Cognitive deficits develop 1 month after diffuse brain injury and are exaggerated by microglia-associated reactivity to peripheral immune challenge
Open accessAbstract
Traumatic brain injury (TBI) elicits immediate neuroinflammatory events that contribute to acute cognitive, motor, and affective disturbance. Despite resolution of these acute complications, significant neuropsychiatric and cognitive issues can develop and progress after TBI. We and others have provided novel evidence that these complications are potentiated by repeated injuries, immune challenges and stressors. A key component to this may be increased sensitization or priming of glia after TBI. Therefore, our objectives were to determine the degree to which cognitive deterioration occurred after diffuse TBI (moderate midline fluid percussion injury) and ascertain if glial reactivity induced by an acute immune challenge potentiated cognitive decline 30 days post injury (dpi). In post-recovery assessments, hippocampal-dependent learning and memory recall were normal 7 dpi, but anterograde learning was impaired by 30 dpi. Examination of mRNA and morphological profiles of glia 30 dpi indicated a low but persistent level of inflammation with elevated expression of GFAP and IL-1β in astrocytes and MHCII and IL-1β in microglia. Moreover, an acute immune challenge 30 dpi robustly interrupted memory consolidation specifically in TBI mice. These deficits were associated with exaggerated microglia-mediated inflammation with amplified (IL-1β, CCL2, TNFα) and prolonged (TNFα) cytokine/chemokine expression, and a marked reactive morphological profile of microglia in the CA3 of the hippocampus. Collectively, these data indicate that microglia remain sensitized 30 dpi after moderate TBI and a secondary inflammatory challenge elicits robust microglial reactivity that augments cognitive decline. Statement of significance Traumatic brain injury (TBI) is a major risk factor in development of neuropsychiatric problems long after injury, negatively affecting quality of life. Mounting evidence indicates that inflammatory processes worsen with time after a brain injury and are likely mediated by glia. Here, we show that primed microglia and astrocytes developed in mice 1 month following moderate diffuse TBI, coinciding with cognitive deficits that were not initially evident after injury. Additionally, TBI-induced glial priming may adversely affect the ability of glia to appropriately respond to immune challenges, which occur regularly across the lifespan. Indeed, we show that an acute immune challenge augmented microglial reactivity and cognitive deficits. This idea may provide new avenues of clinical assessments and treatments following TBI.
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TBI induces a primed microglial phenotype, defined by altered morphology and increased expression of MHC-II and CD68.
“Recent data demonstrate that TBI induces a primed microglial phenotype, defined by altered morphology and increased expression of MHC-II and CD68 (204, 208).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [208]
The Introduction reports increased MHC-II and CD68 after diffuse brain injury and describes this as evidence of microglial priming. But Results §3.9 finds no increase in Iba-1 proportional area from TBI alone at 30 days; the clearest measured microglial morphology changes followed LPS challenge. Thus the paper supports priming and the marker expression, but not unequivocally altered microglial morphology induced by TBI alone. (LLM, conf=0.86)
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Faden, A. I., Barrett, J. P., Stoica, B. A., & Henry, R. J. (2021) · Trends in Neurosciences · doi:10.1016/j.tins.2020.12.004 · Cited by 57 · see citing works
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“Mice that had received a TBI and LPS appeared to have a poorer cognitive outcome, suggesting that microglial priming worsens cognition (Muccigrosso et al., 2016).”
BackgroundLoss of NLRX1 exacerbates neural tissue damage and NF-κB Signaling following brain injury
Theus, M., Brickler, T., Meza, A. L., Coutermarsh-Ott, S. L., Házy, A., Gris, D., & Allen, I. (2017) · Journal of Immunology · doi:10.4049/jimmunol.1700251 · Cited by 54 · see citing works
“Following TBI, microglia in the lesion area undergo proliferation in response to injury and play vital roles in the modulation of secondary injury and recovery (27, 28).”
MethodHanscom, M., Loane, D., Aubretch, T., Leser, J., Molesworth, K., Hedgekar, N., Ritzel, R., Abulwerdi, G., Shea-Donohue, T., & Faden, A. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-020-02067-x · Cited by 53 · see citing works
STAT6 mediates the effect of ethanol on neuroinflammatory response in TBI.
