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PubMed1995

Cellular target of in vitro-induced suppressor cells derived from the spleen of Mycobacterium lepraemurium-infected mice and role of IFN-gamma in their development.

Unfractionated spleen cells from C3H mice infected a few weeks before with Mycobacterium lepraemurium developed a suppressor activity after overnight culture. This requires contact of plastic adherent cells with nonadherent cells distinct from T, B, or natural killer cells. The present study demonstrates that anti-interferon-gamma (IFN-gamma) monoclonal antibody and indomethacin totally abrogate the expression, although not the induction, of this activity. Furthermore, culture-induced suppressor cells selectively inhibit T lymphocyte proliferation, probably by altering the generation of interleukin-2 (IL-2) responsiveness through reduction of the affinity and density of high-affinity IL-2 receptors on activated cells. These and other previously determined properties of culture-induced suppressor cells, similar to those of adherent suppressor cells detected in freshly harvested spleen cells at a later stage of M. lepraemurium infection, suggest a common precursor. If so, the present observations should help in defining a strategy to prevent the impairment of cell-mediated immunity in infected mice.

Animals↗
PubMed2005

Lifelong exposure to di-(2-ethylhexyl)-phthalate induces tumors in liver and testes of Sprague-Dawley rats.

The plasticizer di-(2-ethylhexyl)-phthalate (DEHP) is the most important phthalate with respect to its production, use and occurrence in the environment. In standard carcinogenicity experiments with F344 rats and B6C3F1 mice, DEHP has been shown to induce hepatocellular tumors. Moreover, DEHP is strongly suspected to be a developmental and reproductive toxicant. The present study aimed at determining the long-term toxic effects of lifetime exposure to low concentrations of DEHP in Sprague-Dawley rat strain. Seven hundred and thirty male rats, stratified into four groups, received DEHP with the diet, resulting in dosages of 300, 95, 30 and 0 mg/kg per day for up to 159 weeks and were only sacrificed when moribund. All organs of the dead and sacrificed animals were histopathologically examined. Significantly increased tumor incidences after exposure to 300 mg/kg per day DEHP (P = 0.04 for testes and 0.05 for liver) and a significant dose-related trend (P(Trend) = 0.02 for testes and 0.03 for liver) were detected in both organs liver and testes. Time to tumor analysis revealed that DEHP-induced testicular tumors developed earlier in lifetime than hepatocellular neoplasias, and their multiplicity increased with time. In addition, animals exposed to the highest DEHP dose showed a significantly increased rate of testicular tubular atrophy (P < 0.01). In conclusion, this study shows for the first time that the rat testes are a target organ of DEHP carcinogenicity in Sprague-Dawley rats upon lifetime exposure. This new finding indicates the importance of evaluating the effects of lifetime exposure in assessing the potential human health risks of DEHP. In addition, the carcinogenicity should be evaluated in rat strains with low spontaneous tumor incidence in the organs known as target of DEHP toxicity.

Animals↗
PubMed2007

Conditional transgenesis and recombination to study the molecular mechanisms of brain plasticity and memory.

In the postgenomic era, a primary focus of mouse genetics is to elucidate the role of individual genes in vivo. However, in the nervous system, studying the contribution of specific genes to brain functions is difficult because the brain is a highly complex organ with multiple neuroanatomical structures, orchestrating virtually every function in the body. Further, higher-order brain functions such as learning and memory simultaneously recruit several signaling cascades in different subcellular compartments and have highly fine-tuned spatial and temporal components. Conditional transgenic and gene targeting methodologies, however, now offer valuable tools with improved spatial and temporal resolution for appropriate studies of these functions. This chapter provides an overview of these tools and describes how they have helped gain better understanding of the role of candidate genes such as the NMDA receptor, the protein kinase CaMKIIIalpha, the protein phosphatases calcineurin and PP1, or the transcription factor CREB, in the processes of learning and memory. This review illustrates the broad and innovative applicability of these methodologies to the study of brain plasticity and cognitive functions.

Animals↗
PubMed2004

Physiological roles of neuronal nicotinic receptor subtypes: new insights on the nicotinic modulation of neurotransmitter release, synaptic transmission and plasticity.

