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PubMed1997

Neurosteroids in the Hippocampus: Neuronal Plasticity and Memory.

The hippocampus, which is critically involved in learning and memory processes, is known to be a target for the neuromodulatory actions of steroid hormones produced by the adrenal glands and gonads. Much of the work of B.S. McEwen and collaborators has focused on the role of glucocorticosteroids and estrogen in modulating hippocampal plasticity and functions. In addition to hormones derived from the endocrine glands, cells in the hippocampus may be exposed to locally synthesized neurosteroids, including pregnenolone, dehydroepiandrosterone and their sulfated esters as well as progesterone and its reduced metabolites. In contrast to hormones derived from the circulation, neurosteroids have paracrine and/or autocrine activities. In the hippocampus, they have been shown to have trophic effects on neurons and glial cells and to modulate the activity of a variety of neurotransmitter receptors and ion channels, including type A gamma-aminobutyric acid, N-methyl-D-aspartate and sigma receptors and N- and L-type Ca2+ channels. There is accumulating evidence that some neurosteroids, in particular pregnenolone sulfate, have strong influences on learning and memory processes, most likely by regulating neurotransmission in the hippocampus. However, the hippocampus is not the only target for the mnesic effects of neurosteroids. Associated brain regions, the basal nuclei of the forebrain and the amygdaloid complex, are also involved. Some neurosteroids may thus be beneficial for treating age- or disease-related cognitive impairments.

Journal Article↗
PubMed2003

Neuronal growth factors and development of respiratory control.

Neurotrophic molecules, released by neurons and neural target tissues, play a pivotal role in regulating neuronal development and plasticity. This article reviews recent work demonstrating the pivotal role of two such molecules, brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), in the growth and maturation of respiratory neurons and the expression of normal ventilatory behavior. Although BDNF and GDNF are structurally dissimilar and signal through wholly distinct receptors, they are both required for development of peripheral chemoafferent neurons that provide hypoxic drive to the brainstem respiratory network. Studies of genetically engineered mice carrying targeted deletions in the genes encoding BDNF and GDNF, as well as genetic linkage analysis in humans, indicate that these trophic molecules may be candidate genes for human developmental disorders of breathing.

Animals↗
PubMed2006

Forebrain-specific knockout of B-raf kinase leads to deficits in hippocampal long-term potentiation, learning, and memory.

Raf kinases are downstream effectors of Ras and upstream activators of the MEK-ERK cascade. Ras and MEK-ERK signaling play roles in learning and memory (L&M) and neural plasticity, but the roles of Raf kinases in L&M and plasticity are unclear. Among Raf isoforms, B-raf is preferentially expressed in the brain. To determine whether B-raf has a role in synaptic plasticity and L&M, we used the Cre-LoxP gene targeting system to derive forebrain excitatory neuron B-raf knockout mice. This conditional knockout resulted in deficits in ERK activation and hippocampal long-term potentiation (LTP) and impairments in hippocampus-dependent L&M, including spatial learning and contextual discrimination. Despite the widespread expression of B-raf, this mutation did not disrupt other forms of L&M, such as cued fear conditioning and conditioned taste aversion. Our findings demonstrate that B-raf plays a role in hippocampal ERK activation, synaptic plasticity, and L&M.

Animals↗
PubMed1994

Analysis of synaptic inputs and targets of physiologically characterized neurons in rat frontal cortex: combined in vivo intracellular recording and immunolabeling.

Ultrastructural immunocytochemical identification of transmitters in afferent terminals and targets of individual physiologically characterized neurons is essential for understanding the complex circuitry within the mammalian neocortex. For this type of analysis, we examined the utility of combining in vivo intracellular recording and biocytin injections with silver intensified 1 nm immunogold labeling of GABA and the catecholamine synthesizing enzyme, tyrosine hydroxylase (TH). These transmitters are found to local neurons and afferents known to prominently modulate the activity of pyramidal neurons in the neocortex. Individual neurons were physiologically characterized and filled with biocytin in the frontal cortex of anesthetized rats. The brains were then preserved by vascular perfusion with aldehydes. Single vibratome sections through the recording site were reacted (1) for immunoperoxidase detection of biocytin and (2) for immunogold labeling of GABA or TH. Dually labeled sections were processed for light microscopy or embedded in plastic for electron microscopy. The dense peroxidase product for biocytin was detected in pyramidal neurons. These were located in superficial as well as deep cortical laminae, and were readily distinguished from immunogold silver labeling. GABA labeled terminals formed symmetric synapses with larger biocytin filled dendrites, whereas the TH labeled terminals contacted distal dendrites and spines. Peroxidase labeling for biocytin also was seen in a few axon terminals forming synapses with unlabeled and with GABA immunoreactive dendrites. These results suggest that single pyramidal neurons of the rat frontal cortex receive dual input from both GABA and catecholamine terminals. Additionally, this study demonstrates the usefulness of silver enhancement of 1 nm colloidal gold prior to plastic embedding for electron microscopic detection of neurotransmitters within afferents and targets of neurons physiologically characterized in vivo.

