Abstract
In the United States, 1.4 million people suffer from traumatic brain injury (TBI) each year because of traffic, sports, or war-related injuries. The majority of TBI victims suffer mild to minimal TBI (mTBI), but most are released undiagnosed. Detailed pathologies are poorly understood. We characterized the microscopic changes of neurons of closed-head mTBI mice after increased unilateral trauma using hematoxylin and eosin (H&E) stain, and correlated it with the expression of the apoptotic proteins c-jun, p53, and BCL-2. Minimal damage to the brain increases the number of pyknotic appearing neurons and activates the apoptotic proteins in both hemispheres. Although minimal, increased impact was positively correlated with the increased number of damaged neurons. These results may explain the wide variety of behavioral and cognitive deficits closed-head mTBI causes in mice. Our cumulative results point to the pathological origin of post-concussion syndrome and may aid in the development of future neuroprotective strategies for the disease.
Similar content being viewed by others
Abbreviations
- TBI:
-
traumatic brain injury
- mTBI:
-
minimal traumatic brain injury
- BBB:
-
blood–brain barrier
References
Albensi, B. C. (2001). Models of brain injury and alterations in synaptic plasticity. Journal of Neuroscience Research, 65, 279–283.
Angel, P., Hattori, K., Smeal, T., & Karin, M. (1988). The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1. Cell, 55, 875–885.
Berger, E., Leven, F., Pirente, N., Bouillon, B., & Neugebauer, E. (1999). Quality of life after traumatic brain injury; a systematic review of the literature. Restorative Neurology and Neuroscience, 14, 93–102.
Bogolepov, N. N., Popova, E. N., Koplik, E. V., Krivitskaya, G. N., & Sudakov, K. V. (2004). Structural-functional organization of neurons in the cerebral cortex of rats with different levels of resistance to emotional stress in conditions of exposure to delta sleep-inducing peptide. Neuroscience and Behavioral Physiology, 34, 611–616.
Bonny, C., Borsello, T., & Zine, A. (2005). Targeting the JNK pathway as a therapeutic protective strategy for nervous system diseases. Reviews in the Neurosciences, 16, 57–67.
Brown, A. W., & Brierley, J. B. (1972). Anoxic-ischaemic cell change in rat brain light microscopic and fine-structural observations. Journal of the Neurological Sciences, 16, 59–84.
Carbonell, W. S., & Grady, M. S. (1999). Regional and temporal characterization of neuronal, glial, and axonal response after traumatic brain injury in the mouse. Acta Neuropathologica (Berl), 98, 396–406.
Clark, R. S., Kochanek, P. M., Chen, M., Watkins, S. C., Marion, D. W., Chen, J., et al. (1999). Increases in Bcl-2 and cleavage of caspase-1 and caspase-3 in human brain after head injury. FASEB Journal, 13, 813–821.
Finset, A., Anke, A. W., Hofft, E., Roaldson, K. S., Pillgram- Larson, J., & Stanghelle, J. K. (1999). Cognitive performance in multiple trauma patients 3 years after injury. Psychosomatic Medicine, 61, 576–583.
Kibby, M. Y., & Long, C. J. (1996). Minor head injury, attempts at clarifying the confusion. Brain Injury, 10, 159–186.
Laurer, H. L., & McIntosh, T. K. (1999). Experimental models of brain trauma. Current Opinion in Neurology, 12, 715–721.
Levin, H. S., Mattis, S., Ruff, R. M., Eisenberg, H. M., Marshall, L. F., Tabaddor, K., et al. (1987). Neurobehavioral outcome following minor head injury, a three-center study. Journal of Neurosurgery, 66, 234–243.
Lu, J., Moochhala, S., Kaur, C., & Ling, E. (2000). Changes in apoptosis-related protein (p53, Bax, Bcl-2 and Fos) expression with DNA fragmentation in the central nervous system in rats after closed head injury. Neuroscience Letters, 290, 89–92.
Margulies, S. (2002). The postconcussion syndrome after mild head trauma, is brain damage over diagnosed? Part 1. Journal of Clinical Neuroscience, 7, 400–408.
Milman, A., Rosenberg, A., Weizman, R., & Pick, C. G. (2005). Mild traumatic brain injury induces persistent cognitive deficits and behavioral disturbances in mice. Journal of Neurotrauma, 22, 1003–1010.
