Apoptotic and behavioral sequelae of mild brain trauma in mice.
Mild traumatic brain injury (mTBI) is a not uncommon event in adolescents and young adults. Although it does not result in clear morphological brain defects, it is associated with long-term cognitive, emotional, and behavioral problems. Herein, we characterized the biochemical and behavioral changes associated with experimental mTBI in mice that may act as either targets or surrogate markers for interventional therapy. Specifically, mTBI was induced by 30-g and 50-g weight drop, and at 8 and 72 hr thereafter markers of cellular apoptosis-caspase-3, Bax, apoptosis-inducing factor (AIF), and cytochrome-c (Cyt-c)-were quantified by Western blot analysis in hippocampus ipsilateral to the impact. Levels of amyloid-beta precursor protein (APP) were also measured, and specific behavioral tests-passive avoidance, open field, and forced swimming (Porsolt) paradigms-were undertaken to assess learning, emotionality, and emotional memory. In the absence of hemorrhage or infarcts, as assessed by triphenyltetrazolium chloride staining, procaspase-3 and Bax levels were markedly altered following mTBI at both times. No cleaved caspase-3 was detected, and levels of AIF and Cyt-c, but not APP, were significantly changed at 72 hr. Mice subjected to mTBI were indistinguishable from controls by neurological examination at 1 and 24 hr, and by passive avoidance/open field at 72 hr, but could be differentiated in the forced swimming paradigm. In general, this model mimics the diffuse effects of mTBI on brain function associated with the human condition and highlights specific apoptotic proteins and a behavioral paradigm as potential markers for prospective interventional strategies.
Tweedie
David
D
Drug Design and Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, Baltimore, Maryland 21224, USA. greign@grc.nia.nih.gov
Milman
Anat
A
Holloway
Harold W
HW
Li
Yazhou
Y
Harvey
Brandon K
BK
Shen
Hui
H
Pistell
Paul J
PJ
Lahiri
Debomoy K
DK
Hoffer
Barry J
BJ
Wang
Yun
Y
Pick
Chaim G
CG
Greig
Nigel H
NH
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001362:Avoidance Learning / Q000502:physiology; D001522:Behavior, Animal / Q000502:physiology*; D001930:Brain Injuries / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D053148:Caspase 3 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D005106:Exploratory Behavior; D007839:Functional Laterality; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D013550:Swimming; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D051033:Apoptosis Inducing Factor; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D053148:Caspase 3