Nicotinic acetylcholine receptors (nAChRs) are widely expressed in the mammalian central nervous system (CNS). Despite this, very little was known, until recently, about their physiological role. In the periphery, nicotinic receptors mediate vital excitatory fast synaptic cholinergic transmission at both the neuromuscular junction and ganglia. In the brain, this role has been mainly "delegated" to glutamate receptors. The very broad cholinergic innervations of most brain areas, including the cortex, have implicated this system, and brain nicotinic receptors in particular, in a unique "modulatory" role of other transmitters systems. Recent evidence confirms, on one hand, that brain nicotinic receptors have a dominant "presynaptic" modulatory function, controlling the release of both acetylcholine (auto-receptors) and other neurotransmitters (hetero-receptors). On the other hand, more experimental data support the idea that a variable component of fast synaptic transmission in the brain can also be mediated by "postynaptic" nicotinic receptors, which, in turn, can control cell excitability. A challenging goal is to identify which one of the plethora of nicotinic receptor subtypes is mediating each effect in different brain areas, and which of these receptors and functions are lost or affected in different human neuro-psychiatric disorders. Needless to say, a better understanding of the physiological role of brain nicotinic receptors will drive our quest for more selective and efficacious nicotinic receptor targeted therapeutic agents.

Animals↗
PubMedDate not supplied

Role of function-associated molecules in target cell lysis: analysis of rat adherent lymphokine-activated killer cells.

Monoclonal antibodies (MAbs) against fish nonspecific cytotoxic cells (NCC) inhibit the lysis of target cells by NCC and by human and rat natural killer (NK) cells. We now show that the anti-function-associated molecule (anti-FAM) MAb 5C6 also inhibits the cytolytic activity of rat (F344) nonadherent lymphokine-activated killer (LAK) cells and adherent LAK (ALAK) cells. Rat nylon-wool-nonadherent (NWNA) cells were cultured for 48 h in recombinant human interleukin-2 (IL-2). Nonadherent cells were then removed and the plastic-adherent (ALAK) cells were recultured for 9 days. Cells were daily analyzed by cytometry (using MAb 5C6 and the rat NK cell MAb 3.2.3) and cytotoxicity. Approximately 40% of the initially cultured NWNA cells, 50-60% of the LAK cells and 87-98% of the ALAK cells were positive for MAb 5C6. Tissue culture supernatants containing MAb 5C6 caused a dose-dependent inhibition of cytotoxicity against P815 and YAC-1 targets. Approximately 50% inhibition was obtained at MAb concentrations of 1.25-2.5 micrograms/ml. Maximum inhibition of ALAK cytotoxicity was 86% on day 4 of culture. Two-dimensional SDS-PAGE and Western blot analysis of acetone-precipitated cell membrane preparations identified a 55-kD molecule (pI 6.1-6.3) on NWNA and ALAK cells and an additional slightly more acidic 45-kD protein on ALAK cells. These data indicate that rat ALAK cells may initiate lysis of target cells via receptor binding.

Animals↗
PubMed2001

Variable practice with lenses improves visuo-motor plasticity.

Novel sensorimotor situations present a unique challenge to an individual's adaptive ability. Using the simple and easily measured paradigm of visual-motor rearrangement created by the use of visual displacement lenses, we sought to determine whether an individual's ability to adapt to visuo-motor discordance could be improved through training. Subjects threw small balls at a stationary target during a 3-week practice regimen involving repeated exposure to one set of lenses in block practice (x 2.0 magnifying lenses), multiple sets of lenses in variable practice (x 2.0 magnifying, x 0.5 minifying and up-down reversing lenses) or sham lenses. At the end of training, adaptation to a novel visuo-motor situation (20-degree right shift lenses) was tested. We found that (1) training with variable practice can increase adaptability to a novel visuo-motor situation, (2) increased adaptability is retained for at least 1 month and is transferable to further novel visuo-motor permutations and (3) variable practice improves performance of a simple motor task even in the undisturbed state. These results have implications for the design of clinical rehabilitation programs and countermeasures to enhance astronaut adaptability, facilitating adaptive transitions between gravitational environments.

Adaptation, Physiological↗
PubMed1999

Function, signal transduction mechanisms and plasticity of presynaptic muscarinic receptors in the urinary bladder.

Presynaptic M1 muscarinic receptors on parasympathetic nerve terminals in rat urinary bladder strips are involved in an autofacilitatory mechanism that markedly enhances acetylcholine release during continuous electrical field stimulation. The facilitatory muscarinic mechanism is dependent upon a PKC mediated second messenger pathway and influx of extracellular Ca2+ into the parasympathetic nerve terminals via L and N-type Ca2+ channels. Prejunctional muscarinic facilitation has also been detected in human bladders. The muscarinic facilitatory mechanism is upregulated in hyperactive bladders from chronic spinal cord transected rats; and the facilitation in these preparations is primarily mediated by M3 muscarinic receptors. Presynaptic muscarinic receptors represent a new target for pharmacological treatment of bladder hyperactivity. If presynaptic facilitation is restricted to the bladder and not present in other tissues then drugs acting at this site might be expected to exhibit uroselectivity.

