The short and long term effects of docetaxel chemotherapy on rodent object recognition and spatial reference memory

Aims

Previous animal studies have examined the potential for cytostatic drugs to induce learning and memory deficits in laboratory animals but, to date, there is no pre-clinical evidence that taxanes have the potential to cause cognitive impairment. Therefore our aim was to explore the short- and long-term cognitive effects of different dosing schedules of the taxane docetaxel (DTX) on laboratory rodents.

Main methods

Healthy male hooded Wistar rats were treated with DTX (6 mg/kg, 10 mg/kg) or physiological saline (control), once a week for 3 weeks (Experiment 1) or once only (10 mg/kg; Experiment 2). Cognitive function was assessed using the novel object recognition (NOR) task and spatial water maze (WM) task 1 to 3 weeks after treatment and again 4 months after treatment.

Key findings

Shortly after DTX treatment, rats perform poorly on NOR regardless of treatment regimen. Treatment with a single injection of 10 mg/kg DTX does not appear to induce sustained deficits in object recognition or peripheral neuropathy.

Significance

Overall these findings show that treatment with the taxane DTX in the absence of cancer and other anti-cancer treatments causes cognitive impairment in healthy rodents.     

Effects of testosterone on spatial learning and memory in adult male rats

A male advantage over females for spatial tasks has been well documented in both humans and rodents, but it remains unclear how the activational effects of testosterone influence spatial ability in males. In a series of experiments, we tested how injections of testosterone influenced the spatial working and reference memory of castrated male rats. In the eight-arm radial maze, testosterone injections (0.500 mg/rat) reduced the number of working memory errors during the early blocks of testing but had no effect on the number of reference memory errors relative to the castrated control group. In a reference memory version of the Morris water maze, injections of a wide range of testosterone doses (0.0625-1.000 mg/rat) reduced path lengths to the hidden platform, indicative of improved spatial learning. This improved learning was independent of testosterone dose, with all treatment groups showing better performance than the castrated control males. Furthermore, this effect was only observed when rats were given testosterone injections starting 7 days prior to water maze testing and not when injections were given only on the testing days. We also observed that certain doses of testosterone (0.250 and 1.000 mg/rat) increased perseverative behavior in a reversal-learning task. Finally, testosterone did not have a clear effect on spatial working memory in the Morris water maze, although intermediate doses seemed to optimize performance. Overall, the results indicate that testosterone can have positive activational effects on spatial learning and memory, but the duration of testosterone replacement and the nature of the spatial task modify these effects.     

Roles of oxytocin in spatial learning and memory in the nucleus basalis of Meynert in rats

The present study was performed to explore the role of oxytocin (OT) in spatial learning and memory in the nucleus basalis of Meynert (NBM) of rats. The latency, distance and swimming path to find the platform were tested by Morris water maze and recorded by a video camera connected to a computer. Intra-NBM injections of 2 or 10 nmol of OT, but not 0.2 nmol of OT, induced significant increase on the latency of spatial learning. Rats receiving intra-NBM administrations of 2 or 10 nmol of OT showed a more random search pattern. There were no significant changes in the swimming speed in Morris water maze test after the injection of OT. Furthermore, the impaired effect of OT on the latency of spatial learning was blocked by intra-NBM injection of the selective OT antagonist Atosiban, indicating that the effect of OT was mediated by OT receptor in the NBM of rats. Moreover, there were no influences of OT or Atosiban on the retention performance in rats. The results suggest that OT plays an inhibitory role in spatial learning in the NBM; the effect is mediated by OT receptor.     

Vasopressin analogues and spatial short-term memory in rats

The effect of vasopressin analogues on short-term memory was tested in the 12-arm radial maze. After the first 6 choices rats (n=6) were removed from the apparatus and allowed to complete the remaining 6 choices 20 min later. Whereas desgly-NH₂-VP, AVP, dAVP and DAVP (3.0 μ/kg) administered 40 min before or immediately after the first 6 choices did not change the incidence of errors in the second series of choices (2.0 errors under control conditions), similarly applied dDAVP deteriorated the rat's performance almost to the chance level of 3 errors. The significance of short-term memory tests for assessing the mnestic role of peptide hormones is stressed.     

