Aberrant cortical spine dynamics after concussive injury are reversed by integrated stress response inhibition
| Autor: | Elma S. Frias, Mahmood S. Hoseini, Karen Krukowski, Maria Serena Paladini, Katherine Grue, Gonzalo Ureta, Kira D.A. Rienecker, Peter Walter, Michael P. Stryker, Susanna Rosi |
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| Rok vydání: | 2022 |
| Předmět: |
Traumatic
Physical Injury - Accidents and Adverse Effects 6.6 Psychological and behavioural Traumatic Brain Injury (TBI) Basic Behavioral and Social Science Mice mouse parietal cortex Behavioral and Social Science Brain Injuries Traumatic Acquired Cognitive Impairment 2.1 Biological and endogenous factors Animals Cognitive Dysfunction Aetiology closed-head injury Traumatic Head and Spine Injury Brain Concussion in vivo two-photon imaging Memory Disorders Multidisciplinary dendritic spine Neurosciences Evaluation of treatments and therapeutic interventions Injuries and accidents integrated stress response Brain Disorders Brain Injuries Neurological Mental health Dementia |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, vol 119, iss 42 |
| ISSN: | 1091-6490 |
| Popis: | 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 >2-fold 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, axsnd 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 the 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 for the clinical treatment of chronic cognitive deficits after TBI.Significance StatementAfter 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 suggests 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 for the clinical treatment of chronic cognitive deficits after brain injuries. |
| Databáze: | OpenAIRE |
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