Heuvel, F. O., Holl, S., Chandrasekar, A., Li, Z.-H., Wang, Y.-B., Rehman, R., Förstner, P., Sinske, D., Palmer, A., Wiesner, D., et al. (2019) · Brain, behavior, and immunity · doi:10.1016/j.bbi.2019.06.019 · Cited by 51 · see citing works
Mollayeva, T., Mollayeva, S., Pacheco, N., D’Souza, A., & Colantonio, A. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.01.011 · Cited by 56 · see citing works
Microglia dynamics in adolescent traumatic brain injury
Eyolfson, E., Khan, A. C., Mychasiuk, R., & Lohman, A. W. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01994-z · Cited by 62 · see citing works
Sleep Disruption Exacerbates and Prolongs the Inflammatory Response to Traumatic Brain Injury
Tapp, Z. M., Kumar, J. E., Witcher, K. G., Atluri, R. R., Velasquez, J., O’Neil, S. M., Dziabis, J. E., Bray, C. E., Sheridan, J. F., Godbout, J. P., et al. (2020) · Journal of Neurotrauma · doi:10.1089/neu.2020.7010 · Cited by 53 · see citing works
Self-citationIncretin Mimetics as Rational Candidates for the Treatment of Traumatic Brain Injury
Glotfelty, E. J., Delgado, T., Tovar‐y‐Romo, L. B., Luo, Y., Hoffer, B. J., Olson, L., Karlsson, T. E., Mattson, M. P., Harvey, B. K., Tweedie, D., et al. (2019) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.9b00003 · Cited by 48 · see citing works
Doran, S. J., Henry, R. J., Shirey, K. A., Barrett, J. P., Ritzel, R. M., Lai, W., Blanco, J. C. G., Faden, A. I., Vogel, S. N., & Loane, D. J. (2020) · Critical Care Medicine · doi:10.1097/ccm.0000000000004273 · Cited by 61 · see citing works
“In fact, systemic injection of lipopolysaccharide following diffuse TBI in mice exaggerates glial activation and worsens cognitive outcomes (53, 54).”
BackgroundZiebell, J. M., Rowe, R. K., Muccigrosso, M. M., Reddaway, J., Adelson, P. D., Godbout, J. P., & Lifshitz, J. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.03.008 · Cited by 52 · see citing works
Self-citationNeuroimmune Activation Drives Multiple Brain States
Tchessalova, D., Posillico, C. K., & Tronson, N. C. (2018) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2018.00039 · Cited by 46 · see citing works
“…3 August 2018 | Volume 12 | Article 39 priming effects after immune challenge in adults, with changes in microglial and astrocytic function and behavior (Fenn et al., 2014; Norden et al., 2015; Muccigrosso et al., 2016; Liddelow and Barres, 2017; Olivieri et al., 2018; Wendeln et al., 2018).”
BackgroundCollins‐Praino, L. E., Arulsamy, A., Katharesan, V., & Corrigan, F. (2017) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.08.035 · Cited by 43 · see citing works
Packer, J., Bray, C., Beckman, N. B., Wangler, L., Davis, A. C., Goodman, E. J., Klingele, N. E., & Godbout, J. (2023) · Glia · doi:10.1002/glia.24475 · Cited by 41 · see citing works
“This matches well with previous work that reported astro-gliosis remains 30 dpi following diffuse TBI (mFPI), (Fenn et al., 2014; Muccigrosso et al., 2016) and is dependent on STING (Abdullah et al., 2018).”
BackgroundResultInfluentialSelf-citationAntimicrobial immunity impedes CNS vascular repair following brain injury
Mastorakos, P., Russo, M. V., Zhou, T., Johnson, K. R., & McGavern, D. B. (2021) · Nature Immunology · doi:10.1038/s41590-021-01012-1 · Cited by 44 · see citing works
Glial Fibrillary Acidic Protein: A Biomarker and Drug Target for Alzheimer’s Disease
Ganne, A., Balasubramaniam, M., Griffin, W., Reis, R. S., & Ayyadevara, S. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14071354 · Cited by 40
The influence of immunological stressors on traumatic brain injury
Sun, M., McDonald, S. J., Brady, R. D., O'Brien, T. J., & Shultz, S. R. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.01.007 · Cited by 41 · see citing works
“Mice given a systemic LPS challenge at 1 month post-TBI also had worse cognitive deficits compared to their saline-treated counterparts (Muccigrosso et al., 2016).”
