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1
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Wang G, Wang W, Zhang Y, Gou X, Zhang Q, Huang Y, Zhang K, Zhang H, Yang J, Li Y. Ethanol changes Nestin-promoter induced neural stem cells to disturb newborn dendritic spine remodeling in the hippocampus of mice. Neural Regen Res 2024; 19:416-424. [PMID: 37488906 PMCID: PMC10503613 DOI: 10.4103/1673-5374.379051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 02/14/2023] [Accepted: 05/04/2023] [Indexed: 07/26/2023] Open
Abstract
Adolescent binge drinking leads to long-lasting disorders of the adult central nervous system, particularly aberrant hippocampal neurogenesis. In this study, we applied in vivo fluorescent tracing using NestinCreERT2::Rosa26-tdTomato mice and analyzed the endogenous neurogenesis lineage progression of neural stem cells (NSCs) and dendritic spine formation of newborn neurons in the subgranular zone of the dentate gyrus. We found abnormal orientation of tamoxifen-induced tdTomato+ (tdTom+) NSCs in adult mice 2 months after treatment with EtOH (5.0 g/kg, i.p.) for 7 consecutive days. EtOH markedly inhibited tdTom+ NSCs activation and hippocampal neurogenesis in mouse dentate gyrus from adolescence to adulthood. EtOH (100 mM) also significantly inhibited the proliferation to 39.2% and differentiation of primary NSCs in vitro. Adult mice exposed to EtOH also exhibited marked inhibitions in dendritic spine growth and newborn neuron maturation in the dentate gyrus, which was partially reversed by voluntary running or inhibition of the mammalian target of rapamycin-enhancer of zeste homolog 2 pathway. In vivo tracing revealed that EtOH induced abnormal orientation of tdTom+ NSCs and spatial misposition defects of newborn neurons, thus causing the disturbance of hippocampal neurogenesis and dendritic spine remodeling in mice.
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Affiliation(s)
- Guixiang Wang
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, China
| | - Wenjia Wang
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, China
| | - Ye Zhang
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, China
| | - Xiaoying Gou
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, China
| | - Qingqing Zhang
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, China
| | - Yanmiao Huang
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, China
| | - Kuo Zhang
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, China
| | - Haotian Zhang
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, China
| | - Jingyu Yang
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, China
| | - Yuting Li
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, China
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2
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Zisiadis GA, Alevyzaki A, Nicola E, Rodrigues CFD, Blomgren K, Osman AM. Memantine increases the dendritic complexity of hippocampal young neurons in the juvenile brain after cranial irradiation. Front Oncol 2023; 13:1202200. [PMID: 37860190 PMCID: PMC10584145 DOI: 10.3389/fonc.2023.1202200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 09/20/2023] [Indexed: 10/21/2023] Open
Abstract
Introduction Cranial irradiation (IR) negatively regulates hippocampal neurogenesis and causes cognitive dysfunctions in cancer survivors, especially in pediatric patients. IR decreases proliferation of neural stem/progenitor cells (NSPC) and consequently diminishes production of new hippocampal neurons. Memantine, an NMDA receptor antagonist, used clinically to improve cognition in patients suffering from Alzheimer's disease and dementia. In animal models, memantine acts as a potent enhancer of hippocampal neurogenesis. Memantine was recently proposed as an intervention to improve cognitive impairments occurring after radiotherapy and is currently under investigation in a number of clinical trials, including pediatric patients. To date, preclinical studies investigating the mechanisms underpinning how memantine improves cognition after IR remain limited, especially in the young, developing brain. Here, we investigated whether memantine could restore proliferation in the subgranular zone (SGZ) or rescue the reduction in the number of hippocampal young neurons after IR in the juvenile mouse brain. Methods Mice were whole-brain irradiated with 6 Gy on postnatal day 20 (P20) and subjected to acute or long-term treatment with memantine. Proliferation in the SGZ and the number of young neurons were further evaluated after the treatment. We also measured the levels of neurotrophins associated with memantine improved neural plasticity, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Results We show that acute intraperitoneal treatment with a high, non-clinically used, dose of memantine (50 mg/kg) increased the number of proliferating cells in the intact brain by 72% and prevented 23% of IR-induced decrease in proliferation. Long-term treatment with 10 mg/kg/day of memantine, equivalent to the clinically used dose, did not impact proliferation, neither in the intact brain, nor after IR, but significantly increased the number of young neurons (doublecortin expressing cells) with radial dendrites (29% in sham controls and 156% after IR) and enhanced their dendritic arborization. Finally, we found that long-term treatment with 10 mg/kg/day memantine did not affect the levels of BDNF, but significantly reduced the levels of NGF by 40%. Conclusion These data suggest that the enhanced dendritic complexity of the hippocampal young neurons after treatment with memantine may contribute to the observed improved cognition in patients treated with cranial radiotherapy.
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Affiliation(s)
| | - Androniki Alevyzaki
- Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
| | - Elene Nicola
- Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
| | | | - Klas Blomgren
- Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
- Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden
| | - Ahmed M. Osman
- Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
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3
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Brégère C, Fisch U, Halbeisen FS, Schneider C, Dittmar T, Stricker S, Aghlmandi S, Guzman R. Doublecortin and Glypican-2 concentrations in the cerebrospinal fluid from infants are developmentally downregulated. PLoS One 2023; 18:e0279343. [PMID: 36800341 PMCID: PMC9937498 DOI: 10.1371/journal.pone.0279343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 12/05/2022] [Indexed: 02/18/2023] Open
Abstract
OBJECTIVE Doublecortin (DCX) and glypican-2 (GPC2) are neurodevelopmental proteins involved in the differentiation of neural stem/progenitor cells (NSPCs) to neurons, and are developmentally downregulated in neurons after birth. In this study, we investigated whether the concentrations of DCX and GPC2 in the cerebrospinal fluid (CSF) from human pediatric patients reflect this developmental process or are associated with cerebral damage or inflammatory markers. METHODS CSF was collected from pediatric patients requiring neurosurgical treatment. The concentrations of DCX, GPC2, neuron-specific enolase (NSE), S100 calcium-binding protein B (S100B), and cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-13, IFN-γ, and TNF-⍺) were measured using immunoassays. RESULTS From March 2013 until October 2018, 63 CSF samples were collected from 38 pediatric patients (20 females; 17 patients with repeated measurements); the median term born-adjusted age was 3.27 years [Q1: 0.31, Q3: 7.72]. The median concentration of DCX was 329 pg/ml [Q1: 192.5, Q3: 1179.6] and that of GPC2 was 26 pg/ml [Q1: 13.25, Q3: 149.25]. DCX and GPC2 concentrations independently significantly associated with age, and their concentration declined with advancing age, reaching undetectable levels at 0.3 years for DCX, and plateauing at 1.5 years for GPC2. Both DCX and GPC2 associated with hydrocephalus, NSE, IL-1β, IL-2, IL-8, IL-13. No relationship was found between sex, acute infection, S100B, IL-4, IL-6, IL-10, IFN-γ, TNF-α and DCX or GPC2, respectively. CONCLUSIONS Concentrations of DCX and GPC2 in the CSF from pediatric patients are developmentally downregulated, with the highest concentrations measured at the earliest adjusted age, and reflect a neurodevelopmental stage rather than a particular disease state.
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Affiliation(s)
- Catherine Brégère
- Department of Biomedicine, Brain Ischemia and Regeneration, University Hospital Basel, Basel, Switzerland
| | - Urs Fisch
- Department of Biomedicine, Brain Ischemia and Regeneration, University Hospital Basel, Basel, Switzerland,Department of Neurology, University Hospital Basel, Basel, Switzerland
| | - Florian Samuel Halbeisen
- Basel Institute for Clinical Epidemiology and Biostatistics, University of Basel, Basel, Switzerland
| | - Christian Schneider
- Division of Pediatric Neurosurgery, University of Basel Children’s Hospital, Basel, Switzerland
| | - Tanja Dittmar
- Department of Biomedicine, Brain Ischemia and Regeneration, University Hospital Basel, Basel, Switzerland
| | - Sarah Stricker
- Department of Neurosurgery, University Hospital Basel, Basel, Switzerland
| | - Soheila Aghlmandi
- Basel Institute for Clinical Epidemiology and Biostatistics, University of Basel, Basel, Switzerland
| | - Raphael Guzman
- Department of Biomedicine, Brain Ischemia and Regeneration, University Hospital Basel, Basel, Switzerland,Division of Pediatric Neurosurgery, University of Basel Children’s Hospital, Basel, Switzerland,Department of Neurosurgery, University Hospital Basel, Basel, Switzerland,Medical Faculty, University of Basel, Basel, Switzerland,* E-mail:
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4
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Blackmore DG, Waters MJ. The multiple roles of GH in neural ageing and injury. Front Neurosci 2023; 17:1082449. [PMID: 36960169 PMCID: PMC10027725 DOI: 10.3389/fnins.2023.1082449] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 02/17/2023] [Indexed: 03/09/2023] Open
Abstract
Advanced age is typically associated with a decrease in cognitive function including impairment in the formation and retention of new memories. The hippocampus is critical for learning and memory, especially spatial learning, and is particularly affected by ageing. With advanced age, multiple neural components can be detrimentally affected including a reduction in the number of neural stem and precursor cells, a decrease in the formation of adult born neurons (neurogenesis), and deficits in neural circuitry, all of which ultimately contribute to impaired cognitive function. Importantly, physical exercise has been shown to ameliorate many of these impairments and is able to improve learning and memory. Relevantly, growth hormone (GH) is an important protein hormone that decreases with ageing and increases following physical exercise. Originally described due to its role in longitudinal growth, GH has now been identified to play several additional key roles, especially in relation to the brain. Indeed, the regular decrease in GH levels following puberty is one of the most well documented components of neuroendocrine ageing. Growth hormone deficiency (GHD) has been described to have adverse effects on brain function, which can be ameliorated via GH replacement therapy. Physical exercise has been shown to increase circulating GH levels. Furthermore, we recently demonstrated the increase in exercise-mediated GH is critical for improved cognitive function in the aged mouse. Here we examine the multiple roles that GH plays, particularly in the aged brain and following trauma, irradiation and stroke, and how increasing GH levels can ameliorate deficits in cognition.
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Affiliation(s)
- Daniel G. Blackmore
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
- Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Michael J. Waters
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
- *Correspondence: Michael J. Waters,
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5
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Al Dahhan NZ, Cox E, Nieman BJ, Mabbott DJ. Cross-translational models of late-onset cognitive sequelae and their treatment in pediatric brain tumor survivors. Neuron 2022; 110:2215-2241. [PMID: 35523175 DOI: 10.1016/j.neuron.2022.04.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 03/21/2022] [Accepted: 04/08/2022] [Indexed: 10/18/2022]
Abstract
Pediatric brain tumor treatments have a high success rate, but survivors are at risk of cognitive sequelae that impact long-term quality of life. We summarize recent clinical and animal model research addressing pathogenesis or evaluating candidate interventions for treatment-induced cognitive sequelae. Assayed interventions encompass a broad range of approaches, including modifications to radiotherapy, modulation of immune response, prevention of treatment-induced cell loss or promotion of cell renewal, manipulation of neuronal signaling, and lifestyle/environmental adjustments. We further emphasize the potential of neuroimaging as a key component of cross-translation to contextualize laboratory research within broader clinical findings. This cross-translational approach has the potential to accelerate discovery to improve pediatric cancer survivors' long-term quality of life.
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Affiliation(s)
- Noor Z Al Dahhan
- Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada
| | - Elizabeth Cox
- Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada; Department of Psychology, University of Toronto, Toronto, ON, Canada
| | - Brian J Nieman
- Translational Medicine, Hospital for Sick Children, Toronto, ON, Canada; Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Donald J Mabbott
- Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada; Department of Psychology, University of Toronto, Toronto, ON, Canada; Department of Psychology, Hospital for Sick Children, Toronto, ON, Canada.
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6
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Kovalchuk A, Mychasiuk R, Muhammad A, Hossain S, Ghose A, Kirkby C, Ghasroddashti E, Kovalchuk O, Kolb B. Complex housing partially mitigates low dose radiation-induced changes in brain and behavior in rats. Restor Neurol Neurosci 2022; 40:109-124. [DOI: 10.3233/rnn-211216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Purpose: In recent years, much effort has been focused on developing new strategies for the prevention and mitigation of adverse radiation effects on healthy tissues and organs, including the brain. The brain is very sensitive to radiation effects, albeit as it is highly plastic. Hence, deleterious radiation effects may be potentially reversible. Because radiation exposure affects dendritic space, reduces the brain’s ability to produce new neurons, and alters behavior, mitigation efforts should focus on restoring these parameters. To that effect, environmental enrichment through complex housing (CH) and exercise may provide a plausible avenue for exploration of protection from brain irradiation. CH is a much broader concept than exercise alone, and constitutes exposure of animals to positive physical and social stimulation that is superior to their routine housing and care conditions. We hypothesized that CHs may lessen harmful neuroanatomical and behavioural effects of low dose radiation exposure. Methods: We analyzed and compared cerebral morphology in animals exposed to low dose head, bystander (liver), and scatter irradiation on rats housed in either the environmental enrichment condos or standard housing. Results: Enriched condo conditions ameliorated radiation-induced neuroanatomical changes. Moreover, irradiated animals that were kept in enriched CH condos displayed fewer radiation-induced behavioural deficits than those housed in standard conditions. Conclusions: Animal model-based environmental enrichment strategies, such as CH, are excellent surrogate models for occupational and exercise therapy in humans, and consequently have significant translational possibility. Our study may thus serve as a roadmap for the development of new, easy, safe and cost-effective methods to prevent and mitigate low-dose radiation effects on the brain.