Acetylcholine↗
PubMed1996

A mathematical model of activity-dependent, anatomical segregation induced by competition for neurotrophic support.

Mathematical or computational models of activity-dependent neural competition typically impose competition in anatomically fixed networks by the use of synaptic normalisation, for which there is very little experimental support. Recent experimental evidence, however, strongly implicates neurotrophic factors in neural plasticity and competition, in addition to their well-known potent effects on neurite outgrowth and synaptogenesis. We therefore present a simple, mathematical model of anatomical segregation induces by activity-dependent competition for a limited supply of a neurotrophic factor provided by target cells to afferents. We extract the behaviour of the model in various regimes, in which the neurotrophic factor is either in critical supply or in abundant supply, by a combination of analytical and numerical methods, and study the effects of correlations in afferent inputs on competition. We apply the model to three different systems: ocular dominance column formation; elimination of polyneuronal innervation at the vertebrate neuromuscular junction; trigeminal brain stem whisker-related structure formation. Several classes of related predictions emerge, including the prediction that kittens reared with strabismus should require a higher concentration of neurotrophic factor infusion into their primary visual cortex than normally reared cats in order to induce the anatomical desegregation of ocular dominance columns. We also speculate on the mechanisms of support of inhibitory rather than excitatory neurons, and suggest the existence of a separate, (Cl-)-mediated activity-dependent pathway for their neurotrophic support.

Animals↗
PubMed1996

Elucidation of the molecular actions of NCAM and structurally related cell adhesion molecules.

The Neural Cell Adhesion Molecule (NCAM) is a founder member of a large family of cell surface glycoproteins that share structural motifs related to immunoglobulin and fibronectin type III (FN III) domains [Walsh and Doherty (1991) (Fig. 1). These glycoproteins have been grouped based on the respective number of each type of domain. In vertebrates members of this family of glycoproteins include L1/NILE, NgCAM, axonin-1/TAG-1, and Thy-1 as well as NCAM. In addition structural homologs of NCAM and L1 have been identified in Drosophila and Grasshoppers [Walsh and Doherty (1991)]. These insect homologs are called fasciclins and a series of mutants corresponding to these aspects of synaptic plasticity [Mayford et al. (1992) Science 256:638-644]. In vertebrates all of these glycoproteins are expressed in the developing nervous system where they have been identified as candidate molecules for mediating axon outgrowth, fasciculation, regeneration, and target recognition. In addition, NCAM is expressed in a number of different tissues and cell types. For example, NCAM is expressed in a dynamic pattern in developing and regenerating adult muscle. In this review we aim to describe important aspects of the role of these CAMS in development of the nervous system, including the neuromuscular junction. Furthermore, we will explore the prospective use of molecular biology, cell biology, and molecular genetic techniques, such as transgenic mice, to understand the role and molecular action of this family of cell adhesion molecules in vivo.

Amino Acid Sequence↗
PubMed1984

Regulation of NK cell activity by prostaglandin E2: the role of T cells.

The influence of T cells on the production of prostaglandins (PGE2) and on PGE2-mediated regulation of natural killer (NK) activity was studied. Supernatants from peripheral blood mononuclear cells (PBMC) and from PBMC depleted of T cells ((PBMC)-T), both of which had been incubated in plastic petri dishes overnight, contained similar amounts of PGE2, as detected by radioimmunoassay and by their potential to inhibit NK activity of peripheral blood mononuclear cells in a 51Cr release assay with K 562 cells as the target population. However, the NK activity of PBMC was inhibited significantly more strongly (P less than 0.005) by PGE2-containing supernatants than was the NK activity of (PBMC)-T. In further assays, in which synthetic PGE2 in concentrations of 10(-4) and 10(-5)M was added, a significant inhibition of NK activity was observed in PBMC populations (P less than 0.05), but not in (PBMC)-T. Thus, T cells did not seem to be involved in the control of PGE2 production, but their presence was necessary for PGE2-mediated inhibition of NK activity.

Adult↗
PubMed2006

Associative and spatial learning and memory deficits in transgenic mice overexpressing the RNA-binding protein HuD.

