Different types of environmental enrichment have discrepant effects on spatial memory and synaptophysin levels in female mice

Environmental enrichment paradigms that incorporate cognitive stimulation, exercise, and motor learning benefit memory and synaptic plasticity across the rodent lifespan. However, the contribution each individual element of the enriched environment makes to enhancing memory and synaptic plasticity has yet to be delineated. Therefore, the current study tested the effects of three of these elements on memory and synaptic protein levels. Young female C57BL/6 mice were given 3h of daily exposure to either rodent toys (cognitive stimulation) or running wheels (exercise), or daily acrobatic training for 6 weeks prior to and throughout behavioral testing. Controls were group housed, but did not receive enrichment. Spatial working and reference memory were tested in a water-escape motivated radial arm maze. Levels of the presynaptic protein synaptophysin were then measured in frontoparietal cortex, hippocampus, striatum, and cerebellum. Exercise, but not cognitive stimulation or acrobat training, improved spatial working memory relative to controls, despite the fact that both exercise and cognitive stimulation increased synaptophysin levels in the neocortex and hippocampus. These data suggest that exercise alone is sufficient to improve working memory, and that enrichment-induced increases in synaptophysin levels may not be sufficient to improve working memory in young females. Spatial reference memory was unaffected by enrichment. Acrobat training had no effect on memory or synaptophysin levels, suggesting a minimal contribution of motor learning to the mnemonic and neuronal benefits of enrichment. These results provide the first evidence that different elements of the enriched environment have markedly distinct effects on spatial memory and synaptic alterations.     

Effects of environmental enrichment on spatial memory and neurochemistry in middle-aged mice

The present study compared the effects of environmental enrichment on spatial memory, glutamic acid decarboxylase (GAD) activity, and synaptophysin levels in middle-aged male and female mice. Prior to testing, a subset of 18-month-old male and female C57BL/6 mice was housed with two to three toys and a running wheel in the home cage for up to 29 d. Adult mice (7 mo) of both sexes and the remaining middle-aged mice were group (social) housed, but not exposed to enriching objects. After the enrichment period, all mice were tested in a 1-day version of the Morris water maze, in which both spatial and nonspatial memory were assessed. Immediately after testing, the hippocampus and frontoparietal cortex were dissected, and GAD activity and synaptophysin levels were measured. Environmental enrichment reduced the age-related impairment in spatial acquisition and retention; relative to adult social controls, middle-aged enriched mice were unimpaired, whereas middle-aged social controls were impaired. This reduction was similar in middle-aged males and females. Enrichment did not affect cued memory in either sex. Although hippocampal GAD activity was increased by enrichment in males, all other neurochemical measurements were unaffected by enrichment or aging in either sex. These data suggest that environmental enrichment initiated at middle age can reduce age-related impairments in spatial memory in males and females, although the underlying neurobiological mechanisms of this effect remain unknown.     

Long-term continuous, but not daily, environmental enrichment reduces spatial memory decline in aged male mice

Although environmental enrichment improves spatial memory and alters synaptic plasticity in aged rodents, it is unclear whether all types of enrichment treatments yield similar benefits. The present study examined the effects in aged male mice of three types of enrichment on spatial memory in Morris water maze and radial arm maze tasks, and on levels of the presynaptic protein synaptophysin in several brain regions. Non-enriched young and aged males were compared with males exposed to one of the following treatments for 10 weeks: 5 min of daily handling, 3 h of daily basic enrichment, or 24 h of continuous complex enrichment. Young controls outperformed aged controls in both tasks. Neither daily handling nor daily enrichment affected spatial memory or synaptophysin levels. In contrast, continuous enrichment significantly reduced age-related spatial memory decline in both tasks, such that this group was statistically indistinguishable from young controls in most measures of performance. Continuously enriched mice were also significantly better than other aged mice in several spatial memory measures. Despite these improvements, synaptophysin levels in the continuous enrichment group were significantly lower than those of young and aged controls in the frontoparietal cortex, hippocampus, and striatum, suggesting a negative relationship between synaptophysin levels and spatial memory in aged males. These data demonstrate that different types of enrichment in aged male mice have disparate effects on spatial memory, and that the relationship between enrichment-induced changes in synaptophysin levels and spatial memory in aged males differs from that we have previously reported in aged female mice.     

