Total body 4.5 Gy gamma irradiation-induced early delayed learning and memory dysfunction in the rat.

In an attempt to determine the consequences of total body radiation damage on learning and memory in the rat, twenty-eight male Wistar rats aged 4 months received 4.5 Gy total body gamma-irradiation (TBI) while 28 rats received sham irradiation. Sequential behavioral studies of negative reinforcement including a/ one- and b/ two-way avoidance tasks were undertaken. a/ One-way avoidance test: this test was performed before and after TBI. Prior to irradiation both groups were similar. At 20 days (D) and at 3 months post-TBI, irradiated rats had a significantly lower percentage of avoidance than controls but no statistical difference was found at 5 months post-TBI. b/ Two-way avoidance test: this test was performed only after TBI. At days 21, 22, 23, 24, (leaming) and at 4 or 6 months (recalls) post-TBI the mean percentage of avoidance was significantly lower in irradiated than in control rats. This study demonstrates that total-body exposure to 4.5 Gy gamma-irradiation induces behavioral dysfunction affecting learning and transitorily memory. These results suggest that a relatively low dose of total body irradiation can induce neurological complications, which persist 4-6 months later.     

Antiphlogistic action of phenylbutazone in normal and adrenalectomized rats of different ages relation to the 5-hydroxytryptamine blood concentration.

The authors have attempted to demonstrate the effect of bilateral adrenalectomy on carrageenin-induced oedema and on the antiphlogistic action of phenylbutazone in relation to the changes of blood 5-hydroxtryptamine (5-HT) in rats of different ages (21 days, 42 days, 3 months and 18 months old). It was found that the influence of adrenalectomy on the antiphlogistic action of phenylbutazone and on the blood 5-HT concentration is related to the age of rats. The lowest antiphlogistic action of phenylbutazone was found in 21-day-old rats and highest in the 18-month-old ones. In adrenalectomized 21- and 42-day-old rats the antiphlogistic action is decreased and fully suppressed in rats 3 and 18 months old. Adrenalectomy does not influenced basal values of blood 5-HT concentration. Blood 5-HT in adrenalectomized rats with inflammationadrenalectomized rats 42 days and 3 months old with inflammation after injection of phenylbutazone an increase of 5-HT was observed, but in 18-month-old animals in which antiphlogistic action is highest a decrease of 5-HT was observed.     

Sex- and APOE isoform-dependent effects of radiation on cognitive function

Clinical irradiation of the brain induces hippocampus-dependent cognitive impairments in some but not all individuals, suggesting the involvement of genetic risk factors. Deficiency of apolipoprotein E (APOE), which is important for the metabolism and redistribution of lipoproteins and cholesterol, increases behavioral impairments after irradiation, supporting a protective role for APOE against radiation-induced cognitive injury. Compared to APOE3, APOE4 increases while APOE2 decreases the risk of developing age-related cognitive decline and Alzheimer's disease, particularly in women. To determine the potential effects of APOE isoform and sex on radiation-induced cognitive impairments, we irradiated 2-month-old male and female APOE2, APOE3 and APOE4 mice and assessed their cognitive performance 3 months later. When hippocampus-dependent spatial learning and memory were assessed in the water maze, sham-irradiated female APOE2, APOE3 and APOE4 and irradiated female APOE2 mice showed spatial memory retention, but irradiated female APOE3 and APOE4 mice did not. Compared to sham-irradiated female APOE4 mice, irradiated female APOE4 mice also required more trials to reach criterion in the hippocampus-dependent passive avoidance test. Radiation had no effects on water maze or passive avoidance learning and memory of male APOE2, APOE3 or APOE4 mice, indicating that the effects of radiation on cognitive performance are dependent on sex- and APOE isoform.     

Influence of ethosuximide on metrazol-induced seizures during ontogenesis in rats

Effects of metrazol (pentylenetetrazole and ethosuximide were studied in male albino rats aged 7, 12, 18 and 90 days. The 18-day-old rats exhibited the highest sensitivity to metrazol. CD50s in the remaining three age groups were nearly the same. Ethosuximide was reliably effective against metrazol only in adult rats; in young animals it did not significantly change CD50s. Metrazol induced in ethosuximide-pretreated young rats either modified (long-lasting minimal seizures in 18-day-old animals) or new seizure patterns (minimal seizures in 7- and 12-day-old rats).     

