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R Paylor

Publications and source records attributed to R Paylor.

At least 37 records · Page 2Linked to original sources
PubMed1997

Identification of quantitative trait loci involved in contextual and auditory-cued fear conditioning in BXD recombinant inbred strains.

Fear conditioning shows associations formed between contextual or auditory stimuli with an unconditioned stimulus. Inbred mouse strains differ in their ability to demonstrate fear conditioning, suggesting at least a partial genetic influence. The present study identified the possible chromosomal loci regulating fear conditioning in BXD recombinant inbred strains using quantitative trait loci (QTL) analysis. Estimates of heritability for all 3 measures of conditioning were about .28. Correlational analyses between genetic markers and strain means identified multiple putative QTLs. The strongest associations were on Chromosomes 1 and 17 for freezing to the context, Chromosome 12 for freezing to an altered context, and Chromosome 1 for freezing to the auditory stimulus. Overlapping QTLs may indicate some common genes that underlie aspects of this learning task.

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PubMed1996

Atm-deficient mice: a paradigm of ataxia telangiectasia.

A murine model of ataxia telangiectasia was created by disrupting the Atm locus via gene targeting. Mice homozygous for the disrupted Atm allele displayed growth retardation, neurologic dysfunction, male and female infertility secondary to the absence of mature gametes, defects in T lymphocyte maturation, and extreme sensitivity to gamma-irradiation. The majority of animals developed malignant thymic lymphomas between 2 and 4 months of age. Several chromosomal anomalies were detected in one of these tumors. Fibroblasts from these mice grew slowly and exhibited abnormal radiation-induced G1 checkpoint function. Atm-disrupted mice recapitulate the ataxia telangiectasia phenotype in humans, providing a mammalian model in which to study the pathophysiology of this pleiotropic disorder.

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PubMed1996

The use of null mutant mice to study complex learning and memory processes.

A number of neural substrates have been proposed to mediate complex learning and memory processes in mammalian organisms. One strategy for testing the involvement of a particular gene in learning and memory is to create a mouse line with a null mutation in that gene. Recently, embryonic stem cell-based gene-targeted homologous recombination techniques have been employed to create a number of such mutant mouse lines that do not express interesting candidate genes. These animals have been examined for impairments in several complex learning paradigms which are known to depend on the integrity of the hippocampus. In this review several complex learning and memory paradigms are described, the techniques to create null mutants are reviewed, and the results of recent studies with null mutants are described. Finally, the limitations for interpretation of behavioral data using null mutants are discussed.

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PubMed1996

Developmental differences in place-learning performance between C57BL/6 and DBA/2 mice parallel the ontogeny of hippocampal protein kinase C.

This study determined the ontogenic changes in learning and hippocampal protein kinase C (PKC) in C57 and DBA mice. Mice were tested on the visible- or hidden-platform versions of the Morris water task starting at 17, 24, 31, or 60 days of age. Both strains learned to locate the visible platform at all ages. C57 mice learned to solve the hidden-platform task when they were 24 days old, whereas DBA mice never learned to solve this task. Using a [3H]-phorbol ester binding assay, the authors found that both strains had similar amounts of hippocampal PKC at 10 and 17 days of age but that C57 mice had significantly more PKC at 24, 31, and 60 days of age. Immunoblotting results revealed that C57 mice had more gamma-PKC, but not alpha-PKC, than DBA mice. Thus, the development of performance differences in spatial learning between C57 and DBA mice parallels the ontogeny of hippocampal PKC.

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PubMed1995

Mutant mice lacking the gamma isoform of protein kinase C show decreased behavioral actions of ethanol and altered function of gamma-aminobutyrate type A receptors.

Calcium/phospholipid-dependent protein kinase (protein kinase C, PKC) has been suggested to play a role in the sensitivity of gamma-aminobutyrate type A (GABAA) receptors to ethanol. We tested a line of null mutant mice that lacks the gamma isoform of PKC (PKC gamma) to determine the role of this brain-specific isoenzyme in ethanol sensitivity. We found that the mutation reduced the amount of PKC gamma immunoreactivity in cerebellum to undetectable levels without altering the levels of the alpha, beta I, or beta II isoforms of PKC. The mutant mice display reduced sensitivity to the effects of ethanol on loss of righting reflex and hypothermia but show normal responses to flunitrazepam or pentobarbital. Likewise, GABAA receptor function of isolated brain membranes showed that the mutation abolished the action of ethanol but did not alter actions of flunitrazepam or pentobarbital. These studies show the unique interactions of ethanol with GABAA receptors and suggest protein kinase isoenzymes as possible determinants of genetic differences in response to ethanol.

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PubMed1995

Enhancement of hippocampally-mediated learning and protein kinase C activity by oxiracetam in learning-impaired DBA/2 mice.

