How to Translate Time? The Temporal Aspect of Human and Rodent Biology

Agoston, Denes V.

doi:10.3389/fneur.2017.00092

Cited by 138 publications

(107 citation statements)

References 21 publications

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“…The model was optimized so as to potentiate clinical relevance by limiting the amount of injury induced by each individual closed head injury, i.e., by rendering the individual impacts mild (single impact being negative on neuroimaging). Mice were young adults (9 weeks old) at the time of first impact; in the human population, young adults suffer a disproportionate number of mild head injuries through participation in athletics and military service 18 , 29 . Of note, however, rodent and human ages should not be conflated due to the different time scales of important complex biological processes 18 , 29 .…”

Section: Discussionmentioning

confidence: 99%

“…Mice were young adults (9 weeks old) at the time of first impact; in the human population, young adults suffer a disproportionate number of mild head injuries through participation in athletics and military service 18 , 29 . Of note, however, rodent and human ages should not be conflated due to the different time scales of important complex biological processes 18 , 29 . They suggest that rodents may reach sexual maturity around 50 days of age, but do not enter adulthood until 210 days; hence, the mice in this study are sexually mature but not yet adults.…”

Section: Discussionmentioning

confidence: 99%

“…Thirty-six 9-week-old transgenic Thy1-ChR2 mice underwent either repeated CHI (n=19, 10 male, 9 female) or sham preparation (n=17, 9 male, 8 female). This age is considered equivalent to puberty/young adulthood in humans 18 . Repeated TBI was induced via three electromagnetically actuated impacts delivered at 3-day intervals to the skull region corresponding to the forelimb region in the primary somatosensory cortex (S1FL).…”

Section: Methodsmentioning

confidence: 99%

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Neurogliovascular dysfunction in a model of repeated traumatic brain injury

et al. 2018

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Traumatic brain injury (TBI) research has focused on moderate to severe injuries as their outcomes are significantly worse than those of a mild TBI (mTBI). However, recent epidemiological evidence has indicated that a series of even mild TBIs greatly increases the risk of neurodegenerative and psychiatric disorders. Neuropathological studies of repeated TBI have identified changes in neuronal ionic concentrations, axonal injury, and cytoskeletal damage as important determinants of later life neurological and mood compromise; yet, there is a paucity of data on the contribution of neurogliovascular dysfunction to the progression of repeated TBI and alterations of brain function in the intervening period.Methods: Here, we established a mouse model of repeated TBI induced via three electromagnetically actuated impacts delivered to the intact skull at three-day intervals and determined the long-term deficits in neurogliovascular functioning in Thy1-ChR2 mice. Two weeks post the third impact, cerebral blood flow and cerebrovascular reactivity were measured with arterial spin labelling magnetic resonance imaging. Neuronal function was investigated through bilateral intracranial electrophysiological responses to optogenetic photostimulation. Vascular density of the site of impacts was measured with in vivo two photon fluorescence microscopy. Pathological analysis of neuronal survival and astrogliosis was performed via NeuN and GFAP immunofluorescence.Results: Cerebral blood flow and cerebrovascular reactivity were decreased by 50±16% and 70±20%, respectively, in the TBI cohort relative to sham-treated animals. Concomitantly, electrophysiological recordings revealed a 97±1% attenuation in peri-contusional neuronal reactivity relative to sham. Peri-contusional vascular volume was increased by 33±2% relative to sham-treated mice. Pathological analysis of the peri-contusional cortex demonstrated astrogliosis, but no changes in neuronal survival.Conclusion: This work provides the first in-situ characterization of the long-term deficits of the neurogliovascular unit following repeated TBI. The findings will help guide the development of diagnostic markers as well as therapeutics targeting neurogliovascular dysfunction.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Neurogliovascular dysfunction in a model of repeated traumatic brain injury

et al. 2018

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“…While these intervals seem (and are) unrealistic for humans, available experimental evidence show that in addition to normal biological processes, such as gestation, reaching sexual maturity, and life span among others, 116 TBI-induced pathological processes (e.g., altered cerebral glucose metabolism, inflammation, axonal pathology, vascular changes/water transport) may run five to 100 times faster in rats that in humans. Accordingly, when it comes to complex pathobiological processes, as opposed to simple enzyme kinetics, rat hours seem to be more comparable to human days than to human hours.…”

Section: S-46 Agostonmentioning

confidence: 99%

Modeling the Long-Term Consequences of Repeated Blast-Induced Mild Traumatic Brain Injuries

Agoston

2017

Journal of Neurotrauma

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Repeated mild traumatic brain injury (rmTBI) caused by playing collision sports or by exposure to blasts during military operations can lead to late onset, chronic diseases such as chronic traumatic encephalopathy (CTE), a progressive neurodegenerative condition that manifests in increasingly severe neuropsychiatric abnormalities years after the last injury. Currently, because of the heterogeneity of the clinical presentation, confirmation of a CTE diagnosis requires post-mortem examination of the brain. The hallmarks of CTE are abnormal accumulation of phosphorylated tau protein, TDP-43 immunoreactive neuronal cytoplasmic inclusions, and astroglial abnormalities, but the pathomechanism leading to these terminal findings remains unknown. Animal modeling can play an important role in the identification of CTE pathomechanisms, the development of early stage diagnostic and prognostic biomarkers, and pharmacological interventions. Modeling the long-term consequences of blast rmTBI in animals is especially challenging because of the complexities of blast physics and animal-to-human scaling issues. This review summarizes current knowledge about the pathobiologies of CTE and rmbTBI and discusses problems as well as potential solutions related to high-fidelity modeling of rmbTBI and determining its long-term consequences.

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“…Experimental models of TBI have been used with 14 at 1 d and recovery by 7-10 d post injury in both the cortex and hippocampus. 23 A similar pattern of CMRglc changes were also observed with 18 F-deoxyglucose PET (FDG-PET) in adult mild fluid percussion injured rats with metabolic recovery by 16 d post injury.…”

Section: Experimental Studiesmentioning

confidence: 99%