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At least 1,225 records · Page 68Linked to original sources
PubMed2004

Stroke-prone rats exhibit prolonged behavioral deficits without increased brain injury: an indication of disrupted post-stroke brain recovery of function.

Stroke-prone rat strains exhibit an increased stroke risk and sensitivity, and reduced endogenous mechanisms of ischemic brain tolerance. This experiment provides a comparative, serial evaluation of neurological deficits and brain injury following middle cerebral artery occlusion/permanent focal stroke in this high-risk strain. Stroke-prone spontaneously hypertensive (SHR-SP), spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats were evaluated over 28 days using magnetic resonance imaging (MRI), histopathology, and neurobehavioral testing. T2- and diffusion weighted-MRI was performed after 1, 10 and 28 days to measure the degree of stroke-induced brain injury. Normotensive WKY rats receiving the same stroke and other SHR-SP rats receiving sham surgery were used for control comparisons. Functional deficits were scored after 1, 4, 11, 18 and 28 days. The degree of brain infarction/injury was practically identical in hypertensive and stroke-prone rats. WKY rats exhibited significantly smaller infarcts (P<0.05), with neurological function recovering quickly to normal by day 11 in this strain. Functional deficits persisted longer in hypertensive rats, with function recovering to normal by day 18 (P<0.05). Functional deficits in SHR-SP rats persisted the longest, and were observed even after 28 days (P<0.05). This increased and prolonged neurologic dysfunction exhibited by SHR-SP compared to SHR rats, while exhibiting practically identical degrees of brain injury/infarction, reflects the increased stroke risk and sensitivity of this strain and suggests a reduced SHR-SP brain plasticity following injury. Therefore, the stroke-prone rat provides an enhanced and prolonged functional deficit model that can be used to elucidate those mechanisms/novel targets critical to longitudinal neurobehavioral recovery post-stroke.

Animals↗
PubMed2006

Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking.

Arc/Arg3.1 is an immediate-early gene whose mRNA is rapidly transcribed and targeted to dendrites of neurons as they engage in information processing and storage. Moreover, Arc/Arg3.1 is known to be required for durable forms of synaptic plasticity and learning. Despite these intriguing links to plasticity, Arc/Arg3.1's molecular function remains enigmatic. Here, we demonstrate that Arc/Arg3.1 protein interacts with dynamin and specific isoforms of endophilin to enhance receptor endocytosis. Arc/Arg3.1 selectively modulates trafficking of AMPA-type glutamate receptors (AMPARs) in neurons by accelerating endocytosis and reducing surface expression. The Arc/Arg3.1-endocytosis pathway appears to regulate basal AMPAR levels since Arc/Arg3.1 KO neurons exhibit markedly reduced endocytosis and increased steady-state surface levels. These findings reveal a novel molecular pathway that is regulated by Arc/Arg3.1 and likely contributes to late-phase synaptic plasticity and memory consolidation.

Acyltransferases↗
PubMed2001

Serotonergic gene expression and depression: implications for developing novel antidepressants.

The development and configuration of several neural networks is dependent on the actions of serotonin (5-HT) acting through multiple hetero- and autoreceptor subtypes. During early brain development 5-HT modulates morphogenetic activities, such as neural differentiation, axon outgrowth, and synaptic modeling. In the adult brain, midbrain raphe serotonergic neurons project to a variety of brain regions and modulate a wide range of physiological functions. Several lines of evidence indicate that genetically determined variability in serotonergic gene expression, as it has been documented for the 5-HT transporter, influences temperamental traits and may lead to psychopathological conditions with increased anxiety, depression, and aggression. Investigation of the regulation of serotonergic gene transcription and its impact on neuronal development, synaptic plasticity, and neurogenesis spur interest to identify serotonergic gene-related molecular factors underlying disease states and to develop more effective antidepressant treatment strategies. Gene targeting strategies have increasingly been integrated into investigations of brain function and along with the fading dogma of a limited capacity of neurons for regeneration and reproducibility, it is realized that gene transfer techniques using efficient viral vectors in conjunction with neuron-selective transcriptional control systems may also be applicable to complex disorders of the brain. Given the fact that the 5-HT system continues to be an important target for drug development and production, novel strategies aiming toward the modification of 5-HT function at the level of gene expression are likely to be exploited by enterprises participating actively in the introduction of alternative therapeutic approaches.

Antidepressive Agents↗
PubMedDate not supplied

Development and regulation of substance P expression in neurons of the tadpole optic tectum.

