Citation

Algamal M, Saltiel N, Pearson AJ, Ager B, Burca I, Mouzon BC, Diamond D, Mullan M, Ojo J, Crawford FC. J. Neurotrauma 2019; ePub(ePub): ePub.

Affiliation

Roskamp Institute, 138517, Sarasota, Florida, United States ; FCrawford@roskampinstitute.org.

Copyright

(Copyright © 2019, Mary Ann Liebert Publishers)

DOI

10.1089/neu.2018.6314

PMID

30963958

Abstract

Clinical studies examining the interaction between traumatic brain injury and stress-related disorders such as PTSD are often complicated by methodological constraints such as heterogeneity in injury type and severity, time post-trauma, and predisposing risk factors. Developing relevant animal models whereby many variables can be efficiently controlled is thus essential towards understanding this elusive relationship. Here, we use our repeated unpredictable stress (RUS) paradigm, in combination with our established mouse model of repetitive mild TBI (r-mTBI), to assess the impact of repeated exposures to these paradigms on behavioral and neurobiological measures. C57BL/6J male mice were exposed to RUS and r-mTBI at 3 and 6-month of age followed by batteries of behavioral testing. Mice were euthanized 10 days and 3 months post-exposure, with brain and plasma samples collected for molecular profiling. The RUS paradigm involved exposure to a predator odor (TMT) whilst under restraint, daily unstable social housing, five inescapable footshocks on separate days, and chronic social isolation. Animals receiving r-mTBI (x5) and stress were exposed to a single closed head injury 1hr after each footshock. Stress-alone mice showed significant weight loss, recall of traumatic memories, anxiety-like and passive stress-coping behavior when compared to control mice. However, in stress+r-mTBI animals, the changes in cued fear memory, anxiety and stress-coping tests were diminished, possibly due to TBI-induced hyperactivity. We also report complex brain molecular and neuropathological findings. Stress and r-mTBI either individually or comorbidly were associated with a chronic reduction in dendritic spine, GluN2A/GluN2B ratio in the hippocampus. While stress augmented the r-mTBI-dependent astrogliosis in the corpus callosum, it mitigated r-mTBI-induced increases in hippocampal proBDNF. We anticipate that our model will be a good platform to untangle the complex comorbid pathophysiology in stress disorders and r-mTBI.

Language: en

Keywords

ANIMAL STUDIES; Behavior; LOCOMOTOR FUNCTION; NEUROPLASTICITY; TRAUMATIC BRAIN INJURY