Higher levels of estradiol replacement correlate with better spatial memory in surgically menopausal young and middle-aged rats

The current study investigated whether, for spatial reference memory, age impacts (1) sensitivity to surgical ovarian hormone loss (Ovx), (2) response to estradiol therapy (ET), and (3) the relation between circulating estradiol levels and memory scores in ovary-intact sham and Ovx plus ET rats. Young, middle-aged and aged Fischer-344 rats received sham, Ovx or Ovx plus ET treatments, and were then tested on the Morris maze. After the last test trial, a probe trial was given whereby the platform was removed. Circulating estradiol levels were then determined and correlated with performance. In Study 1, Ovx facilitated learning on day one, but impaired performance after day one, in young rats. Ovx did not influence performance in middle-aged rats. In young and middle-aged Ovx rats, ET enhanced performance with higher exogenous estradiol levels correlating with better performance during testing and the probe trial. There was no relationship between endogenous estradiol levels and performance in sham young or middle-aged rats. Study 2 showed that, like middle-aged rats, aged rats were not impacted by Ovx. Further, for aged Ovx rats, the ET regimen that was beneficial at earlier ages was no longer effective during test trials, and had only minor benefits for platform localization as assessed by the probe trial. Collectively, the findings suggest that the effects of Ovx as well as responsivity to the currently utilized ET regimen changes with age. Further, there appears to be a distinction between sensitivity to Ovx and responsiveness to ET after Ovx for spatial reference memory performance.     

Effects of neocortical ectopias and environmental enrichment on Hebb-Williams maze learning in BXSB mice

Approximately 40-60% of BXSB mice have neocortical ectopias, a developmental anomaly characterized by migration of neurons into the neuron-sparse layer I of cortex. Previous studies have shown that ectopic BXSB mice have superior reference, but inferior working, memory on spatial tasks. Female BXSB mice were housed either in an enriched environment or in standard cages at weaning. Subsequently, these animals were tested on four of the Hebb-Williams mazes in a water-based version of this maze. Theoretically, two of the maze configurations placed greater emphasis on reference memory to find the goal, whereas the other two favored working memory. Ectopics reared in standard housing conditions were better than nonectopics on mazes that favored the use of reference memory, but poorer on mazes that favored working memory. In contrast, subjects raised in the enriched environment showed no ectopia differences. A comparison of enriched and standard housing conditions found that the enriched animals had better reference memory but poorer working memory. The latter effect may be because the enriched environment, although more stimulating, did not change in time or space; and other researchers have shown that daily replacement of stimuli in complex environments is correlated with better working memory.     

Enhanced cognitive activity--over and above social or physical activity--is required to protect Alzheimer's mice against cognitive impairment, reduce Abeta deposition, and increase synaptic immunoreactivity

Although social, physical, and cognitive activities have each been suggested to reduce the risk of Alzheimer's disease (AD), epidemiologic studies cannot determine which activity or combination of activities is most important. To address this question, mutant APP transgenic AD mice were reared long-term in one of four housing conditions (impoverished, social, social+physical, or complete enrichment) from 1(1/2) through 9 months of age. Thus, a stepwise layering of social, physical, and enhanced cognitive activity was created. Behavioral evaluation in a full battery of sensorimotor, anxiety, and cognitive tasks was carried out during the final 5 weeks of housing. Only AD mice raised in complete enrichment (i.e., enhanced cognitive activity) showed: (1) protection against cognitive impairment, (2) decreased brain beta-amyloid deposition, and (3) increased hippocampal synaptic immunoreactivity. The protection provided by enhanced cognitive activity spanned multiple cognitive domains (working memory, reference learning, and recognition/identification). Cognitive and neurohistologic benefits of complete enrichment occurred without any changes in blood cytokine or corticosterone levels, suggesting that enrichment-dependent mechanisms do not involve changes in the inflammatory response or stress levels, respectively. These results indicate that the enhanced cognitive activity of complete enrichment is required for cognitive and neurologic benefit to AD mice-physical and/or social activity are insufficient. Thus, our data suggest that humans who emphasize a high lifelong level of cognitive activity (over and above social and physical activities) will attain the maximal environmental protection against AD.     

