TY - JOUR
T1 - The pathophysiology of repetitive concussive traumatic brain injury in experimental models; new developments and open questions
AU - Brody, David L.
AU - Benetatos, Joseph
AU - Bennett, Rachel E.
AU - Klemenhagen, Kristen C.
AU - Mac Donald, Christine L.
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - In recent years, there has been an increasing interest in the pathophysiology of repetitive concussive traumatic brain injury (rcTBI) in large part due to the association with dramatic cases of progressive neurological deterioration in professional athletes, military personnel, and others. However, our understanding of the pathophysiology of rcTBI is less advanced than for more severe brain injuries. Most prominently, the mechanisms underlying traumatic axonal injury, microglial activation, amyloid-beta accumulation, and progressive tau pathology are not yet known. In addition, the role of injury to dendritic spine cytoskeletal structures, vascular reactivity impairments, and microthrombi are intriguing and subjects of ongoing inquiry. Methods for quantitative analysis of axonal injury, dendritic injury, and synaptic loss need to be refined for the field to move forward in a rigorous fashion. We and others are attempting to develop translational approaches to assess these specific pathophysiological events in both animals and humans to facilitate clinically relevant pharmacodynamic assessments of candidate therapeutics. In this article, we review and discuss several of the recent experimental results from our lab and others. We include new initial data describing the difficulty in modeling progressive tau pathology in experimental rcTBI, and results demonstrating that sertraline can alleviate social interaction deficits and depressive-like behaviors following experimental rcTBI plus foot shock stress. Furthermore, we propose a discrete set of open, experimentally tractable questions that may serve as a framework for future investigations. In addition, we also raise several important questions that are less experimentally tractable at this time, in hopes that they may stimulate future methodological developments to address them.This article is part of a Special Issue entitled "Traumatic Brain Injury".
AB - In recent years, there has been an increasing interest in the pathophysiology of repetitive concussive traumatic brain injury (rcTBI) in large part due to the association with dramatic cases of progressive neurological deterioration in professional athletes, military personnel, and others. However, our understanding of the pathophysiology of rcTBI is less advanced than for more severe brain injuries. Most prominently, the mechanisms underlying traumatic axonal injury, microglial activation, amyloid-beta accumulation, and progressive tau pathology are not yet known. In addition, the role of injury to dendritic spine cytoskeletal structures, vascular reactivity impairments, and microthrombi are intriguing and subjects of ongoing inquiry. Methods for quantitative analysis of axonal injury, dendritic injury, and synaptic loss need to be refined for the field to move forward in a rigorous fashion. We and others are attempting to develop translational approaches to assess these specific pathophysiological events in both animals and humans to facilitate clinically relevant pharmacodynamic assessments of candidate therapeutics. In this article, we review and discuss several of the recent experimental results from our lab and others. We include new initial data describing the difficulty in modeling progressive tau pathology in experimental rcTBI, and results demonstrating that sertraline can alleviate social interaction deficits and depressive-like behaviors following experimental rcTBI plus foot shock stress. Furthermore, we propose a discrete set of open, experimentally tractable questions that may serve as a framework for future investigations. In addition, we also raise several important questions that are less experimentally tractable at this time, in hopes that they may stimulate future methodological developments to address them.This article is part of a Special Issue entitled "Traumatic Brain Injury".
KW - Amyloid-beta
KW - Concussion
KW - Depression
KW - Microglia
KW - Mouse
KW - Sertraline
KW - Social behavior
KW - Tau
KW - Traumatic axonal injury
KW - Traumatic brain injury
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U2 - 10.1016/j.mcn.2015.02.005
DO - 10.1016/j.mcn.2015.02.005
M3 - Review article
C2 - 25684677
AN - SCOPUS:84937968110
SN - 1044-7431
VL - 66
SP - 91
EP - 98
JO - Molecular and Cellular Neuroscience
JF - Molecular and Cellular Neuroscience
IS - PB
ER -