Age-related learning and memory impairments in adult-onset hypothyroidism in Kunming mice

The memory impairment induced by adult-onset hypothyroidism is a common symptom. However, the exact onset time that will influence on memory function is still an issue of debate. The purpose of this study is to determine the onset effect of hypothyroidism on the memory during adulthood. Three age groups of Kunming (KM) mice were used, including 2, 8, and 15-month-old mice. Adult-onset hypothyroidism was made by adding PTU to drinking water and hypothyroid states were documented by the measurement of serum thyroid hormones level. A battery of tasks, i.e. novel-object recognition, olfactory discrimination, Morris water maze, was used to test mice's memory. The results showed that adult-onset hypothyroidism induced the impairment of odor and spatial memory consolidation whereas it did not affect visual memory encoding or consolidated spatial memory retention. Age at onset of hypothyroidism was an important factor for the memory impairment induced by hypothyroidism. The 2-month-old hypothyroid mice had significantly impaired abilities in both the olfactory discrimination and the spatial cognitive tasks relative to the 2-month-old controls. The 8-month-old hypothyroid mice had only impaired ability in the spatial cognitive task relative to the same age controls. The 15-month-old hypothyroid mice retained these cognitive abilities relative to the same age controls. These results suggested that adult-onset hypothyroidism could induce an age- and task-dependent impairment of memory in female KM mice.     

Reference memory, anxiety and estrous cyclicity in C57BL/6NIA mice are affected by age and sex

Age-related changes in learning and memory are common in rodents. However, direct comparisons of the effects of aging on learning and memory in both males and females are lacking. The present study examined whether memory deteriorates with increasing age in C57BL/6NIA mice, and whether age-related changes in learning and memory are similar in both sexes. Male and female mice (five, 17 and 25 months of age) were tested in a battery of behavioral tasks including the Morris water maze (spatial and non-spatial reference memory), simple odor discrimination (olfactory reference memory), plus maze (anxiety/exploration), locomotor activity, and basic reflexes. Five-month-old mice learned the water maze and odor discrimination tasks rapidly. Relative to five-month-old mice, 25-month-old mice exhibited impaired spatial and olfactory reference memory, but intact non-spatial reference memory. The spatial reference memory of 17-month-old mice was also impaired, but less so than 25-month mice. Seventeen-month-old mice exhibited intact non-spatial (visual and olfactory) reference memory. Five and 25-month-old mice had similar levels of plus maze exploration and locomotor activity, whereas 17-month-old mice were more active than both groups and were slightly less exploratory than five-month-old mice. Although sex differences were not observed in the five- and 25-month groups, 17-month-old females exhibited more impaired spatial reference memory and increased anxiety relative to 17-month-old males. Estrous cycling in females deteriorated significantly with increased age; all 25-month-old females had ceased cycling and 80% of 17-month-old females displayed either irregular or absent estrous cycling. This study is the first to directly compare age-related mnemonic decline in male and female mice. The results suggest that: (i) aged mice exhibit significant deficits in spatial and olfactory reference memory relative to young mice, whereas middle-aged mice exhibit only a moderate spatial memory deficit and; (ii) spatial reference memory decline begins at an earlier age in females than in males, a finding that may be related to the cessation of estrous cycling.     

Reference memory,anxiety and estrous cyclicity in C57BL/6NIA mice are affected by age and sex