HuD is a neuronal specific RNA-binding protein associated with the stabilization of short-lived mRNAs during brain development, nerve regeneration and synaptic plasticity. To investigate the functional significance of this protein in the mature brain, we generated transgenic mice overexpressing HuD in forebrain neurons under the control of the alphaCaMKinII promoter. We have previously shown that one of the targets of HuD, GAP-43 mRNA, was stabilized in neurons in the hippocampus, amygdala and cortex of transgenic mice. Animals from two independent lines expressing different levels of the transgene were subjected to a battery of behavioral tests including contextual fear conditioning and the Morris water maze. Our results show that although HuD is increased after learning and memory, constitutive HuD overexpression impaired the acquisition and retention of both cued and contextual fear and the ability to remember the position of a hidden platform in the Morris water maze. No motor-sensory abnormalities were observed in HuD transgenic mice, suggesting that the poor performance of the mice in these tests reflect a true cognitive impairment. We conclude that posttranscriptional regulation of gene expression by stabilization of specific mRNAs may have to be restricted temporally and spatially for proper acquisition and storage of memories.

Analysis of Variance↗
PubMed2004

The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions.

Antiepileptic drugs (AEDs) are commonly prescribed for nonepileptic conditions, including migraine headache, chronic neuropathic pain, mood disorders, schizophrenia and various neuromuscular syndromes. In many of these conditions, as in epilepsy, the drugs act by modifying the excitability of nerve (or muscle) through effects on voltage-gated sodium and calcium channels or by promoting inhibition mediated by gamma-aminobutyric acid (GABA) A receptors. In neuropathic pain, chronic nerve injury is associated with the redistribution and altered subunit compositions of sodium and calcium channels that predispose neurons in sensory pathways to fire spontaneously or at inappropriately high frequencies, often from ectopic sites. AEDs may counteract this abnormal activity by selectively affecting pain-specific firing; for example, many AEDs suppress high-frequency action potentials by blocking voltage-activated sodium channels in a use-dependent fashion. Alternatively, AEDs may specifically target pathological channels; for example, gabapentin is a ligand of alpha2delta voltage-activated calcium channel subunits that are overexpressed in sensory neurons after nerve injury. Emerging evidence suggests that effects on signaling pathways that regulate neuronal plasticity and survival may be a factor in the delayed clinical efficacy of AEDs in some neuropsychiatric conditions, including bipolar affective disorder.

Anticonvulsants↗
PubMed1999

Coloured overlays, text, and texture.

In four studies children were asked to read aloud a passage of randomly ordered common words with and without a coloured sheet of plastic (overlay) placed upon the page. The children's rate of reading increased with the overlay, for some children more than for others. The children were also asked to undertake a test of texture segmentation in which targets consisting of a structured texture had to be distinguished from within a random background texture. The texture segmentation was improved when the overlay was used, again for some children more than for others. The improvement in texture segmentation was, in general, correlated with the improvement in rate of reading. Slower readers were generally poorer at texture segmentation. The implications for reading, for texture segmentation, and for clinical tests of vision are discussed.

Adolescent↗
PubMed2005

Memory-influencing intra-basolateral amygdala drug infusions modulate expression of Arc protein in the hippocampus.

Activation of beta-adrenoceptors in the basolateral complex of the amygdala (BLA) modulates memory storage processes and long-term potentiation in downstream targets of BLA efferents, including the hippocampus. Here, we show that this activation also increases hippocampal levels of activity-regulated cytoskeletal protein (Arc), an immediate-early gene (also termed Arg 3.1) implicated in hippocampal synaptic plasticity and memory consolidation processes. Infusions of the beta-adrenoreceptor agonist, clenbuterol, into the BLA immediately after training on an inhibitory avoidance task enhanced memory tested 48 h later. The same dose of clenbuterol significantly increased Arc protein levels in the dorsal hippocampus. Additionally, posttraining intra-BLA infusions of a memory-impairing dose of lidocaine significantly reduced Arc protein levels in the dorsal hippocampus. Increases in Arc protein levels were not accompanied by increases in Arc mRNA, suggesting that amygdala modulation of Arc protein and synaptic plasticity in efferent brain regions occurs at a posttranscriptional level. Finally, infusions of Arc antisense oligodeoxynucleotides into the dorsal hippocampus impaired performance of an inhibitory avoidance task, indicating that the changes in Arc protein expression are related to the observed changes in memory performance.

Adrenergic beta-Agonists↗
PubMed1997

Cleft palate and decreased brain gamma-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase.

In addition to its role as an inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) is presumed to be involved in the development and plasticity of the nervous system. GABA is synthesized by glutamic acid decarboxylase (GAD), but the respective roles of its two isoforms (GAD65 and 67) have not been determined. The selective elimination of each GAD isoform by gene targeting is expected to clarify these issues. Recently we have produced GAD65 -/- mice and demonstrated that lack of GAD65 does not change brain GABA contents or animal behavior, except for a slight increase in susceptibility to seizures. Here we report the production of GAD67 -/- mice. These mice were born at the expected frequency but died of severe cleft palate during the first morning after birth. GAD activities and GABA contents were reduced to 20% and 7%, respectively, in the cerebral cortex of the newborn GAD67 -/- mice. Their brain, however, did not show any discernible defects. Previous pharmacological and genetic investigations have suggested the involvement of GABA in palate formation, but this is the first demonstration of a role for GAD67-derived GABA in the development of nonneural tissue.

