Age-at-Injury Determines the Extent of Long-Term Neuropathology and Microgliosis After a Diffuse Brain Injury in Male Rats

Doust, Yasmine V.; Rowe, Rachel K.; Adelson, P. David; Lifshitz, Jonathan; Ziebell, Jenna M.

doi:10.3389/fneur.2021.722526

Cited by 20 publications

(31 citation statements)

References 108 publications

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“…Approximately 60–120 min after surgery, rats were subjected to mFPI with methods we have previously described for PND17 and PND35 rats ( 13 , 23 , 24 ). Rats were re-anesthetized with 5% isoflurane in 100% oxygen delivered for 3 min.…”

Section: Methodsmentioning

confidence: 99%

“…The hub assembly on the skull was filled with saline and attached to the FPI device (custom design and fabrication, Virginia Commonwealth University, Richmond, VA). When a toe pinch withdrawal response was detected, the pendulum was released causing a fluid pulse directly onto the dura resulting in a mild to moderate brain injury in all rats [PND17 = 1.5 atmospheres pressure (atm), PND35 = 1.9 atm] ( 13 , 23 , 24 ). Sham rats were connected to the device, but the pendulum was not released.…”

Section: Methodsmentioning

confidence: 99%

“…Activation of microglia in juveniles following experimental TBI may also be important for the removal of dying neurons ( 12 ). However, long-term persistence of glial activation and cytokine release causes a self-perpetuating state of chronic inflammation, exacerbates the brain injury, and can lead to neuronal damage and neurodegeneration ( 11 , 13 ). Microglia morphology is altered in response to injury ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, we used a comprehensive time course after experimental TBI in rats to examine the acute and sub-acute cortical glial response (microglial activation and GFAP expression) to TBI. We used juvenile rats subjected to TBI at post-natal day (PND) 17, which models early childhood in humans, or PND35, which models adolescence in humans ( 13 , 16 ).…”

Section: Introductionmentioning

confidence: 99%

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Age-At-Injury Influences the Glial Response to Traumatic Brain Injury in the Cortex of Male Juvenile Rats

et al. 2022

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Few translational studies have examined how age-at-injury affects the glial response to traumatic brain injury (TBI). We hypothesized that rats injured at post-natal day (PND) 17 would exhibit a greater glial response, that would persist into early adulthood, compared to rats injured at PND35. PND17 and PND35 rats (n = 75) received a mild to moderate midline fluid percussion injury or sham surgery. In three cortical regions [peri-injury, primary somatosensory barrel field (S1BF), perirhinal], we investigated the glial response relative to age-at-injury (PND17 or PND35), time post-injury (2 hours, 1 day, 7 days, 25 days, or 43 days), and post-natal age, such that rats injured at PND17 or PND35 were compared at the same post-natal-age (e.g., PND17 + 25D post-injury = PND42; PND35 + 7D post-injury = PND42). We measured Iba1 positive microglia cells (area, perimeter) and quantified their activation status using skeletal analysis (branch length/cell, mean processes/cell, cell abundance). GFAP expression was examined using immunohistochemistry and pixel analysis. Data were analyzed using Bayesian multivariate multi-level models. Independent of age-at-injury, TBI activated microglia (shorter branches, fewer processes) in the S1BF and perirhinal cortex with more microglia in all regions compared to uninjured shams. TBI-induced microglial activation (shorter branches) was sustained in the S1BF into early adulthood (PND60). Overall, PND17 injured rats had more microglial activation in the perirhinal cortex than PND35 injured rats. Activation was not confounded by age-dependent cell size changes, and microglial cell body sizes were similar between PND17 and PND35 rats. There were no differences in astrocyte GFAP expression. Increased microglial activation in PND17 brain-injured rats suggests that TBI upregulates the glial response at discrete stages of development. Age-at-injury and aging with an injury are translationally important because experiencing a TBI at an early age may trigger an exaggerated glial response.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Age-At-Injury Influences the Glial Response to Traumatic Brain Injury in the Cortex of Male Juvenile Rats

et al. 2022

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“…Doust et al, found that aged rats (10 months), that had received a recent (2, 4, or 6 months) moderate mFPI had increased dendrite neurofilament pathology and higher CD68 activity in microglia. Additionally rats that received the brain injury earlier in life (PND 17–35) had higher colocalization between TREM2 and microglia in the hippocampus (Doust et al, 2021 ). These indicate that age at time of injury impacts neuropathology but even brain injuries received earlier in life can continue to interact with aging neuroinflammation.…”

Section: Age-related Inflammationmentioning

confidence: 99%

A Levee to the Flood: Pre-injury Neuroinflammation and Immune Stress Influence Traumatic Brain Injury Outcome

Houle

Kokiko-Cochran

2022

Front. Aging Neurosci.

