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Biomedical subjects

H P Lipp

Publications and source records attributed to H P Lipp.

At least 55 records · Page 3Linked to original sources
PubMed1997

A role for the Ras signalling pathway in synaptic transmission and long-term memory.

Members of the Ras subfamily of small guanine-nucleotide-binding proteins are essential for controlling normal and malignant cell proliferation as well as cell differentiation. The neuronal-specific guanine-nucleotide-exchange factor, Ras-GRF/CDC25Mm, induces Ras signalling in response to Ca2+ influx and activation of G-protein-coupled receptors in vitro, suggesting that it plays a role in neurotransmission and plasticity in vivo. Here we report that mice lacking Ras-GRF are impaired in the process of memory consolidation, as revealed by emotional conditioning tasks that require the function of the amygdala; learning and short-term memory are intact. Electrophysiological measurements in the basolateral amygdala reveal that long-term plasticity is abnormal in mutant mice. In contrast, Ras-GRF mutants do not reveal major deficits in spatial learning tasks such as the Morris water maze, a test that requires hippocampal function. Consistent with apparently normal hippocampal functions, Ras-GRF mutants show normal NMDA (N-methyl-D-aspartate) receptor-dependent long-term potentiation in this structure. These results implicate Ras-GRF signalling via the Ras/MAP kinase pathway in synaptic events leading to formation of long-term memories.

3T3 Cells↗
PubMed1997

Assessing the effects of the 129/Sv genetic background on swimming navigation learning in transgenic mutants: a study using mice with a modified beta-amyloid precursor protein gene.

The Morris water maze is frequently used to screen mutant mice generated by gene targeting. Targeted ES-cells are often derived from 129/Sv or BALB/c mice, known as poor swimming navigation learners. After mating the founders with C57BL/6 mice, the F2 or F3 hybrid generation is typically used for behavioral testing. In hybrid 129/Sv x C57BL/6 mice, a modification of the betaAPP gene entails impaired swimming navigation learning. This is readily detected despite behavioral variability, because wild-type 129/Sv x C57BL/6 hybrids outperform either of the parental strains and provide a control sample with good baseline performance. However, after backcrossing to the 129/Sv(ev) strain, the mutation effects are no longer detectable, masked by the very poor performance of wild-type 129/Sv(ev) mice. We conclude that F2 and F3 generations of 129/Sv x C57BL/6 crosses provide a suitable genetic background for behavioral testing of transgenic mice, provided that the samples are large enough to compensate for genetic and epigenetic variability and provided that normal performance in the control group is verified by comparison against a large database of mice tested under identical conditions. Creating congenic lines by backcrossing to an inbred strain is unlikely to enhance the sensitivity of the Morris test. Backcrossing to 129/Sv(ev) may even reduce it.

Amyloid beta-Protein Precursor↗
PubMed1997

Impaired long-term potentiation induction in dentate gyrus of calretinin-deficient mice.

Calretinin (Cr) is a Ca2+ binding protein present in various populations of neurons distributed in the central and peripheral nervous systems. We have generated Cr-deficient (Cr-/-) mice by gene targeting and have investigated the associated phenotype. Cr-/- mice were viable, and a large number of morphological, biochemical, and behavioral parameters were found unaffected. In the normal mouse hippocampus, Cr is expressed in a widely distributed subset of GABAergic interneurons and in hilar mossy cells of the dentate gyrus. Because both types of cells are part of local pathways innervating dentate granule cells and/or pyramidal neurons, we have explored in Cr-/- mice the synaptic transmission between the perforant pathway and granule cells and at the Schaffer commissural input to CA1 pyramidal neurons. Cr-/- mice showed no alteration in basal synaptic transmission, but long-term potentiation (LTP) was impaired in the dentate gyrus. Normal LTP could be restored in the presence of the GABAA receptor antagonist bicuculline, suggesting that in Cr-/- dentate gyrus an excess of gamma-aminobutyric acid (GABA) release interferes with LTP induction. Synaptic transmission and LTP were normal in CA1 area, which contains only few Cr-positive GABAergic interneurons. Cr-/- mice performed normally in spatial memory task. These results suggest that expression of Cr contributes to the control of synaptic plasticity in mouse dentate gyrus by indirectly regulating the activity of GABAergic interneurons, and that Cr-/- mice represent a useful tool to understand the role of dentate LTP in learning and memory.

Animals↗
PubMed1996

Mice lacking the gene encoding tissue-type plasminogen activator show a selective interference with late-phase long-term potentiation in both Schaffer collateral and mossy fiber pathways.