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Affiliation(s)
- Anna. Kovalchuk
- Department of Neuroscience, University of Lethbridge, Lethbridge, AB, Canada
| | | | - Arif. Muhammad
- Department of Neuroscience, University of Lethbridge, Lethbridge, AB, Canada
| | - Shakhawat. Hossain
- Department of Neuroscience, University of Lethbridge, Lethbridge, AB, Canada
| | - Abhijit. Ghose
- Jack Ady Cancer Center, Alberta Health Services, Lethbridge, AB, Canada
| | - Charles. Kirkby
- Jack Ady Cancer Center, Alberta Health Services, Lethbridge, AB, Canada
- Department of Physics and Astronomy and Department of Oncology, University of Calgary, AB, Canada
| | - Esmaeel. Ghasroddashti
- Jack Ady Cancer Center, Alberta Health Services, Lethbridge, AB, Canada
- Department of Physics and Astronomy and Department of Oncology, University of Calgary, AB, Canada
| | - Olga. Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, Canada
| | - Bryan. Kolb
- Department of Neuroscience, University of Lethbridge, Lethbridge, AB, Canada
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7
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p27, The Cell Cycle and Alzheimer´s Disease. Int J Mol Sci 2022; 23:ijms23031211. [PMID: 35163135 PMCID: PMC8835212 DOI: 10.3390/ijms23031211] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/18/2022] [Accepted: 01/20/2022] [Indexed: 12/29/2022] Open
Abstract
The cell cycle consists of successive events that lead to the generation of new cells. The cell cycle is regulated by different cyclins, cyclin-dependent kinases (CDKs) and their inhibitors, such as p27Kip1. At the nuclear level, p27Kip1 has the ability to control the evolution of different phases of the cell cycle and oppose cell cycle progression by binding to CDKs. In the cytoplasm, diverse functions have been described for p27Kip1, including microtubule remodeling, axonal transport and phagocytosis. In Alzheimer’s disease (AD), alterations to cycle events and a purported increase in neurogenesis have been described in the early disease process before significant pathological changes could be detected. However, most neurons cannot progress to complete their cell division and undergo apoptotic cell death. Increased levels of both the p27Kip1 levels and phosphorylation status have been described in AD. Increased levels of Aβ42, tau hyperphosphorylation or even altered insulin signals could lead to alterations in p27Kip1 post-transcriptional modifications, causing a disbalance between the levels and functions of p27Kip1 in the cytoplasm and nucleus, thus inducing an aberrant cell cycle re-entry and alteration of extra cell cycle functions. Further studies are needed to completely understand the role of p27Kip1 in AD and the therapeutic opportunities associated with the modulation of this target.
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8
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Blackmore DG, Steyn FJ, Carlisle A, O'Keeffe I, Vien KY, Zhou X, Leiter O, Jhaveri D, Vukovic J, Waters MJ, Bartlett PF. An exercise "sweet spot" reverses cognitive deficits of aging by growth-hormone-induced neurogenesis. iScience 2021; 24:103275. [PMID: 34761193 PMCID: PMC8567379 DOI: 10.1016/j.isci.2021.103275] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/09/2021] [Accepted: 10/12/2021] [Indexed: 11/02/2022] Open
Abstract
Hippocampal function is critical for spatial and contextual learning, and its decline with age contributes to cognitive impairment. Exercise can improve hippocampal function, however, the amount of exercise and mechanisms mediating improvement remain largely unknown. Here, we show exercise reverses learning deficits in aged (24 months) female mice but only when it occurs for a specific duration, with longer or shorter periods proving ineffective. A spike in the levels of growth hormone (GH) and a corresponding increase in neurogenesis during this sweet spot mediate this effect because blocking GH receptor with a competitive antagonist or depleting newborn neurons abrogates the exercise-induced cognitive improvement. Moreover, raising GH levels with GH-releasing hormone agonist improved cognition in nonrunners. We show that GH stimulates neural precursors directly, indicating the link between raised GH and neurogenesis is the basis for the substantially improved learning in aged animals.
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Affiliation(s)
- Daniel G Blackmore
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Frederik J Steyn
- Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4029, Australia
| | - Alison Carlisle
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Imogen O'Keeffe
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
| | - King-Year Vien
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Xiaoqing Zhou
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Odette Leiter
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Dhanisha Jhaveri
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.,Mater Research Institute, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Jana Vukovic
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.,School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Michael J Waters
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Perry F Bartlett
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
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9
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Wei M, Feng S, Zhang L, Wang C, Chu S, Shi T, Zhou W, Zhang Y. Active Fraction Combination From Liuwei Dihuang Decoction Improves Adult Hippocampal Neurogenesis and Neurogenic Microenvironment in Cranially Irradiated Mice. Front Pharmacol 2021; 12:717719. [PMID: 34630096 PMCID: PMC8495126 DOI: 10.3389/fphar.2021.717719] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 08/02/2021] [Indexed: 02/02/2023] Open
Abstract
Background: Cranial radiotherapy is clinically used in the treatment of brain tumours; however, the consequent cognitive and emotional dysfunctions seriously impair the life quality of patients. LW-AFC, an active fraction combination extracted from classical traditional Chinese medicine prescription Liuwei Dihuang decoction, can improve cognitive and emotional dysfunctions in many animal models; however, the protective effect of LW-AFC on cranial irradiation–induced cognitive and emotional dysfunctions has not been reported. Recent studies indicate that impairment of adult hippocampal neurogenesis (AHN) and alterations of the neurogenic microenvironment in the hippocampus constitute critical factors in cognitive and emotional dysfunctions following cranial irradiation. Here, our research further investigated the potential protective effects and mechanisms of LW-AFC on cranial irradiation–induced cognitive and emotional dysfunctions in mice. Methods: LW-AFC (1.6 g/kg) was intragastrically administered to mice for 14 days before cranial irradiation (7 Gy γ-ray). AHN was examined by quantifying the number of proliferative neural stem cells and immature neurons in the dorsal and ventral hippocampus. The contextual fear conditioning test, open field test, and tail suspension test were used to assess cognitive and emotional functions in mice. To detect the change of the neurogenic microenvironment, colorimetry and multiplex bead analysis were performed to measure the level of oxidative stress, neurotrophic and growth factors, and inflammation in the hippocampus. Results: LW-AFC exerted beneficial effects on the contextual fear memory, anxiety behaviour, and depression behaviour in irradiated mice. Moreover, LW-AFC increased the number of proliferative neural stem cells and immature neurons in the dorsal hippocampus, displaying a regional specificity of neurogenic response. For the neurogenic microenvironment, LW-AFC significantly increased the contents of superoxide dismutase, glutathione peroxidase, glutathione, and catalase and decreased the content of malondialdehyde in the hippocampus of irradiated mice, accompanied by the increase in brain-derived neurotrophic factor, insulin-like growth factor-1, and interleukin-4 content. Together, LW-AFC improved cognitive and emotional dysfunctions, promoted AHN preferentially in the dorsal hippocampus, and ameliorated disturbance in the neurogenic microenvironment in irradiated mice. Conclusion: LW-AFC ameliorates cranial irradiation–induced cognitive and emotional dysfunctions, and the underlying mechanisms are mediated by promoting AHN in the dorsal hippocampus and improving the neurogenic microenvironment. LW-AFC might be a promising therapeutic agent to treat cognitive and emotional dysfunctions in patients receiving cranial radiotherapy.
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Affiliation(s)
- Mingxiao Wei
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.,State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Shufang Feng
- Department of Poisoning and the Treatment, Affiliated Hospital to Academy of Military Medical Sciences (the 307 Hospital), Beijing, China
| | - Lin Zhang
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.,State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Chen Wang
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Shasha Chu
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Tianyao Shi
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Wenxia Zhou
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Yongxiang Zhang
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.,State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China
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10
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Zheng Z, Wang B, Zhao Q, Zhang Y, Wei J, Meng L, Xin Y, Jiang X. Research progress on mechanism and imaging of temporal lobe injury induced by radiotherapy for head and neck cancer. Eur Radiol 2021; 32:319-330. [PMID: 34327577 DOI: 10.1007/s00330-021-08164-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 06/07/2021] [Accepted: 06/22/2021] [Indexed: 12/15/2022]
Abstract
Radiotherapy (RT) is an effective treatment for head and neck cancer (HNC). Radiation-induced temporal lobe injury (TLI) is a serious complication of RT. Late symptoms of radiation-induced TLI are irreversible and manifest as memory loss, cognitive impairment, and even temporal lobe necrosis (TLN). It is currently believed that the mechanism of radiation-induced TLI involves microvascular injury, neuron and neural stem cell injury, glial cell damage, inflammation, and the production of free radicals. Significant RT-related structural changes and dose-dependent changes in gray matter (GM) and white matter (WM) volume and morphology were observed through computed tomography (CT) and magnetic resonance imaging (MRI) which were common imaging assessment tools. Diffusion tensor imaging (DTI), dispersion kurtosis imaging (DKI), susceptibility-weighted imaging (SWI), resting-state functional magnetic resonance (rs-fMRI), magnetic resonance spectroscopy (MRS), and positron emission tomography (PET) can be used for early diagnosis and prognosis evaluation according to functional, molecular, and cellular processes of TLI. Early diagnosis of TLI is helpful to reduce the incidence of TLN and its related complications. This review summarizes the clinical features, mechanisms, and imaging of radiation-induced TLI in HNC patients. KEY POINTS: • Radiation-induced temporal lobe injury (TLI) is a clinical complication and its symptoms mainly include memory impairment, headache, and cognitive impairment. • The mechanisms of TLI include microvascular injury, cell injury, and inflammatory and free radical injury. Significant RT-related structural changes and dose-dependent changes in TL volume and morphology were observed through CT and MRI. • SWI, MRS, DTI, and DKI and other imaging examinations can detect anatomical and functional, molecular, and cellular changes of TLI.
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Affiliation(s)
- Zhuangzhuang Zheng
- Department of Radiation Oncology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, China.,Jilin Provincial Key Laboratory of Radiation Oncology& Therapy, The First Hospital of Jilin University, Changchun, 130021, China.,NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, 130021, China
| | - Bin Wang
- Department of Radiation Oncology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, China.,Jilin Provincial Key Laboratory of Radiation Oncology& Therapy, The First Hospital of Jilin University, Changchun, 130021, China.,NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, 130021, China
| | - Qin Zhao
- Department of Radiation Oncology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, China.,Jilin Provincial Key Laboratory of Radiation Oncology& Therapy, The First Hospital of Jilin University, Changchun, 130021, China.,NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, 130021, China
| | - Yuyu Zhang
- Department of Radiation Oncology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, China.,Jilin Provincial Key Laboratory of Radiation Oncology& Therapy, The First Hospital of Jilin University, Changchun, 130021, China.,NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, 130021, China
| | - Jinlong Wei
- Department of Radiation Oncology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, China.,Jilin Provincial Key Laboratory of Radiation Oncology& Therapy, The First Hospital of Jilin University, Changchun, 130021, China.,NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, 130021, China
| | - Lingbin Meng
- Department of Hematology and Medical Oncology, Moffitt Cancer Center, Tampa, FL, 33612, USA
| | - Ying Xin
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, 126 Xinmin Street, Changchun, 130021, China.
| | - Xin Jiang
- Department of Radiation Oncology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, China. .,Jilin Provincial Key Laboratory of Radiation Oncology& Therapy, The First Hospital of Jilin University, Changchun, 130021, China. .,NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, 130021, China.
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11
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Kim DS, Weber T, Straube U, Hellweg CE, Nasser M, Green DA, Fogtman A. The Potential of Physical Exercise to Mitigate Radiation Damage-A Systematic Review. Front Med (Lausanne) 2021; 8:585483. [PMID: 33996841 PMCID: PMC8117229 DOI: 10.3389/fmed.2021.585483] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 03/10/2021] [Indexed: 12/12/2022] Open
Abstract
There is a need to investigate new countermeasures against the detrimental effects of ionizing radiation as deep space exploration missions are on the horizon. Objective: In this systematic review, the effects of physical exercise upon ionizing radiation-induced damage were evaluated. Methods: Systematic searches were performed in Medline, Embase, Cochrane library, and the databases from space agencies. Of 2,798 publications that were screened, 22 studies contained relevant data that were further extracted and analyzed. Risk of bias of included studies was assessed. Due to the high level of heterogeneity, meta-analysis was not performed. Five outcome groups were assessed by calculating Hedges' g effect sizes and visualized using effect size plots. Results: Exercise decreased radiation-induced DNA damage, oxidative stress, and inflammation, while increasing antioxidant activity. Although the results were highly heterogeneous, there was evidence for a beneficial effect of exercise in cellular, clinical, and functional outcomes. Conclusions: Out of 72 outcomes, 68 showed a beneficial effect of physical training when exposed to ionizing radiation. As the first study to investigate a potential protective mechanism of physical exercise against radiation effects in a systematic review, the current findings may help inform medical capabilities of human spaceflight and may also be relevant for terrestrial clinical care such as radiation oncology.
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Affiliation(s)
- David S. Kim
- Space Medicine Team (HRE-OM), European Astronaut Centre, European Space Agency, Cologne, Germany
- Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Tobias Weber
- Space Medicine Team (HRE-OM), European Astronaut Centre, European Space Agency, Cologne, Germany
- KBR GmbH, Cologne, Germany
| | - Ulrich Straube
- Space Medicine Team (HRE-OM), European Astronaut Centre, European Space Agency, Cologne, Germany
| | - Christine E. Hellweg
- Radiation Biology Department, Institute of Aerospace Medicine, German Aerospace Centre (DLR), Cologne, Germany
| | - Mona Nasser
- Peninsula Dental School, Plymouth University, Plymouth, United Kingdom
| | - David A. Green
- Space Medicine Team (HRE-OM), European Astronaut Centre, European Space Agency, Cologne, Germany
- KBR GmbH, Cologne, Germany
- Centre of Human & Applied Physiological Sciences (CHAPS), King's College London, London, United Kingdom
| | - Anna Fogtman
- Space Medicine Team (HRE-OM), European Astronaut Centre, European Space Agency, Cologne, Germany
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12
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Ren BX, Huen I, Wu ZJ, Wang H, Duan MY, Guenther I, Bhanu Prakash KN, Tang FR. Early postnatal irradiation-induced age-dependent changes in adult mouse brain: MRI based characterization. BMC Neurosci 2021; 22:28. [PMID: 33882822 PMCID: PMC8061041 DOI: 10.1186/s12868-021-00635-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 04/13/2021] [Indexed: 02/08/2023] Open
Abstract
Background Brain radiation exposure, in particular, radiotherapy, can induce cognitive impairment in patients, with significant effects persisting for the rest of their life. However, the main mechanisms leading to this adverse event remain largely unknown. A study of radiation-induced injury to multiple brain regions, focused on the hippocampus, may shed light on neuroanatomic bases of neurocognitive impairments in patients. Hence, we irradiated BALB/c mice (male and female) at postnatal day 3 (P3), day 10 (P10), and day 21 (P21) and investigated the long-term radiation effect on brain MRI changes and hippocampal neurogenesis. Results We found characteristic brain volume reductions in the hippocampus, olfactory bulbs, the cerebellar hemisphere, cerebellar white matter (WM) and cerebellar vermis WM, cingulate, occipital and frontal cortices, cerebellar flocculonodular WM, parietal region, endopiriform claustrum, and entorhinal cortex after irradiation with 5 Gy at P3. Irradiation at P10 induced significant volume reduction in the cerebellum, parietal region, cingulate region, and olfactory bulbs, whereas the reduction of the volume in the entorhinal, parietal, insular, and frontal cortices was demonstrated after irradiation at P21. Immunohistochemical study with cell division marker Ki67 and immature marker doublecortin (DCX) indicated the reduced cell division and genesis of new neurons in the subgranular zone of the dentate gyrus in the hippocampus after irradiation at all three postnatal days, but the reduction of total granule cells in the stratum granulosun was found after irradiation at P3 and P10. Conclusions The early life radiation exposure during different developmental stages induces varied brain pathophysiological changes which may be related to the development of neurological and neuropsychological disorders later in life.
