Irradiation to the Young Mouse Brain Caused Long-Term, Progressive Depletion of Neurogenesis but did not Disrupt the Neurovascular Niche

Boström, Martina; Kalm, Marie; Karlsson, Niklas; Erkenstam, Nina Hellström; Blomgren, Klas

doi:10.1038/jcbfm.2013.34

Cited by 45 publications

(51 citation statements)

References 42 publications

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“…LPS alone did not reduce cytogenesis in the DG or the GCL, rather the opposite. IR, on the other hand, greatly reduced cytogenesis in the DG and the GCL, as also demonstrated earlier [10,12,22,29,30], and IR itself induces oxidative stress and an inflammatory reaction [10,26]. Apparently, in this study LPS pretreatment sensitized the DG to a subsequent IR insult, but it is known that neurogenesis can be both up- and downregulated in response to injurious stimuli [31], and whether an injurious stimulus will induce sensitization (as in the current study) or the opposite (a protective, preconditioning effect) depends on both dose and timing, as described below.…”

Section: Discussionsupporting

confidence: 65%

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Lipopolysaccharide-Induced Inflammation Aggravates Irradiation-Induced Injury to the Young Mouse Brain

Roughton¹,

Andréasson

Blomgren

et al. 2013

Dev Neurosci

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Radiotherapy is an effective treatment strategy in the treatment of brain tumors, but it is also a major cause of long-term complications, especially in survivors of pediatric brain tumors. Cognitive decline caused by cranial radiotherapy is thought, at least partly, to depend on injury to stem and progenitor cells in the dentate gyrus of the hippocampus. This study investigated the effects of lipopolysaccharide (LPS)-induced inflammation at the time of irradiation (IR) in the growing mouse brain. A single injection of LPS (0.3 mg/kg) was administered 24 h prior to cranial IR of 14-day-old male mice. LPS pretreatment increased the levels of the chemokine CCL2 and the cytokine IL-1β in the brain by 440 and 560%, respectively, compared to IR alone. IR disrupted hippocampal neurogenesis and the growth of the dentate gyrus, and the mice pretreated with LPS displayed an even more pronounced lack of growth than the vehicle-treated group 2 months after IR. The density of microglia was not affected, but LPS-pretreated mice displayed 48% fewer bromodeoxyuridine-positive cells and 43% fewer doublecortin-positive cells in the granule cell layer 2 months after IR compared with the vehicle-treated group. In conclusion, an ongoing inflammation in the brain at the time of IR further enhanced the IR-induced loss of neurogenesis, and may aggravate future cognitive deficits in patients treated with cranial radiotherapy.

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Section: Discussionsupporting

confidence: 65%

“…It is well known that IR retards or even stops growth of the DG if performed before the DG has reached its full size [12,22,28,29]. The group pretreated with LPS displayed a more pronounced lack of growth than the vehicle-treated group after IR (fig.…”

Section: Resultsmentioning

confidence: 99%

Lipopolysaccharide-Induced Inflammation Aggravates Irradiation-Induced Injury to the Young Mouse Brain

Roughton¹,

Andréasson

Blomgren

et al. 2013

Dev Neurosci

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“…Rapidly proliferating neuronal progenitors are a sensitive target of irradiation, and especially their integration in the DG is progressively impaired following this treatment [5,37,38]. According to recent findings, lithium positively regulates the neurogenic process and facilitates the reintegration of newly generated neurons after ablation of neurogenesis [26,27,28,29].…”

Section: Resultsmentioning

confidence: 99%

Irradiation of the Juvenile Brain Provokes a Shift from Long-Term Potentiation to Long-Term Depression

