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Results for “Target plasticity”

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At least 523 records · Page 29Linked to original sources
PubMed1994

Prenatal haloperidol induces a selective reduction in the expression of plasticity-related genes in neonate rat forebrain.

Haloperidol, a dopamine receptor antagonist clinically used as an antipsychotic drug, induces long-term deleterious effects in offspring development when administered prenatally. However, the basis for this overall response to the drug remains unknown. Here we describe that prenatal administration of haloperidol in rats induces a drastic and selective reduction in the expression of plasticity-related genes in neonate forebrain, but not in mesencephalon. GABAergic and enkephalinergic markers such as glutamic acid decarboxylase activity and mRNA, and preproenkephalin mRNA were also diminished in forebrain. However, the expression of other genes such as epidermal growth factor-receptor, glial fibrillary acidic protein, and several proto-oncogenes (src, fos and myc), and a cholinergic marker such as choline acetyltransferase activity were unaltered. In addition, haloperidol promoted a significant decrease in mitotic cell number and cellular density in the striatum, one of the forebrain regions with the highest dopamine receptor density. These findings suggest that prenatal dopamine receptor occupancy may be a critical factor in controlling the development of forebrain target cells through mechanisms involving changes in the expression of plasticity-related genes.

Actins↗
PubMed2005

Corticofugal feedback for auditory midbrain plasticity elicited by tones and electrical stimulation of basal forebrain in mice.

The auditory cortex (AC) is the major origin of descending auditory projections and is one of the targets of the cholinergic basal forebrain, nucleus basalis (NB). In the big brown bat, cortical activation evokes frequency-specific plasticity in the inferior colliculus and the NB augments this collicular plasticity. To examine whether cortical descending function and NB contributions to collicular plasticity are different between the bat and mouse and to extend the findings in the bat, we induced plasticity in the central nucleus of the mouse inferior colliculus by a tone paired with electrical stimulation of the NB (hereafter referred to as tone-ES(NB)). We show here that tone-ES(NB) shifted collicular best frequencies (BFs) towards the frequency of the tone paired with ES(NB) when collicular BFs were different from tone frequency. The shift in collicular BF was linearly correlated to the difference between collicular BFs and tone frequencies. The changes in collicular BFs after tone-ES(NB) were similar to those found in the big brown bat. Compared with cortical plasticity evoked by tone-ES(NB), the pattern of collicular BF shifts was identical but the shifting range of collicular BFs was narrower. A GABA(A) agonist (muscimol) or a muscarinic acetylcholine receptor antagonist (atropine) applied to the AC completely abolished the collicular plasticity evoked by tone-ES(NB). Therefore, our findings strongly suggest that the AC plays a critical role in experience-dependent auditory plasticity through descending projections.

Acoustic Stimulation↗
PubMed2004

Developmental plasticity of photoreceptors.

During development, retinal ganglion cells undergo conspicuous structural remodeling as they gradually attain their mature morphology and connectivity. Alterations in their dendritic organization and in their axonal projections can also be achieved following early insult to their targets or their afferents. Other retinal cell types are thought not to display this same degree of developmental plasticity. The present review will consider the evidence, drawn largely from recent experimental studies in the carnivore retina, that photoreceptors also undergo structural remodeling, extending their terminals transiently into inner plexiform layer before retracting to the outer plexiform layer. The determinants of this transient targeting to the inner plexiform layer are considered, and the role of cholinergic amacrine cells is discussed. The factors triggering this retraction are also considered, including the concurrent maturational changes in outer segment formation and in the differentiation of the outer plexiform layer. These results provide new insight into the life history of the photoreceptor cell and its connectivity, and suggest a transient role for the photoreceptors in the circuitry of the inner retina during early development, prior to the onset of phototransduction.

Aging↗
PubMed2026

Genome-wide mapping of stress-responsive lncRNA, uc.104, reveals the chromatin-mediated regulation of stress and plasticity-related genes in the hippocampus of chronic restraint rats.

