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Biomedical subjects

L A Hyde

Publications and source records attributed to L A Hyde.

At least 19 recordsLinked to original sources
PubMed2005

Characterization of the nociceptin receptor (ORL-1) agonist, Ro64-6198, in tests of anxiety across multiple species.

RATIONALE: Previous studies have demonstrated behaviors indicative of anxiolysis in rats pretreated with the nociceptin receptor (opioid receptor like-1, ORL-1) agonist, Ro64-6198. OBJECTIVES: The aim of this study was to examine the effects of Ro64-6198 in anxiety models across three species: rat, guinea pig, and mouse. In addition, the receptor specificity of Ro64-6198 was studied, using the ORL-1 receptor antagonist, J-113397, and ORL-1 receptor knockout (KO) mice. Finally, neurological studies examined potential side effects of Ro64-6198 in the rat and mouse. RESULTS: Ro64-6198 (3-10 mg/kg) increased punished responding in a rat conditioned lick suppression test similarly to chlordiazepoxide (6 mg/kg). This effect of Ro64-6198 was attenuated by J-113397 (10 mg/kg), but not the mu opioid antagonist, naltrexone (3 mg/kg). In addition, Ro64-6198 (1-3 mg/kg) reduced isolation-induced vocalizations in rat and guinea pig pups. Ro64-6198 (3 mg/kg) increased the proportion of punished responding in a mouse Geller-Seifter test in wild-type (WT) but not ORL-1 KO mice, whereas diazepam (1-5.6 mg/kg) was effective in both genotypes. In rats, Ro64-6198 reduced locomotor activity (LMA) and body temperature and impaired rotarod, beam walking, and fixed-ratio (FR) performance at doses of 10-30 mg/kg, i.e., three to ten times higher than an anxiolytic dose. In WT mice, Ro64-6198 (3-10 mg/kg) reduced LMA and rotarod performance, body temperature, and FR responding, but these same measures were unaffected in ORL-1 KO mice. Haloperidol (0.3-3 mg/kg) reduced these measures to a similar extent in both genotypes. These studies confirm the potent, ORL-1 receptor-mediated, anxiolytic-like effects of Ro64-6198, extending the findings across three species. Ro64-6198 has target-based side effects, although the magnitude of these effects varies across species.

Animals↗
PubMed2005

Transgenic overexpression of neuromedin U promotes leanness and hypophagia in mice.

Recent work has shown that neuromedin U (NmU), a peptide initially identified as a smooth muscle contractor, may play a role in regulating food intake and energy homeostasis. To further evaluate this putative function, we measured food intake, body weight, energy expenditure and glucose homeostasis in transgenic mice that ubiquitously overexpress murine proNmU. NmU transgenic mice were lighter and had less somatic and liver fat, were hypophagic, and had improved insulin sensitivity as judged by an intraperitoneal insulin tolerance test. Transgenic mice had higher levels of hypothalamic NPY, POMC and MCH mRNA. There was no difference in O2 consumption between genotypes; however, NmU transgenic mice displayed a modest increase in respiratory quotient during food deprivation and refeeding. There were no behavioral disturbances in the NmU transgenic mice that could account for the results (e.g. changes in locomotor activity). When placed on a high-fat diet, transgenic mice remained lighter than wild-type mice and ate less, but gained weight at a rate similar to wild-type mice. Despite the increased weight gain with high-fat feeding, glucose tolerance was significantly improved in the transgenic mice. These findings support the hypothesized role of NmU as an endogenous anorexigenic peptide.

Animals↗
PubMed2001

Ts65Dn mice, a model for Down syndrome, have deficits in context discrimination learning suggesting impaired hippocampal function.

