Brain irradiation leads to persistent neuroinflammation and long-term neurocognitive dysfunction in a region-specific manner.

Long-term cognitive deficits are observed after treatment of brain tumors or metastases by radiotherapy. Treatment optimization thus requires a better understanding of the effects of radiotherapy on specific brain regions, according to their sensitivity and interconnectivity. In the present study, behavioral tests supported by immunohistology and magnetic resonance imaging provided a consistent picture of the persistent neurocognitive decline and neuroinflammation after the onset of irradiation-induced necrosis in the right primary somatosensory cortex of Fischer rats. Necrosis surrounded by neovascularization was first detected 54 days after irradiation and then spread to 110 days in the primary motor cortex, primary somatosensory region, striatum and right ventricle, resulting in fiber bundle disruption and demyelination in the corpus callosum of the right hemisphere. These structural damages translated into selective behavioral changes including spatial memory loss, disinhibition of anxiety-like behaviors, hyperactivity and pain hypersensitivity, but no significant alteration in motor coordination and grip strength abilities. Concomitantly, activated microglia and reactive astrocytes, accompanied by infiltration of leukocytes (CD45+) and T-cells (CD3+) cooperated to shape the neuroinflammation response. Overall, our study suggests that the slow and gradual onset of cellular damage would allow adaptation in brain regions that are susceptible to neuronal plasticity; while other cerebral structures that do not have this capacity would be more affected. The planning of radiotherapy, adjusted to the sensitivity and adaptability of brain structures, could therefore preserve certain neurocognitive functions; while higher doses of radiation could be delivered to brain areas that can better adapt to this treatment. In addition, strategies to block early post-radiation events need to be explored to prevent the development of long-term cognitive dysfunction.

Fluoxetine reverses brain radiation and temozolomide-induced anxiety and spatial learning and memory defect in mice.

Radiation therapy and concomitant temozolomide chemotherapy are commonly used in treatment of brain tumors, but they may also result in behavioral impairments such as anxiety and cognitive deficit. The present study sought to investigate the effect of fluoxetine on the behavioral impairments caused by radiation and temozolomide treatment. C57BL/6J mice were subjected to a single cranial radiation followed by 6-wk cyclic temozolomide administration and were then treated with chronic administration of fluoxetine. Behavioral tests were carried out to determine the anxiety-like behavior and cognition function of these animals. Long-term potentiation (LTP) in the hippocampus was measured by electrophysiology, and neurogenesis in the dentate gyrus was evaluated by immunohistochemistry. Mice treated with radiation and temozolomide showed increased anxiety-like behavior and cognitive impairment, along with LTP impairment and neurogenesis deficit. Chronic fluoxetine administration could reverse the behavioral dysfunction, enhance LTP, and increase neurogenesis in the hippocampus. NEW & NOTEWORTHY Mice treated with radiation and temozolomide showed increased anxiety-like behavior and cognitive impairment. Chronic fluoxetine administration could reverse the behavioral dysfunction. The effect of fluoxetine might be via rescuing the neurogenesis deficit caused by radiation and temozolomide treatment.

Adult Neurogenesis Conserves Hippocampal Memory Capacity.

The hippocampus is crucial for declarative memories in humans and encodes episodic and spatial memories in animals. Memory coding strengthens synaptic efficacy via an LTP-like mechanism. Given that animals store memories of everyday experiences, the hippocampal circuit must have a mechanism that prevents saturation of overall synaptic weight for the preservation of learning capacity. LTD works to balance plasticity and prevent saturation. In addition, adult neurogenesis in the hippocampus is proposed to be involved in the down-scaling of synaptic efficacy. Here, we show that adult neurogenesis in male rats plays a crucial role in the maintenance of hippocampal capacity for memory (learning and/or memory formation). Neurogenesis regulated the maintenance of LTP, with decreases and increases in neurogenesis prolonging or shortening LTP persistence, respectively. Artificial saturation of hippocampal LTP impaired memory capacity in contextual fear conditioning, which completely recovered after 14 d, which was the time required for LTP to decay to the basal level. Memory capacity gradually recovered in parallel with neurogenesis-mediated gradual decay of LTP. Ablation of neurogenesis by x-ray irradiation delayed the recovery of memory capacity, whereas enhancement of neurogenesis using a running wheel sped up recovery. Therefore, one benefit of ongoing adult neurogenesis is the maintenance of hippocampal memory capacity through homeostatic renewing of hippocampal memory circuits. Decreased neurogenesis in aged animals may be responsible for the decline in cognitive function with age.SIGNIFICANCE STATEMENT Learning many events each day increases synaptic efficacy via LTP, which can prevent the storage of new memories in the hippocampal circuit. In this study, we demonstrate that hippocampal capacity for the storage of new memories is maintained by ongoing adult neurogenesis through homoeostatic renewing of hippocampal circuits in rats. A decrease or an increase in neurogenesis, respectively, delayed or sped up the recovery of memory capacity, suggesting that hippocampal adult neurogenesis plays a critical role in reducing LTP saturation and keeps the gate open for new memories by clearing out the old memories from the hippocampal memory circuit.

