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Biomedical subjects

V H Denenberg

Publications and source records attributed to V H Denenberg.

At least 19 recordsLinked to original sources
PubMed2002

Behavioral characterization of mice lacking the ubiquitin ligase UBR1 of the N-end rule pathway.

The N-end rule pathway, a subset of the ubiquitin pathway, relates the in vivo half-life of a protein to the identity of its N-terminal residue. Mice lacking NTAN1, a component of the N-end rule pathway, showed altered learning and memory, and socially conditioned behavioral alteration (Balogh, Kwon, & Denenberg 1999, 2000; Kwon, Balogh et al. 2000; Balogh et al. 2001). Mice lacking UBR1 (E3alpha), one of at least three recognition components of the N-end rule pathway, are viable and outwardly normal. Here we describe behavioral characterizations of UBR1 knockout (UBR1-/-) mice. Compared to congenic littermates, UBR1-/- mice exhibited less spontaneous activity in an open field and took longer to locate the hidden platform during eight-week Morris water maze retention. In contrast, they performed better in horizontal-vertical discrimination and Lashley III maze testing. No statistically significant differences in inhibitory learning were observed. With the exception of enhanced Lashley III maze performance, these data parallel findings with NTAN1-/- mice lacking the upstream component of UBR1. These results suggest that, like NTAN1, UBR1 is involved in learning and memory.

Animals↗
PubMed2001

Facilitated stimulus-response associative learning and long-term memory in mice lacking the NTAN1 amidase of the N-end rule pathway.

The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. Inactivation of the NTAN1 gene encoding the asparagine-specific N-terminal amidase in mice results in impaired spatial memory [26]. The studies described here were designed to further characterize the effects upon learning and memory of inactivating the NTAN1 gene. NTAN1-deficient mice were found to be better than wild-type mice on black-white and horizontal-vertical discrimination learning. They were also better at 8-week Morris maze retention testing when a reversal trial was not included in the testing procedures. In all three tasks NTAN1-deficient mice appeared to use a strong win-stay strategy. It is concluded that inactivating the asparagine-specific branch of the N-end rule pathway in mice results in impaired spatial learning with concomitant compensatory restructuring of the nervous system in favor of non-spatial (stimulus-response) learning.

Amidohydrolases↗
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 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.

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↗
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

Neonatal estrogen blockade prevents normal callosal responsiveness to estradiol in adulthood.

The rat corpus callosum (CC) is larger in males than females, and is responsive to hormone manipulations during development. We previously demonstrated that P25 ovariectomy (Ovx) enlarged (defeminized) adult CC, while P70 ovary transfer (OvT) counteracted this enlarging effect, resulting in smaller (feminized) CC. Since OvT females were not Ovx'd until P25, they received some neonatal estrogen (E) exposure. Behavioral data suggest that adult responsiveness to ovarian hormones depends upon prior organization by neonatal E. It has not been determined whether a similar phenomenon occurs for the feminization of brain morphology. The current experiment examined whether our previous finding of adult CC responsiveness to ovarian hormones depended upon neonatal E exposure. We investigated this by assessing the effects of P70 ovarian hormone replacement (via ovary transfer or E pellet) in females that received either (1) normal ovarian hormone exposure until P25 Ovx, or (2) the E receptor blocker tamoxifen from birth to P25 Ovx. Females receiving normal neonatal hormone exposure responded to P70 E in the female-typical manner: E reduced CC size. In contrast, females receiving neonatal E blockade responded to adult E in the opposite manner: E increased CC size. As far as we are aware, this is the first report suggesting that neonatal E exposure organizes the female brain so that it responds normally to the organizing actions of E when later exposure occurs. These findings further challenge the traditional model of female brain development, which asserts that normal female brain organization occurs by default, in the absence of gonadal hormone exposure.

Aging↗
PubMed2000

Adult ovary transfer counteracts the callosal enlargement resulting from prepubertal ovariectomy.

The rat corpus callosum (CC) is larger in males than females, and is sensitive to hormone manipulations during development. Previous research found that, in rats, CC sensitivity to testosterone ended by postnatal day 8 (P8). In contrast, more recent findings demonstrated that CC responsivity to ovarian hormones continued at least through P70. The current experiment extends these findings by showing that the female callosum is still sensitive to ovarian hormones as late as P130, well into adulthood.

Analysis of Variance↗
PubMed2000

Ovarian hormones can organize the rat corpus callosum in adulthood.

The rat corpus callosum (CC) is larger in males than females, and is responsive to hormone manipulations during development. Previous data suggest that CC sensitivity to testosterone ends by postnatal day 8 (P8). In contrast, responsivity to ovarian hormones extends as late as P25. The current series of experiments investigates whether ovarian hormone effects on the callosum are permanent and whether CC sensitivity to ovarian hormones extends beyond P25. We found that P70 ovariectomy (Ovx) did not affect callosal size, suggesting that ovarian hormone exposure sometime prior to P70 is sufficient to feminize the CC, and that once the callosum is feminized, the effects can not be reversed. We also found that P25 ovariectomy enlarged, or defeminized, adult female CC, whereas ovary transfer starting on P55 or P70 counteracted this enlarging effect, resulting in feminized adult CC. Thus, although a previously feminized callosum is not affected by P70 ovarian hormone removal, a not-yet feminized callosum can still be feminized after P70. These findings indicate that there is flexibility in the developmental window within which the female brain is responsive to the active feminization process initiated by ovarian hormones.

