Defining the Critical Period for Neocortical Neurogenesis after Pediatric Brain Injury

Covey, Matthew; Jiang, Yuhui; Alli, Vamsi V.; Yang, Zhengang; Levison, Steven W.

doi:10.1159/000321607

Cited by 33 publications

(39 citation statements)

References 67 publications

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“…77 Several TBI studies using a cortical impact injury model in mice and rats have demonstrated new neurons near the focal site of injury from 3 days to 3 weeks postinjury. 7,66,70 Indeed, Covey et al 13 showed that the critical period for neocortical neurogenesis in postnatal Day 6 mice was between 4 and 7 days after cryoinjury. Our studies in the 7-dayold (infant) piglet revealed, 7 days after injury, a modest increase in migrating neuroblasts in the white matter of the hemisphere injured via cortical impact.…”

Section: Discussionmentioning

confidence: 99%

Maturation-dependent response of neurogenesis after traumatic brain injury in children

Taylor

Smith²,

Harris

et al. 2013

PED

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Object Traumatic brain injury (TBI) is the leading cause of acquired disability in children, yet innate repair mechanisms are incompletely understood. Given data from animal studies documenting neurogenesis in response to trauma and other insults, the authors investigated whether similar responses could be found in children of different ages after TBI. Methods Immunohistochemistry was used to label doublecortin (DCX), a protein expressed by immature migrating neuroblasts (newborn neurons), in specimens from patients ranging in age from 3 weeks to 10 years who had died either after TBI or from other causes. Doublecortin-positive (DCX+) cells were examined in the subventricular zone (SVZ) and periventricular white matter (PWM) and were quantified within the granule cell layer (GCL) and subgranular zone (SGZ) of the dentate gyrus to determine if age and/or injury affect the number of DCX+ cells in these regions. Results The DCX+ cells decreased in the SVZ as patient age increased and were found in abundance around a focal subacute infarct in a 1-month-old non-TBI patient, but were scarce in all other patients regardless of age or history of trauma. The DCX+ cells in the PWM and dentate gyrus demonstrated a migratory morphology and did not co-localize with markers for astrocytes, microglia, or macrophages. In addition, there were significantly more DCX+ cells in the GCL and SGZ of the dentate gyrus in children younger than 1 year old than in older children. The density of immature migrating neuroblasts in infants (under 1 year of age) was significantly greater than in young children (2–6 years of age, p = 0.006) and older children (7–10 years of age, p = 0.007). Conclusions The main variable influencing the number of migrating neuroblasts observed in the SVZ, PWM, and hippocampus was patient age. Trauma had no discernible effect on the number of migrating neuroblasts in this cohort of patients in whom death typically occurred within hours to days after TBI.

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Section: Discussionmentioning

confidence: 99%

Maturation-dependent response of neurogenesis after traumatic brain injury in children

Taylor

Smith²,

Harris

et al. 2013

PED

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“…While neurogenesis peaks during gestational periods, by adulthood the generation of neurons is restricted to the dentate gyrus (DG) of the hippocampus and the lateral wall of the subventricular zone (SVZ) [64,67].…”

Section: Age-at-injury Response To Preclinical Tbimentioning

confidence: 99%

“…No comparisons to adult CCI injury were made. Unfortunately, data regarding age effects on neurogenesis are still lacking since numerous studies in mice or rats either have not performed adult comparisons [72] or have not used relevant TBI models [67,73]. Of note, while naïve P9 mice display increased proliferation in the DG compared to P21, hypoxic-ischemic injury adversely affected neurogenesis in P9 but greatly enhanced it in P21 suggesting that early adolescence may display a critical window of regenerative potential that may be lost in adulthood.…”

