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Biomedical subjects

K Braun

Publications and source records attributed to K Braun.

At least 55 records · Page 3Linked to original sources
PubMed2000

Quantitative changes in reduced nicotinamide adenine dinucleotide phosphate-diaphorase-reactive neurons in the brain of Octodon degus after periodic maternal separation and early social isolation.

The influence of preweaning maternal separation and postweaning social isolation on the development of reduced nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase-reactive neurons in prefrontal cortical areas, in subdivisions of the nucleus accumbens and in the corpus callosum was quantitatively investigated in the precocious rodent Octodon degus. Forty-five-day-old degus from three animal groups were compared: (i) degus that were reared under normal undisturbed social conditions; (ii) degus that were repeatedly separated from their mothers during the first three postnatal weeks and thereafter reared with their family; and (iii) degus that remained undisturbed with the family until weaning (postnatal day 21) and thereafter were reared in social isolation. Preweaning maternal separation led to a significant decrease in NADPH-diaphorase-containing neurons in the corpus callosum in both genders (down to 33%) compared with the social control group. No significant changes were found in the subregions of the medial prefrontal cortex and nucleus accumbens. Postweaning social isolation led to a reduced density of NADPH-diaphorase-containing neurons in the corpus callosum in both genders (down to 52%) compared with the social control group. Furthermore, in the precentral medial cortex of female pups, a significant reduction in NADPH-diaphorase-reactive neurons (down to 72%) was detectable. All other regions of the medial prefrontal cortex and the nucleus accumbens remained unchanged. The observed deprivation-induced changes may reflect either an excessive reduction in NADPH-diaphorase-positive neurons or a down-regulation of the enzyme in neurons that normally express it.Our results indicate a link between early adverse socio-emotional experience and the maturation of NADPH-reactive neurons. Further studies are required to analyse the functional implications of this experience-induced brain pathology.

Animals↗
PubMed2000

Maternal separation followed by early social deprivation affects the development of monoaminergic fiber systems in the medial prefrontal cortex of Octodon degus.

The influence of early postnatal socio-emotional deprivation on the development of tyrosine hydroxylase- and 5-hydroxytryptamine-immunoreactive fiber innervation in the medial prefrontal cortex was quantitatively investigated in the precocial rodent Octodon degus. Forty-five-days-old degus from two groups were compared: (i) degus which were repeatedly separated from their mothers during the first three postnatal weeks and after weaning reared in complete isolation; and (ii) degus which were reared under normal undisturbed social conditions. The two monoaminergic fiber systems in the four subregions of the medial prefrontal cortex responded differentially to the deprivation. While the infralimbic cortex was the only subregion that displayed an increase in 5-hydroxytryptamine-positive fiber densities (129.2%) but no changes in tyrosine hydroxylase-immunoreactive fibers, the precentral medial (82.2%), anterior cingulate (74.6%) and prelimbic cortex (86.9%) showed significantly reduced tyrosine hydroxylase-positive fiber innervation, but no changes in 5-hydroxytryptamine-immunoreactive fiber densities. The number of tyrosine hydroxylase-positive somata in the ventral tegmental area and in the substantia nigra remained unchanged. In cortical areas the number of tyrosine hydroxylase-immunoreactive somata was increased (depending on the medial prefrontal cortex subregion between 241.8% and 398.7%) in deprived animals. This altered balance between the serotonergic and dopaminergic cortical innervation in the different subregions of the medial prefrontal cortex may reflect a counter-regulative anatomical and functional adaptation, which may be triggered by an altered activity of these transmitter systems during the phases of maternal separation and social isolation.

Animals↗
PubMed2000

[Juvenile experience and learning modulate the functional maturation of the brain: relevance for the genesis and therapy of mental disorders].

