The effects of pregnancy,lactation, and primiparity on object-in-place memory of female rats

Maternal physiology and behavior change dramatically over the course of pregnancy to nurture the fetus and prepare for motherhood. Further, the experience of motherhood itself continues to influence brain functioning well after birth, shaping behavior to promote the survival of offspring. To meet these goals, cognitive abilities, such as spatial memory and navigation, may be enhanced to facilitate foraging behavior. Existing studies on pregnant and maternal rats demonstrate enhanced cognitive function in specific spatial domains. We adopted a novel object-in-place task to assess the ability of female rats to integrate information about specific objects in specific locations, a critical element of foraging behavior. Using a longitudinal design to study changes in spatial memory across pregnancy and motherhood, an advantage in the object-in-place memory of primiparous female rats compared to nulliparous females emerged during lactation not during pregnancy, and was maintained after weaning at 42 days postpartum. This enhancement was not dependent on the non-mnemonic variables of anxiety or neophobia. Parity did not affect the type of learning strategy used by females to locate a cued escape platform on a dual-solution water maze task. Results indicate that the enhancement of object-in-place memory, a cognitive function that facilitates foraging, emerged after pregnancy during the postpartum period of lactation and persisted for several weeks after weaning of offspring.     

Testosterone modulates performance on a spatial working memory task in male rats

Gonadal hormones have been shown to modulate memory retention in female rats. The current experiments examine the role of testicular hormones in modulating the performance of male rats on two spatial water maze tasks. In the first study, castrated and intact rats were trained on the visible platform and hidden platform versions of the Morris water maze task. Castration did not affect performance on either version of this reference memory task with castrated and intact rats demonstrating similar performance both during acquisition and on post-training probe trials. In the second experiment, castrated and intact rats were tested on a delayed-matching-to-place version of the water maze. Rats received a series of trial pairs in the maze with a hidden platform located in the same pool location on the exposure and retention trials of each pair; between pairs of trials, however, the platform was repositioned to a novel pool location. The interval between trials was either 10- or 60-min and memory retention, taken as the difference between the pathlengths on the exposure and retention trials, declined as the interval increased. Relative to intact males, castrated males demonstrated impaired working memory retention at 60-min but not at 10-min retention intervals. This interval-dependent impairment in working memory retention was reversed by physiologic levels of testosterone replacement. These findings indicate that castration does not significantly affect acquisition or probe trial performance on a classic reference memory task but does impair spatial working memory retention, an effect that is reversed by exogenous testosterone.     

Effects of multiparity on recognition memory, monoaminergic neurotransmitters, and brain-derived neurotrophic factor (BDNF)

Recognition memory and anxiety were examined in nulliparous (NP: 0 litters) and multiparous (MP: 5-6 litters) middle-aged female rats (12 months old) to assess possible enduring effects of multiparity at least 3 months after the last litter was weaned. MP females performed significantly better than NP females on the non-spatial memory task, object recognition, and the spatial memory task, object placement. Anxiety as measured on the elevated plus maze did not differ between groups. Monoaminergic activity and levels were measured in prefrontal cortex, CA1 hippocampus, CA3 hippocampus, and olfactory bulb (OB). NP and MP females differed in monoamine concentrations in the OB only, with MP females having significantly greater concentrations of dopamine and metabolite DOPAC, norepinephrine and metabolite MHPG, and the serotonin metabolite 5-HIAA, as compared to NP females. These results indicate a long-term change in OB neurochemistry as a result of multiparity. Brain-derived neurotrophic factor (BDNF) was also measured in hippocampus (CA1, CA3, dentate gyrus) and septum. MP females had higher BDNF levels in both CA1 and septum; as these regions are implicated in memory performance, elevated BDNF may underlie the observed memory task differences. Thus, MP females (experiencing multiple bouts of pregnancy, birth, and pup rearing during the first year of life) displayed enhanced memory task performance but equal anxiety responses, as compared to NP females. These results are consistent with previous studies showing long-term changes in behavioral function in MP, as compared to NP, rats and suggest that alterations in monoamines and a neurotrophin, BDNF, may contribute to the observed behavioral changes.     