León‐Rodríguez, A., Fernández‐Arjona, M. D. M., Grondona, J. M., Pedraza, C., & López-Ávalos, M. D. (2022) · Scientific Reports · doi:10.1038/s41598-022-15617-5 · Cited by 37 · see citing works
Salmani, H., Hosseini, M., Beheshti, F., Baghcheghi, Y., Sadeghnia, H., Soukhtanloo, M., Shafei, M., & Khazaei, M. (2018) · Life Science · doi:10.1016/j.lfs.2018.04.033 · Cited by 36 · see citing works
Modulation of Neural Networks by Interleukin-1
Nemeth, D. P., & Quan, N. (2020) · Brain Plasticity · doi:10.3233/bpl-200109 · Cited by 44 · see citing works
“In contrast, in models of severe stress [14, 82], brain injury [83, 84], or IL-1 overexpression [85], IL-1 was found to impair memory.”
BackgroundXie, S.-T., Chen, A.-X., Song, B., Fan, J., Li, W., Xing, Z., Peng, S.-Y., Zhang, Q.-P., Dong, L., Yan, C., et al. (2020) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2020.07.027 · Cited by 33 · see citing works
Neuroimmune and neuroinflammation response for traumatic brain injury
Wu, J., Ren, R., Chen, T., Su, L., & Tang, T. (2024) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2024.111066 · Cited by 30 · see citing works
“Also, they found that secondary immune challenge leads to memory and learning impairments (Muccigrosso et al., 2016).”
Sharma, R., Zamani, A., Dill, L. K., Sun, M., Chu, E., Robinson, M. J., O'Brien, T. J., Shultz, S. R., & Semple, B. D. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02114-1 · Cited by 40 · see citing works
“Here, we hypothesized that pediatric TBI and LPS would separately initiate a broad range of immune responses, while in combination, this dual-insult would have additive effects, as has been previously reported in the few studies performed to date in adult animals [17, 24, 59].”
ResultMechanisms of tertiary neurodegeneration after neonatal hypoxic-ischemic brain damage
Levison, S. W., Rocha‐Ferreira, E., Kim, B. H., Hagberg, H., Fleiss, B., Gressèns, P., & Dobrowolski, R. (2021) · Pediatric Medicine · doi:10.21037/pm-20-104 · Cited by 34 · see citing works
“The majority of experimental descriptions of tertiary phase microglial reactivity comes from models of maternal (101-103) or early postnatal life immune activation (104) and from studies of adult traumatic brain injury (91,105,106).”
BackgroundBromberg, C. E., Condon, A. M., Ridgway, S. W., Krishna, G., Garcia-Filion, P. C., Adelson, P. D., Rowe, R. K., & Thomas, T. C. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.00946 · Cited by 38 · see citing works
Altered Blood Biomarker Profiles in Athletes with a History of Repetitive Head Impacts
Battista, A. P. D., Rhind, S. G., Richards, D. W., Churchill, N. W., BAKER, A. J., & Hutchison, M. G. (2016) · PLoS ONE · doi:10.1371/journal.pone.0159929 · Cited by 60 · see citing works
“Nevertheless, peripheral blood samples have the potential to provide meaningful information regarding inflammatory processes both in the CNS and periphery in response to brain injury, in a relatively cost-effective, non-invasive manner [18,30,31].”
BackgroundResultPerispinal Delivery of CNS Drugs
Tobinick, E. L. (2016) · CNS Drugs · doi:10.1007/s40263-016-0339-2 · Cited by 31 · see citing works
“These new findings and accumulating evidence of the central involvement of neuroinflammatory mechanisms in brain disorders challenge existing dogma regarding brain physiology, support the rapid neurological effects seen following PSE administration, and underscore the importance of further research exploring CNS deliv…”
BackgroundDeplete and repeat: microglial CSF1R inhibition and traumatic brain injury
Boland, R., & Kokiko‐Cochran, O. N. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1352790 · Cited by 31 · see citing works
Lu, X., Xue, Z.-Y., Yu, Q., Wei, S., Qiao, Y., Zhang, W., & Lü, H. (2022) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2022.945851 · Cited by 27 · see citing works
“The model of preterm rats with cognitive impairment was established as described previously (Muccigrosso et al., 2016).”
MethodZhang, L.-M., Zhang, D.-X., Zheng, W.-C., Hu, J.-S., Fu, L., Li, Y., Xin, Y., & Wang, X.-P. (2021) · Experimental Neurology · doi:10.1016/j.expneurol.2021.113683 · Cited by 27 · see citing works
Packer, J., Giammo, S. G., Wangler, L., Davis, A. C., Bray, C., & Godbout, J. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03451-1 · Cited by 26 · see citing works
“C. influence microglial proliferation [11, 39].”
