Newfound sex differences in axonal structure underlie differential outcomes from in vitro traumatic axonal injury
Open accessAbstract
Since traumatic axonal injury (TAI) is implicated as a prominent pathology of concussion, we examined potential sex differences in axon structure and responses to TAI. Rat and human neurons were used to develop micropatterned axon tracts in vitro that were genetically either male or female. Ultrastructural analysis revealed for the first time that female axons were consistently smaller with fewer microtubules than male axons. Computational modeling of TAI showed that these structural differences place microtubules in female axons at greater risk of failure during trauma under the same applied loads than in male axons. Likewise, in an in vitro model of TAI, dynamic stretch-injury to axon tracts induced greater pathophysiology of female axons than male axons, including more extensive undulation formations resulting from mechanical breaking of microtubules, and greater calcium influx shortly after the same level of injury. At 24h post-injury, female axons exhibited significantly more swellings and greater loss of calcium signaling function than male axons. Accordingly, sexual dimorphism of axon structure in the brain may also contribute to more extensive axonal pathology in females compared to males exposed to the same mechanical injury.
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Following a stretch-induced injury in vitro, axons from females exhibited greater swelling and loss of calcium signaling compared with those from males.
“Also, following a stretch-induced injury in vitro , axons from females exhibited greater swelling and loss of calcium signaling compared with those from males. 102”
From Sex Differences in Traumatic Brain Injury: What We Know and What We Should Know (2019) · cites this paper as [102]
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Cites
Flexural rigidity of microtubules and actin filaments measured from thermal fluctuations in shape
Gittes, F., Mickey, B., Nettleton, J., & Howard, J. (1993) · Journal of Cell Biology · doi:10.1083/jcb.120.4.923 · Cited by 1,788 · see citing works
Rapid single-step induction of functional neurons from human pluripotent stem cells
Zhang, Y., Pak, C., Han, Y., Ahlenius, H., Zhang, Z., Chanda, S., Marro, S., Patzke, C., Acuna, C., Covy, J., et al. (2013) · Neuron · doi:10.1016/j.neuron.2013.05.029 · Cited by 1,644 · see citing works
Fiber composition of the human corpus callosum
Aboitiz, F., Scheibel, A. B., Fisher, R. S., & Eran Zaidel, B. (1992) · Brain Research · doi:10.1016/0006-8993(92)90178-c · Cited by 1,467 · see citing works
Biomechanics and biophysics of cancer cells☆
SURESH, S. (2007) · Acta Biomaterialia · doi:10.1016/j.actbio.2007.04.002 · Cited by 1,284 · see citing works
Axonal pathology in traumatic brain injury
Johnson, V. E., Stewart, W., & Smith, D. H. (2013) · Experimental Neurology · doi:10.1016/j.expneurol.2012.01.013 · Cited by 1,273 · see citing works
Self-citationDekaban, A. S., & Sadowsky, D. (1978) · Annals of Neurology · doi:10.1002/ana.410040410 · Cited by 1,014 · see citing works
Epidemiology of Concussions Among United States High School Athletes in 20 Sports
Marar, M., McIlvain, N. M., Fields, S. K., & Comstock, R. D. (2012) · The American Journal of Sports Medicine · doi:10.1177/0363546511435626 · Cited by 955 · see citing works
Gur, R. C., Turetsky, B. I., Matsui, M., Yan, M., Bilker, W., Hughett, P., & Gur, R. E. (1999) · The Journal of Neuroscience · doi:10.1523/jneurosci.19-10-04065.1999 · Cited by 909 · see citing works
Neurofilaments and Neurofilament Proteins in Health and DiseasePreprint
Yuan, A., Rao, M. V., Veeranna, & Nixon, R. A. (2017) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a018309 · Cited by 741 · see citing works
Viscoelastic properties of vimentin compared with other filamentous biopolymer networks.
Janmey, P. A., Euteneuer, U., Traub, P., & Schliwa, M. (1991) · The Journal of Cell Biology · doi:10.1083/jcb.113.1.155 · Cited by 708 · see citing works
Chronic neuropathologies of single and repetitive TBI: substrates of dementia?
