Integrated Stress Response Inhibitor Reverses Sex-Dependent Behavioral and Cell-Specific Deficits after Mild Repetitive Head Trauma

Karen Krukowski; Amber Nolan; Elma S Frias; Katherine Grue; McKenna Becker; Gonzalo Ureta; Luz Delgado; Sebastian Bernales; Vikaas S Sohal; Peter Walter; Susanna Rosi

doi:10.1089/neu.2019.6827

Integrated Stress Response Inhibitor Reverses Sex-Dependent Behavioral and Cell-Specific Deficits after Mild Repetitive Head Trauma

J Neurotrauma. 2020 Jun 1;37(11):1370-1380. doi: 10.1089/neu.2019.6827. Epub 2020 Feb 11.

Authors

Karen Krukowski^{1

2}, Amber Nolan^{1

2

3}, Elma S Frias^{1

2

4}, Katherine Grue^{1

2}, McKenna Becker^{1

2}, Gonzalo Ureta⁵, Luz Delgado⁵, Sebastian Bernales⁵, Vikaas S Sohal⁶, Peter Walter^{7

8}, Susanna Rosi^{1

2

9

10

11}

Affiliations

¹ Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, California, USA.
² Department of Brain and Spinal Injury Center, University of California, San Francisco, California, USA.
³ Department of Pathology, University of California, San Francisco, California, USA.
⁴ Department of Biomedical Sciences, University of California, San Francisco, California, USA.
⁵ Fundación Ciencia & Vida, Santiago, Chile.
⁶ Department of Psychiatry, University of California, San Francisco, California, USA.
⁷ Department of Biochemistry and Biophysics, University of California, San Francisco, California, USA.
⁸ Howard Hughes Medical Institute, University of California, San Francisco, California, USA.
⁹ Department of Neurological Surgery, University of California, San Francisco, California, USA.
¹⁰ Weill Institute for Neuroscience, University of California, San Francisco, California, USA.
¹¹ Kavli Institute of Fundamental Neuroscience, University of California, San Francisco, California, USA.

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. 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.

Keywords: integrated stress response; prefrontal cortex; repetitive mild traumatic brain injury; risk-taking behavior; synaptic function.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Acetamides / administration & dosage*
Animals
Brain Concussion / drug therapy*
Brain Concussion / pathology
Brain Concussion / psychology*
Cyclohexylamines / administration & dosage*
Female
Male
Mice
Mice, Inbred C57BL
Neuroprotective Agents / administration & dosage
Risk-Taking*
Sex Characteristics*

Substances

2-(4-chlorophenoxy)-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide
Acetamides
Cyclohexylamines
Neuroprotective Agents

Abstract

Publication types

MeSH terms

Substances

Grants and funding