Sex differences in chronic stress effects on memory in rats

Recent studies in rodent models and in humans have shown that the status of both the gonadal and adrenal axes (hypothalamic-pituitary-gonadal, HPG and hypothalamic-pituitary-adrenal, HPA, respectively) can influence learning and memory function. In this article, the effects of activating the HPA axis (stress) on performance of memory tasks in rats are reviewed. More importantly, results are presented which show that chronic stress has a different impact on performance of these tasks depending upon the sex of the rat. These observations are novel and potentially important since few studies, animal or human, have utilized females as subjects in studies of the stress response. Sex differences in the effects of chronic stress on memory were investigated in rats using an object recognition task and two spatial memory tasks, radial arm maze and object location. Given the same chronic stress--21 days of restraint for 6 h each day--males were impaired in all of the memory tests while females showed enhanced performance of the spatial memory tasks and no changes in object recognition performance. Levels of neurotransmitters and metabolites were measured in brain areas important for cognition in the subjects in order to determine neural systems that may respond to stress and mediate the cognitive responses. These results show that responses of monoamine and amino acid containing neural systems may contribute to or underlie sex differences in stress effects on cognition. Stress decreased dopaminergic activity in the frontal cortex and amygdala of males but not females; whereas, in CA3 of the hippocampus, stress increased levels of 5-HT and norepinephrine in females, but not males, and increased GABA in males, but not females. Finally, a possible role for estradiol in mediating sexually differentiated responses to stress was examined. Behavioral and neurochemical evaluations in ovariectomized, stressed females, with or without estrogen replacement, suggest that sex differences in response to stress are influenced by both the organizing and activating effects of estradiol. A few, recent studies in humans, that show sexually dimorphic relationships between chronic stress and cognition, are also highlighted. These results in humans are consistent with the pattern of results in rats. Clearly, further studies are necessary to substantiate sex differences in stress effects on memory function in humans and to understand mechanisms whereby estrogen may influence the stress response in rats. Nonetheless, recent studies show sexually differentiated cognitive responses to chronic stress and underline the importance of considering the sex/gender of subjects when studying the stress response.     

丰富环境对脑缺血大鼠突触界面结构修饰和PSD-95基因表达的影响

探讨丰富环境干预对局部脑缺血大鼠突触界面结构修饰和突触后致密物-95 (postsynaptic density-95,PSD-95 ) mRNA表达的影响。栓塞健康雄性Sprague-Dawley大鼠的右侧大脑中动脉,建立脑中动脉栓塞(middle cerebral artery occlusion,MCAO)模型后,分为丰富环境缺血组(IE)、标准环境缺血组(IS),同时分别设丰富环境假手术组(SE)、标准环境假手术组(SS)。以Morris水迷宫检测大鼠的空间学习记忆能力,应用透射电镜、图像分析和细胞形态计量学技术,观察海马CA1区和额叶皮层突触界面结构变化,采用RT-PCR检测突触后脚手架蛋白PSD-95 mRNA的表达。结果表明：丰富环境干预能有效改善脑缺血导致的空间学习记忆能力下降,并对正常大鼠的空间学习记忆能力也有改善作用。同时,丰富环境干预能抑制局部脑缺血导致的突触数密度减少,该作用对额叶皮层特别明显;丰富环境干预不同程度地逆转脑缺血造成的突触界面参数变化,特别使突触间隙宽度显著减小、PSD厚度明显增加;并有效抑制因脑缺血诱导的PSD-95 mRNA表达下调。以上结果提示,丰富环境改善脑缺血大鼠的空间学习记忆能力可能与其促进缺血区边缘组织突触界面结构修饰,提高PSD-95 mRNA表达有关     

Systemic and local administration of estradiol into the prefrontal cortex or hippocampus differentially alters working memory