Chronic stress significantly impacts hippocampal function through transcriptional and epigenetic mechanisms. While the roles of lncRNAs in stress-related transcriptional and epigenetic regulation have recently been recognized, their genome-wide functions controlling the transcriptional network remain largely unclear. Evidence indicates that the lncRNA uc.104 is involved in stress responses; however, its genome-wide chromatin interactions and gene regulatory effects are yet to be explored. To examine this, we combined chromatin isolation by RNA purification sequencing (ChIRP-seq) and RNA sequencing (RNA-seq) in the hippocampus from handled control and chronic restraint stress (CRS) rats. ChIRP-seq identified 6,664 uc.104 binding peaks under CRS, including 6,517 enriched and 149 reduced. Many peaks were mapped to intronic and promoter-proximal regions of protein-coding genes. Integration of ChIRP-seq with RNA-seq data revealed 1,839 differentially expressed genes associated with uc.104 binding sites, with 106 high-confidence overlaps. Several genes (Gabra3, Htr7, Irs1, Gpr37, Clu, Hspa1b, Ppp3r2, Nfasc, Pcdhac2, and Cysltr2) identified as regulatory targets of uc.104, have been directly implicated in stress responses, synaptic plasticity, and neuroinflammation. Gene ontology and Synapse GO (SynGO) analyses revealed significant enrichment for processes involving dendritic spine formation, synapse organization, and pre- and postsynaptic signaling. Protein-protein interaction analysis identified hub genes, including EGFR, CDC42, IGF1R, CTNNB1, CALM1, CALM3, POLR2A, MDM2, TBP, and CSNK1E, several of which have been linked to stress-responsive pathways. Together, our findings reveal that uc.104 binding to chromatin near stress- and synapse-related genes may act as a regulator of stress-responsive transcriptional networks in the hippocampus. By linking uc.104 occupancy to stress and synaptic responsive genes, this study highlights uc.104 as a potential mediator of stress-induced hippocampal malfunctions.

Animals↗
PubMed1989

Lymphokine-activated killing of autologous and allogeneic short-term cultured head and neck squamous carcinomas.

Interleukin-2-(IL-2)-activated lymphocytes have been shown to kill a variety of continuously cultured allogeneic (nonself), natural killer cell-sensitive and resistant cell lines, and some autologous (self) tumor cells. Lymphokine-activated killer (LAK) cytotoxicity of autologous head and neck squamous cell carcinoma (HNSCC) cells has not been previously demonstrated, and efforts to demonstrate this have been hampered by the lack of a reliable and reproducible method of obtaining satisfactory tumor targets. In this study, fresh tumor cells were enzymatically dissociated, enriched by adherence to plastic, and used in a 3-hour chromium-51 cytotoxicity assay. Peripheral blood lymphocytes (PBLs) were incubated for 3 days with or without added IL-2. IL-2-activated PBLs showed significant cytotoxicity against autologous and allogeneic targets, while only low levels of tumor lysis occurred with unstimulated PBLs. These findings suggest the possible use of IL-2-activated lymphocytes in the adoptive immunotherapy of HNSCC patients.

Carcinoma, Squamous Cell↗
PubMed2006

Neuron-glia metabolic coupling and plasticity.

The coupling between synaptic activity and glucose utilization (neurometabolic coupling) is a central physiological principle of brain function that has provided the basis for 2-deoxyglucose-based functional imaging with positron emission tomography (PET). Astrocytes play a central role in neurometabolic coupling, and the basic mechanism involves glutamate-stimulated aerobic glycolysis; the sodium-coupled reuptake of glutamate by astrocytes and the ensuing activation of the Na-K-ATPase triggers glucose uptake and processing via glycolysis, resulting in the release of lactate from astrocytes. Lactate can then contribute to the activity-dependent fuelling of the neuronal energy demands associated with synaptic transmission. An operational model, the 'astrocyte-neuron lactate shuttle', is supported experimentally by a large body of evidence, which provides a molecular and cellular basis for interpreting data obtained from functional brain imaging studies. In addition, this neuron-glia metabolic coupling undergoes plastic adaptations in parallel with adaptive mechanisms that characterize synaptic plasticity. Thus, distinct subregions of the hippocampus are metabolically active at different time points during spatial learning tasks, suggesting that a type of metabolic plasticity, involving by definition neuron-glia coupling, occurs during learning. In addition, marked variations in the expression of genes involved in glial glycogen metabolism are observed during the sleep-wake cycle, with in particular a marked induction of expression of the gene encoding for protein targeting to glycogen (PTG) following sleep deprivation. These data suggest that glial metabolic plasticity is likely to be concomitant with synaptic plasticity.