Activity-dependent synaptic plasticity is characteristic of developing visual systems. Using the frog retinotectal system, we investigated the extent to which afferent input affects neurotransmitter expression in a target structure. We have concentrated on a particular subpopulation of tectal cells that is immunoreactive to substance P (SP). Early in development, SP expression in tectal neurons was restricted to the anterior lateral region of the tectum. As tadpoles developed, this expression expanded into progressively more posterior and medial regions in a manner that closely followed the gradient of tectal maturation. At all times, however, anterior and lateral tectal regions had a greater percent of SP-like immunoreactive (SP-ir) cells than posterior and medial ones. Horseradish peroxidase (HRP) labeling of the retinal ganglion cell projection in conjunction with SP immunocytochemistry demonstrated that innervation by retinal ganglion cell terminals preceded the expression of SP by tectal cells. This suggested that the optic nerve may influence SP differentiation and/or expression. In support of this idea, transection of the optic nerve resulted in a decrease in SP expression in the deafferented tectal lobe of tadpoles. This result, opposite to that seen previously in the adult, also indicates that optic nerve-dependent regulation of SP expression in the developing and mature systems occurs through different pathways.

Animals↗
PubMed2000

Neoteny and progenesis as two heterochronic processes involved in paedomorphosis in Triturus alpestris (Amphibia: Caudata).

Current theories on the evolution of paedomorphosis suppose that several ontogenetic pathways have appeared according to different selective pressures. The aim of this study was to find out whether two distinct processes can lead to paedomorphosis in the Alpine newt, Triturus alpestris. In this respect, we compared age structures of paedomorphic and metamorphic individuals in two newt populations where the two forms lived syntopically. Whereas paedomorphosis resulted in a slower rate of somatic development in one population, it resulted in an acceleration of sexual maturation in the other population. These processes correspond to neoteny and progenesis, respectively. These results suggest that phenotypic plasticity can result from contrasted ontogenetic pathways between two populations of the same species. They give support to models that consider gonadic development as the target of selection under different environmental pressures.

Animals↗
PubMed2003

Cluster of type IV secretion genes in Helicobacter pylori's plasticity zone.

Some genes present in only certain strains of the genetically diverse gastric pathogen Helicobacter pylori may affect its phenotype and/or evolutionary potential. Here we describe a new 16.3-kb segment, 7 of whose 16 open reading frames are homologs of type IV secretion genes (virB4, virB7 to virB11, and virD4), the third such putative secretion gene cluster found in H. pylori. This segment, to be called tfs3, was discovered by subtractive hybridization and chromosome walking. Full-length and truncated tfs3 elements were found in 20 and 19%, respectively, of 94 strains tested, which were from Spain, Peru, India, and Japan. A tfs3 remnant (6 kb) was found in an archived stock of reference strain J99, although it was not included in this strain's published genome sequence. PCR and DNA sequence analyses indicated the following. (i) tfs3's ends are conserved. (ii) Right-end insertion occurred at one specific site in a chromosomal region that is varied in gene content and arrangement, the "plasticity zone." (iii) Left-end insertion occurred at different sites in each of nine strains studied. (iv) Sequences next to the right-end target in tfs3-free strains were absent from most strains carrying full-length tfs3 elements. These patterns suggested insertion by a transposition-like event, but one in which targets are chosen with little or no specificity at the left end and high specificity at the right end, thereby deleting the intervening DNA.

Bacterial Proteins↗
PubMed1994

Essential role of endogenous estrogen in directly stimulating mammary growth demonstrated by implants containing pure antiestrogens.

The mammogenic actions of estrogen, although undisputed, lack definition due to uncertainties concerning the relative importance of systemic vs. local actions of the hormone. In addition to its well known, indirect effects on mammary tissue through pituitary intermediaries such as PRL and GH, recent evidence points to, but does not prove, direct estrogen action on mammary targets. The ability of exogenous estrogen to directly and locally stimulate mammary growth in vivo was previously shown in endocrine-ablated animals using small plastic pellets containing estradiol. The more important question of whether the direct action of endogenous estrogen is required for normal mammary growth and morphogenesis in the endocrine-intact animal is now investigated using direct-acting, slow-release plastic implants containing pure antiestrogens (antiestrogens with no estrogenic properties) inserted into the growth region of mammary glands. Local growth inhibition only in the immediate vicinity of the implants and not in other glands in the same mouse demonstrated the requirement of mammary tissues for endogenous, locally acting estrogen. Local actions of antiestrogens on ducts mimicked the ovariectomy-induced loss of systemic estrogen with respect to time course and morphology, with complete inhibition of ductal growth in 14 days. A second effect, in which locally acting antiestrogens simplified the pattern of ductal branching, was observed in both immature and mature animals. Two distinct mitogenic pathways, one governing ductal elongation and the other ductal maintenance, were thus affected. The inhibitory effects of antiestrogen treatment were fully reversible and not accompanied by obvious cytotoxicity. We conclude from these studies of localized estrogen receptor blockade that with respect to ductal mammogenesis, the action of estrogen is direct (acting at the level of the gland itself) and not primarily through the stimulation of pituitary mammogens.

