Magnesium dietary manipulation and recovery of function following controlled cortical damage in the rat.

Previous research has shown that dietary magnesium (Mg2+) deficiency prior to injury worsens recovery of function and that systemic administration of Mg2+ pre or post-injury significantly improves functional recovery. The purpose of the present study was to determine if manipulations in dietary Mg2+ would alter functional recovery following unilateral cortical injuries. Two weeks prior to injury, rats were placed on a customized diet enriched with Mg2+, deficient in Mg2+, or on a standard Mg2+ diet. Rats were then prepared with unilateral cortical contusion injuries (CCI) of the sensorimotor cortex. Two days following CCI, rats were tested on a battery of sensorimotor (vibrissae-forelimb placing and bilateral tactile adhesive removal tests), as well as the acquisition of reference memory in the Morris water maze. Serum analysis for Mg2+ prior to injury showed a diet-dependent modulation in levels. The Mg(2+)-enriched diet showed significantly higher levels of serum Mg2+ compared to the normal diet and the Mg(2+)-deficient diet showed significantly lower levels compared to the Mg(2+)-normal diet. On the placing and tactile removal tests Mg2+ deficiency significantly worsened recovery compared to the Mg(2+)-enriched and Mg(2+-)normal diet conditions. There were no statistically significant differences between the Mg(2+)-normal and Mg(2+)-enriched diets on the sensorimotor tests. On the acquisition of reference memory there were no significant difference between diet conditions; however, the Mg(2+)-deficient diet showed a trend toward impaired performance compared to the other diet conditions. The Mg(2+)-deficient diet resulted in a larger lesion cavity compared to the other diet conditions. These findings suggest that dietary Mg2+ modulates recovery of function.     

Deletion of the Coffin–Lowry Syndrome Gene Rsk2 in Mice is Associated With Impaired Spatial Learning and Reduced Control of Exploratory Behavior

Coffin–Lowry Syndrome (CLS) is an X-linked syndromic form of mental retardation associated with skeletal abnormalities. It is caused by mutations of the Rsk2 gene, which encodes a growth factor regulated kinase. Gene deletion studies in mice have shown an essential role for the Rsk2 gene in osteoblast differentiation and function, establishing a causal link between Rsk2 deficiency and skeletal abnormalities of CLS. Although analyses in mice have revealed prominent expression of Rsk2 in brain structures that are essential for learning and memory, evidence at the behavioral level for an involvement of Rsk2 in cognitive function is still lacking. Here, we have examined Rsk2-deficient mice in two extensive batteries of behavioral tests, which were conducted independently in two laboratories in Zurich (Switzerland) and Orsay (France). Despite the known reduction of bone mass, all parameters of motor function were normal, confirming the suitability of Rsk2-deficient mice for behavioral testing. Rsk2-deficient mice showed a mild impairment of spatial working memory, delayed acquisition of a spatial reference memory task and long-term spatial memory deficits. In contrast, associative and recognition memory, as well as the habituation of exploratory activity were normal. Our studies also revealed mild signs of disinhibition in exploratory activity, as well as a difficulty to adapt to new test environments, which likely contributed to the learning impairments displayed by Rsk2-deficient mice. The observed behavioral changes are in line with observations made in other mouse models of human mental retardation and support a role of Rsk2 in cognitive functions. Edited by Andrew Holmes     

Chronic dietary alpha-lipoic acid reduces deficits in hippocampal memory of aged Tg2576 mice

Oxidative stress may play a key role in Alzheimer's disease (AD) neuropathology. Here, the effects of the antioxidant, alpha-lipoic acid (ALA) were tested on the Tg2576 mouse, a transgenic model of cerebral amyloidosis associated with AD. Ten-month old Tg2576 and wild type mice were fed an ALA-containing diet (0.1%) or control diet for 6 months and then assessed for the influence of diet on memory and neuropathology. ALA-treated Tg2576 mice exhibited significantly improved learning, and memory retention in the Morris water maze task compared to untreated Tg2576 mice. Twenty-four hours after contextual fear conditioning, untreated Tg2576 mice exhibited significantly impaired context-dependent freezing. ALA-treated Tg2576 mice exhibited significantly more context freezing than the untreated Tg2576 mice. Assessment of brain soluble and insoluble beta-amyloid levels revealed no differences between ALA-treated and untreated Tg2576 mice. Brain levels of nitrotyrosine, a marker of nitrative stress, were elevated in Tg2576 mice, while F2 isoprostanes and neuroprostanes, oxidative stress markers, were not elevated in the Tg2576 mice relative to wild type. These data indicate that chronic dietary ALA can reduce hippocampal-dependent memory deficits of Tg2576 mice without affecting beta-amyloid levels or plaque deposition.     