Animals↗
PubMed2002

Morphometric analysis of cytolysis in cultured cell monolayers: a simple and versatile method for the evaluation of the cytotoxic activity and the fate of LAK cells.

In vitro techniques for the evaluation of the cytotoxicity of immune cells are important both for the routine assessment of the cytolytic activity in samples for clinical or experimental use and for basic studies of the interaction between killer and target cells. Especially in the latter case, it is important not only to quantify target cell death as an endpoint, but also to observe the interaction and to recover effectors and targets for further analysis. We present a new method that offers considerable improvements for both types of applications, in comparison with the standard radioactivity release assays used today. The morphometric cytotoxicity assay (Mo.C.A.) estimates the extent of target cell lysis by measuring the openings that appear in a confluent monolayer of adherent cells as killed cells detach from the plastic on which they were spread. Two hours after the inoculation of the effector cells, nonadherent killer and dead target cells are washed off and the remaining monolayer is fixed and stained with Coomassie blue. Elementary computer-assisted image analysis allows then to calculate the percentage of open space, which is a parameter for the extent of lysis. As the Mo.C.A. is easy, and does not rely on the use of radioactive compounds or sophisticated equipment, we provide evidence that it should be valuable for the routine analysis of cytotoxicity in various cell samples. In addition, the method offers great flexibility in the choice of target cells and allows for continuous microscopic observation of the live cultures. The interaction can also be stopped at any time, and the effector and (unlabeled) target cells can be recovered separately. Therefore, the method should also offer new possibilities for the basic study of killer cell biology.

3T3 Cells↗
PubMed1984

Natural cytotoxicity of human blood monocytes: production of monocyte cytotoxic factors (MCF) during interaction with tumor cells.

Human blood monocytes obtained by EDTA-reversible adherence to autologous serum-coated plastic dishes expressed natural cytotoxicity against NK-sensitive K562 cells in a 4-h 51Cr release assay. These monocytes released soluble cytotoxic factors, termed monocyte cytotoxic factors (MCF), when cultured with target cells. In contrast, blood monocytes obtained by adherence to fetal calf serum-coated plastic surfaces failed to kill K562 cells and to produce MCF. Although some lysis could be detected at 18 h, optimal lysis of K562 cells by MCF was observed after 48 h incubation in a microcytotoxicity assay using trypan blue dye exclusion. The addition of actinomycin D to the cytotoxicity assay enhanced the sensitivity and then NCF activity was detectable in a 18-h Cr release assay. Neither supernatants produced by culture of monocytes alone nor lysates of monocytes were cytotoxic. In addition, cytochalasin A inhibited both direct cell-mediated lysis and generation of MCF. Optimal production of MCF occurred after 6-24 h of interaction with K562 cells, although significant activity was already present by 3 h. Treatment of monocytes with OKM1 monoclonal antibody plus complement abrogated both cell-mediated lysis and MCF generation, whereas Leu-11b plus complement were ineffective. These results indicate that human blood monocytes can release MCF during interaction with tumor cells and that this may be involved in the lytic mechanism of monocyte-mediated natural cytotoxicity.

Cells, Cultured↗
PubMed2006

Non-fibrillar beta-amyloid abates spike-timing-dependent synaptic potentiation at excitatory synapses in layer 2/3 of the neocortex by targeting postsynaptic AMPA receptors.