The Ts65Dn mouse is segmentally trisomic for a part of mouse chromosome 16 and is a genetic model for Down syndrome and Alzheimer's disease. Although many studies have examined the learning and memory processes in Ts65Dn mice, it has yet to be determined if Ts65Dn mice are specifically impaired in learning tasks that require an intact hippocampus. Context discrimination learning is dependent on the dorsal hippocampus in mice. In this task, mice learn to discriminate two similar contexts, one of which is associated with foot shock. In the current study, Ts65Dn mice learned almost identically to what has been reported for mice with dorsal hippocampal lesions, while controls behaved similarly to sham lesioned mice. Therefore, Ts65Dn mice have learning deficits in a hippocampal dependent task that may be related to the loss of cholinergic input to the hippocampus, which occurs after 6 months of age.

Age Factors↗
PubMed2001

Motor learning in Ts65Dn mice, a model for Down syndrome.

Ts65Dn mice are a genetic model for Down syndrome. Both individuals with Down syndrome and Ts65Dn mice have reduced cerebellar volumes and the cerebellum is involved in motor learning. Conflicting results have been reported on the motor learning abilities of Ts65Dn mice, which may be related to procedural differences between the motor learning tasks used in different laboratories and/or variability in phenotype because of the segregating background on which the mice are maintained. In this study, we examined learning in three types of motor tasks (peg running, accelerating rotorod, and rotating rod) which were initially easy for mice and gradually increased in difficulty. Ts65Dn mice learned the peg running task as well as controls, and learned the accelerating rotorod and rotating rod tasks as well as, and even better than, controls. These data indicate that Ts65Dn mice are not impaired in motor learning.

Animals↗
PubMed2001

Effects of ectopias and their cortical location on several measures of learning in BXSB mice.

About half of BXSB/MpJ-Yaa mice have ectopias, which are misplaced clusters of neurons located in layer I of cortex. This study replicated several previous findings showing that there are learning differences between mice with ectopias and those without. In addition, we had sufficient numbers of ectopic mice to investigate if ectopics learned differently depending on the cortical location of the ectopia(s). Mice with at least one ectopia located in prefrontal cortex were initially impaired in learning the Morris maze, as well as relearning the Lashley maze when it was inverted, but learned better in the radial-arm maze when compared to ectopic mice with ectopias located in nonprefrontal regions of cortex. Mice with at least one ectopia in motor cortex learned the Lashley maze better than mice with ectopias located outside motor cortex. In sum, the cortical location of the ectopia(s) affected learning performance in certain tasks within the ectopic group, but regardless of the cortical location of the ectopia(s), ectopics still learned differently than nonectopics in several tasks.

Animals↗
PubMed2001

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

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

Animals↗
PubMed2001

Age-related deficits in context discrimination learning in Ts65Dn mice that model Down syndrome and Alzheimer's disease.

All individuals with Down syndrome (DS) eventually develop the neuropathology of Alzheimer's disease (AD), which is characterized by a premature loss of basal forebrain cholinergic neurons. Similarly, between 4 and 6 months of age, Ts65Dn mice, which model DS, lose cholinergic markers in their medial septal neurons. It is not known whether Ts65Dn mice have age-related learning deficits as well. Control and Ts65Dn mice were tested at several ages in context discrimination. Controls at all ages showed no deficits in learning this task. Ts65Dn mice younger than 3 months demonstrated impaired learning, suggesting a possible developmental delay in Ts65Dn mice. Four-month-old Ts65Dn mice showed no deficits, whereas Ts65Dn mice older than 5 months were impaired in learning the task. Therefore, Ts65Dn mice have an age-related learning impairment that coincides with their age-related neuroanatomical abnormalities and, consequently, may be a useful model of AD.

Aging↗
PubMed2000

Avoidance learning in autoimmune mice.

Previous studies have shown that autoimmune mice perform very poorly on active avoidance learning tasks. In the current studies, mice with lupus-like systemic autoimmunity were able to learn active, as well as passive, avoidance protocols with shock as reinforcement. Therefore, the behavioral deficits seen in active avoidance tasks are not a consequence of the use of electric shock. Rather, the current findings suggest that the inability of autoimmune mice to learn shock motivated responding is due to multiple performance factors, including shock level and properties of the testing apparatus.