The gene encoding tissue-type plasminogen activator (t-PA) is an immediate response gene, downstream from CREB-1 and other constitutively expressed transcription factors, which is induced in the hippocampus during the late phase of long-term potentiation (L-LTP). Mice in which the t-PA gene has been ablated (t-PA-/-) showed no gross anatomical, electrophysiological, sensory, or motor abnormalities but manifest a selective reduction in L-LTP in hippocampal slices in both the Schaffer collateral-CA1 and mossy fiber-CA3 pathways. t-PA-/- mice also exhibit reduced potentiation by cAMP analogs and D1/D5 agonists. By contrast, hippocampal-dependent learning and memory were not affected in these mice, whereas performance was impaired on two-way active avoidance, a striatum-dependent task. These results provide genetic evidence that t-PA is a downstream effector gene important for L-LTP and show that modest impairment of L-LTP in CA1 and CA3 does not result in hippocampus-dependent behavioral phenotypes.

Animals↗
PubMed1996

Mice homozygous for a modified beta-amyloid precursor protein (beta APP) gene show impaired behavior and high incidence of agenesis of the corpus callosum.

The amyloid precursor protein (beta APP) gene of the mouse was disrupted by homologous recombination; however, contrary to expectation, brain and other tissues still contained beta APP-specific RNA, albeit at a level 5-10 fold lower than wild-type and lacking the disrupted exon, which had been spliced out. The brain contained shortened beta APP-specific protein at a low level. Mutant mice were severely impaired in spatial learning and exploratory behavior and showed increased incidence of agenesis of the corpus callosum.

Agenesis of Corpus Callosum↗
PubMed1996

Paw preference and intra-/infrapyramidal mossy fibers in the hippocampus of the mouse.

The size of the intra-/infrapyramidal mossy fiber projections (IIP-MF) and their left/right asymmetry were assessed in 86 mice of either sex, including 26 animals from two mouse lines bred for strong or weak paw preference, 38 mice of a randomly bred F3 generation derived from an eight-way cross, and 22 mice with variably sized corpora callosa in which only the left hippocampus was measured. Prior to morphometry, all mice were tested for paw preference. In addition, we compared the strain means in paw preference as observed in nine inbred mouse strains with known differences in their IIP-MF distribution. Mice bred for strong paw preference had a 70% larger IIP-MF projection than weakly lateralized and dyscallosal mice; random-bred mice fell in-between the extremes. The individual scores of the strength of paw preference were positively correlated with the extent of the IIP-MF. Among the inbred strains, the extent of the IIP-MF was similarly correlated with the strength of paw preference. The acallosal mice showed a significant negative correlation between extent of the IIP-MF projection and test-retest reliability of paw use. The left-right asymmetry of the IIP-MF was significantly and positively correlated with the direction of paw preference in the entire sample. We conclude that size and asymmetry of the IIP-MF projection are some of the many factors influencing the direction of paw preference and its strength, albeit moderately. We hypothesize that mice with larger IIP-MF projections use a given paw more consistently, being perhaps more resistant to interferences, and that left-right asymmetries of the IIP-MF may bias and/or reinforce an initial choice of a paw. In addition, the data provide another example of correlations between IIP-MF variations and nonspatial behavior.

Animals↗
PubMed1996

Selective breeding for extremes in open-field activity of mice entails a differentiation of hippocampal mossy fibers.

The brains of mice selectively bred for differential locomotor activity in an open field (DeFries et al., Behav. Genet. 8:3-13, 1978) were analyzed for selection-dependent changes in the size of synaptic fields at the midseptotemporal level for the hippocampus. Timm-stained areas of all hippocampal fields from both left and right hippocampi were measured on five horizontal sections from the midseptotemporal level. The sample included 25 mice from two replicate lines, each one consisting of a high (HI); a low (LO), and a control line (CTL). The main selection effect was an enlargement of the intra-infrapyramidal mossy fiber (IIP-MF) projection in both HI lines by about 70% compared to LO and CTL mice (p < .0001), while other mossy fiber fields did not show differences. These findings confirm that genetic variations of the IIP-MF projection influence hippocampal processes mediating exploratory activities.

Animals↗
PubMed1995

Developmental exposure to ozone induces subtle changes in swimming navigation of adult mice.