Radiation-induced overexpression of transthyretin inhibits retinol-mediated hippocampal neurogenesis.

Cranial irradiation is the main therapeutic strategy for treating primary and metastatic brain tumors. However, radiation is well-known to induce several unexpected side effects including emotional disorders. Although radiation-induced depression may cause decreased quality of life after radiotherapy, investigations of its molecular mechanism and therapeutic strategies are still insufficient. In this study, we found that behavioral symptoms of depression on mice models with the decrease of BrdU/NeuN- and Dcx-positive populations and MAP-2 expression in hippocampus were induced by cranial irradiation, and transthyretin (TTR) was highly expressed in hippocampus after irradiation. It was shown that overexpression of TTR resulted in the inhibition of retinol-mediated neuritogenesis. PAK1 phosphorylation and MAP-2 expression were significantly reduced by TTR overexpression following irradiation. Moreover, we observed that treatment of allantoin and neferine, the active components of Nelumbo nucifera, interrupted irradiation-induced TTR overexpression, consequently leading to the increase of PAK1 phosphorylation, neurite extension, BrdU/NeuN- and Dcx-positive populations, and MAP-2 expression. Behavioral symptoms of depression following cranial irradiation were also relieved by treatment of allantoin and neferine. These findings demonstrate that TTR plays a critical role in neurogenesis after irradiation, and allantoin and neferine could be potential drug candidates for recovering the effects of radiation on neurogenesis and depression.

Radioprotective activity of glutathione on cognitive ability in X-ray radiated tumor-bearing mice.

OBJECTIVES: The use of X-ray for therapeutics always raises the problem of radiation hazards to living beings. In this research, we explored the radioprotective activity of glutathione (GSH) on cognitive ability of X-ray radiated tumor-bearing mice. METHODS: Forty C57BL/6 mice were chosen to establish the GL261 glioma model and randomly divided into four groups: Model group, X-ray group, Pre-GSH group and Pos-GSH group. Morris water maze test was used to test cognitive ability. Moreover, histopathological observation of hippocampus was observed by hematoxylin and eosin (HE) staining. The protein expression of choline acetyl transferase (ChAT) was measured by western blot, simultaneously the contents of acetylcholinesterase (Ach), superoxide dismutase (SOD), methane dicarboxylic aldehyde (MDA),TNF-α and IL-6 were detected by the respective kit. RESULTS: There was a significant difference in X-ray group of the escape latency from the Model group (P<0.05). Besides, HE staining revealed that nucleus in hippocampus cells were pyknotic, glial cells were hyperplastic and the nerve cells were swelling in X-ray group. In X-ray group the expression of ChAT and Ache were decreased versus Model group. Finally, the cognitive ability in Pre-GSH and Pos-GSH group was enhanced than X-ray group, in which the cognitive ability of Pos-GSH group was higher than the Pre-GSH group. DISCUSSION: X-ray impaired the brain tissues and cognitive ability of tumor-bearing mice. The damages of brain tissues were alleviated by Pre-GSH and Pos-GSH protection and the efficacy of Pos-GSH protection was superior to Pre-GSH protection. Abbreviation Ach: Acetylcholinesterase; GSH: Glutathione; HE: Hematoxylin and eosin; MDA: methane dicarboxylic aldehyde; SOD: Superoxide dismutase; TV: Tumor volume; TW: Tumor weight.