The influence of estradiol on learning and memory is dependent on a number of factors. The effects of physiological levels of estradiol on the acquisition of a spatial working memory task mediated by the prefrontal cortex (PFC) and the hippocampus were examined in Experiment 1. Ovariectomized Long-Evans rats received daily injections of estradiol or vehicle were tested on the win-shift version of the radial arm maze. A high dose of estradiol benzoate (5 microg) enhanced acquisition of the task, whereas a low dose of estradiol (0.3 microg) increased the number of errors committed over 17 days of testing. Experiment 2 was conducted to examine site-specific influences of estradiol on spatial working memory in well-trained rats. Saline and estradiol cyclodextrin (0.1 and 0.9 microg) were infused into the prelimbic region of the PFC or dorsal hippocampus 40 min prior to testing on the win-shift task. Infusions of estradiol into both brain areas attenuated saline-infusion disruptions in working memory. Specifically, the higher dose of estradiol facilitated working memory when infused into the PFC, whereas the lower dose of estradiol facilitated performance when infused into the dorsal hippocampus. Moreover, working memory was significantly impaired 24 h after infusions of estradiol into the dorsal hippocampus but not the PFC. These data provide further evidence for the notion that estradiol can dose-dependently alter memory processes and suggest that facilitation or disruptions of working memory by estradiol are site- and time-specific.     

Sex differences in object location memory and spatial navigation in Long-Evans rats

In both humans and rodents, males typically excel on a number of tasks requiring spatial ability. However, human females exhibit advantages in memory for the spatial location of objects. This study investigated whether rats would exhibit similar sex differences on a task of object location memory (OLM) and on the watermaze (WM). We predicted that females should outperform males on the OLM task and that males should outperform females on the WM. To control for possible effects of housing environment, rats were housed in either complex environments or in standard shoebox housing. Eighty Long-Evans rats (40 males and 40 females) were housed in either complex (Complex rats) or standard shoebox housing (Control rats). Results indicated that males had superior performance on the WM, whereas females outperformed males on the OLM task, regardless of housing environment. As these sex differences cannot be easily attributed to differences in cognitive style related to linguistic processing of environmental features or to selection pressures related to the hunting gathering evolutionary prehistory of humans, these data suggest that sex differences in spatial ability may be related to traits selected for by polygynous mating strategies.     

Object appearance and picture-specific viewpoint are not integrated in long-term memory

Previous work has demonstrated that visual long-term memory (VLTM) stores detailed information about object appearance. The current experiments investigate whether object appearance information in VLTM is integrated within representations that contain picture-specific viewpoint information. In three experiments using both incidental and intentional encoding instructions, participants were unable to perform above chance on recognition tests that required recognizing the conjunction of object appearance and viewpoint information (Experiments 1a, 1b, 2, and 3). However, performance was better when object appearance information (Experiments 1a, 1b, and 2) or picture-specific viewpoint information (Experiment 3) alone was sufficient to succeed on the memory test. These results replicate previous work demonstrating good memory for object appearance and viewpoint. However the current results suggest that object appearance and viewpoint are not episodically integrated in VLTM.     

Spatial learning in pigs: effects of environmental enrichment and individual characteristics on behaviour and performance

This study investigated the effects of both environmental enrichment and individual behavioural characteristics on spatial cognitive capabilities of pigs, using a novel latent spatial learning paradigm based on Tolman’s detour experiments (1948). Pigs were housed either in ‘barren’ pens or in pens enriched with straw bedding from birth. Pigs were restrained in a Backtest at 10 and 17 days postpartum. Based on their escape behaviour in this test, which has been shown to reflect their behavioural style, six ‘high-resisting’(HR) and six ‘low-resisting’ (LR) pigs were selected from each housing environment (n = 24 in total). At 12 weeks of age, pairs of pen mates (LR and HR) were exposed to a maze three times (exploration trials). Pigs were then placed individually in the maze, and social reinstatement proved to be a strong incentive to find the exit leading to the home pen. We subsequently blocked the direct route to the exit, forcing animals to find a detour (memory test 1, MT1). This test was repeated once to investigate the relative improvement, i.e. detour learning (memory test 2, MT2). Housing condition and Backtest response strongly affected exploration patterns. In spite of this, no effects on performance during the subsequent memory tests were found. Performance was substantially improved in MT2, indicating that once a goal is apparent, pigs are able to solve a complex spatial memory task easily. In conclusion, social reinstatement provided a good incentive to complete a spatial task, and the substantial improvement in performance between MT1 and MT2 stresses the need for task complexity when testing spatial memory in pigs. Housing conditions or individual behavioural style did not affect spatial memory during MT1 or MT2. However, housing environment and behavioural style strongly affected explorative behaviour of pigs in an unfamiliar maze during both exploration trials and memory tests. This implicates that apparent effects of environmental enrichment on spatial learning and memory in pigs might reflect differences in explorative patterns rather than in cognitive processes.     