Following exposure to ozone (O3, 0.6 ppm) from the beginning of neonatal life until weaning, adult CD-1 mice were tested in swimming navigation, a sensitive indicator for hippocampal damage. Control mice received a sham exposure. All mice were tested at 12-13 weeks of age for their ability to find a submerged platform in a fixed location (acquisition: 18 trials, six trials per day) and for capacity to re-orient towards a new platform position (reversal: 12 trials, six trials per day). Exposure to O3 did not produce any significant impairment of swimming navigation during the acquisition phase while it slightly increased the swimming paths during the last day of the reversal phase. Mice exposed to O3 showed a slightly but significantly higher swimming speed during all the days, which was unrelated to differences in body weight and to navigational performances. Moreover, mice exposed to O3 (with the exception of one animal) had a strong tendency to make turns to the left while the controls, independent of sex, preferred clockwise turns. Data are discussed with respect to possible implications with early CNS and immune alteration leading to behavioral asymmetries at adulthood.

Animals↗
PubMed1995

Evidence for physiological growth of hippocampal mossy fiber collaterals in the guinea pig during puberty and adulthood.

By means of Timm's procedure and computer-assisted morphometry, the left and right hippocampi of 69 hybrid guinea pigs from nine age levels (P5, P10, P20, P40, P80, P160, P320, and P610, and P1100) were analyzed for postnatal growth of recurrent hippocampal mossy fiber collaterals (RMFC) terminating below, within, and above the dentate granule cell layer. Postnatal growth of RMFCs showed, in both sexes, a first peak at P40, with stainable mossy fiber boutons covering the cell bodies of large neurones, some of which were reminiscent of basket cells. No significant changes of the density of mossy fiber collaterals were noticed from P40 to P160. At P320 a remarkable expansion of RMFCs was noted in a few animals, and by P610 all animals showed highly proliferated RMFCs which densely covered cell bodies and dendrites of target cells. The oldest group (P1100) showed an equal or slightly lowered density of RMFCs. We conclude that the growth of recurrent mossy fiber collaterals occurs in two spurts. The first completes just before sexual maturity. The second spurt occurs in the mid-life period, between P160 and P610.

Animals↗
PubMed1995

A comparison of behavioural effects of prenatally administered oxazepam in mice exposed to open-fields in the laboratory and the real world.

Prenatal benzodiazepine exposure has been reported to result in abnormal neurobehavioural development in laboratory animals but little is known about the behavioural relevance of this effect ina naturalistic environment. In this study, outbred CD-1 male mice were prenatally exposed to oxazepam (15 mg/kg per os, twice daily) on days 12-16 of fetal life and fostered at birth to untreated dams. At adulthood, each mouse was fitted with a radio collar and its first reactions assessed. Three hours later, behavioural and exploratory activities were recorded in a laboratory open field, and 24 h later in a natural setting. Immediate reactions to the radio collar were higher in the oxazepam-treated mice than in controls consisting of more attempts to remove it and an increase of push-digging. The attempts to remove the collar were still evident in oxazepam treated mice tested in the laboratory open-field 3 h later. Moreover, oxazepam increased the frequency of grooming and reduced walking in both the laboratory and the natural settings. In the natural settings running was increased during the initial 30-min test, while a pronounced level of grooming and a lower frequency of eating were observed 140 min after release. Frequency of sniffing, grooming, and rearing behaviours were higher in the laboratory test when compared to the natural settings. On the other hand, prolonged bouts of sniffing were recorded in the natural environment. These findings permit separation of robust drug effects (increased grooming, reduced walking) from situation-dependent effects, the natural environment revealing, in addition, more subtle effects.

Animals↗
PubMed1994

Behavioral and anatomical deficits in mice homozygous for a modified beta-amyloid precursor protein gene.

The beta-amyloid precursor protein (beta APP) gene of the mouse was disrupted by inserting into exon 2 a cassette containing a neomycin resistance gene and a putative transcription termination sequence. Contrary to expectation, brain and other tissues from mice homozygous for the insertion still contained beta APP-specific RNA, albeit at a level 5- to 10-fold lower than wild type and lacking the disrupted exon, which had been spliced out. The brain contained shortened beta APP-specific protein at a low level. Mutant mice were severely impaired in spatial learning and exploratory behavior and showed increased incidence of agenesis of the corpus callosum.

Amyloid beta-Protein Precursor↗
PubMed1994

Distribution of TAG-1/axonin-1 in fibre tracts and migratory streams of the developing mouse nervous system.