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Affiliation(s)
- Bo Xu Ren
- Department of Medical Imaging, School of Medicine, Yangtze University, 1 Nanhuan Road, Jingzhou, 434023, Hubei, China
| | - Isaac Huen
- Singapore Bioimaging Consortium (SBIC), Agency for Science, Technology and Research (A*STAR), Singapore, 138667, Singapore
| | - Zi Jun Wu
- Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Wang
- Radiation Physiology Laboratory, Nuclear Research and Safety Initiative, National University of Singapore, CREATE Tower, 1 CREATE Way #04-01, Singapore, 138602, Singapore
| | - Meng Yun Duan
- Department of Medical Imaging, School of Medicine, Yangtze University, 1 Nanhuan Road, Jingzhou, 434023, Hubei, China
| | - Ilonka Guenther
- Comparative Medicine, Centre for Life Sciences (CeLS), National University of Singapore, #05-02, 28 Medical Drive, Singapore, 117456, Singapore
| | - K N Bhanu Prakash
- Singapore Bioimaging Consortium (SBIC), Agency for Science, Technology and Research (A*STAR), Singapore, 138667, Singapore.
| | - Feng Ru Tang
- Radiation Physiology Laboratory, Nuclear Research and Safety Initiative, National University of Singapore, CREATE Tower, 1 CREATE Way #04-01, Singapore, 138602, Singapore.
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13
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Zanni G, Goto S, Fragopoulou AF, Gaudenzi G, Naidoo V, Di Martino E, Levy G, Dominguez CA, Dethlefsen O, Cedazo-Minguez A, Merino-Serrais P, Stamatakis A, Hermanson O, Blomgren K. Lithium treatment reverses irradiation-induced changes in rodent neural progenitors and rescues cognition. Mol Psychiatry 2021; 26:322-340. [PMID: 31723242 PMCID: PMC7815512 DOI: 10.1038/s41380-019-0584-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 10/13/2019] [Accepted: 10/25/2019] [Indexed: 12/21/2022]
Abstract
Cranial radiotherapy in children has detrimental effects on cognition, mood, and social competence in young cancer survivors. Treatments harnessing hippocampal neurogenesis are currently of great relevance in this context. Lithium, a well-known mood stabilizer, has both neuroprotective, pro-neurogenic as well as antitumor effects, and in the current study we introduced lithium treatment 4 weeks after irradiation. Female mice received a single 4 Gy whole-brain radiation dose on postnatal day (PND) 21 and were randomized to 0.24% Li2CO3 chow or normal chow from PND 49 to 77. Hippocampal neurogenesis was assessed on PND 77, 91, and 105. We found that lithium treatment had a pro-proliferative effect on neural progenitors, but neuronal integration occurred only after it was discontinued. Also, the treatment ameliorated deficits in spatial learning and memory retention observed in irradiated mice. Gene expression profiling and DNA methylation analysis identified two novel factors related to the observed effects, Tppp, associated with microtubule stabilization, and GAD2/65, associated with neuronal signaling. Our results show that lithium treatment reverses irradiation-induced loss of hippocampal neurogenesis and cognitive impairment even when introduced long after the injury. We propose that lithium treatment should be intermittent in order to first make neural progenitors proliferate and then, upon discontinuation, allow them to differentiate. Our findings suggest that pharmacological treatment of cognitive so-called late effects in childhood cancer survivors is possible.
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Affiliation(s)
- Giulia Zanni
- Department of Women's and Children's Health, Karolinska Institutet, BioClinicum J9:30, 171 64, Stockholm, Sweden.
- Department of Developmental Neuroscience, New York State Psychiatric Institute, Columbia University, 1051 Riverside, New York, NY, 10032, USA.
| | - Shinobu Goto
- Department of Women's and Children's Health, Karolinska Institutet, BioClinicum J9:30, 171 64, Stockholm, Sweden
- Department of Obstetrics and Gynecology, Nagoya City University Graduate School of Medical Sciences, 467-8601, 1, Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Japan
| | - Adamantia F Fragopoulou
- Department of Women's and Children's Health, Karolinska Institutet, BioClinicum J9:30, 171 64, Stockholm, Sweden
| | - Giulia Gaudenzi
- Department of Neuroscience, Karolinska Institutet, Biomedicum, 171 77, Stockholm, Sweden
- Department of Protein Science, Division of Nanobiotechnology, KTH Royal Institute of Technology, Science for Life Laboratory, 171 21, Stockholm, Sweden
| | - Vinogran Naidoo
- Department of Women's and Children's Health, Karolinska Institutet, BioClinicum J9:30, 171 64, Stockholm, Sweden
- Department of Human Biology, Faculty of Health Sciences, Anzio Road Observatory, 7925, University of Cape Town, Cape Town, South Africa
| | - Elena Di Martino
- Department of Women's and Children's Health, Karolinska Institutet, BioClinicum J9:30, 171 64, Stockholm, Sweden
| | - Gabriel Levy
- Department of Women's and Children's Health, Karolinska Institutet, BioClinicum J9:30, 171 64, Stockholm, Sweden
- Ludwig Institute for Cancer Research, Brussels Branch, Avenue Hippocrate 75, 1200, Brussels, Belgium
| | - Cecilia A Dominguez
- Department of Women's and Children's Health, Karolinska Institutet, BioClinicum J9:30, 171 64, Stockholm, Sweden
| | - Olga Dethlefsen
- National Bioinformatics Infrastructure Sweden (NIBIS), Science for Life Laboratory (SciLifeLab), Svante Arrhenius väg 16C, 106 91, Stockholm, Sweden
- Department of Biochemistry and Biophysics (DBB), Stockholm University, Svante Arrhenius väg 16C, 106 91, Stockholm, Sweden
| | - Angel Cedazo-Minguez
- Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, BioClinicum J9:20, 171 64, Stockholm, Sweden
| | - Paula Merino-Serrais
- Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, BioClinicum J9:20, 171 64, Stockholm, Sweden
| | - Antonios Stamatakis
- Biology-Biochemistry Lab, Faculty of Nursing, School of Health Sciences, National and Kapodistrian University of Athens, Papadiamantopoulou 123, Goudi, 11527, Athens, Greece
| | - Ola Hermanson
- Department of Neuroscience, Karolinska Institutet, Biomedicum, 171 77, Stockholm, Sweden
| | - Klas Blomgren
- Department of Women's and Children's Health, Karolinska Institutet, BioClinicum J9:30, 171 64, Stockholm, Sweden.
- Pediatric Oncology, Karolinska University Hospital, Eugeniavägen 23, 171 64, Stockholm, Sweden.
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14
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Neumann S, Porritt MJ, Osman AM, Kuhn HG. Cranial irradiation at early postnatal age impairs stroke-induced neural stem/progenitor cell response in the adult brain. Sci Rep 2020; 10:12369. [PMID: 32703986 PMCID: PMC7378832 DOI: 10.1038/s41598-020-69266-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 07/09/2020] [Indexed: 11/29/2022] Open
Abstract
Cranial irradiation (IR) is commonly used to treat primary brain tumors and metastatic diseases. However, cranial IR-treated patients often develop vascular abnormalities later in life that increase their risk for cerebral ischemia. Studies in rodents have demonstrated that IR impairs maintenance of the neural stem/precursor cell (NSPC) pool and depletes neurogenesis. We and others have previously shown that stroke triggers NSPC proliferation in the subventricular zone and migration towards the stroke-injured neocortex. Whether this response is sustained in the irradiated brain remains unknown. Here, we demonstrate that cranial IR in mice at an early postnatal age significantly reduced the number to neuronal progenitors responding to cortical stroke in adults. This was accompanied by a reduced number of microglia/macrophages in the peri-infarct cortex; however, the astrocytic response was not altered. Our findings indicate that IR impairs the endogenous repair capacity in the brain in response to stroke, hence pointing to another side effect of cranial radiotherapy which requires further attention.
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Affiliation(s)
- Susanne Neumann
- Department of Clinical Neuroscience, Institute for Neuroscience and Physiology, University of Gothenburg, Box 436, 405 30, Gothenburg, Sweden.,Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, 171 76, Stockholm, Sweden
| | - Michelle J Porritt
- Department of Clinical Neuroscience, Institute for Neuroscience and Physiology, University of Gothenburg, Box 436, 405 30, Gothenburg, Sweden
| | - Ahmed M Osman
- Department of Women's and Children's Health, Karolinska Institutet, 171 64, Stockholm, Sweden
| | - H Georg Kuhn
- Department of Clinical Neuroscience, Institute for Neuroscience and Physiology, University of Gothenburg, Box 436, 405 30, Gothenburg, Sweden.
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15
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Bálentová S, Adamkov M. Pathological changes in the central nervous system following exposure to ionizing radiation. Physiol Res 2020; 69:389-404. [PMID: 32469226 PMCID: PMC8648310 DOI: 10.33549/physiolres.934309] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 03/03/2020] [Indexed: 12/19/2022] Open
Abstract
Experimental studies in animals provide relevant knowledge about pathogenesis of radiation-induced injury to the central nervous system. Radiation-induced injury can alter neuronal, glial cell population, brain vasculature and may lead to molecular, cellular and functional consequences. Regarding to its fundamental role in the formation of new memories, spatial navigation and adult neurogenesis, the majority of studies have focused on the hippocampus. Most recent findings in cranial radiotherapy revealed that hippocampal avoidance prevents radiation-induced cognitive impairment of patients with brain primary tumors and metastases. However, numerous preclinical studies have shown that this problem is more complex. Regarding the fact, that the radiation-induced cognitive impairment reflects hippocampal and non-hippocampal compartments, it is highly important to investigate molecular, cellular and functional changes in different brain regions and their integration at clinically relevant doses and schedules. Here, we provide a literature review in order support the translation of preclinical findings to clinical practice and improve the physical and mental status of patients with brain tumors.
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Affiliation(s)
- S Bálentová
- Institute of Histology and Embryology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovak Republic.
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16
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Gómez-Correa G, Zepeda A. Chronic Bumetanide Infusion Alters Young Neuron Morphology in the Dentate Gyrus Without Affecting Contextual Fear Memory. Front Neurosci 2020; 14:514. [PMID: 32508587 PMCID: PMC7253663 DOI: 10.3389/fnins.2020.00514] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Accepted: 04/24/2020] [Indexed: 11/13/2022] Open
Abstract
Young neurons in the adult brain are key to some types of learning and memory. They integrate in the dentate gyrus (DG) of the hippocampus contributing to such cognitive processes following timely developmental events. While experimentally impairing GABAergic transmission through the blockade or elimination of the ionic cotransporter NKCC1 leads to alterations in the proper maturation of young neurons, it is still unknown if the in vivo administration of common use diuretic drugs that block the cotransporter, alters the development of young hippocampal neurons and affects DG-related functions. In this study, we delivered chronically and intracerebroventricularly the NKCC1 blocker bumetanide to young-adult rats. We analyzed doublecortin density and development parameters (apical dendrite length and angle and dendritic arbor length) in doublecortin positive neurons from different subregions in the DG and evaluated the performance of animals in contextual fear learning and memory. Our results show that in bumetanide-treated subjects, doublecortin density is diminished in the infra and suprapyramidal blades of the DG; the length of primary dendrites is shortened in the infrapyramidal blade and; the growth angle of primary dendrites in the infrapyramidal blade is different from control animals. Behaviorally, treated animals showed the typical learning curve in a contextual fear task, and freezing-time displayed during contextual fear memory was not different from controls. Thus, in vivo icv delivery of bumetanide negatively alters DCX density associated to young neurons and its proper development but not to the extent of affecting a DG dependent task as aversive context learning and memory.
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Affiliation(s)
- Gibrán Gómez-Correa
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Angelica Zepeda
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Institute of Clinical Neuroanatomy, Goethe University Frankfurt, Frankfurt, Germany
- *Correspondence: Angelica Zepeda,
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17
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Corti O, Blomgren K, Poletti A, Beart PM. Autophagy in neurodegeneration: New insights underpinning therapy for neurological diseases. J Neurochem 2020; 154:354-371. [PMID: 32149395 DOI: 10.1111/jnc.15002] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 02/27/2020] [Accepted: 03/05/2020] [Indexed: 12/13/2022]
Abstract
In autophagy long-lived proteins, protein aggregates or damaged organelles are engulfed by vesicles called autophagosomes prior to lysosomal degradation. Autophagy dysfunction is a hallmark of several neurodegenerative diseases in which misfolded proteins or dysfunctional mitochondria accumulate. Excessive autophagy can also exacerbate brain injury under certain conditions. In this review, we provide specific examples to illustrate the critical role played by autophagy in pathological conditions affecting the brain and discuss potential therapeutic implications. We show how a singular type of autophagy-dependent cell death termed autosis has attracted attention as a promising target for improving outcomes in perinatal asphyxia and hypoxic-ischaemic injury to the immature brain. We provide evidence that autophagy inhibition may be protective against radiotherapy-induced damage to the young brain. We describe a specialized form of macroautophagy of therapeutic relevance for motoneuron and neuromuscular diseases, known as chaperone-assisted selective autophagy, in which heat shock protein B8 is used to deliver aberrant proteins to autophagosomes. We summarize studies pinpointing mitophagy mediated by the serine/threonine kinase PINK1 and the ubiquitin-protein ligase Parkin as a mechanism potentially relevant to Parkinson's disease, despite debate over the physiological conditions in which it is activated in organisms. Finally, with the example of the autophagy-inducing agent rilmenidine and its discrepant effects in cell culture and mouse models of motor neuron disorders, we illustrate the importance of considering aspects such a disease stage and aggressiveness, type of insult and load of damaged or toxic cellular components, when choosing the appropriate drug, timepoint and duration of treatment.