Convulsant action of diphenylhydantoin overdose in young rats

Acute toxicity of diphenylhydantoin (DPH) was studied in 241 male albino rats aged 7, 12, 18, 25 and 90 days. Single intraperitoneal dose of DPH (from 200 to 1000 mg/kg) induced only ataxia and loss of righting reflex in 25-day-old and adult rats. In rats aged 18 days or less ataxia of hindlimbs was also marked. In all these age groups generalized convulsions appeared; they were formed by wild running followed by a clonic phase. The dose of DPH necessary for elicitation of seizures was lowest in 7-day-old rats (75 mg/kg) and increased with age up to 200 mg/kg in 18-day-old rats. The 1000 mg/kg dose was lethal for 25- and 12-day-old rats, but not for 7-day-old ones. The uneven development of excitatory and inhibitory action of DPH is suggested.     

Tetrahydroxystilbene glucoside improves learning and (or) memory ability of aged rats and may be connected to the APP pathway

The aim of this study is to evaluate the protective effects of 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) on learning and (or) memory deficit in aged rats, as well as to explore the possible connection between TSG and the β-amyloid precursor protein (APP) pathway. Sprague-Dawley rats were randomly divided into a young control group (age, 4?months), an aged control group (age, 22?months), and a TSG-treated group (age, 22?months). TSG at doses of 50?mg·kg(-1)·day(-1) was intragastrically administered to 22-month-old rats for 4?weeks. The learning and (or) memory ability was measured using the Morris water maze (MWM) test, and the mRNA and protein expression of APP pathway proteins was measured by real-time polymerase chain reaction (RT-PCR) and Western blot, respectively. The aged rats exhibited obvious learning and (or) memory deficit when compared with the young rats, but TSG treatment significantly improved the learning and (or) memory ability in the aged rats, as noted from the MWM test. RT-PCR and Western blot analysis showed an increase in the expression of beta-site APP cleaving enzyme 1 (BACE1) and A Disintegrin And Metalloproteinase 17 (ADAM17) in aged rats, and a decrease in ADAM10; however, TSG treatment significantly increased the mRNA and protein expression of ADAM10 (p?< 0.01, compared with aged control rats). These results provide solid evidence for the therapeutic effect of TSG on age-related cognitive impairment, especially spatial learning and memory deficit. TSG might exert this effect through the APP pathway, although further studies on the topic are required.     

Postnatal dexamethasone and long term learning and memory functions in developing rats: Effect of postnatal age and gender

In this study, we investigated the effect of dexamethasone on the long-term learning and memory functions in developing rats. In Sprague-Dawley rat pups, we administered a daily dose of dexamethasone (0.5 mg/kg/day) for three consecutive days in three groups of animals: the "ultra-early" group received steroids on postnatal days (PND) 1-3; the "early" group received the drug on PNDs 8-10, and the "late" group received the drug on PNDs 28-30. The control group was not given any medication. All animals underwent structured CNS examinations beginning on PND 15, and continued through PND 20. The pups were tested for spatial learning and memory functions using the Morris Water Maze (MWM) on PNDs 31 through 35, 45 through 49, and 59 through 63. They were also tested for reward-based learning and memory functions using Radial Arm Maze (RAM) on PNDs 70 through 72. We analyzed the effect of dexamethasone, postnatal age, and sex on neurological milestones, and learning and memory functions. We found that neurological examination findings were similar in all groups, as were the results of the reward-based learning using RAM. However, in the MWM, the total distance of swimming and the total time to find the hidden platform showed considerable difference among the groups. Although these functions improved with postnatal age, the female pups in all three steroid groups, and the male pups in the late-steroid group lagged significantly in learning and memory functions compared to the controls, and such lags were transient. However, the interaction terms between dexamethasone, age, and sex were also significant in MWM test results. Steroids administered postnatally may have transient, retarding effect on learning and memory functions, and that animal age and sex may modify such effects. Such lags are not global, but specific to the types of memory tests used, implicating different neural circuitries in the pathogenesis of such abnormalities. Although transient, if such adverse effects occur at critical phases during brain maturation, the implications for poor, long-term outcomes may be more significant. The mechanisms underlying such changes need to be explored.     

