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PubMed1985

Promoting functional plasticity in the damaged nervous system.

Damage to the central and peripheral nervous system often produces lasting functional deficits. A major focus of neuroscience research has been to enhance functional restitution of the damaged nervous system and thereby produce recovery of behavioral or physiological processes. Promising procedures include surgical, physical, and chemical manipulations to reduce scar formation and minimize the disruption of support elements, administration of growth-stimulating substances, tissue grafts to bridge gaps in fiber pathways, and embryonic brain tissue grafts to provide new cells with the potential to generate fiber systems. Two elements are required for functional nervous system repair: (i) neurons with the capacity to extend processes must be present, and (ii) the regenerating neurites must find a continuous, unbroken pathway to appropriate targets through a supportive milieu.

Age Factors↗
PubMed2004

Conditional ablation of the neural cell adhesion molecule reduces precision of spatial learning, long-term potentiation, and depression in the CA1 subfield of mouse hippocampus.

NCAM, a neural cell adhesion molecule of the immunoglobulin superfamily, is involved in neuronal migration and differentiation, axon outgrowth and fasciculation, and synaptic plasticity. To dissociate the functional roles of NCAM in the adult brain from developmental abnormalities, we generated a mutant in which the NCAM gene is inactivated by cre-recombinase under the control of the calcium-calmodulin-dependent kinase II promoter, resulting in reduction of NCAM expression predominantly in the hippocampus. This mutant (NCAMff+) did not show the overt morphological and behavioral abnormalities previously observed in constitutive NCAM-deficient (NCAM-/-) mice. However, similar to the NCAM-/- mouse, a reduction in long-term potentiation (LTP) in the CA1 region of the hippocampus was revealed. Long-term depression was also abolished in NCAMff+ mice. The deficit in LTP could be rescued by elevation of extracellular Ca2+ concentrations from 1.5 or 2.0 to 2.5 mm, suggesting an involvement of NCAM in regulation of Ca2+-dependent signaling during LTP. Contrary to the NCAM-/- mouse, LTP in the CA3 region was normal, consistent with normal mossy fiber lamination in NCAMff+ as opposed to abnormal lamination in NCAM-/- mice. NCAMff+ mutants did not show general deficits in short- and long-term memory in global landmark navigation in the water maze but were delayed in the acquisition of precise spatial orientation, a deficit that could be overcome by training. Thus, mice conditionally deficient in hippocampal NCAM expression in the adult share certain abnormalities characteristic of NCAM-/- mice, highlighting the role of NCAM in the regulation of synaptic plasticity in the CA1 region.

Animals↗
PubMed2001

An evolutionarily conserved transmembrane protein that is a novel downstream target of neurotrophin and ephrin receptors.

Appropriate development of nervous system connectivity involves a variety of processes, including neuronal life-and-death decisions, differentiation, axon guidance and migration, and synaptogenesis. Although these activities likely require specialized signaling events, few substrates unique to these neurotrophic functions have been identified. Here we describe the cloning of ankyrin repeat-rich membrane spanning (ARMS), which encodes a novel downstream target of neurotrophin and ephrin receptor tyrosine kinases, Trk and Eph, respectively. The amino acid sequence of ARMS is highly conserved from nematode to human, suggesting an evolutionarily conserved role for this protein. The ARMS protein consists of 1715 amino acids containing four putative transmembrane domains, multiple ankyrin repeats, a sterile alpha motif domain, and a potential PDZ-binding motif. In the rat, ARMS is specifically expressed in the developing nervous system and in highly plastic areas of the adult brain, regions enriched in Trks and Eph receptors. ARMS can physically associate with TrkA and p75 neurotrophin receptors. Moreover, endogenous ARMS protein is tyrosine phosphorylated after neurotrophin treatment of pheochromocytoma 12 cells and primary hippocampal neurons or ephrin B treatment of NG108-15 cells, demonstrating that ARMS is a downstream target for both neurotrophin and ephrin receptors.

Amino Acid Motifs↗
PubMedDate not supplied

Endoscopic therapy for biliary obstruction.

Endoscopic management of biliary obstruction is feasible in most patients and has emerged as standard treatment. Aside from the removal of bile duct stones, placement of a biliary stent is the most commonly employed modality of management. In experienced hands, this is successful in over 90% of patients. Lower procedure-related complications and the relative non-invasive nature of endoscopic treatment has relegated surgical management to a subsidiary role. Hospitalization time rarely exceeds 1-2 days. In most patients with advanced malignant disease and short life expectancy, stenting affords effective palliation. For the majority of patients endoscopic management is preferable to the percutaneous transhepatic approach due to lower overall mortality and morbidity. Stent occlusion necessitating replacement remains a problem, but improvements in this area can be expected. New plastic stent designs are undergoing investigation. Expandable metallic stents are promising but controlled comparative trials with conventional plastic prostheses are needed. Use of expandable stents should be judicious since these cannot be removed. In the future we can look forward to advances in peroral cholangioscopic technology which may permit targeted treatment of intraductal biliary malignancies.

