α-Synuclein Selectively Impairs Motor Sequence Learning and Value Sensitivity: Reversal by the Adenosine A2A Receptor Antagonists
α-Synuclein Selectively Impairs Motor Sequence Learning and Value Sensitivity: Reversal by the Adenosine A2A Receptor Antagonists
复制标题
α-突触核蛋白选择性损害运动序列学习和价值敏感性：腺苷 A2A 受体拮抗剂的逆转
DOI：
10.1093/cercor/bhab244
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发表时间：
2021-08-03
期刊：
影响因子：
3.7
通讯作者：
Chen, Jiang-Fan
中科院分区：
文献类型：
--
作者：
He, Yan;Huang, Linshan;Chen, Jiang-Fan
帕金森病（PD）的病理特征是α -突触核蛋白（α -syn）聚集，临床特征是运动和认知缺陷，包括顺序学习和习惯学习障碍。通过脑内注射WT和A53T突变α - syn原纤维，我们通过严格确定α - syn对基于模型的目标导向行为、无模型（基于概率的）习惯学习和分层组织顺序学习的影响，研究α - syn对PD患者程序学习缺陷的行为机制。1)与人们普遍认为的早期PD的习惯学习缺陷相反，α - syn聚集在背内侧纹状体（DMS）和背外侧纹状体（DLS）中并不影响习惯学习的习得，但选择性地损害了目标导向行为，降低了价值敏感性。2) DLS （DMS）和SNc中的α - syn通过影响序列起始和降低第一步精度来选择性地损害序列学习。3)腺苷A2A受体（A2AR）拮抗剂KW6002选择性改善序列学习，优先改善序列学习的启动和转移以及行为反应性。这些发现证实了α - syn在SN-DLS通路中的序列学习缺陷和DMS α - syn在目标导向行为缺陷中的偶然作用，并提出了一种新的治疗策略，通过增强A2AR拮抗剂的序列启动来改善PD的序列学习缺陷。
Parkinson's disease (PD) is characterized pathologically by alpha-synuclein (alpha-Syn) aggregates and clinically by the motor as well as cognitive deficits, including impairments in sequence learning and habit learning. Using intracerebral injection of WT and A53T mutant alpha-Syn fibrils, we investigate the behavioral mechanism of alpha-Syn for procedure-learning deficit in PD by critically determining the alpha-Syn-induced effects on model-based goal-directed behavior, model-free (probability-based) habit learning, and hierarchically organized sequence learning. 1) Contrary to the widely held view of habit-learning deficit in early PD, alpha-Syn aggregates in the dorsomedial striatum (DMS) and dorsolateral striatum (DLS) did not affect acquisition of habit learning, but selectively impaired goal-directed behavior with reduced value sensitivity. 2) alpha-Syn in the DLS (but not DMS) and SNc selectively impaired the sequence learning by affecting sequence initiation with the reduced first-step accuracy. 3) Adenosine A2A receptor (A2AR) antagonist KW6002 selectively improved sequence learning by preferentially improving sequence initiation and shift of sequence learning as well as behavioral reactivity. These findings established a casual role of alpha-Syn in the SN-DLS pathway in sequence-learning deficit and DMS alpha-Syn in goal-directed behavior deficit and suggest a novel therapeutic strategy to improve sequence-learning deficit in PD with enhanced sequence initiation by A2AR antagonists.