Animals↗
PubMed2003

Novel molecular targets in pain control.

PURPOSE OF REVIEW: The complexity of pain processing in clinical pain conditions and in animal models has revealed many time-related changes and an abundance of molecular drug targets. There continues to be insecurity, however, about new target validation in clinical pain and thus most analgesia development is of high risk for evolving new pain therapies. The present review highlights a number of molecular targets being pursued for pain control. RECENT FINDINGS: Many pain targets are critically dependent on the pain model/lesion type. Neural and glial plasticity, ranging from changes in molecular expression and receptor phosphorylation to profound morphological reorganization, has been described under these conditions. Pain modulation has been shown to involve all major families of regulatory proteins such as the G-protein coupled receptors, ion channels, regulatory enzymes, neurotrophins, and kinases, offering an abundance of targets and therapeutic opportunities for symptomatic pain relief. SUMMARY: Many molecular targets have been highlighted with some being the focus of current analgesia research. Some of these (e.g. vanilloid receptor 1, cannabinoid receptor 1, sodium channel NaV 1.8) have been evaluated in animal studies and in preliminary clinical studies, but others are highly novel and riskier analgesia pain targets (e.g. metabotropic glutamate receptors, sensory neurone specific receptors, kinase inhibitors).

Journal Article↗
PubMed1986

Natural cytotoxic T cells (NCTC) that differ from natural killer (NK) and natural cytotoxic (NC) cells are present in Peyer's patches of mice.

We have examined noninduced cytotoxicity of mouse gut associated and peripheral lymphoid tissues for a wide variety of syngeneic as well as allogeneic cell lines and lymphoblasts. Lymphoid cells from Peyer's patches were found to lyse these targets in a 3-hr chromium release assay whereas lymphoid cells from intestinal mucosa, mesenteric or peripheral lymph nodes, spleen, and thymus did not. The variety of targets toward which Peyer's patch cells were cytotoxic established the latter as nonspecific and H-2 unrestricted. The cell responsible for the lytic event was identified as possessing Thy 1.2 and Ia surface antigens. This naturally cytotoxic T cell (NCTC) was found to be adherent to nylon-wool but not to plastic plates. Although both natural killer cell (NK) and non-NK targets served as targets for the NCTC, the latter were further differentiable from NK cells by lack of asialo GM1 surface marker, which is present on NK cells. In addition, NCTC remained fully functional in mice given either of the drugs cyclophosphamide or cortisone. Each of these drugs, in the doses used, markedly reduced poly(I:C)-induced NK activity. Thus, NCTC differs from NK on the basis of the spectrum of targets against which it is functional, phenotypic surface markers, insusceptibility to stimulation with poly(I:C), and insensitivity to diminution by the immunosuppressive drugs cyclophosphamide and hydrocortisone. Since NCTC is a Thy 1.2 antigen-bearing cell and is detectable in a 3-hr cytotoxic assay, it also differs from the natural cytotoxic (NC) cell. NC lacks the Thy 1.2 marker and becomes detectable only in an 18-hr cytotoxic assay. Thus, NCTC is neither an NK nor an NC cell. We have discussed the possibility that the three naturally occurring cells may be related by being dedifferentiated descendants of an antigen-specific cytotoxic T lymphocyte (CTL). Alternatively, since NCTC is confined to an anatomical site prone to ample antigenic exposure and is still identifiable as a T cell, it may be in linear transition from the CTL to the NK or NC stages.

Animals↗
PubMed1995

An anatomical substrate for experience-dependent plasticity of the rat barrel field cortex.