Aging↗
PubMed2004

Cellular transplantation: hurdles remaining before widespread clinical use.

PURPOSE OF REVIEW: The last few years have witnessed a growing interest in regenerative therapy of the failing heart by cell transplantation. Special emphasis has been put on skeletal myoblasts and bone marrow-derived stem cells, with a flurry of experimental studies generating overall positive but occasionally conflicting results. It is thus appropriate to review the most important of these studies in light of the major issues that still impede widespread clinical use of cell therapy. RECENT FINDINGS: Recent laboratory data demonstrate the ability of autologous skeletal myoblasts to engraft into scarred myocardium and improve its function. Equally successful results have been reported with bone marrow-derived cells which, in contrast to myoblasts, are credited with a plasticity that might allow their transdifferentiation into cardiac or endothelial cells in response to organ-specific cues. However, some major questions remain unanswered; they include the choice of the optimal cell type in relation with the target patient population, the strategies for enhancing cell survival and functional integration, the clarification of the mechanisms of improvement, and the means of reducing invasiveness of cell delivery. SUMMARY: Although laboratory research attempts to overcome these persisting hurdles, the accumulated body of evidence warrants implementation of clinical trials. The earliest ones have now documented the feasibility of cell therapy. It is now appropriate to conduct safety and efficacy studies which, if carefully done, should allow assessment of the extent to which this concept of regenerative therapy can be made a clinical reality.

Bone Marrow Transplantation↗
PubMed2004

Cell surface differentiation of Mycoplasma mobile visualized by surface protein localization.

Mycoplasma mobile has a flask-shaped cell morphology and glides toward its tapered end at a rate of 3-7 cell lengths per s (2.0-4.5 microm s(-1)) by an unknown mechanism. Gliding requires that the surface of the cell is in contact with a solid substrate, such as glass or plastic. In order to characterize the nature of the outer surface of M. mobile, monoclonal antibodies were raised against intact cells and screened for their ability to recognize surface proteins. Four antibodies were identified and their protein targets were determined. One antibody recognized the Gli349 protein, which is known to be involved in glass binding and gliding. This antibody was also able to displace attached M. mobile cells from glass, suggesting that Gli349 is the major adhesion protein in M. mobile. The other three antibodies recognized members of the Mvsp family of proteins, which are presumably the major surface antigens of M. mobile. Immunofluorescence studies were performed to localize these proteins on the surface of M. mobile cells. Gli349 localized to the proximal region of the tapered part of the cell (the 'neck'), while the various Mvsp family members showed several distinct patterns of subcellular localization. MvspN and MvspO localized to the distal end of the tapered part of the cell (the 'head'), MvspK localized to the main part of the cell (the 'body'), and MvspI localized to both the head and body but not the neck. This analysis shows that M. mobile surprisingly expresses multiple versions of its major surface antigen at once but differentiates its surface by differential localization of the various paralogues.

Amino Acid Sequence↗
PubMedDate not supplied

The effects of reversible inactivation of the red nucleus on learning-related and auditory-evoked unit activity in the pontine nuclei of classically conditioned rabbits.

The pontine nuclei carry auditory conditioned stimulus information to the cerebellum during classical conditioning of the nictitating membrane response in rabbits. In well-trained animals learning-related as well as stimulus-evoked unit activity can be recorded throughout the pontine nuclei but particularly in the lateral and dorsolateral pons. Recent work in our laboratory has provided evidence that the learning-related unit activity in the pons is dependent on the interpositus nucleus and that the pons is not a site of essential plasticity for the learned response. In the present study we considered the question of whether learning-related unit activity might be projected from the interpositus nucleus to the pons through the red nucleus, a primary output target of the interpositus and a structure known to be essential for expression of the learned response. Multiple unit recordings were taken from lateral and dorsolateral pontine locations in well-trained rabbits before and during cooling of the red nucleus. Analysis of pooled data for all recording locations within the lateral and dorsolateral pons indicated that reversible inactivation of red nucleus abolished both stimulus-evoked and learning-related unit activity. However, we also found discrete recording locations where stimulus-evoked and learning-related unit activity were attenuated but not abolished by red nucleus cooling.

Animals↗