The effect of anastrozol on spatial memory in adult rats

Androgens are known to affect cognitive functions via organizational and activational effects. It is unknown whether the effects are mediated via the androgen receptor or after conversion to estradiol with aromatase via estrogen receptors. The aim of our study was to find out whether testosterone affects spatial memory directly or through its metabolite estradiol. Rats were treated with testosterone; with testosterone and the aromatase blocker anastrozole or saline. An 8 radial arm maze was used for testing spatial memory twice daily for 4 days. Each arm was baited with food, and the ability of animals to learn the location of food was assessed. Testosterone treated rats and control rats achieved comparable coefficients of spatial memory, although the plasma levels of testosterone differed markedly. Anastrozole treatment resulted in the worst performance in the maze. The differences between groups did not reach the level of significance. It can be concluded that aromatase and, thus, the conversion of testosterone to estradiol may play a role in spatial memory, as pharmacological blockade of aromatase led to a decrease in maze performace of adult male rats. Detailed molecular mechanisms should be the focus of further studies.     

Effects of genistein in the maternal diet on reproductive development and spatial learning in male rats

Endocrine disruptors, chemicals that disturb the actions of endogenous hormones, have been implicated in birth defects associated with hormone-dependent development. Phytoestrogens are a class of endocrine disruptors found in plants. In the current study we examined the effects of exposure at various perinatal time periods to genistein, a soy phytoestrogen, on reproductive development and learning in male rats. Dams were fed genistein-containing (5 mg/kg feed) food during both gestation and lactation, during gestation only, during lactation only, or during neither period. Measures of reproductive development and body mass were taken in the male offspring during postnatal development, and learning and memory performance was assessed in adulthood. Genistein exposure via the maternal diet decreased body mass in the male offspring of dams fed genistein during both gestation and lactation, during lactation only, but not during gestation only. Genistein decreased anogenital distance when exposure was during both gestation and lactation, but there was no effect when exposure was limited to one of these time periods. Similarly, spatial learning in the Morris water maze was impaired in male rats exposed to genistein during both gestation and lactation, but not in rats exposed during only one of these time periods. There was no effect of genistein on cued or contextual fear conditioning. In summary, the data indicate that exposure to genistein through the maternal diet significantly impacts growth in male offspring if exposure is during lactation. The effects of genistein on reproductive development and spatial learning required exposure throughout the pre- and postnatal periods.     

Effects of pregnancy on spatial cognition in female Hooded Long-Evans rats

Studies examining the roles of estrogens and progestins on spatial cognition have been highly contradictory. To determine if the hormonal environment of pregnancy affects spatial cognition, pregnant (n = 7) and virgin (n = 7) Hooded Long-Evans rats were tested in a Morris water maze throughout the 3 weeks of pregnancy and the second week postpartum. Latency to platform, path length, swim velocity, and time in quadrant were compared over trial-days. To compare water maze performance with changes in hormone levels, serum concentrations of estradiol and progesterone were measured on the first, third, and fifth days of testing during the third week of pregnancy. Subjects learned to find the platform as indicated by decreased time and distance to platform over each trial-week and increased time spent in the quadrant where the platform had been located the previous week. However, there were no differences between treatment groups on time or distance to platform over trial-days. Swim velocity did not differ between or within groups over the 4 weeks of testing. Although primigravid and virgin females were similar in their abilities to learn the novel location of a submerged platform and return to it over time, pregnant animals demonstrated less perseveration to previously learned information and were quicker to locate the platform when it moved to a new location. Thus, reproductive status did not affect reference memory but enhanced working memory in the Morris water maze.     

