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Biomedical subjects

J R Simon

Publications and source records attributed to J R Simon.

At least 37 records · Page 2Linked to original sources
PubMed1994

Cholinergic innervation of the retrosplenial cortex via the fornix pathway as determined by high affinity choline uptake, choline acetyltransferase activity, and muscarinic receptor binding in the rat.

The cholinergic projections from basal forebrain nuclei to the retrosplenial cortex (RSC) have previously been studied using a variety of histological approaches. Studies using acetylcholinesterase (AChE) histochemistry and choline acetyltransferase (ChAT) immunocytochemistry have demonstrated that this projection travels via the cingulum on route to the RSC. Preliminary studies from our laboratory, however, have shown that the fornix may also be involved in this projection. The present study uses the combination of pathway lesions, and the analysis of cholinergic neurochemical markers in the RSC to determine the role of the fornix in the cholinergic projection to the RSC. High affinity choline uptake (HACU) and ChAT activity were measured in the RSC of control rats, animals with cingulate lesions, and animals with fornix plus cingulate lesions. Fornix plus cingulate lesions resulted in significant deceases in HACU and ChAT activity in comparison to cingulate lesions alone. Muscarinic receptor binding was also evaluated in combination with the various lesions, and a significant increase in retrosplenial receptor binding was noted following fornix lesions. Together, these results support the concept of a fornix-mediated cholinergic pathway to the RSC.

Animals↗
PubMed1994

Alterations in dopamine and serotonin uptake systems in the striatum of the weaver mutant mouse.

In the striatum of the homozygous weaver mutant mouse (wv/wv), dopamine content, uptake and tyrosine hydroxylase activity are decreased compared to wild-type (+/+) mice. In mice heterozygous for the weaver gene (wv/+), these dopaminergic parameters exhibit only minor reductions compared to +/+ mice. The wv/wv striatum has recently been shown to have an increase in serotonin content. In the present study, the serotonin uptake system of the weaver striatum was investigated. Synaptosomal uptake of [3H] serotonin was determined in the dorsal portion of wv/wv and +/+ striatum, and serotonin uptake sites were examined by the binding of [3H] citalopram in the striatum of wv/wv, wv/+ and +/+ mice. The dopamine uptake system was also investigated in all three genotypes via the binding of [3H] mazindol. Synaptosomal uptake of [3H] serotonin was increased by 79% in the dorsal portion of the wv/wv striatum compared to that seen in the +/+ striatum. The binding of [3H] citalopram was increased by 62% in the dorsolateral and by 111% in the dorsomedial portions of the wv/wv striatum compared to +/+. [3H] Citalopram binding in the wv/+ striatum was also higher than +/+, but this increase did not reach statistical significance. Within the wv/wv striatum, [3H] mazindol binding was almost completely absent (88-89% reduction) in the dorsal portion and severely reduced in the other striatal areas. These data support the notion that the dorsal portion of the wv/wv striatum, which has the severest reduction in dopamine uptake, is hyperinnervated by serotonin fibers.

Animals↗
PubMed1994

Fear-potentiated startle elevates catecholamine levels in the dorsomedial hypothalamus of rats.

The norepinephrine (NE), dopamine (DA), and serotonin (5-HT) systems are thought to be important in the development of anxiety and stress. The dorsomedial hypothalamus (DMH) of rats has been implicated in the regulation of physiological and behavioral responses associated with fear and anxiety. In order to elucidate the interactions between the monoamine systems and the DMH, we studied the effects of subjecting rats to the fear-potentiated startle test, a commonly used test of anxiety in rats, on the NE, DA, and 5-HT levels in the DMH. Rats in the potentiated startle test, but not those exposed to just foot shocks or acoustic startle, showed significantly higher levels of NE and DA in the DMH compared to cage controls. In contrast, foot shocks significantly elevated the 5-HT levels in the DMH.

Animals↗
PubMed1994

Age-dependent alterations in dopamine content, tyrosine hydroxylase activity, and dopamine uptake in the striatum of the weaver mutant mouse.