Human chorionic gonadotropin (a luteinizing hormone homologue) decreases spatial memory and increases brain amyloid-beta levels in female rats

Numerous studies have suggested that estradiol (E) improves spatial memory as female rats with E perform better than those without E. However there is an inverse relationship between E and luteinizing hormone (LH) levels and LH could play a role. We examined whether treatment with the LH homologue human chorionic gonadotropin (hCG), would impair spatial memory of adult E-treated female rats. In the object location memory task, ovariectomized (ovxed) rats treated with E and either a single high dose (400 IU/kg) or a lower repeated dose of hCG (75 IU/kg hourly for 8 h) showed spatial memory disruption compared to ovxed rats treated with estradiol alone. Impairment was attributed to memory disruption as performance improved with shortened delay between task exposure and testing. Tests on another spatial memory task, the Barnes maze, confirmed that hCG (400 IU/kg) can impair memory: although E + veh treated animals made significantly fewer hole errors across time, E + hCG-treated did not. In humans, high LH levels have been correlated with Alzheimer's disease (AD). Because brain amyloid-beta (Aβ) species have been implicated as a toxic factor thought to cause memory loss in AD, we analyzed whether hCG-treated animals had increased Aβ levels. Levels of Aβ from whole brains or hippocampi were assessed by Western blot. hCG treatment to E-implanted females significantly increased soluble Aβ40 and Aβ42 levels. These results indicate that high levels of LH/hCG can impair spatial memory, and an increase in brain Aβ species may account for the memory impairment in hCG-treated rats.     

Differential effects of acute progesterone administration on spatial and object memory in middle-aged and aged female C57BL/6 mice

The present study examined the effects of acute progesterone administration on hippocampal-dependent memory consolidation in ovariectomized middle-aged (16 months old) and aged (22 months old) female mice. Spatial memory was tested in a 2-day Morris water-maze task and object memory was tested using an object recognition task with 24- and 48-h delays. Immediately after water-maze training, mice received i.p. injections of vehicle, or 5.0, 10.0, or 20.0 mg/kg of water-soluble progesterone. Twenty-four hours later, retention of the platform location was tested. No overnight forgetting of the platform location was observed in middle-aged vehicle-treated mice. Acute progesterone administration had no effect on spatial memory in middle-aged mice. However, aged vehicle-treated mice demonstrated impaired memory for the platform location on Day 2 relative to Day 1. Twenty mg/kg, but not 5 or 10 mg/kg, progesterone reversed these deficits, suggesting that 20 mg/kg progesterone can improve spatial memory in aged females. In the object recognition task, mice explored two identical objects and then immediately received vehicle or progesterone injections. In middle-aged mice, 10 and 20 mg/kg progesterone enhanced object memory consolidation, relative to chance, after 24-h, but all doses were ineffective after 48-h. In aged mice, 10 mg/kg progesterone enhanced object memory consolidation, relative to chance, after 24 h, whereas both 5 and 10 mg/kg progesterone enhanced memory after 48 h. Together, these results indicate that acute progesterone differentially enhances hippocampal-dependent memory in middle-aged and aged females.     

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.     

The effect of different stages of the sex cycle on rat behavior in a plus maze

Anxiety and motor activity of female white rats in the elevated plus-maze were studied at different stages of the reproduction cycle (estrus, diestrus, pregnancy and lactation). The level of anxiety was lower, and that of locomotor and exploratory activity was higher during estrus and lactation than during diestrus and pregnancy. Exposure to chronic pain of threshold intensity did not induce behavioral changes in pregnant rats. There was no difference between the control and experimental animals in the level of plasma corticosterone.     

