Astrocytes contribution in brain vulnerability after juvenile mild traumatic brain injury
Astrocytes are crucial for various physiological functions in the brain such as homeostasis, metabolism, neurovascular coupling or neurotransmission regulation. In injuries, astrocytes become reactive and have a crucial role in the neuroinflammatory response. This reactivity is heterogeneous and depends on many parameters such as the type and severity of insult, astrocyte proximity to insult, or state of brain maturity. However, the specific response of astrocytes to mild traumatic brain injury (TBI) in the developmental context has never been studied yet. Mild TBI is the leading cause of emergency department visits in the pediatric population. A significant proportion of mild TBI pediatric patients will suffer of long-lasting cognitive and emotional impairments but the underlying cellular and molecular mechanisms are still poorly understood. Astrocytes might take part to this vulnerability and be partly responsible for the long-term consequences.
We investigated astrocyte response to juvenile mild TBI and hypothesized that: (1) astrocytes display a specific pattern of reactivity evolving over time and brain development; and that (2) astrocytes reactivity differs when the TBI is preceded by an early systemic inflammation inducing a priming of astrocytes, with a different neuroinflammatory and vascular response to juvenile mild TBI, impacting the brain vulnerability and long-term outcome.
We have shown that:
(1) Reactive astrocytes express a specific spatiotemporal reactivity pattern even at distance from the injury site, in terms of intermediate filaments expression and morphological evolution, and that structural alterations are observed in brain imaging on the long-term after juvenile mild TBI.
(2) When the juvenile mild TBI is preceded by perinatal systemic inflammation, astrocytes express a different reactivity phenotype considered as a state of transition towards scar-forming astrocytes, with increased metabolism and extracellular matrix-related gene changes, associated to morphological alterations sustaining over time and delayed over-expression of VEGF, resulting in the absence of vascular alterations induced by TBI alone.
This work brings new insights in the specificities of astrocyte reactivity and in the pathophysiology of vulnerability after juvenile mild TBI, opening possibilities for novel targets for therapeutics.
Keywords: Astrocyte, traumatic brain injury, neuroinflammation, vulnerability
Publications
• Clement, T., Delahaye-Duriez, A., Van Steenwinckel J., Fournier, M.L., Aussudre, J., Blugeon, C., Lemoine, S., Faivre, V., Boccazzi, M., Ogier, M., Canini, F., Konsman, J.P., Gressens, P., Badaut, J. (2021). Transition states towards scar-forming astrocytes and neurovascular remodeling after juvenile TBI in perinatal systemic inflammation sensitized brain. In preparation.
• Fournier, M.L., Clement, T., Aussudre, J., Plesnila, N., Obenaus, A., Badaut., J. (2021). Contusion rodent model of traumatic brain injury: controlled cortical impact. Methods Mol Biol. 2021;2193:49-65. doi: 10.1007/978-1-0716-0845-6_6
• Clement, T., Lee, J.B., Ichkova, A., Rodriguez-Grande, B., Fournier, M.L., Aussudre, J., Ogier, M., Haddad, E., Canini, F., Koehl, M., Abrous, D.N., Obenaus, A., Badaut, J. (2020). Juvenile mild traumatic brain injury elicits distinct spatiotemporal astrocyte responses. Glia. 2020;68(3):528-542. doi:10.1002/glia.23736
• Clement, T., Rodriguez-Grande, B., & Badaut, J. (2018). Aquaporins in brain edema. J Neurosci Res. 2020;98(1):9-18. doi:10.1002/jnr.24354
• Blochet, C., Buscemi, L., Clement, T., Gehri, S., Badaut, J., & Hirt, L. (2018). Involvement of caveolin-1 in neurovascular unit remodeling after stroke: Effects on neovascularization and astrogliosis. J Cereb Blood Flow Metab. 2020;40(1):163-176. doi:10.1177/0271678X18806893
Jury
M. TOURDIAS, Thomas Professeur, Université de Bordeaux Président
Mme ESCARTIN, Carole Directeur de recherche, Université Paris-Saclay Rapporteur
Mme SOHRABJI, Farida Professeur, Texas A&M University Rapporteur
M. GRESSENS, Pierre Professeur, Université Paris Diderot Examinateur
M. CANINI, Frédéric Professeur, IRBA Invité
M. OGIER, Michaël Chargé de recherche, IRBA Invité