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Affiliation(s)
- Olga Corti
- Institut National de la Santé et de la Recherche Médicale, Paris, France.,Centre National de la Recherche Scientifique, Paris, France.,Sorbonne Universités, Paris, France.,Institut du Cerveau et de la Moelle épinière, ICM, Paris, France
| | - Klas Blomgren
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.,Department of Paediatric Oncology, Karolinska University Hospital, Stockholm, Sweden
| | - Angelo Poletti
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milan, Italy
| | - Philip M Beart
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Vic, Australia.,Department of Pharmacology, University of Melbourne, Parkville, Vic, Australia
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18
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Bulin SE, Simmons SJ, Richardson DR, Latchney SE, Deutsch HM, Yun S, Eisch AJ. Indices of dentate gyrus neurogenesis are unaffected immediately after or following withdrawal from morphine self-administration compared to saline self-administering control male rats. Behav Brain Res 2020; 381:112448. [PMID: 31870778 PMCID: PMC7036141 DOI: 10.1016/j.bbr.2019.112448] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 12/01/2019] [Accepted: 12/19/2019] [Indexed: 12/16/2022]
Abstract
Opiates - including morphine - are powerful analgesics with high abuse potential. In rodents, chronic opiate exposure or self-administration negatively impacts hippocampal-dependent function, an effect perhaps due in part to the well-documented opiate-induced inhibition of dentate gyrus (DG) precursor proliferation and neurogenesis. Recently, however, intravenous (i.v.) morphine self-administration (MSA) was reported to enhance the survival of new rat DG neurons. To reconcile these disparate results, we used rat i.v. MSA to assess 1) whether a slightly-higher dose MSA paradigm also increases new DG neuron survival; 2) how MSA influences cells in different stages of DG neurogenesis, particularly maturation and survival; and 3) if MSA-induced changes in DG neurogenesis persist through a period of abstinence. To label basal levels of proliferation, rats received the S-phase marker bromodeoxyuridine (BrdU, i.p.) 24 -h prior to 21 days (D) of i.v. MSA or saline self-administration (SSA). Either immediately after SA (0-D) or after 4 weeks in the home cage (28-D withdrawal), stereology was used to quantify DG proliferating precursors (or cells in cell cycle; Ki67+ cells), neuroblast/immature neurons (DCX+ cells), and surviving DG granule cells (BrdU+ cells). Analysis revealed the number of DG cells immunopositive for these neurogenesis-relevant markers was similar between MSA and SSA rats at the 0-D or 28-D timepoints. These negative data highlight the impact experimental parameters, timepoint selection, and quantification approach have on neurogenesis results, and are discussed in the context of the large literature showing the negative impact of opiates on DG neurogenesis.
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Affiliation(s)
- Sarah E Bulin
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Steven J Simmons
- Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Devon R Richardson
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Sarah E Latchney
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Neurobiology, St. Mary's College of Maryland, St. Mary's City, MD, 20686-3001
| | - Hannah M Deutsch
- Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Sanghee Yun
- Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Amelia J Eisch
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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19
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Turnquist C, Harris BT, Harris CC. Radiation-induced brain injury: current concepts and therapeutic strategies targeting neuroinflammation. Neurooncol Adv 2020; 2:vdaa057. [PMID: 32642709 PMCID: PMC7271559 DOI: 10.1093/noajnl/vdaa057] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Continued improvements in cancer therapies have increased the number of long-term cancer survivors. Radiation therapy remains one of the primary treatment modalities with about 60% of newly diagnosed cancer patients receiving radiation during the course of their disease. While radiation therapy has dramatically improved patient survival in a number of cancer types, the late effects remain a significant factor affecting the quality of life particularly in pediatric patients. Radiation-induced brain injury can result in cognitive dysfunction, including hippocampal-related learning and memory dysfunction that can escalate to dementia. In this article, we review the current understanding of the mechanisms behind radiation-induced brain injury focusing on the role of neuroinflammation and reduced hippocampal neurogenesis. Approaches to prevent or ameliorate treatment-induced side effects are also discussed along with remaining challenges in the field.
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Affiliation(s)
- Casmir Turnquist
- University of Oxford Medical School, John Radcliffe Hospital, Oxford, UK
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Brent T Harris
- Departments of Neurology and Pathology, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Curtis C Harris
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
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20
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Voluntary exercise increases brain tissue oxygenation and spatially homogenizes oxygen delivery in a mouse model of Alzheimer's disease. Neurobiol Aging 2019; 88:11-23. [PMID: 31866158 DOI: 10.1016/j.neurobiolaging.2019.11.015] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 11/20/2019] [Accepted: 11/22/2019] [Indexed: 11/21/2022]
Abstract
Although vascular contributions to dementia and Alzheimer's disease (AD) are increasingly recognized, the potential brain oxygenation disruption associated with AD and whether preventive strategies to maintain tissue oxygenation are beneficial remain largely unknown. This study aimed to examine (1) whether brain oxygenation is compromised by the onset of AD and (2) how voluntary exercise modulates the influence of AD on brain oxygenation. In vivo 2-photon phosphorescence lifetime microscopy was used to investigate local changes of brain tissue oxygenation with the progression of AD and its modulation by exercise in the barrel cortex of awake transgenic AD mice. Our results show that cerebral tissue oxygen partial pressure (PO2) decreased with the onset of AD. Reduced PO2 was associated with the presence of small near-hypoxic areas, an increased oxygen extraction fraction, and reduced blood flow, observations that were all reverted by exercise. AD and age also increased the spatial heterogeneity of brain tissue oxygenation, which was normalized by exercise. Ex vivo staining also showed fewer amyloid-β (Aβ) deposits in the exercise group. Finally, we observed correlations between voluntary running distance and cerebral tissue oxygenation/blood flow, suggesting a dose-response relationship of exercise on the brain. Overall, this study suggests that compromised brain oxygenation is an indicator of the onset of AD, with the emergence of potential deleterious mechanisms associated with hypoxia. Furthermore, voluntary exercise enhanced the neurovascular oxygenation process, potentially offering a means to delay these changes.
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21
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Yang B, Figueroa DM, Hou Y, Babbar M, Baringer SL, Croteau DL, Bohr VA. NEIL1 stimulates neurogenesis and suppresses neuroinflammation after stress. Free Radic Biol Med 2019; 141:47-58. [PMID: 31175982 PMCID: PMC7526462 DOI: 10.1016/j.freeradbiomed.2019.05.037] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Revised: 05/30/2019] [Accepted: 05/31/2019] [Indexed: 02/07/2023]
Abstract
Cellular exposure to ionizing radiation leads to oxidatively generated DNA damage, which has been implicated in neurodegenerative diseases. DNA damage is repaired by the evolutionarily conserved base excision repair (BER) system. Exposure of mice to ionizing radiation affects neurogenesis and neuroinflammation. However, the consequences of deficient DNA repair on adult neurogenesis and neuroinflammation are poorly understood despite their potential relevance for homeostasis. We previously reported that loss of NEIL1, an important DNA glycosylase involved in BER, is associated with deficiencies in spatial memory, olfaction, and protection against ischemic stroke in mice. Here, we show that Neil1-/- mice display an anxiety-mediated behavior in the open field test, a deficient recognitive memory in novel object recognition and increased neuroinflammatory response under basal conditions. Further, mice lacking NEIL1 have decreased neurogenesis and deficient resolution of neuroinflammation following gamma irradiation (IR)-induced stress compared to WT mice. Neil1-/- IR-exposed mice also exhibit increased DNA damage and apoptosis in the hippocampus. Interestingly, behavioral tests two weeks after IR showed impaired stress response in the Neil1-/- mice. Our data indicate that NEIL1 plays an important role in adult neurogenesis and in the resolution of neuroinflammation.
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Affiliation(s)
- Beimeng Yang
- Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA
| | - David M Figueroa
- Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Yujun Hou
- Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Mansi Babbar
- Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Stephanie L Baringer
- Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Deborah L Croteau
- Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Vilhelm A Bohr
- Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA; Danish Center for Healthy Aging, University of Copenhagen, 2200, Copenhagen, Denmark.
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22
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Chronic disturbance in the thalamus following cranial irradiation to the developing mouse brain. Sci Rep 2019; 9:9588. [PMID: 31270437 PMCID: PMC6610082 DOI: 10.1038/s41598-019-45973-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 06/18/2019] [Indexed: 12/14/2022] Open
Abstract
Better survival rates among pediatric brain tumor patients have resulted in an increased awareness of late side effects that commonly appear following cancer treatment. Radiation-induced changes in hippocampus and white matter are well described, but do not explain the full range of neurological late effects in childhood cancer survivors. The aim of this study was to investigate thalamus following cranial irradiation (CIR) to the developing brain. At postnatal day 14, male mice pups received a single dose of 8 Gy CIR. Cellular effects in thalamus were assessed using immunohistochemistry 4 months after CIR. Interestingly, the density of neurons decreased with 35% (p = 0.0431) and the density of astrocytes increased with 44% (p = 0.011). To investigate thalamic astrocytes, S100β+ cells were isolated by fluorescence-activated cell sorting and genetically profiled using next-generation sequencing. The phenotypical characterization indicated a disrupted function, such as downregulated microtubules’ function, higher metabolic activity, immature phenotype and degraded ECM. The current study provides novel insight into that thalamus, just like hippocampus and white matter, is severely affected by CIR. This knowledge is of importance to understand the late effects seen in pediatric brain tumor survivors and can be used to give them the best suitable care.
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23
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Frederiksen KS, Madsen K, Andersen BB, Beyer N, Garde E, Høgh P, Waldemar G, Hasselbalch SG, Law I. Moderate- to high-intensity exercise does not modify cortical β-amyloid in Alzheimer's disease. ALZHEIMER'S & DEMENTIA (NEW YORK, N. Y.) 2019; 5:208-215. [PMID: 31198839 PMCID: PMC6556817 DOI: 10.1016/j.trci.2019.04.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
INTRODUCTION Animal models of Alzheimer's disease show that exercise may modify β-amyloid (Aβ) deposition. We examined the effect of a 16-week exercise intervention on cortical Aβ in patients with mild-to-moderate Alzheimer's disease. METHODS Thirty-six patients with Alzheimer's disease were randomized to either one hour of aerobic exercise three times weekly for 16 weeks or usual care. Pre and post intervention, 11Carbon-Pittsburgh compound B positron emission tomography was carried out to assess cortical Aβ, and quantified using standardized uptake value rations (SUVRs). RESULTS The intervention showed no effect on follow-up SUVRs in a covariance analysis with group allocation, baseline intervention SUVR, age, sex, and baseline Mini-Mental State Examination as predictors. Change in SUVRs did not correlate with changes in measures of physical or aerobic fitness. DISCUSSION The present findings do not support an effect of exercise on Aβ. However, the relatively short intervention period may account for a lack of efficacy. Further studies should test earlier and longer interventions.
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Affiliation(s)
- Kristian S. Frederiksen
- Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Karine Madsen
- Neurobiology Research Unit, Copenhagen, Denmark
- Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Birgitte B. Andersen
- Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Nina Beyer
- Musculoskeletal Rehabilitation Research Unit and Institute of Sports Medicine, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Ellen Garde
- Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
- Department of Public Health and Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark
| | - Peter Høgh
- Zealand University Hospital, Department of Neurology, Roskilde, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Gunhild Waldemar
- Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Steen G. Hasselbalch
- Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Ian Law
- Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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24
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Wang Y, Zhou K, Li T, Xu Y, Xie C, Sun Y, Rodriguez J, Zhang S, Song J, Wang X, Blomgren K, Zhu C. Selective Neural Deletion of the Atg7 Gene Reduces Irradiation-Induced Cerebellar White Matter Injury in the Juvenile Mouse Brain by Ameliorating Oligodendrocyte Progenitor Cell Loss. Front Cell Neurosci 2019; 13:241. [PMID: 31213984 PMCID: PMC6554477 DOI: 10.3389/fncel.2019.00241] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Accepted: 05/14/2019] [Indexed: 11/28/2022] Open
Abstract
Radiotherapy is an effective tool for treating brain tumors, but irradiation-induced toxicity to the normal brain tissue remains a major problem. Here, we investigated if selective neural autophagy related gene 7 (Atg7) deletion has a persistent effect on irradiation-induced juvenile mouse brain injury. Ten-day-old Atg7 knockout under a nestin promoter (KO) mice and wild-type (WT) littermates were subjected to a single dose of 6 Gy whole-brain irradiation. Cerebellar volume, cell proliferation, microglia activation, inflammation, and myelination were evaluated in the cerebellum at 5 days after irradiation. We found that neural Atg7 deficiency partially prevented myelin disruption compared to the WT mice after irradiation, as indicated by myelin basic protein staining. Irradiation induced oligodendrocyte progenitor cell (OPC) loss in the white matter of the cerebellum, and Atg7 deficiency partly prevented this. The mRNA expression of oligodendrocyte and myelination-related genes (Olig2, Cldn11, CNP, and MBP) was higher in the cerebellum in Atg7 KO mice compared with WT littermates. The total cerebellar volume was significantly reduced after irradiation in both Atg7 KO and WT mice. Atg7-deficient cerebellums were in a regenerative state before irradiation, as judged by the increased OPC-related and neurogenesis-related transcripts and the increased numbers of microglia; however, except for the OPC parameters these were the same in both genotypes after irradiation. Finally, there was no significant change in the number of astrocytes in the cerebellum after irradiation. These results suggest that selective neural Atg7 deficiency reduces irradiation-induced cerebellar white matter injury in the juvenile mouse brain, secondary to prevention of OPC loss.
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Affiliation(s)
- Yafeng Wang
- Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital and Institute of Neuroscience, Zhengzhou University, Zhengzhou, China.,Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Pediatrics, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Kai Zhou
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Tao Li
- Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital and Institute of Neuroscience, Zhengzhou University, Zhengzhou, China.,Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Pediatrics, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Yiran Xu
- Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital and Institute of Neuroscience, Zhengzhou University, Zhengzhou, China.,Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Cuicui Xie
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Yanyan Sun
- Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital and Institute of Neuroscience, Zhengzhou University, Zhengzhou, China.,Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Juan Rodriguez
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Shan Zhang
- Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital and Institute of Neuroscience, Zhengzhou University, Zhengzhou, China.,Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Juan Song
- Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital and Institute of Neuroscience, Zhengzhou University, Zhengzhou, China.,Perinatal Center, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Xiaoyang Wang
- Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital and Institute of Neuroscience, Zhengzhou University, Zhengzhou, China.,Perinatal Center, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Klas Blomgren
- Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital and Institute of Neuroscience, Zhengzhou University, Zhengzhou, China.,Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.,Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden
| | - Changlian Zhu
- Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital and Institute of Neuroscience, Zhengzhou University, Zhengzhou, China.,Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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25
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Sahnoune I, Inoue T, Kesler SR, Rodgers SP, Sabek OM, Pedersen SE, Zawaski JA, Nelson KH, Ris MD, Leasure JL, Gaber MW. Exercise ameliorates neurocognitive impairments in a translational model of pediatric radiotherapy. Neuro Oncol 2019; 20:695-704. [PMID: 29121259 DOI: 10.1093/neuonc/nox197] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Background While cranial radiation therapy (CRT) is an effective treatment, healthy areas surrounding irradiation sites are negatively affected. Frontal lobe functions involving attention, processing speed, and inhibition control are impaired. These deficits appear months to years after CRT and impair quality of life. Exercise has been shown to rejuvenate the brain and aid in recovery post-injury through its effects on neurogenesis and cognition. Methods We developed a juvenile rodent CRT model that reproduces neurocognitive deficits. Next, we utilized the model to test whether exercise ameliorates these deficits. Fischer rats (31 days old) were irradiated with a fractionated dose of 4 Gy × 5 days, trained and tested at 6, 9, and 12 months post-CRT using 5-choice serial reaction time task. After testing, fixed rat brains were imaged using diffusion tensor imaging and immunohistochemistry. Results CRT caused early and lasting impairments in task acquisition, accuracy, and latency to correct response, as well as causing stunting of growth and changes in brain volume and diffusion. Exercising after irradiation improved acquisition, behavioral control, and processing speed, mitigated the stunting of brain size, and increased brain fiber numbers compared with sedentary CRT values. Further, exercise partially restored global connectome organization, including assortativity and characteristic path length, and while it did not improve the specific regional connections that were lowered by CRT, it appeared to remodel these connections by increasing connectivity between alternate regional pairs. Conclusions Our data strongly suggest that exercise may be useful in combination with interventions aimed at improving cognitive outcome following pediatric CRT.
