健康与遗传心理学研究室知识库

认知灵活性是个体根据目标需求和环境线索的变化，相应地灵活地选择行为策略、以适应多样环境并得以生存的必要能力。多种精神类与神经发育类疾病都伴随有不同程度的认知灵活性损伤，如自闭症、精神分裂、强迫症、药物成瘾等等。前人的大量研究表明，背侧纹状体是维持与调控认知灵活性的关键脑区，而临床上亦有发现背侧纹状体相关神经环路的异常会导致自闭症病人出现认知灵活性方面的行为障碍。本实验室前期研究提示，背内侧纹状体后侧（pDMStr）在小鼠反转学习中起到更为主导的作用，但该脑区内主要的两类神经元以及它们介导的通路是如何影响认知灵活性的，目前还尚不清楚。
因此，本研究通过小鼠的反转学习行为模型，采用光遗传、免疫组化、钙成像及化学遗传调控等行为学、神经调控和在体成像技术，结合转基因小鼠工具，对pDMStr中的D1R-MSNs与D2R-MSNs在认知灵活性中的调控机制进行探索，并在作为自闭样行为模型的Fmr1-KO小鼠上进行进一步分析和验证。研究结果显示：
（1）人为激活pDMStr中的D1R类神经元能够加快促进反转学习的完成，而特异性抑制D1R类神经元、或激活D2R类神经元则会阻碍减缓反转学习的进行。在整个反转学习的过程中，D1R-MSNs相对起到更为主导的作用，D2R-MSNs从旁平衡协助反转学习的完成。
（2）在pDMStr的D1R-MSNs的下行通路中，纹状体-苍白球通路，特别是背内侧纹状体后部（pDMStr）—内侧苍白球（MGP）通路对认知灵活性起到主要的影响，激活该通路能够促进反转学习。
（3）Fmr1-KO小鼠在虚拟实境T迷宫中表现出反转学习的障碍。实时钙信号记录显示pDMStr-MGP在正确得到奖赏时呈现出短时间的钙信号上升，Fmr1-KO小鼠较WT小鼠的钙信号上升变化幅度更弱；而在反转学习错误未得到奖赏时，pDMStr-MGP通路的钙信号会由于预期获得奖赏而短暂上升，随后由于未能真的得到奖赏而下降，在Fmr1-KO小鼠中，这两个信号变化的幅度也都较WT小鼠更弱。
（4）采用化学遗传提高pDMStr-MGP的神经活性能够成功恢复Fmr1-KO小鼠的反转学习障碍，而对初期训练时的基本学习能力无影响；钙成像记录显示，在初期学习和反转学习中，化学遗传提高Fmr1-KO小鼠pDMStr-MGP活性能够提升通路对奖赏获得、奖赏预期和奖赏缺失这些反馈信息的钙信号变化强度。
（5）对虚拟实境T迷宫反转学习时的特定事件相关神经活动进行调控，采用光遗传刺激特定在小鼠进入正确臂、获得奖赏时激活pDMStr-MGP通路对反转学习未见显著的提升；而特定在小鼠进入错误臂、未能获得奖赏时激活pDMStr-MGP通路，Fmr1-KO小鼠的反转学习水平显著提高。
总体而言，pDMStr-MGP神经通路在个体获取、整合并利用外界信息反馈时发挥着重要作用，个体在进行反转学习时，通过pDMStr-MGP的调节来获取的与奖赏、奖赏缺失的相关信息，从而调整策略、习得新的应对方式

Cognitive flexibility is the ability to flexibly shift strategies to adapt to the ever-changing environment and to survive. Many mental diseases and neurodevelopmental disorders are reported to be accompanied by varying degrees of cognitive flexibility impairments such as autism spectrum disorders (ASD), schizophrenia, obsessive compulsive disorder (OCD), drug addiction and so on. Previous studies have shown that the dorsal striatum is a key brain region for maintaining and regulating cognitive flexibility. Clinically, abnormalities in the dorsal striatum-related neural circuits have been found to result in the cognitive inflexibility in autism patients. Preliminary works in our laboratory suggested that the posterior part of the dorsal medial striatum (pDMStr) plays a more dominant role in reversal learning in mice, but the mechanism of the two main types of neurons in the pDMStr and their projections to modulate the cognitive flexibility are still unclear.
Thus, in this study, we applied the mice reversal learning as a cognitive flexibility testing model. We used several behavioral, immunohistochemistry, neuronal modulating and in vivo calcium imaging techniques to investigate the D1R-MSNs and D2R-MSNs in the pDMStr in influencing the cognitive flexbility. And then we induced the Fmr1-KO mice as a model for repetitive and compulsive behavior to further confirm the circuits functions. We gathered several interesting observations in this study.
1) The D1R-MSNs in the pDMStr played a more crucial role in the cognitive flexibility. Activating the D1R-MSNs in pDMStr promoted the reversal learning, while activating the D2R-MSNs slowed down the reversal learning.
2) The pDMStr-medial global pallidus (MGP) projection mainly played a leading role in the cognitive flexibility.
3) During reversal learning, when the mice went into the wrong arm, the calcium activities in pDMStr-MGP increased as a signal for the ‘reward-expectation’. Since mice would not get the reward eventually, the calcium activities would then decreased as a reaction for the ‘reward-omission’. Those signals were both weaker in the Fmr1-KO mice compared to the WT mice.
4) Chemogenetically enhanced the activity of the D1R-MSNs inthe pDMStr-MGPcircuit in Fmr1-KO mice during the reversal learningcould improve the performance of reversal. The calcium signals for reward, reward-expectation and reward-omission were also been improved.
5) Optogenetically neuronal excitating the pDMStr-MGP during the non-reward period, the performance of the reversallearning significantly promoted, while the excitation during the reward period had less obvious effect on the reversal learning.
In general, the pDMStr-MGP pathway plays an important role in acquisition, integration, and utilization of the environmental information feedbacks. When individuals perfer the reversal learning, they received information related to rewards and non-rewards through pDMStr-MGP neuronal functions. And these information assist individuals to adjust strategies to cope with the changing environment.