Lithium reduced neural progenitor apoptosis in the hippocampus and ameliorated functional deficits after irradiation to the immature mouse brain

Huo, Kaiming; Sun, Yanyan; Li, Hongfu; Du, Xinyue; Wang, Xiaoyang; Karlsson, Niklas; Zhu, Changlian; Blomgren, Klas

doi:10.1016/j.mcn.2012.07.002

Cited by 96 publications

(95 citation statements)

References 75 publications

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“…The smaller volume observed after irradiation is therefore most likely explained by arrested growth, resulting in reduced volumes in irradiated brains compared with control brains. 26 Cell death may also contribute to the smaller volumes through an acute loss of cells, 24,30 and the corresponding volume. This is most evident in areas where postnatal neurogenesis occurs.…”

Section: Discussionmentioning

confidence: 99%

“…Our study revealed only a handful of dying endothelial cells in the entire irradiated hippocampus, in stark contrast to the tens of thousands of dying stem and progenitor cells in the SGZ. 30 This strongly speaks against a role for injury to microvessels being a primary event in the perturbation of neurogenesis in the hippocampus. We speculate that the developmental stage of the brains and the irradiation dose used can explain many of the differences observed.…”

Section: Discussionmentioning

confidence: 99%

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

Boström

Kalm

Karlsson

et al. 2013

J Cereb Blood Flow Metab

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We investigated the effects of ionizing radiation on microvessel structure and complexity in the hippocampus. We also assessed neurogenesis and the neurovascular niche. Postnatal day 14 male C57BL/6 mice received a single dose of 8 Gy to the whole brain and were killed 6 hours, 1 week, 7 weeks, or 1 year later. Irradiation decreased the total number of microvessels and branching points from 1 week onwards and decreased the total microvessel area 1 and 7 weeks after irradiation. After an initial increase in vascular parameter densities, concomitant with reduced growth of the hippocampus, the densities normalized with time, presumably adapting to the needs of the surrounding nonvascular tissue. Irradiation decreased the number of neural stem and progenitor cells in the hippocampus. The relative loss increased with time, resulting in almost completely ablated neurogenesis (DCX þ cells) 1 year after irradiation (77% decreased 1 week, 86% decreased 7 weeks, and 98% decreased 1 year after irradiation compared with controls). After irradiation, the distance between undifferentiated stem cells and microvessels was unaffected, and very few dying endothelial cells were detected. Taken together, these results indicate that the vasculature adjusts to the surrounding neural and glial tissue after irradiation, not vice-versa.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Boström

Kalm

Karlsson

et al. 2013

J Cereb Blood Flow Metab

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“…Lithium appears to restore cognitive function in adult as well as in young [29] mice following cranial irradiation and is thought to act partially through the inhibition of neural apoptosis [30] as well as by boosting endogenous neurogenesis [31]. At present, there is little knowledge of irradiation-induced damage to the brain during development, but since the juvenile brain is even more sensitive to ionizing irradiation than the adult brain [2,5,32], it is of great importance to define the mechanisms that lead to cognitive impairment following such treatment and to conceive therapeutic approaches to rescue the young developing brain from cognitive decline.…”

Section: Introductionmentioning

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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“…The LPS-induced reduction of neurogenesis presumably further aggravates the cognitive deficits observed after IR [22,23,25,45,46,47]. IR has previously been shown to change the microenvironment in the brain and cause progenitor cells in the DG to shift their proliferative response from neurogenesis to gliogenesis [13].…”

Section: Discussionmentioning

confidence: 99%

“…Microglia activated by LPS has been shown to be localized close to newly formed cells, and a negative correlation has been observed between the number of surviving newborn neurons and the number of activated microglia in the neurogenic zone [16,21]. Proliferation is decreased in the neurogenic SGZ and the number of microglia is increased in the acute phase after IR in the young brain [17,22,23]. Hence, both IR and LPS-induced inflammation can have detrimental effects on neurogenesis, but the combination of the two in the young brain has not been investigated before.…”

Section: Introductionmentioning

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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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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Lithium reduced neural progenitor apoptosis in the hippocampus and ameliorated functional deficits after irradiation to the immature mouse brain

Cited by 96 publications

References 75 publications

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

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

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

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

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