Age-related changes in learning and memory are common in rodents. However, direct comparisons of the effects of aging on learning and memory in both males and females are lacking. The present study examined whether memory deteriorates with increasing age in C57BL/6NIA mice, and whether age-related changes in learning and memory are similar in both sexes. Male and female mice (five, 17 and 25 months of age) were tested in a battery of behavioral tasks including the Morris water maze (spatial and non-spatial reference memory), simple odor discrimination (olfactory reference memory), plus maze (anxiety/exploration), locomotor activity, and basic reflexes. Five-month-old mice learned the water maze and odor discrimination tasks rapidly. Relative to five-month-old mice, 25-month-old mice exhibited impaired spatial and olfactory reference memory, but intact non-spatial reference memory. The spatial reference memory of 17-month-old mice was also impaired, but less so than 25-month mice. Seventeen-month-old mice exhibited intact non-spatial (visual and olfactory) reference memory. Five and 25-month-old mice had similar levels of plus maze exploration and locomotor activity, whereas 17-month-old mice were more active than both groups and were slightly less exploratory than five-month-old mice. Although sex differences were not observed in the five- and 25-month groups, 17-month-old females exhibited more impaired spatial reference memory and increased anxiety relative to 17-month-old males. Estrous cycling in females deteriorated significantly with increased age; all 25-month-old females had ceased cycling and 80% of 17-month-old females displayed either irregular or absent estrous cycling.This study is the first to directly compare age-related mnemonic decline in male and female mice. The results suggest that: (i) aged mice exhibit significant deficits in spatial and olfactory reference memory relative to young mice, whereas middle-aged mice exhibit only a moderate spatial memory deficit and; (ii) spatial reference memory decline begins at an earlier age in females than in males, a finding that may be related to the cessation of estrous cycling.     

The effects of nucleus basalis magnocellularis lesions in Long-Evans hooded rats on two learning set formation tasks, delayed matching-to-sample learning, and open-field activity

Rats with quisqualic acid lesions of the nucleus basalis magnocellularis (nBM) and control rats were compared in discrimination reversal learning set (DRLS) and olfactory discrimination learning set (ODLS) tasks, a delayed matching-to-sample task (DMTS), and open-field activity. Evidence of learning set formation was seen in control rats but not in nBM-lesioned rats in both the DRLS and ODLS tasks. Better-than-chance performances were seen for both groups in DMTS, indicating no impairment after nBM lesions. There were no group differences in open-field activity. These findings suggest that the nBM is important for higher cognitive processing such as "learning to learn" and thus is important for a complex form of reference memory. In addition, perseverational, working memory, and attentional deficits could not explain learning set impairment after nBM lesions.     

Effect of age on the radial arm water maze-a test of spatial learning and memory

Aged rats show decrements in performance on cognitive tasks that require the use of spatial learning and memory. We used the 8-arm radial water maze (RAWM) to measure spatial learning as a function of age in young (6 months) and old (21 months) male F344 rats. Rats were placed in the RAWM in different start arms with the same goal arm for 3 days (five trials/day); the goal arm was changed on day 4. Old rats demonstrated spatial impairment as evidenced by increased latencies to find the hidden platform on day 4. Old rats made significantly more errors, both reference and working memory errors, than young rats on all days. It is likely that the old rats utilized non-spatial strategies to solve the task, and therefore were impaired in learning a new platform location. The RAWM is a reliable, sensitive, and powerful additional test to assess age-related spatial learning and memory deficits, combining the advantages of the Morris water maze and the radial arm maze while minimizing the disadvantages.     

Cognitive and motor aging in female chimpanzees

We present the first longitudinal data on cognitive and motor aging in the chimpanzee (Pan troglodytes). Thirty-eight adult female chimpanzees (10–54 years old) were studied. The apes were tested longitudinally for 3 years in a modified Primate Cognition Test Battery, which comprised 12 tests of physical and social cognition. The chimpanzees were also administered a fine motor task requiring them to remove a steel nut from rods of various complexity. There was little evidence for an age-related decline in tasks of Physical Cognition: for most tasks, performance was either stable or improved with repeated testing across age groups. An exception was Spatial Memory, for which 4 individuals more than 50 years old experienced a significant performance decline across the 3 years of testing. Poorer performance with age was found in 2 tasks of Social Cognition, an attention-getting task and a gaze-following task. A slight motor impairment was also observed, with old chimpanzees improving less than younger animals with repeated testing on the simplest rod. Hormonal status effects were restricted to spatial memory, with non-cycling females outperforming cycling females independently of age. Unexpectedly, older chimpanzees were better than younger individuals in understanding causality relationships based on sound.     