Animals↗
PubMedDate not supplied

New cigarette brands with flavors that appeal to youth: tobacco marketing strategies.

Tobacco manufacturers have recently introduced a proliferation of exotic brands featuring candylike flavors. We reviewed internal tobacco industry documents and patents to assess the role of flavored cigarettes in the targeting of young smokers. This research revealed the development of flavor delivery technologies hidden from consumers and public health professionals, including the use of a plastic pellet placed in the cigarette filter. These findings raise concerns as to the potential added health risks associated with using new flavored tobacco products, and they underscore the need for effective assessment and monitoring of tobacco products.

Adolescent↗
PubMedDate not supplied

Nitric oxide, a new second messenger involved in the action of angiotensin II on neuronal differentiation of NG108-15 cells.

Nitric Oxide (NO) is a gas that diffuses freely through membranes of target cells to activate cGMP formation. NO is synthesised from arginine, by a family of Nitric Oxide Synthase (NOS). In the brain, NO influences synaptic plasticity, apoptosis and development. It has been recently shown that angiotensin II (Ang II) could mediate NO production by its two types of receptors, AT1 and AT2. Since we have shown that Ang II, via the AT2 receptor could induce neurite outgrowth and morphological differentiation of NG108-15 cells, the aim of the study was to investigate if NO could be one of the second messengers involved in the Ang II effect. Using the Griess colorimetric assay, we found that Ang II, by its AT2 receptor, induced nitrite formation from NO. This effect was abolished by the N-nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor. We also found that treatment of the cells with S-nitroso-N-acetylpenicillamine (SNAP), an exogenous source of NO, induced the same morphological differentiation. These results demonstrate that the morphological differentiation induced by the AT2 receptor is partly due to an increase in NO production.

Angiotensin II↗
PubMed2006

Stem cells and Helicobacter-induced gastric cancer: where do we stand at the end of 2006.

The process of carcinogenesis, which may well extend over decades, provides an excellent opportunity for early detection and intervention to prevent development of gastric cancer. Evidence supporting a causal association between such tumour and Helicobacter infection has been demonstrated by epidemiological data, ecologic studies and, in experimental animal models. Lately, an increasing amount of evidences point out to bone marrow stem cells (BMSC) as target of neoplastic transformation. The term BMSC includes a heterogenous group of cells that both in vivo and in vitro studies, have shown to have plasticity, with their ability to acquire features of mesoderm, ectoderm and endoderm. In the gastric setting, a recent experiment in C57BL/6 mice has permitted to show that BMSC are the cell of origin of Helicobacter-induced gastric cancer. Based on these results, a model for epithelial cancer by which chronic inflammation leads to tissue injury and with time, to tissue stem cell failure, has been proposed. This phenomenon would induce the recruitment and engraftment of BMSC into the tissue stem cell niche. During differentiation, BMSC fail to regulate growth programme appropriately and progress through stages of metaplasia and dysplasia. Due to several reasons, in humans, data are conflicting. Further studies may shed light on the molecular bases of gastric lesions, leading to the development of preventive strategies.

Animals↗
PubMed1990

Role of protein kinase C in cellular regulation.

Protein kinase C (PKC) consists of a family of closely related enzymes ubiquitously present in animal tissues. These enzymes respond to second messengers, Ca2+, diacylglycerol and arachidonic acid, to express their activities at membrane locations. Numerous hormones, neurotransmitters, growth factors and antigens are believed to transmit their signals by activation of a variety of phospholipases to generate these messengers. The various PKC isozymes, which exhibit distinct biochemical characteristics and unique cellular and subcellular localizations, may be differentially stimulated depending on the duration and strength of these messengers. Activation of PKC has been linked to the regulation of cell surface receptors, ion channels, secretion, gene expression, and neuronal plasticity and toxicity. The mechanisms of action of PKC in the regulation of these cellular functions are not entirely clear. Further study to identify the target substrates relevant to the various cellular functions is essential to define the functional diversity of this enzyme family.

Animals↗
PubMed1983

Naturally occurring cell-mediated cytotoxicity against simian virus 40-transformed 3T3 murine tumor cells.