Early-life education may help bolster declarative memory in old age,especially for women

ABSTRACT

Although declarative memory declines with age, sex and education might moderate these weaknesses. We investigated effects of sex and education on nonverbal declarative (recognition) memory in 704 older adults (aged 58–98, 0–17 years of education). Items were drawings of real and made-up objects. Age negatively impacted declarative memory, though this age effect was moderated by sex and object-type: it was steeper for males than females, but only for real objects. Education was positively associated with memory, but also interacted with sex and object-type: education benefited women more than men (countering the age effects, especially for women), and remembering real more than made-up objects. The findings suggest that nonverbal memory in older adults is associated negatively with age but positively with education; both effects are modulated by sex, and by whether learning relates to preexisting or new information. The study suggests downstream benefits from education, especially for girls.     

A mutant mouse with a highly specific contextual fear-conditioning deficit found in an N-ethyl-N-nitrosourea (ENU) mutagenesis screen

Targeted mutagenesis in mice has shown that genes from a wide variety of gene families are involved in memory formation. The efficient identification of genes involved in learning and memory could be achieved by random mutagenesis combined with high-throughput phenotyping. Here, we provide the first report of a mutagenesis screen that has generated memory mutants in the mouse. We tested a group of N-ethyl-N-nitrosourea (ENU) mutagenized mice in the conditioned fear paradigm. We screened for both dominant and recessive mutations that caused impairments in contextual or tone fear conditioning. Heritability testing confirmed three fear conditioning mutants, i.e., Forgetful, Slowlearner, and Scatterbrain. All three have a learning or short-term memory deficit in contextual fear conditioning. Forgetful was further characterized and showed a highly specific phenotype. The contextual fear-conditioning deficit was apparent when Forgetful was trained with tone-shock pairings, but not when trained with shock alone. The deficit was not due to changes in shock sensitivity or anxiety. Forgetful was not impaired in two other memory tests (hidden platform version of Morris water maze and object recognition). Our data show that a mutagenesis screen can generate mutant mice with highly specific memory phenotypes that can supplement existing mice with targeted mutations. Mapping of Slowlearner found linkage to a region of chromosome 12 (LOD score of 6.5 close to D12Mit171), which suggests that ENU mutants should enable the positional cloning of genes involved in memory formation.     

Influence of object size on baseline identification, priming, and explicit memory

We investigated the influence of size on identification, priming, and explicit memory for color photos of common objects. Participants studied objects displayed in small, medium, and large sizes and memory was assessed with both implicit identification and explicit recognition tests. Overall, large objects were easier to identify than small objects and study-to-test changes in object size impeded performance on explicit but not implicit memory tests. In contrast to previous findings with line-drawings of objects but consistent with predictions from the distance-as-filtering hypothesis, we found that study-test size manipulations had large effects on old/new recognition memory test for objects displayed in large size at test but not for objects displayed small or medium at test. Our findings add to the growing body of literature showing that the findings obtained using line-drawings of objects do not necessarily generalize to color photos of common objects. We discuss implications of our findings for theories of object perception, memory, and eyewitness identification accuracy for objects.     

Selective fimbria and thalamic lesions differentially impair forms of working memory in rats.

Several series of experiments were designed to compare the effects of selective lesions of the fimbria or of thalamic nuclei on three different tasks involving working memory in rats: object recognition, place recognition, and the radial arm maze test. The main effects of fimbria lesions were as follows: they produced deficits in the radial maze; object recognition was spared or even facilitated, whereas place recognition was impaired. Electrolytic lesions of either centromedian-parafascicularis (CM-Pf) or dorsomedialis (DM) nuclei produced highly significant deficits in the radial maze test but spared object and place recognition. Ibotenate lesions of the CM-Pf had no effect on any test, which means that the critical structure in the effects of the electrolytic lesions of the CM-Pf was the fasciculus retroflexus (FR). These data may contribute two main points to animal models of hippocampal and thalamic amnesia: (1) different forms of working memory in rats might have different neural bases and (2) the FR may be involved in learning and memory processes.     

