Zhang Baibing, Geddes Claire E, Jin Xin
New Cornerstone Science Laboratory, Center for Motor Control and Disease, Key Laboratory of Brain Functional Genomics, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Sci Adv. 2025 May 23;11(21):eadt0854. doi: 10.1126/sciadv.adt0854.
Action sequencing is fundamental to behavior. A critical decision for survival and reproduction is whether to repeat a current action or switch to a different one. However, the neural mechanisms governing action repetition and switching remain largely unknown. In mice trained to perform heterogeneous action sequences, we found that the M1-DLS circuit regulates action repetition, while the PrL-DMS pathway controls action switching. These distinct functions arise from preferential innervation of striatal D1-SPNs by M1 and D2-SPNs by PrL, respectively. In a Shank3 knockout mouse model of ASD, the D1/D2 innervation ratio in the PrL-DMS pathway was reversed, leading to impaired action switching and repetitive behaviors. Genetic restoration of Shank3 in the DMS rescued both physiological and behavioral deficits. These findings reveal how the brain orchestrates action sequencing in health and disease.
动作序列对行为至关重要。生存和繁殖的一个关键决定是是否重复当前动作或切换到不同动作。然而，控制动作重复和切换的神经机制在很大程度上仍然未知。在经过训练执行异质动作序列的小鼠中，我们发现M1-DLS回路调节动作重复，而PrL-DMS通路控制动作切换。这些不同的功能分别源于M1对纹状体D1-中型多棘神经元（D1-SPNs）和PrL对D2-中型多棘神经元（D2-SPNs）的优先支配。在一个自闭症谱系障碍（ASD）的Shank3基因敲除小鼠模型中，PrL-DMS通路中的D1/D2支配比例发生逆转，导致动作切换受损和重复行为。在DMS中对Shank3进行基因修复挽救了生理和行为缺陷。这些发现揭示了大脑在健康和疾病状态下如何协调动作序列。
