基底神经节直接通路与间接通路对行为灵活性的差异性调控作用

PSYCH OpenIR > 健康与遗传心理学研究室

	基底神经节直接通路与间接通路对行为灵活性的差异性调控作用
其他题名	Distinct roles for direct and indirect pathway striatal neurons in behavioral flexibility
	乔艳华
	2015-05
摘要	行为灵活性使我们根据目标选择有效的行动策略，灵活地应对环境变化。药物成瘾、精神分裂、强迫症、自闭症等多种临床疾病都伴随有不同程度的行为灵活性障碍，因此研究者及临床工作者常把行为灵活性作为评估执行功能的主要指标。深入探索行为灵活性的脑机制有助于理解相关疾病成因及寻求治疗方法。研究表明纹状体不同亚区对于行为灵活性有差异化调节作用，腹侧纹状体主要参与注意定势转移，背内侧纹状体则参与反转学习。同时，前人研究得出 D1R类和 D2R 类神经元介导的直接通路和间接通路以纹状体为起始端，分别对于运动性、奖赏、成瘾、学习和反应抑制等具有方向相反的调节作用。这两条通路的纹状体神经元如何调控行为灵活性，以及对于动态的具有可塑性的灵活性转变过程有怎样的作用方式的仍然未知。因此，本研究通过建立小鼠行为灵活性模型，用转基因动物和光遗传学等技术，以纹状体不同类型的神经元作为直接通路和间接通路的调控靶点，探索这两条通路对行为灵活性是否具有差异性调控机制。研究发现，（1）纹状体不同亚区对行为灵活性具有差异性调控作用。慢病毒介导的 TeNT失活背内侧纹状体神经元显著促进了反转学习，减少了反转学习早期的固着反应；失活腹侧纹状体的神经元无显著作用。（2）直接通路和间接通路的纹状体 D1R 类和 D2R 类神经元对行为灵活性具体差异性调控作用。大范围失活背内侧纹状体 D1R 类神经元显著地破坏了动物反转学习能力，造成反转早期固着障碍；失活 D2R 类神经元没有显著作用。局部失活背内侧纹状体前侧（ADMS）的 D1R 类神经元显著降低了反转后期的回归错误；失活 ADMS 的 D2R 类神经元没有显著作用。局部失活背内侧纹状体后侧（PDMS）的 D1R 类神经元显著增加了反转早期的固着错误，而失活 PDMS 的 D2R 类神经元阻断显著减少了反转早期的固着错误。（3）直接通路和间接通路的纹状体 D1R 类和 D2R 类神经元对行为灵活性转变过程具有差异化的调控作用。特异性抑制 D1R类神经元或特异性激活 D2R类神经元均能显著减少反转早期的固着错误，而特异性激活 D1R 类神经元显著增加了反转后期的回归错误。总体上研究表明，直接通路在反转学习过程发挥主导作用，且在反转早期和反转后期有不同的作用机制，反转早期适当抑制直接通路有助于降低固着行为，反转后期过度激活直接通路则会干扰新策略的执行；间接通路在反转学习过程中起协同辅助作用，主要参与反转学习早期。这一结果深化了行为灵活性的脑机制研究，丰富了直接通路和间接通路对执行功能作用机理的认识，并且为探索行为灵活性的转变的动态过程提供了参考。
其他摘要	The ability to make adaptive choices is fundamental to survival. Deficits in behavioral flexibility could be found in many of mental diseases, such as, autistic spectrum disorders (ASD), drug addiction, posttraumatic stress disorders (PTSD), schizophrenia, and so on. Moreover, evaluation of behavioral flexibility is important for diagnosis and treatment of these disorders. Basal ganglia are a chain of subcortical nuclei that facilitate action selection. Striatal output is processed through two discrete projections, the direct and indirect pathways, which are formed by different subtypes of medium spiny projection neurons (MSNs) with distinct anatomical and physiological properties, including differential expression of D1- and D2 dopamine receptors (D1R and D2R). Striatum implies a role in behavioral flexibility. However, the relative contributions of the direct and indirect pathways to flexible behavior remain particularly unclear. The aim of our study is to clarify the cell type in striatum and the pathway in basal ganglia engaging flexible behaviors. The results are shown here. 1) Lentivirus-mediated tetanus toxin (TeNT) expression in dorsomedial striatum facilitated reversal learning by decreasing perseverative errors (PE). While TeNT expression in nucleus accumbens (NAc) core did not affect the reversal. 2) Selective expression of TeNT in D1R but not D2R neurons of dorsal striatum impaired the reversal learning by increasing perseverative errors. Furthermore, limited expression of TeNT in D1R neurons of anterior dorsomedial striatum (ADMS) reduced regressive errors, while PE was increased by this treatment that conducted in D1R neurons of posterior dorsomedial striatum (PDMS). In contrast, TeNT inactivation in D2R neurons of PDMS decreased PE number. 3) Activation of D1R neurons in dorsomedial striatum by optic stimulation impaired the reversal learning through increasing REs, while inhibition of this type of neurons facilitated the reversal performance by reducing PEs. Conversely, activation of D2R neurons decreased the PEs and then increased the reversal learning. Together, these results suggest that D1R neurons in dorsomedial striatum, forming direct pathway, may pay more contributions to strategy switching, compared to D2R neurons in this brain region. Dynamic inhibition of D1R neurons in the early stage of reversal learning reduces perserverative responses and thus accelerates the reversal procedure, while excessive activation of D1R neurons in the late stage disturbs the execution of new strategy. Whereas D2R neurons, as a collaborative role in the process of reversal learning, are mainly involved in the early stage of reversal learning. This study provides convergent support for a dynamic role of direct and indirect pathways in behavioral flexibility. Using this knowledge to guide investigation of circuitry mechanism should lead to the efficacious therapeutic interventions for behavioral inflexibility.
学科领域	医学心理学
关键词	行为灵活性直接通路和间接通路纹状体反转学习光遗传学
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/311026/19649
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	乔艳华. 基底神经节直接通路与间接通路对行为灵活性的差异性调控作用[D]. 北京. 中国科学院研究生院,2015.

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