No sex differences in spatial location memory for abstract designs

Previous research has demonstrated a female advantage, albeit imperfectly, on tests of object location memory where object identity information is readily available. However, spatial and visual elements are often confounded in the experimental tasks used. Here spatial and visual memory performance was compared in 30 men and 30 women by presenting 12 abstract designs in a spatial array for recall and recognition (visual memory) and spatial location ("object" location memory). Object location memory was measured via a sensitive absolute displacement score defined as the distance in mms between the position assigned to the object during recall and the actual position it originally occupied. There were no sex differences in either the visual or spatial location tests. Controlling for age and estimated IQ scores made no impact on the results. These data suggest an absence of a sex difference in purely visual and spatial aspects of object location memory.     

Deletion of the GluA1 AMPA receptor subunit impairs recency-dependent object recognition memory

Deletion of the GluA1 AMPA receptor subunit impairs short-term spatial recognition memory. It has been suggested that short-term recognition depends upon memory caused by the recent presentation of a stimulus that is independent of contextual-retrieval processes. The aim of the present set of experiments was to test whether the role of GluA1 extends to nonspatial recognition memory. Wild-type and GluA1 knockout mice were tested on the standard object recognition task and a context-independent recognition task that required recency-dependent memory. In a first set of experiments it was found that GluA1 deletion failed to impair performance on either of the object recognition or recency-dependent tasks. However, GluA1 knockout mice displayed increased levels of exploration of the objects in both the sample and test phases compared to controls. In contrast, when the time that GluA1 knockout mice spent exploring the objects was yoked to control mice during the sample phase, it was found that GluA1 deletion now impaired performance on both the object recognition and the recency-dependent tasks. GluA1 deletion failed to impair performance on a context-dependent recognition task regardless of whether object exposure in knockout mice was yoked to controls or not. These results demonstrate that GluA1 is necessary for nonspatial as well as spatial recognition memory and plays an important role in recency-dependent memory processes.     

Adult age differences in memory for schema-consistent and schema-inconsistent objects in a real-world setting

The present study examined age-related differences in the inconsistency effect, in which memory is enhanced for schema-inconsistent information compared to schema-consistent information. Young and older adults studied schema-consistent and schema-inconsistent objects in an academic office under either intentional or incidental encoding instructions, and were given two recognition tests either immediately or after 48 hr: A yes/no item recognition test that included modified remember/know judgments and a token recognition test that required determining whether an original object was replaced with a different object with the same name. Young and older adults showed equivalent inconsistency effects in both item and token recognition tests, although older adults reported phenomenologically less rich memories of schema-inconsistent objects relative to young adults. These findings run counter to previous reports suggesting that aging is associated with processing declines at encoding that impair memory for details of schema-inconsistent or distinctive events. The results are consistent with a retrieval-based account in which age-related difficulties in retrieving contextual details can be offset by environmental support.     

Social enrichment improves social recognition memory in male rats

The social environment is thought to have a strong impact on cognitive functions. In the present study, we investigated whether social enrichment could affect rats’ memory ability using the “Different Objects Task (DOT),” in which the levels of memory load could be modulated by changing the number of objects to be remembered. In addition, we applied the DOT to a social discrimination task using unfamiliar conspecific juveniles instead of objects. Animals were housed in one of the three different housing conditions after weaning [postnatal day (PND) 21]: social-separated (1 per cage), standard (3 per cage), or social-enriched (10 per cage) conditions. The object and social recognition tasks were conducted on PND 60. In the sample phase, the rats were allowed to explore a field in which 3, 4, or 5 different, unfamiliar stimuli (conspecific juveniles through a mesh or objects) were presented. In the test phase conducted after a 5-min delay, social-separated rats were able to discriminate the novel conspecific from the familiar ones only under the condition in which three different conspecifics were presented; social-enriched rats managed to recognize the novel conspecific even under the condition of five different conspecifics. On the other hand, in the object recognition task, both social-separated and social-enriched rats were able to discriminate the novel object from the familiar ones under the condition of five different objects. These results suggest that social enrichment can enhance social, but not object, memory span.