| 1. |
- Kalm, Marie, 1981, et al.
(författare)
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Loss of hippocampal neurogenesis, increased novelty-induced activity, decreased home cage activity, and impaired reversal learning one year after irradiation of the young mouse brain
- 2013
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886 .- 1090-2430. ; 247, s. 402-409
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Tidskriftsartikel (refereegranskat)abstract
- Radiotherapy is a major cause of long-term complications in survivors of pediatric brain tumors. These complications include intellectual and memory impairments as well as perturbed growth and puberty. We investigated the long-term effects of a single 8Gy irradiation dose to the brains of 14-day-old mice. Behavior was assessed one year after irradiation using IntelliCage and open field, followed by immunohistochemical investigation of proliferation and neurogenesis in the dentate gyrus of the hippocampus. We found a 61% reduction in proliferation and survival (BrdU incorporation 4weeks prior to sacrifice), 99% decrease in neurogenesis (number of doublecortin-positive cells) and gliosis (12% higher astrocyte density) one year following irradiation. Irradiated animals displayed increased activity in a novel environment but decreased activity in their home cage. Place learning in the IntelliCage was unaffected by irradiation but reversal learning was impaired. Irradiated animals persevered in visiting previously correct corners to a higher extent compared to control animals. Hence, despite the virtual absence of neurogenesis in these old mice, spatial learning could take place. Reversal learning however, where a previous memory was replaced with a new one, was partly impaired. This model is useful to study the so called late effects of radiotherapy to the young brain and to evaluate possible interventions.
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| 2. |
- Karlsson, Niklas, et al.
(författare)
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Learning and activity after irradiation of the young mouse brain analyzed in adulthood using unbiased monitoring in a home cage environment.
- 2011
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Ingår i: Radiation research. - 1938-5404. ; 175:3, s. 336-46
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Tidskriftsartikel (refereegranskat)abstract
- Cranial radiotherapy during the treatment of pediatric malignancies may cause adverse late effects. It is important to find methods to assess the functional effects of ionizing radiation in animal models and to evaluate the possible ameliorating effects of preventive or reparative treatment strategies. We investigated the long-term effects of a single 8-Gy radiation dose to the brains of 14-day-old mice. Activity and learning were evaluated in adulthood using open field and trace fear conditioning (TFC). These established methods were compared with the novel IntelliCage platform, which enables unbiased analysis of both activity and learning over time in a home cage environment. Neither activity nor learning was changed after irradiation, as judged by the open field and TFC analyses. The IntelliCage, however, revealed both altered activity and learning impairment after irradiation. Place learning and reversal learning were both impaired in the IntelliCage 3 months after irradiation. These results indicate that activity and learning should be assessed using multiple methods and that unbiased analysis over time in a home cage environment may offer advantages in the detection of subtle radiation-induced effects on the young brain.
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| 3. |
- Blomstrand, Malin, 1974, et al.
(författare)
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Different reactions to irradiation in the juvenile and adult hippocampus
- 2014
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Ingår i: International Journal of Radiation Biology. - : Informa UK Limited. - 0955-3002 .- 1362-3095. ; 90:9, s. 807-815
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Cranial radiotherapy is an important tool in the cure of primary brain tumors. Unfortunately, it is associated with late-appearing toxicity to the normal brain tissue, including cognitive impairment, particularly in children. The underlying mechanisms are not fully understood but involve changes in hippocampal neurogenesis. Recent studies report essentially different responses in the juvenile and the adult brain after irradiation, but this has never been verified in a comparative study. Materials and methods: We subjected juvenile (9-day-old) and adult (6-month-old) male rats to a single dose of 6 Gray (Gy) whole brain irradiation and euthanized them 6 hours, 7 days or 4 weeks later. Hippocampal lysates were analyzed for caspase-3 activity (apoptosis) and the expression of cytokines, chemokines and growth factors. Four weeks after irradiation, the number of microglia (expressing ionized calcium-binding adapter molecule 1, Iba-1), activated microglia (expressing cluster of differentiation 68 [CD68]), bromodeoxyuridine (BrdU) incorporation and granule cell layer (GCL) volume were assessed. Results: The major findings were (i) higher baseline BrdU incorporation (cell proliferation) in juvenile than in adult controls, which explains the increased susceptibility to irradiation and higher level of acute cell death (caspase activity) in juvenile rats, leading to impaired growth and subsequently a smaller dentate gyrus volume 4 weeks after irradiation, (ii) more activated (CD68-positive) microglia in adult compared to juvenile rats, regardless of irradiation, and (iii) differently expressed cytokines and chemokines after cranial irradiation in the juvenile compared to the adult rat hippocampus, indicating a more pro-inflammatory response in adult brains. Conclusion: We found essentially diverse irradiation reactions in the juvenile compared to the adult hippocampus, indicating different mechanisms involved in degeneration and regeneration after injury. Strategies to ameliorate the cognitive deficits after cranial radiotherapy should therefore likely be adapted to the developmental level of the brain.