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Increasing evidence demonstrates that aging influences the brain's response to traumatic brain injury (TBI), setting the stage for neurodegenerative pathology like Alzheimer's disease (AD). This topic is often dominated by discussions of post-injury aging and inflammation, which can diminish the consideration of those same factors before TBI. In fact, pre-TBI aging and inflammation may be just as critical in mediating outcomes. For example, elderly individuals suffer from the highest rates of TBI of all severities. Additionally, pre-injury immune challenges or stressors may alter pathology and outcome independent of age. The inflammatory response to TBI is malleable and influenced by previous, coincident, and subsequent immune insults. Therefore, pre-existing conditions that elicit or include an inflammatory response could substantially influence the brain's ability to respond to traumatic injury and ultimately affect chronic outcome. The purpose of this review is to detail how age-related cellular and molecular changes, as well as genetic risk variants for AD affect the neuroinflammatory response to TBI. First, we will review the sources and pathology of neuroinflammation following TBI. Then, we will highlight the significance of age-related, endogenous sources of inflammation, including changes in cytokine expression, reactive oxygen species processing, and mitochondrial function. Heightened focus is placed on the mitochondria as an integral link between inflammation and various genetic risk factors for AD. Together, this review will compile current clinical and experimental research to highlight how pre-existing inflammatory changes associated with infection and stress, aging, and genetic risk factors can alter response to TBI.

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Temporal changes in the microglial proteome of male and female mice after a diffuse brain injury using label‐free quantitative proteomics

Doust

Bindoff

Holloway

et al. 2022

Glia

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Traumatic brain injury (TBI) triggers neuroinflammatory cascades mediated by microglia, which promotes tissue repair in the short-term. These cascades may exacerbate TBI-induced tissue damage and symptoms in the months to years post-injury. However, the progression of the microglial function across time postinjury and whether this differs between biological sexes is not well understood. In this study, we examined the microglial proteome at 3-, 7-, or 28-days after a midline fluid percussion injury (mFPI) in male and female mice using label-free quantitative proteomics. Data are available via ProteomeXchange with identifier PXD033628. We identified a reduction in microglial proteins involved with clearance of neuronal debris via phagocytosis at 3-and 7-days post-injury. At 28 days post-injury, pro-inflammatory proteins were decreased and anti-inflammatory proteins were increased in microglia. These results indicate a reduction in microglial clearance of neuronal debris in the days post-injury with a shift to antiinflammatory function by 28 days following TBI. The changes in the microglial proteome that occurred across time post-injury did not differ between biological sexes. However, we did identify an increase in microglial proteins related to proinflammation and phagocytosis as well as insulin and estrogen signaling in males compared with female mice that occurred with or without a brain injury. Although the microglial response was similar between males and females up to 28 days following TBI, biological sex differences in the microglial proteome, regardless of TBI, has implications for the efficacy of treatment strategies targeting the microglial response post-injury.

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Age-at-Injury Determines the Extent of Long-Term Neuropathology and Microgliosis After a Diffuse Brain Injury in Male Rats

Cited by 20 publications

References 108 publications

Age-At-Injury Influences the Glial Response to Traumatic Brain Injury in the Cortex of Male Juvenile Rats

Age-At-Injury Influences the Glial Response to Traumatic Brain Injury in the Cortex of Male Juvenile Rats

A Levee to the Flood: Pre-injury Neuroinflammation and Immune Stress Influence Traumatic Brain Injury Outcome

Temporal changes in the microglial proteome of male and female mice after a diffuse brain injury using label‐free quantitative proteomics

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