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Previously we developed an animal model of rTBI that recapitulates the cognitive and behavioral deficits observed in humans. We now report that rTBI results in an increase in risk-taking behavior in male but not female mice. This behavioral phenotype is associated with chronic activation of the integrated stress response and cell-specific synaptic alterations in the type A subtype of layer V pyramidal neurons in the medial prefrontal cortex. Strikingly, by briefly treating animals weeks after injury with ISRIB, a selective inhibitor of the integrated stress response (ISR), we (1) relieve ISR activation, (2) reverse the increased risk-taking behavioral phenotype and maintain this reversal, and (3) restore cell-specific synaptic function in the affected mice. Our results indicate that targeting the ISR even at late time points after injury can permanently reverse behavioral changes. As such, pharmacological inhibition of the ISR emerges as a promising avenue to combat rTBI-induced behavioral dysfunction.<\/jats:p>","DOI":"10.1089\/neu.2019.6827","type":"journal-article","created":{"date-parts":[[2019,12,28]],"date-time":"2019-12-28T04:35:10Z","timestamp":1577507710000},"page":"1370-1380","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":41,"title":["Integrated Stress Response Inhibitor Reverses Sex-Dependent Behavioral and Cell-Specific Deficits after Mild Repetitive Head Trauma"],"prefix":"10.1177","volume":"37","author":[{"given":"Karen","family":"Krukowski","sequence":"first","affiliation":[{"name":"Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, California, USA."},{"name":"Department of Brain and Spinal Injury Center, University of California, San Francisco, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber","family":"Nolan","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, California, USA."},{"name":"Department of Brain and Spinal Injury Center, University of California, San Francisco, California, USA."},{"name":"Department of Pathology, University of California, San Francisco, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elma S.","family":"Frias","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, California, USA."},{"name":"Department of Brain and Spinal Injury Center, University of California, San Francisco, California, USA."},{"name":"Department of Biomedical Sciences, University of California, San Francisco, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Grue","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, California, USA."},{"name":"Department of Brain and Spinal Injury Center, University of California, San Francisco, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"McKenna","family":"Becker","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, California, USA."},{"name":"Department of Brain and Spinal Injury Center, University of California, San Francisco, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gonzalo","family":"Ureta","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n Ciencia &amp; 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