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PubMed2005

Motherhood mitigates aging-related decrements in learning and memory and positively affects brain aging in the rat.

The current work examined spatial learning and memory (i.e., latencies to find a baited food well) in age-matched nulliparous, primiparous and multiparous (NULL, PRIM and MULT, zero, one or two pregnancies and lactations, respectively). We tested at 6, 12, 18 and 24 months of age in a dry land version of the Morris water maze (Main task), and at 12, 18 and 24 months in the same task in which the original location of the baited well was changed (Reversal task). We show that PRIM/MULT rats, compared to the age-matched NULL females, learned the spatial tasks significantly better and exhibited attenuated memory decline, up to 24 months of age. Furthermore, at the conclusion of behavioral testing, we investigated levels of these animals' hippocampal (CA1 and dentate gyrus) immunoreactive amyloid precursor protein (APP), a marker of neurodegeneration and age-related cognitive loss. MULTs had significantly reduced APP in both CA1 and DG, relative to PRIMs and NULLs, and PRIMs had a trend (p<0.06) toward a reduction in APP compared to NULLs in DG. Further, level of APP was negatively correlated with performance in the two tasks (viz., more APP, worse maze performance). Reproduction, therefore, with its attendant natural endocrine and postpartum sensory experiences, may facilitate lifelong learning and memory, and may mitigate markers of neural aging, in the rat. Combining natural hormonal exposure with subsequent substantial experience with stimuli from the offspring may preserve the aged parous female brain relative to that of NULL females.

Age Factors↗

PubMed2006

Interactions between child and parent temperament and child behavior problems.

OBJECTIVE: Few studies of temperament have tested goodness-of-fit theories of child behavior problems. In this study, we test the hypothesis that interactions between child and parent temperament dimensions predict levels of child psychopathology after controlling for the effects of these dimensions individually. METHODS: Temperament and psychopathology were assessed in a total of 175 children (97 boys, 78 girls; mean age, 10.99 years; SD, 3.66 years) using composite scores from multiple informants of the Junior Temperament and Character Inventory and the Achenbach System of Empirically Based Assessment. Parent temperament was assessed using the adult version of the Temperament and Character Inventory. Statistical analyses included multiple regression procedures to assess the contribution of child-parent temperament interactions after controlling for demographic variables, other types of child psychopathology, and the individual Temperament and Character Inventory and Junior Temperament and Character Inventory dimensions. RESULTS: Interactions between child and parent temperament dimensions predicted higher levels of externalizing, internalizing, and attention problems over and above the effects of these dimensions alone. Among others, the combination of high child novelty seeking with high maternal novelty was associated with child attention problems, whereas the combination of high child harm avoidance and high father harm avoidance was associated with increased child internalizing problems. Many child temperament dimensions also exerted significant effects independently. CONCLUSIONS: The association between a child temperament trait and psychopathology can be dependent upon the temperament of parents. These data lend support to previous theories of the importance of goodness-of-fit.

Age Factors↗

PubMed2004

Behavioral characterization in a comprehensive mouse test battery reveals motor and sensory impairments in growth-associated protein-43 null mutant mice.

The growth-associated protein (GAP)-43 is a major neuronal protein associated with axonal growth, neuronal plasticity and learning. The observation that only 5-10% of mice with a full GAP-43 gene deletion survive weaning suggests that basic neural functions are disturbed. Here we used a comprehensive test battery to characterise and quantify the motor and sensory function of surviving adult homozygous GAP-43 (-/-) mice as compared with GAP-43 (+/-) and wild-type animals. The test battery was comprised of motor, sensory, and reflex tests producing 25 measures of locomotion, as well as epicritic, auditory, olfactory and visual function. The analysis revealed significant impairments in muscle strength, limb coordination and balance in GAP-43 (-/-) mice. Furthermore, GAP-43 (-/-) animals were hyperactive and showed reduced anxiety as measured by open field and light dark tests. In sensory tests, GAP-43 (-/-) mice were tested for impaired tactile and labyrinthine function. Abnormal reflexes were found in the contact and vibrissa placing responses, and in the crossed extensor reflex. GAP-43 (+/-) animals showed only moderate abnormalities as compared with wild-type animals. We conclude that GAP-43 is necessary for the development and function of a variety of neuronal systems. The results also show that the comprehensive test battery used in the present study represents a sensitive approach to assess the functional integrity of ascending and descending pathways in genetically manipulated mice.