This article summarizes experimental data that indicate how juvenile experience and learning events modulate the functional maturation of the brain, shaping thereby the neuronal substrate for the development of intellectual and socio-emotional abilities. The fact that early experience occurs during early postnatal brain development, i.e. phases of elevated neuronal and synaptic plasticity, results in an "imprinting" of synaptic connectivity and neural circuitry in the infant brain. Results from experimental research in animal models support the hypothesis that impoverished intellectual stimulation and disturbance of the socio-emotional environment during early childhood may disturb the formation of functional brain pathways, in particular of the limbic circuits, which play a major role in emotion and learning. Such defective brain systems, representing neurofunctional "scars" in the brain, may be the neuronal basis of a variety of mental disorders and clinical symptoms caused by early stressful psychosocial environment. Ultimately, the goal will be to apply the knowledge gained to the development of biological and psychosocial intervention strategies by utilizing remaining plasticity of the adult human brain aimed at promoting human health, decreasing susceptibility and increasing resistance to disease.

Adult↗
PubMed2000

FMRP involvement in formation of synapses among cultured hippocampal neurons.

Fragile-X, the main cause of inherited human mental retardation is associated with the absence of a recently identified fragile-X mental retardation protein (FMRP). Mice in which this protein is lacking due to a knockout (KO) mutation are reported to express altered dendritic spines on their cortical neurons compared with wild type (WT) controls. We have used tissue-cultured neurons to examine differences in morphology and synaptic connectivity between WT and FMRP-deficient mice. Hippocampal neurons taken from KO mice and grown in culture for 3 weeks have shorter dendrites and fewer dendritic spines than their WT counterparts. Also, KO cells tend to express fewer functional synaptic connections, which develop more slowly and produce smaller excitatory synaptic currents than WT controls. These observations may have important implications for the understanding of mental retardation associated with the absence of FMRP.

Animals↗
PubMed2000

Parental deprivation induces N-methyl-D-aspartate-receptor upregulation in limbic brain areas of Octodon degus: protective role of the maternal call.

An optimal coordination between parents and their offspring involves a sequence of reciprocal behaviors to ensure the adequate care of the young, which is critical for a healthy physical, emotional, and social development. Parental deprivation, particularly an impaired child-mother attachment, induces lasting changes in emotional as well as in cognitive capacities in later life. We assessed in the South American precocial species, Octodon degus, whether alterations of glutamatergic function of the limbic system induced by parental deprivation may be a neural correlate for such behavioral changes. Further, we analyzed whether the mother's voice can protect from separation-induced changes of brain function. Changes of N-methyl-D-aspartate (NMDA) receptor expression were examined in the following three groups of 2-week-old Octodon degus pups: (I) control animals who remained undisturbed with the family; (II) animals who were repeatedly separated from the family and individually placed in an unfamiliar environment for behavioral analysis (open field); and (III) animals who were treated like the group described under (II) but were presented with maternal vocalizations during separation. Relative to those in the control group I, the animals in group II showed an upregulation of NMDA receptor density in the (a) anterior cingulate, prelimbic, infralimbic, and anterior insular cortices; (b) CA1/stratum radiatum; (c) CA1/stratum lacunosum moleculare and CA3/stratum radiatum; and (d) in the basomedial amygdaloid nucleus. Presentation of the maternal call during the separation period (group III) suppressed the separation-induced NMDA receptor upregulation in all regions. The results demonstrate that early life events can influence the expression of transmitter receptors and that maternal behavior, acting to control the pup's socio-emotional environment, is a key factor for regulating such developmental events.

Animals↗
PubMed2000

Pharmacodynamic monitoring of mycophenolate mofetil.