Biliary Tract Neoplasms↗
PubMed2003

Reduced phosphorylation of cyclic AMP-responsive element binding protein in the postmortem orbitofrontal cortex of patients with major depressive disorder.

In this study, we examined the amounts of cAMP-responsive element binding protein (CREB) and its phosphorylated form in homogenate preparations from postmortem orbitofrontal cortices of antidepressant drug-free patients with major depressive disorder and age-matched controls by immunoblotting. Immunoreactivies of both CREB and phosphorylated CREB were significantly decreased in depressive subjects compared to controls. The immunoreactivity of phosphorylated CREB was diminished to a greater extent than that of CREB in depressive patients. It has been indicated from animal studies that a transcription factor likely mediates neural plasticity in the mammalian brain and neural tissues. Our results suggest that alterations in the cAMP signaling system, especially in CREB, may be involved in the pathophysiology of depression and be potential targets for antidepressant treatment.

Aged↗
PubMed1984

Molecular regulators of brain function: a new view.

A working hypothesis is proposed based on two mutually dependent concepts: neurons may be functionally regulated not only by presently known neurotransmitters but by many kinds of informational substances. Known informational substances are considered in categories corresponding to major regulators of the central nervous system, including transmitters, peptides, hormones, "factors" and various proteins. Many new informational substances are being discovered by the application of DNA technology. Alongside neuronal circuitry that forms the basis for conventional neuroanatomy and neurophysiology, and that operates through conventional synaptic junctions, is a system here called parasynaptic, i.e. in "parallel with" synapse-linked circuitry. In the parasynaptic system, informational substances reach specific target cell receptors by diffusion from release points through extracellular fluids. The parasynaptic system has the same degree of selectivity as synaptic circuitry but possesses, in addition, a domain of versatility and plasticity lacking in "hardwired" circuitry; the latter is, however, also influenced by highly potent informational substances in the ambient extracellular fluid.

Animals↗
PubMed2004

Integration of cardiac magnetic resonance imaging with three-dimensional electroanatomic mapping to guide left ventricular catheter manipulation: feasibility in a porcine model of healed myocardial infarction.

OBJECTIVES: In a series of in vitro and in vivo experiments, we evaluated the feasibility of integrating three-dimensional (3D) magnetic resonance imaging (MRI) and electroanatomic mapping (EAM) data to guide real-time left ventricular (LV) catheter manipulation. BACKGROUND: Substrate-based catheter ablation of post-myocardial infarction ventricular tachycardia requires delineation of the scarred myocardium, typically using an EAM system. Cardiac MRI might facilitate this procedure by localizing this myocardial scar. METHODS: A custom program was employed to integrate 3D MRI datasets with real-time EAM. Initially, a plastic model of the LV was used to determine the optimal alignment/registration strategy. To determine the in vivo accuracy of the registration process, ablation lesions were directed at iatrogenic MRI-visible "targets" (iron oxide injections) within normal porcine LVs (n = 5). Finally, this image integration strategy was assessed in a porcine infarction model (n = 6) by targeting ablation lesions to the scar border. RESULTS: The in vitro experiments revealed that registration of the LV alone results in inaccurate alignment due primarily to rotation along the chamber's long axis. Inclusion of the aorta in the registration process rectified this error. In the iron oxide injection experiments, the ablation lesions were 1.8 +/- 0.5 mm from the targets. In the porcine infarct model, the catheter could be reliably navigated to the mitral valve annulus, and the ablation lesions were uniformly situated at the scar borders. CONCLUSIONS: These data suggest that registration of pre-acquired magnetic resonance images with real-time mapping is sufficiently accurate to guide LV catheter manipulation in a reliable and clinically relevant manner.

Animals↗
PubMed2026

The IL-1 system in inflammation and cancer.

