The Jackson Laboratory, Bar Harbor, ME, 04609, USA.
Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Commun Biol. 2024 Aug 25;7(1):1048. doi: 10.1038/s42003-024-06723-3.
Stroke causes death of brain tissue leading to long-term deficits. Behavioral evidence from neurorehabilitative therapies suggest learning-induced neuroplasticity can lead to beneficial outcomes. However, molecular and cellular mechanisms that link learning and stroke recovery are unknown. We show that in a mouse model of stroke, which exhibits enhanced recovery of function due to genetic perturbations of learning and memory genes, animals display activity-dependent transcriptional programs that are normally active during formation or storage of new memories. The expression of neuronal activity-dependent genes are predictive of recovery and occupy a molecular latent space unique to motor recovery. With motor recovery, networks of activity-dependent genes are co-expressed with their transcription factor targets forming gene regulatory networks that support activity-dependent transcription, that are normally diminished after stroke. Neuronal activity-dependent changes at the circuit level are influenced by interactions with microglia. At the molecular level, we show that enrichment of activity-dependent programs in neurons lead to transcriptional changes in microglia where they differentially interact to support intercellular signaling pathways for axon guidance, growth and synaptogenesis. Together, these studies identify activity-dependent transcriptional programs as a fundamental mechanism for neural repair post-stroke.
中风导致脑组织死亡，从而导致长期缺陷。神经康复治疗的行为证据表明，学习诱导的神经可塑性可以带来有益的结果。然而，将学习与中风恢复联系起来的分子和细胞机制尚不清楚。我们发现，在一种由于学习和记忆基因的遗传扰动而表现出功能增强恢复的中风小鼠模型中，动物表现出活性依赖性转录程序，这些程序通常在新记忆的形成或存储过程中活跃。神经元活性依赖性基因的表达可预测恢复情况，并占据运动恢复特有的分子潜在空间。随着运动恢复，活性依赖性基因的网络与转录因子靶标共同表达，形成支持活性依赖性转录的基因调控网络，而这些网络通常在中风后减少。神经元水平的活性依赖性变化受与小胶质细胞相互作用的影响。在分子水平上，我们发现神经元中活性依赖性程序的富集导致小胶质细胞中的转录变化，它们通过差异相互作用来支持轴突导向、生长和突触发生的细胞间信号通路。总之，这些研究将活性依赖性转录程序确定为中风后神经修复的基本机制。