Cognitive decline in Alzheimer's disease (AD) stems from the progressive dysfunction of synaptic connections within cortical neuronal microcircuits. Recently, soluble amyloid beta protein oligomers (Abeta(ol)s) have been identified as critical triggers for early synaptic disorganization. However, it remains unknown whether a deficit of Hebbian-related synaptic plasticity occurs during the early phase of AD. Therefore, we studied whether age-dependent Abeta accumulation affects the induction of spike-timing-dependent synaptic potentiation at excitatory synapses on neocortical layer 2/3 (L2/3) pyramidal cells in the APPswe/PS1dE9 transgenic mouse model of AD. Synaptic potentiation at excitatory synapses onto L2/3 pyramidal cells was significantly reduced at the onset of Abeta pathology and was virtually absent in mice with advanced Abeta burden. A decreased alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/N-methyl-D-aspartate (NMDA) receptor-mediated current ratio implicated postsynaptic mechanisms underlying Abeta synaptotoxicity. The integral role of Abeta(ol)s in these processes was verified by showing that pretreatment of cortical slices with Abeta((25-35)ol)s disrupted spike-timing-dependent synaptic potentiation at unitary connections between L2/3 pyramidal cells, and reduced the amplitude of miniature excitatory postsynaptic currents therein. A robust decrement of AMPA, but not NMDA, receptor-mediated currents in nucleated patches from L2/3 pyramidal cells confirmed that Abeta(ol)s perturb basal glutamatergic synaptic transmission by affecting postsynaptic AMPA receptors. Inhibition of AMPA receptor desensitization by cyclothiazide significantly increased the amplitude of excitatory postsynaptic potentials evoked by afferent stimulation, and rescued synaptic plasticity even in mice with pronounced Abeta pathology. We propose that soluble Abeta(ol)s trigger the diminution of synaptic plasticity in neocortical pyramidal cell networks during early stages of AD pathogenesis by preferentially targeting postsynaptic AMPA receptors.

Action Potentials↗
PubMed2000

Identification of a juxtamembrane segment of the glutamate receptor delta2 subunit required for the plasma membrane localization.

Glutamate receptor delta2 subunit (GluRdelta2) is selectively expressed in cerebellar Purkinje cells and is specifically targeted to parallel fiber synapses, where GluRdelta2 plays important roles in synaptic plasticity, motor learning and synapse formation. Here, we investigated the mechanism of GluRdelta2 sorting using MDCK epithelial cells. Immunocytochemical analysis of subcellular localization showed that GluRdelta2 expressed in MDCK cells was predominantly distributed in the plasma membrane. By examining the subcellular localization of GluRdelta2 mutants with various deletions in the carboxyl-terminal cytoplasmic region, we identified J segment adjacent to transmembrane segment M4 as a key region for the efficient targeting of GluRdelta2 to the plasma membrane. On the other hand, the carboxyl terminus of GluRdelta2 essential for interaction with PDZ domain proteins was dispensable for the plasma membrane localization. Our results suggest that the juxtamembrane segment and the PDZ domain target site at the carboxyl terminus of GluRdelta2 play differential roles in plasma membrane targeting, synapse localization and signal transduction.

Animals↗
PubMed2005

Targeting neurite growth inhibitors to induce CNS regeneration.

Prominent among the several endogenous inhibitors known to limit recovery and plasticity after CNS injury are Nogo (neurite outgrowth inhibitor) and MAG (myelin associated glycoprotein). The effects of these inhibitors on axonal regeneration can be reduced by administration of specific antagonists, some of which are commercially available for experimental investigation. There are three aspects of therapeutic manipulations: targeting the inhibitory proteins, antagonizing the known receptor, and inhibiting the intracellular signal transduction of these inhibitory molecules. Infusion of an antibody against Nogo improves behavioral deficits and enhances corticospinal tract regeneration in animals after stroke and spinal cord injury (SCI). Similarly, peripheral injection of a mouse monoclonal antibody directed against MAG results in dramatic preferential motor reinnervation in mice after transection of the femoral nerve, indicating that interference with the repellant function of MAG facilitates reinnervation of correct pathways by motor neurons. Further, antagonism of the Nogo receptor by the peptide NEP 1-40 (Nogo extracellular peptide residues 1-40) can promote axonal regeneration in rats after SCI. Blockade of signal transduction also can be effective. The p75 neurotrophin receptor probably represents the signaling part of the receptor complex for neurite growth inhibitors. There is evidence in vitro that the inhibitory actions of MAG and myelin are blocked if neurons are primed with a variety of neurotrophins. Thus, there are several therapeutic approaches to overcome the actions of endogenous neurite growth inhibitors so as to promote CNS regeneration.

