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J Neurotrauma. 2019 Dec 28. doi: 10.1089/neu.2019.6827. [Epub ahead of print]

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

Author information

1
University of California San Francisco Brain and Spinal Injury Center, 466700, Physical Therapy and Rehabilitation, 1001 Potrero Ave., Building 1, Room 101, San Francisco, California, United States, 94110.
2
University of California San Francisco, Department of Physical Therapy and Rehabilitation Science, San Francisco, California, United States; karen.krukowski@ucsf.edu.
3
University of California San Francisco Division of Neuropathology, 220109, 505 Parnassus Ave, Rm M545, San Francisco, California, United States, 94143-0102; amber.nolan2@ucsf.edu.
4
University of California San Francisco, 8785, Brain and Spinal Cord Injury Center, San Francisco, California, United States; elma.frias@ucsf.edu.
5
University of California San Francisco, 8785, Brain and Spinal Cord Injury Center, San Francisco, California, United States; katherine.grue@ucsf.edu.
6
University of California San Francisco, 8785, Brain and Spinal Cord Injury Center, San Francisco, California, United States; mckenna.becker@ucsf.edu.
7
Santiago, Chile; g.ureta.diaz@gmail.com.
8
Santiago, Chile; delgado.luz@gmail.com.
9
Santiago, Chile; sbernales@gmail.com.
10
University of California San Francisco Department of Psychiatry, 166302, San Francisco, California, United States; vikaas.sohal@ucsf.edu.
11
University of California San Francisco, 8785, Biochemistry and Biophysics, San Francisco, California, United States.
12
Howard Hughes Medical Institute, San Francisco, United States; peter@walterlab.ucsf.edu.
13
University of California San Francisco Brain and Spinal Injury Center, 466700, Neurological Surgery, 1001 Potrero Av, San Francisco, California, United States, 94110.
14
University of California San Francisco, Department of Physical Therapy and Rehabilitation Science, San Francisco, California, United States.
15
University of California San Francisco , Department of Neurological Surgery, San Francisco, California, United States.
16
University of California San Francisco, Weill Institute for Neuroscience, San Francisco, California, United States; susanna.rosi@ucsf.edu.

Abstract

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.

KEYWORDS:

Behavior; COGNITIVE FUNCTION; ELECTROPHYSIOLOGY; TRAUMATIC BRAIN INJURY

PMID:
31884883
DOI:
10.1089/neu.2019.6827

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