Smith, D. H., Johnson, V. E., & Stewart, W. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2013.29 · Cited by 699 · see citing works
Self-citationOrientationally invariant indices of axon diameter and density from diffusion MRI
Alexander, D. C., Hubbard, P. L., Hall, M. G., Moore, E. A., Ptito, M., Parker, G. J. M., & Dyrby, T. B. (2010) · NeuroImage · doi:10.1016/j.neuroimage.2010.05.043 · Cited by 683 · see citing works
Espuny-Camacho, I., Michelsen, K. A., Gall, D., Linaro, D., Hasche, A., Bonnefont, J., Bali, C., Orduz, D., Bilheu, A., Herpoel, A., et al. (2013) · Neuron · doi:10.1016/j.neuron.2012.12.011 · Cited by 568 · see citing works
Sex differences in outcome following sports-related concussion
Broshek, D. K., Kaushik, T., Freeman, J. R., Erlanger, D. M., Webbe, F. M., & Barth, J. T. (2005) · Journal of neurosurgery · doi:10.3171/jns.2005.102.5.0856 · Cited by 524 · see citing works
Stalning af amyloid percursor protein to study axonal damage in mild head Injury
Blumbergs, P. C., Scott, G., Manavis, J., Wainwright, H., Simpson, D. A., & McLean, A. J. (1994) · The Lancet · doi:10.1016/s0140-6736(94)91712-4 · Cited by 454 · see citing works
Traumatic Axonal Injury Induces Calcium Influx Modulated by Tetrodotoxin-Sensitive Sodium Channels
Wolf, J., Stys, P., Lusardi, T., Meaney, D., & Smith, D. H. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-06-01923.2001 · Cited by 438 · see citing works
Self-citationMagnetic resonance imaging improves 3‐month outcome prediction in mild traumatic brain injury
Yuh, E. L., Mukherjee, P., Lingsma, H. F., Yue, J. K., Ferguson, A. R., Gordon, W. A., Valadka, A. B., Schnyer, D. M., Okonkwo, D. O., Maas, A. I. R., et al. (2012) · Annals of Neurology · doi:10.1002/ana.23783 · Cited by 415 · see citing works
Tang‐Schomer, M. D., Patel, A., Baas, P. W., & Smith, D. H. (2009) · The FASEB Journal · doi:10.1096/fj.09-142844 · Cited by 392 · see citing works
Self-citationGrowth of white matter in the adolescent brain: role of testosterone and androgen receptor
Perrin, J. S., Hervé, P.-Y., Leonard, G., Perron, M., Pike, G. B., Pitiot, A., Richer, L., Veillette, S., Pausova, Z., & Paus, T. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.1212-08.2008 · Cited by 331 · see citing works
Tang-Schomer, M., Johnson, V., Baas, P. W., Stewart, W., & Smith, D. H. (2011) · Experimental Neurology · doi:10.1016/j.expneurol.2011.10.030 · Cited by 330 · see citing works
Self-citationHigh Tolerance and Delayed Elastic Response of Cultured Axons to Dynamic Stretch Injury
Smith, D. H., Wolf, J., Lusardi, T., Lee, V., & Meaney, D. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-11-04263.1999 · Cited by 310 · see citing works
Self-citationFunctional Trade-Offs in White Matter Axonal Scaling
Wang, S. S. ‐., Shultz, J. R., Burish, M. J., Harrison, K. H., Hof, P. R., Towns, L. C., WAGERS, M. W., & Wyatt, K. D. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.5559-05.2008 · Cited by 299 · see citing works
Sex Differences and the Incidence of Concussions Among Collegiate Athletes.