Animals↗
PubMed2026

The genomic alchemist's arsenal: A comprehensive review of gene recruitment, regulatory rewiring, and the evolutionary arms race in snake envenomation.

Snake venom represents a striking example of evolutionary innovation, in which ancestral physiological gene networks have been co-opted into potent biochemical weapons. Advances in multi-omics, single-cell genomics, and structural bioinformatics have catalyzed a conceptual shift from descriptive toxin cataloging to a systems-level understanding of venom evolution, regulation, and function. This Review integrates genomic, cellular, and structural perspectives to delineate the molecular architecture underpinning venom diversification and target-site co-evolution. Emphasis is placed on regulatory mechanisms driving rapid expression plasticity, including super-enhancer activity, transposable element insertion, spatial heterogeneity within the venom gland, and non-coding RNA-mediated modulation. At the protein level, the review examines how hypervariable toxins engage in structural arms races with prey targets, and how multi-toxin complex formation, functional synergy, and molecular dynamics simulations inform models of lethality and resistance. A comparative framework is provided by contrasting high-potency predatory snake venoms with low-potency defensive venoms of hymenopterans such as bees and wasps, revealing how ecological selective pressures shape toxin potency, composition, and target specificity across taxa. Finally, current translational strategies are evaluated, with a focus on the relative merits of recombinant human monoclonal antibodies versus catalytic-site small-molecule inhibitors as deployable interventions for snakebite. By synthesizing evolutionary genomics, structural biology, comparative toxinology, and synthetic antivenomics, this Review outlines a predictive framework for anticipating venom evolutionary trajectories and for designing broad-spectrum, next-generation therapeutics.

Animals↗
PubMed2006

Reversible, activity-dependent targeting of profilin to neuronal nuclei.

The actin cytoskeleton in pyramidal neurons plays a major role in activity-dependent processes underlying neuronal plasticity. The small actin-binding protein profilin shows NMDA receptor-dependent accumulation in dendritic spines, which is correlated with suppression of actin dynamics and long-term stabilization of synaptic morphology. Here we show that following NMDA receptor activation profilin also accumulates in the nucleus of hippocampal neurons via a process involving rearrangement of the actin cytoskeleton. This simultaneous targeting to dendritic spines and the cell nucleus suggests a novel mechanism of neuronal plasticity in which profilin both tags activated synapses and influences nuclear events.

Actins↗
PubMed2006

The extracellular signal-regulated kinase pathway: an emerging promising target for mood stabilizers.

PURPOSE OF REVIEW: There exists a growing appreciation that, though not classical neurodegenerative disorders, severe mood disorders are associated with regional impairments of structural plasticity and cellular resilience. Exciting recent data suggest that synaptic plasticity probably is involved in mechanisms of actions of mood stabilizers and antidepressants. Notably, the extracellular signal-regulated kinase pathway is a critical 'plasticity pathway' in the brain. The present review summarizes neurobiological, pharmacological, and behavioral data on the role of the extracellular signal-regulated kinase pathway in regulating some of the symptoms of bipolar disorder and as a therapeutically relevant target for mood stabilizers. RECENT FINDINGS: The extracellular signal-regulated kinase pathway is known to mediate neurotrophic actions and synaptic plasticity. Treatment with lithium and valproate activates the extracellular signal-regulated kinase pathway in cultured cells and in prefrontal cortex and hippocampus. In addition, lithium or valproate treatment promotes neurogenesis, neurite growth, and cell survival. The extracellular signal-regulated kinase pathway is also targeted by antipsychotics. Modulation of the central nervous system extracellular signal-regulated kinase pathway induces animal behavioral alterations reminiscent of manic symptoms; these complex behaviors probably depend on the effects of extracellular signal-regulated kinase on discrete brain regions and the presence of other interacting molecules. SUMMARY: The extracellular signal-regulated kinase pathway may represent a novel target for the development of improved therapeutics for bipolar disorder.