Analysis of Variance↗

PubMed2006

Allosteric enhancement of metabotropic glutamate receptor 5 function promotes spatial memory.

Group I metabotropic glutamate receptors (mGluRs) have been implicated in learning and memory formation. Recent findings indicate an important function of the group I mGluR subtype 5. Here, we used the Y-maze spatial alternation task and examined whether enhancement of intrinsic mGluR5 activity immediately after learning, i.e. during a critical period for memory consolidation, would have any consequences on long-term memory retention in rats. Intracerebroventricular application of the allosteric mGluR5 potentiator DFB (3,3'-difluorobenzaldazine) resulted in a marked improvement in spatial alternation retention when it was tested 24 h after training. The promnesic effect increased with the difficulty of the task and was apparently due to a substantial enhancement of consolidation. The applied dose of DFB did not cause behavioral changes in the open field, and was devoid of structural side-effects as evaluated by immunohistochemical examination. Our results suggest an important function of post-training mGluR5 activation in some types of hippocampus-dependent spatial learning.

Allosteric Regulation↗

PubMed2005

Persisting behavioral consequences of prenatal domoic acid exposure in rats.

To investigate the behavioral effects of prenatal exposure to the marine toxin domoic acid, pregnant female rats were injected subcutaneously with 0, 0.3, 0.6, or 1.2 mg/kg of domoic acid on gestational day 13. The offspring were then run through a behavioral testing battery to determine the developmental effects of the toxin on spontaneous alternation in the T-maze, on locomotor activity in the Figure-8 maze, and on working memory in the 8-arm radial maze. In the T-maze, no significant domoic acid induced differences were seen on spontaneous alternation, but there were significant domoic acid effects on latency. Prenatal domoic acid exposure caused a dose-related increase in response latency in the second spontaneous alternation test. There was also a significant domoic acid effect seen in the 1-h long Figure-8 maze test. Locomotor activity measured in the Figure-8 maze detected a persisting effect of the 1.2 mg/kg domoic acid dose, which significantly increased the rate of habituation over the activity test session. This was characterized by higher initial activity followed by greater decline in activity. In the radial-arm maze the control vehicle treated rats showed the normal sex-related difference in spatial learning and memory with males outperforming females. Developmental domoic acid exposure decreased this effect such that the normal sex difference in spatial memory was not seen with the 1.2 mg/kg domoic acid dose. The rats of both sexes with a history of prenatal domoic acid exposure showed increased susceptibility to the amnestic effects of the muscarinic acetylcholine scopolamine, suggesting that they had less functional reserve with which to solve the radial-arm maze memory task. This study demonstrates persisting neurobehavioral effects of acute prenatal exposure to domoic acid at doses that do not cause overt clinical signs of toxicity.

Animals↗

PubMed2004

Increased grooming behavior in mice lacking vitamin D receptors.

Vitamin D is a neuroactive secosteroid with several important functions in the nervous system. Many human and animal findings link alterations in the vitamin D system to various neurological and behavioral disorders. Since grooming is an important element of animal behavior, here we studied whether genetic ablation of vitamin D receptors (VDR) in mice may be associated with altered grooming behaviors. Overall, VDR knockout (VDRko) mice presented longer duration and higher frequency of grooming when tested in the actimeter, open field, elevated plus maze, and horizontal rod tests. Increased grooming did not, however, correlate with unaltered general activity level (actimeter test), anxiety-like behaviors (hole board and elevated plus maze tests), and emotional reactivity index (defecation boli). In general, our results confirm the role of vitamin D and VDR in the regulation of behavior, including grooming, and suggest that increased grooming behavioral phenotype may be associated with genetic ablation of VDR in mutant mice.

