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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,10,18]]},"abstract":"<jats:p>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\u2014even weeks after injury\u2014can 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\u00a0vivo 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.<\/jats:p>","DOI":"10.1073\/pnas.2209427119","type":"journal-article","created":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T13:46:50Z","timestamp":1665668810000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":20,"title":["Aberrant cortical spine dynamics after concussive injury are reversed by integrated stress response inhibition"],"prefix":"10.1073","volume":"119","author":[{"given":"Elma S.","family":"Frias","sequence":"first","affiliation":[{"name":"Department of Physical Therapy and Rehabilitation, University of California, San Francisco, CA 94143"},{"name":"Brain and Spinal Injury Center, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmood S.","family":"Hoseini","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Krukowski","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy and Rehabilitation, University of California, San Francisco, CA 94143"},{"name":"Brain and Spinal Injury Center, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Serena","family":"Paladini","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy and Rehabilitation, University of California, San Francisco, CA 94143"},{"name":"Brain and Spinal Injury Center, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Grue","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy and Rehabilitation, University of California, San Francisco, CA 94143"},{"name":"Brain and Spinal Injury Center, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gonzalo","family":"Ureta","sequence":"additional","affiliation":[{"name":"Department of Translational Research, Protein Folding and Disease Laboratory, Fundaci\u00f3n Ciencia &amp; Vida, Santiago, 7750000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kira D. A.","family":"Rienecker","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy and Rehabilitation, University of California, San Francisco, CA 94143"},{"name":"Brain and Spinal Injury Center, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6849-708X","authenticated-orcid":false,"given":"Peter","family":"Walter","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143"},{"name":"HHMI, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1546-5831","authenticated-orcid":false,"given":"Michael P.","family":"Stryker","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of California, San Francisco, CA 94143"},{"name":"Kavli Institute of Fundamental Neuroscience, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"Rosi","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy and Rehabilitation, University of California, San Francisco, CA 94143"},{"name":"Brain and Spinal Injury Center, University of California, San Francisco, CA 94143"},{"name":"Kavli Institute of Fundamental Neuroscience, University of California, San Francisco, CA 94143"},{"name":"Department of Neurological Surgery, University of California, San Francisco, CA 94143"},{"name":"Weill Institute for Neuroscience, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,10,13]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.apmr.2015.07.001"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.ss6609a1"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24367"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"e0169650","DOI":"10.1371\/journal.pone.0169650","article-title":"Head injury as a risk factor for dementia and Alzheimer\u2019s disease: A systematic review and meta-analysis of 32 observational studies","volume":"12","author":"Li Y.","year":"2017","unstructured":"Y. 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