Enduring cognitive, neurobehavioral and histopathological changes persist for up to one year following severe experimental brain injury in rats
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Clinical studies have demonstrated that patients sustain prolonged behavioral deficits following traumatic brain injury, in some cases culminating in the cognitive and histopathological hallmarks of Alzheimer's disease. However, few studies have examined the long-term consequences of experimental traumatic brain injury. In the present study, anesthetized male Sprague-Dawley rats (n = 185) were subjected to severe lateral fluid-percussion brain injury (n = 115) or sham injury (n = 70) and evaluated up to one year post-injury for cognitive and neurological deficits and histopathological changes. Compared with sham-injured controls, brain-injured animals showed a spatial learning impairment that persisted up to one year post-injury. In addition, deficits in specific neurologic motor function tasks also persisted up to one year post-injury. Immunohistochemistry using multiple antibodies to the amyloid precursor protein and/or amyloid precursor protein-like proteins revealed novel axonal degeneration in the striatum, corpus callosum and injured cortex up to one year post-injury and in the thalamus up to six months post-injury. Histologic evaluation of injured brains demonstrated a progressive expansion of the cortical cavity, enlargement of the lateral ventricles, deformation of the hippocampus, and thalamic calcifications. Taken together, these findings indicate that experimental traumatic brain injury can cause long-term cognitive and neurologic motor dysfunction accompanied by continuing neurodegeneration.
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Many biological pathways are disrupted by experimental TBI resulting in progressive neurodegeneration including atrophy, neuronal loss, and axonal degeneration which are often associated with neuroinflammation including macrophage reactivity.
“Many biological pathways are disrupted by experimental TBI resulting in progressive neurodegeneration including atrophy, neuronal loss, and axonal degeneration which are often associated with neuroinflammation including macrophage reactivity (82–85).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [85]
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“In contrast, ionic restoration can lead to axonal recovery,(204) while a host of secondary injury mechanisms likely contribute to progressive axonal degeneration.(200,205) Hyperphosphorylation of tau also occurs in TBI,(206) resulting in reduced microtubule binding,(207) which causes disassembly of microtubules and th…”
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“TBI-related cognitive deficits related to spatial learning can persist as long as 1 year post-injury in these animal models (Pierce et al., 1998; Dixon et al., 1999), whereas significant motor skills deficits are more transient.”
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“This is not a simple endeavor since neurodegeneration caused by TBI occurs as a result of a number of complex and dynamic inter-related mechanisms (Smith et al., 1991; Hicks et al., 1993; Pierce et al., 1998; Hall and Lifshitz, 2010; McNamara et al., 2010).”
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“Axonal pathology has been shown to develop over the course of hours to days following injury and has even been observed for months (Christman et al., 1994; Pierce et al., 1998).”
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“One of the attributes of the LFP model of TBI is its ability to model axonal injury (Graham et al., 2000; Pierce et al., 1998), a common consequence of TBI (Maxwell et al., 1997).”
BackgroundInfluentialExperimental models of brain trauma
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Self-citationRao, V. L. R., Dogan, A., Bowen, K., Todd, K., & Dempsey, R. J. (2001) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2001.01367.x · Cited by 115 · see citing works
Age-dependent synuclein pathology following traumatic brain injury in mice.
Uryu, K., Giasson, B. I., Longhi, L., Martinez, D., Murray, I. V. J., Conte, V., Nakamura, M., Saatman, K., Talbot, K., Horiguchi, T., et al. (2003) · Experimental Neurology · doi:10.1016/s0014-4886(03)00245-0 · Cited by 113 · see citing works
“Recognition of CCI-injured areas APP immunoreactivity (IR) was used to detect axons damaged by CCI in brain subjacent to the impact site as described (Pierce et al., 1998).”
Self-citationAnimal Models of Post-Traumatic Epilepsy
Pitkänen, A., & McIntosh, T. (2006) · Journal of Neurotrauma · doi:10.1089/neu.2006.23.241 · Cited by 112 · see citing works
“Based on published reports concerning long-term behavioral consequences of lateral FPI, we can assume that at least a subpopulation of our epileptic rats had impaired motor behavior (Pierce et al., 1998) and spatial memory (Browne et al., 2004).”
