腺苷A2A受体通过时相精确性整合多巴胺和谷氨酸信号调控操作性行为

Goal-directed behavior is fundamental to human to adapt to a changing environment and abnormal instrumental learning may underlie obsessive disorders and drug addiction. Adenosine A2A receptors (A2AR) are expressed highly in the cortico-stiratal pathway and can integrate dopamine and glutamate signaling to control striatal synaptic plasticity. Thus, the cortico-stiratal A2ARs are uniquely positioned to control instrumental behavior, a review supported by our recent demonstration that optogenetic activation of striatal A2AR suppressed goal-directed. But how exactly the striatal A2AR integrate the nigro-striatal dopamine and the cortico-striatal glutamate signaling to control instrumental learning? Our main working hypothesis is that the temporally précised arrival and integration of three neurochemical signaling (the striatopallidal A2AR, the cortico-striatal glutamate and the nigro-striatal dopamine) upon the striatal neurons is critical to the coding for the action-reward relationship underlying instrumental behavioral learning. In this study, we will employ our newly developed opto-A2AR method to optogenetically control A2AR signaling in the striatopallidal neurons, coupled with optogenetic control of the cortical glutamatergic neurons and nigral dopaminergic neurons, and with well-controlled instrumental behavioral paradigm, to critically define the temporal relationship among three neurochemical signaling in control of instrumental behavior. The findings from this study will provide the new insight into neurochemical signaling mechanism underlying striatum-dependent instrumental learning but also provide the experimental evidence for developing A2AR-based novel pharmacological approach to control abnormal habit formation with high translational potential for the safety profile of A2AR antagonists in clinical trials.

操作性行为是人和动物适应环境的必备技能，包括目标导向性行为和习惯性行为，二者之间转换的异常是导致强迫症、药物成瘾的重要机制和帕金森病等神经退行性疾病的主要临床症状。目前认为皮层-纹状体通路是调控操作性行为的主要神经环路，来自皮层的谷氨酸信号与来自黑质的多巴胺信号同时到达纹状体并改变突触可塑性，但具体调控机制尚未明确。研究发现高表达于纹状体中的腺苷A2A受体（A2AR）可以调控谷氨酸或多巴胺信号，我们发现与奖赏同步光激活纹状体A2AR可抑制目标导向性行为。因此我们假设：纹状体A2AR在时相上精确整合谷氨酸信号和多巴胺信号，编码行为和奖赏的联系，从而调控操作性行为。本项目采用我们新近建立的瞬时光控A2AR信号（opto-A2AR）结合光遗传学控制谷氨酸和多巴胺信号，阐明A2AR对两种信号的时相精确整合机制。这将有助于深入理解纹状体调控认知功能的机制以及探索A2AR调控精神行为异常的应用价值。

操作性行为是人和动物适应环境的必备技能，包括目标导向性行为和习惯性行为，二者之间转换的异常是导致强迫症、药物成瘾的重要机制和帕金森病等神经退行性疾病的主要临床症状。目前其具体的神经机制尚知之甚少，也缺乏有效的治疗药物。腺苷A2A受体特异性高表达在纹状体的间接通路，可以调控多巴胺和谷氨酸信号。因此，本项目利用光控A2A受体技术、探针信号光纤记录结合双策略平行训练行为范式，阐明研究A2A受体对多巴胺和谷氨酸信号的时相精确性调控。研究发现：1）伏隔核A2A受体对操作性行为具有重要的调控作用，同时不影响“行为-结果”联系建立但影响对奖赏贬值敏感性。2）伏隔核腺苷A2A受体通过调控多巴胺编码的“动机”信号，主要是觉醒成分，影响操作性行为。3）谷氨酸神经元对行为控制有一定的作用，伏隔核A2AR对进一步增强了谷氨酸神经元的行为控制作用。说明谷氨酸信号和A2AR两者发挥协同作用。4）谷氨酸发挥着“感觉-运动/既往学习经验” 信号，在学习的过程谷氨酸信号和腺苷信号存在很小的一个时间窗(0.4-0.8s) ，确定了两者信号在时相精确性的整合机制。综上结果不仅有解析基底神经节调控认知加工理论价值，还有基于A2A受体控制精神行为异常的转化医学意义。