The objective of this study was to examine the influence of sensory experience on the synaptic circuitry of the cortex. For this purpose, the quantitative distribution of the overall and of the gamma-aminobutyric acid (GABA) population of synaptic contacts was investigated in each layer of the somatosensory barrel field cortex of rats which were sensory deprived from birth by continuously removing rows of whiskers. Whereas there were no statistically significant changes in the quantitative distribution of the overall synaptic population, the number and proportion of GABA-immunopositive synaptic contacts were profoundly altered in layer IV of the somatosensory cortex of sensory-deprived animals. These changes were attributable to a specific loss of as many as two-thirds of the GABA contacts targeting dendritic spines. Thus, synaptic contacts made by GABA terminals in cortical layer IV and, in particular, those targeting dendritic spines represent a structural substrate of experience-dependent plasticity. Furthermore, since in this model of cortical plasticity the neuronal receptive-field properties are known to be affected, we propose that the inhibitory control of dendritic spines is essential for the elaboration of these functional properties.

Animals↗
PubMed2004

Intrathecal therapy with trastuzumab may be beneficial in cases of refractory schizophrenia.

Refractory schizophrenia has limited therapeutic options. Schizophrenia can be considered to be a disease of abnormal synaptic plasticity. Neuregulin is a member of the epithelial growth factor family, which induces growth and differentiation of epithelial, glial and muscle cells in culture. Neuregulin has been documented to be important in synaptic plasticity. The important role of neuregulin in synaptic plasticity as well as its developmental role have increasingly been documented recently. The actions of neuregulin are mediated through ERB receptors. Neuregulin can bind directly to erbB3 and erbB4 receptors and receptor heterodimerization allows neuregulin dependent activation of erbB2. The role of Erb 2 could make it possible to use the monoclonal antibody against it for improving the synaptic plasticity through the action on neuregulin. The use of trastuzumab (Her2 antibody) as targeted therapy is well documented in metastatic carcinoma of breast. Also intra-thecal administration of trastuzumab has been reported to be safe in carcinomatous meningitis. Here it is being hypothesized that intra-thecal administration of trastuzumab would improve synaptic plasticity there by making refractory schizophrenia amenable to treatment.

Antibodies, Monoclonal↗
PubMed2003

The PDZ domains of mLin-10 regulate its trans-Golgi network targeting and the surface expression of AMPA receptors.

Dynamic regulation of synaptic AMPA receptor localization underlies certain forms of synaptic plasticity and researchers are just beginning to identify molecules that may play a role in the synaptic delivery of glutamate receptors. One candidate is mLin-10, the mammalian homolog of the C. elegans receptor targeting protein LIN-10. Here, we investigated the role of mLin-10 in glutamate receptor trafficking. Cellular localization studies, in both whole brain and cultured neurons, revealed that mLin-10 is enriched in the trans-Golgi network and present in dendrites and spines--regions where protein sorting and synaptic delivery are known to occur. The specific localization of mLin-10 in Golgi is disrupted by a point mutation in an mLin-10 PDZ domain, indicating that a PDZ domain mediates this localization. Interactions between mLin-10 and glutamate receptors in both intracellular and synaptic membrane fractions were detected through biochemical assays. GST-pull down and co-immunoprecipitation experiments in heterologous cells delineated the protein domains required for interaction. These results demonstrated that glutamate receptors interact directly with mLin-10 through a PDZ domain-mediated mechanism. A PDZ point mutation enhances surface delivery of exogenous glutamate receptors in transfected neurons, suggesting that mLin-10 may regulate AMPA receptor trafficking in vivo.

Amino Acid Sequence↗
PubMed2002

Investigating the site of human saccadic adaptation with express and targeting saccades.