Cerebral impact of prenatal irradiation by 131I: an experimental model of clinical neuroradioembryological effects. / VPLYV PRENATAL'NOGO OPROMINENNIa 131I NA GOLOVNYY̆ MOZOK: EKSPERYMENTAL'NA MODEL' KLINIChNYKh NEY̆RORADIOEMBRIOLOGIChNYKh EFEKTIV.

Human brain in prenatal period is a most vulnerable to ionizing radiation body structure. Unlike atomic bombings or radiological interventions in healthcare leading at most to external irradiation the intensive internal exposure may occur upon nuclear reactor accidents followed by substantial release and fallout of radioactive 131I. The latter can lead to specific neuroradioembryological effects. OBJECTIVE: To create an experimental model of prenatal cerebral radiation effects of 131I in human and to determine the experimental and clinical neuroradioembryological effects.Study object. The neuroradioembryological effects in Vistar rats exposed to 131I in prenatal period. Nervous system status and mental status in 104 persons exposed to ionizing radiation in utero due to the ChNPP accident and the same in 78 not exposed subjects. METHODS: Experimental i.e. behavioral techniques, including the spontaneous locomotive, exploratory activity and learning ability assessment, clinical i.e. neuropsychiatric, neuro and psychometric, neuropsychological, neurophys iological methods, both with dosimetric and statistical methods were applied. RESULTS: Intrauterine irradiation of Wistar rats by 131I was simulated on a model of one time oral 27.5 kBq radionu clide administration in the mid gestation period (0.72±0.14 Gy fetal thyroid dose), which provides extrapolation of neuroradioembryological effects in rats to that in humans exposed to intrauterine radiation as a result of the Chornobyl catastrophe. Abnormalities in behavioral reactions and decreased output of conditioned reflex reactions identified in the 10 month old rats suggest a deterioration of cerebral cognition in exposed animals. Specific cog nitive deficit featuring a disharmonic intellectual development through the relatively decreased verbal intelligence versus relative increase of nonverbal one is remained in prenatally exposed persons. This can indicate to dysfunc tion of cortical limbic system with especial involvement of a dominant hemisphere hippocampus. Decreased theta band spectral power (4-7 Hz range) of cerebral bioelectrical activity in the left frontotemporal area is suggestive of hippocampal dysfunction mainly in dominant hemisphere of prenatally irradiated persons. Disorders of hippocam pal neurogenesis due to prenatal exposure by radioactive iodine can be a biologic basis here. Innovative approach es in social adaptation, psychoprophylaxis and psychorehabilitation involve the maximum effective application and development of just the most developed psychological and cognitive abilities in survivors.

Long-Term Deficits in Behavior Performances Caused by Low- and High-Linear Energy Transfer Radiation.

Efforts to protect astronauts from harmful galactic cosmic radiation (GCR) require a better understanding of the effects of GCR on human health. In particular, little is known about the lasting effects of GCR on the central nervous system (CNS), which may lead to behavior performance deficits. Previous studies have shown that high-linear energy transfer (LET) radiation in rodents leads to short-term declines in a variety of behavior tests. However, the lasting impact of low-, medium- and high-LET radiation on behavior are not fully defined. Therefore, in this study C57BL/6 male mice were irradiated with 100 or 250 cGy of γ rays (LET ∼0.3 KeV/µm), 10 or 100 cGy of 1H at 1,000 MeV/n (LET ∼0.2 KeV/µm), 28Si at 300 MeV/n (LET ∼69 KeV/µm) or 56Fe at 600 MeV/n (LET of ∼180 KeV/µm), and behavior metrics were collected at 5 and 9 months postirradiation to analyze differences among radiation qualities and doses. A significant dose effect was observed on recognition memory and activity levels measured 9 months postirradiation, regardless of radiation source. In contrast, we observed that each ion species had a distinct effect on anxiety, motor coordination and spatial memory at extended time points. Although 28Si and 56Fe are both regarded as high-LET particles, they were shown to have different detrimental effects on behavior. In summary, our findings suggest that GCR not only affects the CNS in the short term, but also has lasting damaging effects on the CNS that can cause sustained declines in behavior performance.