The tumorigenicity and host protective mechanisms induced by simian virus 40 (SV40)-transformed 3T3 cells (SV403T3) were evaluated in syngeneic BALB/c mice. Tumors were regularly produced by sc inoculation of SV403T3 cells; the incidence, latent period, and survival were proportional to the size of the initial inoculum. With the use of an in vitro 18-hour 51Cr cytotoxicity assay, spleen cells from normal mice showed a dose-related killing activity against the SV403T3 cells. At an effector cell-to-target cell ratio of 200:1, the average lysis was 56 +/- 6%. This reaction appeared specific for the virally transformed targets; the mean lysis of parent 3T3 cells was 23 +/- 5%. Effectors were resistant to anti-theta serum and not removed by adherence to plastic or nylon wool. Tissue distribution studies indicated that these effectors were present in high concentrations in spleen, bone marrow, lymph nodes, and peritoneal cavity. Low levels of activity were associated with cells from the thymus. In the present studies specific T-cell cytotoxicity against the SV403T3 cells could not be demonstrated. Animals challenged with nonviable SV403T3 cells prior to tumor cell inoculation did not show increased in vivo resistance. In parallel, the in vitro cytotoxicity of animals inoculated with SV403T3 tumor cells showed no heightened cell killing compared to the cytotoxicity of normal controls.

Animals↗
PubMed1996

[Nerve transplantation in the central nervous system: a strategy for inducing nerve fiber regeneration in lesions of the brain and spinal cord].

Nerve grafts have long been used as a reconstructive strategy in the human peripheral nervous system. In the nervous system (brain and spinal cord), peripheral nerve grafts have been used experimentally for promoting axonal regeneration in lesioned pathways. Peripheral nerve grafts play the role of physical and trophic supports that are favourable for the regeneration of central fibres that normally present only abortive regeneration in adult mammals. On the basis of several experimental models (axonal regeneration of retinal ganglion cells, respiratory neurones, ...) it has now been established that central fibres that have regenerated within the nerve grafts retain their ability to transmit normal nervous information and can make functional synaptic contact with a target. If such a strategy is not yet used in man, it nevertheless constitutes a promising approach for the investigation of the central nervous system plasticity, and could be useful in the treatment of spinal cord injuries.

Adult↗
PubMed1998

Dendritic growth of arcuate neuroendocrine neurons following orchidectomy in adult rats.

Recent studies have shown that changes in dendritic architecture are an important component of functional plasticity in the adult central nervous system. In the present study, we determined whether gonadectomy induces changes in dendritic architecture in the arcuate nucleus, a target tissue for gonadal hormones. A combination of retrograde labeling with systemically injected Fluoro-Gold and intracellular injection of neurons in a fixed-slice preparation was used to examine the morphology of neuroendocrine neurons in the rat arcuate nucleus. Intracellullary filled arcuate neuroendocrine neurons (8-21 neurons per brain) from intact (n = 5) and orchidectomized (n = 5) animals were reconstructed with the aid of a computer microscope. A quantitative analysis revealed that orchidectomy had no effect on the number and distribution of Fluoro-Gold-labeled neuroendocrine neurons in the rat arcuate nucleus. The morphology of arcuate neuroendocrine neurons in intact animals was relatively simple, with the majority of neurons (79%) having only two primary dendrites and few dendritic spines. Compared with intact controls, arcuate neuroendocrine neurons in the orchidectomized group had significantly larger somatic profile areas and exhibited significant increases in dendrite length, dendrite volume, terminal branch number, and spines per unit length of dendrite. The increase in terminal branch number in orchidectomized animals was due primarily to the appearance of short branches that gave a striking, claw-like appearance to many of the distal dendrites. These results provide evidence for hormonal regulation of dendritic morphology of arcuate neuroendocrine neurons in adult mammals.

Animals↗
PubMed2000

Mechanism and regulation of calcium/calmodulin-dependent protein kinase II targeting to the NR2B subunit of the N-methyl-D-aspartate receptor.