Inflammation is a pathogenetic driver of several pathological conditions, including cancer. The tumor microenvironment, which includes cellular, molecular, and structural components, is an essential component of cancer, involved in tumor promoting or controlling processes. In particular, inflammatory players contribute to the establishment of a tumor-promoting microenvironment, which affects all stages of tumor development, from initiation to metastasis, as well as response to therapy. The IL-1 system includes two large sets of structurally related ligands and receptors, with agonist or regulatory activity, playing non-redundant roles in inflammation and immunity. Each of them has specific functions in tissue homeostasis, inflammation, innate and adaptive immune responses, and potentially contributes to processes related to carcinogenesis and metastasis, or immune-mediated control of cancer cells. Depending on the context and cellular target, IL-1 family members may play dual roles in cancer, driving both pro- or anti-tumor processes. IL-1α and IL-1β can directly promote cancer cell proliferation, survival, and plasticity, in addition to contribute to the establishment of a pro-inflammatory environment that promotes tissue remodeling, cellular stress responses, and genomic instability. On the other hand, IL-1 is a lymphoproliferative and activating molecule in innate and adaptive responses, thus contributing to anti-tumor immune mediated responses. In addition, members of the IL-1 system act as regulators of mechanisms involved in cancer, including emergency hematopoiesis, trained immunity, and metabolism. Here, we will provide an overview of the IL-1 system in cancer and discuss the functional complexity of IL-1 family cytokines, which orchestrate both protective and pro-tumorigenic responses, by directly acting on cancer cells and by driving environmental stimuli which indirectly act on cancer cells.

Humans↗
PubMed1998

Regulation of a site-specific phosphorylation of the microtubule-associated protein 2 during the development of cultured neurons.

The phosphorylation state of cytoskeletal proteins, including certain microtubule-associated proteins, may influence the development and plasticity of axons and dendrites in mammalian neuron in response to appropriate extracellular stimuli. In particular, high molecular weight microtubule-associated protein 2, has been implicated in dendrite growth and synaptic plasticity and is thought to be modulated by phosphorylation and dephosphorylation. We have previously determined that threonines 1620/1623 on the microtubule-associated protein 2 molecule become phosphorylated in vivo and are targets for proline-directed protein kinases in vitro. Using the phosphorylated site-specific antibody 305, we now report the decreased phosphorylation state of high molecular weight microtubule-associated protein 2 during the development of cultured cerebellar granule neurons. Phosphorylation of high molecular weight microtubule-associated protein 2 at this site is significantly inhibited by lithium in short-term cultured neurons, which suggests the implication of glycogen synthase kinase-3. In long-term cultured neurons, it is also partially inhibited by PD098059, an inhibitor of extracellular signal-regulated protein kinase activation, which indicates an additional contribution of this kinase to high molecular weight microtubule-associated protein 2 phosphorylation at this stage. Both in short-term and long-term cultured neurons, okadaic acid augments high molecular weight microtubule-associated protein 2 phosphorylation at this site through the inhibition of protein phosphatases 1 and/or 2A. Finally, glutamate receptor activation leads to a dephosphorylation of high molecular weight microtubule-associated protein 2 at this site which can also be effectively prevented by okadaic acid. These results are consistent with the participation of glycogen synthase kinase-3, extracellular signal-regulated protein kinases and protein phosphatases 1 and 2A, in the regulation of microtubule-associated protein 2 phosphorylation within living neurons, which may be modulated by extracellular signals like the neurotransmitter glutamate.

Animals↗
PubMed2002

Conformational change coupling the dimerization and activation of KSHV protease.

The mechanism of herpesviral protease activation upon dimerization was studied using two independent spectroscopic assays augmented by directed mutagenesis. Spectroscopic changes, attributable to dimer interface conformational plasticity, were observed upon dimerization of Kaposi's sarcoma-associated herpesvirus protease (KSHV Pr). KSHV Pr's dissociation constant of 585 +/- 135 nM at 37 degrees C was measured by a concentration-dependent, 100-fold increase in specific activity to a value of 0.275 +/- 0.023 microM product min(-1) (microM enzyme)(-1). A 4 nm blue-shifted fluorescence emission spectrum and a 25% increase in ellipticity at 222 nm were detected by circular dichroism upon dimer association. This suggested enhanced hydrophobic packing within the dimer interface and/or core, as well as altered secondary structures. To better understand the structure-activity relationship between the monomer and the dimer, KSHV Pr molecules were engineered to remain monomeric via substitution of two separate residues within the dimer interface, L196 and M197. These mutants were proteolytically inactive while exhibiting the spectroscopic signature and thermal stability of wild type, dissociated monomers (T(M) = 75 degrees C). KSHV Pr conformational changes were found to be relevant in vivo, as the autoproteolytic inactivation of KSHV Pr at its dimer disruption site [Pray et al. (1999) J. Mol. Biol. 289, 197-203] was detected in viral particles from KSHV-infected cells. This characterization of structural plasticity suggests that the structure of the KSHV Pr monomer is stable and significantly different from its structure in the dimer. This structural uniqueness should be considered in the development of compounds targeting the dimer interface of KSHV Pr monomers.