Mice of different ages and homozygous or heterozygous for the weaver gene (wv) were used to study the time course for the effect of the weaver gene on several striatal dopaminergic parameters. Dopamine uptake was decreased in the homozygous weaver at all ages examined. The deficit in uptake at the earliest age studied, postnatal day 3, was approximately 50% and increased to greater than 70% at older ages. In control mice, dopamine uptake reached a maximum by postnatal day 22, but in homozygous weaver mice, development of uptake activity was curtailed by postnatal day 7. Dopamine content and tyrosine hydroxylase activity were significantly decreased in the homozygous weaver at all ages studied except postnatal days 7 and 10. The magnitude of the deficit in dopamine content ranged from approximately 40% at postnatal days 3 and 5 to about 70% in adults (6 months to 1 year of age). The magnitude of the deficit in tyrosine hydroxylase activity ranged from 40 to 70%. In general, no major differences between heterozygotes and controls were observed for any of the dopaminergic parameters investigated. The results of the present investigation indicate that neurochemical alterations can be observed in the striata of weaver mice as early as postnatal day 3 and raise the possibility that the striatal dopamine transporter may be an early target of the weaver mutation.

Aging↗
PubMed1993

Intrahippocampal transplants of septal cholinergic neurons: choline acetyltransferase activity, muscarinic receptor binding, and spatial memory function.

Recent studies have demonstrated that intrahippocampal cholinergic septal grafts can ameliorate deficits in spatial memory function and hippocampal cholinergic neurochemical activity in animals with disruptions of the septohippocampal pathway. Further studies have revealed that hippocampal cholinergic activity, as measured by high affinity choline uptake, correlates significantly with performance on tests of spatial memory function. The present study was designed to examine the effect of cholinergic septal grafts on reversing deficits in hippocampal choline acetyltransferase activity and on normalizing muscarinic receptor binding in animals with lesions of the septohippocampal system, and to examine the correlations between these cholinergic parameters and performance of spatial memory tasks. The results of this study indicated that in animals with lesions plus septal grafts, hippocampal ChAT activity was restored significantly and muscarinic receptor binding was normalized to a level not different from the control animals. Regression analyses indicated that ChAT activity was significantly correlated with performance on spatial reference memory, spatial navigation and spatial working memory, while muscarinic receptor binding correlated significantly with spatial reference memory performance.

Animals↗
PubMed1993

Serotonin content is elevated in the dopamine deficient striatum of the weaver mutant mouse.

In the present study, we measured the striatal serotonin content of weaver and control mice at different ages. Overall, weaver mutant mice exhibited 50% more striatal serotonin than controls. Neither a rostrocaudal gradient nor an age effect was found for either genotype. An analysis of serotonin content across the dorsoventral extent of the striatum revealed that in the dorsal striatum of the weaver, serotonin content was increased 200%, and in the ventral striatum, the increase amounted to 50% relative to control mice. Serotonin immunocytochemistry also revealed an increase in the dorsal striata of weaver mice. The major increase in striatal serotonin content seen in the weaver striatum occurs in the same region that exhibits the severest dopamine depletion. This observation is consistent with the notion that the increase in serotonin levels may be secondary to the decrease in dopamine content and may play an adaptive or compensatory role.

Aging↗
PubMed1993

In-vitro recombination in rad and rnc mutants of Saccharomyces cerevisiae.

Extracts of S. cerevisiae cells can catalyze homologous recombination between plasmids in vitro. Extracts prepared from rad50, rad52 or rad54 disruption mutants all have reduced recombinational activity compared to wild-type. The rad52 and rad54 extracts are more impaired in the recombination of plasmids containing double-strand breaks than of intact plasmids, whereas rad50 extracts are deficient equally for both types of substrate. The nuclease RhoNuc (previously designated yNucR), encoded by the RNC1 (previously designated NUC2) gene and regulated by the RAD52 gene, is not required for recombination when one substrate is single-stranded but is essential for the majority of recombination events when both substrates are double-stranded. Furthermore, elimination of this nuclease restores recombination in rad52 extracts to levels comparable to those in wild-type extracts.

Deoxyribonucleases↗
PubMed1993

Dopamine-depleting effects of MPTP and reserpine in weaver mutant mice.

