Differential neuropathology and functional outcome after equivalent traumatic brain injury in aged versus young adult mice

Islam, Mecca B.A.R.; Davis, Booker T; Kando, Mary J.; Mao, Qinwen; Procissi, Daniele; Weiss, Craig; Schwulst, Steven J.

doi:10.1016/j.expneurol.2021.113714

Cited by 19 publications

(31 citation statements)

References 48 publications

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“…In fact, older individuals are twice as likely to die from a brain injury than children ( 69 ). More recent research suggests that individuals who sustain a TBI in juvenile years will have different outcomes to those who sustain a TBI when older ( 16 , 25 , 70 ). For example, after a pediatric TBI, mice displayed social deficits in adulthood ( 71 ).…”

Section: Discussionmentioning

confidence: 99%

“…Due to the high prevalence of 18-to 25-year-old male individuals that sustain a TBI (7), clinical and experimental research has focused on the behavioral and neuropathological outcomes in young adult males. There is cumulative research in humans and various animal models that demonstrate a TBI at any age can result in long-term sensorimotor, cognitive, and endocrine symptoms in addition to neuropathology and glial activation, but it remains unclear whether age-at-injury affects these outcomes (11)(12)(13)(14)(15)(16)).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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Traumatic brain injury (TBI) can occur at any age, from youth to the elderly, and its contribution to age-related neuropathology remains unknown. Few studies have investigated the relationship between age-at-injury and pathophysiology at a discrete biological age. In this study, we report the immunohistochemical analysis of naïve rat brains compared to those subjected to diffuse TBI by midline fluid percussion injury (mFPI) at post-natal day (PND) 17, PND35, 2-, 4-, or 6-months of age. All brains were collected when rats were 10-months of age (n = 6–7/group). Generalized linear mixed models were fitted to analyze binomial proportion and count data with R Studio. Amyloid precursor protein (APP) and neurofilament (SMI34, SMI32) neuronal pathology were counted in the corpus callosum (CC) and primary sensory barrel field (S1BF). Phosphorylated TAR DNA-binding protein 43 (pTDP-43) neuropathology was counted in the S1BF and hippocampus. There was a significantly greater extent of APP and SMI34 axonal pathology and pTDP-43 neuropathology following a TBI compared with naïves regardless of brain region or age-at-injury. However, age-at-injury did determine the extent of dendritic neurofilament (SMI32) pathology in the CC and S1BF where all brain-injured rats exhibited a greater extent of pathology compared with naïve. No significant differences were detected in the extent of astrocyte activation between brain-injured and naïve rats. Microglia counts were conducted in the S1BF, hippocampus, ventral posteromedial (VPM) nucleus, zona incerta, and posterior hypothalamic nucleus. There was a significantly greater proportion of deramified microglia, regardless of whether the TBI was recent or remote, but this only occurred in the S1BF and hippocampus. The proportion of microglia with colocalized CD68 and TREM2 in the S1BF was greater in all brain-injured rats compared with naïve, regardless of whether the TBI was recent or remote. Only rats with recent TBI exhibited a greater proportion of CD68-positive microglia compared with naive in the hippocampus and posterior hypothalamic nucleus. Whilst, only rats with a remote brain-injury displayed a greater proportion of microglia colocalized with TREM2 in the hippocampus. Thus, chronic alterations in neuronal and microglial characteristics are evident in the injured brain despite the recency of a diffuse brain injury.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…Abbreviations: ↑: increase; ↓: decrease; BBB: blood-brain barrier; CCI: controlled cortical impact; d: day post-injury; FP: fluid percussion; h: hour post-injury; LFP: lateral fluid percussion; M: post-natal month; NC: not compared; TBI: traumatic brain injury; W: post-natal week; YA: young adult . Animal Age (Aged) Comparison Age (YA) Main Highlights Reference Neuronal Death and Brain Lesion Functional Deficits and Other Consequences Mice LFP, open skull, unilateral M12 M1.5/3 - axonal degeneration aged > YA at 28 d - epothilone D ↑ axonal degeneration in aged at 28 d [ 199 ] Mice CCI, open skull, unilateral M18 M3 - ↓ motor coordination aged > YA from 1 to 3 d - weight loss in aged from 2 d [ 200 ] Mice CCI, open skull, unilateral M18 M3 - white mater injuries aged < YA at 30 d - ventriculomegaly aged < YA at 30 d - inhibition of anxiety-like behavior aged > YA at 31 d - exploration deficit aged > YA at 67 d - learning and memory deficits aged > YA at 32 and 93 d [ 213 ] Mice CCI, open skull, unilateral M19 NC - lesion size aged > previous adult studies from 1 to 28 d - ↓ synapse at 30 d (hippocampus) [ 202 ] ...…”