Deficits across multiple cognitive domains in a subset of aged Fischer 344 rats

Rodent models of cognitive aging routinely use spatial performance on the water maze to characterize medial temporal lobe integrity. Water maze performance is dependent upon this system and, as in the aged human population, individual differences in learning abilities are reliably observed among spatially characterized aged rats. However, unlike human aging in which cognitive deficits rarely occur in isolation, few non-spatial learning deficits have been identified in association with spatial impairment among aged rats. In this study, a subset of male aged Fischer 344 rats was impaired both in water maze and odor discrimination tasks, whereas other aged cohorts performed on par with young adult rats in both settings. The odor discrimination learning deficits were reliable across multiple problems. Moreover, these deficits were not a consequence of anosmia and were specific to olfactory learning, as cognitively impaired aged rats performed normally on an analogous non-olfactory discrimination task. These are among the first data to describe an aging model in which individual variability among aged rat cognition occurs across two independent behavioral domains.     

Sex-differences in age-related cognitive decline in C57BL/6J mice associated with increased brain microtubule-associated protein 2 and synaptophysin immunoreactivity

Understanding cognitive aging is becoming more important as the elderly population grows. Here, the effects of age and sex on learning and memory performance were compared in female and male young (3-4 months old) middle-aged (10-12 months old) and old (18-20 months old) wild-type C57BL/6J mice. Old males and females performed worse than young or middle-aged mice in novel location, but not novel object recognition tasks. Old mice, of both sexes, also showed impaired spatial water maze performance during training compared with young or middle-aged mice, however only old females failed to show robust spatial bias during probe trials. While there was no age-difference in passive avoidance performance for males, females showed an age-related decline. There was no difference in cognitive performance between young and middle-age mice of either sex on any task. Cognitive performance was associated with alterations in immunoreactivity of microtubule-associated protein 2-positive dendrites and synaptophysin-positive pre-synaptic terminals in hippocampal CA1, CA3, and dentate, entorhinal cortex, and central nucleus of amygdala. Overall, microtubule-associated protein 2 immunoreactivity was increased in old females compared with both young and middle-age females with no significant difference in males. In contrast, synaptophysin immunoreactivity increased from young to middle-age in females, and from middle-age to old in males; females had higher levels of synaptophysin immunoreactivity than males in middle-age only. Elevated levels of microtubule-associated protein 2 and synaptophysin may constitute a compensatory response to age-related functional decline in mice.     

Sex-dependent changes in anxiety, memory, and monoamines following one week of stress

Chronic restraint stress alters performance of rats on cognitive tasks, and anxiety measurements, and these stress-induced behavioral alterations are sexually dimorphic. Following a long stress period (21 days restraint) males show cognitive impairments while females are either not affected or enhanced on the same tasks. The current study examined whether sexually differentiated responses are also induced following shorter restraint stress durations. Male and female Sprague Dawley rats, aged 2.5 months, served as controls or received restraint stress (6 h/day, 7 days) and were tested for anxiety (plus maze), non-spatial memory (object recognition), and spatial memory (object placement). Plus maze performance was altered by sex and stress exposure. Stress impaired male object recognition but did not affect female performance. Stress did not affect male spatial memory; however, control females could not significantly discriminate between the old and new locations, but stress exposure enhanced female performance. Following behavioral testing, monoamines and metabolites were measured in prefrontal cortex (PFC), hippocampus (CA1, CA3), and amygdala. Notably, PFC and CA3 indices for noradrenergic activity (MHPG levels and MHPG/NE ratios) were increased in stress females, but decreased in males, and similar changes were found in CA1 and BLA dopaminergic indices. Thus, these sexually dimorphic neurochemical changes following stress may underlie the behavioral differences. Current results show that short-term restraint elicits sex-dependent behavioral and neural changes different from those previously reported for longer term stresses and suggest that the temporal relationship between the change from adaptive to maladaptive responses to stress is shorter in male than female rats.     