Self-citationAbd‐El‐Basset, E. M., Rao, M. S. R., & Alsaqobi, A. K. (2020) · Neuroscience Insights · doi:10.1177/2633105520947081 · Cited by 30 · see citing works
Traumatic Brain Injury and Suicidal Behavior: A Review
Wadhawan, A., Stiller, J. W., Potocki, E., Okusaga, O. O., Dagdag, A., Lowry, C. A., Benros, M. E., & Postolache, T. T. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-181055 · Cited by 32 · see citing works
A negative allosteric modulator of PDE4D enhances learning after traumatic brain injury
Titus, D. J., Wilson, N. M., Alcazar, O., Calixte, D. A., Dietrich, W. D., Gurney, M. E., & Atkins, C. M. (2017) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2017.12.008 · Cited by 29 · see citing works
The Role of Microglia in the Etiology and Evolution of Chronic Traumatic Encephalopathy
Makinde, H. M., Just, T. B., Cuda, C. M., Perlman, H., & Schwulst, S. J. (2017) · Shock · doi:10.1097/shk.0000000000000859 · Cited by 23 · see citing works
“That is, primed microglia from an initial injury may respond in an amplified manner to subsequent insults, even if milder in nature (70, 71).”
de la Tremblaye, P. B., O’Neil, D. A., LaPorte, M. J., B, J. P. C. A., Beitchman, J. A., Thomas, T. C., Bondi, C. O., & Kline, A. E. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.05.022 · Cited by 25 · see citing works
“Muccigrosso et al. (2016) measured cognitive deficits at one month following midline FP injury in adult male BALB/C mice using the Barnes maze.”
Ovariectomy in mice primes hippocampal microglia to exacerbate behavioral sickness responses
Sanchez, K. G., Wu, S. L., Kakkar, R., Darling, J. S., Harper, C., & Fonken, L. K. (2023) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2023.100638 · Cited by 16 · see citing works
“For example, traumatic brain injury can modulate the neuroimmune system and cause marked behavioral changes reminiscent of the aforementioned sickness behaviors (Muccigrosso et al., 2016; Niraula et al., 2017; Tapp et al., 2019).”
BackgroundFernández‐Arjona, M. D. M., León‐Rodríguez, A., Grondona, J. M., & López-Ávalos, M. D. (2022) · Glia · doi:10.1002/glia.24217 · Cited by 28 · see citing works
“MHC II has been reported as a marker of primed microglia (Ling et al., 2004; Muccigrosso et al., 2016) which, in non-injured rats, is expressed by an increasing proportion of hippocampal microglial cells during aging progression (VanGuilder et al., 2011).”
BackgroundInfluentialYamakawa, G. R., Brady, R. D., Sun, M., McDonald, S. J., Shultz, S. R., & Mychasiuk, R. (2020) · Neurobiology of Sleep and Circadian Rhythms · doi:10.1016/j.nbscr.2020.100058 · Cited by 25 · see citing works
“The P55 or TNFR1 receptor is ubiquitously expressed at low levels in ependymal walls, the arcuate, supraoptic nucleus, and cerebellum (Nadeau and Rivest, 1999).”
BackgroundWang, Y., Wei, Y., Oguntayo, S., Wilder, D. M., Tong, L. C., Su, Y., Gist, I. D., Arun, P., & Long, J. B. (2016) · Journal of Neurotrauma · doi:10.1089/neu.2016.4465 · Cited by 20 · see citing works
Wang, H., Huang, Q., Zhang, Z., Ji, J., Sun, T., & Wang, D. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02535-6 · Cited by 20 · see citing works
“Previous studies have found that LPS stimulation promotes the inflammatory response of microglia in TBI mice and increases the risk of depression-like behavior and cognitive impairment [24, 25], and therefore drove the important effects of subsequent systemic immune activation, induced by post-injury infection, on the…”
BackgroundGreen, T. R. F., Murphy, S. M., Ortiz, J. B., & Rowe, R. K. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2021.804139 · Cited by 22 · see citing works
Long COVID in Children: A Multidisciplinary Review
Sansone, F., Pellegrino, G. M., Caronni, A., Bonazza, F., Vegni, E. A. M., Luè, A., Bocci, T., Pipolo, C., Giusti, G., Filippo, P. D., et al. (2023) · Diagnostics · doi:10.3390/diagnostics13121990 · Cited by 24 · see citing works
Huo, X., Xu, X., Li, M., Xiao, L., Wang, Y., Li, W., Wang, C., & Sun, T. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1001363 · Cited by 22 · see citing works
“PTE following TBI may further exacerbate the effects of TBI on memory and cognition, damage the cerebrovascular system or blood-brain barrier, and lead to depression or post-traumatic stress disorder (Castriotta et al., 2007; Luo et al., 2014; Muccigrosso et al., 2016; Vos et al., 2018).”
