Integrated stress response inhibitor reverses sex-dependent behavioral and cell-specific deficits after mild repetitive head trauma

Mild  repetitive  traumatic  brain  injury  (rTBI)  induces  chronic  behavioral  and  cognitive  alterations  and  increases  the  risk  for  dementia.  Currently  there  are  no  therapeutic  strategies  to  prevent  or  mitigate  chronic  deficits  associated  with  rTBI.  We  previously developed an animal model of rTBI that recapitulates some of the cognitive and behavioral  deficits observed in humans.  Here we 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  (mPFC).  Strikingly, by briefly treating animals weeks after injuries with ISRIB, a selective inhibitor of  the integrated stress response (ISR), we (i) relieve ISR activation (ii) reverse the increased  risk‐taking  behavioral  phenotype  and  (iii)  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.