Milman, A., Zohar, O., Maayan, R., Weizman, R., & Pick, C. G. (2008). DHEAS repeated treatment improves cognitive and behavioral deficits after mild traumatic brain injury. European Neuropsychopharmacology, 18(3), 181–187.
O’Dell, D. M., Raghupathi, R., Crino, P. B., Eberwine, J. H., & McIntosh, T. K. (2000). Traumatic brain injury alters the molecular fingerprint of TUNEL-positive cortical neurons In vivo, A single-cell analysis. Journal of Neuroscience, 20, 4821–4828.
Ooigawa, H., Nawashiro, H., Fukui, S., Otani, N., Osumi, A., Toyooka, T., et al. (2006). The fate of Nissl-stained dark neurons following traumatic brain injury in rats, difference between neocortex and hippocampus regarding survival rate. Acta Neuropathologica (Berl), 112, 471–481.
Ortega, S., Ittmann, M., Tsang, S. H., Ehrlich, M., & Basilico, C. (1998). Neuronal defects and delayed wound healing in mice lacking fibroblast growth factor 2. Proceedings of the National Academy of Sciences of the United States of America, 95, 5672–5677.
Ottens, A. K., Kobeissy, F. H., Golden, E. C., Zhang, Z., Haskins, W. E., Chen, S. S., et al. (2006). Neuroproteomics in neurotrauma. Mass Spectrometry Reviews, 25, 380–408.
Ozaki, T., Katsumoto, E., Mui, K., Furutsuka, D., & Yamagami, S. (1998). Distribution of Fos- and Jun-related proteins and activator protein-1 composite factors in mouse brain induced by neuroleptics. Neuroscience, 84, 1187–1196.
Pan, W., Kastin, A. J., Rigai, T., McLay, R., & Pick, C. G. (2003). Increased hippocampal uptake of tumor necrosis factor alpha and behavioral changes in mice. Experimental Brain Research, 149, 195–199.
Polster, B. M., & Fiskum, G. (2004). Mitochondrial mechanisms of neural cell apoptosis. Journal of Neurochemistry, 90(6), 1281–1289.
Rink, A., Fung, K. M., Trojanowski, J. Q., Lee, V. M., Neugebauer, E., & McIntosh, T. K. (1995). Evidence of apoptotic cell death after experimental traumatic brain injury in the rat. American Journal of Pathology, 147, 1575–1583.
Runnerstam, M., Bao, F., Huang, Y., Shi, J., Gutierrez, E., Hamberger, A., et al. (2001). A new model for diffuse brain injury by rotational acceleration, II. Effects on extracellular glutamate, intracranial pressure, and neuronal apoptosis. Journal of Neurotrauma, 18, 259–273.
Tashlykov, V., Katz, Y., Gazit, V., Zohar, O., Schreiber, S., & Pick, C. G. (2007). Apoptotic changes in the cortex and hippocampus following minimal brain trauma in mice. Brain Research, 1130, 197–205.
Tweedie, D., Milman, A., Holloway, H. W., Li, Y., Harvey, B. K., Shen, H., et al. (2007). Apoptotic and behavioral sequelae of mild brain trauma in mice. Journal of Neuroscience Research, 85, 805–815.
Ward, N. L., & Hagg, T. (2000). SEK1/MKK4, c-Jun and NFKappaB are differentially activated in forebrain neurons during postnatal development and injury in both control and p75NGFR-deficient mice. European Journal of Neuroscience, 12, 1867–1881.
Zohar, O., Getslev, V., Miller, A. L., Schreiber, S., & Pick, C. G. (2006). Morphine protects for head trauma induced cognitive deficits in mice. Neuroscience Letters, 394, 239–242.
Zohar, O., Schreiber, S., Getslev, V., Schwartz, J. P., Mullins, P. G., & Pick, C. G. (2003). Closed-head minimal traumatic brain injury produces long-term cognitive deficits in mice. Neuroscience, 118, 949–955.
Author information
Authors and Affiliations
Corresponding author
Additional information
Ofer Zohar and Chaim G. Pick contributed equally to this work.
Rights and permissions
About this article
Cite this article
Tashlykov, V., Katz, Y., Volkov, A. et al. Minimal Traumatic Brain Injury Induce Apoptotic Cell Death in Mice. J Mol Neurosci 37, 16–24 (2009). https://doi.org/10.1007/s12031-008-9094-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-008-9094-2