Increased daily handling of ovariectomized rats enhances performance on a radial-maze task and obscures effects of estradiol replacement

Estrogen impacts performance on tasks of learning and memory, although there are inconsistencies in the direction and magnitude of the reported effects. Contributory factors to the inconsistencies may be methodological differences associated with different regimens of treatment. The goal of the present experiment was to assess the effect of increased handling, such as that commonly associated with pharmacological or other experimental manipulations, on the ability of estrogen to influence working memory performance. Young adult rats were ovariectomized and implanted with capsules containing either cholesterol or 25% estradiol diluted in cholesterol. Half of each hormone treatment group received standard handling, which consisted of handling required to carry out experimental procedures and half received increased handling, which consisted of standard handling as well as 2 min of additional daily handling by the experimenter. Animals were trained daily on a working memory task on an eight-arm radial maze for 24 days of acquisition and for eight additional daily trials in which delays of either 1 min or 3 h were imposed between the fourth and fifth arm choices. Animals that received increased handling exhibited significantly enhanced performance during acquisition and delay trials compared to those that received standard handling. Estradiol significantly enhanced performance during delay trials in animals that received standard handling but had no effect in animals that received increased handling. These results suggest that the amount of handling that animals receive as part of experimental procedures may obscure the memory enhancing effects of estradiol replacement on certain tasks of cognition.     

Phylogeny and oscillating expression of period and cryptochrome in short and long photoperiods suggest a conserved function in Nasonia vitripennis

Photoperiodism, the ability to respond to seasonal varying day length with suitable life history changes, is a common trait in organisms that live in temperate regions. In most studied organisms, the circadian system appears to be the basis for photoperiodic time measurement. In insects this is still controversial: while some data indicate that the circadian system is causally involved in photoperiodism, others suggest that it may have a marginal or indirect role. Resonance experiments in the parasitic wasp Nasonia vitripennis have revealed a circadian component in photoperiodic time measurement compatible with a mechanism of internal coincidence where a two components oscillator system obtains information from dawn and dusk, respectively. The identity of this oscillator (or oscillators) is still unclear but possible candidates are the oscillating molecules of the auto-regulatory feedback loops in the heart of the circadian system. Here, we show for the first time the circadian oscillation of period and cryptochrome mRNAs in the heads of Nasonia females kept under short and long photoperiods. Period and cryptochrome mRNA levels display a synchronous oscillation in all conditions tested and persist, albeit with reduced amplitude, during the first day in constant light as well as constant darkness. More importantly, the signal for the period and cryptochrome oscillations is set by the light-on signal. These results, together with phylogenetic analyses, indicate that Nasonia’s period and cryptochrome display characteristics of homologous genes in other hymenopteran species.     

Effects of suprachiasmatic nuclei lesions on circadian and ultradian rhythms in body temperature in ocular enucleated rats

Abstract

To test the hypothesis that an oscillator located outside the suprachiasmatic nuclei (SCN) controls the circadian rhythm of body temperature, we conducted a study with 14 blinded rats, 10 of which receiving a SCN lesion. Body temperature was automatically and continuously recorded for about one month by intraperitoneal radio transmitters. Food intake, drinking and locomotor activity were also recorded. Periodograms revealed that 3 rats with histologically verified total bilateral SCN lesions did not exhibit any circadian rhythmicity. The 7 other rats appeared to have partial lesions. They showed shortening of period and severe amplitude reduction in all functions. Thus, no support was found for the hypothesis of a separate circadian ‘temperature oscillator’ located outside the SCN. Nevertheless, after large partial lesions body temperature showed more persistency than some of the other behavioral rhythms.

Ultradian rhythms in temperature persisted after partial and total lesions. Other functions showed parallel ultradian rhythms. In intact rats the ultradian peaks were restricted predominantly to the subjective night. After total lesions these peaks became more or less homogeneously distributed in time but more heterogeneously after partial lesions. So the SCN plays a role in the temporal structure of ultradian rhythms but does not generate them. Non‐24‐hour actograms showed instabilities of period and phase of ultradian rhythms. Intact and lesioned rats were similar with respect to the mean (about 3.5 hrs) and standard deviation (about 1.5 hrs) of ultradian periods in temperature. These features indicate that a mechanism outside the SCN is underlying ultradian rhythmicity, capable of generating short‐term oscillations. Two approaches, homeostatic sleep‐wake relaxation oscillations and multiple circadian oscillators, are discussed.     

