前额叶皮层−纹状体的谷氨酸能神经投射在认知弹性行为中的作用研究

PSYCH OpenIR > 健康与遗传心理学研究室

	前额叶皮层−纹状体的谷氨酸能神经投射在认知弹性行为中的作用研究
其他题名	The role of cortico-striatal glutamatergic transmission in cognitive flexibility
	丁学坤
	2014-05
摘要	认知弹性（cognitive flexibility）是生物体适应不断变化的环境所必须的认知功能。多种精神障碍和神经退行性疾病的病人表现出认知弹性功能受损，如药物成瘾、创伤后应激障碍，孤独症和帕金森病等。有研究发现，内侧前额叶皮层−纹状体（medial prefrontal cortex−striatum，mPFC−striatum）的神经回路参与维度外策略转换任务的调控，而眶额叶皮层−纹状体（orbital frontal cortex−striatum, OFC−striatum）的神经通路在维度内策略转换上发挥重要作用。纹状体接收来自额叶皮层的谷氨酸能投射。NMDA受体和AMPA受体是两种主要的离子型谷氨酸受体。这两种受体通过调控突触可塑性，参与学习和记忆的过程。本研究运用行为操作箱评估大鼠定势转移和反转学习两个维度的认知弹性任务。为阐明额叶皮层−纹状体的谷氨酸能神经环路在认知弹性中的作用，本课题从下面两个方面展开研究。 1. 为探索纹状体NMDA受体拮抗对认知弹性的影响，本实验在认知弹性测试前，将AP5（NMDA受体竞争性拮抗剂）分别注射到纹状体的四个亚区，伏隔核核心部（nucleus accumbens，NAc）、NAc壳部、背内侧纹状体和背外侧纹状体。结果显示，拮抗NAc核心部NMDA受体导致动物定势转移功能受损，表现出对先前策略的固着；抑制NAc壳部NMDA受体介导的分子转运过程同样阻碍了定势转移任务的顺利完成，但以回归错误和未强化错误的增加为主。定势转移任务测试完成24小时后，我们测试了动物维度内策略转换的能力，即反转学习。NAc核心部和壳部的AP5注射，都能显著增加反转学习任务完成所需的试次数和回归错误数。该结果提示，阻断NAc的NMDA受体影响了反转学习任务动物对新策略的习得和/或维持。然而，NAc脑区的AP5灌注造成的策略转换功能受损并非由于该处理导致的简单学习能力下降。因为，控制实验结果显示，在初始的视觉线索辨别策略和空间辨别策略习得前对NAc进行NMDA受体拮抗剂灌注没有影响动物的学习能力。与之相对应，背内侧和背外侧纹状体给予AP5灌注对定式转移和反转学习均未诱发显著性改变。已知GluA1亚基的磷酸化和去鳞酸化与GluA2-缺乏的AMPA受体膜浆转位和突触可塑性改变相关。而NMDA受体激活的细胞内分子路径又是调控GluA1受体磷酸化与去磷酸化的关键因素。因此，我们进一步应用NASPM（GluA2-缺乏的AMPA受体拮抗剂）评估纹状体不同亚区GluA2-缺乏的AMPA受体在认知弹性中的作用。结果显示，除在NAc核心部灌注对于反转学习具有易化作用外，纹状体其他脑区的NASPM注射未能显著影响影响动物认知弹性样行为。该部分实验结果提示，相对于背侧纹状体，NAc的NMDA受体介导的谷氨酸能神经传递在调控认知弹性中发挥更大作用。 2. 为明确前额叶皮层−纹状体神经环路是否特异性地参与了维度外策略的任务转换，我们应用c-Fos蛋白免疫组织化学印迹的方法，检测了定势转移任务中mPFC和纹状体的神经元激活状态。结果显示，单独的记忆提取和策略转换都使得mPFC和纹状体的大量细胞激活。然而，与仅接受旧策略的提取和表达组动物相比，在记忆提取后进行策略转换的动物边缘前皮层（prelimbic cortex，PL）和NAc核心部c-Fos表达量显著降低。提示PL到NAc核心部神经投射的动态活性改变可能参与了从已习得策略到新策略转换的整个过程。此外，我们应用神经逆行示踪技术标记了投射到NAc的脑区。我们发现，NAc核心部接收来自PL，边缘下皮层（infralimbic cortex, IL），前扣带回（anterior cingulated cortex, ACC），丘脑背外侧核（mediodorsal thalamic nucleus, MD），杏仁核（amygdala, AMY）和腹侧海马（ventral hippocampus, vHIP）的神经投射，而NAc壳部接受来自OFC，MD、AMY和vHIP的神经投射。最后，我们发现GABA(A)受体激动剂muscimol定位失活PL脑区促进了定势转移任务的完成，对反转学习没有任何影响。该部分研究结果提示，PL-NAc核心部的谷氨酸能神经传递可能主要参与维度外策略转换过程，并通过抑制先前策略的提取或降低对不适合策略的应答发挥对认知弹性的调控作用。
其他摘要	Cognitive flexibility is a critical ability for adapting ever-changing environment in human and animal. Deficits in cognitive flexibility are observed in many kinds of psychic disorders and neurodegenerative diseases, such as drug addiction, post-traumatic stress disorder (PTSD), autistic spectrum disorder (ASD) and Parkinson’s disease. Previous studies reveals the circuits of medial prefrontal cortex (mPFC) and orbital frontal cortex (OFC) to striatum respectively play important roles in extra-and intra-dimensional strategies switch. However, exact function of striatum in flexible behaviors is still unclear.Striatum receives glutamatergic projections from frontal cortex. N-methyl D-aspartatereceptor (NMDA receptor) and α-amino-3-hydroxy-5-methylisoxazole-4-propionatereceptor (AMPA receptor, AMPAR) are two main kinds of glutamatergic receptors, which participate in controlling synaptic plasticity required in learning and memory processes. In the present study, set-shifting and reversal learning tasks were tested in operant chambers in rats. In order to elucidate the role of cortical-striatal glutamatergic transmission in cognitive flexibility, we conducted two parts of experiments as belows: 1. To clarify the effects of blocking NMDA receptor in striatum on flexible behaviors, AP5 was respectively infused into different subregions, including nucleus accumben (NAc) core, NAc shell, dorsalmedial striatum (DMStr) and dorsalateral striatum (DLStr), before behavioral tests. The results showed that blockade of NMDA receptor in NAc core impaired set-shifting function by elevating perseverative errors, whereas suppression of NMDA receptors-mediated