Self-citationBarrett, J. P., Henry, R. J., Shirey, K. A., Doran, S. J., Makarevich, O. D., Ritzel, R. M., Meadows, V. A., Vogel, S. N., Faden, A. I., Stoica, B. A., et al. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.2516-19.2020 · Cited by 126 · see citing works
“…addition, experimental models of repeated mild or moderate-to-severe TBI result in persistent brain inflammation and neurodegeneration leading to long-term motor and cognitive function deficits (Pierce et al., 1998; Dixon et al., 1999; Aungst et al., 2014; Loane et al., 2014; Mouzon et al., 2014).”
BackgroundChen, X., Iwata, A., Nonaka, M., Browne, K. D., & Smith, D. H. (2003) · Journal of Neurotrauma · doi:10.1089/089771503322144545 · Cited by 104 · see citing works
“…laboratories and ours have found that brain trauma in rats produces long-term neurodegenerative changes similar to those found in humans, including progressive brain atrophy, reactive astrocytosis, neuron death and axonal degeneration (Dixon et al, 1999; Pierce et al., 1998; Smith et al., 1997).”
Self-citationBrain injury, neuroinflammation and Alzheimer's disease
Breunig, J. J., Guillot‐Sestier, M., & Town, T. (2013) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2013.00026 · Cited by 104 · see citing works
Pischiutta, F., Micotti, E., Hay, J., Marongiu, I., Sammali, E., Tolomeo, D., Vegliante, G., Stocchetti, N., Forloni, G., Simoni, M. D., et al. (2017) · Experimental Neurology · doi:10.1016/j.expneurol.2017.11.003 · Cited by 107 · see citing works
“Abbreviations: AD, axial diffusivity; CC, corpus callosum; CCI, controlled cortical impact; cl, contralateral; CTE, chronic traumatic encephalopathy; CV, Cresyl violet; DTI, diffusion tensor imaging; EC, external capsule; EPI, echo-planar imaging; FA, fractional anisotropy; FPI, fluid percussion injury; il, ipsilatera…”
InfluentialSchuhmann, M., Stiller, D., Skardelly, M., Bernarding, J., Klinge, P., Samii, A., Samii, M., & Brinker, T. (2003) · Journal of Neurotrauma · doi:10.1089/089771503767869962 · Cited by 107 · see citing works
“In contrary, animal studies applying fluid-percussion or diffuse rotational injury, did not show any change in Cho up to 7 days post TBI (Cecil et al., 1998b; Rubin et al., 1997; Smith et al., 1998).”
Neuropathology of the vegetative state after head injury
Graham, D. I., Adams, J., Murray, L. S., & Jennett, B. (2005) · Neuropsychological Rehabilitation · doi:10.1080/09602010443000452 · Cited by 106 · see citing works
Inflammation in Traumatic Brain Injury
Postolache, T. T., Wadhawan, A., Can, A., Lowry, C. A., Woodbury, M., Makkar, H., Hoisington, A. J., Scott, A. J., Potocki, E., Benros, M. E., et al. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-191150 · Cited by 150 · see citing works
Lin, K., Niu, K.-C., Tsai, K., Kuo, J., Wang, L., Chio, C., & Chang, C. (2012) · The Journal of Trauma: Injury, Infection, and Critical Care · doi:10.1097/ta.0b013e31823c575f · Cited by 112 · see citing works
Huh, J. W., Widing, A. G., & Raghupathi, R. (2007) · Journal of Neurotrauma · doi:10.1089/neu.2006.0072 · Cited by 72 · see citing works
“Manual shaking for 12 min followed by hypoxia for 5 min on 3 consecutive days in 6-day-old rats demonstrated evidence of cortical hemorrhage associated with free radical formation and atrophy of cortical tissue (Smith et al., 1998).”
Pathophysiology and Treatment of Memory Dysfunction After Traumatic Brain Injury
Paternò, R., Folweiler, K. A., & Cohen, A. S. (2017) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-017-0762-x · Cited by 119 · see citing works
Rodriguez-Paez, A. C., Brunschwig, J. P., & Bramlett, H. M. (2005) · Acta Neuropathologica · doi:10.1007/s00401-005-1010-z · Cited by 94 · see citing works
“Atrophy of both gray and white matter structures after clinical and experimental traumatic brain injury (TBI) have been well documented [3, 7, 8, 9, 10, 20, 21, 70, 72, 79, 83].”
