Sustained neuronal and microglial alterations are associated with diverse neurobehavioral dysfunction long after experimental brain injury
JournalNeurobiology of Disease
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AbstractTraumatic brain injury (TBI) can cause progressive neurodegeneration, sustained neuroinflammation and chronic neurological dysfunction. Few experimental studies have explored the long-term neurobehavioral and functional cellular changes beyond several months. The present study examined the effects of a single moderate-level TBI on functional outcome 8 months after injury. Male C57BL/6 mice were subjected to controlled cortical impact injury and followed for changes in motor performance, learning and memory, as well as depressive-like and social behavior. We also used a novel flow cytometry approach to assess cellular functions in freshly isolated neurons and microglia from the injured tissue. There were marked and diverse, sustained neurobehavioral changes in injured mice. Compared to sham controls, chronic TBI mice showed long-term deficits in gait dynamics, nest building, spatial working memory and recognition memory. The tail suspension, forced swim, and sucrose consumption tests showed a marked depressive-like phenotype that was associated with impaired sociability. At the cellular level, there were lower numbers of Thy1+Tuj1+ neurons and higher numbers of activated CD45loCD11b+ microglia. Functionally, both neurons and microglia exhibited significantly higher levels of oxidative stress after injury. Microglia exhibited chronic deficits in phagocytosis of E. coli bacteria, and increased uptake of myelin and dying neurons. Living neurons showed decreased expression of synaptophysin and postsynaptic density (PSD)-95, along with greater numbers of microtubule-associated protein light chain 3 (LC3)-positive autophagosomes and increased mitochondrial mass that suggest dysregulation of autophagy. In summary, the late neurobehavioral changes found after murine TBI are similar to those found chronically after moderate-severe human head injury. Importantly, such changes are associated with microglial dysfunction and changes in neuronal activity. Copyright 2019 The Authors
SponsorsThis study was supported by the National Institute of Neurological Disorders and Stroke for R01 NS094527 (JW), R01 NS110635 (JW/AIF), R01 NS110567 (JW), F32 NS105355 (RMR), the National Institute of Nursing Research for 2R01 NR013601 (JW/AIF), and the National Institute on Aging for RF1 NS110637 (JW).
KeywordChronic traumatic brain injury
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85076889055&doi=10.1016%2fj.nbd.2019.104713&partnerID=40&md5=c34f8855918462b460b11796505b78ea; http://hdl.handle.net/10713/11577