The number of nigral dopamine neurons and striatal dopamine levels are reduced by 70% in the adult weaver mutant mouse (wv/wv), whereas these parameters are essentially unchanged in the heterozygote (wv/+). We hypothesized that the remaining nigral dopamine neurons and/or striatal dopamine levels in the weaver would be less sensitive to neurotoxic or dopamine-depleting agents and that nigral neurons in the heterozygote would be more vulnerable. Mice were treated with the dopaminergic neurotoxin MPTP using different injection schedules and also with reserpine. There was a similar percent decrease in striatal DA in weavers and heterozygotes compared to normal mice after these treatments. We did observe a gene-dose-related lethality to the highest dose treatment with MPTP. These results suggest that the remaining dopaminergic neurons in the weaver are not different from those in normal mice in their capacity to respond to MPTP and reserpine.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

Is there a significant somatodendritic uptake of dopamine in the substantia nigra? Evidence from the weaver mutant mouse.

Slices of the substantia nigra from normal mice and from mice with the weaver gene were used to study somatodendritic uptake of dopamine. The substantia nigra of the homozygous weaver mouse is deficient in both cell bodies and dendrites whereas the substantia nigra of the heterozygous weaver mouse is deficient only in dendrites. Accumulation of [3H]dopamine by nigral slices obtained from each genotype was not different from that observed in slices obtained from control mice. The observed accumulation of [3H]dopamine was apparently taking place predominantly into serotonergic and noradrenergic elements since significant reductions were obtained by both fluoxetine and desipramine at concentrations that were selective for the serotonin and norepinephrine carriers, respectively. In the absence, as well as in the presence of fluoxetine and desipramine, dopamine accumulation in the substantia nigra was only slightly attenuated by the known dopamine uptake blocker GBR 12909. These data argue against a significant presence of somatodendritic uptake systems for dopamine in the substantia nigra and suggest that caution be used in the interpretation of results from studies on dopamine release from nigral slices when [3H]dopamine has been used to preload the tissue. Under such experimental conditions, it is likely that a large proportion of the released tritium might come from neurons other than those which contain endogenous neurotransmitter dopamine.

Animals↗
PubMed1992

Buffer conditions and non-tubulin factors critically affect the microtubule dynamic instability of sea urchin egg tubulin.

The dynamic instability of individual microtubules (Mts) in cytoplasmic extracts or assembled from highly purified sea urchin egg tubulin was examined using video-enhanced, differential-interference contrast (VE-DIC) light microscopy. Extract Mts (endogenous tubulin = 12.1 microM) displayed only plus-ended growth. The elongation velocity was 7.8 microns/min for an average duration of 1.3 min before switching (catastrophe) to rapid shortening, which occurred at 13.0 microns/min for an average duration of 0.5 min before switching (rescue) back to the elongation phase. These parameters are typical of interphase Mt dynamic instability. Surprisingly, Mts assembled from purified urchin egg tubulin in standard buffers were less dynamic that those reported for purified brain tubulin or Mts in the extract. Buffer parameters were changed in an attempt to mimic the extract Mt results. The pH buffer itself, Hepes or Pipes, drastically altered Mt dynamics but could not achieve high elongation velocity with high catastrophe frequencies. Calcium at 1 microM had negligible effects, while increasing pH from 6.9 to 7.2 stimulated elongation velocity. Finally, Mt dynamics of purified egg tubulin (11.9 microM) were assayed in ultrafiltrates (MW cut-off less than 30 kD) of the cytoplasmic extracts. Mts elongated slowly at 1.2 microns/min for 26 min before a catastrophe and rapid shortening at 11.8 microns/min. Rescue was less frequent than unfiltered extracts, minus-ended growth was observed, and self-assembly occurred at slightly higher tubulin concentrations. Therefore, the egg extracts and cytoplasm must contain non-buffer factors which stimulate elongation velocity by 6.5-fold without self-assembly, increase catastrophe frequency by 20-fold, and block minus-ended growth.

Animals↗
PubMed1992

Topographic distribution of dopamine uptake, choline uptake, choline acetyltransferase, and GABA uptake in the striata of weaver mutant mice.