Animals↗

PubMed2004

Home cage activity and activity-based measures of anxiety in 129P3/J, 129X1/SvJ and C57BL/6J mice.

We investigated the home cage activity and emotional behavior in mouse strains used as background for many studies of altered genes [C57BL/6J (B6, n=20), 129X1/SvJ (X1, n=20) and 129P3/J (P3, n=19)]. In their home cages, X1 and P3 mice exhibited less locomotion than did B6 mice, and the X1 mice showed significantly greater rearing than B6 and P3 mice did. A battery of three tests conducted in an open field (open field, emergence and novel object) revealed strain rankings of B6>X1>P3 or B6>X1=P3 in most activity variables. Significant correlations were found between home cage activity and activity in each of three tests, but not in all observation periods. Strain rankings on the elevated zero maze test were B6=X1>P3 in the number of stretched-attend body postures (SAPS) during the initial 6-min exposure for naive mice. Naive and nonnaive mice showed significantly different behaviors on the elevated zero maze. The results suggest that rankings on anxiety are P3>X1>B6 and that B6 mice have greater exploration in a novel environment compared with X1 and P3 mice. However, anxiety-like behaviors differed among strains in open-field-based tests and in the zero maze, and testing experience impacted performance on the zero maze. The findings illustrate that test variations and experience can influence performance and suggest the need for the consideration of how these factors interact with background strains in assessing gene-altered mice.

Analysis of Variance↗

PubMed2005

Exploration and risk assessment in female wild house mice (Mus musculus musculus) and two laboratory strains.

In an evolutionary prospective, it is possible that female mice have a differential perception of novel events than male mice and use a different behavioural strategy for risk assessment. However, female mice are less studied than male mice in behavioural tests of emotional reactivity. The aim of the present study was to investigate how wild-derived female house mice differ from domesticated female mice in their risk assessment strategy. A total of 46 adult female mice, 14 BALB/c, 16 C57BL/6 and 14 Wild mice were tested in the Concentric Square Field (CSF), Open Field (OF) and Elevated Plus Maze (EPM) at three consecutive days. Parameters from all three tests were categorized according to their relevance to activity, exploration, approach-avoidance and use of open areas-shelter. Principal Component Analysis (PCA-SIMCA) of the animals' behaviour in the CSF arena was performed both for females alone and in comparison with earlier findings in male mice under the same test conditions. The results clearly show that female wild mice had a higher avoidance of open areas than the laboratory strains. There was also a trend indicating differences in exploration and approach-avoidance between female Wild and the laboratory strains. The multivariate test, CSF, was able to detect differences between Wild and laboratory strains in three (exploration, approach-avoidance, open-shelter) of the four functional categories measured. Wild female mice also had a higher frequency of rearing and grooming and a lower duration in the corridors in the CSF. Clear strain differences were found between BALB and C57BL in all tests where BALB generally had higher risk assessment and lower risk taking than C57BL. No general sex differences were found, however the sex differences were greater in Wild mice compared to the laboratory strains.

Analysis of Variance↗

PubMed2005

Effects of social isolation on aging-induced orofacial movements in rats.

World population is becoming older, and aging is a common risk factor for a number of pathologies. In this respect, it is important to study possible factors that could modify alterations implicated in the process of aging. The aim of the present study is to verify the effects of social isolation on the expression of orofacial movements in adult and old rats. Adult and old rats were housed isolated for 5 days or kept in their home cages in groups of six. Before and after this period, orofacial movements and open-field general activity were evaluated. Aging-induced orofacial movements were abolished by isolation. On the other hand, isolated adult rats presented an increase in orofacial movements. General activity was decreased by aging but was not modified by isolation. Our results indicate that social isolation produces different effects in adult and old rats, and these effects are specific for orofacial movements and not related to a decrease in general motor activity.