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Affiliation(s)
- Iman Sahnoune
- Department of Psychology, University of Houston, Houston, Texas
| | - Taeko Inoue
- Department of Pediatrics, Texas Children's Cancer Center, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas
| | - Shelli R Kesler
- Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Omaima M Sabek
- Department of Surgery, Houston Methodist Hospital, Houston, Texas
| | - Steen E Pedersen
- Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, Texas
| | - Janice A Zawaski
- Department of Pediatrics, Texas Children's Cancer Center, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas
| | - Katharine H Nelson
- Department of Pediatrics, Texas Children's Cancer Center, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas
| | - M Douglas Ris
- Department of Pediatrics, Texas Children's Cancer Center, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.,Psychology Service, Texas Children's Hospital, Houston, Texas
| | - J Leigh Leasure
- Department of Psychology, University of Houston, Houston, Texas
| | - M Waleed Gaber
- Department of Pediatrics, Texas Children's Cancer Center, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas
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26
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Cacao E, Kapukotuwa S, Cucinotta FA. Modeling Reveals the Dependence of Hippocampal Neurogenesis Radiosensitivity on Age and Strain of Rats. Front Neurosci 2018; 12:980. [PMID: 30618596 PMCID: PMC6306485 DOI: 10.3389/fnins.2018.00980] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Accepted: 12/07/2018] [Indexed: 12/13/2022] Open
Abstract
Cognitive dysfunction following radiation treatment for brain cancers in both children and adults have been correlated to impairment of neurogenesis in the hippocampal dentate gyrus. Various species and strains of rodent models have been used to study radiation-induced changes in neurogenesis and these investigations have utilized only a limited number of doses, dose-fractions, age and time after exposures conditions. In this paper, we have extended our previous mathematical model of radiation-induced hippocampal neurogenesis impairment of C57BL/6 mice to delineate the time, age, and dose dependent alterations in neurogenesis of a diverse strain of rats. To the best of our knowledge, this is the first predictive mathematical model to be published about hippocampal neurogenesis impairment for a variety of rat strains after acute or fractionated exposures to low linear energy transfer (low LET) radiation, such as X-rays and γ-rays, which are conventionally used in cancer radiation therapy. We considered four compartments to model hippocampal neurogenesis and its impairment following radiation exposures. Compartments include: (1) neural stem cells (NSCs), (2) neuronal progenitor cells or neuroblasts (NB), (3) immature neurons (ImN), and (4) glioblasts (GB). Additional consideration of dose and time after irradiation dependence of microglial activation and a possible shift of NSC proliferation from neurogenesis to gliogenesis at higher doses is established. Using a system of non-linear ordinary differential equations (ODEs), characterization of rat strain and age-related dynamics of hippocampal neurogenesis for unirradiated and irradiated conditions is developed. The model is augmented with the description of feedback regulation on early and late neuronal proliferation following radiation exposure. Predictions for dose-fraction regimes compared to acute radiation exposures, along with the dependence of neurogenesis sensitivity to radiation on age and strain of rats are discussed. A major result of this work is predictions of the rat strain and age dependent differences in radiation sensitivity and sub-lethal damage repair that can be used for predictions for arbitrary dose and dose-fractionation schedules.
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Affiliation(s)
| | | | - Francis A. Cucinotta
- Department of Health Physics and Diagnostic Sciences, University of Nevada, Las Vegas, NV, United States
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27
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Whole-Body 12C Irradiation Transiently Decreases Mouse Hippocampal Dentate Gyrus Proliferation and Immature Neuron Number, but Does Not Change New Neuron Survival Rate. Int J Mol Sci 2018; 19:ijms19103078. [PMID: 30304778 PMCID: PMC6213859 DOI: 10.3390/ijms19103078] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 09/17/2018] [Accepted: 09/21/2018] [Indexed: 02/08/2023] Open
Abstract
High-charge and -energy (HZE) particles comprise space radiation and they pose a challenge to astronauts on deep space missions. While exposure to most HZE particles decreases neurogenesis in the hippocampus—a brain structure important in memory—prior work suggests that 12C does not. However, much about 12C’s influence on neurogenesis remains unknown, including the time course of its impact on neurogenesis. To address this knowledge gap, male mice (9–11 weeks of age) were exposed to whole-body 12C irradiation 100 cGy (IRR; 1000 MeV/n; 8 kEV/µm) or Sham treatment. To birthdate dividing cells, mice received BrdU i.p. 22 h post-irradiation and brains were harvested 2 h (Short-Term) or three months (Long-Term) later for stereological analysis indices of dentate gyrus neurogenesis. For the Short-Term time point, IRR mice had fewer Ki67, BrdU, and doublecortin (DCX) immunoreactive (+) cells versus Sham mice, indicating decreased proliferation (Ki67, BrdU) and immature neurons (DCX). For the Long-Term time point, IRR and Sham mice had similar Ki67+ and DCX+ cell numbers, suggesting restoration of proliferation and immature neurons 3 months post-12C irradiation. IRR mice had fewer surviving BrdU+ cells versus Sham mice, suggesting decreased cell survival, but there was no difference in BrdU+ cell survival rate when compared within treatment and across time point. These data underscore the ability of neurogenesis in the mouse brain to recover from the detrimental effect of 12C exposure.
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28
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Sato Y, Shinjyo N, Sato M, Nilsson MKL, Osato K, Zhu C, Pekna M, Kuhn HG, Blomgren K. Grafting Neural Stem and Progenitor Cells Into the Hippocampus of Juvenile, Irradiated Mice Normalizes Behavior Deficits. Front Neurol 2018; 9:715. [PMID: 30254600 PMCID: PMC6141740 DOI: 10.3389/fneur.2018.00715] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 08/08/2018] [Indexed: 11/17/2022] Open
Abstract
The pool of neural stem and progenitor cells (NSPCs) in the dentate gyrus of the hippocampus is reduced by ionizing radiation. This explains, at least partly, the learning deficits observed in patients after radiotherapy, particularly in pediatric cases. An 8 Gy single irradiation dose was delivered to the whole brains of postnatal day 9 (P9) C57BL/6 mice, and BrdU-labeled, syngeneic NSPCs (1.0 × 105 cells/injection) were grafted into each hippocampus on P21. Three months later, behavior tests were performed. Irradiation impaired novelty-induced exploration, place learning, reversal learning, and sugar preference, and it altered the movement pattern. Grafting of NSPCs ameliorated or even normalized the observed deficits. Less than 4% of grafted cells survived and were found in the dentate gyrus 5 months later. The irradiation-induced loss of endogenous, undifferentiated NSPCs in the dentate gyrus was completely restored by grafted NSPCs in the dorsal, but not the ventral, blade. The grafted NSPCs did not exert appreciable effects on the endogenous NSPCs; however, more than half of the grafted NSPCs differentiated. These results point to novel strategies aimed at ameliorating the debilitating late effects of cranial radiotherapy, particularly in children.
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Affiliation(s)
- Yoshiaki Sato
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.,Division of Neonatology, Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, Japan
| | - Noriko Shinjyo
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Machiko Sato
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.,Department of Obstetrics and Gynecology, Narita Hospital, Nagoya, Japan
| | - Marie K L Nilsson
- Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Kazuhiro Osato
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.,Department of Obstetrics and Gynecology, Mie University, Tsu, Japan
| | - Changlian Zhu
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.,Department of Pediatrics, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Marcela Pekna
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Hans G Kuhn
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Klas Blomgren
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.,Department of Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden.,Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
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29
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Youssef M, Krish VS, Kirshenbaum GS, Atsak P, Lass TJ, Lieberman SR, Leonardo ED, Dranovsky A. Ablation of proliferating neural stem cells during early life is sufficient to reduce adult hippocampal neurogenesis. Hippocampus 2018; 28:586-601. [PMID: 29742815 PMCID: PMC6167166 DOI: 10.1002/hipo.22962] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 04/19/2018] [Accepted: 05/01/2018] [Indexed: 12/26/2022]
Abstract
Environmental exposures during early life, but not during adolescence or adulthood, lead to persistent reductions in neurogenesis in the adult hippocampal dentate gyrus (DG). The mechanisms by which early life exposures lead to long-term deficits in neurogenesis remain unclear. Here, we investigated whether targeted ablation of dividing neural stem cells during early life is sufficient to produce long-term decreases in DG neurogenesis. Having previously found that the stem cell lineage is resistant to long-term effects of transient ablation of dividing stem cells during adolescence or adulthood (Kirshenbaum, Lieberman, Briner, Leonardo, & Dranovsky, ), we used a similar pharmacogenetic approach to target dividing neural stem cells for elimination during early life periods sensitive to environmental insults. We then assessed the Nestin stem cell lineage in adulthood. We found that the adult neural stem cell reservoir was depleted following ablation during the first postnatal week, when stem cells were highly proliferative, but not during the third postnatal week, when stem cells were more quiescent. Remarkably, ablating proliferating stem cells during either the first or third postnatal week led to reduced adult neurogenesis out of proportion to the changes in the stem cell pool, indicating a disruption of the stem cell function or niche following stem cell ablation in early life. These results highlight the first three postnatal weeks as a series of sensitive periods during which elimination of dividing stem cells leads to lasting alterations in adult DG neurogenesis and stem cell function. These findings contribute to our understanding of the relationship between DG development and adult neurogenesis, as well as suggest a possible mechanism by which early life experiences may lead to lasting deficits in adult hippocampal neurogenesis.
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Affiliation(s)
- Mary Youssef
- Department of Psychiatry, Columbia University, New York, NY 10032, USA; Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, NY 10032, USA
- Graduate Program in Neurobiology and Behavior, Columbia University, New York, NY 10032, USA
| | - Varsha S. Krish
- Department of Psychiatry, Columbia University, New York, NY 10032, USA; Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, NY 10032, USA
- Neuroscience and Behavior, Barnard College, New York, NY 10027, USA
| | - Greer S. Kirshenbaum
- Department of Psychiatry, Columbia University, New York, NY 10032, USA; Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, NY 10032, USA
| | - Piray Atsak
- Department of Psychiatry, Columbia University, New York, NY 10032, USA; Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, NY 10032, USA
- Department of Cognitive Neuroscience, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
- Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6525 EN Nijmegen, The Netherlands
| | - Tamara J. Lass
- Department of Psychiatry, Columbia University, New York, NY 10032, USA; Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, NY 10032, USA
| | - Sophie R. Lieberman
- Department of Psychiatry, Columbia University, New York, NY 10032, USA; Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, NY 10032, USA
- Neuroscience and Behavior, Barnard College, New York, NY 10027, USA
| | - E. David Leonardo
- Department of Psychiatry, Columbia University, New York, NY 10032, USA; Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, NY 10032, USA
| | - Alex Dranovsky
- Department of Psychiatry, Columbia University, New York, NY 10032, USA; Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, NY 10032, USA
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30
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Tong J, Li J, Zhang QS, Yang JK, Zhang L, Liu HY, Liu YZ, Yuan JW, Su XM, Zhang XX, Jiao BH. Delayed cognitive deficits can be alleviated by calcium antagonist nimodipine by downregulation of apoptosis following whole brain radiotherapy. Oncol Lett 2018; 16:2525-2532. [PMID: 30013647 PMCID: PMC6036595 DOI: 10.3892/ol.2018.8968] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 01/29/2018] [Indexed: 01/30/2023] Open
Abstract
Radiation therapy is important for the comprehensive treatment of intracranial tumors. However, the molecular mechanisms underlying the pathogenesis of delayed cognitive dysfunction are not well-defined and effective treatments or prevention measures remain insufficient. In the present study, 60 adult male Wistar rats were randomly divided into three groups, which included a control, whole brain radiotherapy (WBRT) (single dose of 30 Gy of WBRT) and nimodipine (single dose of 30 Gy of WBRT followed by nimodipine injection intraperitoneally) groups. The rats were sacrificed 7 days or 3 months following irradiation. At 3 months, the Morris water maze test was used to assess spatial learning and memory function in rats. The results demonstrated that the WBRT group demonstrated a significantly impaired cognitive performance, decreased numbers of hippocampal Cornu Ammonis (CA)1 neurons and upregulated expression of caspase-3 in the dentate gyrus compared with those in the control and nimodipine groups. Reverse transcription-quantitative polymerase chain reaction analysis demonstrated that the WBRT group exhibited increased ratio of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax)/Bcl-2 compared with that in control and nimodipine groups on day 7 following irradiation. However, the WBRT group exhibited decreased levels of brain-derived neurotrophic factor (BDNF) compared with that in control and nimodipine groups at 3 months following brain irradiation. The levels of growth-associated protein 43 and amyloid precursor protein between the nimodipine group and WBRT group were not statistically significant. The present study demonstrated that neuron apoptosis may lead to delayed cognitive deficits in the hippocampus, in response to radiotherapy. The cognitive impairment may be alleviated in response to a calcium antagonist nimodipine. The molecular mechanisms involved in nimodipine-mediated protection against cognitive decline may involve the regulation of Bax/Bcl-2 and BDNF in the hippocampus.