BackgroundInfluentialXue, W.-K., Zhao, W.-J., Meng, X.-F., Shen, H.-F., & Huang, P.-Z. (2019) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2018.12.002 · Cited by 18
Bai, R., Gao, H., Han, Z., Ge, X.-T., Huang, S., Chen, F.-L., & Lei, P. (2017) · Medical Science Monitor · doi:10.12659/msm.901124 · Cited by 17 · see citing works
“We carried out FCM to show that microglia strongly infiltrated the brain in the entire phase, with an initial peak of CD206+/CD11b+ M2-like microglia at 1 week and a secondary peak of CD86+/CD11b+ M1like microglia at 4 weeks, which is consistent with results of a previous study [27].”
ResultTargeting Kv1.3 channels to reduce white matter pathology after traumatic brain injury
Reeves, T. M., Trimmer, P., Colley, B. S., & Phillips, L. (2016) · Experimental Neurology · doi:10.1016/j.expneurol.2016.06.011 · Cited by 17 · see citing works
“…become apoptotic following CFZ administration (Fukutomi et al., 2011), which, with TBI, could reduce the number of activated inflammatory macrophages available to infiltrate injured white matter (Hsieh et al., 2014; Muccigrosso et al., 2016; Semple et al., 2010; Szmydynger-Chodobska et al., 2011).”
Epigenetic and 3D genome reprogramming during the aging of human hippocampus
Zemke, N. R., Lee, S., Mamde, S., Yang, B., Berchtold, N. C., Garduño, B. M., Indralingam, H. S., Bartosik, W. M., Lau, P., Dong, K., et al. (2024) · bioRxiv · doi:10.1101/2024.10.14.618338 · Cited by 16
Traumatic Brain Injury and Immunological Outcomes: the double-edged Killer
Datta, S., Lin, F., Jones, L., Pingle, S. C., Kesari, S., & Ashili, S. (2023) · Future Science OA · doi:10.2144/fsoa-2023-0037 · Cited by 15 · see citing works
Hosseini, M., Salmani, H., & Baghcheghi, Y. (2021) · Physiological Reports · doi:10.14814/phy2.14874 · Cited by 15 · see citing works
“This time point (72 h after the LPS injection) was chosen since the acute effects of LPS have been shown to diminish at this time point (Godbout et al., 2008; Muccigrosso et al., 2016),”
MethodInfluentialClausen, F., Hansson, H., Raud, J., & Marklund, N. (2017) · Frontiers in Neurology · doi:10.3389/fneur.2017.00039 · Cited by 15 · see citing works
“(51-2700) Axonal deposits Life technologies 1:200”
Taylor, M. A., & Kokiko‐Cochran, O. N. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1351685 · Cited by 15 · see citing works
Brett, B., Savitz, J., Nitta, M. E., España, L., Teague, T., Nelson, L. D., McCrea, M., & Meier, T. B. (2020) · Brain, behavior, and immunity · doi:10.1016/j.bbi.2020.07.024 · Cited by 13 · see citing works
“There is also evidence that chronic inflammation can change the reactive state of immune cells, sensitizing or “priming” the immune system to react more strongly to additional inflammatory triggers (Dilger and Johnson, 2008; Muccigrosso et al., 2016).”
BackgroundMollayeva, T., Pacheco, N., D'Souza, A., & Colantonio, A. (2017) · BMJ Open · doi:10.1136/bmjopen-2017-017165 · Cited by 13 · see citing works
“The abstracted data will include the following: (1) study characteristics (author names, publication year, country of study, study setting, study design, sample size, method of measuring cognition and cognitive domains covered, number of participants assessed for at each time point, time between assessments and time s…”
BackgroundHoule, S., Tapp, Z. M., Dobres, S., Ahsan, S., Reyes, Y., Cotter, C., Mitsch, J., Zimomra, Z., Peng, J., Rowe, R. K., et al. (2024) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2024.100797 · Cited by 8 · see citing works
“6D), a key region in spatial learning and memory, which is also vulnerable to TBI induced inflammation (Muccigrosso et al., 2016; Tapp et al., 2022).”