The immunosuppressive activity of Mycophenolate Mofetil (MMF) is based on the reversible inhibition of inosine-5'-monophosphate dehydrogenase (IMPDH) by mycophenolic acid. Pharmacodynamic monitoring by measurement of IMPDH activity reflects directly the biological response to MMF. For measurement of IMPDH activity in peripheral mononuclear cells we established a modified non-radioactive procedure, based on the incubation of cell lysates with inosine-5'-monophosphate and the chromatographic quantification of produced xanthosine-5'-monophosphate by isocratic ion-pair reversed phase HPLC. The between-run precision and within-run precision were 7% and 5%, respectively. We determined the time course of IMPDH activity in five patients after 1 g MMF and in five healthy subjects without administration of MMF. Additionally, IMPDH activity was determined in a population study of 40 healthy volunteers. In healthy volunteers, we observed a wide range of IMPDH activity (4.7-32.9 nmol/h/mg) with only weak diurnal variation. All patients receiving MMF had a significant reduction of IMPDH activity (65-100%) after administration of the drug. Inhibition persisted for up to 6 hours, and after 11 hours IMPDH activity returned to predose activities. The interindividual variability of IMPDH activity may account for pharmacodynamic differences in MMF-treated patients. Based on pharmacodynamic monitoring better dosing strategies for MMF-treated patients may evolve.

Adult↗
PubMed2000

Results of a pilot program for training bar staff in preventing aggression.

One hundred and twenty-one staff from eight bars in Ontario, Canada participated in a three-hour training program that used a peer learning model to teach problem-solving skills regarding the prevention and management of aggressive behavior in bars. Participants showed significant positive changes in knowledge and attitudes regarding effective approaches to preventing aggression. The majority of participants reported that the training made them think about ways they handed problem situations and that they would change the way they handle problems in the future. Participants rated most aspects of the training as very useful, especially the group discussion. The program illustrates the potential for increasing skills and knowledge of bar staff in preventing aggression and associated injury.

Adult↗
PubMed2000

The Medical Education Commission report at the turn of then new millennium 2000.

The State of Louisiana Medical Education Commission was formed by Act 3 of the 1997 Louisiana Legislature. The members are appointed by the Louisiana State University Health Sciences Center, Tulane University Medical Center, and Alton Ochsner Medical Foundation and report to and advise the Department of Health and Hospitals (DHH). This summation from the Medical Education Committee is designed to answer three questions. First, how does the State of Louisiana compare nationally in the renewal of physician supply and capability? Second, what are the current status and trends of graduate medical education in Louisiana? Third, what recommendations are proposed to continue and improve the important relationship between the State public hospitals and educational programs? The State of Louisiana has participated proportionately relative to population in the growth and progress of medical education in this last century and compares favorably with other states and the nation. Louisiana exceeds national averages in the increase of primary care residency programs and positions and in the retention of trainees in practice sites in the State. The three-year trends in total number of graduate medical education filled positions has been consistent with only 0.4% change, with primary care showing an overall increase of 9%, reflecting increases in Family Medicine (56%) and Medicine/Pediatrics (41%).

Education, Medical, Graduate↗
PubMed1999

Blockade of N-methyl-D-aspartate receptor activation suppresses learning-induced synaptic elimination.

Auditory filial imprinting in the domestic chicken is accompanied by a dramatic loss of spine synapses in two higher associative forebrain areas, the mediorostral neostriatum/hyperstriatum ventrale (MNH) and the dorsocaudal neostriatum (Ndc). The cellular mechanisms that underlie this learning-induced synaptic reorganization are unclear. We found that local pharmacological blockade of N-methyl-D-aspartate (NMDA) receptors in the MNH, a manipulation that has been shown previously to impair auditory imprinting, suppresses the learning-induced spine reduction in this region. Chicks treated with the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (APV) during the behavioral training for imprinting (postnatal day 0-2) displayed similar spine frequencies at postnatal day 7 as naive control animals, which, in both groups, were significantly higher than in imprinted animals. Because the average dendritic length did not differ between the experimental groups, the reduced spine frequency can be interpreted as a reduction of the total number of spine synapses per neuron. In the Ndc, which is reciprocally connected with the MNH and not directly influenced by the injected drug, learning-induced spine elimination was partly suppressed. Spine frequencies of the APV-treated, behaviorally trained but nonimprinted animals were higher than in the imprinted animals but lower than in the naive animals. These results provide evidence that NMDA receptor activation is required for the learning-induced selective reduction of spine synapses, which may serve as a mechanism of information storage specific for juvenile emotional learning events.