To focus on various objects of interest within the visual environment, primates employ rapid eye movements called saccades. When the accuracy of these movements becomes impaired, the brain can adjust their amplitude by a process known as saccadic adaptation. To investigate the locus of this plasticity in the human brain, we behaviorally adapted two types of saccade thought to be generated through different neuronal pathways. Targeting saccades, which are made to sequentially illuminated targets and have long latencies, are thought to involve higher cortical processing whereas express saccades, which have very short latencies, apparently do not. If adaptation transfers between these two types of saccade, one may conclude that the plasticity must exist at a locus common to the two pathways generating these saccades. We directly reduced the gain of either targeting or express saccades by intrasaccadically moving the target one-third of its amplitude back toward the initial fixation location and then examined whether the gain was also reduced in the other type of saccade. When targeting saccades were adapted directly, all subjects showed significant reductions in the gain of these saccades. In 75% of the 32 experimental target conditions across all subjects, there were also significant reductions in the gain of express saccades, thus providing evidence of adaptation transfer. In 71% of these conditions (i.e., 53% of all target conditions) there was no significant difference between the reductions in gain of the two types of saccade, suggesting that adaptation transfer was complete (100%). Similar results were obtained when express saccades were adapted directly: significant reductions in gain occurred in 91% of express saccades and in 100% of targeting saccades. In 86% of the target conditions, across subjects, in which both express and targeting saccades showed significant reductions in gain, the two types of saccade did not differ significantly in the amount of gain reduction. This suggests that adaptation transfer was complete for 78% of all target conditions. Therefore, we conclude that saccadic adaptation transfers robustly between targeting and express saccades. These results suggest that adaptation in humans occurs after the pathways generating these two types of saccade converge, probably at or downstream from the superior colliculus.

Adaptation, Physiological↗
PubMed1979

Autoimmune interaction measured in a postlabelling microcytostasis assay.

A postlabelling microcytostasis assay was developed to assess primary immune interaction between normal rat lymphocytes and autologous testis cells. In this vitro model of experimental autoimmune orchitis (EAO) unprimed T cells respond to a Sertoli-like subpopulation of testis cells during a 4 day culture period. The T effector cells exert a cytostatic effect on the monolayer-forming target cells. The number of remaining target cells, which inversely correlates with the intensity of the autoimmune reaction, is quantified by 51Cr incorporation. The assay is performed in multiple well plastic plates which allow rapid harvesting by cutting off the bottoms of each well. The attached labelled target cells are directly measured on the bottoms without any further transfer step. The method is adapted for the EAO model but may be useful to study primary T cell interaction with any other monolayer-forming target cells.

Animals↗
PubMed2003

Regulation of cellular plasticity cascades in the pathophysiology and treatment of mood disorders: role of the glutamatergic system.

There is increasing evidence from a variety of sources that mood disorders are associated with regional reductions in brain volume, as well as reductions in the number, size, and density of glia and neurons in discrete brain areas. Although the precise pathophysiology underlying these morphometric changes remains to be fully elucidated, the data suggest that severe mood disorders are associated with impairments of structural plasticity and cellular resilience. In this context, it is noteworthy that a growing body of data suggests that the glutamatergic system--which is known to play a major role in neuronal plasticity and cellular resilience--may be involved in the pathophysiology and treatment of mood disorders. Preclinical studies have shown that the glutamatergic system represents targets (often indirect) for the actions of antidepressants and mood stabilizers. There are a number of glutamatergic "plasticity enhancing" strategies that may be of considerable utility in the treatment of mood disorders. Among the most immediate ones are NMDA antagonists, inhibitors of glutamate-release agents, and AMPA potentiators; this research progress holds much promise for the development of novel therapeutics for the treatment of severe, refractory mood disorders.

Animals↗
PubMed1985

[Methodological variants in the optimal determination of the activity of natural killers and mononuclear phagocytes by analysis at the single-cell level].

Variants of the method for determination of the natural killer cells (NK-cells), and monocytes-macrophages both in human beings and in mice have been described. Usage of agarose which permits fixing conjugates of the effector cells and a tumour target cell allows determining simultaneously the quantity of effector cells bound with the target and percentage of the cytotoxic effectors. The results in acceptable definition of the effector cells' activity with the use of various kinds of plastic ware, its treatment, diverse types of agarose, temperature and time regimen are adduced. The di-target method of testing is approved using the target cells labelled with fluorescein as well as unlabelled ones. Peculiarities of function disturbances of the NK-cells and monocytes in patients with lung cancer as well as changes in the activity of these effectors in mice CBA depending on the terms of Krebs-2 carcinoma inoculation and on repeated BCG vaccine injection were detected.

Animals↗
PubMed2005

The automatic detection of known beta-propeller structural motifs from protein tertiary structure.

