Aberrant cortical spine dynamics after concussive injury are reversed by integrated stress response inhibition

• DOI: 10.1073/pnas.2209427119
• Publication Date: 2022-10-13T17:46:50Z
• Authors: Elma S. Frias; Mahmood S. Hoseini; Karen Krukowski; Maria Serena Pala...; Katherine Grue; Gonzalo Ureta; Kira D. A. Rienecker; Peter Walter; Michael P. Stryker; Susanna Rosi
• Keywords: Traumatic; 0301 basic medicine; Aging; Physical Injury - Accidents and Adverse Effects; Biological Psychology; 610; Traumatic Brain Injury (TBI); Neurodegenerative; Basic Behavioral and Social Science; Mice; 03 medical and health sciences; mouse parietal cortex; Behavioral and Social Science; Brain Injuries, Traumatic; Acquired Cognitive Impairment; Psychology; 2.1 Biological and endogenous factors; Animals; Cognitive Dysfunction; closed-head injury; Traumatic Head and Spine Injury; Brain Concussion; in vivo two-photon imaging; Memory Disorders; 0303 health sciences; Biomedical and Clinical Sciences; dendritic spine; Neurosciences; integrated stress response; Biological Sciences; Brain Disorders; 3. Good health; Brain Injuries; Neurological; in vivo two-photon imaging; Mental health; Dementia

Traumatic brain injury (TBI) is a leading cause of long-term neurological disability in the world and strongest environmental risk factor for development dementia. Even mild TBI (resulting from concussive injuries) associated with greater than twofold increase dementia onset. Little known about cellular mechanisms responsible progression long-lasting cognitive deficits. The integrated stress response (ISR), phylogenetically conserved pathway involved to stress, activated after TBI, inhibition ISR-even weeks injury-can reverse behavioral However, by which ISR restores cognition are unknown. Here, we used longitudinal two-photon imaging vivo mice study dendritic spine dynamics parietal cortex, region working memory. Concussive profoundly altered measured up month injury. Strikingly, brief pharmacological treatment drug-like small-molecule inhibitor ISRIB entirely reversed structural changes cortex memory Thus, both neural consequences mediated part activation can be corrected its inhibition. These findings suggest that targeting could serve as promising approach clinical chronic deficits TBI.