Biomedical subjects
Publications and source records attributed to V H Denenberg.
To determine if mice could perceive differences among several complex black/white patterns, a water version of a radial-arm maze was modified into a T-maze. BXSB mice were able to discriminate between multiple pairs of stimuli.
A water-escape version of the radial-arm maze was used to assess rat spatial working memory performance. Intact females and ovariectomized females receiving a physiologically low dose, physiologically moderate dose or no estradiol replacement were studied. Subjects were given seven trials a day for 12 days. Females receiving moderate dose estradiol made fewer errors than the other three groups during the latter portion of testing. As trials progressed within a session, the elements of information to be remembered increased. Assessment of individual trials revealed that when the demand on an animal's working memory system was limited to one to four elements of information, the three groups with estrogen (including intact females) maintained successful performance, whereas the ovariectomized females made more errors. However, when the demand on an animal's working memory system was increased to six elements of information, only the moderate dose estradiol females maintained successful performance. These data suggest that, although moderate levels of estradiol replacement are the most beneficial for working memory function, even low-dose estradiol replacement can act to protect working memory systems from the decline seen with the removal of ovarian hormones.
Anomalies in the laterality of numerous neurocognitive dimensions associated with schizophrenia have been documented, but their role in the etiology and early development of the disorder remain unclear. In the study of normative neurobehavioral organization, animal models have shed much light on the mechanisms underlying and the factors affecting adult patterns of both functional and structural asymmetry. Nonhuman species have more recently been used to investigate the environmental, genetic, and neuroendocrine factors associated with developmental language disorders in humans. We propose that the animal models used to study the basis of lateralization in normative development and language disorders such as dyslexia could be modified to investigate lateralized phenomena in schizophrenia.
Direct behavioral observation and motility monitoring procedures provide reliable data, and both are appropriate for sleep/wake state measurements starting immediately after birth. Using these procedures, newborn rats, rabbits, and humans were found to have a greater amount of quiet sleep on the day of birth rather than 24 hr later. Changes in active sleep and wake were inconsistent across the 2 days. The quiet sleep findings are contrary to the developmental course which increases with age. The findings are interpreted as a temporary adaptive response to the stress of the birth process.
BXSB mice have a 40-60% incidence of small, focal, neocortical dysplasias called ectopias. Ectopics and non-ectopics were compared on horizontal-vertical discrimination learning, a non-spatial cognitive task. No differences were found during acquisition. Ectopic mice, however, were superior when retested 8 weeks later. The results support prior findings that ectopic mice have better long-term spatial memory and extend this conclusion to the non-spatial domain.
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Genetically identical mouse embryos were transferred into same-strain uteri (transfer controls) or into hybrid uteri. A third group was not transferred. When adult, the mice were given a series of behavioral tests. In-strain transfer controls differed from non-transfer mice only on two activity measures, and did not differ on any cognitive variable. In contrast, mice reared in hybrid uteri were found to be superior to in-strain transfer mice on discrimination learning. Lashley maze learning and Morris maze learning; they also showed better adaptation in an avoidance learning shuttlebox. To our knowledge this is the first study showing that the uterine environment can have a general enhancing effect upon cognitive competence across a broad range of behaviors.
Genetically identical mouse embryos were transferred into same-strain uteri (transfer controls) or into hybrid uteri. A third group was not transferred. When adult, the mice were given a series of behavioral tests. In-strain transfer controls differed from non-transfer mice only on two activity measures, and did not differ on any cognitive variable. In contrast, mice reared in hybrid uteri were found to be superior to in-strain transfer mice on discrimination learning, Lashley maze learning and Morris maze learning; they also showed better adaptation in an avoidance learning shuttlebox. To our knowledge this is the first study showing that the uterine environment can have a general enhancing effect upon cognitive competence across a broad range of behaviors.
The conventional land radial-arm maze has several disadvantages, including requiring a complicated automated apparatus, the elimination of odors as cues, and the use of food deprivation. We have created a water version of the maze, based on the principles of the land version, which maintains the advantages and excludes some of the disadvantages. In our maze, BXSB and C57BL/6 mice significantly reduced the number of working and reference memory errors committed over sessions, while NZB mice did not. For each strain, as the working memory 'load' increased during a session, the number of errors increased. However, with practice the BXSB and C57BL/6 strains were able to handle this memory load more effectively. Mice were able to learn the maze without extensive adaptation, training, or testing and they did not exhibit 'chaining'. This maze can also be considered to be an example of a water win-shift task that mice can easily learn. Therefore, the water version of the radial-arm maze can be a simple and useful tool for studying rodent learning and memory.
