Lee Andrew S, Arefin Tanzil M, Gubanova Alina, Stephen Daniel N, Liu Yu, Lao Zhimin, Krishnamurthy Anjana, De Marco García Natalia V, Heck Detlef H, Zhang Jiangyang, Rajadhyaksha Anjali M, Joyner Alexandra L
Developmental Biology Program, Sloan Kettering Institute, New York, NY, USA.
Neuroscience Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.
Nat Commun. 2025 Feb 21;16(1):1858. doi: 10.1038/s41467-025-57080-6.
The capacity of the brain to compensate for insults during development depends on the type of cell loss, whereas the consequences of genetic mutations in the same neurons are difficult to predict. We reveal powerful compensation from outside the mouse cerebellum when the excitatory cerebellar output neurons are ablated embryonically and demonstrate that the main requirement for these neurons is for motor coordination and not basic learning and social behaviors. In contrast, loss of the homeobox transcription factors Engrailed1/2 (EN1/2) in the cerebellar excitatory lineage leads to additional deficits in adult learning and spatial working memory, despite half of the excitatory output neurons being intact. Diffusion MRI indicates increased thalamo-cortico-striatal connectivity in En1/2 mutants, showing that the remaining excitatory neurons lacking En1/2 exert adverse effects on extracerebellar circuits regulating motor learning and select non-motor behaviors. Thus, an absence of cerebellar output neurons is less disruptive than having cerebellar genetic mutations.
大脑在发育过程中补偿损伤的能力取决于细胞损失的类型，而同一神经元中基因突变的后果则难以预测。我们发现，当兴奋性小脑输出神经元在胚胎期被切除时，小鼠小脑外部会产生强大的补偿作用，并证明这些神经元的主要作用是参与运动协调，而非基础学习和社交行为。相比之下，小脑兴奋性谱系中同源盒转录因子Engrailed1/2（EN1/2）的缺失会导致成年期学习和空间工作记忆出现额外缺陷，尽管仍有一半的兴奋性输出神经元保持完整。扩散磁共振成像显示，En1/2突变体的丘脑 - 皮质 - 纹状体连接性增加，表明剩余缺乏En1/2的兴奋性神经元对调节运动学习和特定非运动行为的小脑外回路产生了不利影响。因此，缺少小脑输出神经元的破坏性小于存在小脑基因突变的情况。