Social behavioral testing and brain magnetic resonance imaging in chicks exposed to mobile phone radiation during development.

BACKGROUND: The potential adverse effect of mobile phone radiation is currently an area of great concern in the field of public health. In the present study, we aimed to investigate the effect of mobile phone radiation (900 MHz radiofrequency) during hatching on postnatal social behaviors in chicks, as well as the effect on brain size and structural maturity estimated using 3.0 T magnetic resonance imaging. At day 4 of incubation, 76 normally developing chick embryos were divided into the control group (n = 39) and the radiation group (n = 37). Eggs in the radiation group were exposed to mobile phone radiation for 10 h each day from day 4 to 19 of incubation. Behavioral tests were performed 4 days after hatching. T2-weighted MR imaging and diffusion tensor imaging (DTI) were subsequently performed. The size of different brain subdivisions (telencephalon, optic lobe, brain stem, and cerebellum) and corresponding DTI parameters were measured. The Chi-square test and the student's t test were used for statistical analysis. P < 0.05 was considered statistically significant. RESULTS: Compared with controls, chicks in the radiation group showed significantly slower aggregation responses (14.87 ± 10.06 vs. 7.48 ± 4.31 s, respectively; P < 0.05), lower belongingness (23.71 ± 8.72 vs. 11.45 ± 6.53 s, respectively; P < 0.05), and weaker vocalization (53.23 ± 8.60 vs. 60.01 ± 10.45 dB/30 s, respectively; P < 0.05). No significant differences were found between the radiation and control group for brain size and structural maturity, except for cerebellum size, which was significantly smaller in the radiation group (28.40 ± 1.95 vs. 29.95 ± 1.41 cm(2), P < 0.05). The hatching and heteroplasia rates were also calculated and no significant difference was found between the two groups. CONCLUSIONS: Mobile phone radiation exposure during chick embryogenesis impaired social behaviors after hatching and possibly induced cerebellar retardation. This indicates potential adverse effects of mobile phone radiation on brain development.

A preclinical murine model for the early detection of radiation-induced brain injury using magnetic resonance imaging and behavioral tests for learning and memory: with applications for the evaluation of possible stem cell imaging agents and therapies.

Stem cell therapies are being developed for radiotherapy-induced brain injuries (RIBI). Magnetic resonance imaging (MRI) offers advantages for imaging transplanted stem cells. However, most MRI cell-tracking techniques employ superparamagnetic iron oxide particles (SPIOs), which are difficult to distinguish from hemorrhage. In current preclinical RIBI models, hemorrhage occurs concurrently with other injury markers. This makes the evaluation of the recruitment of transplanted SPIO-labeled stem cells to injury sites difficult. Here, we developed a RIBI model, with early injury markers reflective of hippocampal dysfunction, which can be detected noninvasively with MRI and behavioral tests. Lesions were generated by sub-hemispheric irradiation of mouse hippocampi with single X-ray beams of 80 Gy. Lesion formation was monitored with anatomical and contrast-enhanced MRI and changes in memory and learning were assessed with fear-conditioning tests. Early injury markers were detected 2 weeks after irradiation. These included an increase in the permeability of the blood-brain barrier, demonstrated by a 92 ± 20 % contrast enhancement of the irradiated versus the non-irradiated brain hemispheres, within 15 min of the administration of an MRI contrast agent. A change in short-term memory was also detected, as demonstrated by a 40.88 ± 5.03 % decrease in the freezing time measured during the short-term memory context test at this time point, compared to that before irradiation. SPIO-labeled stem cells transplanted contralateral to the lesion migrated toward the lesion at this time point. No hemorrhage was detected up to 10 weeks after irradiation. This model can be used to evaluate SPIO-based stem cell-tracking agents, short-term.

Relationship between irradiation-induced neuro-inflammatory environments and impaired cognitive function in the developing brain of mice.