Cell Line↗
PubMedDate not supplied

A combinatorial approach for development of materials for optical sensing of gases.

We present a combinatorial approach for development of materials for use in optical gas sensors, with oxygen being used as an exemplary target gas. Combinatorial chemistry is shown to be a promising tool for speeding up the search for new sensor materials. The method is based on the use of various polymers, solvents, indicators, plasticizers, and other additives. Solutions of the respective materials are prepared in appropriate organic solvents, and a robotic station is programmed to mix the components. Spots of the sensing materials are deposited in the wells of glass substrates resembling microtiterplates. After drying off the solvent, the sensor spots are automatically analyzed in a test stand, where they are exposed to a carrier gas containing oxygen in various concentrations. Changes in the decay time of fluorescence of the indicator probes are measured and used (along with sensor response time) as a main criterion for sensor assessment. It is shown that the combinatorial approach can reduce the time and effort needed to establish libraries of sensor materials by a factor of at least 1000. We describe in detail the device for preparation of sensor libraries and for testing the respective materials. The potential of the system is demonstrated for the characterization of optical oxygen sensors.

Journal Article↗
PubMed2004

[Endocannabinoids in the central nervous system].

The major psychoactive component of cannabis derivatives, delta9-THC, activates two G-protein coupled receptors: CB1 and CB2. Soon after the discovery of these receptors, their endogenous ligands were identified: lipid metabolites of arachidonic acid, named endocannabinoids. The two major main and most studied endocannabinoids are anandamide and 2-arachidonyl-glycerol. The CB1 receptor is massively expressed through-out the central nervous system whereas CB2 expression seems restricted to immune cells. Following endocannabinoid binding, CB1 receptors modulate second messenger cascades (inhibition of adenylate cyclase, activation of mitogen-activated protein kinases and of focal-adhesion kinases) as well as ionic conductances (inhibition of voltage-dependent calcium channels, activation of several potassium channels). Endocannabinoids transiently silence synapses by decreasing neurotransmitter release, play major parts in various forms of synaptic plasticity because of their ability to behave as retrograde messengers and activate non-cannabinoid receptors (such as vanilloid receptor type-1), illustrating the complexity of the endocannabinoid system. The diverse cellular targets of endocannabinoids are at the origin of the promising therapeutic potentials of the endocannabinoid system.

Cannabinoid Receptor Modulators↗
PubMed2003

Cerebellar deficits and hyperactivity in mice lacking Smad4.

Smad4 is a central mediator of TGF-beta signals, which are known to play essential roles in many biological processes. Using a Cre-loxP approach to overcome early embryonic lethality, we have studied functions of TGF-beta/Smad4 signals in the central nervous system (CNS). No obvious deficits were detected in mice carrying the targeted disruption of Smad4 in the CNS. The overall morphology of the hippocampus appeared normal. There was no change in the proliferation of neuronal precursor cells, nor in several forms of synaptic plasticity. In contrast, deletion of Smad4 resulted in a marked decrease in the number of cerebellar Purkinje cells and parvalbumin-positive interneurons. Accompanied by the abnormality in the cerebellum, mutant mice also exhibited significantly increased vertical activity. Thus, our study reveals an unexpected role for Smad4 in cerebellar development and in the control of motor function.

Animals↗
PubMed2006

Activity-dependent synaptic Wnt release regulates hippocampal long term potentiation.

Wnts are important for various developmental and oncogenic processes. Here we show that Wnt signaling functions at synapses in hippocampal neurons. Tetanic stimulations induce N-methyl-d-aspartate receptor-dependent synaptic Wnt3a release, nuclear beta-catenin accumulations, and the activation of Wnt target genes. Suppression of Wnt signaling impairs long term potentiation. Conversely, activation of Wnt signaling facilitates long term potentiation. These findings suggest that Wnt signaling plays a critical role in regulating synaptic plasticity.

Action Potentials↗
PubMed2005

Common garden and natural selection experiments support ecotypic differentiation in the Dominican anole (Anolis oculatus).