Enhanced susceptibility to MPTP neurotoxicity in magnesium-deficient C57BL/6N mice

We evaluated the effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57BL/6N mice fed a magnesium (Mg(2+))-deficient diet. On the 3rd week, Mg(2+)-deficient mice displayed increased anxiety- and depression-like behavior. In the Mg(2+)-deficient mice, a low does (10mg/kg) of MPTP treatment decreased dopamine (DA) and its metabolites contents in the striatum, but not in control mice. The same dose of MPTP did not influence these neurochemical markers in the mice fed Mg(2+)-deficient diet for 1 week which did not exhibit the altered emotional behavior. These results indicate that Mg(2+)-deficient mice with altered emotional behavior appear to increase the susceptibility to MPTP neurotoxicity in C57BL/6N mice.     

Spatial conditional discrimination learning in developing rats

The present study established an effective procedure for studying spatial conditional discrimination learning in juvenile rats using a T-maze. Wire mesh located on the floor of the maze as well as a second, identical T-maze apparatus served as conditional cues which signaled whether a left or a right response would be rewarded. In Experiment 1, conditional discrimination was evident on Postnatal Day (PND) 30 when mesh+maze or maze-alone were the conditional cues, but not when mesh-alone was the cue. Experiment 2 confirmed that mesh-alone was sufficiently salient to support learning of a simple (nonconditional) discrimination. Its failure to serve as a conditional cue in Experiment 1 does not reflect its general ineffectiveness as a stimulus. Experiment 3 confirmed that the learning shown in Experiment 1 was indeed conditional in nature by comparing performance on conditional versus nonconditional versions of the task. Experiment 4 showed that PND19 and PND23 pups also were capable of performing the task when maze+mesh was the cue; however, the findings indicate that PND19 subjects do not use a conditional strategy to learn this task. The findings suggest postnatal ontogeny of conditional discrimination learning and underscore the importance of conditional cue salience, and of identifying task strategies, in developmental studies of conditional discrimination learning.     

Paternal methyl donor deficient diets during development affect male offspring behavior and memory-related gene expression in mice

It has become increasingly evident that the methylation of DNA, known as an epigenetic marker, affects behavior in animals. In our previous study, a methyl-donors (folate, methionine, and choline)-deficient (FMCD) diet during the juvenile period could be shown to affect anxiety-like behavior and fear memory, accompanied by alteration in some gene expression and their methylations in the hippocampus. One question is whether the fear memory of a parent affects the fear responses of offspring. To explore this question in the present study, C57BL/6 J male (F0) mice were given a FMCD diet from 3 to 12 weeks of age. After confirming the effect of the FMCD diet on the behavior and gene expression of F0 mice, their male offspring (F1-FMCD mice) were examined using the same behavioral batteries and genetic analysis. F0 diet-based differences in F1 behavior were observed, accompanied by the differences in the expression of memory-related genes (Camk2α and PP1) and promoter methylation of the PP1 gene in the hippocampus. Our results add evidence that behavior and gene expression of the F1 generation could be altered due to differences in the father's intake of methyl-donor nutrients.     

Cognitive deficits in docosahexaenoic acid-deficient rats

This study investigated the influence of brain docosahexaenoic acid (DHA) deficiency on simple and complex olfactory-based learning and memory in 2nd generation (F2) adult male rats. Rats raised and maintained on either an n-3-adequate or an n-3-deficient diet were tested for acquisition of an olfactory learning set and an olfactory memory task, and for motivation to obtain a water reward. Despite a 76% decrease in brain DHA, n-3-deficient rats were able to acquire most simple 2-odor discrimination tasks but were deficient in the acquisition of a 20-problem olfactory learning set. This deficit could not be attributed to changes in sensory capacity but, instead, appeared to represent a deficit in higher order learning.     