The axonal cell adhesion molecule, TAG-1/axonin-1, stimulates axonal growth and supports neurite fasciculation in vitro. Using a polyclonal antiserum raised against chick axonin-1, which shares 75% of its sequence with TAG-1 of the rat, we have mapped the distribution of TAG-1/axonin-1 throughout the developing nervous system of the mouse. Although absent from proliferating neuroepithelia and from non-neuronal cells, immunoreactivity for TAG-1/axonin-1 is expressed by stage-specific subpopulations of differentiating neurons from embryonic day 10 to postnatal day 15. It stains their axons and the surface of their parent somata during the early phases of axogenesis. In agreement with a putative role of TAG-1/axonin-1 as an axon-bound growth substrate, immunoreactivity is found in developing spinal and cranial nerves, in corticothalamic projections, as well as in subsets of fasciculating long projecting tracts of the central nervous system, such as the dorsal funiculi of the spinal cord, the lateral olfactory and optic tracts, the fasciculus retroflexus, and the predorsal bundle. High levels of immunoreactivity characterise the development of the cerebellar molecular layer, the corpus callosum, anterior and hippocampal commissure, and of crossed projections in the spinal cord and at several levels of the brainstem. Intense immunoreactivity in fine collaterals of cutaneous afferents, including their growth cones that are in contact with the embryonic skin, suggests a role of TAG-1/axonin-1 in target recognition. While staining is weak on the somata of radially migrating neurons such as cortical neurons and cerebellar granule cells, strong immunoreactivity is associated with neural somata and processes of the three tangential migrations that form the precerebellar nuclei, indicating a possible involvement of TAG-1/axonin-1 in contacts between these neurons and the processes they migrate upon.

Aging↗
PubMed1994

Hippocampal mossy fibers and swimming navigation in mice: correlations with size and left-right asymmetries.

Individual differences in the extent of the infrapyramidal mossy fiber projection (IIP-MF) correlate with performance in tasks sensitive to hippocampal lesions, notably two-way avoidance, radial maze learning, and swimming navigation. Previous studies of swimming navigation suggested that the capacity of reversal learning and measures of directionality might also be related to asymmetries in the distribution of the IIP-MF. In order to verify these findings, the authors crossed the Collins High- and Low-lateralized mice (known to differ in mossy fiber morphology and brain asymmetries) and obtained a F2-generation characterized by strong individual differences in these traits. Twenty-three (13 females, 10 males) mice were tested during 3 days for acquisition of swimming navigation (16 trials) toward a central platform, and during two days (12 trials) for their capacity of reversal learning toward a shifted platform. Morphometry of Timm-stained hippocampi revealed several, partially independent correlations: Larger IIP-MF projections were associated with prolonged crossing over the former platform position during the entire reversal learning; larger IIP-MF projections on the left were correlated with more precise crossing of the former platform position during the first 45 seconds of reversal learning; both extent and asymmetry of IIP-MF correlated positively with overnight improvement of reversal learning; the size of the entire mossy fiber projection (CA4, suprapyramidal and IIP-MF) correlated positively with the time spent in the platform quadrant and measures of initial orientation during acquisition of the task; and the mice showed an ipsilateral turning bias (spin) toward the side with the larger mossy fiber projection. The authors conclude that an intact hippocampus mediates differential processes underlying swimming navigation, and that left and right subfields may have differential functions.

Animals↗
PubMed1994

Swimming navigation, open-field activity, and extrapolation behavior of two inbred mouse strains with Robertsonian translocation of chromosomes 8 and 17.

Female mice from inbred strains carrying a Robertsonian translocation (nine CBARb and eight C57BL/6Rb) were compared with animals from their respective strains (seven CBA and nine C57BL/6) first in open-field activity (two exposures of 10-min duration), then during 5 days (with six trials each) in Morris' swimming navigation test, and finally, in their ability to extrapolate the future position of a food reward being moved slowly out of their reach. ANOVA (strain and translocation) revealed significant effects of Robertsonian translocations (Rb) in swimming navigation, Rb mice being impaired primarily in the initial phases of acquisition and during the first trials of platform reversal and the impairment being stronger in C57BL/6 mice. In the open field, Rb mice were as active as the normal strains but showed significantly increased path tortuosity and moved slightly faster. In the extrapolation task, Rb mice showed above-chance levels in moving to the target indicated by the disappearance of the stimulus, while normal mice chose at chance levels, but the translocation effects were not statistically significant. These data indicate that telocentric fusion of chromosomes may entail behavioral alterations, perhaps by subtle changes in neurotransmitters or limbic circuitry. The expression of such alterations, however, can be remarkably strain dependent.

Animals↗
PubMed1994

Cerebral blood flow in preterm infants affected by sex, mechanical ventilation, and intrauterine growth.