The theory behind ecotypic differentiation and ecological speciation assumes a predominant role for natural selection working on characteristics with genetic variance, but experimental support for these assumptions is limited. Lesser Antillean anoles show marked ecotypic variation within islands and the potential for ecological speciation. Common garden rearing experiments on the Dominican anole (Anolis oculatus) suggest that the characters showing geographic variation have genetic variance and are not primarily determined by environmental plasticity. Replicated natural selection experiments using large-scale enclosures show that translocated montane samples experience significant (multivariate) directional selection in both wet and dry seasons in both males and females. The targets of selection appear to be spread among the various character systems. An experiment on 12 geographically segregated populations along a coastal xeric-montane rainforest gradient (four replicate enclosures) clearly showed that the magnitude of the directional selection intensity is positively related to the position along this gradient. The results of the common garden and natural selection experiments support the interpretation that the geographic differentiation is primarily driven by natural selection and are compatible with the potential for ecological speciation in this system.

Animals↗
PubMed2004

Acquisition and performance of delayed-response tasks: a neural network model.

We study the time evolution of a neural network model as it learns the three stages of a visual delayed-matching-to-sample (DMS) task: identification of the sample, retention during delay, and matching of sample and target, ignoring distractors. We introduce a neurobiologically plausible, uncommitted architecture, comprising an "executive" subnetwork gating connections to and from a "working" layer. The network learns DMS by reinforcement: reward-dependent synaptic plasticity generates task-dependent behaviour. During learning, working layer cells exhibit stimulus specialization and increased tuning of their firing. The emergence of top-down activity is observed, reproducing aspects of prefrontal cortex control on activity in the visual areas of inferior temporal cortex. We observe a lability of neural systems during learning, with a tendency to encode spurious associations. Executive areas are instrumental during learning to prevent such associations; they are also fundamental for the "mature" network to keep passing DMS. In the mature model, the working layer functions as a short-term memory. The mature system is remarkably robust against cell damage and its performance degrades gracefully as damage increases. The model underlines that executive systems, which regulate the flow of information between working memory and sensory areas, are required for passing tests such as DMS. At the behavioural level, the model makes testable predictions about the errors expected from subjects learning the DMS.

Animals↗
PubMed1996

Impairment of hippocampal mossy fiber LTD in mice lacking mGluR2.

Subtype 2 of the metabotropic glutamate receptor (mGluR2) is expressed in the presynaptic elements of hippocampal mossy fiber-CA3 synapses. Knockout mice deficient in mGluR2 showed no histological changes and no alterations in basal synaptic transmission, paired-pulse facilitation, or tetanus-induced long-term potentiation (LTP) at the mossy fiber-CA3 synapses. Long-term depression (LTD) induced by low-frequency stimulation, however, was almost fully abolished. The mutant mice performed normally in water maze learning tasks. Thus, the presynaptic mGluR2 is essential for inducing LTD at the mossy fiber-CA3 synapses, but this hippocampal LTD does not seem to be required for spatial learning.

Animals↗
PubMed2005

Plasticity of vagal afferents at the site of an incision in the wall of the stomach.

Our objectives were to determine whether the vagal afferent innervation of the stomach reorganizes after surgery and to observe how different wound closure techniques might influence such a process. The smooth muscle wall of the stomach served as a model because it is densely innervated by vagal axons and is frequently compromised by gastric surgery. Male Sprague-Dawley rats were assigned to one of six groups: three groups served as controls in which the stomach was exposed surgically and a) subjected to no further manipulation, b) traumatized with suture needle punctures of the muscle wall, or c) insulted by the placement of knotted suture thread in the stomach muscle; three surgical groups received a 1.0 cm incision through the ventral muscle wall of the stomach that was closed using either a) absorbable sutures, b) fibrin glue, or c) n-butyl cyanoacrylate. Rats were killed 4 to 7 months post-surgery. Prior to euthanasia, Micro-Ruby was injected into the left nodose ganglion of each rat to label vagal afferent axons and terminals. Twelve days post-injection, the stomachs were processed for microscopy. All groups recovered quickly from surgery, without differences in body weight. The presence of suture material in the muscle wall of the stomach was sufficient to produce reorganization of nearby vagal afferents. In addition, we observed that an incision of the smooth muscle wall of the stomach and the associated damage to vagal afferents provoked reorganization and regeneration of vagal afferents. Vagal remodeling at the incision was characteristic of axonal patterns found in neuromas (unlike the organized regeneration and differentiation that can occur after axotomy central to the target organ). Vagal afferent terminals located at the site of the incision were free nerve endings and growth cone profiles, and not the characteristically complex end organs normally found in the smooth muscle. Finally, the pattern of vagal plasticity was influenced by the wound closure technique used. Overall, the remodeling of afferents was aberrant in nature, and such neural pathology could contribute to the neuropathic symptoms and hyperalgesias associated with gastrointestinal trauma and bariatric surgery.

Animals↗