2-Amino-5-phosphonovalerate↗
PubMed1999

The dorsocaudal neostriatum of the domestic chick: a structure serving higher associative functions.

The dorsocaudal neostriatal (dNC) complex consists of at least three functionally distinct subregions and is part of an 'imprinting' pathway, which interconnects several forebrain regions that are known to be involved in juvenile learning. Based on its anatomical features, at least one subregion of the dNC complex, the neostriatum dorsocaudale (Ndc) may be considered as the equivalent of the mammalian polysensory association cortices. Several lines of evidence point to a role for this forebrain region in learning and memory formation. After auditory or visual imprinting changes of stimulus-evoked metabolic activities and of synaptic densities have been measured in the Ndc. Pharmacological behavioral studies revealed that the activation of NMDA receptors plays a critical role during this learning process and that NMDA receptor activation is required for the associated metabolic and synaptic changes. In addition to glutamatergic afferents, anatomical studies revealed a massive input from monoaminergic and peptidergic pathways into the dNC complex, suggesting a modulatory role for these systems during imprinting. The results presented here together with data from other avian species support the view that the dNc complex, and in particular the Ndc, plays an important role in juvenile and adult learning.

Animals↗
PubMed1999

N-methyl-D-aspartate receptor-mediated modulation of monoaminergic metabolites and amino acids in the chick forebrain: an in vivo microdialysis and electrophysiology study.

The associative avian forebrain region medio-rostral neostriatum/hyperstriatum ventrale (MNH) is involved in auditory filial imprinting and may be considered the avian analogue of the mammalian prefrontal cortex. In search of the neurochemical and physiological mechanisms which play a role in this learning process, we introduced microdialysis and a combined microdialysis/electrophysiological approach in domestic chicks a few days old. With this technique, we were able to follow changes of the extracellular levels of glutamate, taurine, 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of serotonin, and homovanillic acid (HVA), a metabolite of dopamine, and neuronal activity simultaneously in freely moving animals. We obtained first evidence of a modulatory interaction between glutamatergic and monoaminergic neurotransmission mediated by N-methyl-D-aspartate (NMDA) receptors. During local intracerebral infusion of 300 microM NMDA via reverse microdialysis, an increase of taurine and a decrease of 5-HIAA and HVA were detected, accompanied by enhanced extracellular spike rates. Glutamate was increased only during consecutive infusion of increasing NMDA concentrations, when higher (1 mM) NMDA concentrations were infused. The effects of NMDA were antagonized by D, L-2-amino-5-phosphonovaleric acid (1 mM). Infusion of high potassium induced similar changes in taurine, 5-HIAA, and HVA, as found during infusion of NMDA, but decreased extracellular spike rates, which indicates that different cellular mechanisms may underlie the observed neurochemical changes. Neither urethane anesthesia nor different delays between probe implantation and experiment influenced the neurochemical and electrophysiological results; however, changes of taurine were observed only in chronically implanted, awake animals. In summary, microdialysis in combination with electrophysiology provides a powerful tool to detect changes of neuronal activity and transmitter release in the avian brain, with which the role of transmitter interactions can be followed during and after different learning events.

Amino Acids↗
PubMed1999

Maternal separation and early social deprivation in Octodon degus: quantitative changes of nicotinamide adenine dinucleotide phosphate-diaphorase-reactive neurons in the prefrontal cortex and nucleus accumbens.