The effects of oxiracetam on hippocampally-mediated learning performance and hippocampal protein kinase C (PKC) were examined in C57BL/6Ibg (C57) and DBA/2Ibg (DBA) mice. C57 and DBA mice were subjected to daily injections of oxiracetam (50 mg/kg i.p.) or vehicle (0.9% saline) for a total of 9 days. C57 and DBA mice were examined on a modified version of the Morris water maze task and the contextual fear conditioning task on the last 5 or 2 days, respectively, of the 9-day treatment schedule. When compared with controls, C57 and DBA oxiracetam-treated mice showed no difference in motor skill capability to perform these complex learning tasks (swim speed or ability to freeze). Hippocampal PKC activity was measured in cytosolic, loosely-bound, and membrane-bound homogenate fractions. Oxiracetam-treated DBA mice demonstrated a significant increase in spatial learning performance as determined by the Morris task. DBA performance was also improved in contextual learning as determined by the fear conditioning task. The increase in spatial learning performance was correlated to an increase in membrane-bound PKC. No substantial improvements in C57 mice were observed on either learning task nor did hippocampal PKC activity change in response to oxiracetam treatment. These data demonstrate that the learning impairment of DBA mice can be reversed by treatment with a nootropic agent and support previous studies suggesting that PKC may be one mechanism of action for oxiracetam.

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PubMed1995

Protein and molecular characterization of hippocampal protein kinase C in C57BL/6 and DBA/2 mice.

Measures of protein kinase C (PKC) in C57BL/6 and DBA/2 mice using [3H]phorbol 12,13-dibutyrate binding to tissue homogenates and brain slices demonstrated that levels of activated, membrane-bound PKC were greater in C57BL hippocampus than in DBA hippocampus. Western analysis of alpha-, beta I-, beta II-, gamma-, delta-, and epsilon-PKC using isozyme-specific antibodies indicated that the increase observed in C57BL hippocampus was due primarily to the gamma-PKC protein, whose immunoreactivity was greater in the membrane-bound fraction in C57BL mice. Characterization of alpha-, beta I,II-, and gamma-PKC hippocampal mRNA using northern analysis and isozyme-specific nucleic acid probes did not reveal differences between the strains in levels of gene expression. Restriction fragment length polymorphisms (RFLP) were found in the alpha- and gamma-, but not beta-PKC genomic DNA. The RFLPs appeared to be located in noncoding, nonregulatory regions of the gene. These findings suggest that the gamma-PKC isozyme is largely responsible for the PKC activity difference in C57BL and DBA hippocampus that has been reported previously and may be closely associated with differences in learning ability observed in these strains.

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PubMed1994

Behavioral assessment of c-fos mutant mice.

Induction of the proto-oncogene c-fos has been associated with a number of neural and behavioral responses to acute stimuli. Behavioral characterization of mice containing a mutant c-fos allele created via homologous recombination-based gene targeting was performed to analyze the role of this protein in baseline neurological properties as well as paradigms that require neural adaptive responses. Performance of 9 out of 11 c-fos-deficient animals was impaired in the spatial version of the Morris water task. However, this poor performance in the spatial version of the task was highly correlated to their performance in the non-spatial version of the task which suggests that they have a behavioral impairment that interrupts their ability to perform adequately on both versions of the task with the same proficiency as wild-type and heterozygous litter mates. To examine learning impairments further, a simple left/right discrimination in a T-maze was used. Mutants were not impaired in this simple learning task. These results suggest that c-fos mutants have some behavioral impairments that interfere with evaluation of complex learning on the Morris water task, but because all genotypes could perform a simple discrimination task, it is clear that c-fos is not essential for this simpler form of learning and memory.

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PubMed1994

DBA/2 and C57BL/6 mice differ in contextual fear but not auditory fear conditioning.

It has been proposed that DBA/2 and C57BL/6 mice perform differently on some learning and memory tasks because of functional differences in the hippocampal formation. To evaluate this hypothesis, DBA/2 and C57BL/6 mice were tested on 2 forms of conditioned fear: contextual fear conditioning, which depends on the integrity of the hippocampal formation, and auditory cue conditioning, which does not. Both mouse strains displayed equivalent conditioning when the auditory cue was paired with shock, but DBA/2 mice showed significantly less conditioning to the context in which shock was experienced. These results are consistent with the hypothesis that the pattern of spared and impaired performance, which DBA/2 mice display on a variety of learning and memory tasks, is related to impaired hippocampal formation function.

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PubMed1993

PKC gamma mutant mice exhibit mild deficits in spatial and contextual learning.

We are undertaking a genetic approach to investigate the role that synaptic modulation in the mammalian central nervous system plays in learning and memory and to identify relevant molecular components. We have generated mice deficient in the gamma isoform of protein kinase C (PKC gamma), an enzyme that has previously been implicated in both long-term potentiation (LTP) and learning and memory. These mice have a modified LTP of synaptic transmission in the hippocampus. We demonstrate that PKC gamma-mutant mice can learn to carry out hippocampus-dependent tasks, although mild deficits are evident. Thus, hippocampal CA1 LTP induced by the conventional tetanic stimulation is not essential for the mice to exhibit spatial and contextual learning. Furthermore, the modification of hippocampal synaptic plasticity correlates with the learning deficits we observe.

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PubMed1992

Brief exposure to an enriched environment improves performance on the Morris water task and increases hippocampal cytosolic protein kinase C activity in young rats.