PURPOSE: Radiation-induced brain injury (RIBI) is the most common side-effect after cranial radiation therapy (CRT). In the present study, the RIBI mice model was established and the changes in the expression of tumor necrosis factor alpha (TNF-α) and interleukin-1beta (IL-1ß) mRNA, and the related signal pathways in the hippocampus of this model were investigated. MATERIALS AND METHODS: 10 Gy CRT or sham-irradiation was given to the three-week old mice. The water maze test was used to test the RIBI model in mice. The expression of pro-inflammatory cytokines was detected by real-time polymerase chain reaction (PCR) in vivo. The changes of microglial activation and neurogensis in the hippocampus were analyzed by immunofluorescence and immunohistochemistry. The cytoplasm to nuclei translocation of Nuclear factor kappa B (NF-κB), and the protein expressions of IkappaB-alpha (IκB-α), NF-κB essential modulator (NEMO), p53-induced protein with a death domain (PIDD), TNF-α and IL-1ß were examined by Western blotting. A RIBI model was established by Morris water maze test 6 weeks after 10 Gy CRT in three-week old C57BL/6J mice. RESULTS: The mRNA and protein expression levels of TNF-α and IL-1ß reached the peak during the early phase after CRT. Increases in cytokine levels also were observed after irradiation of mouse BV-2 microglial cells. Neurogensis was significantly inhibited in the hippocampus with an increase of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells. The total number of microglia was decreased after CRT, but microglial activation was significantly increased. Western blotting revealed, in the RIBI mice, the expression of IκB-α was down-regulated, accompanied by the up-regulated expression of NEMO and regulated auto-proteolysis of PIDD. Also the NF-κB pathway activation was observed in BV-2 cells after irradiation. CONCLUSIONS: CRT-induced pro-inflammatory cytokines release in the brain tissues and inhibition of neurogenesis in the hippocampus might be contributed by the microglial activation and play an important role in RIBI.

Purple grape juice as a protector against acute x-irradiation induced alterations on mobility, anxiety, and feeding behaviour in mice.

The aim of this work was to test the hypothesis that a moderate intake of organic purple grape juice shows a positive radiomodifier effect over early behavioural damage following acute X-irradiation in mice. Anxiety-, locomotion-, and feeding-related responses to 6 Gy total body X-irradiation (TBI) were studied via open field, Rotarod, and feeding/drinking recording. Thirty-two male mice weighing 25-30 g were grouped according grape juice (J) or water (W) ad libitum drinking and either non-irradiated (N) or irradiated (R). 24 h post-TBI the access frequency to the center and corners of the open field was decreased, and the total stay in the corners increased, in RW vs. NW mice. Anxiety-related parameters decreased in RJ vs. RW mice. Rotarod latency times increased 72 h post-TBI in RJ vs RW mice. No overall changes in food and drink intake were observed along the experimental period. On the irradiation day, bout number was increased and bout duration was decreased in RW mice. The changes were reversed by purple grape juice intake. Grape juice intake before and after TBI can overcome several radiation-induced changes in behaviour within 24-72 hours after sub-lethal X-irradiation. This beneficial effect on short-term anxiety and mobilityrelated activities could probably be included in the list of flavonoid bio-effects. The present findings could be relevant in designing preventive interventions aimed to enhance body defense mechanisms against short-term irradiation damage.

El presente estudio tiene como objetivo comprobar la hipótesis de que una ingesta moderada de mosto ecológico de uva tinta presenta un efecto radiomodificador positivo sobre los daños comportamentales tempranos inducidos por la irradiación aguda con rayos X en el ratón. Se estudiaron respuestas relacionadas con el comportamiento ingestivo, ansiedad y locomoción frente a la irradiación aguda a cuerpo entero (TBI) con 6 Gy de rayos X, mediante registro directo de la ingestión de agua y alimento, rotarod y open field. Se utilizaron 32 ratones macho con un peso corporal entre 25 y 30 g, agrupados en función de haber sido sometidos a irradiación a cuerpo entero (R) o no (N) y de su ingesta de mosto (J) o agua (W) ad libitum. La frecuencia de acceso al centro y a las esquinas del open field disminuyó 24 horas después de la irradiación, mientras que aumentó la duración de la estancia en las esquinas en los ratones RW respecto a los NW. Los parámetros relacionados con ansiedad disminuyeron en ratones RJ respecto a los RW. No se observaron cambios significativos en la ingestión total de alimento y bebida durante los días analizados; sin embargo, en el día de la irradiación disminuyó el número total de episodios ingestivos al tiempo que aumentó el tamaño de los mismos. Estos cambios revirtieron en los animales que bebieron mosto. La ingesta de mosto antes y después de la irradiación puede revertir cambios comportamentales agudos inducidos por la irradiación subletal. El efecto beneficioso sobre la ansiedad y actividad motora a corto plazo podría ser relevante para diseñar intervenciones preventivas encaminadas a incrementar los mecanismos de defensa del cuerpo frente al daño por irradiación a corto plazo.