Aging↗

PubMed2005

Neonatal handling increases fear and aggression in lactating rats.

Neonatal handling reduces fear in male and cycling female rats, but increases maternal aggressive behavior against intruders to the nest area. Present study aimed to analyze the effects of neonatal handling on the maternal aggressive behavior and the activity in the open field with a predator of lactating rats on the 8th and the 18th postpartum days (periods of high and low aggressiveness). As pups, animals were divided into two groups: nonhandled (no neonatal manipulation) and handled (handling for 1 min during the first 10 days after delivery). As adults, females of both groups were impregnated and tested against a male intruder for aggressive behavior and in the open field with a cat inside a wire-meshed cage. Results showed that on the 8th day frequency of aggressive behaviors of handled females was higher than that of the nonhandled ones, but on the 18th day, no significant difference was detected. Surprisingly, in the open field test, handled females showed decreased locomotion and increased freezing on the 8th day compared to the nonhandled ones. The opposite relationship between increased aggressiveness with reduced fear is observed in the nonhandled control females in early and late lactation periods. However, neonatal handling abolishes this relationship. Apparently, the increased aggressiveness in neonatal handled lactating females does not depend on a decrease in fear. Our findings support the hypothesis that long lasting effects of early life stimulation is a dynamic function depending on the behavioral system and the period of life analyzed. Moreover, they caution the relationship between aggressive behavior and fear.

Age Factors↗

PubMed2005

Early emergence of increased fearful behavior in prenatally stressed rats.

We have been studying the mildly prenatally stressed (PS) rat as a potentially useful animal model of anxiety disorders. Previously we have demonstrated that there are anatomical and biochemical alterations in the amygdalas of adult PS offspring and that these offspring show increased fearful behaviors. However, human data indicate that anxiety disorders often present first in early childhood and then persist throughout adolescence and adulthood. To determine if PS rats also model this characteristic of human anxiety disorders, here we asked whether behavioral indices of increased fear would be detectable at an early age. We tested the hypotheses that young PS rats would show increased behavioral fearfulness in response to an acute stressor and that this would increase with age. A mild prenatal stressor, consisting of removal of the dam from the home cage and administration of a subcutaneous injection of 0.1 ml of 0.9% saline daily, was administered during the last week of pregnancy. Offspring were tested in the defensive-withdrawal apparatus before and after exposure to restraint stress at 25, 45 and 60 days of age. PS animals showed increased defensive-withdrawal behavior following the stressor and were more fearful following restraint when compared to controls (CON). This was significant at P45 and increased to P60. Hence, fearful behaviors in PS rats emerge prior to sexual maturation and increase in magnitude thereafter, further validating our model as a means to investigate the underpinnings of anxiety disorders.

Animals↗

PubMed2005

The use of behavioral test batteries, II: effect of test interval.

Test batteries are commonly used to assess the behavioral phenotype of genetically modified and inbred strains of mice. However, few systematic studies have been employed to address several key issues concerning the use of a test battery. The current study was designed to address whether inter-test interval affects behavioral performance. Male mice of 3 different inbred strains and one F1 hybrid strain were randomly assigned to either a test battery with 1 week inter-test intervals, or a rapid test battery with 1-2 day inter-test intervals. The test battery included a neurological exam, open-field activity, light-dark exploration, rotarod test, prepulse inhibition, and startle habituation. The experiment was repeated with female animals of 2 different strains. As expected, there were strain differences on each of the behavioral assays; however, there was no major difference in performance between mice of the standard test battery and the rapid test battery. Similar results were found with females. These results indicate that the interval between most tests could be as little as 1-2 days, with little significant effect on overall performance. Thus, it is possible with the current test battery to reduce the inter-test interval to facilitate the rate of studying and identifying behavioral phenotypes in mice.