Osier, N. D., Carlson, S. W., DeSana, A. J., & Dixon, C. E. (2014) · Journal of Neurotrauma · doi:10.1089/neu.2014.3680 · Cited by 109 · see citing works
“One of the studies found that deficits persisted out to 2 months postinjury.(27) The MWM, discussed below in relation to its use for assessment of cognitive”
BackgroundInfluentialBondi, C. O., Klitsch, K. C., Leary, J. B., & Kline, A. E. (2014) · Journal of Neurotrauma · doi:10.1089/neu.2014.3328 · Cited by 101 · see citing works
Overview of Traumatic Brain Injury: An Immunological Context
Nizamutdinov, D., & Shapiro, L. A. (2017) · Brain Sciences · doi:10.3390/brainsci7010011 · Cited by 99 · see citing works
“It is often deduced that the neuropathology in these regions underlies the observed neurobehavioral and cognitive deficits that are commonly seen in the FPI model [36,49,50].”
BackgroundHead Injury, Alpha-Synuclein Rep1 and Parkinson’s Disease
Goldman, S., Kamel, F., Ross, G., Jewell, S., Bhudhikanok, G. S., Umbach, D., Marras, C., Hauser, R., Jankovic, J., Factor, S., et al. (2012) · Annals of Neurology · doi:10.1002/ana.22499 · Cited by 96 · see citing works
Immonen, R., Kharatishvili, I., Gröhn, H., Pitkänen, A., & Gröhn, O. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2008.11.022 · Cited by 96 · see citing works
“In rats the cell death continues up to one year (Bramlett and Dietrich 2002; Pierce et al., 1998; Smith et al., 1997) and the corresponding time period in humans can be several years.”
Kline, A., Massucci, J., Ma, X.-C., Zafonte, R. D., & Dixon, C. E. (2004) · Journal of Neurotrauma · doi:10.1089/neu.2004.21.1712 · Cited by 95
“…attenuation of spatial learning acquisition deficits with BRO has significant relevance for human TBI considering that both clinical and experimental studies have demonstrated persistent cognitive impairments after brain injury (Levin et al., 1987, 1990; Pierce et al., 1998; Dixon et al., 1999a).”
Behavioral consequences of minimal traumatic brain injury in mice.
Zohar, O., Rubovitch, V., Milman, A., Schreiber, S., & Pick, C. G. (2011) · Acta Neurobiologiae Experimentalis · doi:10.55782/ane-2011-1821 · Cited by 93
“Studies utilizing various experimental models of TBI indicate that the primary brain damage triggers cellular pathologies, which in turn lead to long-lasting secondary neuronal and glial damage (Pierce et al. 1996, 1998, Berger et al. 1999, Graham et al. 2000, Albensi 2001).”
MethodWatson, D., Longhi, L., Lee, E. B., Fulp, C. T., Fujimoto, S. T., Royo, N., Passini, M., Trojanowski, J., Lee, V., McIntosh, T., et al. (2003) · Journal of Neuropathology and Experimental Neurology · doi:10.1093/jnen/62.4.368 · Cited by 93 · see citing works
Self-citationBrain Trauma in Aged Transgenic Mice Induces Regression of Established Aβ Deposits
Nakagawa, Y., Reed, L., Nakamura, M., McIntosh, T. K., Smith, D. H., Saatman, K. E., Raghupathi, R., Clemens, J., Saido, T. C., Lee, V. M.-Y., et al. (2000) · Experimental Neurology · doi:10.1006/exnr.2000.7375 · Cited by 91 · see citing works
Self-citationAnimal models of post-traumatic epilepsy.
Ostergard, T., Sweet, J., Kusyk, D., Herring, E., & Miller, J. P. (2016) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2016.03.023 · Cited by 90 · see citing works
Atomic force microscopy reveals important differences in axonal resistance to injury.
Magdesian, M. H., Sánchez, F. S., López, M., Thostrup, P., Durisic, N., Belkaid, W., Liazoghli, D., Grütter, P., & Colman, D. (2012) · Biophysical Journal · doi:10.1016/j.bpj.2012.07.003 · Cited by 90 · see citing works
“Dynamic deformation of axons rarely leads to primary disconnection during brain trauma (1,4,39).”