Animals↗
PubMed2000

Non-spatial water radial-arm maze learning in mice.

Recently, we published a method for examining working and reference memory in mice using a spatial version of the water radial-arm maze. Here we describe a non-spatial version of the same maze. BXSB mice were able to learn the maze as shown by the decrease in the number of working and reference memory errors over sessions. This maze was used to examine learning differences between males and females and between mice with misplaced clusters of neurons in layer I of cortex (ectopias) and those without. In a prior study using the spatial version of the water radial-arm maze, male BXSB mice had poorer working memory than females during the acquisition phase. Similarly, in this study male BXSB mice demonstrated impaired working memory during the asymptotic phase of non-spatial radial-arm maze learning. Two prior studies showed that mice with neocortical ectopias demonstrated working memory impairments compared to non-ectopic littermates in the spatial version of the water radial-arm maze. Contrary to this, in the non-spatial radial-arm maze used here, ectopic mice were not impaired in working memory and showed better memory when the working memory 'load' was the highest. Overall, both versions of the maze can be useful tools to assess spatial and non-spatial working and reference memory in mice.

Animals↗
PubMed2000

Spatial ability of XY sex-reversed female mice.

Perinatal gonadal hormones significantly affect subsequent sex differences in reproductive and non-reproductive behaviors in rodents. However, the influence of the sex chromosomes on these behaviors has been largely ignored. To assess the influence of the non-pseudoautosomal region of the Y chromosome, C57BL/JEi male and female mice and mice from the C57BL/6JEi-Y(POS) consomic strain were given behavioral tests known to distinguish males from females. The C57BL/6JEi-Y(POS) strain contains sex-reversed XY-females which, when compared to their XX-female siblings, allow assessment of the influence of the Y chromosome in a female phenotype. XX-females and XY-females did not differ on open-field activity, the Lashley maze, or active avoidance learning, but XY-females were significantly better than XX-females on the Morris hidden platform spatial maze. These findings suggest that males may have both a genetic and a hormonal mechanism to ensure visuospatial superiority.

Animals↗
PubMed2000

Effects of the non-pseudoautosomal region of the Y-chromosome on behavior in female offspring of two congenic strains of mice.

The learning behavior of female offspring of two strains of mice congenic for the Y-chromosome, BXSX/MpJ-Yaa and BXSB/MpJ-Yaa+, was examined. Significant differences were found in the Morris water maze and the Lashley III maze, demonstrating that the fathers' Y-chromosome can indirectly affect their daughters' behavior. Approximately half the mice had neocortical ectopias, and females from the two paternal groups reacted differently to the presence or absence of ectopias. Since females do not have a Y-chromosome, these effects must be through non-genetic mechanisms. Prenatal factors that could have played a role include possible differences in gonadal growth and the presence of different H-Y antigens. Postnatally, the sires and male siblings of the two strains may not have behaved the same toward the female offspring and/or the dams, creating differences in behavior. In summary, the behavior of female offspring of two groups of males, genetically the same except for their Y-chromosomes, was examined. Since females do not receive a Y-chromosome from their fathers, in theory their behavior should not differ. Significant differences were found, indicating that the Y-chromosome, through some indirect mechanism, can affect females of the next generation.

Animals↗
PubMed1999

BXSB mice can learn complex visual pattern discriminations.

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.

Analysis of Variance↗
PubMed1998

Effects of neocortical ectopias upon the acquisition and retention of a non-spatial reference memory task in BXSB mice.

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.

Animals↗
PubMed1998

Water version of the radial-arm maze: learning in three inbred strains of mice.

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.

Animals↗
PubMed1998

Learning in year-old female autoimmune BXSB mice.

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.

Age Factors↗
PubMed1997

Lack of shuttlebox avoidance learning in autoimmune BXSB mice: a test of learned helplessness.

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.

Animals↗
PubMed1996

Absence of postnatal testosterone fails to demasculinize the male rat's corpus callosum.

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.

Analysis of Variance↗