Covassin, T., Swanik, C. B., & Sachs, M. (2003) · PubMed · Cited by 294 · see citing works
Fineman, I., Hovda, D. A., Smith, M. L., Yoshino, A., & Becker, D. P. (1993) · Brain Research · doi:10.1016/0006-8993(93)90064-t · Cited by 287 · see citing works
Nixon, R. A., Paskevich, P. A., Sihag, R. K., & Thayer, C. Y. (1994) · The Journal of Cell Biology · doi:10.1083/jcb.126.4.1031 · Cited by 277 · see citing works
REEVES, T., PHILLIPS, L., & POVLISHOCK, J. (2005) · Experimental Neurology · doi:10.1016/j.expneurol.2005.07.014 · Cited by 270 · see citing works
Risk factors for sports concussion: an evidence-based systematic review
Abrahams, S., Fie, S. M., Patricios, J., Posthumus, M., & September, A. V. (2013) · British Journal of Sports Medicine · doi:10.1136/bjsports-2013-092734 · Cited by 264 · see citing works
Saatman, K. E., Bozyczko‐Coyne, D., Marcy, V. R., Siman, R., & McIntosh, T. K. (1996) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199607000-00010 · Cited by 236 · see citing works
Iwata, A., Stys, P., Wolf, J., Chen, X.-H., Taylor, A. G., Meaney, D., & Smith, D. H. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.0515-03.2004 · Cited by 233 · see citing works
Self-citationBenson, R. R., Meda, S. A., Vasudevan, S., Kou, Z., Govindarajan, K. A., Hanks, R. A., Millis, S. R., Makki, M., Latif, Z., Coplin, W. M., et al. (2007) · Journal of Neurotrauma · doi:10.1089/neu.2006.0153 · Cited by 219 · see citing works
Sex differences in the growth of white matter during adolescence
Perrin, J. S., Leonard, G., Perron, M., Pike, G. B., Pitiot, A., Richer, L., Veillette, S., Pausova, Z., & Paus, T. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2009.01.023 · Cited by 197 · see citing works
Povlishock, J. T., Marmarou, A., McIntosh, T. K., Trojanowski, J. Q., & Moroi, J. (1997) · PubMed · Cited by 185 · see citing works
Ahmadzadeh, H., Smith, D. H., & Shenoy, V. B. (2014) · Biophysical Journal · doi:10.1016/j.bpj.2014.01.024 · Cited by 162 · see citing works
Self-citationImpact Acceleration Injury in the Rat
Povlishock, J. T., Marmarou, A., McIntosh, T. K., Trojanowski, J. Q., & Moroi, J. (1997) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199704000-00003 · Cited by 158 · see citing works
MLPA: a rapid, reliable, and sensitive method for detection and analysis of abnormalities of 22q
Vorstman, J. A. S., Jalali, G. R., Rappaport, E. F., et al. (2006) · Human Mutation · doi:10.1002/humu.20330 · Cited by 139 · see citing works
Sodium channelopathy induced by mild axonal trauma worsens outcome after a repeat injury
Yuen, T. J., Browne, K. D., Iwata, A., & Smith, D. H. (2009) · Journal of Neuroscience Research · doi:10.1002/jnr.22161 · Cited by 131 · see citing works
Self-citationDevelopment of Patient-Specific Neurons in Schizophrenia Using Induced Pluripotent Stem Cells
Pedrosa, E., Sandler, V., Shah, A., Carroll, R., Chang, C.-J., Rockowitz, S., Guo, X.-Y., Zheng, D.-Y., & Lachman, H. (2011) · Journal of neurogenetics · doi:10.3109/01677063.2011.597908 · Cited by 123 · see citing works
Maxwell, W. L., McCreath, B. J., Graham, D. I., & Gennarelli, T. A. (1995) · Journal of Neurocytology · doi:10.1007/bf01215643 · Cited by 114 · see citing works
Predicting Postconcussion Syndrome after Minor Traumatic Brain Injury
Bazarian, J. J., & Atabaki, S. M. (2001) · Academic Emergency Medicine · doi:10.1111/j.1553-2712.2001.tb00208.x · Cited by 112 · see citing works
Lin, M., Pedrosa, E., Hrabovsky, A., Chen, J., Puliafito, B. R., Gilbert, S. R., Zheng, D., & Lachman, H. M. (2016) · BMC Systems Biology · doi:10.1186/s12918-016-0366-0 · Cited by 108 · see citing works
Evolution of neurofilament subtype accumulation in axons following diffuse brain injury in the pig.
Chen, X. H., Meaney, D., Xu, B. N., Nonaka, M., McIntosh, T., Wolf, J., Saatman, K., & Smith, D. H. (1999) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/00005072-199906000-00003 · Cited by 106 · see citing works
Self-citationLü, W., Winding, M., Lakonishok, M., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1522424113 · Cited by 101 · see citing works
Could sex differences in white matter be explained by g ratio?