BackgroundSelf-citationBi-directional neuro-immune dysfunction after chronic experimental brain injury
Ritzel, R., Li, Y., Jiao, Y., Doran, S. J., Khan, N. Z., Henry, R., Brunner, K., Loane, D., Faden, A. I., Szeto, G. L., et al. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03082-y · Cited by 12 · see citing works
“Impor-tantly, we found that bone marrow-derived macrophage cultures harvested from chronic (90d) TBI mice exhibited significantly higher sensitivity to LPS stimulation compared to macrophages cultured from sham mice [54, 55].”
BackgroundMollayeva, T., Hurst, M., Chan, V., Escobar, M., Sutton, M., & Colantonio, A. (2020) · Preventive Medicine · doi:10.1016/j.ypmed.2020.106213 · Cited by 12 · see citing works
Long‐term reprogramming of primed microglia after moderate inhibition of CSF1R signaling
León‐Rodríguez, A., Grondona, J. M., Marín‐Wong, S., López‐Aranda, M. F., & López-Ávalos, M. D. (2024) · Glia · doi:10.1002/glia.24627 · Cited by 13 · see citing works
Shi, S., Zhang, S., & Kong, L. (2023) · Life · doi:10.3390/life13091829 · Cited by 10 · see citing works
Beitchman, J. A., Lifshitz, J., Harris, N., Thomas, T. C., Lafrenaye, A. D., Hånell, A., Dixon, C. E., Povlishock, J., & Rowe, R. K. (2020) · bioRxiv · doi:10.1089/neur.2020.0046 · Cited by 10 · see citing works
Self-citationSrinivasan, G. R., & Brafman, D. A. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.813544 · Cited by 10 · see citing works
“…dpi ↑ at 120 dpi Kokiko-Cochran et al., 2015 Non-transgenic (BALB/c) mFPI 3 months 7, 30 days LPS challenge 30 dpi ↑inflammation and cognitive deficits Muccigrosso et al., 2016 Non-transgenic (C57BL/6) CCI 3 months ↑Microglial mGluR5 expression which when inhibited ↓neuronal loss Byrnes et al.,…”
BackgroundShi, R., Liu, H., Tan, P., Hu, Z., Ma, Y., Ye, M., Gu, Y., Wang, Y., Ye, T., Gu, Y., et al. (2022) · Neuropharmacology · doi:10.1016/j.neuropharm.2022.108950 · Cited by 9 · see citing works
Wang, Y., Andrade, P., & Pitkänen, A. (2021) · Biomedicines · doi:10.3390/biomedicines9121946 · Cited by 9 · see citing works
“For example, LPS administration at 30 days post-TBI exacerbated cognitive impairment and induced depression-like behavior, both of which were associated with microglial reactivation and an exaggerated production of pro-inflammatory cytokines IL1-β and TNFα [45,46].”
BackgroundExacerbated immune response of the brain to peripheral immune challenge in post-septic mice
Salmani, H., Hosseini, M., Nabi, M. M., Noshahr, Z. S., Baghcheghi, Y., & Sadeghi, M. (2022) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2022.04.013 · Cited by 7 · see citing works
Hadanny, A., & Efrati, S. (2025) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2025.2515061 · Cited by 8 · see citing works
Law, L., Griffiths, D. R., & Lifshitz, J. (2023) · Behavioural Brain Research · doi:10.1016/j.bbr.2023.114355 · Cited by 6 · see citing works
Self-citationRichter, M., Negro-Demontel, M. L., Blanco-Ocampo, D., Taranto, E., Lago, N., & Peluffo, H. (2018) · Current Protocols in Immunology · doi:10.1002/cpim.42 · Cited by 6
“Accordingly, cognitive deficits develop at 1 month post-mild TBI that were not present at 7 dpl (Muccigrosso et al., 2016).”