The role of spatial and temporal information in learning interval time-place tasks

In time-place learning (TPL) paradigms animals are thought to form tripartite memory codes consisting of the spatiotemporal characteristics of biologically significant events. In Phase I, rats were trained on a modified TPL task in which either the spatial or temporal component was constant, while the other component varied randomly. If the memory codes are tripartite then when one aspect of the code is random the rats should have difficulty learning the constant aspect of the code. However, rats that were trained with a fixed spatial sequence of food availability and a random duration did in fact learn the task. Rats that were trained with a fixed duration and a random sequence did not learn the task. In Phase II all rats were placed on a TPL task in which food availability was contingent upon both spatial and temporal information. According to the tripartite theory, prior knowledge of either aspect of the code should have little effect on the acquisition of the task. The rats that received fixed spatial training learned the task relatively more quickly. The use of bipartite, rather than tripartite codes, is better able to explain the results of the current study.     

Sex Differences in Long-Term Potentiation at Temporoammonic-CA1 Synapses: Potential Implications for Memory Consolidation

Sex differences in spatial memory have long been observed in humans, non-human primates and rodents, but the underlying cellular and molecular mechanisms responsible for these differences remain obscure. In the present study we found that adolescent male rats outperformed female rats in 7 d and 28 d retention probes, but not in learning trials and immediate probes, in the Morris water maze task. Male rats also had larger long-term potentiation (LTP) at hippocampal temproammonic-CA1 (TA-CA1) synapses, which have been implicated to play a key role in place field and memory consolidation, when protocols designed to elicit late-stage LTP (LLTP) were used. Interestingly, the ratio of evoked AMPA/NMDA currents was found to be smaller at TA-CA1 synapses in male rats compared to female rats. Protein biotinylation experiments showed that male rats expressed more surface GluN1 receptors in hippocampal CA1 stratum lacunosum-moleculare (SLM) than female rats, although GluA1 expression was also slightly higher in male rats. Taken together, our results suggest that differences in the expression of AMPA and NMDA receptors may affect LTP expression at TA-CA1 synapses in adolescent male and female rats, and thus possibly contribute to the observed sex difference in spatial memory.     

The Effect of Severe Zinc Deficiency and Zinc Supplement on Spatial Learning and Memory

Zinc deficiency during pregnancy and during lactation has been shown to impair cognitive function and motor activity in offspring rats. In the present study, the effect of zinc deficiency and zinc supplement on spatial learning and memory in Morris Water Maze (MWM) and motor activity in open field were investigated. Pregnant rats after mating were divided to three groups. Control group fed a standard diet and a zinc deficient (ZnD) group fed a diet deficient in zinc (0.5–1.5 ppm) and a zinc supplement (ZnS) group fed a standard diet and enhanced zinc in the drinking water (10 ppm). All the diets were exposed during the last trisemester of pregnancy and during lactation. Rat’s offspring in these groups were tested for spatial learning and memory in MWM at post natal day (PND) 56 and were tested for motor activity in open field at PND 66.The Escape Latency (EL) and Traveled Distance (TD) in the ZnD group were increased but Percentage of Time Spent in the target quadrant (PTS) was decreased compared to the control group. In addition, these were no significant differences in EL and TD, but PTS had significant increase in ZnS compared to the control group. In the open field, Total Distance Moved (TDM) and Time of Motor Activity (TMA) for the ZnD were decreased compared to the control group, but there were no significant differences in TDM and TMA between control and ZnS groups. These findings suggest that zinc deficiency during the last trimester of pregnancy and during lactation impaired spatial learning and memory in their offsprings and has also negative effect on motor activity. In addition, ZnS has a significant effect on spatial learning and memory but no effect on motor activity in their offsprings.     