Sex differences in the acquisition of appetitively motivated learning in rats

Learning ability of male and female rats (70 and 100 days old) was compared on different learning tasks. No evidence was found for sex-related differences at the age of 70 days, but the 100-day-old males learned a discrimination task with chain schedules better than females. In a stimulus discrimination task females suppressed bar-pressing while males only reduced their response rates when wrong responses were punished with shock. Males and females failed to learn an active avoidance response. They only learned to terminate the shocks. Differences between 100-day-old males and females in the performance of the appetitively motivated tasks are explained by differences in food motivation.     

Prenatal cocaine exposure impairs selective attention: evidence from serial reversal and extradimensional shift tasks

This study assessed the effects of prenatal cocaine exposure on cognitive functioning, using an intravenous (IV) rodent model that closely mimics the pharmacokinetics seen in humans after smoking or IV injection and that avoids maternal stress and undernutrition. Cocaine-exposed males were significantly impaired on a 3-choice, but not 2-choice, olfactory serial reversal learning task. Both male and female cocaine-exposed rats were significantly impaired on extradimensional shift tasks that required shifting from olfactory to spatial cues; however, they showed no impairment when required to shift from spatial to olfactory cues. In-depth analyses of discrete learning phases implicated deficient selective attention as the basis of impairment in both tasks. These data provide clear evidence that prenatal cocaine exposure produces long-lasting cognitive dysfunction, but they also underscore the specificity of the impairment.     

Estrogen replacement improves spatial reference memory and increases hippocampal synaptophysin in aged female mice

Estrogen deficiency during menopause is often associated with memory dysfunction. However, inconsistencies regarding the ability of estrogen to improve memory in menopausal women highlight the need to evaluate, in a controlled animal model, the potential for estrogen to alleviate age-related mnemonic decline. The current study tested whether estrogen could ameliorate spatial reference memory decline in aged female mice. At the conclusion of testing, levels of the presynaptic protein synaptophysin, and activities of the synthetic enzymes for acetylcholine and GABA, were measured in the hippocampus and neocortex. Aged (27-28-month-old) female C57BL/6 mice were given daily subcutaneous injections of 1 microg or 5 microg of beta-estradiol-3-benzoate dissolved in sesame oil. Control mice received daily injections of sesame oil or no injections. Estradiol treatment began 5 days prior to behavioral testing and continued throughout testing. Spatial and non-spatial memory were assessed in the Morris water maze. The 5 microg dose of estradiol significantly improved spatial learning and memory in aged females. The performance of 5 microg females improved significantly more rapidly than that of control females; estradiol-treated females performed at asymptotic levels by session 2. Furthermore, 5 microg females exhibited a more robust spatial bias than controls during probe trials. In contrast, 1 microg of estradiol did not improve spatial task performance. Neither dose affected performance of the non-spatial task. In the hippocampus, synaptophysin was increased in 5 microg females relative to controls. Estrogen did not affect enzyme activities in either brain region.This study is the first to examine the effects of estrogen replacement on spatial reference memory and synaptophysin expression in aged post-estropausal female rodents. The results suggest that: (1) estrogen can profoundly improve spatial reference memory in aged females, and (2) this improvement may be related to increased hippocampal synaptic plasticity, but not modulation of the synthetic enzymes for acetylcholine and GABA.     

Task Complexity and Signal Detection Analyses of Lexical Decision Performance in Alzheimer's Disease

This experiment addressed the issue of whether the changes in semantic memory performance associated with Alzheimer's disease (AD) could be distinguished from a generalized cognitive slowing. Young adults, healthy older adults, and AD patients performed 3 different reaction time (RT) tasks involving yes-no responses to visually presented letter strings. Task complexity analyses indicated that performance in the semantic task (lexical decision) was consistent with a generalized slowing of cognitive function that was greater in magnitude for AD than for normal aging. Signal detection analyses of the lexical decision data demonstrated AD-related changes in word-nonword discrimination, response bias, and the relation between discrimination and RT. The general cognitive slowing associated with AD was accompanied by additional changes specific to the performance of this semantic memory task.     