Section: Age-at-injury Response To Preclinical Tbimentioning

confidence: 99%

Age-Dependent Responses Following Traumatic Brain Injury

Brickler¹,

Morton²,

Hazy³

et al. 2018

Traumatic Brain Injury - Pathobiology, Advanced Diagnostics and Acute Management

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Traumatic brain injury (TBI) is a growing health concern worldwide that affects a broad range of the population. As TBI is the leading cause of disability and mortality in children, several preclinical models have been developed using rodents at a variety of different ages; however, key brain maturation events are overlooked that leave some age groups more or less vulnerable to injury. Thus, there has been a large emphasis on producing relevant animal models to elucidate molecular pathways that could be of therapeutic potential to help limit neuronal injury and improve behavioral outcome. TBI involves a host of different biochemical events, including disruption of the cerebral vasculature and breakdown of the blood-brain barrier (BBB) that exacerbates secondary injuries. A better understanding of age-related mechanism(s) underlying brain injury will aid in establishing more effective treatment strategies aimed at improving restoration and preventing further neuronal loss. This review looks at studies that focus on modeling the adolescent population and highlights the importance of individualized aged therapeutics to TBI.

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“…Immunofluorescence was performed on the 40-μm-thick frozen sections as previously described [19] and the sections were counterstained with 1 μg/ml DAPI for 5-10 min. The slides were coverslipped with Fluoro-Gel.…”

Section: Brdu Immunofluorescencementioning

confidence: 99%

Neural Stem Cells in the Immature, but Not the Mature, Subventricular Zone Respond Robustly to Traumatic Brain Injury

Goodus¹,

Guzman²,

Calderón³

et al. 2014

Dev Neurosci

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Pediatric traumatic brain injury is a significant problem that affects many children each year. Progress is being made in developing neuroprotective strategies to combat these injuries. However, investigators are a long way from therapies to fully preserve injured neurons and glia. To restore neurological function, regenerative strategies will be required. Given the importance of stem cells in repairing damaged tissues and the known persistence of neural precursors in the subventricular zone (SVZ), we evaluated regenerative responses of the SVZ to a focal brain lesion. As tissues repair more slowly with aging, injury responses of male Sprague Dawley rats at 6, 11, 17, and 60 days of age and C57Bl/6 mice at 14 days of age were compared. In the injured immature animals, cell proliferation in the dorsolateral SVZ more than doubled by 48 h. By contrast, the proliferative response was almost undetectable in the adult brain. Three approaches were used to assess the relative numbers of bona fide neural stem cells, as follows: the neurosphere assay (on rats injured at postnatal day 11, P11), flow cytometry using a novel 4-marker panel (on mice injured at P14) and staining for stem/progenitor cell markers in the niche (on rats injured at P17). Precursors from the injured immature SVZ formed almost twice as many spheres as precursors from uninjured age-matched brains. Furthermore, spheres formed from the injured brain were larger, indicating that the neural precursors that formed these spheres divided more rapidly. Flow cytometry revealed a 2-fold increase in the percentage of stem cells, a 4-fold increase in multipotential progenitor-3 cells and a 2.5-fold increase in glial-restricted progenitor-2/multipotential-3 cells. Analogously, there was a 2-fold increase in the mitotic index of nestin+/Mash1- immunoreactive cells within the immediately subependymal region. As the early postnatal SVZ is predominantly generating glial cells, an expansion of precursors might not necessarily lead to the production of many new neurons. On the contrary, many BrdU+/doublecortin+ cells were observed streaming out of the SVZ into the neocortex 2 weeks after injuries to P11 rats. However, very few new mature neurons were seen adjacent to the lesion 28 days after injury. Altogether, these data indicate that immature SVZ cells mount a more robust proliferative response to a focal brain injury than adult cells, which includes an expansion of stem cells, primitive progenitors and neuroblasts. Nonetheless, this regenerative response does not result in significant neuronal replacement, indicating that new strategies need to be implemented to retain the regenerated neurons and glia that are being produced.

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Defining the Critical Period for Neocortical Neurogenesis after Pediatric Brain Injury

Cited by 33 publications

References 67 publications

Maturation-dependent response of neurogenesis after traumatic brain injury in children

Maturation-dependent response of neurogenesis after traumatic brain injury in children

Age-Dependent Responses Following Traumatic Brain Injury

Neural Stem Cells in the Immature, but Not the Mature, Subventricular Zone Respond Robustly to Traumatic Brain Injury

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