两种不同训练时程方法对海马损伤大鼠水迷宫成绩的影响

为探讨训练时程对大鼠水迷宫成绩的影响,采用直流电解法建立双侧背侧海马损伤大鼠模型,并通过5d(5dtraining)和7d训练(7dtraining)两种不同时程法检测海马损伤大鼠的空间学习记忆能力。结果表明,两种训练法均反映大鼠空间学习能力减退,而在检测空间记忆障碍时则略有不同。与5d训练法相比,7d训练法不仅显示大鼠穿台次数下降,且其在目标象限中的停留时间百分比亦下降。     

Spatial learning and memory deficits induced by exposure to iron-56-particle radiation

It has previously been shown that exposing rats to particles of high energy and charge (HZE) disrupts the functioning of the dopaminergic system and behaviors mediated by this system, such as motor performance and an amphetamine-induced conditioned taste aversion; these adverse behavioral and neuronal effects are similar to those seen in aged animals. Because cognition declines with age, spatial learning and memory were assessed in the Morris water maze 1 month after whole-body irradiation with 1.5 Gy of 1 GeV/nucleon high-energy (56)Fe particles, to test the cognitive behavioral consequences of radiation exposure. Irradiated rats demonstrated cognitive impairment compared to the control group as seen in their increased latencies to find the hidden platform, particularly on the reversal day when the platform was moved to the opposite quadrant. Also, the irradiated group used nonspatial strategies during the probe trials (swim with no platform), i.e. less time spent in the platform quadrant, fewer crossings of and less time spent in the previous platform location, and longer latencies to the previous platform location. These findings are similar to those seen in aged rats, suggesting that an increased release of reactive oxygen species may be responsible for the induction of radiation- and age-related cognitive deficits. If these decrements in behavior also occur in humans, they may impair the ability of astronauts to perform critical tasks during long-term space travel beyond the magnetosphere.     

A partial agonist at strychnine-insensitive glycine sites facilitates spatial learning in aged rats.

1-Aminocyclopropanecarboxylic acid (ACPC) is a high affinity ligand at strychnine-insensitive glycine sites of the N-methyl-D-aspartate (NMDA) channels and exhibits partial agonist properties in both biochemical and electrophysiological measures. While ACPC was reported active in animal models used to evaluate potential antidepressants and anxiolytics, its effects on learning and memory are unknown. In the present study we investigated the effects of ACPC on spatial learning in the Morris water maze. On a schedule of 12 learning trials, one trial per day, mature male Wistar rats (3 months of age) rapidly acquired the task. Electroconvulsive shocks applied after each of the learning trials markedly inhibited the consolidation of spatial memory. Administration of either a muscarinic agonist, arecoline (1 mg/kg) or ACPC (250 or 400 mg/kg) 20 min before each of the learning trials did not affect the acquisition of spatial learning. Aged (16 months old) male Wistar rats demonstrated difficulties in the acquisition of spatial learning task. In these subjects, ACPC administered 20 min before each of the learning trials at a dose of 400, but not 250 mg/kg, facilitated the acquisition of spatial memory as indicated on trials 3-5. ACPC did not affect the strength of spatial memory as assessed at the end of conditioning, by measuring swimming behavior of rats in the pool with platform removed. It is suggested that ACPC may alleviate learning deficits observed in the elderly.     

Transgenic expression of androgen receptors improves spatial memory retention in both sham-irradiated and 137Cs gamma-irradiated female mice

Using a water maze, it has been shown that both wild-type and apoE4-expressing female mice are at greater risk of developing age-related hippocampal-dependent impairments in spatial learning and memory than age-matched male mice of the same genotype. In addition, apoE4-expressing female mice were more sensitive to 137Cs gamma-radiation-induced impairment in spatial learning and memory than age-matched male mice of the same genotype. These findings imply that androgen receptors (ARs) contribute to spatial learning and memory, posing the question as to whether transgenic expression of AR in female mice might modulate hippocampal-dependent learning and memory under baseline conditions and after local brain irradiation. Hippocampal-dependent novel location recognition was comparable in wild-type and AR-Tg female mice. This function was impaired after irradiation in AR-Tg but not wild-type mice. In contrast, sham-irradiated wild-type and AR-Tg female mice showed hippocampal-independent novel location recognition, and this was not affected by radiation. After the second day of hidden platform training, in a water maze probe trial, sham-irradiated and irradiated AR-Tg female mice showed spatial memory retention but irradiated wild-type mice did not. After the third day of hidden platform training, only irradiated wild-type female mice did not show spatial memory retention in the water maze probe trial. Both sham-irradiated and irradiated wild-type and AR-Tg female mice showed passive avoidance learning and memory. These data support an important role for AR in spatial memory retention in water maze probe trials in female mice under baseline conditions and after cranial irradiation.     