BXSB/ MpJ-Yaa and NZB/BINJ mice have been used as animal models for both developmental learning disability and systemic autoimmune disease. Approximately 40-60% of these animals show ectopic clusters of neurons in Layer I of cortex similar to those found in postmortem analyses of human dyslexics, and all exhibit an autoimmune condition similar to systemic lupus erythematosus (SLE) in humans. The expression of immune disease in the BXSB strain, unlike in humans, is more severe in males than females. Most previous studies have examined the behavioral sequelae of neocortical ectopias at a relatively young age, when the BXSB females (unlike the male BXSB and female and male NZBs) are not yet showing high titers of autoantibodies associated with their lupus-like form of autoimmune disease. This study examined the behavior of BXSB females at an age subsequent to autoimmune disease onset. When contrasted with younger animals, year-old BXSB females showed good learning behavior, with no differences in Lashley maze learning and remarkably good performance in a visual discrimination learning task. These results are consistent with other data which indicate that many types of learning behavior are apparently unperturbed by systemic autoimmune disease. Results also showed significant interactions between a measure of lateral paw preference and the presence or absence of ectopias in Lashley maze learning. Animals without ectopias that exhibited a right lateral paw preference showed the greatest number of errors on a number of test measures. These findings support previous results indicating that behavioral effects associated with ectopias may vary based upon the behavioral laterality of affected animals.
Historically, studies of the role of endogenous hormones in developmental differentiation of the sexes have suggested that mammalian sexual differentiation is mediated primarily by testicular androgens, and that exposure to androgens in early life leads to a male brain as defined by neuroanatomy and behavior. The female brain has been assumed to develop via a hormonal default mechanism, in the absence of androgen or other hormones. Ovarian hormones have significant effects on the development of a sexually dimorphic cortical structure, the corpus callosum, which is larger in male than in female rats. In the females, removal of the ovaries as late as Day 16 increases the cross-sectional area of the adult corpus callosum. Treatment with low-dose estradiol starting on Day 25 inhibits this effect. Female callosa are also enlarged by a combination of daily postnatal handling and exogenous testosterone administered prior to Day 8. The effects of androgen treatment are expressed early in development, with males and testosterone-treated females having larger callosa than control females as early as Day 30. The effects of ovariectomy do not appear until after Day 55. These findings are more consistent with other evidence of a later sensitive period for ovarian feminization as compared to androgenic masculinization.
Autoimmune mice perform poorly in two-way active avoidance tasks, and the extent of this performance deficit appears to be related to the extent of autoimmunity following developmental manipulations. In the current study, the pituitary hormone prolactin, which has immune-enhancing effects, was used to manipulate this behavioral disorder in adulthood. Prolatinergic manipulation may be achieved by the use of dopaminergic drugs. In two experiments, autoimmune NZB X NZW F1 (BW) mice received either pimozide (PIM; a D2 antagonist) or bromocriptine (CB154; a dopamine agonist) in their drinking water. Control subjects received plain water. Following treatment, subjects were tested in an activity monitor, and active avoidance learning. Circulating PRL levels, as measured by RIA, were significantly increased by PIM and significantly decreased by CB154. Neither drug affected circulating levels of autoantibodies to DNA or cardiolipin, a phospholipid. In Experiment 1, in which mice were tested at 12 weeks of age, after 6 weeks of drug treatment, PIM treated animals of both sexes showed significantly more failures to escape the shock in avoidance conditioning, while CB154 did not have significant effects. In Experiment 2, in which mice were tested at 16 weeks of age, after 12 weeks of drug treatment, CB154 treated females (males were not tested) showed significantly fewer failures to escape, while PIM did not have significant effects. The effects of PRL on behavior, and its relation to immune system function, are discussed.
BXSB mice have small neocortical anomalies (ectopic collections of neurons in layer I), with an incidence of about 40-60%. Previous studies have found that ectopic mice from this strain are faster than non-ectopics in learning the Morris water maze (reference memory), but have poorer working memory for spatial learning. The current study continues the investigation of working memory by testing ectopic and non-ectopic BXSB mice on a spatial delayed-matching-to-sample test (S-DMTS; also called spatial learning sets or 'working memory' water maze). In this test, the mice must find a submerged platform in a pool of water. The platform changes location with every problem, or block of four trials. The subject has 'matched to sample' if it locates the platform in less time on the second trial of each problem than it did on the first. Of 33 subjects, 8 had cortical ectopias, one had a small neuron-free gliotic area, and 24 were normal. The normal subjects showed a decrease in time to escape over the first 2 trials of the first 5 problems, while the ectopic subjects did not show a decrease until the third trial, indicating that ectopic mice required more trials to put the platform location into working memory. The site of the ectopias is prefrontal/motor cortex, and we hypothesize that is the cause of the poorer working memory.