Characterization of nociceptive behavioural responses in the awake pig following UV-B-induced inflammation.

BACKGROUND: Among the current translational inflammatory pain models, the ultraviolet (UV) irradiation is of rapidly growing interest. The development of primary thermal and mechanical hyperalgesia has been observed in humans and rodents. The pig as a translational animal model might be advantageous due to its great homology with humans. METHODS: The skin in the flank of awake pigs was irradiated by a UV-B light source (1 J/cm(2) ) and changes in thermal and mechanical sensitivity 24 and 48 h following irradiation were measured via assessment of nociceptive behaviours. RESULTS: Thermal sensitivity increased significantly within the inflamed site 24 h after irradiation as indicated by the reduction of latency to respond to thermal stimulation from baseline to 24 h (P < 0.05). At 48 h, the response latency had not decreased any further (P = 0.414). Thermal sensitivity was also higher at the inflamed skin site than at the control site 24 and 48 h following irradiation (P < 0.05). An overall decrease of 50% of the baseline mechanical threshold was observed 24 and 48 h following UV-B irradiation (P = 0.092). Following the inflammatory challenge, the mechanical sensitivity was higher at the site of irradiation compared with the control skin at both 24 and 48 h (P < 0.05). CONCLUSIONS: Our study shows that behavioural recordings are a valid tool for the assessment of thermal hyperalgesia following UV-B inflammation in porcine skin, but they were not capable of providing a clear indication of the development of mechanical hyperalgesia.

Experimental study of radiomodifying properties of N-stearoilethanolamine under a combined impact of ionizing radiation and stress.

OBJECTIVE: to investigate the radiomodifying properties of N-stearoilethanolamine (NSE) in experiment under different conditions of a combined impact of ionizing radiation and stress. METHODS: biochemical, statistical. RESULTS: The radiomodifying properties of N-stearoilethanolamine were revealed under different conditions of a combined impact of ionizing radiation and stress according to the indices of plasma concentrations of TBA-active products, nitrite-anions and catalase activity. CONCLUSIONS: The radioprotective properties of NSE at a dose of 10.0 mg/kg before and after a single total 6.0 Gy irradiation of animals. The radioprotective properties of NSE are identified at a dose of 10.0 mg/kg of animal bodyweight before and after stress. The radiosensitizing properties of NSE occur upon the drug administration in a dose of 10.0 mg/kg before the combined impact of 6.0 Gy ionizing radiation and stress.

Effects of prenatal irradiation on behaviour and hippocampal neurogenesis in adult rats.

Prenatal irradiation is known to have aversive effects on the brain development, manifested in changes in some behavioural parameters in adult individuals. The aim of our work was to assess the effect of prenatal irradiation on different forms of behaviour and on hippocampal neurogenesis in rats. Pregnant female rats were irradiated with a dose of 1 Gy of gamma rays on the 16th day of gravidity. The progeny of irradiated and control animals aged 3 months were tested in Morris water maze (MWM), open field (OF) and in elevated plus maze test (PM). The prenatal irradiation negatively influenced the short-term spatial memory in MWM in female rats, although the long-term memory was not impaired. A statistically significant increase of basic locomotor activity in OF was observed in irradiated rats. The comfort behaviour was not altered. The results of PM showed an increase of anxiety in irradiated females. The level of hippocampal neurogenesis, assessed as the number of cells labelled with 5-bromo-2-deoxyuridine in the area of gyrus dentatus, was not statistically different in irradiated rats. Our results indicate, that prenatal irradiation with a low dose of gamma-rays can affect some innate and learned forms of behaviour in adult rats. We did not confirm a relation of behavioural changes to the changes of hippocampal neurogenesis.