Analysis of Variance↗

PubMed2006

Troubles shared are troubles halved: stress in rats is reduced in proportion to social propinquity.

The mitigation of stress by social support is of obvious interest and widely studied. Animal models have been used extensively to elucidate the mechanisms involved. Typically, these examine the effects of social housing versus isolation, imparting resistance to stress before it is applied, or ameliorating its effects post hoc. Few experiments directly compare stress impinging upon an individual alone or in a social milieu. Here we compare the effects of stress on a solitary rat and on pairs of rats in a structured rank order of social propinquity. Rats were placed on a raised platform for 30 min under four conditions manipulating the degree of proximity between the rats: alone on the platform in the test room, on the platform with a cagemate in a cage elsewhere in the room, two rats each on a raised platform 40 cm apart and two rats each on a raised platform 0 cm apart. Immediately after the stress, the rats were tested in an open field. We find that stress is mitigated proportionally: stress was reduced the more salient the other rat's cues were and the closer the rats were to each other.

Analysis of Variance↗

PubMed2006

Time course of alterations after olfactory bulbectomy in mice.

Olfactory bulbectomy in rodents causes behavioral alterations, which result in a model of depression, validated for pharmacological screening of antidepressant drugs. To unravel the appearance and time course of the major behavioral effects which follow surgery, mice underwent olfactory bulb ablation or sham operation, and were analyzed after 1, 2, or 4 weeks. Bulbectomized (BX) mice were anosmic, and hyperactive when tested under stressful situations in the forced swimming test. Predatory aggression was upregulated in a time-dependent way: only after 4 weeks BX mice were faster than controls in attacking prey. At the same time, they were less aggressive against intruders; they did not differ from controls in open field exploration, but displayed a cognitive impairment in water maze. Behavioral tests thus indicated a marked hyperreactivity, a dissociation among different aggressive behaviors, and also a cognitive impairment induced by bulbectomy. Histological confirmation of the damage revealed that major modifications took place in the rostral pole of frontal lobes, with a significant increase in the width of the rostral migratory stream, 2 weeks after surgery, and in the subventricular zone, 4 weeks after surgery. These results suggest a base for the time-course of appearance of behavioral symptoms in BX mice.

Aggression↗

PubMed2006

The effects of individual housing on 'anxious' behaviour in male and female gerbils.

Gerbils are social animals and live in family groups in the wild, suggesting that individual housing may be a psychosocial stressor in this species. In the present study, gerbils were housed in same sex groups for 4 weeks, and then were either individually housed or remained with their cage mates for 1 week. Gerbils were tested in the black/white box (BWB), elevated plus maze (EPM) and social interaction test. Results indicated no significant differences in behaviour in the BWB. In contrast, on the EPM individually housed males showed increased anxiety compared to other groups, whilst there were no specific effects in females. In the social interaction test, however, individual housing in males increased social investigation, whilst females showed a decrease in exploration, accompanied by increased immobility. Passive immobility (freezing) was also increased in both sexes following individual housing. Thus, data from the EPM suggest that individual housing leads to increased anxiety mainly in males, whilst data from the SI suggests broadly the opposite. Therefore, individual housing results in different behavioural changes in male and female gerbils, which are dependent upon the test situation. This study highlights two key points. Firstly, it is important to use our knowledge of the species natural ecology in interpreting and designing anxiety tests. Secondly, it is important to assess behaviour in a range of situations when attempting to measure 'anxiety', particularly where tests developed for use in one species/sex are being used in another.

Animals↗

PubMed2006

Progesterone withdrawal effects in the open field test can be predicted by elevated plus maze performance.