Age and hormonal status as determinants of cataractogenesis induced by ionizing radiation. I. Densely ionizing (high-LET) radiation

Astronauts participating in extended lunar missions or the projected mission to Mars would likely be exposed to significant doses of high-linear energy transfer (LET) heavy energetic charged (HZE) particles. Exposure to even relatively low doses of such space radiation may result in a reduced latent period for and an increased incidence of lens opacification. However, the determinants of cataractogenesis induced by densely ionizing radiation have not been clearly elucidated. In the current study, we show that age at the time of exposure is a key determinant of cataractogenesis in rats whose eyes have been exposed to 2 Gy of (56)Fe ions. The rate of progression of cataractogenesis was significantly greater in the irradiated eyes of 1-year-old rats compared to young (56-day-old) rats. Furthermore, older ovariectomized rats that received exogenous estrogen treatment (17-β-estradiol) commencing 1 week prior to irradiation and continuing throughout the period of observation of up to approximately 600 days after irradiation showed an increased incidence of cataracts and faster progression of opacification compared to intact rats with endogenous estrogen or ovariectomized rats. The same potentiating effect (higher incidence, reduced latent period) was observed for irradiated eyes of young rats. Modulation of estrogen status in the 1-year-old animals (e.g., removal of estrogen by ovariectomy or continuous exposure to estrogen) did not increase the latent period or reduce the incidence to that of intact 56-day-old rats. Since the rapid onset and progression of cataracts in 1-year-old compared to 56-day-old rats was independent of estrogen status, we conclude that estrogen cannot account for the age-dependent differences in cataractogenesis induced by high-LET radiation.     

Geropsychotropic properties of an antioxidant of the 3-hydroxypyridine class in an experiment

Comparative experimental investigation of albino male rats 3 and 16 months old has been performed. 16-month-old rats demonstrated age-dependent functional insufficiency in some behavioural tests. 2 month injection of 3-hydroxypyridine antioxidant (50 mg/kg/day) normalized memory function, motor skill learning and motor coordination function in 16-month-old rats.     

Effect of sex and age on serum aldosterone and thyroid hormones in the laboratory rat

Serum levels of aldosterone, tri-iodo thyronine (T3) and thyroxine (T4) were measured in male and female rats aged 3 months, 12 months, and 18 months. Female rats were found to have higher aldosterone and T3 levels, and lower T4 level than the male. No age-related change was observed in serum aldosterone in either sex. In contrast, serum T4 were found to decrease with age in both sexes while serum T3 showed an age-associated diminution in the male only. Serum testosterone was also measured in the male rats and was found to decline with age.     

Auditory brainstem responses in aging dark agouti rats

The present study examined auditory function across age in the dark agouti (DA) rat strain. Auditory brainstem responses (ABRs) were measured for frequencies 8, 16, and 32 kHz in male and female DA rats from 3 to 18 months of age. Hearing thresholds and absolute and interpeak latencies (IPLs) were analyzed. Male hearing thresholds remained stable for the first year of life and then significantly increased at 18 months across all frequencies; female hearing remained stable at all tested ages out to 18 months. At 12 months, male DA rats showed significantly longer absolute latencies by age (i.e., compared with 3-month-old males) and sex (compared with 12-month-old females), with no differences in IPLs. At 18 months, female DA rats showed significantly longer absolute latencies with age (compared with 3-month-old females) and sex (compared with 18-month-old males), particularly for the later waves. Female IPLs were also significantly longer with age and by sex for the later waves. This report supports the feasibility of using male DA rats in studies to investigate age-related hearing loss (ARHL; presbycusis).     

Dose dependent effects of oxytocin on cognitive defects and anxiety disorders in adult rats following acute infantile maternal deprivation stress

ABSTRACT

Maternal deprivation at an early age is a powerful stressor that causes permanent alterations in cognitive and behavioral functions during the later stages of life. We investigated the effects of oxytocin on cognitive defects and anxiety disorders caused by acute infantile maternal deprivation in adult rats. We used 18-day-old Wistar albino rats of both sexes. The experimental groups included control (C), maternally deprived (MD), maternally deprived and treated with 0.02 μg/kg oxytocin (MD-0.02 µg/kg oxy), maternally deprived and treated with 2 μg/kg oxytocin (MD-2 µg/kg oxy). When the rats were 60 days old, the open field (OF) and elevated plus maze (EPM) behavioral tests, and the Morris water maze (MWM) test for spatial learning and memory were performed. In addition, the number of neurons in the hippocampus, prefrontal cortex (PFC) and amygdala were determined using quantitative histology. We also measured vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) levels in the PFC. In both sexes, the MD group failed the learning test and the MD-2 μg/kg oxy group failed in the memory test. The MD-0.02 μg/kg oxy group spent more time in the open arm of the EPM device and their locomotor activities were greater in the OF test. The VEGF and BDNF levels in the PFC were higher in the MD-0.02 μg/kg oxy groups than the other maternally deprived groups (oxytocin ±). The number of PFC neurons was low in all male maternally deprived (oxytocin ±) groups, while the number of amygdala neurons was low in both female and male maternally deprived (oxytocin ±) groups. Male rats were more affected by maternal deprivation; administration of oxytocin had dose-dependent biphasic effects on learning, memory and anxiety.     