Following our previous work on the analysis of 'structural plasticity' associated with the beta-propeller structural motifs, we have now developed a simple method that can automatically detect all the known beta-propellers in protein tertiary structure, given a list of Protein Data Bank (PDB) codes as input to the computer program. Our beta-propeller detection (BPD) method identifies the location of beta-propellers in the protein structure, specifies the beta-propeller type, the beta-sheet associated beta-strand pattern and the structurally similar beta-propellers observed in other proteins. When tested on 21,566 proteins in the PDB, the BPD method was capable of correctly identifying all the known 245 beta-propellers described in the structural classification of proteins (SCOP) with the number of false positives detected being less than 0.2%. Forty-one false positives were detected that correspond to eight known protein families. When compared with some of the popular web-based programs that can automatically detect 'structural similarities' between the query and target proteins, our method has the advantage of also being capable of detecting beta-propellers associated with 'structural plasticity' and in situations where the target and query proteins differ in amino acid sequence length.

Amino Acid Motifs↗
PubMed2001

Semaphorin-neuropilin-1 interactions in plasticity and regeneration of adult neurons.

During development, axonal growth cones are guided to their appropriate targets by many attractive and repulsive cues. It has become increasingly clear over the last few years that how the growth cone responds to these cues depends both on the molecular nature of the cue and on the internal state of the neuron. The unexpected result is that the same molecule can act as an attractor or as a repellent. A number of guidance cues used by neurons during development are retained in the adult nervous system, where their function is often still unclear. Most of these molecules are implicated in plasticity in the adult nervous system and can play a role (sometimes maladaptive) in neuronal regeneration after injury. A group of axonal guidance cues that has been well studied in development is the semaphorin family of secreted and membrane-anchored proteins, which has been implicated in axon steering, fasciculation, branching and synapse formation. This review focuses on semaphorin-3A (probably the best-characterized semaphorin) and its receptors (in particular neuropilin-1) in the adult nervous system and argues that semaphorin-3A plays a role in the maintenance and regeneration of adult sensory neurons.

Adult↗
PubMed2006

Learning and neural plasticity in visual object recognition.

The capability of the adult primate visual system for rapid and accurate recognition of targets in cluttered, natural scenes far surpasses the abilities of state-of-the-art artificial vision systems. Understanding this capability remains a fundamental challenge in visual neuroscience. Recent experimental evidence suggests that adaptive coding strategies facilitated by underlying neural plasticity enable the adult brain to learn from visual experience and shape its ability to integrate and recognize coherent visual objects.

Animals↗
PubMedDate not supplied

Exclusive measurements of light fragment production at forward angles in Ne-Pb and Ne-NaF collisions at E/A=400 MeV and 800 MeV.

Emission of light fragments at small angles is studied in relativistic heavy ion collisions using the Diogene plastic wall for both symmetrical and non-symmetrical target-projectile systems with 400 MeV per nucleon and 800 MeV per nucleon incident neon nuclei. Efficiency of multiplicity measurements in the small angle range for the selection of central or peripheral collisions is confirmed for asymmetric systems. Differential production cross sections of Z = 1 fragments show evidence for the existence of two emitting sources. The apparent temperature of each source is obtained from comparison with a thermodynamical model.

Elementary Particles↗
PubMed2004

Differential regulation of MAP2 and alphaCamKII expression in hippocampal neurones by forskolin and calcium ionophore treatment.

The genes encoding microtubule-associated protein 2 (MAP2), and the alpha subunit of calcium/calmodulin-dependent protein kinase II (alphaCaMKII), are members of a small number of genes whose expression is increased in hippocampal neurones during the intermediate phase of long-term potentiation (LTP)-a phase dependent on mRNA translation but not on gene transcription. However, the intracellular signalling pathways which mediate these increases in expression are largely unknown. Organotypic slice cultures of rat hippocampus were exposed to either forskolin (to elevate cAMP levels), A23187 (to increase intracellular Ca(2+) levels) or the corresponding vehicle. The levels of immunoreactive (ir-) MAP2 were increased 4 h after forskolin treatment, but were unaffected by A23187 treatment. Conversely, the levels of ir-alphaCaMKII were increased 4 h after A23187 treatment, but were unaffected by forskolin. The regulation of the expression of these proteins was the same in the CA3 region as in the CA1 and dentate gyrus of the hippocampus. While rapamycin reduced the basal levels of ir-MAP2, it did not affect the ability of either forskolin or A23187 to enhance ir-MAP2 or ir-alphaCaMKII levels. These results suggest that cAMP and Ca(2+) differentially modulate the expression of these two plasticity-related genes, and that translational enhancement via the mammalian target of rapamycin kinase is not involved in these effects.

Animals↗