Heart rate dynamics and behavioral responses during acute emotional challenge in corticotropin-releasing factor receptor 1-deficient and corticotropin-releasing factor-overexpressing mice

The role of corticotropin-releasing factor in autonomic regulation of heart rate, heart rate variability and behavior responses was investigated in two genetic mouse models: corticotropin-releasing factor receptor 1-deficient mice, and corticotropin-releasing factor-transgenic mice overexpressing corticotropin-releasing factor. Heart rate was recorded by radio-telemetry during novelty exposure and auditory fear conditioning. Locomotor activity and freezing served as behavioral indices. Locomotor activity and heart rate were invariably increased in response to novelty exposure in both corticotropin-releasing factor receptor 1-deficient mice and littermate wild-type controls. The heart rate responses during retention of conditioned auditory fear and the exponential relationship between heart rate and heart rate variability were unaffected by genotype. Moreover, conditioned fear responses inferred from multiple behavioral measures including freezing did not differ between corticotropin-releasing factor receptor 1-deficient and corticotropin-releasing factor receptor 1 wild-type control mice. Corticotropin-releasing factor-transgenic mice exhibited markedly reduced locomotor activity during novelty exposure when compared with littermate wild-type controls. Baseline and novelty-driven heart rate was slightly elevated in corticotropin-releasing factor-transgenic mice, whereas the novelty-induced increase of heart rate was not different between genotypes. In contrast, corticotropin-releasing factor-transgenic mice did not display a heart rate response indicative of conditioned auditory fear. It is concluded that corticotropin-releasing factor receptor 1-deficiency does not affect heart rate adjustment and behavioral responses to acute fearful stimuli. The resiliency of behavioral and cardiovascular patterns elevation argues against the involvement of corticotropin-releasing factor receptor 1 in acute emotional regulation on these two functional levels despite an absent corticosterone elevation in corticotropin-releasing factor receptor 1-deficient mice. It is hypothesized that the lack of a conditioned heart rate response in corticotropin-releasing factor-transgenic mice is attributable to an impairment of cognitive function. The results are compared with those of corticotropin-releasing factor receptor 2-deficient mice, and the role of the corticotropin-releasing factor system in cardiovascular regulation is discussed.     

Fmr1 knockout mouse has a distinctive strain-specific learning impairment

The Fmr1 gene knockout mouse is a model for the human Fragile X mental retardation syndrome. Fmr1 knockout mice with a C57BL/6-129/OlaHsd hybrid background have been reported to have only a very mild deficiency in learning the Morris water maze task. We compared the effect of this knockout mutation on learning in mice with either an FVB/N-129/OlaHsd hybrid background or a C57BL/6 background. When FVB-129 mice were tested in a cross-shaped water maze task, the knockout mice showed a pronounced deficiency in their ability to learn the position of a hidden escape platform in comparison to normal littermates. In contrast, knockout mice with a C57BL/6 background learned the maze just as well as their normal littermates. Fear conditioning did not reveal differences between knockout and normal mice in either background.These results show that silencing the Fmr1 gene clearly interfered with learning a specific visuospatial task in FVB/N-129 hybrid mice but not in C57BL/6 mice. The strain dependence may model the influence of genetic background in the human Fragile X syndrome.     

Progesterone enhances performance of aged mice in cortical or hippocampal tasks

Ovarian steroids alter cognitive performance of young individuals. Whether progesterone enhances learning and memory in tasks involving the prefrontal cortex and/or hippocampus in aged mice was investigated. Aged mice received progesterone (10 mg/kg, SC) or vehicle and were tested for cortical and/or hippocampal learning and memory. Progesterone increased spontaneous alterations in the T-maze and time spent exploring novel objects in the object recognition task. Progesterone increased the time mice spent in the quadrant of the water maze where the hidden platform had been during training, increased latencies to crossover to the shock-associated side of the inhibitory avoidance chamber, and increased freezing in the contextual fear conditioning task. Progesterone did not enhance performance in tasks mediated by the amygdala (cued conditioning), striatum (conditioned place preference), or cerebellum (rotarod) in these aged mice. Thus, progesterone improved learning and memory in tasks mediated by the prefrontal cortex and/or hippocampus of aged mice.     