Effect of intrahippocampal administration of anti-melanin-concentrating hormone on spatial food-seeking behavior in rats

Melanin-concentrating hormone (MCH) is a hypothalamic peptide that plays a critical role in the regulation of food intake and energy metabolism. In this study, we investigated the potential role of dense hippocampal MCH innervation in the spatially oriented food-seeking component of feeding behavior. Rats were trained for eight sessions to seek food buried in an arena using the working memory version of the food-seeking behavior (FSB) task. The testing day involved a bilateral anti-MCH injection into the hippocampal formation followed by two trials. The anti-MCH injection did not interfere with the performance during the first trial on the testing day, which was similar to the training trials. However, during the second testing trial, when no food was presented in the arena, the control subjects exhibited a dramatic increase in the latency to initiate digging. Treatment with an anti-MCH antibody did not interfere with either the food-seeking behavior or the spatial orientation of the subjects, but the increase in the latency to start digging observed in the control subjects was prevented. These results are discussed in terms of a potential MCH-mediated hippocampal role in the integration of the sensory information necessary for decision-making in the pre-ingestive component of feeding behavior.     

Serial conditional discrimination and temporal bisection in rats selectively lesioned in the dentate gyrus

In positive serial conditional discrimination, animals respond during a target stimulus when it is preceded by a feature stimulus, but they do not respond when the same target stimulus is presented alone. Moreover, the feature and target stimuli are separated from each other by an empty interval. The present work aimed to investigate if two durations (4 or 16 s) of the same feature stimulus (light) could modulate the operant responses of rats to different levers (A and B) during a 5-s target stimulus (tone). In the present study, lever A was associated with the 4-s light, and lever B was associated with the 16-s light. A 5-s empty interval was included between the light and the tone. In the same training procedure, the rats were also presented with the 5-s tone without the preceding light stimuli. In these trials, the responses were not reinforced. We evaluated the hippocampal involvement of these behavioral processes by selectively lesioning the dentate gyrus with colchicine. Once trained, the rats were submitted to a test using probe trials without reinforcement. They were presented with intermediate durations of the feature stimulus (light) to obtain a temporal bisection curve recorded during the exposure to the target stimuli. The rats from both groups learned to respond with high rates during tones preceded by light and with low rates during tones presented alone, which indicated acquisition of the serial conditional discrimination. The rats were able to discriminate between the 4- and 16-s lights by correctly choosing lever A or B. In the test, the temporal bisection curves from both experimental groups showed a bisection point at the arithmetic mean between 4 and 16 s. Such processes were not impaired by the dentate gyrus lesion. Thus, our results showed that different durations of a feature stimulus could result in conditional properties. However, this processing did not appear to depend on the dentate gyrus alone.     

Evidence for the influence of testosterone in the performance of spatial navigation in a virtual water maze in women but not in men

Testosterone (T) may be associated with enhanced spatial navigation in a number of rodent species, although the nature of the relation is equivocal. Similarly, numerous studies in humans generally have found that T is associated with enhanced spatial ability on a variety of paper and pencil tasks that may relate to navigational ability. However, relatively few studies have reported effects of T on navigational ability in humans. We investigated the relationship between endogenous T and performance on a virtual water maze (vWM) and mental rotations test (MROT). ELISA for T was performed on salivary samples that were obtained from participants before and after completion of both spatial tasks. Results indicated that women with low T required more time to locate the hidden platform in the vWM than either group of men or women with high T. Significant negative correlations were found for the entire sample between vWM performance and T, and between vWM latency to escape and MROT. Similar significant correlations were found in women but not men. Thus, our data support the position that T improves performance in the vWM in a linear fashion, most strongly in women. However, further work is needed to confirm this hypothesis in humans.     

Daily rhythms of nonshivering thermogenesis in common spiny mice Acomys cahirinus under short and long photoperiods

Daily rhythms of nonshivering thermogenesis NST were studied in common spiny mice Acomys cahirinus, acclimated to different photoperiod regimes (16L:8D and 8L:16D) at a constant ambient temperature of 26°C. Noradrenaline NA (1.5 mg/kg subcutaneous) was injected at: 06:00, 12:00, 18:00 and 24:00 h (±15 min). NST was measured as the ratio between the maximal oxygen consumption (VO₂) as response to NA — VO₂NA and VO₂ measured at 26°C — VO_{2 min}. Rectal temperatures T_bNA and T_{b min} respectively were recorded at the end of VO₂ measurements. Significant variations in T_{b min}, T_bNA, and NST were revealed, under the two different photoperiod regimes. Significant differences in VO_{2 min}, NST, T_{b min} and T_bNA were also recorded within each photoperiod acclimation group. These results suggest that daily and photoperiod depended variations in the brown adipose tissue activity, presumably emerge from amount of unoccupied receptors or changes in the receptors affinity to NA.     