The influence of postnatal socio-emotional deprivation on the development of nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase-reactive neurons in prefrontal cortical areas and in subdivisions of the nucleus accumbens was quantitatively investigated in the precocious rodent Octodon degus. Forty-five-days-old O. degus from two animal groups were compared: (i) degus which were repeatedly separated from their mothers during the first three postnatal weeks and after weaning reared in complete isolation; and (ii) degus which were reared under normal undisturbed social conditions. Socially-deprived animals displayed a significant decrease of NADPH-diaphorase-containing neurons in anterior cingulate cortex (85.5%), the same tendency was observed in the infralimbic, precentral medial and prelimbic prefrontal areas. Similarly, the core region of nucleus accumbens expressed reduced NADPH-diaphorase-reactive neuron numbers in deprived animals (70%), whereas the shell region remained unchanged. Since during normal postnatal development the number of NADPH-diaphorase-reactive neurons gradually decreases in all prefrontal cortical and accumbal regions, the observed deprivation-induced changes may reflect either an excessive reduction of NADPH-diaphorase-positive neurons or a down-regulation of the enzyme in neurons that normally express it. Since some NADPH-diaphorase-containing neurons in the prefrontal cortex have been shown to be GABAergic, it is tempting to speculate that a reduction of these inhibitory neurons in the anterior cingulate cortex may result in an enhanced excitatory output activity of disinhibited projection neurons in this cortical region, including those that project to the core region of the nucleus accumbens. Our results indicate a link between early adverse socio-emotional experience and the maturation of NADPH-reactive neurons and further studies are required to analyse the functional implication for this experience-induced brain pathology.

Aging↗
PubMed1999

Cyclin-dependent kinases at the G1-S transition of the mammalian cell cycle.

In the mammalian cell cycle, the transition from the G1 phase to S phase, in which DNA replication occurs, is dependent on tight cell size control and has been shown to be regulated by the cyclin-dependent kinases (Cdks) 2, 3, 4 and 6. Activities of Cdks are controlled by association with cyclins and reversible phosphorylation reactions. An additional level of regulation is provided by inhibitors of Cdks. G1-S and S phase substrates of these enzymes include proteins implicated in replication and transcription. Whereas the regulation and role of Cdk2, 4 and 6 has intensively been studied, less is known about Cdk3. Recent data provide first insights into the regulation of Cdk3-associate kinase activity and suggest a model how Cdk3 participates in the regulation of the G1-S transition. Although it has been shown that these G1-Cdks are absolutely essential for a proper transition into S phase, their physiological activation is not sufficient to directly initiate replication independently of cell size. Evidence obtained from yeast and Xenopus indicate the initiation of DNA replication to be a two-step process: the origin recognition complex, Cdc6 and Mcm proteins are required for establishing the prereplicative complex and the activities of Cdks and of Cdc7 kinase then trigger the G1-S transition. Recent findings provide evidence that the overall mechanism of initiation of replication is conserved in mammalian cells.

Animals↗
PubMed1999

Benzamide riboside induces apoptosis independent of Cdc25A expression in human ovarian carcinoma N.1 cells.

One of the mechanisms of action of a new oncolytic agent, benzamide riboside (BR) is by inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH) which catalyzes the formation of xanthine 5'-monophosphate from inosine 5'-monophosphate and nicotinamide adenine dinucleotide, thereby restricting the biosynthesis of guanylates. In the present study BR (10 - 20 microM) induced apoptosis in a human ovarian carcinoma N.1 cell line (a monoclonal derivative of its heterogenous parent line HOC-7). This was ascertained by DNA fragmentation, TUNEL assay, [poly(ADP)ribose polymerase]-cleavage and alteration in cell morphology. Apoptosis was accompanied by sustained c-Myc expression, concurrent down-regulation of cdc25A mRNA and protein, and by inhibition of Cdk2 activity. Both Cdk2 and cdc25A are G1 phase specific genes and Cdk2 is the target of Cdc25A. These studies demonstrate that BR exhibits dual mechanisms of action, first by inhibiting IMPDH, and second by inducing apoptosis, which is associated with repression of components of the cell cycle that are downstream of constitutive c-Myc expression.

Adenocarcinoma↗
PubMed1999

Filial imprinting in domestic chicks is associated with spine pruning in the associative area, dorsocaudal neostriatum.