Behavior of streptozotocin-diabetic mice in tests of exploration, locomotion, anxiety, depression and aggression

The present study examined behavior of streptozotocin-diabetic mice in Porsolt's swim test, a putative animal model of depression, in the holeboard test of exploration and locomotor activity, in the plus maze test of anxiety, and in the resident-intruder paradigm of aggression. Two weeks after an IP injection of 200 mg/kg streptozotocin, which caused a 20% weight loss and increased fluid consumption and urination, male NIH Swiss mice were found to show lengthened duration of immobility in the swim test. One week of insulin treatment (0.1 IU/g/day) partially antagonized this change. The locomotor activity scores in the streptozotocin-treated mice were lower in the holeboard but higher in the plus maze than in the controls; therefore, the lengthened immobility was not likely to be due to a general motor impairment. No significant changes in the time spent in social interaction or aggressive behavior were found in the streptozotocin-treated mice. The results indicate that streptozotocin-treated mice show lengthened immobility in the swim test.     

Sex differences in the acquisition of a radial maze task in the CD-1 mouse

The purpose of the present study was to investigate spatial processing performance in male and female CD-1 mice. A substantial literature supports the existence of significant sex differences in both human and rodent models of learning and memory. The nature of these differences is dependent upon the parameters of the task, species and strain of animal. In the present study, male and female CD-1 mice were trained for 3 days to perform a 4/8 spatial memory task in an eight-arm radial maze and then tested for a total of 5 days. On the final day of radial maze testing, male CD-1 mice committed marginally significantly fewer reference memory (RM) and significantly fewer working memory (WM) errors on the radial maze task than female CD-1 mice. In addition, female mice obtained significantly fewer rewards during the final two testing sessions. The present data provide the first evidence for sex differences in radial maze learning in the CD-1 mouse, a strain known for its estrogen insensitivity. Consistent with the majority of literature that supports sex differences in spatial processing in rodents, female CD-1 mice acquired significantly fewer rewards than male CD-1 mice during an eight-arm radial maze task.     

Rapid eye movement sleep deprivation selectively impairs recall of fear extinction in hippocampus-independent tasks in rats

Previous studies have shown that rapid eye movement (REM) sleep deprivation (RSD) exerts a detrimental effect on some memory tasks. However, whether post-learning RSD impairs memory for fear extinction, an important model of inhibitory learning, remains to be elucidated. The present study examined the effects of post-extinction RSD from 0 to 6 h and 6 to 12 h on recall of fear extinction tested 24 h after extinction training. We found that RSD from 0 to 6 h significantly increased freezing when recall of extinction of cued fear was tested in the context in which rats received extinction training whereas RSD from 6 to 12 h had no effect (experiments 1 and 2, two hippocampus-independent memory tasks). RSD at either time point had no effect on freezing when recall of extinction of cued fear was tested in the context different from that in which extinction training occurred (experiment 3, a hippocampus-dependent memory task). Additionally, we observed no effect of RSD at either time point on freezing during recall test for extinction of contextual fear (experiment 4, a hippocampus-dependent memory task). These results suggest that the effects of post-extinction RSD on memory for fear extinction are complex. RSD impairs recall of fear extinction in hippocampus-independent tasks, but does not affect recall of fear extinction in hippocampus-dependent tasks. Our findings extend previous research on the effects of RSD on learning and memory and support the notion that REM sleep is involved in memory process of certain tasks.     

Antidepressant-like behavior in brain-specific angiogenesis inhibitor 2-deficient mice

Brain-specific angiogenesis inhibitor 2 (BAI2) is a transmembrane protein that is predominantly expressed in the brain. Although BAI2 is supposed to correlate with antiangiogenesis in the brain, its psychiatric function is still unclear. In this study, we examined the influence of BAI2 gene disruption on mood-related behavior using BAI2-deficient mice. BAI2-deficient mice showed significant antidepressant-like behavior in the social defeat test and in the tail suspension test compared with wild-type mice. On the other hand, BAI2-deficient mice had normal basal locomotor activity in the home cage and in the open field test, and normal learning ability and memory retention in the Morris water maze test. Additionally, we found that hippocampal cell proliferation in BAI2-deficient mice was higher than that in wild-type mice. These results indicate that BAI2 has an important role related to depression and influences the hippocampal neurogenesis. BAI2 may be a novel therapeutic target for mood-related disorders.     