Animals↗
PubMed2006

Study of ultraintense laser-produced fast-electron propagation and filamentation in insulator and metal foil targets by optical emission diagnostics.

The transport of an intense electron beam produced by ultrahigh intensity laser pulses through metals and insulators has been studied by high resolution imaging of the optical emission from the targets. In metals, the emission is mainly due to coherent transition radiation, while in plastic, it is due to the Cerenkov effect and it is orders of magnitude larger. It is also observed that in the case of insulators the fast-electron beam undergoes strong filamentation and the number of filaments increases with the target thickness. This filamented behavior in insulators is due to the instability of the ionization front related to the electric field ionization process. The filamentary structures characteristic growth rate and characteristic transversal scale are in agreement with analytical predictions.

Journal Article↗
PubMed1997

Molecular genetic analysis of synaptic plasticity, activity-dependent neural development, learning, and memory in the mammalian brain.

Recently, dozens of mutant mice generated with gene targeting or transgenic technologies have been shown to exhibit a distinct set of impairments in the brain and behavior. In this review, we discuss how studies of mutant mice have helped elucidate the mechanisms that underlie synaptic plasticity and the relationship of these synaptic mechanisms to the activity-dependent phase of neural development and learning and memory. We focus on the recent progress in the analysis of whisker-related pattern formation, elimination of climbing fibers, long-term potentiation, long-term depression, and various learning and memory tasks in mutant mice.

Animals↗
PubMed1998

Regulation of neuronal plasticity in the central nervous system by phosphorylation and dephosphorylation.

Neuronal plasticity can be defined as adaptive changes in structure and function of the nervous system, an obvious example of which is the capacity to remember and learn. Long-term potentiation and long-term depression are the experimental models of memory in the central nervous system (CNS), and have been frequently utilized for the analysis of the molecular mechanisms of memory formation. Extensive studies have demonstrated that various kinases and phosphatases regulate neuronal plasticity by phosphorylating and dephosphorylating proteins essential to the basic processes of adaptive changes in the CNS. These proteins include receptors, ion channels, synaptic vesicle proteins, and nuclear proteins. Multifunctional kinases (cAMP-dependent protein kinase, Ca2+/phospholipid-dependent protein kinase, and Ca2+/calmodulin-dependent protein kinases) and phosphatases (calcineurin, protein phosphatases 1, and 2A) that specifically modulate the phosphorylation status of neuronal-signaling proteins have been shown to be required for neuronal plasticity. In general, kinases are involved in upregulation of the activity of target substrates, and phosphatases downregulate them. Although this rule is applicable in most of the cases studied, there are also a number of exceptions. A variety of regulation mechanisms via phosphorylation and dephosphorylation mediated by multiple kinases and phosphatases are discussed.

Animals↗
PubMed2003

The outs and ins of bacterial type IV secretion substrates.

Bacteria use type IV secretion systems (T4SS) to translocate macromolecular substrates destined for bacterial, plant or human target cells. The T4SS are medically important, contributing to virulence-gene spread, genome plasticity and the alteration of host cellular processes during infection. The T4SS are ancestrally related to bacterial conjugation machines, but present-day functions include (i) conjugal transfer of DNA by cell-to-cell contact, (ii) translocation of effector molecules to eukaryotic target cells, and (iii) DNA uptake from or release to the extracellular milieu. Rapid progress has been made toward identification of type IV secretion substrates and the requirements for substrate recognition.

Bacterial Proteins↗