Age dictates brain functional connectivity and axonal integrity following repetitive mild traumatic brain injuries in mice
Marangelie Criado-Marrero,
Sakthivel Ravi,
Ekta Bhaskar,
Daylin Barroso,
Michael A. Pizzi,
Lakiesha Williams,
Cheryl L. Wellington,
Marcelo Febo,
Jose Francisco Abisambra
Affiliations
Marangelie Criado-Marrero
Center for Translational Research in Neurodegenerative Disease (CTRND), University of Florida, Gainesville, FL 32610, USA; Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA; McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA
Sakthivel Ravi
Center for Translational Research in Neurodegenerative Disease (CTRND), University of Florida, Gainesville, FL 32610, USA; Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA; McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA
Ekta Bhaskar
Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA; Department of Computer of Information Science and Engineering (CISE), University of Florida, Gainesville, FL 32610, USA
Daylin Barroso
Center for Translational Research in Neurodegenerative Disease (CTRND), University of Florida, Gainesville, FL 32610, USA; Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA; McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA
Michael A. Pizzi
Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA; McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA; Department of Neurology, University of Florida, Gainesville, FL 32610, USA; Brain Injury Rehabilitation and Neuroresilience (BRAIN) Center University of Florida, Gainesville, FL 32610, USA
Lakiesha Williams
J. Crayton Pruitt Family Department of Biomedical Engineering, Gainesville, FL 32610, USA
Cheryl L. Wellington
Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Center for Brain Health, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada
Marcelo Febo
McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA; Department of Psychiatry, University of Florida, Gainesville, FL 32610, USA; Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL 32610, USA
Jose Francisco Abisambra
Center for Translational Research in Neurodegenerative Disease (CTRND), University of Florida, Gainesville, FL 32610, USA; Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA; McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA; Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL 32610, USA; Brain Injury Rehabilitation and Neuroresilience (BRAIN) Center University of Florida, Gainesville, FL 32610, USA; Corresponding author.
Traumatic brain injuries (TBI) present a major public health challenge, demanding an in-depth understanding of age-specific symptoms and risk factors. Aging not only significantly influences brain function and plasticity but also elevates the risk of hospitalizations and death following TBIs. Repetitive mild TBIs (rmTBI) compound these issues, resulting in cumulative and long-term brain damage in the brain. In this study, we investigate the impact of age on brain network changes and white matter properties following rmTBI by employing a multi-modal approach that integrates resting-state functional magnetic resonance imaging (rsfMRI), graph theory analysis, diffusion tensor imaging (DTI), and neurite orientation dispersion and density imaging (NODDI). Our hypothesis is that the effects of rmTBI are worsened in aged animals, with this group showing more pronounced alterations in brain connectivity and white matter structure. Utilizing the closed-head impact model of engineered rotational acceleration (CHIMERA) model, we conducted rmTBIs or sham (control) procedures on young (2.5–3-months-old) and aged (22-months-old) male and female mice to model high-risk groups. Functional and structural imaging unveiled age-related reductions in communication efficiency between brain regions, while injuries induced opposhigh-risking effects on the small-world index across age groups, influencing network segregation. Functional connectivity analysis also identified alterations in 79 out of 148 brain regions by age, treatment (sham vs. rmTBI), or their interaction. Injuries exerted pronounced effects on sensory integration areas, including insular and motor cortices. Age-related disruptions in white matter integrity were observed, indicating alterations in various diffusion directions (mean diffusivity, radial diffusivity, axial diffusivity, and fractional anisotropy) and density neurite properties (dispersion index, intracellular and isotropic volume fraction). Neuroinflammation, assessed through Iba-1 and GFAP markers, correlated with higher dispersion in the optic tract, suggesting a neuroinflammatory response in injured aged animals compared to sham aged. These findings offer insight into the interplay between age, injuries, and brain connectivity, shedding light on the long-term consequences of rmTBI.