The topographic distribution of dopamine (DA) uptake, choline uptake, choline acetyltransferase (ChAT) activity and GABA uptake within the striata of weaver mutant mice and control mice was determined. Uptake of [3H]dopamine, [3H]choline and [14C]GABA, as well as ChAT activity were determined in samples prepared from the dorsolateral, dorsomedial, ventrolateral and ventromedial portions of the striatum. In 45-60 day old control mice, dopamine uptake was homogeneously distributed throughout the striatum. On the other hand, striata from weaver mice exhibited an uneven distribution with the ventral aspects having greater uptake activity than the dorsal regions. Thus, although the ventral portion of the striatum is less severely affected than the dorsal portion, all areas of the striatum exhibited significantly reduced uptake rates. In 9 and 12 month old mice, choline uptake was higher in lateral than medial zones of the striatum of both genotypes and no differences were observed between genotypes. GABA uptake was higher in the ventral striatum than in the dorsal striatum but again no differences were found between weaver and control mice. The results of this study indicate that the entire weaver striatum is severely deficient in its ability to recapture dopamine and thus is functionally compromised. The results also indicate that the striatal cholinergic and GABAergic interneurons are not directly or indirectly affected by the weaver gene.

Animals↗
PubMed1992

Comparison of alterations in tyrosine hydroxylase, dopamine levels, and dopamine uptake in the striatum of the weaver mutant mouse.

Previous reports have shown that among the markers for the nigro-striatal dopamine (DA) system measured in the striatum, dopamine uptake seems to be more severely affected than the others in the weaver mutant mouse. In the present study we examined DA levels, tyrosine hydroxylase (TH) activity, and high-affinity DA uptake to determine if the DA uptake is most affected when all the measurements are made in the same striatal homogenate in the same laboratory. We found that the DA uptake activity was most altered (93% lower) compared to DA levels (68% lower) and TH activity (64% lower). The DA uptake was so low in the weaver that we could not obtain reliable kinetic parameters. For TH activity we found that the Vmax was 36% lower while the Km for L-tyrosine was 92% higher in the weaver striatum. This lower affinity for substrate suggests that the TH enzyme itself may be altered in the nigro-striatal system of the weaver mutant mouse.

Animals↗
PubMed1992

Some regional anatomical relationships of TRH to 5-HT in rat limbic forebrain.

It is now a recognized principle that various neuropeptides are neuronally co-localized with biogenic amine or aminoacid neurotransmitters. In the rat CNS it has previously been shown that TRH is co-localized with 5-HT (and also with substance P) in cell bodies of the posterior raphe that project to the spinal cord. Although TRH cell bodies are known to be widely distributed throughout the forebrain there is no other known co-localization with 5-HT. In this study we further specify the forebrain there is no other known co-localization with 5-HT. In this study we further specify the anatomical relationship of TRH with 5-HT by use of surgical and neurotoxic lesioning with reference to limbic forebrain regions wherein TRH is greatly increased following seizures. In groups of rats, the fimbria-fornix was lesioned alone, or combined with a lesion of the dorsal perforant path or the ventral perforant path. There was a sham lesioned control group. Additional groups were lesioned with 5,7 dihydroxytryptamine, 100 micrograms i.v.t., 45 min. after i.p. desipramine, 25 mg/kg. All rats were sacrificed three weeks after lesions. Indoleamines were determined by HPLC in left anterior cortex, left pyriform/olfactory cortex, left dorsal hippocampus and left ventral hippocampus. TRH was determined by specific RIA in the corresponding right brain regions. The modal n was 7 rats.(ABSTRACT TRUNCATED AT 250 WORDS)

5,7-Dihydroxytryptamine↗
PubMed1992

Intrahippocampal grafts of cholinergic-rich striatal tissue ameliorate spatial memory deficits in rats with fornix lesions.

Previous studies have shown that cholinergic grafts derived from the medial septal nucleus are capable of restoring behavioral function in rats with lesions that sever the cholinergic inputs to the hippocampal formation. In this study, we demonstrate that intrahippocampal grafts of cholinergic-rich striatal tissue also ameliorate spatial memory deficits of rats with fornix lesions. We also found that atropine administration dramatically disrupted spatial navigation performance of rats with striatal grafts and control rats, thus suggesting that the striatal graft effects are mediated by cholinergic mechanisms of action. Measurements of high affinity choline uptake (HACU) and muscarinic receptor binding revealed that intrahippocampal striatal grafts increased HACU and normalized muscarinic receptor binding in animals with fornix lesions. Regression analyses demonstrated significant correlations between the amelioration of spatial memory deficits and hippocampal HACU and receptor binding. We conclude that intrahippocampal grafts of cholinergic-rich striatal tissue can ameliorate spatial memory deficits and that this amelioration is associated with the reinstatement of functional cholinergic terminations.