1. The authors investigated whether learned helplessness was a possible explanation for the observed learning deficits demonstrated by autoimmune mice in shuttlebox avoidance. If mice were experiencing learned helplessness during the avoidance testing, one would expect this to transfer to other behavioral tests resulting in lower learning scores. 2. One group of BXSB mice was tested in avoidance first, a water version of the Lashley III maze second, and water escape last, while another group was given these tests in the reverse order. 3. Animals who were exposed to avoidance first did not demonstrate any learning deficits in subsequent tests, suggesting that there were no adverse effects of avoidance training on later water maze learning. 4. However, correlations between number of null responses during avoidance learning and two other measures suggest that the null response measure may be an index of a continuum of learned helplessness within the BXSB strain.
The current study examined the contribution of early postnatal experience to the functional lateralisation of spatial ability in the male rat. Litters were handled (H) or non-handled (NH) during the first 20 days of life, and three males from each litter were tested in the Morris water maze in adulthood. Two subjects from each litter were monocularly tested, one with the right eye patched and the other with the left eye patched. A third subject in each litter was tested with both eyes open. Handling interacted with Eye Patch for time and distance measures. Performance of Right- and Left-Patched rats was equivalent for the NH group, but the H subjects tested with the Right Patch outperformed H subjects with the Left Patch. These results confirm studies that found spatial navigation performance to be lateralised to the right hemisphere in male rats. The data indicate that functional asymmetry of spatial navigation behaviour in the adult male rat is sensitive to environmental influences during early development.
We had previously shown that elimination of testosterone from embryonic day 17 through adulthood reduced the midsagittal area of the male rat corpus callosum (CC). However, day 1 castration, performed after the 2-h post-birth testosterone surge, was without effect. To elucidate the contribution of this surge on the CC, male rats were delivered by cesarean section and castrated within 20 min. This procedure eliminated the 2-h postnatal rise in testosterone levels. The prenatal surge in testosterone, which occurs on embryonic day 18, remained intact. In adulthood, callosal area was examined in castrate males, sham males, and intact females. Castrate males and sham males had significantly larger CCs as compared to females. The two male groups did not differ from each other. Body weight was significantly higher in sham versus castrate males, establishing the effectiveness of the castration. These results show that hormonal organization of the CC in the male is the result of the independent action of prenatal testicular androgens, and suggest that the end of this period marks the end of callosal sensitivity to testicular hormone influence. In addition, this report documents sexual dimorphism of the CC in a third rat strain.
Approximately 40-60% of BXSB mice have ectopic cell clusters in layer 1 of neocortex. Prior studies have shown distinct behavioral differences between those with ectopias and their non-ectopic littermates. In this study, female BXSB mice were reared after weaning in either enriched environments or standard cages. Following an initial round of behavioral testing, all mice were housed in standard cages and retested. Enriched cage mice (both ectopic and non-ectopic) showed increased activity, greater speed, and enhanced learning scores across a variety of tests. Additionally, prior test experience itself had significant positive effects on Hebb-Williams maze learning. The presence of ectopias resulted in better Morris maze learning for standard cage reared mice. Further, ectopic mice, regardless of their housing condition, showed better long-term retention in the Morris maze than did their non-ectopic counterparts. These findings show that abnormalities in corticogenesis need not always result in functional deficit.
Behavioral laterality has been shown to be related to immunological and endocrinological responsiveness in mice. The current study extended these findings by examining the pituitary hormone prolactin, and its response to stress, in left- and right-pawed mice. In two experiments, mice were tested on two measures of behavioral laterality, the Collins paw preference test and the Lateral Paw Preference (LPP) test. Circulating PRL levels were then measured in all subjects under baseline and stressed conditions. In Experiment 1, the PRL stress response was related to Collins paw preference in interaction with coat-color among females of a genetically heterogeneous group. Left-pawed black females showed a significant increase in PRL, while right-pawed black females did not. Among agouti mice, left-pawed females showed a significant decrease, while right-pawed did not. Experiment 2 used a genetically homogeneous group of agouti C3H mice. Again there were effects of Collins paw preference among females, with the right-pawed showing a significant increase in PRL following stress. In neither experiment were there effects of LPP. In neither experiment were there lateralized differences among males. These results indicate lateralized regulation of PRL among females, similar to that previously observed for ACTH regulation.