Paus, T. (2009) · Frontiers in Neuroanatomy · doi:10.3389/neuro.05.014.2009 · Cited by 98 · see citing works
Miyata, Y., Hoshi, M. M., Nishida, E., Minami, Y., & Sakai, H. (1986) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)69265-8 · Cited by 91 · see citing works
Emergency department visits for head trauma in the United States
Gaw, C. E., & Zonfrillo, M. R. (2016) · BMC Emergency Medicine · doi:10.1186/s12873-016-0071-8 · Cited by 90 · see citing works
Mechanical Effects of Dynamic Binding between Tau Proteins on Microtubules during Axonal Injury
Ahmadzadeh, H., Smith, D. H., & Shenoy, V. B. (2015) · Biophysical Journal · doi:10.1016/j.bpj.2015.09.010 · Cited by 78 · see citing works
Self-citationReeves, T. M., Smith, T. L., Williamson, J. C., & Phillips, L. L. (2012) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3182482590 · Cited by 75 · see citing works
Axon diameter and axonal transport: In vivo and in vitro effects of androgens
Pesaresi, M., Soon-Shiong, R., French, L., Kaplan, D., Miller, F., & Paus, T. (2015) · NeuroImage · doi:10.1016/j.neuroimage.2015.04.048 · Cited by 73 · see citing works
Sex differences in the distribution of axon types within the genu of the rat corpus callosum
Mack, C. M., Boehm, G. W., Berrebi, A. S., & Denenberg, V. H. (1995) · Brain Research · doi:10.1016/0006-8993(95)00804-y · Cited by 56 · see citing works
Competing Interactions Stabilize Pro- and Anti-aggregant Conformations of Human Tau
Wegmann, S., Schöler, J., Bippes, C. A., Mandelkow�, E., & Müller, D. J. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.237875 · Cited by 48 · see citing works
Small-Diameter Nonmyelinated Axons in the Primate Corpus Callosum
Swadlow, H. A., Waxman, S. G., & Geschwind, N. (1980) · Archives of Neurology · doi:10.1001/archneur.1980.00500510072016 · Cited by 43 · see citing works
Selective Vulnerability of Non-Myelinated Axons to Stretch Injury in an In Vitro Co-Culture System
Staal, J. A., & Vickers, J. C. (2011) · Journal of Neurotrauma · doi:10.1089/neu.2010.1658 · Cited by 39 · see citing works
Özdoğmuş, Ö., Çavdar, S., Ersoy, Y., et al. (2009) · Anatomical Science International · doi:10.1007/s12565-008-0001-2 · Cited by 26 · see citing works
Sex Stratified Neuronal Cultures to Study Ischemic Cell Death Pathways
Fairbanks, S. L., Vest, R. S., Verma, S., Traystman, R. J., & Herson, P. S. (2013) · Journal of Visualized Experiments · doi:10.3791/50758 · Cited by 7 · see citing works
Simulated Cytoskeletal Collapse via Tau Degradation
Sendek, A. D., Fuller, H. R., Hayre, N. R., Singh, R., & Cox, D. (2014) · PLoS ONE · doi:10.1371/journal.pone.0104965 · Cited by 6 · see citing works
Sex Stratified Neuronal Cultures to Study Ischemic Cell Death Pathways
Fairbanks, S. L., Vest, R. S., Verma, S., et al. (2013) · Journal of Visualized Experiments · doi:10.3791/50758-v · Cited by 4 · see citing works
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Sex Differences in Traumatic Brain Injury: What We Know and What We Should Know
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- Authors
- Dollé, J.-P., Jaye, A., Anderson, S. A., Ahmadzadeh, H., Shenoy, V. B., & Smith, D. H.
- Affiliations
- University of Pennsylvania (US)
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Smith, Douglas H.
- Venue
- Experimental Neurology
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 300
- Pages
- 121-134
- ISSN
- 0014-4886 (ISSN-L)
- PMC
- PMC6495524
- OpenAlex
- W2770931845
- Cited by
- 128
- References
- 56
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 15 · 2023: 11 · 2022: 20 · 2021: 13 · 2020: 35 · 2019: 11 · 2018: 4
- FWCI
- 10.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Experimental Neurology (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (MH110185, NS092398, NS038104, EB021293)
- Paul G. Allen Family Foundation
- Topics
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Automotive and Human Injury Biomechanics
- Keywords
- traumatic axonal injury, sex differences, axon ultrastructure, microtubules, axon diameter, concussion, computational modeling, stretch injury, calcium influx, axonal swellings, mechanical damage, sexual dimorphism, axonal pathology
- MeSH terms
- Animals, Axons, Cells, Cultured, Female, Humans, Male, Sex Characteristics, Diffuse Axonal Injury, Rats, Induced Pluripotent Stem Cells
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