Sex differences in cerebral blood flow (CBF) values have been demonstrated in adults but not in newborns. This study evaluated the influence of sex, intrauterine growth, and need of mechanical ventilation on resting cerebral blood flow in preterm neonates. Sixty-eight preterm infants with gestational ages of less than 34 weeks and birth weights of less than 1,500 gm were enrolled into the study. Cerebral blood flow was measured by the noninvasive intravenous xenon 133 method 3 times. Measurements were classified into 3 groups: group 1: measurement at 2-36 hours (n = 46); group 2: measurement at 36-108 hours (n = 39); and group 3: measurement at 108-240 hours (n = 41). In all 3 groups, the CBF in girls was significantly lower than in boys (group 1: 11.5 +/- 2.8 ml/100 gm/min vs 14.0 +/- 4.1 ml/100 gm/min; group 2: 13.4 +/- 2.9 ml/100 gm/min vs 16.3 +/- 4.3 ml/100 gm/min; group 3: 12.9 +/- 3.2 ml/100 gm/min vs 15.3 +/- 3.1 ml/100 gm/min). In group 1, the CBF in neonates requiring mechanical ventilation was significantly lower (P < .05) than in patients who were spontaneously breathing (11.5 +/- 3.7 ml/100 gm/min vs 14.2 +/- 3.1 ml/100 gm/min), and the CBF in neonates who were too small for gestational age was significantly higher (P < .005) than in children with appropriate intrauterine growth (16.1 +/- 4.1 ml/100 gm/min vs 11.5 +/- 2.6 ml/100 gm/min). It is concluded that in preterm neonates CBF is substantially affected by sex, intrauterine growth retardation, and the need of mechanical ventilation.

Birth Weight↗
PubMed1994

Promotion of preneoplastic foci in rat liver with 2,3,7,8-tetrachlorodibenzo-p-dioxin, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin and a defined mixture of 49 polychlorinated dibenzo-p-dioxins.

In a two-stage initiation-promotion experiment the hypothesis was investigated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalents (TE), calculated from data of CYP1A induction in hepatocytes in primary culture, or international TCDD equivalents (ITE) are useful for evaluating the tumor-promoting potency of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) and of a defined mixture (M2) of 49 polychlorinated dibenzo-p-dioxins (PCDDs) in comparison with TCDD. Therefore, female Wistar rats were treated with an initiating dose of N-nitrosomorpholine, and subsequently received daily doses of 2, 20 and 200 ng TCDD/kg or equivalent doses of HpCDD or M2, based on TE values. After a promotion phase of 13 weeks, hepatic PCDD levels, CYP1A activity and the relative hepatic volume of adenosinetriphosphatase-negative or glutathione S-transferase P-positive preneoplastic foci were determined. After logarithmic transformation, linear PCDD level-response relationships were obtained for induction of CYP1A activity with TCDD, HpCDD or M2. Based on TE values, inducing potencies of both HpCDD and M2 were over-estimated at higher doses, whereas induction was approximately equivalent at the lowest dose. The best fit of PCDD level-response relationships of relative hepatic volumes of preneoplastic lesions was achieved using a four-parameter logistic model. Significantly different functions were calculated for promotion with TCDD or HpCDD. It is concluded that (i) different PCDD level-response relationships exist for the induction of hepatic CYP1A activity and the promotion of preneoplastic liver foci, and (ii) that TE or ITE factors provide only a rough estimate of the tumor-promoting potency of a PCDD mixture but may overestimate the risk from exposure to higher-chlorinated 2,3,7,8-substituted congeners such as HpCDD.

Animals↗
PubMed1993

Impaired acquisition of swimming navigation in adult mice exposed prenatally to oxazepam.

Prenatally administered oxazepam (OX) impairs adult radial maze performance in mice, possibly by permanent hippocampal changes. CDI mice were tested in swimming navigation, a sensitive indicator for hippocampal damage. Ten males and ten females were exposed to OX on fetal days 12-16 by maternal administration PO of 30 mg/kg/day and fostered at birth to untreated dams, while control mice received vehicle solution. All mice were tested at 8-9 weeks for ability to find a submerged platform in a fixed location (acquisition: 18 trials, 6 trials per day) and for capacity to re-orient towards a new platform position (reversal: 12 trials, 6 trials per day). OX mice showed a slight but significant impairment of swimming navigation during the initial part of training, as indicated by longer swimming paths during the fourth and fifth trial (day 1), an impairment due both to delayed habituation to the novel stressfull condition and acquisition of platform climbing but unrelated to navigational abilities. No treatment-dependent differences were observed in the reversal phase. During reversal, both OX and control females spent significantly more time in swimming across the location of the old platform. Unrelated to navigational performance, females showed a slightly but significantly higher swimming speed than males. Due to the absence of any navigational impairment, data suggest that prenatal exposure to oxazepam exerts long-term influence on adult learning capacities primarily through interaction with brain systems located outside the hippocampus.

Animals↗