This study was designed to determine whether brief exposure to an enriched environment around the time of weaning would affect learning and memory processes in young rats. In addition, this study sought to determine if experience in an enriched environment would alter hippocampal protein kinase C (PKC) which is thought to be a possible neural substrate that underlies learning and memory processes. Animals were either reared in an enriched environment or standard laboratory cages starting at 15 days old. After 6 (21 days old) or 12 (27 days old) days subjects were either tested in the Morris water task, or had the hippocampus removed for biochemical analysis of PKC activity. Morris water task results showed that compared to laboratory reared controls, the performance of subjects reared in the enriched environment for 12 days, but not 6 days, was improved. In addition, 12 days of exposure to the enriched environment, but not 6 days, produced more cytosolic hippocampal PKC activity. The particulate fraction appeared not to be affected by rearing in the enriched environment. Brief exposure to an enriched environment around weaning, therefore, both improved Morris water task performance and increased hippocampal PKC activity. These outcomes suggest that performance in the Morris water task and hippocampal PKC may be functionally related.

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PubMed1992

Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice.

Although long-term potentiation (LTP) has been studied as the mechanism for hippocampus-dependent learning and memory, evidence for this hypothesis is still incomplete. The mice with a mutation in the alpha-calcium-calmodulin-dependent kinase II (alpha-CaMKII), a synaptic protein enriched in the hippocampus, are appropriate for addressing this issue because the hippocampus of these mice is deficient in LTP but maintains intact postsynaptic mechanisms. These mutant mice exhibit specific learning impairments, an indication that alpha-CaMKII has a prominent role in spatial learning, but that it is not essential for some types of non-spatial learning. The data considerably strengthen the contention that the synaptic changes exhibited in LTP are the basis for spatial memory.

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PubMed1991

Acute phorbol ester treatment improves spatial learning performance in rats.

Recent findings have lead researchers to speculate that hippocampal protein kinase C (PKC) in rodents is involved in spatial learning and memory. The purpose of this study was to determine if treating rats with a compound known to increase PKC activity would improve performance in a task that requires spatial learning processes. Rats were treated with a single intracerebroventricular injection of a phorbol ester, phorbol 12,13-dibutyrate (PDBu) that is known to increase PKC activity and then tested on the hidden-platform version of the Morris water taks. Results showed that PDBu-treated subjects' ability to learn to locate the escape platform was better than controls. In addition, PDBu-treated subjects showed signs of having remembered the location of the platform better than controls when tested 24 h later. These results support a role of brain PKC in processes required to learn the Morris water task.

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PubMed1990

Cholinergic receptor blockade can impair the rat's performance on both the place learning and cued versions of the Morris water task: the role of age and pool wall brightness.

It is known that the administration of a cholinergic receptor blocker impairs the rat's performance on the place learning version of the Morris water task. We confirm this finding but in addition report that animals receiving the cholinergic antagonist, scopolamine hydrobromide, are significantly impaired on the cued platform version of the Morris water task. This latter result, however, is dependent on both the age of the subject and the training context. Weanling animals were more impaired on the cued platform task than were adult animals, and the magnitude of the impairment was much larger when animals were trained in a pool with a gray interior wall than when the pool wall was white. Our findings suggest that the influence of cholinergic systems on performance in the Morris task extend beyond their contribution to place learning and memory processes. We suggest that functional central cholinergic systems also contribute to the processes that enable the animal to inhibit behaviors that are incompatible with the requirements of the task.

Age Factors↗
PubMed1990

The cholinergic agent physostigmine enhances short-term-memory-based performance in the developing rat.

There are age-related differences in the rat's short-term memory processes. Rats 24-25 days old are 90% correct when the delay interval separating the forced run and choice run of a trial is either 10 or 30 s, but they perform at chance when the delay interval is 60 s. In contrast, the choice performance of 30-day-old rats remains constant across all delay intervals. It is reported that the cholinergic agent physostigmine dramatically improved the short-term-memory-based performance of rats 24-25 days old such that they displayed no loss in choice accuracy even when the delay interval was 60 s. No such enhanced performance was seen in rats treated with neostigmine, a peripherally acting anticholinesterase. The results support the hypothesis that postnatal maturational differences in central cholinergic systems may contribute to age-related differences in short-term memory.

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PubMed1987

Development of interocular equivalence of place learning in the rat requires convergence sites established prior to training.

Interocular equivalence for spatial-navigation learning requires that the neural pathways originating in each eye converge on common memory sites. Rats fail to display interocular equivalence if they are trained and tested on the Morris (1981) place-navigation task when they are 22 days old, but they succeed if they are trained and tested when they are 28 days old (Rudy & Stadler-Morris, 1987). This delay suggests that there is a period in development when the interhemispheric connections necessary for convergence are immature and rats behave temporarily as split-brain organisms. In the present experiment, rats completed training when they were 22 days old but were not tested for interocular equivalence until they were 28 days old. Nevertheless, these subjects failed to demonstrate equivalence. Thus, for interocular equivalence to be observed, the neural pathways from each eye must converge on common neural sites that are functional at the time the memory representation is established.

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