Juvenile emotionally modulated learning events are fundamental for the normal development of socio-emotional competence and intellectual capabilities. Filial imprinting in the domestic chick provides a suitable model to investigate the neural mechanisms underlying such juvenile learning events. The forebrain area dorsocaudal neostriatum (Ndc), a multimodal integration area and presumed equivalent to mammalian parietotemporal association cortices, has been shown to be critically involved in this learning process. We investigated whether filial imprinting is associated with changes of synaptic connectivity in the Ndc. Quantitative measurements of spine densities of a large neuron type in the Ndc revealed a massive pruning of spine synapses after filial imprinting. Compared with 7-day-old naive control chicks, imprinted chicks displayed significantly lower spine frequencies on all dendritic segments. Since the average length of the dendritic segments did not change during imprinting, these results can be interpreted as a reduction of the absolute number of spine synapses on this neuron type. In a control region, the primary sensory forebrain area ectostriatum, spine density and dendritic length remained unchanged. These results indicate that synaptic pruning may represent a mechanism of selective synaptic reorganization in higher associative forebrain areas as a fundamental feature of juvenile learning events.

Animals↗
PubMed1999

Effect of social experience on dopamine-stimulated adenylyl cyclase activity and G protein composition in chick forebrain.

The stimulation of adenylyl cyclase (AC) by dopamine was investigated in membrane fractions of the forebrain areas mediorostral neostriatum/hyperstriatum ventrale (MNH) and lobus parolfactorius (LPO) of 8-day-old domestic chicks that had been raised under different social conditions: group A, socially isolated; group B, imprinted on an acoustic stimulus; group C, trained but nonimprinted; and group D, reared in small groups. Only in the brain of the socially experienced groups could cyclic AMP (cAMP) synthesis be stimulated by dopamine, but not in the socially isolated animals (group A). Ligand binding studies of dopamine D1- and D2-type receptors in membrane fractions did not reveal differences between socially experienced and isolated animals. Forskolin stimulation of total AC in MNH and LPO membrane fractions revealed a significantly enhanced AC stimulation in the socially reared but not in the imprinted group compared with isolated controls. Stimulation of AC by the G protein activator guanylylimidodiphosphate was significantly increased in the MNH and the LPO of socially reared chicks compared with isolated control animals. These results suggest that early postnatal social experience modulates the rate of cAMP synthesis and that these lasting changes are not due to changes of dopamine receptors but are related to increased AC activities and to increased sensitivity of Gs protein.

Adenylyl Cyclases↗
PubMed1998

Investigation of the cell cycle regulation of cdk3-associated kinase activity and the role of cdk3 in proliferation and transformation.

The G1-S transition in mammalian cells has been demonstrated to require the cyclin-dependent kinases cdk2, cdk3 and cdk4/6. Here we show that a novel kinase activity associated with cdk3 fluctuates throughout the cell cycle differently from the expression of cyclin D1-, E- and A-associated kinase activities. Cdk3 kinase activity is neither affected by p16 (in contrast to cdk4/6) nor by E2F-1 (in contrast to cdk2), but is downregulated upon transient p27 expression. We found cdk3 to bind to p21 and p27. We provide evidence that p27 could be involved in the regulation of the cell cycle fluctuation of cdk3 activity: cdk3 protein does not fluctuate and interaction of cdk3 with p27, but not with p21, is lost when cdk3 kinase becomes active during the cell cycle. In Myc-overexpressing cells, but not in normal Ratl cells, constitutive ectopic expression of cdk3 induces specific upregulation of cdk3-associated kinase activity that is still cell cycle phase dependent. Ectopic cdk3, but not cdk2, enhances Myc-induced proliferation and anchorage-independent growth associated with Myc activation, without effects on cyclin D1, E and A protein expression or kinase activities. High levels of cdk3 in Myc-overexpressing cells trigger up- and deregulation of E2F-dependent transcription without inducing the E2F-DNA binding capacity. In contrast to all other studied positive G regulators, cdk3 is unable to cooperate with ras in fibroblast transformation suggesting a function of cdk3 in G1 progression that is different from cyclin D- or E-associated kinase activities. Our data provide first insights into the regulation of cdk3-associated kinase activity and suggest a model how cdk3 participates in the regulation of the G1-S transition.

Animals↗