Section: Post-traumatic Neuroinflammation and Its Consequences In Vivomentioning

confidence: 99%

“…Neurodegeneration and neuronal death are exacerbated at 3 and 7 dpi in the damaged area and hippocampus of aged mice, as compared with young adults [ 204 , 210 , 214 , 220 ]. Aged mice also showed more important WMI than young adults [ 213 ]. The evolution of axonal injuries differs by age, with early injury at 7 dpi in younger animals resolved by 28 dpi, whereas, in older animals, axonal injuries are less severe at 7 dpi but worsen by 28 dpi [ 199 ].…”

Section: Post-traumatic Neuroinflammation and Its Consequences In Vivomentioning

confidence: 99%

“…Indeed, TBI induces deficits in learning and memory, locomotor and motor coordination and anxiety-like behaviors [ 200 , 202 , 214 , 217 , 220 ]. Compared with young adults, aged mice show more important sensori- and locomotor [ 200 , 211 , 214 , 217 , 218 ], anxiety-like, exploratory behavior [ 213 ] and learning and memory deficits [ 213 , 217 , 218 , 220 ]. These neurobehavioral deficits persist up to 3 mpi [ 213 ].…”

Section: Post-traumatic Neuroinflammation and Its Consequences In Vivomentioning

confidence: 99%

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Traumatic Brain Injury: An Age-Dependent View of Post-Traumatic Neuroinflammation and Its Treatment

et al. 2021

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Traumatic brain injury (TBI) is a leading cause of death and disability all over the world. TBI leads to (1) an inflammatory response, (2) white matter injuries and (3) neurodegenerative pathologies in the long term. In humans, TBI occurs most often in children and adolescents or in the elderly, and it is well known that immune responses and the neuroregenerative capacities of the brain, among other factors, vary over a lifetime. Thus, age-at-injury can influence the consequences of TBI. Furthermore, age-at-injury also influences the pharmacological effects of drugs. However, the post-TBI inflammatory, neuronal and functional consequences have been mostly studied in experimental young adult animal models. The specificity and the mechanisms underlying the consequences of TBI and pharmacological responses are poorly understood in extreme ages. In this review, we detail the variations of these age-dependent inflammatory responses and consequences after TBI, from an experimental point of view. We investigate the evolution of microglial, astrocyte and other immune cells responses, and the consequences in terms of neuronal death and functional deficits in neonates, juvenile, adolescent and aged male animals, following a single TBI. We also describe the pharmacological responses to anti-inflammatory or neuroprotective agents, highlighting the need for an age-specific approach to the development of therapies of TBI.

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Recombinant human erythropoietin induces neuroprotection, activates MAPK/CREB pathway, and rescues fear memory after traumatic brain injury with delayed hypoxemia in mice

et al. 2022

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Differential neuropathology and functional outcome after equivalent traumatic brain injury in aged versus young adult mice

Cited by 19 publications

References 48 publications

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

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

Traumatic Brain Injury: An Age-Dependent View of Post-Traumatic Neuroinflammation and Its Treatment

Recombinant human erythropoietin induces neuroprotection, activates MAPK/CREB pathway, and rescues fear memory after traumatic brain injury with delayed hypoxemia in mice

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