transmission in NAc shell induced a deficit in set-shifting by enhancing regressive and non-reinforced errors. These findings indicate that activation of NMDA receptors in NAc core contributes to modify existing knowledge, while NMDA receptors in NAc shell play more important roles in novel strategy learning and maintenance. Reversal learning, an intra-dimensional strategy switch task, was tested 24 hours after set-shifting test. Infusion of AP5 into NAc shell and core significantly increased the total trials to criterion and regressive errors, indicating that AP5 treated rats have dysfunction in novel strategy learning and/or maintenance. Behavioral inflexibility induced by blocking NMDA receptors in NAc does not result from learning disability, because AP5 infusion into neither NAc core nor shell produced any change in initially cue-associated or spatial-discriminated learning. In contrast, no alteration was induced by AP5 infusion into DMStr or DLStr in set-shifting or reversal learning. Activation of NMDA modulates GluA1 subunit phosphorylation and dephosphorylation which is associated to GluA2-lacking AMPARs trafficking and long-term plastic changes. Here we further used NASPM, a selective GluA2-lacking AMPAR antagonist,to assess the effects of blocking GluA2-lacking AMPARs in the different striatal subregions on behavioral flexibility. Intriguingly, NASPM only facilitated reversal learning in NAc core but not NAc shell or dorsal striatum. These findings together suggestthat NMDA receptor-mediated glutamate transmission in NAc makes more contribution to cognitive execution than that in dorsal striatum. 2. To elucidate whether mPFC-striatum circuit specifically participates in the shifting between extra-dimensional strategies, we assessed the neuronal activation of mPFC and striatum areas after set-shifting test by immunohistochemical staining of cFos protein. Both tasks of memory retrieval and strategy switch induced robust increases in mPFC and striatum. However, compared to those that only retrieved the previous memory of reward and cue association, the rats which experienced the strategy switch from the visual-cue to location response showed a significant decreased cFos expression in prelimbic cortex (PL) and NAc core, butnot other subregions of mPFC or striatum. These results indicate that the dynamic changes in activation of projection from PL to NAc core may be involved in the shifting from utilizing the previous learned strategy to developing a new appropriate tactic. Furthermore, using retrograde tract-tracing approach, we presented the brain regions projecting to striatum. NAc core receives the projections from PL, infralimbic cortex (IL), anterior cingulated cortex (ACC), mediodorsal thalamic nucleus (MD), amygdala (AMY) and ventral hippocampus (vHIP), whereas NAc shell gets projections from orbitofrontal cortex (OFC), MD, AMY and vHIP. Finally, we demonstrated that inactivation of PL area by infusion muscimol, a GABA(A) receptor agonist, facilitated set-shifting performance but did not affect reversal learning. Together with results of cFos expression and retrograde tracing, the findings here suggest that PL-NAc core glutamatergic transmission might make a contribution to extra-dimensional strategies switch by suppressing the memory retrieval or inhibiting the response that is no longer appropriate.
学科领域	医学心理学
学位类型	硕士
语种	中文
学位专业	心理学
学位授予单位	中国科学院研究生院
学位授予地点	北京
文献类型	学位论文
条目标识符	http://ir.psych.ac.cn/handle/311026/19507
专题	健康与遗传心理学研究室
作者单位	中国科学院心理研究所
推荐引用方式 GB/T 7714	丁学坤. 前额叶皮层−纹状体的谷氨酸能神经投射在认知弹性行为中的作用研究[D]. 北京. 中国科学院研究生院,2014.

条目包含的文件
文件名称/大小	文献类型	版本类型	开放类型	使用许可
丁学坤-硕士学位论文.pdf（6488KB）	学位论文		限制开放	CC BY-NC-SA	请求全文