Aberrant cortical spine dynamics after concussive injury are reversed by integrated stress response inhibition.
Aberrant cortical spine dynamics after concussive injury are reversed by integrated stress response inhibition.
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DOI：
10.1073/pnas.2209427119
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发表时间：
2022-10-18
影响因子：
11.1
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中科院分区：
文献类型：
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创伤性脑损伤后，用小分子抑制剂（ISRIB）暂时性抑制综合应激反应（ISR）可挽救长期创伤诱导的认知缺陷。在这里，我们发现，ISRIB治疗迅速和持续逆转顶叶皮质中皮质脊柱动力学的异常变化，同时挽救工作记忆缺陷。这些数据表明，ISR和记忆功能之间的联系至少部分涉及神经元结构的变化。靶向ISR激活可作为脑损伤后慢性认知障碍的临床治疗的一种有前途的方法。创伤性脑损伤（TBI）是世界上长期神经功能障碍的主要原因，也是痴呆症发展的最强环境风险因素。即使是轻微的TBI（由震荡性损伤引起）也与痴呆发作风险的两倍以上增加有关。对于导致长期认知缺陷进展的细胞机制知之甚少。综合应激反应（ISR），一个参与细胞应激反应的遗传学保守途径，在TBI后被激活，抑制ISR-即使在损伤后几周-可以逆转行为和认知缺陷。然而，ISR抑制恢复认知的细胞机制尚不清楚。在这里，我们使用纵向双光子成像在小鼠脑震荡损伤后的体内研究顶叶皮层，一个涉及工作记忆的大脑区域的树突棘动力学。脑震荡损伤深刻地改变了脊柱动力学测量长达一个月后受伤。引人注目的是，用药物样小分子ISR抑制剂ISRIB进行的短暂药物治疗完全逆转了顶叶皮层中测量的结构变化和相关的工作记忆缺陷。因此，脑震荡损伤的神经和认知后果部分是通过ISR的激活介导的，并且可以通过其抑制来纠正。这些发现表明，靶向ISR激活可以作为TBI后慢性认知障碍的临床治疗的一种有前途的方法。
After traumatic brain injury, temporary pharmacological inhibition of the integrated stress response (ISR) with a small-molecule inhibitor (ISRIB) rescued long-lasting trauma-induced cognitive deficits. Here, we found that ISRIB treatment rapidly and persistently reversed the aberrant changes in cortical spine dynamics in the parietal cortex while rescuing working memory deficits. These data suggest that the link between the ISR and memory function involves, at least in part, changes in neuronal structure. Targeting ISR activation could serve as a promising approach to the clinical treatment of chronic cognitive deficits after brain injuries. Traumatic brain injury (TBI) is a leading cause of long-term neurological disability in the world and the strongest environmental risk factor for the development of dementia. Even mild TBI (resulting from concussive injuries) is associated with a greater than twofold increase in the risk of dementia onset. Little is known about the cellular mechanisms responsible for the progression of long-lasting cognitive deficits. The integrated stress response (ISR), a phylogenetically conserved pathway involved in the cellular response to stress, is activated after TBI, and inhibition of the ISR—even weeks after injury—can reverse behavioral and cognitive deficits. However, the cellular mechanisms by which ISR inhibition restores cognition are unknown. Here, we used longitudinal two-photon imaging in vivo after concussive injury in mice to study dendritic spine dynamics in the parietal cortex, a brain region involved in working memory. Concussive injury profoundly altered spine dynamics measured up to a month after injury. Strikingly, brief pharmacological treatment with the drug-like small-molecule ISR inhibitor ISRIB entirely reversed structural changes measured in the parietal cortex and the associated working memory deficits. Thus, both neural and cognitive consequences of concussive injury are mediated in part by activation of the ISR and can be corrected by its inhibition. These findings suggest that targeting ISR activation could serve as a promising approach to the clinical treatment of chronic cognitive deficits after TBI.
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