Allopregnanolone (3alpha-hydroxy-5alpha-pregnane-20-one) is a ring-A-reduced metabolite of progesterone, which is naturally produced during the luteal phase of the menstrual cycle, during pregnancy and by stressful events. The steroid hormone inhibits neural functions through increased chloride ion flux through the GABA(A) receptor. The effects and subsequent withdrawal symptoms are similar to those caused by alcohol, benzodiazepines and barbiturates. This study examined the withdrawal effects of progesterone with regards to the influence of individual baseline exploration and risk taking. Rats were tested on the elevated plus maze (EPM) before hormonal treatment, in order to evaluate differences in risk taking and exploration of open and elevated areas. Treatment consisted of ten consecutive once a day progesterone or vehicle s.c. injections. On the last day of treatment, estradiol was injected in addition to progesterone, followed by a 24-h withdrawal before testing in the open field test (OF). Progesterone-treated rats showed a withdrawal effect of open area avoidance in the OF. The vehicle-treated control rats showed strong correlations between the EPM and OF parameters. This relationship was not found for the progesterone group at withdrawal. Rats with greater numbers of open arm entrance in the EPM pretest showed an increased sensitivity to progesterone withdrawal (PWD) compared to rats with low exploration and risk taking. The results indicate that the effects of PWD relate to individual exploration and risk taking. Furthermore, the possible analogy of PWD and PMS/PMDD in relation to individual traits is discussed.

Animals↗

PubMed1998

Differential influence of a selective melanocortin MC4 receptor antagonist (HS014) on melanocortin-induced behavioral effects in rats.

We injected i.c.v. the natural agonist alpha-MSH (melanocyte-stimulating hormone) and the first selective melanocortin MC4 receptor antagonist HS014 (cyclic [AcCys11, D-Nal14, Cys18, Asp-NH(2)22]-beta-MSH(11-22) in rats and scored a number of behavioral effects which have been related to the melanocortic peptides. The results showed that HS014 (5 microg/rat) completely blocked alpha-MSH (3 and 5 microg/rat)-induced grooming, yawning and stretching. Penile erections induced by alpha-MSH were, however, only partially blocked by HS014. Injections of alpha-MSH decreased food intake in food-deprived rats, whereas HS014 increased food intake. When the peptides were given together, the food intake was similar to that of saline treated controls. Locomotion/exploration and resting were not influenced by either peptide. Our data show that exogenous beta-MSH decreases food intake, and that an endogenous central melanocortinergic inhibitory tone on feeding prevails which can be blocked with HS014, leading to an increase in food intake. Our data also provide evidence that grooming, stretching and yawning in rats may be mediated by the melanocortin MC4 receptor, whereas penile erections might perhaps be mediated by some other melanocortin receptor.

Animals↗

PubMed2001

Strain and gender differences in the behavior of mouse lines commonly used in transgenic studies.

The present study was aimed at establishing behavioral differences between three inbred mouse strains (129S2/SvHsd, C57BL/6JOlaHsd, FVB/NHsd) and two F1 hybrid lines derived from them (129 x C57BL/6 and 129 x FVB). The choice of the given strains was based on the frequent use of these mice in transgenic research. For the behavioral phenotyping, we employed a test battery consisting of the following models: elevated plus-maze (EPM), open field (OF), light-dark exploration, spontaneous locomotor activity, rota-rod (RR), Porsolt's forced-swimming test (FST), and Morris water task. Significant variations between the strains were established in all tests. Anxiety-like behavior was more pronounced in the 129S2/Sv and 129 x C57BL/6 mice, the FVB/N mice were spontaneously hyperactive, the best coordination ability was demonstrated by the C57BL/6 and 129 x C57BL/6 groups. A good performance in the learning test was established in both hybrid lines and the 129S2/Sv mice, whereas the well-known visual impairment of the FVB strain was confirmed by low performance in spatial and non-spatial tasks. Differences related to the gender were revealed occasionally; most importantly, 129 x C57BL/6 males had a higher anxiety level than their female counterparts in the EPM. Several other gender dissociations suggest the strain and task specificity. In conclusion, we would like to highlight the importance of the genetic background and gender of mice for the molecular biological and pharmacological studies and also the need for well-established testing protocols to obtain wide information at the first stage of behavioral screening of genetically modified mice.

Animals↗