脑心通对急性低压低氧小鼠空间记忆功能及脑水肿的影响

目的:探讨脑心通对急性低压低氧诱发的空间记忆功能损害及脑水肿的预防作用及机制。方法:144只小鼠随机分为6组:即常压常氧组、常压常氧给药组、模拟海拔4km组(4km组)、模拟海拔8km组(8km组)、模拟海拔4km给药组(4km给药组)、模拟海拔8km给药组(8km给药组)。比较各组实验前后及组间的Y型电迷宫测试成绩及脑组织水含量、伊文思兰(EB)含量。结果:各组实验前的Y型电迷宫训练成绩无显著差异,实验后常压常氧组、常压常氧给药组、4km组、4km给药组、8km组和8km给药组,Y型电迷宫测试成绩分别为90.00±6.32、93.33±5.16、56.67±8.16、86.67±8.16、45.00±10.49和85.00±5.48(P<0.01);常压常氧组、常压常氧给药组、4km组、4km给药组、8km组和8km给药组比较,脑组织水含量结果分别为77.79±0.27、77.66±0.23、78.42±0.18、77.81±0.18、79.04±0.33、77.94±0.42,EB含量结果分别为0.44±0.04、0.43±0.02、0.98±0.07、0.46±0.06、1.17±0.07、0.49±0...     

The effects of exogenous testosterone on spatial memory in rats

Testosterone (T) is known to affect spatial abilities in men and women. Studies focusing on this relationship showed that both endogenous variability of T and administration of exogenous T, altered mental rotation and spatial visualization. Organizational and activational effects of T can be separately identified. The aim of our study was to evaluate the activational effects of exogenous T on spatial memory in male and female rats. T was administered 3 times a week over a two week period in either 1 mg/kg for low testosterone group or 10 mg/kg for high testosterone group. The Morris water maze was performed to assess the rat’s working and reference spatial memory. T and estradiol levels were measured in plasma. Increase in plasma T levels was confirmed in the experimental groups in comparison to the control groups (receiving sterile oil, 3 times a week over a two week period). Low dose T impaired working, but improved reference memory in female rats. In male rats the negative effects of T (both doses) on reference memory were shown. This experiment showed that the activational effects of exogenous testosterone on spatial memory of rats were gender and dose-dependent.     

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.     

慢性束缚应激对SD和Wistar大鼠学习记忆能力的影响

目的探讨慢性束缚应激对Wistar、SD两种品系大鼠学习记忆能力的影响,为应激模型中实验动物的选择提供依据。方法对两种品系大鼠(Wistar、SD)采用每天束缚10 h,束缚28 d建立慢性应激模型。采用物体认知新物体识别实验和Morris水迷宫空间学习、工作记忆行为学检测方法,观察束缚应激对两种品系实验动物学习记忆能力的影响。结果束缚28 d后,物体识别实验中,Wistar、SD模型组的辨别指数(discrimination index,DI)均低于对照组,但只有SD两组间差异存在显著性(P0.05);水迷宫空间学习阶段,SD模型组潜伏期高于对照组,第5天差异有显著性(P0.05),而Wistar模型组与对照组间的潜伏期没有差异;水迷宫工作记忆阶段,SD大鼠模型组与正常组比较,潜伏期显著增加(P0.05),Wistar模型大鼠的潜伏期与对照组比较没有显著差异。结论新物体识别实验和水迷宫实验,这两种反应动物不同学习记忆能力的行为学实验结果都表明,慢性束缚应激(10 h,28 d)对SD大鼠学习记忆能力的损伤较Wistar大鼠明显。SD大鼠可能更适合作为慢性应激所致学习记忆损伤动物模型。