Long-lasting effects of neonatal ionizing radiation exposure on spatial memory and anxiety-like behavior.

Neonatal ionizing radiation exposure has been shown to induce a cerebellar cytoarchitecture disarrangement. Since cerebellar abnormalities have been linked to an impairment of behavioral functions, the aim of the present work was to investigate whether exposure of developing rats to ionizing radiations can produce behavioral deficits in the adult. Male Wistar rats were X-irradiated with 5Gy within 48h after birth and were tested in a radial maze and in an open field at 30 and 90 days post irradiation. Irradiated rats showed significative changes in spatial, exploratory, and procedural parameters in the radial maze, as well as a significative decrease in anxiety-like behavior, assessed in the open field. These results suggest that ionizing radiations can induce long-lasting spatial memory and anxiety-related changes. A relationship with radiation-induced cerebellar cytoarchitecture abnormalities supports the hypothesis that cerebellar integrity seems to be critical to achieve spatial performance and emotional behavior establishment.

Passive avoidance learning and memory of 56Fe sham-irradiated and irradiated human apoE transgenic mice.

Cranial irradiation is associated with long-term cognitive impairments, including deficits in hippocampus-dependent learning and memory. Not all people exposed to cranial radiation develop cognitive injury, suggesting the involvement of genetic risk factors. There may also be sex differences in susceptibility to develop radiation-induced cognitive injury. The three major human apolipoprotein E (apoE) isoforms are encoded by distinct alleles (epsilon2, epsilon3, and epsilon4). Compared with epsilon3, epsilon4 increases the risk of cognitive impairments following various challenges while epsilon2 provides relative protection. Women are at higher risk to develop Alzheimer's disease (AD) than men, particularly those carrying epsilon4. In previous experiments using male and female mice expressing human apoE-isoforms E2, E3 or E4 under the mouse apoE promoter, we showed that cranial irradiation with 137Cs (10 Gy) results in hippocampus-dependent cognitive impairments that are sex- and apoE-isoform dependent. 137Cs is a form of irradiation often used in the clinical setting. To investigate whether 56Fe irradiation also has sex- and apoE-isoform dependent effects on hippocampus-dependent cognitive function in human apoE mice, we sham-irradiated and irradiated 2-month old male and female human apoE mice at 3 Gy and assessed their performance in a passive avoidance learning and memory test three to five months later.

Callosal agenesis and absence of primary visual cortex induced by prenatal X rays impair navigation's strategy and learning in tasks involving visuo-spatial working but not reference memory in mice.

This study was designed for the identification of possible and distinct abilities for behavioral recovery after prenatal cerebral damage. We adopted an interesting tool for promotion of cell's death. Due to the fact that neuroblastic cells and early postmitotic neurons on the beginning of differentiation are particularly sensible for the promotion of apoptosis, we used a low whole-body dose of X radiation on pregnant female mice on E16 (sixteenth gestational day) to promote damage on specific cerebral areas of the progeny, given that the pattern of cerebral neurogenesis is not homogeneous. The morphological results were previously described by our team. Here we noticed that the recovery of behavioral functions after prenatal damage seems to be related to specific factors of local cortical circuitry organization. The deficits found on visual navigation and working memory contrast with the recovery of primary visual functions and also with reference memory, where the mice have a delay on acquisition of learning but get it. As a conclusion we reasoning that changes on laminar organization on frontal cortex as well as the inter hemispheric cortical integration through the corpus callosum could promote relatively fixed cognitive dysfunctions, as those observed on performances that require strategies for navigation (decision making) and working memory, with consequences also observed on the subsequent learning.

Exposure of the rat tail to ultraviolet A light produces sustained hyperalgesia to noxious thermal and mechanical challenges.