Estradiol reduces anxiety- and depression-like behavior of aged female mice

Beneficial effects of the ovarian steroid, 17β-estradiol (E₂), for affective behavior have been reported in young individuals, but less is known about the effects of E₂ among older individuals, and the capacity of older individuals to respond to E₂ following its decline. In the present study, the effects of acute E₂ administration to aged mice for anxiety-like and depression-like behaviors were investigated. Intact female C57BL/6 mice (N = 18) that were approximately 24 months old were administered vehicle (sesame oil, n = 9) or E₂ (10 μg, n = 9) subcutaneously 1 h prior to behavioral testing. Mice were tested for anxiety-like behavior (open field, elevated plus maze, mirror chamber, light-dark transition task, Vogel conflict task) and depression-like behavior (forced swim task). To assess the role of general motor behavior and coordination in these aged mice, performance in an activity monitor and rotarod task, and total entries made in tasks (open field, elevated plus maze, light-dark transition task) were determined. Mice administered E₂, compared to vehicle, demonstrated anti-anxiety behavior in the open field, mirror chamber, and light-dark transition task, and anti-depressive-like behavior in the forced swim task. E₂ also tended to have anti-anxiety effects in the elevated plus maze and Vogel task compared to vehicle administration, but these effects did not reach statistical significance. E₂ did not alter motor behavior and/or coordination in the activity monitor, open field, or rotarod tasks. Thus, an acute E₂ regimen produced specific anti-anxiety and anti-depressant effects, independent of effects on motor behavior, when administered to aged female C57BL/6 mice.     

Effects of the uterine environment and neocortical ectopias upon behavior of BXSB-Yaa+ mice

Between 40-60% of BXSB-Yaa+mice have neocortical ectopias, a genetically based brain anomaly. The presence of ectopias is known to affect several cognitive measures. A second way to affect cognition is by transferring embryos into foreign uteri. These variables were jointly investigated in three experiments. BXSB-Yaa+mouse embryos were transferred into same-strain uteri, or into uteri of hybrid mice. At birth, pups were cross-fostered to hybrid mothers or were reared by their birth mothers. When adult, the mice were given a series of behavioral tests with primary emphasis upon cognitive competence. Across all three studies, mice transferred into hybrid uteri were superior in the Morris maze and the Lashley III maze, and performed more effectively in shuttlebox avoidance learning. They were less effective in the simple water escape task, and the uterus groups did not differ in discrimination learning. Thus, development within a foreign uterus enhanced spatial learning and fear-based conditioning. Ectopic mice were superior to non-ectopics in learning the Morris maze, a finding consistent with prior research using the congenic BXSB-Yaa strain. There were Uterus x Ectopia interactions on a few measures, indicating that, under certain condition, whether the presence of ectopias is beneficial or detrimental is contingent upon the uterine environment within which the organism develops.     

Sex differences, context preexposure, and the immediate shock deficit in Pavlovian context conditioning with mice

The acquisition of context fear in rats is affected by variables such as the sex of the animal, the placement to shock interval (PSI), and preexposure to the context. The current experiments assessed the effects of these variables on context conditioning in mice (C57BL/6). In Experiment 1, mice were placed in a chamber and received a single shock 5s, 20 s, 40s, 60s, 180s, or 720s later. Increasing the PSI produced corresponding increases in conditional freezing during the context test. In addition, male mice acquired more context conditioning than female mice did but only at intermediate PSIs. In Experiment 2, preexposure to the context before training alleviated the sex difference found with an intermediate PSI. The results are discussed in terms of configural learning theory and are argued to be contrary to the predictions of scalar expectancy theory.     

Differences in Measures of Exploration and Fear in MHC-Congenic C57BL/6J and B6-H-2K Mice

MHC-congenic mice prefer to mate with mice of different MHC types and are able to discriminate between MHC-congenic mice by their urine odors, but nothing is known about behavioral differences among MHC-congenic mice. The present experiments examine the strain and sex differences in MHC-congenic C57BL/6J and B6-H-2K mice with respect to exploration and fear motivated behaviors in the elevated plus maze, the elevated zero maze, and the open field. In the elevated plus maze and elevated zero maze, C57BL/6J mice spent more time in the open areas than B6-H-2K mice, suggesting that they were less fearful and more exploratory. No sex differences for exploration were found but male mice defecated more than females in the elevated plus maze. In the open field there were no significant strain or sex differences in measures of exploration or fear. There were no strain differences in the investigation of a novel object placed into the open field, but males investigated the novel object more than females. These results indicate that there are differences in exploratory and fear behavior in MHC-congenic mice that may contribute to mate preferences and that behavioral differences in these mice might be further examined advantageously.