BackgroundTapp, Z., Ren, C., Palmer, K., Kumar, J., Atluri, R., Fitzgerald, J. A., Velasquez, J., Godbout, J., Sheridan, J. F., & Kokiko-Cochran, O. (2023) · Neurotrauma Reports · doi:10.1089/neur.2023.0018 · Cited by 5 · see citing works
Self-citationKaukas, L., Krieg, J. L., Collins‐Praino, L. E., & Corrigan, F. (2021) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2021.659679 · Cited by 5 · see citing works
“Even remote inflammatory stimuli can drive this response, with a peripheral immune challenge at 1-month post-injury acutely worsening memory consolidation on the Barnes Maze (Muccigrosso et al., 2016) and enhancing depressive-like behavior on the tail suspension test (Fenn et al., 2014).”
BackgroundInfluentialKamal, K., Keiter, J. A., Binyamin, T., Dapula, J. N. D. L. C., Vergara, A., Hawk, C., Izadi, A., Lyeth, B. G., Gurkoff, G. G., Sharp, F., et al. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.105084 · Cited by 5 · see citing works
Apple cider vinegar attenuates lipopolysaccharide-induced neurobehavioral deficits in mice
Asejeje, F., Abiola, M. A., Ben-Azu, B., Adeosun, A., Ighodaro, O., & Ajayi, A. (2020) · Nutrire · doi:10.1186/s41110-020-00125-1 · Cited by 5 · see citing works
Zhang, Z., Xiao, T.-G., Hall, M. R., Crodian, J., Alford, A., Kimbrough, A., & Shi, R. (2024) · Neuroscience · doi:10.1016/j.neuroscience.2024.10.003 · Cited by 4
Neurodegenerative Disorders in the Context of Vascular Changes after Traumatic Brain Injury
Segherlou, Z. H., Masheghati, F., Shakeri-Darzehkanani, M., Siyanaki, M. R. H., & Lucke-Wold, B. P. (2024) · Journal of Vascular Diseases · doi:10.3390/jvd3030025 · Cited by 5 · see citing works
“They are one of the initial groups to react to brain injury, and their continuous activation in animal models and individuals with TBI could play a role in causing long-term functional impairments [97,108–111].”
Microbial neuraminidase induces TLR4-dependent long-term immune priming in the brain
Fernández‐Arjona, M. D. M., León‐Rodríguez, A., Grondona, J. M., & López-Ávalos, M. D. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.945229 · Cited by 4 · see citing works
“, 2017), some authors have reported evidences of priming in astrocytes (Hennessy et al., 2015; Muccigrosso et al., 2016).”
BackgroundDavis, A. C., Goodman, E. J., Wangler, L. M., Packer, J. M., Thammachack, R., Yildiz, V. O., Sharma, P., Pietrzak, M., Xiaokui, M., Quan, N., et al. (2026) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2026.106524 · Cited by 3 · see citing works
Self-citation
- Authors
- Muccigrosso, M. M., Ford, J., Benner, B., Moussa, D., Burnsides, C., Fenn, A. M., Popovich, P. G., Lifshitz, J., Walker, F. R., Eiferman, D. S., & Godbout, J. P.
- Affiliations
- The Ohio State University (US)
- The Ohio State University Wexner Medical Center (US)
- Barrow Neurological Institute (US)
- University of Newcastle Australia (AU)
- Corresponding author
- Godbout, Jonathan P.
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 54
- Pages
- 95-109
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC4828283
- OpenAlex
- W2237921172
- Cited by
- 146
- References
- 70
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 14 · 2023: 11 · 2022: 18 · 2021: 23 · 2020: 19 · 2019: 10 · 2018: 11 · 2017: 16 · 2016: 11
- FWCI
- 12.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- NOVA (University of Newcastle Australia) (submittedVersion)
- Funders
- NIA Grant (R01-AG-033028)
- College of Medicine Dean’s Discovery Grant
- Center for Brain and Spinal Cord Repair
- American Surgical Society Fellowship
- P30 Core Grant
- National Institute of Dental and Craniofacial Research Training Grant
- Topics
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Keywords
- traumatic brain injury, diffuse brain injury, fluid percussion injury, microglial activation, neuroinflammation, cognitive impairment, memory consolidation, anterograde amnesia, hippocampus, CA3, astrocytes, IL-1β, TNF-α, MCP-1, MHC class II, glial fibrillary acidic protein, immune challenge
- MeSH terms
- Brain Injuries, Diffuse, Brain Injuries, Traumatic, Animals, Astrocytes, Cognition, Cognition Disorders, Disease Models, Animal, Inflammation, Male, Memory, Mice, Inbred BALB C, Quality of Life, Cytokines, Microglia, Inflammation Mediators, Chemokines, Mice
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