We aimed to establish whether exposing the tails of rats to ultraviolet A (UVA) light generated sustained hyperalgesia to noxious thermal and mechanical challenges. The tails of 21 rats underwent eight 40s exposures of UVA light, with 260s between each exposure. As a control procedure, during UVA-light exposure the tails of 11 of those rats were shielded with aluminium foil. Thermal hyperalgesia was assessed by immersing the rat tail in 49 degrees C water (modified tail flick test). Mechanical hyperalgesia was assessed by applying a bar algometer onto the tail and timing the escape response. Exposure to direct UVA light produced hyperalgesia for 8 days to the noxious thermal challenge (P<0.05, two-way ANOVA, Tukey post hoc tests) and at least 16 days to the noxious mechanical challenge (P<0.05, two-way ANOVA, Tukey post hoc tests). They gained mass throughout the study at the same rate as the control rats. The control rats did not develop thermal nor mechanical hyperalgesia. The tails of a further 20 rats were exposed similarly, and tail tissue examined histologically. Both exposed and control rats developed mild chronic inflammation unrelated to the hyperalgesia.

Amaranthus paniculatus (Linn.) improves learning after radiation stress.

Brain is highly susceptible to oxidative damage due to its high utilization of oxygen and rather poorly developed antioxidative defense mechanism. Free radicals formation is greatly augmented during ionizing radiation exposure, which causes damage in cerebellum responsible for locomotor activity. Amaranthus paniculatus (Linn.) having high content of beta-carotene (about 15 mg/100g), ascorbic acid, Vitamin C and folate, may prove efficient antioxidants. To evaluate its antioxidative efficacy, healthy Swiss albino mice from an inbred colony were selected and divided into three groups having equal number of male and female in each group. All of these animals were initially trained in Hebb William's Maze, model D(1). After initial training of 10 days, two groups were supplemented with methanolic extract of A. paniculatus (Linn.) at a dose of 600 and 800 mg/kg bw per day, respectively for 15 days. One group without any treatment served as normal. It has been observed that mice, supplemented with extract took lesser time to reach goal than normal (without any treatment). Furthermore after supplementation of Amaranthus, followed by exposure to 9 Gy of gamma radiation by 60Co beam therapy unit, the survived mice took lesser time to reach to their goals than those without plant extract. Control mice (not supplemented with AE extract) showed continuous decline in their learning performance. Mice of Control group died within 12 days after exposure. Irradiated males try to recover from 10th day onwards but they died up to day 12. But in Experimental mice (AE treated), after initial decline in learning ability after exposure, recovery was noticed and not only this 70% of them survived beyond the observation period. Besides male mice showed faster learning ability as compared to females in all groups. After irradiation too, males took lesser time to reach to goals. Learning in all the groups before exposure has been much faster in between 9 and 15 days. After radiation, however it was followed by a sudden spurt and delayed learning response up to 12 days. Recovery was greater in males than females in treated groups. Recovery was greater in males of 600 mg/kg bw per day than other groups. Learning has been almost at the same level from 14th day onward, which indicates that both the dose levels have been found equally effective.

[The influence of age on radiation-induced cognitive deficit:experimental studies on brain irradiation of 30 gy in 10 sessions and 12 hours in the Wistar rat at 1 1/2, 4 and 18 months age]. / Influence de l'âge sur les troubles cognitifs radio-induits: études expérimentales avec irradiation cérébrale de 30 gy en 10 seances et 12 jours chez le rat Wistar de 1 1/2, 4 et 18 mois.

The objective of this study was to determine the influence of age on the learning and memory dysfunction induced by cranial radiation in the male Wistar rat. Ninety-six 45-day-old, 70 4-month-old, and 78 18-month-old male rats were divided in two equal groups: (i) irradiated and (ii) control. A course of whole-brain radiation therapy (30 Gy in 10 fractions over 12 days) was administered to the irradiated group, while the control group received sham irradiation. Sequential behavioral studies including one and two-way avoidance tests were undertaken before and after the 7 months following radiation. The results suggest that radiation induced progressive and irreversible memory dysfunction in elderly (18-month-old) rats, but this effect was partial or almost reversible in the 4-month-old and 45-day-old rats, respectively. In return, the learning dysfunction was age non-dependent despite the fact that is occurs more rapidly in the young (45 days, 4 months) rats.