Ionizing radiation-induced mutant frequencies increase transiently in male germ cells of older mice

Spontaneous mutant frequency in the male germline increases with age, thereby increasing the risk of siring offspring with genetic disorders. In the present study we investigated the effect of age on ionizing radiation-induced male germline mutagenesis. lacI transgenic mice were treated with ionizing radiation at 4-, 15- and 26-month-old, and mutant frequencies were determined for pachytene spermatocytes and round spermatids at 15 days or 49 days after ionizing radiation treatment. Cells collected 15 days after treatment were derivatives of irradiated differentiating spermatogenic cells while cells collected 49 days later were derivatives of spermatogonial stem cells. The results showed that (1) spontaneous mutant frequency increased in spermatogenic cells recovered from nonirradiated old mice (26-months-old), particularly in the round spermatids; (2) mutant frequencies were significantly increased in round spermatids obtained from middle-aged mice (15-months-old) and old age mice (26-months-old) at 15 and 49 days after irradiation compared to the sham-treated old mice; and (3) pachytene spermatocytes obtained from 15- or 26-month-old mice displayed a significantly increased mutant frequency at 15 days post irradiation. This study indicates that age modulates the mutagenic response to ionizing radiation in the male germline.     

Age dependence of somatostatin levels and somatostatin binding in the rat brain

1. Somatostatin-like immunoreactivity (SLI) and 125I-Tyrl-somatostatin binding were measured from the brains of rats aged 1, 8 and 18 months. 2. Somatostatin binding was reduced in the striatum, frontal cortex, hypothalamus and hippocampus of the 8-month-old rats compared to the 1-month-old group. 3. Somatostatin binding was reduced in the striatum, frontal cortex and hippocampus of the 18-month-old rats compared to the 1-month-old group. 4. The reduction (40%) was most striking in the frontal cortex. 5. In no area of the brain did changes in SLI differ significantly between the different age groups.     

Effect of K,MG aspartate on some biological parameters of aging rats

The effect of K and Mg salts of aspartic acid (Cardilan) on the serum concentration of selected proteins and phagocytic activity in aging male Wistar rats was investigated. Cardilan was administered in tap water for 7 days a month for 3 months before the last observed interval (12, 18 and 24 month). In a part of animals, the aging process was accelerated by sublethally gamma-irradiation. The administration of Cardilan slowed down the changes in the concentration of prealbumin, albumin, haptoglobin, haemopexin, C3 complement in non-irradiated rats (DC). This effect was extended to the changes in transferrin level in irradiated rats (IDC). The phagocytic activity in both DC, IDC rats was lower compared with controls drinking water (DW, IDW), but not significantly. The effect of Cardilan administration appears to be the greatest in 24-month-old rats, when the treated animals survived better by 25% in IDC group and by 26% better in DC rats, compared with those of the same age controls. Potassium and magnesium salts of aspartates are suitable compounds for life prolongation in the experimental conditions.     

Effect of nonionizing radiation on the purkinje cells of the rat cerebellum

In one experiment, Sprague Dawley rats (16–21 days of gestation) and their offspring were exposed to 100-MHz (CW) electromagnetic radiation at 46 mW/cm² (SAR 2.77 mW/g) for 4 h/day for 97 days. In another experiment, the pregnant rats were irradiated daily from 17 to 21 days of gestation with 2450-MHz (CW) microwaves at 10 mW/cm² (SAR 2 mW/g) for 21 h/day. In a third experiment, 6-day-old rat pups were irradiated 7 h/day for five days with 2450-MHz radiation at 10 mW/cm². Equal numbers of animals were sham irradiated in each group. Quantitative studies of Purkinje cells showed a significant and irreversible decrease in rats irradiated during fetal or fetal and early postnatal life. In animals exposed postnatally, and euthanized immediately after irradiation, significant decrease in the relative number of Purkinje cells was apparent. However, restoration apparently occurred after forty days of recovery.     