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Affiliation(s)
- Jing Tong
- Department of Neurosurgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Juan Li
- Department of Radiotherapy, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Qiu-Shi Zhang
- Department of Neurosurgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Jian-Kai Yang
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Lei Zhang
- Department of Neurosurgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Hai-Ying Liu
- Department of Neurosurgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Ying-Zi Liu
- Department of Neurosurgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Jiang-Wei Yuan
- Department of Neurosurgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Xu-Ming Su
- Department of Neurosurgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Xue-Xin Zhang
- Department of Neurosurgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Bao-Hua Jiao
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
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Karlsson L, González-Alvarado MN, Larrosa-Flor M, Osman A, Börjesson M, Blomgren K, Kuhn HG. Constitutive PGC-1α Overexpression in Skeletal Muscle Does Not Improve Morphological Outcome in Mouse Models of Brain Irradiation or Cortical Stroke. Neuroscience 2018; 384:314-328. [PMID: 29859976 DOI: 10.1016/j.neuroscience.2018.05.036] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Revised: 04/19/2018] [Accepted: 05/23/2018] [Indexed: 12/22/2022]
Abstract
Physical exercise can improve morphological outcomes after ischemic stroke and ameliorate irradiation-induced reduction of hippocampal neurogenesis in rodents, but the mechanisms underlying these effects remain largely unknown. The transcription factor peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is considered to be one of the central factors responsible for exercise-induced benefits in skeletal muscle, including the release of neurotrophic factors into the circulation. In order to test if PGC-1α overexpression in skeletal muscle could simulate the exercise-induced effects on recovery after cranial irradiation and stroke, we used male adult transgenic mice overexpressing murine PGC-1α under the control of muscle creatinine kinase promoter and subjected them to either whole brain irradiation at a dose of 4 Gy or photothrombotic stroke to the sensory motor cortex. Muscular PGC-1α overexpression did not ameliorate irradiation-induced reduction of newborn BrdU-labeled cells in the dentate gyrus, immature neurons, or newborn mature neurons. In the stroke model, muscular overexpression of PGC-1α resulted in an increased infarct size without any changes in microglia activation or reactive astrocytosis. No difference could be detected in the number of migrating neural progenitor cells from the subventricular zone to the lesioned neocortex or in vascular density of the contralateral neocortex in comparison to wildtype animals. We conclude that forced muscular overexpression of PGC-1α does not have a beneficial effect on hippocampal neurogenesis after irradiation, but rather a detrimental effect on the infarct volume after stroke in mice. This suggests that artificial muscle activation through the PGC-1α pathway is not sufficient to mimic exercise-induced recovery after cranial irradiation and stroke.
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Affiliation(s)
- Lars Karlsson
- Institute for Neuroscience and Physiology, University of Gothenburg, Box 436, 405 30 Gothenburg, Sweden; The Queen Silvia Children's Hospital, Sahlgrenska University Hospital, 416 85 Gothenburg, Sweden.
| | | | - Mar Larrosa-Flor
- Institute for Neuroscience and Physiology, University of Gothenburg, Box 436, 405 30 Gothenburg, Sweden
| | - Ahmed Osman
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Mats Börjesson
- Institute for Neuroscience and Physiology, University of Gothenburg, Box 436, 405 30 Gothenburg, Sweden; Center for Health and Performance, Department of Food and Nutrition, University of Gothenburg, Box 300, 405 30 Gothenburg, Sweden; Sahlgrenska University Hospital/Östra, 416 50 Gothenburg, Sweden
| | - Klas Blomgren
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden
| | - Hans Georg Kuhn
- Institute for Neuroscience and Physiology, University of Gothenburg, Box 436, 405 30 Gothenburg, Sweden
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32
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Fernström E, Minta K, Andreasson U, Sandelius Å, Wasling P, Brinkmalm A, Höglund K, Blennow K, Nyman J, Zetterberg H, Kalm M. Cerebrospinal fluid markers of extracellular matrix remodelling, synaptic plasticity and neuroinflammation before and after cranial radiotherapy. J Intern Med 2018; 284:211-225. [PMID: 29664192 DOI: 10.1111/joim.12763] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND Advances in the treatment of brain tumours have increased the number of long-term survivors, but at the cost of side effects following cranial radiotherapy ranging from neurocognitive deficits to outright tissue necrosis. At present, there are no tools reflecting the molecular mechanisms underlying such side effects, and thus no means to evaluate interventional effects after cranial radiotherapy. Therefore, fluid biomarkers are of great clinical interest. OBJECTIVE Cerebrospinal fluid (CSF) levels of proteins involved in inflammatory signalling, synaptic plasticity and extracellular matrix (ECM) integrity were investigated following radiotherapy to the brain. METHODS Patients with small-cell lung cancer (SCLC) eligible for prophylactic cranial irradiation (PCI) were asked to participate in the study. PCI was prescribed either as 2 Gy/fraction to a total dose of 30 Gy (limited disease) or 4 Gy/fraction to 20 Gy (extensive disease). CSF was collected by lumbar puncture at baseline, 3 months and 1 year following PCI. Protein concentrations were measured using immunobased assays or mass spectrometry. RESULTS The inflammatory markers IL-15, IL-16 and MCP-1/CCL2 were elevated in CSF 3 months following PCI compared to baseline. The plasticity marker GAP-43 was elevated 3 months following PCI, and the same trend was seen for SNAP-25, but not for SYT1. The investigated ECM proteins, brevican and neurocan, showed a decline following PCI. There was a strong correlation between the progressive decline of soluble APPα and brevican levels. CONCLUSION To our knowledge, this is the first time ECM-related proteins have been shown to be affected by cranial radiotherapy in patients with cancer. These findings may help us to get a better understanding of the mechanisms behind side effects following radiotherapy.
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Affiliation(s)
- E Fernström
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - K Minta
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology at the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
| | - U Andreasson
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology at the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Å Sandelius
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology at the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
| | - P Wasling
- Department of Physiology, Institute of Neuroscience and Physiology at the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - A Brinkmalm
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology at the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - K Höglund
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology at the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - K Blennow
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology at the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - J Nyman
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - H Zetterberg
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology at the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden
- Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
- UK Dementia Research Institute at UCL, London, UK
| | - M Kalm
- Department of Pharmacology, Institute of Neuroscience and Physiology at the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
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Kalm M, Andreasson U, Björk-Eriksson T, Zetterberg H, Pekny M, Blennow K, Pekna M, Blomgren K. C3 deficiency ameliorates the negative effects of irradiation of the young brain on hippocampal development and learning. Oncotarget 2017; 7:19382-94. [PMID: 27029069 PMCID: PMC4991390 DOI: 10.18632/oncotarget.8400] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 03/09/2016] [Indexed: 02/06/2023] Open
Abstract
Radiotherapy in the treatment of pediatric brain tumors is often associated with debilitating late-appearing adverse effects, such as intellectual impairment. Areas in the brain harboring stem cells are particularly sensitive to irradiation (IR) and loss of these cells may contribute to cognitive deficits. It has been demonstrated that IR-induced inflammation negatively affects neural progenitor differentiation. In this study, we used mice lacking the third complement component (C3−/−) to investigate the role of complement in a mouse model of IR-induced injury to the granule cell layer (GCL) of the hippocampus. C3−/− and wild type (WT) mice received a single, moderate dose of 8 Gy to the brain on postnatal day 10. The C3−/− mice displayed 55 % more microglia (Iba-1+) and a trend towards increase in proliferating cells in the GCL compared to WT mice 7 days after IR. Importantly, months after IR C3−/− mice made fewer errors than WT mice in a reversal learning test indicating better learning capacity in C3−/− mice after IR. Notably, months after IR C3−/− and WT mice had similar GCL volumes, survival of newborn cells (BrdU), microglia (Iba-1) and astrocyte (S100β) numbers in the GCL. In summary, our data show that the complement system contributes to IR-induced loss of proliferating cells and maladaptive inflammatory responses in the acute phase after IR, leading to impaired learning capacity in adulthood. Targeting the complement system is hence promising for future strategies to reduce the long-term adverse consequences of IR in the young brain.
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Affiliation(s)
- Marie Kalm
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Ulf Andreasson
- Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden
| | | | - Henrik Zetterberg
- Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.,Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK
| | - Milos Pekny
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.,Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.,Hunter Medical Research Institute, University of Newcastle, New South Wales, Australia
| | - Kaj Blennow
- Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden
| | - Marcela Pekna
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.,Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.,Hunter Medical Research Institute, University of Newcastle, New South Wales, Australia
| | - Klas Blomgren
- Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
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Yousuf S, Brat DJ, Shu HK, Wang Y, Stein DG, Atif F. Progesterone improves neurocognitive outcomes following therapeutic cranial irradiation in mice. Horm Behav 2017; 96:21-30. [PMID: 28866326 DOI: 10.1016/j.yhbeh.2017.08.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 07/20/2017] [Accepted: 08/23/2017] [Indexed: 12/13/2022]
Abstract
Despite improved therapeutic methods, CNS toxicity resulting from cancer treatment remains a major cause of post-treatment morbidity. More than half of adult patients with cranial irradiation for brain cancer develop neurobehavioral/cognitive deficits that severely impact quality of life. We examined the neuroprotective effects of the neurosteroid progesterone (PROG) against ionizing radiation (IR)-induced neurobehavioral/cognitive deficits in mice. Male C57/BL mice were exposed to one of two fractionated dose regimens of IR (3Gy×3 or 3Gy×5). PROG (16mg/kg; 0.16mg/g) was given as a pre-, concurrent or post-IR treatment for 14days. Mice were tested for short- and long-term effects of IR and PROG on neurobehavioral/cognitive function on days 10 and 30 after IR treatment. We evaluated both hippocampus-dependent and -independent memory functions. Locomotor activity, elevated plus maze, novel object recognition and Morris water maze tests revealed behavioral deficits following IR. PROG treatment produced improvement in behavioral performance at both time points in the mice given IR. Western blot analysis of hippocampal and cortical tissue showed that IR at both doses induced astrocytic activation (glial fibrillary acidic protein), reactive macrophages/microglia (CD68) and apoptosis (cleaved caspase-3) and PROG treatment inhibited these markers of brain injury. There was no significant difference in the degree of deficit in any test between the two dose regimens of IR at either time point. These findings could be important in the context of patients with brain tumors who may undergo radiotherapy and eventually develop cognitive deficits.
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Affiliation(s)
- Seema Yousuf
- Brain Research Laboratory, Department of Emergency Medicine, 1365 B Clifton Rd NE, Suite 5100, Atlanta, GA 30322, USA.
| | - Daniel J Brat
- Department of Pathology, Emory University Hospital Room H183, 1364 Clifton Rd NE, Atlanta, GA 30322, USA.
| | - Hui-Kuo Shu
- Department of Radiation Oncology, 1365 C Clifton Rd NE, Emory University School of Medicine, Atlanta, GA 30322, USA.
| | - Ya Wang
- Department of Radiation Oncology, 1365 C Clifton Rd NE, Emory University School of Medicine, Atlanta, GA 30322, USA.
| | - Donald G Stein
- Brain Research Laboratory, Department of Emergency Medicine, 1365 B Clifton Rd NE, Suite 5100, Atlanta, GA 30322, USA.
| | - Fahim Atif
- Brain Research Laboratory, Department of Emergency Medicine, 1365 B Clifton Rd NE, Suite 5100, Atlanta, GA 30322, USA.
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Bull C, Malipatlolla D, Kalm M, Sjöberg F, Alevronta E, Grandér R, Sultanian P, Persson L, Boström M, Eriksson Y, Swanpalmer J, Wold AE, Blomgren K, Björk-Eriksson T, Steineck G. A novel mouse model of radiation-induced cancer survivorship diseases of the gut. Am J Physiol Gastrointest Liver Physiol 2017; 313:G456-G466. [PMID: 28729245 DOI: 10.1152/ajpgi.00113.2017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 07/06/2017] [Accepted: 07/16/2017] [Indexed: 01/31/2023]
Abstract
A deeper understanding of the radiation-induced pathophysiological processes that develop in the gut is imperative to prevent, alleviate, or eliminate cancer survivorship diseases after radiotherapy to the pelvic area. Most rodent models of high-dose gastrointestinal radiation injury are limited by high mortality. We therefore established a model that allows for the delivering of radiation in fractions at high doses while maintaining long-term survival. Adult male C57/BL6 mice were exposed to small-field irradiation, restricted to 1.5 cm of the colorectum using a linear accelerator. Each mouse received 6 or 8 Gy, two times daily in 12-h intervals in two, three, or four fractions. Acute cell death was examined at 4.5 h postirradiation and histological changes at 6 wk postirradiation. Another group was given four fractions of 8 Gy and followed over time for development of visible symptoms. Irradiation caused immediate cell death, mainly limited to the colorectum. At 6 wk postirradiation, several crypts displayed signs of radiation-induced degeneration. The degenerating crypts were seen alongside crypts that appeared perfectly healthy. Crypt survival was reduced after the fourth fraction regardless of dose, whereas the number of macrophages increased. Angiogenesis was induced, likely as a compensatory mechanism for hypoxia. Four months postirradiation, mice began to show radiation-induced symptoms, and histological examination revealed an extensive crypt loss and fibrosis. Our model is uniquely suitable for studying the long-term trajectory and underlying mechanisms of radiation-induced gastrointestinal injury.NEW & NOTEWORTHY A novel mouse model for studying the long-term trajectory of radiation-induced gut injury. The method allows for the use of high doses and multiple fractions, with minor impact on animal health for at least 3 mo. Crypt loss and a slow progression of fibrosis is observed. Crypt degeneration is a process restricted to isolated crypts. Crypt degeneration is presented as a convenient proxy endpoint for long-term radiation-induced gut injury.
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Affiliation(s)
- Cecilia Bull
- Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Dilip Malipatlolla
- Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Marie Kalm
- Department of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Fei Sjöberg
- Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Eleftheria Alevronta
- Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Rita Grandér
- Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Pedram Sultanian
- Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Linda Persson
- Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Martina Boström
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Yohanna Eriksson
- Department of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - John Swanpalmer
- Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden
| | - Agnes E Wold
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; and
| | - Klas Blomgren
- Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden
| | - Thomas Björk-Eriksson
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Gunnar Steineck
- Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;
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Diabetes-Induced Dysfunction of Mitochondria and Stem Cells in Skeletal Muscle and the Nervous System. Int J Mol Sci 2017; 18:ijms18102147. [PMID: 29036909 PMCID: PMC5666829 DOI: 10.3390/ijms18102147] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 10/11/2017] [Indexed: 12/21/2022] Open
Abstract
Diabetes mellitus is one of the most common metabolic diseases spread all over the world, which results in hyperglycemia caused by the breakdown of insulin secretion or insulin action or both. Diabetes has been reported to disrupt the functions and dynamics of mitochondria, which play a fundamental role in regulating metabolic pathways and are crucial to maintain appropriate energy balance. Similar to mitochondria, the functions and the abilities of stem cells are attenuated under diabetic condition in several tissues. In recent years, several studies have suggested that the regulation of mitochondria functions and dynamics is critical for the precise differentiation of stem cells. Importantly, physical exercise is very useful for preventing the diabetic alteration by improving the functions of both mitochondria and stem cells. In the present review, we provide an overview of the diabetic alterations of mitochondria and stem cells and the preventive effects of physical exercise on diabetes, focused on skeletal muscle and the nervous system. We propose physical exercise as a countermeasure for the dysfunction of mitochondria and stem cells in several target tissues under diabetes complication and to improve the physiological function of patients with diabetes, resulting in their quality of life being maintained.