Zanni

Zhou²,

Riebe

et al. 2015

Dev Neurosci

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Radiotherapy is common in the treatment of brain tumors in children but often causes deleterious, late-appearing sequelae, including cognitive decline. This is thought to be caused, at least partly, by the suppression of hippocampal neurogenesis. However, the changes in neuronal network properties in the dentate gyrus (DG) following the irradiation of the young, growing brain are still poorly understood. We characterized the long-lasting effects of irradiation on the electrophysiological properties of the DG after a single dose of 6-Gy whole-brain irradiation on postnatal day 11 in male Wistar rats. The assessment of the basal excitatory transmission in the medial perforant pathway (MPP) by an examination of the field excitatory postsynaptic potential/volley ratio showed an increase of the synaptic efficacy per axon in irradiated animals compared to sham controls. The paired-pulse ratio at the MPP granule cell synapses was not affected by irradiation, suggesting that the release probability of neurotransmitters was not altered. Surprisingly, the induction of long-term synaptic plasticity in the DG by applying 4 trains of high-frequency stimulation provoked a shift from long-term potentiation (LTP) to long-term depression (LTD) in irradiated animals compared to sham controls. The morphological changes consisted in a virtually complete ablation of neurogenesis following irradiation, as judged by doublecortin immunostaining, while the inhibitory network of parvalbumin interneurons was intact. These data suggest that the irradiation of the juvenile brain caused permanent changes in synaptic plasticity that would seem consistent with an impairment of declarative learning. Unlike in our previous study in mice, lithium treatment did unfortunately not ameliorate any of the studied parameters. For the first time, we show that the effects of cranial irradiation on long-term synaptic plasticity is different in the juvenile compared with the adult brain, such that while irradiation of the adult brain will only cause a reduction in LTP, irradiation of the juvenile brain goes further and causes LTD. Although the mechanisms underlying the synaptic alterations need to be elucidated, these findings provide a better understanding of the effects of irradiation in the developing brain and the cognitive deficits observed in young patients who have been subjected to cranial radiotherapy.

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“…After IR of the growing brain, the loss of endogenous NSPCs leads to a long-lasting, progressive reduction of neurogenesis (8), so a strategy aiming to replenish both undifferentiated NSPCs and differentiated granule neurons would appear ideal. Transplanted BNSPCs have the capacity to produce neural cells in different CNS disease models.…”

Section: Discussionmentioning

confidence: 99%

“…Owing to their high proliferative capacity, these cells are susceptible to IR damage (16,35,42). IR-induced depletion of neural stem/progenitor cells appears to be long lasting, even after a single moderate dose of radiation (8,24). Interventions after IR have been investigated.…”

Section: Introductionmentioning

confidence: 99%

Transplantation of Enteric Neural Stem/Progenitor Cells into the Irradiated Young Mouse Hippocampus

et al. 2014

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Radiotherapy is an effective treatment for brain tumors but often results in cognitive deficits in survivors. Transplantation of embryonic or brain-derived neural stem/progenitor cells (BNSPCs) ameliorated cognitive impairment after irradiation (IR) in animal models. However, such an approach in patients requires a clinically relevant source of cells. We show for the first time the utilization of enteric neural stem/progenitor cells (ENSPCs) from the postnatal intestinal wall as a source of autologous cells for brain repair after injury caused by IR. Cells were isolated from the intestinal wall and propagated in vitro for 1 week. Differentiation assays showed that ENSPCs are multipotent and generated neurons, astrocytes, and myofibroblasts. To investigate whether ENSPCs can be used in vivo, postnatal day 9 mice were subjected to a single moderate irradiation dose (6 or 8 Gy). Twelve days later, mice received an intrahippocampal injection of syngeneic ENSPCs. Four weeks after transplantation, 0.5% and 1% of grafted ENSPCs were detected in the dentate gyrus of sham and irradiated animals, respectively, and only 0.1% was detected after 16 weeks. Grafted ENSPCs remained undifferentiated but failed to restore IR-induced loss of BNSPCs and the subsequent impaired growth of the dentate gyrus. We observed microglia activation, astrogliosis, and loss of granule neurons associated with grafted ENSPC clusters. Transplantation of ENSPCs did not ameliorate IR-induced impaired learning and memory. In summary, while autologous ENSPC grafting to the brain worked technically, even in the absence of immunosuppression, the protocols need to be modified to improve survival and integration.

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Irradiation to the Young Mouse Brain Caused Long-Term, Progressive Depletion of Neurogenesis but did not Disrupt the Neurovascular Niche

Cited by 45 publications

References 42 publications

Lipopolysaccharide-Induced Inflammation Aggravates Irradiation-Induced Injury to the Young Mouse Brain

Lipopolysaccharide-Induced Inflammation Aggravates Irradiation-Induced Injury to the Young Mouse Brain

Irradiation of the Juvenile Brain Provokes a Shift from Long-Term Potentiation to Long-Term Depression

Transplantation of Enteric Neural Stem/Progenitor Cells into the Irradiated Young Mouse Hippocampus

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