Estradiol does not influence strategy choice but place strategy choice is associated with increased cell proliferation in the hippocampus of female rats

Adult neurogenesis occurs in the hippocampus of most mammals. While the function of adult hippocampal neurogenesis is not known, there is a relationship between neurogenesis and hippocampus-dependent learning and memory. Ovarian hormones can influence learning and memory and strategy choice. In competitive memory tasks, higher levels of estradiol shift female rats towards the use of the place strategy. Previous studies using a cue-competition paradigm find that 36% of male rats will use a hippocampus-dependent place strategy and place strategy users had lower levels of cell proliferation in the hippocampus. Here, we used the same paradigm to test whether endogenous or exogenous ovarian hormones influence strategy choice in the cue-competition paradigm and whether cell proliferation was related to strategy choice. We tested ovariectomized estradiol-treated (10 μg of estradiol benzoate) or sham-operated female rats on alternating blocks of hippocampus-dependent and hippocampus-independent versions of the Morris water task. Rats were then given a probe session with the platform visible and in a novel location. Preferred strategy was classified as place strategy (hippocampus-dependent) if they swam to the old platform location or cue strategy (hippocampus-independent) if they swam to the visible platform. All groups showed a preference for the cue strategy. However, proestrous rats were more likely to be place strategy users than rats not in proestrus. Female place strategy users had increased cell proliferation in the dentate gyrus compared to cue strategy users. Our study suggests that 78% of female rats chose the cue strategy instead of the place strategy. In summary the present results suggest that estradiol does not shift strategy use in this paradigm and that cell proliferation is related to strategy use with greater cell proliferation seen in place strategy users in female rats.     

Hippocampal Sharp Wave/Ripples during Sleep for Consolidation of Associative Memory

The beneficial effect of sleep on memory has been well-established by extensive research on humans, but the neurophysiological mechanisms remain a matter of speculation. This study addresses the hypothesis that the fast oscillations known as ripples recorded in the CA1 region of the hippocampus during slow wave sleep (SWS) may provide a physiological substrate for long term memory consolidation. We trained rats in a spatial discrimination task to retrieve palatable reward in three fixed locations. Hippocampal local field potentials and cortical EEG were recorded for 2 h after each daily training session. There was an increase in ripple density during SWS after early training sessions, in both trained rats and in rats randomly rewarded for exploring the maze. In rats learning the place -reward association, there was a striking further significant increase in ripple density correlated with subsequent improvements in behavioral performance as the rat learned the spatial discrimination aspect of the task. The results corroborate others showing an experience-dependent increase in ripple activity and associated ensemble replay after exploratory activity, but in addition, for the first time, reveal a clear further increase in ripple activity related to associative learning based on spatial discrimination.     

Disorders in memory and learning in offspring of alcoholized female rats,and a possibility for correction of these changes

We studied the effect of alcohol intoxication of albino female rats on the process of learning and memory of their adult (two-month-old) offspring and also a possibility for correction of the observed changes using dolivin. During pregnancy and lactation, female rat of the experimental group obtained 15% solution of ethanol instead of water. To estimate the successfulness of spatial learning of their offspring, we used a multiway elevated labyrinth; the level of consolidation of memory traces was estimated using a passive avoidance test in a chamber with dark and illuminated sections. In the tested offspring rats, prenatal exposure to ethanol induced dramatic drops in the indices of both the above tests. The use of dolivin simultaneously with ethanol exposure allowed us to demonstrate the clear protective properties of this complex preparation containing such antioxidants as hypoxen and vitamin E: disorders in behavior of the offspring of alcoholized females were smoothed significantly. Neirofiziologiya/Neurophysiology, Vol. 40, No. 2, pp. 130–136, March–April, 2008.     