Animals↗
PubMed1991

Intrahippocampal transplants of septal cholinergic neurons: high-affinity choline uptake and spatial memory function.

Recent studies have demonstrated that intrahippocampal cholinergic septal grafts can ameliorate deficits in spatial memory function and hippocampal cholinergic neurochemical activity in animals with disruptions of the septohippocampal system. However, no study has determined if the restoration of spatial memory function is correlated to the restoration of cholinergic activity, as measured by high-affinity choline uptake (HACU). The present study was designed to determine if such a correlation between behavioral and neurochemical restoration exists. Male Sprague-Dawley rats received either sham lesions (SHAM), bilateral lesions of the septohippocampal pathway (LES), or bilateral lesions along with intrahippocampal septal grafts (SG). After 8 months, rats were tested for their ability to perform spatial reference, spatial navigation and working memory tasks. Upon completion of the behavioral testing, neurochemical activity of the hippocampus was measured by HACU. The results indicate that animals in the SG group had significantly higher behavioral scores and hippocampal HACU rates than animals in the LES group. Regression analysis indicates that a significant correlation exists between performance on each behavioral task and HACU rates. These results demonstrate that hippocampal cholinergic activity, as measured by HACU, correlates significantly with performance on tests of spatial memory function.

Animals↗
PubMed1991

In vitro release of endogenous dopamine from the striatum of the weaver mutant mouse.

The weaver mutant mouse has a genetically determined defect in the nigrostriatal dopaminergic system. The present study was undertaken to test the hypothesis that in the weaver mutant mouse, striatal nerve terminals undergo compensatory changes in response to this deficiency. To test this hypothesis, we studied the basal and stimulated release of dopamine from striatal slices of weaver mutant mice and matched controls. By using a superfusion system and concentrating the superfusate by passage over alumina, resting dopamine release could be determined in the weaver mutant despite the fact that striatal tissue content of dopamine in these mice is reduced by greater than 75% compared with control mice. Fractional resting release of dopamine in weaver striatal slices was significantly elevated compared with that in controls, suggesting that the release mechanisms in the weaver may be adapting to overcome the dopamine deficit. Potassium-evoked release (24 and 48 mM potassium) was not significantly different between the two genotypes. In contrast, amphetamine-evoked release (1 microM) was significantly greater in the weaver mice than in controls. In both genotypes, release evoked by amphetamine was completely inhibited by cocaine, implicating the dopamine uptake carrier in this release process. These findings suggest that fundamental differences in dopamine release mechanisms exist between weaver and control mice and support the hypothesis that compensatory mechanisms may develop in neurons in response to dopamine deficits.

Amphetamine↗
PubMed1990

Age-related changes in striatal dopamine D2 receptor binding in weaver mice and effects of ventral mesencephalic grafts.

Dopamine (DA) D2 receptor binding is increased in the striatum of 5-6 months old weaver mutant mice (Kaseda et al. 1987). This may occur in response to the loss of DA neurons in the midbrain and the decrease in DA content in the striatum of homozygous mutants. One purpose of the present study was to determine if the diminished DA innervation is associated with changes in D2 receptors at earlier ages and if the increase in DA D2 receptor binding seen at 5-6 months is a lasting phenomenon. Specific [3H]spiperone binding was measured in the dorsolateral (DL), dorsomedial (DM) and ventrolateral (VL) striatum and in the nucleus accumbens (AC) of homozygous weaver mutant mice (wv/wv), heterozygous littermates (wv/+) and wild-type controls (+/+). Mice were studied at 20 days and 1, 3, 6, 9 and 12 months of age. The difference in specific [3H]spiperone binding in DL striatum between wv/wv and +/+ mice was significantly greater at 6 months than the difference at 1 month and at 12 months of age. Foetal ventral mesencephalic grafts survive and establish functional innervation in the striatum of weaver mice as shown by the induction of a contralateral turning bias (Low et al. 1987). The second aim of the present studies was to determine if such grafts would also reverse the increase in DA D2 receptor binding in the striatum. Aspiration cavities were prepared in the cortex of weaver mice, and ventral mesencephalic tissue from E14-E15 +/+ foetuses was subsequently placed on the surface of the right dorsal striatum when the recipients were 3 months old.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