BackgroundBareyre, F. M., Saatman, K. E., Raghupathi, R., & McIntosh, T. K. (2000) · Journal of Neurotrauma · doi:10.1089/neu.2000.17.1029 · Cited by 77 · see citing works
“To better Hicks et al., 1996; Pierce et al., 1998; Smith et al., 1997a). understand the mechanisms underlying histological dam-Several studies have evaluated the deleterious neuro-age associated with human head injury, a number of ex-chemical processes leading to neuronal cell death fol-perimental…”
Self-citationZlotnik, A., Sinelnikov, I., Gruenbaum, B., Gruenbaum, S. E., Dubilet, M., Dubilet, E., Leibowitz, A., Ohayon, S., Regev, A., Boyko, M., et al. (2012) · Anesthesiology · doi:10.1097/aln.0b013e31823d7731 · Cited by 88 · see citing works
“Moreover, long-term investigations have found long-term neurologic dysfunction when using the latter model.(49) The applicability of treatment with blood glutamate scavengers in human subjects remains a major concern.”
BackgroundSaber, M., Kokiko‐Cochran, O. N., Puntambekar, S. S., Lathia, J. D., & Lamb, B. T. (2016) · Journal of Neurotrauma · doi:10.1089/neu.2016.4401 · Cited by 95 · see citing works
Functional Assessment of Long-Term Deficits in Rodent models of Traumatic Brain Injury
Gold, E. M., Su, D., López-Velázquez, L., Haus, D. L., Perez, H. D., Lacuesta, G. A., Anderson, A. J., & Cummings, B. J. (2013) · Regenerative Medicine · doi:10.2217/rme.13.41 · Cited by 87 · see citing works
Rostami, E., Davidsson, J., Ng, K. C., Jia, L., Gyorgy, A. B., Walker, J., Wingo, D., Plantman, S., Bellander, B., Agoston, D. V., et al. (2012) · Frontiers in Neurology · doi:10.3389/fneur.2012.00115 · Cited by 93 · see citing works
“Persisted behavioral deficits following severe TBI has previously been reported in other TBI models (Pierce et al., 1998).”
Immonen, R., Kharatishvili, I., Niskanen, J., Gröhn, H., Pitkänen, A., & Gröhn, O. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2008.09.009 · Cited by 87 · see citing works
“The fact that all three measured parameters were so highly increased indicates a massive increase of the extracellular water content of the tissue, increasing amount of so called free water (that is, water molecules lacking interactions with surrounding macromolecules) reflecting the progressive loss of proteins in ex…”
BackgroundResultInfluentialOsteen, C., Giza, C. C., & Hovda, D. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.06.034 · Cited by 86 · see citing works
- Authors
- Pierce, J. E. S., Smith, D. H., Trojanowski, J. Q., & McIntosh, T. K.
- Affiliations
- UConn Health (US)
- University of Pennsylvania (US)
- Corresponding author
- Smith, D.H
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 1998-07
- Volume
- 87
- Issue
- 2
- Pages
- 359-369
- ISSN
- 0306-4522 (ISSN-L)
- OpenAlex
- W2019544787
- Cited by
- 385
- References
- 61
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 9 · 2023: 10 · 2022: 10 · 2021: 11 · 2020: 16 · 2019: 16 · 2018: 16 · 2017: 11 · 2016: 21 · 2015: 15 · 2014: 15 · 2013: 22 · 2012: 14
- FWCI
- 11.56
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuroscience (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (AG12527, R01AG012527)
- National Institute of Neurological Disorders and Stroke (NS-08803, NS26818)
- Topics
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Automotive and Human Injury Biomechanics
- Keywords
- traumatic brain injury, fluid percussion injury, long-term cognitive deficits, spatial learning impairment, motor impairment, axonal degeneration, amyloid precursor protein, neurodegeneration, thalamic calcification, ventriculomegaly, Alzheimer's disease
- MeSH terms
- Animals, Behavior, Animal, Brain, Brain Chemistry, Brain Injuries, Cognition Disorders, Forelimb, Male, Psychomotor Performance, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Rats, Sprague-Dawley, Maze Learning, Rats
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