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Kozareva DA, O'Leary OF, Cryan JF, Nolan YM. Deletion of TLX and social isolation impairs exercise-induced neurogenesis in the adolescent hippocampus. Hippocampus 2017; 28:3-11. [DOI: 10.1002/hipo.22805] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 09/07/2017] [Accepted: 09/20/2017] [Indexed: 12/19/2022]
Affiliation(s)
- Danka A. Kozareva
- Department of Anatomy and Neuroscience; University College Cork; Ireland
- APC Microbiome Institute; University College Cork; Ireland
| | - Olivia F. O'Leary
- Department of Anatomy and Neuroscience; University College Cork; Ireland
- APC Microbiome Institute; University College Cork; Ireland
| | - John F. Cryan
- Department of Anatomy and Neuroscience; University College Cork; Ireland
- APC Microbiome Institute; University College Cork; Ireland
| | - Yvonne M. Nolan
- Department of Anatomy and Neuroscience; University College Cork; Ireland
- APC Microbiome Institute; University College Cork; Ireland
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Riggs L, Piscione J, Laughlin S, Cunningham T, Timmons BW, Courneya KS, Bartels U, Skocic J, de Medeiros C, Liu F, Persadie N, Scheinemann K, Scantlebury N, Szulc KU, Bouffet E, Mabbott DJ. Exercise training for neural recovery in a restricted sample of pediatric brain tumor survivors: a controlled clinical trial with crossover of training versus no training. Neuro Oncol 2017; 19:440-450. [PMID: 27555603 DOI: 10.1093/neuonc/now177] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Accepted: 07/01/2016] [Indexed: 01/26/2023] Open
Abstract
Background Exercise promotes repair processes in the mouse brain and improves cognition in both mice and humans. It is not known whether these benefits translate to human brain injury, particularly the significant injury observed in children treated for brain tumors. Methods We conducted a clinical trial with crossover of exercise training versus no training in a restricted sample of children treated with radiation for brain tumors. The primary outcome was change in brain structure using MRI measures of white matter (ie, fractional anisotropy [FA]) and hippocampal volume [mm3]). The secondary outcome was change in reaction time (RT)/accuracy across tests of attention, processing speed, and short-term memory. Linear mixed modeling was used to test the effects of time, training, training setting, and carryover. Results Twenty-eight participants completed training in either a group (n=16) or a combined group/home (n=12) setting. Training resulted in increased white matter FA (Δ=0.05, P<.001). A carryover effect was observed for participants ~12 weeks after training (Δ=0.05, P<.001). Training effects were observed for hippocampal volume (Δ=130.98mm3; P=.001) and mean RT (Δ=-457.04ms, P=0.36) but only in the group setting. Related carryover effects for hippocampal volume (Δ=222.81mm3, P=.001), and RT (Δ=-814.90ms, P=.005) were also observed. Decreased RT was predicted by increased FA (R=-0.62, P=.01). There were no changes in accuracy. Conclusions Exercise training is an effective means for promoting white matter and hippocampal recovery and improving reaction time in children treated with cranial radiation for brain tumors.
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Affiliation(s)
- Lily Riggs
- Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Psychology, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Janine Piscione
- Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Rehabilitation Services, Hospital for Sick Children, Toronto, Ontario,Canada
| | - Suzanne Laughlin
- Diagnostic Imaging, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Todd Cunningham
- Department of Applied Psychology and Human Development, University of Toronto, Toronto, Ontario, Canada
| | - Brian W Timmons
- Department of Paediatrics, McMaster University, Hamilton, Ontario, Canada
| | - Kerry S Courneya
- Faculty of Physical Education and Recreation, University of Alberta, Edmonton, Alberta, Canada
| | - Ute Bartels
- Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Paediatrics, University of Toronto, Toronto, Ontario,Canada
| | - Jovanka Skocic
- Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Cynthia de Medeiros
- Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Fang Liu
- Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Nicholas Persadie
- Department of Paediatrics, McMaster University, Hamilton, Ontario, Canada
| | - Katrin Scheinemann
- Department of Paediatrics, McMaster University, Hamilton, Ontario, Canada
| | - Nadia Scantlebury
- Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Kamila U Szulc
- Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Eric Bouffet
- Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Paediatrics, University of Toronto, Toronto, Ontario,Canada
| | - Donald J Mabbott
- Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Psychology, Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Psychology, University of Toronto, Toronto, Ontario, Canada
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Kimura A, Matsuda T, Sakai A, Murao N, Nakashima K. HMGB2 expression is associated with transition from a quiescent to an activated state of adult neural stem cells. Dev Dyn 2017; 247:229-238. [PMID: 28771884 DOI: 10.1002/dvdy.24559] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2017] [Revised: 07/17/2017] [Accepted: 07/28/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Although quiescent neural stem cells (NSCs) in the adult hippocampus proliferate in response to neurogenic stimuli and subsequently give rise to new neurons continuously throughout life, misregulation of NSCs in pathological conditions, including aging, leads to the impairment of learning and memory. High mobility group B family 1 (HMGB1) and HMGB2, HMG family proteins that function as transcriptional activators through the modulation of chromatin structure, have been assumed to play some role in the regulation of adult NSCs; however, their precise functions and even expression patterns in the adult hippocampus remain elusive. RESULTS Here we show that expression of HMGB2 but not HMGB1 is restricted to the subset of NSCs and their progenitors. Furthermore, running, a well-known positive neurogenic stimulus, increased the proliferation of HMGB2-expressing cells, whereas aging was accompanied by a marked decrease in these cells. Intriguingly, HMGB2-expressing quiescent NSCs, which were shifted toward the proliferative state, were decreased as aging progressed. CONCLUSIONS HMGB2 expression is strongly associated with transition from the quiescent to the proliferative state of NSCs, supporting the possibility that HMGB2 is involved in the regulation of adult neurogenesis and can be used as a novel marker to identify NSCs primed for activation in the adult hippocampus. Developmental Dynamics 247:229-238, 2018. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Ayaka Kimura
- Stem Cell Biology and Medicine, Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Taito Matsuda
- Stem Cell Biology and Medicine, Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Atsuhiko Sakai
- Stem Cell Biology and Medicine, Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Naoya Murao
- Stem Cell Biology and Medicine, Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kinichi Nakashima
- Stem Cell Biology and Medicine, Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Tian Z, Zhao Q, Biswas S, Deng W. Methods of reactivation and reprogramming of neural stem cells for neural repair. Methods 2017; 133:3-20. [PMID: 28864354 DOI: 10.1016/j.ymeth.2017.08.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 07/21/2017] [Accepted: 08/24/2017] [Indexed: 12/27/2022] Open
Abstract
Research on the biology of adult neural stem cells (NSCs) and induced NSCs (iNSCs), as well as NSC-based therapies for diseases in central nervous system (CNS) has started to generate the expectation that these cells may be used for treatments in CNS injuries or disorders. Recent technological progresses in both NSCs themselves and their derivatives have brought us closer to therapeutic applications. Adult neurogenesis presents in particular regions in mammal brain, known as neurogenic niches such as the dental gyrus (DG) in hippocampus and the subventricular zone (SVZ), within which adult NSCs usually stay for long periods out of the cell cycle, in G0. The reactivation of quiescent adult NSCs needs orchestrated interactions between the extrinsic stimulis from niches and the intrinsic factors involving transcription factors (TFs), signaling pathway, epigenetics, and metabolism to start an intracellular regulatory program, which promotes the quiescent NSCs exit G0 and reenter cell cycle. Extrinsic and intrinsic mechanisms that regulate adult NSCs are interconnected and feedback on one another. Since endogenous neurogenesis only happens in restricted regions and steadily fails with disease advances, interest has evolved to apply the iNSCs converted from somatic cells to treat CNS disorders, as is also promising and preferable. To overcome the limitation of viral-based reprogramming of iNSCs, bioactive small molecules (SM) have been explored to enhance the efficiency of iNSC reprogramming or even replace TFs, making the iNSCs more amenable to clinical application. Despite intense research efforts to translate the studies of adult and induced NSCs from the bench to bedside, vital troubles remain at several steps in these processes. In this review, we examine the present status, advancement, pitfalls, and potential of the two types of NSC technologies, focusing on each aspects of reactivation of quiescent adult NSC and reprogramming of iNSC from somatic cells, as well as on progresses in cell-based regenerative strategies for neural repair and criteria for successful therapeutic applications.
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Affiliation(s)
- Zuojun Tian
- Department of Neurology, The Institute of Guangzhou Respiratory Disease, State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, PR China; Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA 95817, USA; Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, USA
| | - Qiuge Zhao
- Department of Neurology, The Institute of Guangzhou Respiratory Disease, State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, PR China
| | - Sangita Biswas
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA 95817, USA; Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, USA.
| | - Wenbin Deng
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA 95817, USA; Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, USA.
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Bull C, Cooper C, Lindahl V, Fitting S, Persson AI, Grandér R, Alborn AM, Björk-Eriksson T, Kuhn HG, Blomgren K. Exercise in Adulthood after Irradiation of the Juvenile Brain Ameliorates Long-Term Depletion of Oligodendroglial Cells. Radiat Res 2017; 188:443-454. [PMID: 28777696 DOI: 10.1667/rr14737.1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Cranial radiation severely affects brain health and function, including glial cell production and myelination. Recent studies indicate that voluntary exercise has beneficial effects on oligodendrogenesis and myelination. Here, we hypothesized that voluntary running would increase oligodendrocyte numbers in the corpus callosum after irradiation of the juvenile mouse brain. The brains of C57Bl/6J male mice were 6 Gy irradiated on postnatal day 9 during the main gliogenic developmental phase, resulting in a loss of oligodendrocyte precursor cells. Upon adulthood, the mice were injected with bromodeoxyuridine and allowed to exercise on a running wheel for four weeks. Cell proliferation and survival, Ascl1+ oligodendrocyte precursor and Olig2+ oligodendrocyte cell numbers as well as CC1+ mature oligodendrocytes were quantified using immunohistology. Radiation induced a reduction in the number of Olig2+ oligodendrocytes by nearly 50% without affecting production or survival of new Olig2+ cells. Ascl1+ cells earlier in the oligodendroglial cell lineage were also profoundly affected, with numbers reduced by half. By three weeks of age, Olig2+ cell numbers had not recovered, and this was paralleled by a volumetric loss in the corpus callosum. The deficiency of Olig2+ oligodendrocytes persisted into adulthood. Additionally, the depletion of Ascl1+ progenitor cells was irreversible, and was even more pronounced at 12 weeks postirradiation compared to day 2 postirradiation. Furthermore, the overall number of CC1+ mature oligodendrocytes decreased by 28%. The depletion of Olig2+ cells in irradiated animals was reversed by 4 weeks of voluntary exercise. Moreover, voluntary exercise also increased the number of Ascl1+ progenitor cells in irradiated animals. Taken together, these results demonstrate that exercise in adulthood significantly ameliorates the profound and long-lasting effects of moderate exposure to immature oligodendrocytes during postnatal development.
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Affiliation(s)
- Cecilia Bull
- a Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Christiana Cooper
- b Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Veronica Lindahl
- b Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Sylvia Fitting
- c Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Anders I Persson
- d Department of Neurology, University of California, San Francisco, California
| | - Rita Grandér
- a Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ann-Marie Alborn
- b Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Thomas Björk-Eriksson
- a Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - H Georg Kuhn
- b Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Klas Blomgren
- e Karolinska Institutet, Department of Women's and Children's Health, Stockholm, Sweden.,f Department of Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden
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Home sweet home: the neural stem cell niche throughout development and after injury. Cell Tissue Res 2017; 371:125-141. [PMID: 28776186 DOI: 10.1007/s00441-017-2658-0] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 05/29/2017] [Indexed: 12/26/2022]
Abstract
Neural stem cells and their progeny reside in two distinct neurogenic niches within the mammalian brain: the subventricular zone and the dentate gyrus. The interplay between the neural stem cells and the niche in which they reside can have significant effects on cell kinetics and neurogenesis. A comprehensive understanding of the changes to the niche that occur through postnatal development and aging, as well as following injury, is relevant for developing therapeutics and interventions to promote neural repair. We discuss changes that occur within the neural stem and progenitor cell populations, the vasculature, extracellular matrix, microglia, and secreted proteins through aging which impact cell behavior within the neurogenic niches. We examine neural precursor cell and niche responses to injury in neonatal hypoxia-ischemia, juvenile cranial irradiation, and adult stroke. This review examines the interplay between the niche and stem cell behavior through aging and following injury as a means to understand intrinsic and extrinsic factors that regulate neurogenesis in vivo.