Calcium influx through the N-methyl-d-aspartate (NMDA)-type glutamate receptor and activation of calcium/calmodulin-dependent kinase II (CaMKII) are critical events in certain forms of synaptic plasticity. We have previously shown that autophosphorylation of CaMKII induces high-affinity binding to the NR2B subunit of the NMDA receptor (Strack, S., and Colbran, R. J. (1998) J. Biol. Chem. 273, 20689-20692). Here, we show that residues 1290-1309 in the cytosolic tail of NR2B are critical for CaMKII binding and identify by site-directed mutagenesis several key residues (Lys(1292), Leu(1298), Arg(1299), Arg(1300), Gln(1301), and Ser(1303)). Phosphorylation of NR2B at Ser(1303) by CaMKII inhibits binding and promotes slow dissociation of preformed CaMKII.NR2B complexes. Peptide competition studies imply a role for the CaMKII catalytic domain, but not the substrate-binding pocket, in the association with NR2B. However, analysis of monomeric CaMKII mutants indicates that the holoenzyme structure may also be important for stable association with NR2B. Residues 1260-1316 of NR2B are sufficient to direct the subcellular localization of CaMKII in intact cells and to confer dynamic regulation by calcium influx. Furthermore, mutation of residues in the CaMKII-binding domain in full-length NR2B bidirectionally modulates colocalization with CaMKII after NMDA receptor activation, suggesting a dynamic model for the translocation of CaMKII to postsynaptic targets.

Amino Acid Sequence↗
PubMed2000

Common mechanisms underlying growth cone guidance and axon branching.

During development, growth cones direct growing axons into appropriate targets. However, in some cortical pathways target innervation occurs through the development of collateral branches that extend interstitially from the axon shaft. How do such branches form? Direct observations of living cortical brain slices revealed that growth cones of callosal axons pause for many hours beneath their cortical targets prior to the development of interstitial branches. High resolution imaging of dissociated living cortical neurons for many hours revealed that the growth cone demarcates sites of future axon branching by lengthy pausing behaviors and enlargement of the growth cone. After a new growth cone forms and resumes forward advance, filopodial and lamellipodial remnants of the large paused growth cone are left behind on the axon shaft from which interstitial branches later emerge. To investigate how the cytoskeleton reorganizes at axon branch points, we fluorescently labeled microtubules in living cortical neurons and imaged the behaviors of microtubules during new growth from the axon shaft and the growth cone. In both regions microtubules reorganize into a more plastic form by splaying apart and fragmenting. These shorter microtubules then invade newly developing branches with anterograde and retrograde movements. Although axon branching of dissociated cortical neurons occurs in the absence of targets, application of a target-derived growth factor, FGF-2, greatly enhances branching. Taken together, these results demonstrate that growth cone pausing is closely related to axon branching and suggest that common mechanisms underlie directed axon growth from the terminal growth cone and the axon shaft.

Animals↗
PubMed2002

Insights into immediate-early gene function in hippocampal memory consolidation using antisense oligonucleotide and fluorescent imaging approaches.

In the 14 years since it was discovered that specific genes could be dynamically regulated in the brain by neural activity, there has been a substantial research focus attempting to understand the role immediate-early genes (IEGs) play in various brain functions. This article examines the involvement of IEGs in hippocampal synaptic plasticity and in memory consolidation processes performed by the hippocampus. Studies employing conventional IEG detection methodologies and a novel gene-imaging approach that provides temporal and cellular resolution (cellular compartment analysis of emporal activity by fluorescence in situ hybridization or catFISH) provide evidence supporting the assertion that IEG expression reflects the integration of information processed by hippocampal neurons. However, IEG expression is not merely correlated with neural activity, but also plays a pivotal role in stabilizing recent changes in synaptic efficacy. As such, localized disruption of IEGs Arc or c-fos by intrahippocampal administration of antisense oligonucleotides or germline disruption of the IEGs c-fos, tissue plasminogen activator, or zif268 impairs consolidation of long-term memory formation, without affecting learning or short-term memory. Further investigation into the expression and function of IEGs using catFISH and antisense approaches will likely increase understanding of the molecular and cellular bases of information processing involving the hippocampus.

Animals↗
PubMedDate not supplied

A target of thrombin activation promotes cell cycle re-entry by urodele muscle cells.

A key early event of newt limb regeneration is the local dedifferentiation of cells to form dividing progenitor cells. This involves the plasticity of differentiation and the ability to re-enter the cell cycle. In culture, differentiated newt myotubes are able to re-enter S-phase in response to serum stimulation. Here, we analyzed the intracellular and extracellular requirements for this process. Cell cycle re-entry depends on the phosphorylation of the retinoblastoma protein, which is a key regulator of the G1-S transition. This is in contrast to mammalian myotubes, which are refractory to serum stimulation and cannot phosphorylate retinoblastoma protein in response to serum. The serum factor responsible for this phosphorylation appears to be distinct from common polypeptide growth factors and is enriched in crude preparations of bovine thrombin. Fractionation and analysis of this preparation indicate that the factor is regulated by thrombin and plasmin proteolysis. These results indicate that factors involved in acute responses to wounding such as clotting may be important initiators of the regenerative response.

Animals↗