Acute pretreatment with estradiol protects against CA1 cell loss and spatial learning impairments resulting from transient global ischemia

Estradiol can act to protect against hippocampal damage resulting from transient global ischemia, but little is known about the functional consequences of such neuroprotection. The present study examines whether acute estradiol administered prior to the induction of transient global ischemia protects against hippocampal cell death and deficits in performance on a spatial learning task. Ovariectomized female rats were primed with estradiol benzoate or oil vehicle 48 and 24 h prior to experiencing one of three durations of 4-vessel occlusion (0, 5, or 10 min). Performance on the cued and hidden platform versions of the Morris water maze was assessed 1 week following ischemia. On the cued platform task, neither hormone treatment nor ischemia significantly influenced acquisition. When tested on the hidden platform task, however, oil-treated rats exhibited impairments in spatial learning after either 5 or 10 min of ischemia while estradiol-treated rats showed no impairments after 5 min of ischemia and only mild impairments after 10 min of ischemia. Immediately following behavioral testing, rats were perfused and survival of CA1 pyramidal cells was assessed. Ischemia was associated with the loss of CA1 pyramidal cells but rats that received estradiol prior to ischemia showed less severe damage. Furthermore, the extent of cell loss was correlated with degree of spatial bias expressed on a probe trial following hidden platform training. These findings indicate that acute exposure to estradiol prior to ischemia is both neuroprotective and functionally protective.     

Impaired striatum-dependent behavior in GASP-1-knock-out mice

G protein-coupled receptor (GPCR) associated sorting protein-1 (GASP-1) is suspected to play a key role in recycling and degradation of several GPCRs. In a previous study, we have shown that GASP-1-knock-out (GASP-1-KO) mice displayed deficits in acquiring a cocaine self-administration task, associated with an exacerbated down-regulation of striatal dopaminergic and cholinergic receptors. Among several possibilities, GASP-1 deficiency could have impaired memory processes underlying the acquisition of the operant conditioning task. Therefore, the present study investigated cognitive performances of GASP-1-KO mice and their wild-type littermates (WT) in a broad variety of memory tasks. Consistent with a deficit in procedural memory, GASP-1-KO mice showed delayed acquisition of a food-reinforced bar-press task. During water-maze training in hidden- or visible-platform paradigms, mutant and WT mice acquired the tasks at the same rate. However, GASP-1 mice exhibited persistent thigmotaxic swimming, longer distance to the platform, and reduced swim speed. There was no deficit in several tasks requiring simple behavioral responses (Barnes maze, object recognition and passive avoidance tasks). Thus, the ability to acquire and/or express complex responses seems affected in GASP-1-deficient mice. Hippocampal functions were preserved, as the retention of an acquired memory in spatial tasks remained unaffected. The pattern of behavioral deficits observed in GASP-1-KO mice is coherent with current knowledge on the role of striatal GPCRs in acquisition/expression of skilled behavior and in motivation. Together with the previous findings, the so far established phenotype of GASP-1-KO mice makes them a potentially exciting tool to study striatal functions.     

Effects of the neurogenesis stimulator Ro 25-6981 upon formation of spatial skill in adult rats depend on the term of its administration and the animals' ability to learn

Effect of administration of selective N-methyl-D-aspartate (NMDA) receptor antagonist Ro 25-6981 on learning and memory in a dose which is known to stimulate neoneurogenesis was assessed in adult rats with different abilities to formation of spatial skills in different time periods after the antagonist injection. Wistar male rats were trained to find hidden platform in the Morris water maze for 5 consecutive days. Rats' learning ability for spatial skill formation was evaluated depending on platform speed achievements. In re-training sessions (cues and platform location changed), it was found that all rats received Ro 25-6981 13 days before the re-training demonstrated impaired spatial memory. At the same time the inhibitor injected 29 days before re-training selectively facilitated the formation of spatial skill in animals with initially low learning abilities.