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Decker AL, Szulc KU, Bouffet E, Laughlin S, Chakravarty MM, Skocic J, de Medeiros CB, Mabbott DJ. Smaller hippocampal subfield volumes predict verbal associative memory in pediatric brain tumor survivors. Hippocampus 2017; 27:1140-1154. [DOI: 10.1002/hipo.22758] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 06/16/2017] [Accepted: 06/20/2017] [Indexed: 11/06/2022]
Affiliation(s)
- Alexandra L. Decker
- Neurosciences and Mental Health; Hospital for Sick Children; Toronto Canada
- Department of Psychology; University of Toronto; Toronto Canada
| | - Kamila U. Szulc
- Neurosciences and Mental Health; Hospital for Sick Children; Toronto Canada
| | - Eric Bouffet
- Department of Hematology/Oncology; Hospital for Sick Children; Toronto Canada
| | - Suzanne Laughlin
- Diagnositic Imaging; The Hospital for Sick Children; Toronto Canada
| | - M. Mallar Chakravarty
- Cerebral Imaging Centre, Douglas Mental Health University Institute; Montreal Canada
- Departments of Psychiatry and Biological and Biomedical Engineering; McGill University; Montreal Canada
| | - Jovanka Skocic
- Neurosciences and Mental Health; Hospital for Sick Children; Toronto Canada
| | | | - Donald J. Mabbott
- Neurosciences and Mental Health; Hospital for Sick Children; Toronto Canada
- Department of Psychology; University of Toronto; Toronto Canada
- Department of Psychology; Hospital for Sick Children; Toronto Canada
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Abbink MR, Naninck EFG, Lucassen PJ, Korosi A. Early-life stress diminishes the increase in neurogenesis after exercise in adult female mice. Hippocampus 2017; 27:839-844. [PMID: 28558121 DOI: 10.1002/hipo.22745] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 05/02/2017] [Accepted: 05/18/2017] [Indexed: 11/07/2022]
Abstract
Exposure to early-life stress (ES) has long-lasting consequences for later cognition and hippocampal plasticity, including adult hippocampal neurogenesis (AHN), i.e., the generation of new neurons from stem/progenitor cells in the adult hippocampal dentate gyrus. We had previously demonstrated a sex-specific vulnerability to ES exposure; female mice exposed to ES from P2-P9 exhibited only very mild cognitive changes and no reductions in AHN as adult, whereas ES-exposed male mice showed impaired cognition closely associated with reductions in AHN. Given the apparent resilience of AHN to ES in females, we here questioned whether ES has also altered the capacity to respond to positive stimuli for neurogenesis. We therefore investigated whether exercise, known for its strong pro-neurogenic effects, can still stimulate AHN in adult female mice that had been earlier exposed to ES. We confirm a strong pro-neurogenic effect of exercise in the dorsal hippocampus of 8-month-old control female mice, but this positive neurogenic response is less apparent in female ES mice. These data provide novel insights in the lasting consequences of ES on hippocampal plasticity in females and also indicate that ES might lastingly reduce the responsiveness of the hippocampal stem cell pool, to exercise, in female mice.
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Affiliation(s)
- M R Abbink
- Swammerdam Institute for Life Sciences, Center for Neuroscience, Brain plasticity group, University of Amsterdam, Amsterdam, The Netherlands
| | - E F G Naninck
- Swammerdam Institute for Life Sciences, Center for Neuroscience, Brain plasticity group, University of Amsterdam, Amsterdam, The Netherlands
| | - P J Lucassen
- Swammerdam Institute for Life Sciences, Center for Neuroscience, Brain plasticity group, University of Amsterdam, Amsterdam, The Netherlands
| | - A Korosi
- Swammerdam Institute for Life Sciences, Center for Neuroscience, Brain plasticity group, University of Amsterdam, Amsterdam, The Netherlands
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Ruitenberg MJ, Wells J, Bartlett PF, Harvey AR, Vukovic J. Enrichment increases hippocampal neurogenesis independent of blood monocyte-derived microglia presence following high-dose total body irradiation. Brain Res Bull 2017; 132:150-159. [PMID: 28552674 DOI: 10.1016/j.brainresbull.2017.05.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Revised: 05/12/2017] [Accepted: 05/22/2017] [Indexed: 10/19/2022]
Abstract
Birth of new neurons in the hippocampus persists in the brain of adult mammals and critically underpins optimal learning and memory. The process of adult neurogenesis is significantly reduced following brain irradiation and this correlates with impaired cognitive function. In this study, we aimed to compare the long-term effects of two environmental paradigms (i.e. enriched environment and exercise) on adult neurogenesis following high-dose (10Gy) total body irradiation. When housed in standard (sedentary) conditions, irradiated mice revealed a long-lasting (up to 4 months) deficit in neurogenesis in the granule cell layer of the dentate gyrus, the region that harbors the neurogenic niche. This depressive effect of total body irradiation on adult neurogenesis was partially alleviated by exposure to enriched environment but not voluntary exercise, where mice were single-housed with unlimited access to a running wheel. Exposure to voluntary exercise, but not enriched environment, did lead to significant increases in microglia density in the granule cell layer of the hippocampus; our study shows that these changes result from local microglia proliferation rather than recruitment and infiltration of circulating Cx3cr1+/gfp blood monocytes that subsequently differentiate into microglia-like cells. In summary, latent neural precursor cells remain present in the neurogenic niche of the adult hippocampus up to 8 weeks following high-dose total body irradiation. Environmental enrichment can partially restore the adult neurogenic process in this part of the brain following high-dose irradiation, and this was found to be independent of blood monocyte-derived microglia presence.
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Affiliation(s)
- Marc J Ruitenberg
- School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia; Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia
| | - Julia Wells
- Telethon Kids Institute, Perth, Western Australia, Australia
| | - Perry F Bartlett
- Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia
| | - Alan R Harvey
- School of Human Sciences, The University of Western Australia, Perth, Western Australia, Australia; Perron Institute for Neurological and Translational Science, Perth, Western Australia, Australia
| | - Jana Vukovic
- School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia; Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
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Zhou K, Xie C, Wickström M, Dolga AM, Zhang Y, Li T, Xu Y, Culmsee C, Kogner P, Zhu C, Blomgren K. Lithium protects hippocampal progenitors, cognitive performance and hypothalamus-pituitary function after irradiation to the juvenile rat brain. Oncotarget 2017; 8:34111-34127. [PMID: 28415806 PMCID: PMC5470955 DOI: 10.18632/oncotarget.16292] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 03/01/2017] [Indexed: 11/25/2022] Open
Abstract
Cranial radiotherapy in children typically causes delayed and progressive cognitive dysfunction and there is no effective preventive strategy for radiation-induced cognitive impairments. Here we show that lithium treatment reduced irradiation-induced progenitor cell death in the subgranular zone of the hippocampus, and subsequently ameliorated irradiation-reduced neurogenesis and astrogenesis in the juvenile rat brain. Irradiation-induced memory impairment, motor hyperactivity and anxiety-like behaviour were normalized by lithium treatment. Late-onset irradiation-induced hypopituitarism was prevented by lithium treatment. Additionally, lithium appeared relatively toxic to multiple cultured tumour cell lines, and did not improve viability of radiated DAOY cells in vitro. In summary, our findings demonstrate that lithium can be safely administered to prevent both short- and long-term injury to the juvenile brain caused by ionizing radiation.
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Affiliation(s)
- Kai Zhou
- Centre for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
- Karolinska Institutet, Department of Women's and Children's Health, Stockholm, Sweden
| | - Cuicui Xie
- Centre for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
- Henan Key Laboratory of Child Brain Injury, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Malin Wickström
- Centre for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Amalia M. Dolga
- Institute of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg, Germany
- Department of Molecular Pharmacology, University of Groningen, Groningen Research Institute of Pharmacy, Groningen, The Netherlands
| | - Yaodong Zhang
- Centre for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
- Department of Paediatrics, Zhengzhou Children's Hospital, Zhengzhou, China
| | - Tao Li
- Centre for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
- Henan Key Laboratory of Child Brain Injury, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Paediatrics, Zhengzhou Children's Hospital, Zhengzhou, China
| | - Yiran Xu
- Centre for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
- Henan Key Laboratory of Child Brain Injury, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Carsten Culmsee
- Institute of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg, Germany
| | - Per Kogner
- Karolinska Institutet, Department of Women's and Children's Health, Stockholm, Sweden
- Department of Paediatric Oncology, Karolinska University Hospital, Stockholm, Sweden
| | - Changlian Zhu
- Centre for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
- Henan Key Laboratory of Child Brain Injury, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Klas Blomgren
- Karolinska Institutet, Department of Women's and Children's Health, Stockholm, Sweden
- Department of Paediatric Oncology, Karolinska University Hospital, Stockholm, Sweden
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Radiation induces progenitor cell death, microglia activation, and blood-brain barrier damage in the juvenile rat cerebellum. Sci Rep 2017; 7:46181. [PMID: 28382975 PMCID: PMC5382769 DOI: 10.1038/srep46181] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Accepted: 03/10/2017] [Indexed: 02/03/2023] Open
Abstract
Posterior fossa tumors are the most common childhood intracranial tumors, and radiotherapy is one of the most effective treatments. However, irradiation induces long-term adverse effects that can have significant negative impacts on the patient’s quality of life. The purpose of this study was to characterize irradiation-induced cellular and molecular changes in the cerebellum. We found that irradiation-induced cell death occurred mainly in the external germinal layer (EGL) of the juvenile rat cerebellum. The number of proliferating cells in the EGL decreased, and 82.9% of them died within 24 h after irradiation. Furthermore, irradiation induced oxidative stress, microglia accumulation, and inflammation in the cerebellum. Interestingly, blood-brain barrier damage and blood flow reduction was considerably more pronounced in the cerebellum compared to other brain regions. The cerebellar volume decreased by 39% and the migration of proliferating cells to the internal granule layer decreased by 87.5% at 16 weeks after irradiation. In the light of recent studies demonstrating that the cerebellum is important not only for motor functions, but also for cognition, and since treatment of posterior fossa tumors in children typically results in debilitating cognitive deficits, this differential susceptibility of the cerebellum to irradiation should be taken into consideration for future protective strategies.
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Fan XW, Liu HH, Wang HB, Chen F, Yang Y, Chen Y, Guan SK, Wu KL. Electroacupuncture Improves Cognitive Function and Hippocampal Neurogenesis after Brain Irradiation. Radiat Res 2017; 187:672-681. [PMID: 28375680 DOI: 10.1667/rr14561.1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Cognitive impairments after brain irradiation seriously affect quality of life for patients, and there is currently no effective treatment. In this study using an irradiated rat model, the role of electroacupuncture was investigated for treatment of radiation-induced brain injury. Animals received 10 Gy exposure to the entire brain, and electroacupuncture was administered 3 days before irradiation as well as up to 2 weeks postirradiation. Behavioral tests were performed one month postirradiation, and rats were then sacrificed for histology or molecular studies. Electroacupuncture markedly improved animal performance in the novel place recognition test. In the emotion test, electroacupuncture reduced defecation during the open-field test, and latency to consumption of food in the novelty suppressed feeding test. Brain irradiation inhibited the generation of immature neurons, but did not cause neural stem cell loss. Electroacupuncture partially restored hippocampal neurogenesis. Electroacupuncture decreased the amount of activated microglia and increased resting microglia in the hippocampus after irradiation. In addition, electroacupuncture promoted mRNA and protein expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. In conclusion, electroacupuncture could improve cognitive function and hippocampal neurogenesis after irradiation, and the protective effect of electroacupuncture was associated with the modulation of microglia and upregulation of BDNF in the hippocampus.
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Affiliation(s)
- Xing-Wen Fan
- a Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China, 200032; Departments of.,b Oncology and
| | - Huan-Huan Liu
- d Department of Radiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China 200092
| | - Hong-Bing Wang
- a Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China, 200032; Departments of.,b Oncology and
| | - Fu Chen
- c Integrative Medicine and Neurobiology, State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, China, 200032; and
| | - Yu Yang
- a Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China, 200032; Departments of
| | - Yan Chen
- c Integrative Medicine and Neurobiology, State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, China, 200032; and
| | - Shi-Kuo Guan
- a Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China, 200032; Departments of
| | - Kai-Liang Wu
- a Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China, 200032; Departments of.,b Oncology and
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Tang FR, Loke WK, Khoo BC. Postnatal irradiation-induced hippocampal neuropathology, cognitive impairment and aging. Brain Dev 2017; 39:277-293. [PMID: 27876394 DOI: 10.1016/j.braindev.2016.11.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Revised: 11/04/2016] [Accepted: 11/04/2016] [Indexed: 12/26/2022]
Abstract
Irradiation of the brain in early human life may set abnormal developmental events into motion that last a lifetime, leading to a poor quality of life for affected individuals. While the effect of irradiation at different early developmental stages on the late human life has not been investigated systematically, animal experimental studies suggest that acute postnatal irradiation with ⩾0.1Gy may significantly reduce neurogenesis in the dentate gyrus and endotheliogenesis in cerebral vessels and induce cognitive impairment and aging. Fractionated irradiation also reduces neurogenesis. Furthermore, irradiation induces hippocampal neuronal loss in CA1 and CA3 areas, neuroinflammation and reduces gliogenesis. The hippocampal neurovascular niche and the total number of microvessels are also changed after radiation exposures. Each or combination of these pathological changes may cause cognitive impairment and aging. Interestingly, acute irradiation of aged brain with a certain amount of radiation has also been reported to induce brain hormesis or neurogenesis. At molecular levels, inflammatory cytokines, chemokines, neural growth factors, neurotransmitters, their receptors and signal transduction systems, reactive oxygen species are involved in radiation-induced adverse effect on brain development and functions. Further study at different omics levels after low dose/dose rate irradiation may not only unravel the mechanisms of radiation-induced adverse brain effect or hormesis, but also provide clues for detection or diagnosis of radiation exposure and for therapeutic approaches to effectively prevent radiation-induced cognitive impairment and aging. Investigation focusing on radiation-induced changes of critical brain development events may reveal many previously unknown adverse effects.
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Affiliation(s)
- Feng Ru Tang
- Singapore Nuclear Research and Safety Initiative, National University of Singapore, Singapore 138602, Singapore.
| | - Weng Keong Loke
- Defence Medical and Environmental Research Institute, DSO National Laboratories, 11 Stockport Road, Singapore 11760, Singapore
| | - Boo Cheong Khoo
- Temasek Laboratories, National University of Singapore, 5A, Engineering Drive 1, Singapore 117411, Singapore
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SDF-1/CXCR4 Signaling Maintains Stemness Signature in Mouse Neural Stem/Progenitor Cells. Stem Cells Int 2017; 2017:2493752. [PMID: 28408934 PMCID: PMC5376953 DOI: 10.1155/2017/2493752] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 01/29/2017] [Accepted: 02/01/2017] [Indexed: 11/17/2022] Open
Abstract
SDF-1 and its primary receptor, CXCR4, are highly expressed in the embryonic central nervous system (CNS) and play a crucial role in brain architecture. Loss of SDF-1/CXCR4 signaling causes abnormal development of neural stem/progenitor cells (NSCs/NPCs) in the cerebellum, hippocampus, and cortex. However, the mechanism of SDF-1/CXCR4 axis in NSCs/NPCs regulation remains unknown. In this study, we found that elimination of SDF-1/CXCR4 transduction caused NSCs/NPCs to lose their stemness characteristics and to encounter neurogenic differentiation. Moreover, Notch and RE1 silencing transcription factor (REST) both play an essential role in NSCs/NPCs maintenance and neuronal differentiation and were dramatically downregulated following SDF-1/CXCR4 cascade inhibition. Finally, we demonstrated that the expression of achaete-scute homolog 1 (Ascl1), a proneural gene, and p27, an antiproliferative gene, were significantly increased after genetic elimination of SDF-1 alleles. Our results support that the loss of functional SDF-1/CXCR4 signaling pathway in NSCs/NPCs induces exit of cell cycle and promotes premature neural differentiation.
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