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| 4. |
- Boström, Martina, et al.
(författare)
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Irradiation to the young mouse brain caused long-term, progressive depletion of neurogenesis but did not disrupt the neurovascular niche
- 2013
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Ingår i: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016. ; 33:6, s. 935-943
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Tidskriftsartikel (refereegranskat)abstract
- 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 8Gy 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(+) 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.Journal of Cerebral Blood Flow & Metabolism advance online publication, 13 March 2013; doi:10.1038/jcbfm.2013.34.
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| 5. |
- Boström, Martina, et al.
(författare)
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The hippocampal neurovascular niche during normal development and after irradiation to the juvenile mouse brain.
- 2014
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Ingår i: International journal of radiation biology. - : Informa UK Limited. - 1362-3095 .- 0955-3002. ; 90:9, s. 778-89
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the effects of cranial irradiation on the neurovascular niche in the young brain. Disruption of this niche has previously been observed in the adult rat brain after irradiation.We subjected postnatal day 14 (P14) mice to a single dose of 8 Gy whole brain irradiation and measured the distance between microvessels and either neural progenitor cells (doublecortin-positive, DCX(+)) or proliferating cells (Ki-67(+)) in the dorsal hippocampal subgranular zone (SGZ) 6 hours, 1 week and 7 weeks post-irradiation. In addition, pericyte coverage of microvessels in the SGZ was measured.DCX(+) and Ki-67(+) cells were located closer to microvessels in the adult brain compared to young, still growing brains, constituting new information on normal development. We found an increased distance between microvessels and DCX(+) cells 6 h post-irradiation and between microvessels and Ki-67(+) cells 1 week post-irradiation. Furthermore, pericyte coverage was transiently decreased by 17% 6 h post-irradiation.The hippocampal neurovascular niche in the young, growing brain is transiently disrupted by irradiation. It remains to be elucidated what role these transient changes play in the apparently permanent ablation of hippocampal neurogenesis previously demonstrated in the same model.
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| 6. |
- Kalm, Marie, 1981, et al.
(författare)
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Lipopolysaccharide sensitized male and female juvenile brains to ionizing radiation
- 2013
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Ingår i: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 4:e962
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Tidskriftsartikel (refereegranskat)abstract
- Radiotherapy is an effective tool in the treatment of pediatric malignancies but it is associated with adverse side effects, both short- and long-term. One common long-term side effect after cranial radiotherapy is cognitive impairment and this is, at least partly, thought to be caused by reduced hippocampal neurogenesis. Neuroinflammation and a perturbed microenvironment are thought to be important in the dysregulation of neurogenesis seen after irradiation (IR). We investigated the effects of a preexisting, lipopolysaccharide (LPS)-induced systemic inflammation at the time of IR in both males and females. A single dose of 8 Gy to the brain of postnatal day 14 mice caused an upregulation of cytokinesichemokines (IL-1/1, MIP-1 IL-12, GM-CSF, MIP1 z, IL-17, CCL2 and KC) 6 h after IR, more so in females. Caspase-3 activity, reflecting apoptosis and possibly microglia activation, was elevated 6 h after IR. Females treated with LPS before IR showed a higher caspase-3 activity compared with males. During the chronic phase (3 months post IR), we found that LPS-induced inflammation at the time of IR aggravated the IR-induced injury in both male and female mice, as judged by reduced bromodeoxyuridine incorporation and neurogenesis (doublecortin-positive cells) in the hippocampus. At this late time point, the microglia density was increased by IR, more so in females, indicating long-term effects on the microenvironment. IR increased anxiety-related behavior in vehicle-, but not LPS-, treated animals. However, exploratory behavior was affected by IR in both vehicle- and LPS-treated mice. In conclusion, we found that LPS administration before IR of the young mouse brain aggravated the injury, as judged by reduced hippocampal neurogenesis. This supports the clinical practice to postpone radiotherapy if the patient shows signs of infection. Systemic inflammation is not always obvious, though, for example because of concurrent corticosteroid treatment, so careful monitoring of inflammation is warranted.