Detecting spatial memory deficits beyond blindness in tg2576 Alzheimer mice

The retinal degeneration Pde6b^rd1 (rd) mutation can be a major pitfall in behavioral studies using tg2576 mice bred on a B6:SJL genetic background, 1 of the most widely used models of Alzheimer's disease. After a pilot study in wild type mice, performance of 8- and 16-month-old tg2576 mice were assessed in several behavioral tasks with the challenge of selecting 1 or more task(s) showing robust memory deficits on this genetic background. Water maze acquisition was impossible in rd homozygotes, whereas Y-maze alternation, object recognition, and olfactory discrimination were unaffected by both the transgene and the rd mutation. Spatial memory retention of 8- and 16-month-old tg2576 mice, however, was dramatically affected independently of the rd mutation when mice had to recognize a spatial configuration of objects or to perform the Barnes maze. Thus, the latter tasks appear extremely useful to evaluate spatial memory deficits and to test cognitive therapies in tg2576 mice and other mouse models bred on a background susceptible to visual impairment.     

Sex differences in object-in-place memory of adult rats

Male rodents typically display an advantage over female conspecifics in tasks that assess memory for the identity or location of objects. However, the performance of female rodents on object recognition and object location tasks often is enhanced by elevated levels of ovarian steroids. The novel object-in-place task, combines elements of object recognition and object location tasks used to assess rodent object memory. Until now, only male rats have been tested on the object-in-place task, therefore, a study was conducted to compare the performance of males to females under different hormone conditions. Rats were given a sample phase to study the locations of four objects in an open field. After various delays, a test phase was administered with the locations of two objects reversed. Increased investigation of moved objects indicates memory for these objects and their original locations. Rats were able to discriminate moved from unmoved objects after a brief 5-min delay, regardless of biological sex or hormone status. However, gonadally intact males, but not diestrous females, were able to discriminate object locations after a 30-min delay. In contrast, ovariectomized females treated with estradiol and progesterone discriminated moved from unmoved objects after a 60-min delay while ovariectomized vehicle-treated females and gonadally intact males did not. Results indicate that female rats outperform males on a memory task that combines object recognition and location but only when circulating levels of the ovarian steroids, estradiol and progesterone, are elevated and only when memory is challenged by an extended retention interval.     

Accelerated senescence prone mouse-8 shows early onset of deficits in spatial learning and memory in the radial six-arm water maze

Available data indicate that the senescence-accelerated prone mouse 8 (SAMP8) is an appropriate model of brain aging, with impairments in nonspatial learning and memory beginning as early as 2 months of age, and spatial learning and memory deficiencies not becoming apparent until after 4 months of age. However, with other strains (e.g., C57BL mice), the impairment in spatial memory was found earlier than that in nonspatial memory. We considered the possibility that the observed differences could be due to strain-specific differences in the training equipment. In the present study, a new optimized testing apparatus-the radial six-arm water maze (RAWM)-for detecting spatial learning and memory in mice, was employed, to determine whether there is impairment of spatial learning and memory in young SAMP8. The relationship between the spatial learning measures observed with the RAWM and the Morris maze, a classic spatial learning and memory testing apparatus, was also explored. It was found that, in the RAWM, rather than in the Morris maze, the impairment in spatial learning could be measured in SAMP8 mice as early as 3 months old, and the impairment in spatial memory in SAMP8 mice aged 5 months. These results suggested that the spatial learning and memory deficiencies could be found in early life of SAMP8 mice, and that RAWM and Morris maze each detect different aspects of spatial learning and memory.     