Age Factors↗
PubMed2000

Evolution proposes and ontogeny disposes.

Genes, the basic building blocks of evolution, are highly conserved. For example, the mouse and human have approximately the same number of genes, and around 94% are identical in the two species. Since species differ on multiple dimensions (e.g., anatomy, physiology, and behavior), it follows that identical genes may subserve different functions in different species. Two reasons for this are gene-gene interaction and gene-environment interaction (and it is the presence of these interactions which prevents one from making deterministic statements about genetics, thus rendering obsolete the nature-nurture controversy). Behavioral examples of both types of interactions are presented, including studies showing that (1) the uterine environment enhances later cognitive competence, (2) early postnatal experiences affect learning and emotionality and can extend into future generations, (3) maternal behavior changes the offspring's later behavior and physiology, and (4) knocking out one gene results in an animal less competent in one learning process but more competent in a complementary learning process.

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

Sex differences in vicarious trial-and-error behavior during radial arm maze learning.

We investigated sex differences in VTE behavior in rats during radial arm maze learning. Females made more VTEs than males, although there were no sex differences in learning. Further, VTEs and errors were positively correlated during the latter testing sessions in females, but not in males. This sex difference may be a reflection of differences between the sexes in conflict behavior or cognitive strategy while solving the maze.

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↗
PubMed2000

Altered activity, social behavior, and spatial memory in mice lacking the NTAN1p amidase and the asparagine branch of the N-end rule pathway.

The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. N-terminal asparagine and glutamine are tertiary destabilizing residues, in that they are enzymatically deamidated to yield secondary destabilizing residues aspartate and glutamate, which are conjugated to arginine, a primary destabilizing residue. N-terminal arginine of a substrate protein is bound by the Ubr1-encoded E3alpha, the E3 component of the ubiquitin-proteasome-dependent N-end rule pathway. We describe the construction and analysis of mouse strains lacking the asparagine-specific N-terminal amidase (Nt(N)-amidase), encoded by the Ntan1 gene. In wild-type embryos, Ntan1 was strongly expressed in the branchial arches and in the tail and limb buds. The Ntan1(-/-) mouse strains lacked the Nt(N)-amidase activity but retained glutamine-specific Nt(Q)-amidase, indicating that the two enzymes are encoded by different genes. Among the normally short-lived N-end rule substrates, only those bearing N-terminal asparagine became long-lived in Ntan1(-/-) fibroblasts. The Ntan1(-/-) mice were fertile and outwardly normal but differed from their congenic wild-type counterparts in spontaneous activity, spatial memory, and a socially conditioned exploratory phenotype that has not been previously described with other mouse strains.

Amidohydrolases↗
PubMed1999

A behavioral and neuroanatomical assessment of an inbred substrain of 129 mice with behavioral comparisons to C57BL/6J mice.

The inbred 129 substrains have been characterized as poor learners that display hypoplasia of the corpus callosum. However, they are used extensively as a source of embryonic stem (ES) cells for creating mice carrying altered copies of a targeted gene ('knockout mice'). The present research investigated callosal agenesis and behavior in the 129/SvEvTac substrain and compared their behavior to that of C57BL/6J mice. In addition, the degree to which callosal agenesis affected behavior was assessed. Nearly 80% of 129/SvEvTac mice in the current sample exhibited callosal hypoplasia, although this was not subsequently found to be associated with any measure of cognition. They learned the Morris maze and a non-spatial pattern discrimination task, though at a level inferior to C57BL/6J mice. They were unable to learn shuttlebox avoidance or the Lashley III maze. The only measure on which they performed better than C57BL/6J mice was a simple water escape task. Thus, 129/SvEvTac mice, in addition to displaying aberrant neuroanatomy, perform poorly on many behavioral tasks, resulting in potential interpretational difficulties.

Agenesis of Corpus Callosum↗
PubMed1999

Commentary: is maternal stimulation the mediator of the handling effect in infancy?

In a recent report, a series of studies is described showing that individual differences in rat maternal licking and grooming are correlated with their offsprings' later adrenal response to a stressor (Liu et al., 1997). Pups that received more maternal stimulation in infancy had lower ACTH, corticosterone, and CRH mRNA, while they had greater amounts of GR mRNA. Liu et al. also compared maternal behavior in litters where rat pups were handled daily to maternal behavior of nonhandled litters. They found that mothers of handled pups licked and groomed their young significantly more often than did mothers of control litters. In their discussion, Liu et al. proposed that their data support Levine's (1975) thesis that handling effects in infancy are mediated via the mother. Levine had proposed that handling of pups will modify the mother--pup interaction, thereby causing a change in maternal behavior. The purpose of this commentary is to summarize data obtained with mice and rabbits which, in part, support and, in part, challenge the conclusions of Liu et al.

Adaptation, Physiological↗