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| 7. |
- Kalm, Marie, 1981, et al.
(författare)
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Neurochemical Evidence of Potential Neurotoxicity After Prophylactic Cranial Irradiation.
- 2014
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Ingår i: International journal of radiation oncology, biology, physics. - : Elsevier BV. - 1879-355X .- 0360-3016. ; 89:3, s. 607-614
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Tidskriftsartikel (refereegranskat)abstract
- Toexamine whether cerebrospinal fluid biomarkers for neuroaxonal damage, neuroglial activation, and amyloid β-related processes could characterize the neurochemical response to cranial radiation.
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| 8. |
- Perez-Alcazar, Marta, et al.
(författare)
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Altered cognitive performance and synaptic function in the hippocampus of mice lacking C3.
- 2014
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Ingår i: Experimental neurology. - : Elsevier BV. - 1090-2430 .- 0014-4886. ; 253C, s. 154-164
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Tidskriftsartikel (refereegranskat)abstract
- Previous work implicated the complement system in adult neurogenesis as well as elimination of synapses in the developing and injured CNS. In the present study, we used mice lacking the third complement component (C3) to elucidate the role the complement system plays in hippocampus-dependent learning and synaptic function. We found that the constitutive absence of C3 is associated with enhanced place and reversal learning in adult mice. Our findings of lower release probability at CA3-CA1 glutamatergic synapses in combination with unaltered overall efficacy of these synapses in C3 deficient mice implicate C3 as a negative regulator of the number of functional glutamatergic synapses in the hippocampus. The C3 deficient mice showed no signs of spontaneous epileptiform activity in the hippocampus. We conclude that C3 plays a role in the regulation of the number and function of glutamatergic synapses in the hippocampus and exerts negative effects on hippocampus-dependent cognitive performance.
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| 9. |
- Roughton, Karolina, 1977, et al.
(författare)
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Irradiation to the young mouse brain impaired white matter growth more in females than in males
- 2013
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Ingår i: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Modern therapy cures 80% of all children with brains tumors, but may also cause long-lasting side effects, so called late effects. Radiotherapy is particularly prone to cause severe late effects, such as intellectual impairment. The extent and nature of the resulting cognitive deficits may be influenced by age, treatment and gender, where girls suffer more severe late effects than boys. The reason for this difference between boys and girls is unknown, but very few experimental studies have addressed this issue. Our aim was to investigate the effects of ionizing radiation on the corpus callosum (CC) in both male and female mice. We found that a single dose of 8 Gray (Gy) to the brains of postnatal day 14 mice induced apoptosis in the CC and reduced the number of proliferating cells by one third, as judged by the number of phospho-histone H3 positive cells 6 h after irradiation (IR). BrdU incorporation was reduced (62% and 42% lower in females and males, respectively) and the number of oligodendrocytes (Olig2(+) cells) was lower (43% and 21% fewer in females and males, respectively) 4 months after IR, so the lack of developing and differentiated cells was more pronounced in females. The number of microglia was unchanged in females but increased in males at this late time point. The density of microvessel profiles was unchanged by IR. This single, moderate dose of 8 Gy impaired the brain growth to some extent (8.1% and 0.4% lower brain/body weight ratio in females and males, respectively) but the CC growth was even more impaired (31% and 19% smaller in females and males, respectively) 4 months after IR compared with non-irradiated mice. In conclusion, this is the first study to our knowledge demonstrating that IR to the young rodent brain affects white matter development more in females than in males.
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| 10. |
- Roughton, Karolina, 1977, et al.
(författare)
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Lipopolysaccharide-Induced Inflammation Aggravates Irradiation-Induced Injury to the Young Mouse Brain.
- 2013
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Ingår i: Developmental neuroscience. - : S. Karger AG. - 1421-9859 .- 0378-5866. ; 35:5, s. 406-415
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Tidskriftsartikel (refereegranskat)abstract
- 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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