Age effect on olfactory discrimination in a non-human primate, Microcebus murinus

In order to characterize age-related cognitive changes, olfactory discrimination was assessed in Microcebus murinus, a prosimian primate. We compared young (n = 10) and old (n = 8) animals for individual performance on three olfactory tasks. Animals had to perform a detection, a transfer, and a reversal learning task using a go, no go conditioning procedure. No differences were observed between the two groups, indicating that aging is not inevitably associated with a decline in cognitive function. We did, however, observe two aged animals showing altered behavior. One animal displayed impairments in the reversal learning task, and the other showed impairments in both the transfer and reversal tasks. Transfer impairment may be due to a hippocampal alteration, whereas the perseverative tendency noted in the reversal task may be associated with frontal lobe dysfunction. Because some aged M. murinus display lesions that are pathognomonic of Alzheimer's disease, our observations highlight its potential utility as a primate model for studying cognitive deficits in relation to age and associated pathologies.     

Acquisition of conditioned taste aversion is impaired in the amyloid precursor protein/presenilin 1 mouse model of Alzheimer's disease

Research into the underlying mechanisms of cognitive dysfunction in Alzheimer's disease (AD) has relied traditionally on tasks such as the water maze which evaluate spatial learning and memory. Since non-spatial forms of memory are also disrupted by AD, it is critical to establish other paradigms capable of investigating these deficits. Utilizing a non-spatial learning task, acquisition of conditioned taste aversion (CTA) was evaluated in a mouse model of AD. This line of transgenic mice encode a mutated allele of the human amyloid precursor protein (APP) and presenilin 1 (PS1) genes and exhibit extensive amyloid plaque deposition in the brain by 6-7 mo of age. Compared with wild-type mice, 10-17 month old APP/PS1 mice failed to acquire CTA to saccharin. Mice that only possessed one of the two mutations were able to acquire CTA to the saccharin. In 2-5 month old APP/PS1 mice acquisition of CTA was disrupted despite the lack of extensive plaque deposition. However, further analysis indicated a potential gender difference in both the CTA deficit and onset of plaque deposition with females showing greater conditioned aversion.     

Female CREBalphadelta- deficient mice show earlier age-related cognitive deficits than males

Age-related changes in the hippocampus increase vulnerability to impaired learning and memory. Our goal is to understand how a genetic vulnerability to cognitive impairment can be modified by aging and sex. Mice with a mutation in the cAMP response element binding (CREB) protein gene (CREB(alphadelta-) deficient mice) have a mild cognitive impairment and show test condition-dependent learning and memory deficits. We tested three ages of CREB(alphadelta-) deficient and wild-type (WT) mice in two Morris water maze (MWM) protocols: four trials per day with a 3-5 min inter-trial interval (ITI) (MWM4) and two trials per day with a 1 min ITI (MWM2). All CREB(alphadelta-) deficient mice performed well in the easier MWM4, except for the aged females that performed poorly. In the harder MWM2, young male and female and middle-aged male CREB(alphadelta-) deficient mice performed well, but aged male and all middle-aged and aged female CREB(alphadelta-) deficient mice were impaired. These results show that mice with a genetic vulnerability to impaired learning and memory exhibit increased vulnerability with age that is most apparent among females. Thus, a genetic predisposition to cognitive impairment may render females more vulnerable than males to such deficits with age.     

Olfactory sensitivity, learning and cognition in young adult and aged male Wistar rats

Psychophysical experiments with male Wistar rats, ranging from 2 to more than 25 months old, revealed age-related differences in olfactory sensitivity. The highest sensitivities were found in rats 13 months old, and the lowest sensitivity was found in the group aged 25 months and older. Consequently, we considered the hypotheses that young rats will require less time and less trials than aged conspecifics to learn an olfactory discrimination task and that olfactory cognitive abilities will be reduced in older individuals. Rats were initially trained in an olfactometer using operant techniques to discriminate between the odor ethyl acetate (EA) and clean air. Next, young adult and 28-month-old rats were tested on seven different go/no-go odor discrimination tasks. Aged rats performed as well as young adults did on all tasks and we conclude that, for a variety of odor discrimination problems, aged rats show no deterioration in learning ability. This is the first report on olfactory sensitivity, learning ability and cognition in Wistar rats that have passed the normal life span for this strain. Data show that the inability to learn and cognitive deficits do not necessarily develop with age.