Low (20 cGy) doses of 1 GeV/u (56)Fe--particle radiation lead to a persistent reduction in the spatial learning ability of rats

Exposure to galactic cosmic radiation (GCR) is considered to be a potential health risk in long-term space travel, and it represents a significant risk to the central nervous system (CNS). The most harmful component of GCR is the HZE [high-mass, highly charged (Z), high-energy] particles, e.g. (56)Fe. In previous ground-based experiments, exposure to high doses of HZE-particle radiation induced pronounced deficits in hippocampus-dependent learning and memory in rodents. Recent data suggest that glutamatergic transmission in hippocampal synaptosomes is impaired after low (60 cGy) doses of 1 GeV/u (56)Fe particles, which could lead to impairment of hippocampus-dependent spatial memory. To assess the effects of mission-relevant (20-60 cGy) doses of 1 GeV/u (56)Fe particles on hippocampus-dependent spatial memory, male Wistar rats either received sham treatment or were irradiated and tested 3 months later in the Barnes maze test. Compared to the controls, rats that received 20, 40 and 60 cGy 1 GeV/u (56)Fe particles showed significant impairments in their ability to locate the escape box in the Barnes maze, which was manifested by progressively increasing escape latency times over the 3 days of testing. However, this increase was not due to a lack of motivation of the rats to escape, because the total number of head pokes (and especially incorrect head pokes) remained constant over the test period. Given that rats exposed to X rays did not exhibit spatial memory impairments until >10 Gy was delivered, the RBE for 1 GeV/u (56)Fe-particle-induced hippocampal spatial memory impairment is ～50. These data demonstrate that mission-relevant doses of 1 GeV/u (56)Fe particles can result in severe deficits in hippocampus-dependent neurocognitive tasks, and the extreme sensitivity of these processes to 1 GeV/u (56)Fe particles must arise due to the perturbation of multiple processes in addition to killing neuronal cells.     

Acquisition of avoidance reaction in rats with different social experience in youth

The acquisition of both active and passive avoidance response, the extinction of the former and the retention of the long-term memory trace of the latter were studied in 30- and 90-day-old male rats of the Wistar strain. The rats were in 3 groups which had had a different history between 15 and 30 days of age: (1) normally weaned rats lived from birth in a cage together with mother and siblings, i.e. under usual laboratory breeding conditions; (2) prematurely weaned rats lived under the same conditions for the first 15 days; after this period, their mother was removed from the cage; (3) community-reared rats had the same history up to 15 days of age; then they began to live in a community (5 connected cages) in contact with both young and adult rats from other cages. Ninety- day-old male rats acquired an active avoidance response at the same rate irrespective of their history in youth but 30-day-old rats were relatively slower if they had been prematurely weaned. Among both normally and prematurely weaned 30-day-old rats, the extinction was slower than in community-reared rats of the same age. Passive avoidance response was acquired by all rats at the same rate irrespective of their history and age. The long- term memory trace was always more stable in adult rats than in young ones.     

Radiation-induced and transposon-induced chromosome damage in Drosophila: translocations and transmission distortion

The possible interaction between X-ray- and transposon-induced chromosome damage was monitored in the P-M system of hybrid dysgenesis in Drosophila melanogaster. One- to two-day-old F1 dysgenic males originating from a cross between M strain females and P strain males were irradiated with 5.5 Gy (550 rad) or used as controls to monitor X-Y translocations and transmission ratio distortion. Two 3-day sperm broods were sampled for the former and two 4-day broods for the latter to detect damage induced in the most radiosensitive cells. F1 nondysgenic males derived from M female to M male crosses (controls) were treated identically. X-Y chromosome translocations induced by P element mobility alone declined sharply with a decrease in temperature (18 versus 21 degrees C) and they were significantly reduced with aging of hybrid males from brood 2, 4-8 days of age, to brood 3, 7-11 days of age. No significant increase in translocations was observed when X irradiation and P-M dysgenesis were combined, showing no interaction between damages induced by the two mutator systems. In contrast, interaction was observed in transmission ratio distortion which was significantly increased by X irradiation of hybrid males derived from both reciprocal M X P and P x M crosses. The preferential elimination of P element-bearing autosomes occurred when either spermatocytes or spermatids were irradiated. An aging effect was also observed, resulting in less distortion in 9- to 14-day-old dysgenic males compared to 5- to 10-day-old hybrids.     

Role of age at the moment of irradiation on the induction of tumors

The probability that rats develop tumours following a 3 Gy exposure to gamma rays from cobalt 60 was observed to depend on age at exposure. Lifetime excess of neoplasia decreased by a factor of about 10 in 9-month-old rats as compared to animals irradiated in utero. The 3-month age group developed slightly fewer tumours than the group irradiated in utero, and tumour location was different. The higher incidence of tumours observed in the foetal group was mainly due to the high sensitivities of central nervous system and gonads during organogenesis.