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Analysis of saccadic short-term plasticity in three dimensions.

The capacity for short-term adaptation is a well-established property of the horizontal (H) and vertical (V) components of saccades. It allows these directional components, which clearly serve the goal of foveation, to maintain their precision even under changing circumstances. Torsional (T) saccade components, on the other hand, which deal with the orientation of the target on the fovea, have hardly been investigated in adaptation experiments. They appear to be severely restricted by Listing's law during fixations and saccades. The main purpose of Listing's law is far from obvious but could be visual or oculomotor. Better knowledge of the adaptive capacity of the saccadic system in the torsional direction could throw new light on the functional significance of this interesting neural strategy. To study short-term plasticity in the torsional components of saccades, binocular 3D-eye positions were measured, using magnetic search coils. Five normal human subjects were instructed to make uni-directional refixation saccades, while they viewed a large visual scene. To induce a change in the torsional component, the complete stimulus was rapidly rotated during these saccades. We thoroughly investigated the torsional responses of the saccadic system, to see if any short-term adaptive response in torsional direction was induced, in which case the notion of a visual purpose for Listing's law would be strengthened. In none of our experiments, however, did we find any clear adaptive response in torsional direction. To further investigate the reliability of this result and to ascertain that our experimental conditions allowed classical gain adaptation, we also did experiments designed to achieve a combination of torsional adaptation and classic gain shortening in one of the directional components. While gain adaptation was very obvious, none of the experiments provided evidence for a short-term effect in torsion. We conclude that our experiments do not support a purely visual basis for Listing's law.

Adaptation, Physiological↗

Repetitive transcranial magnetic stimulation (rTMS): insights into the treatment of Parkinson's disease by cortical stimulation.

Repetitive transcranial magnetic stimulation (rTMS) is a potent tool that can be used to modify activity of targeted cortical areas. Significant clinical effects have been obtained in patients with Parkinson's disease (PD) by stimulating different cortical regions with rTMS at inhibitory (low) or excitatory (high) frequency. These effects were thought to result from plastic changes in motor cortical networks. Actually cortical dysfunction has been documented in PD by neuroimaging and neurophysiologic studies showing either hypo- or hyper-activation of various brain areas. In addition, cortical excitability studies using transcranial magnetic stimulation disclosed significant alterations in intracortical facilitatory or inhibitory processes according to the resting state or to phases of movement preparation or execution. These observations clearly support the therapeutic potential of cortical neuromodulation in PD. Motor cortex stimulation could impact on any station within the cortico-basal ganglia-thalamo-cortical loops that are involved in motor control, providing alleviation of parkinsonian symptoms. Depending on the target, cortical stimulation might improve motor performance or other symptoms associated with PD, like depression. Clinical application of rTMS to treat PD patients is limited by the short duration of the effects beyond the time of stimulation, even if long-lasting improvements have been observed after repeated rTMS sessions. In any case, the place of cortical stimulation in the therapeutic management of PD patients remains to be determined, as an alternative or a complementary technique to deep brain stimulation. The rTMS technique could be used to better define the targets and the parameters of stimulation subsequently applied in chronic epidural stimulation.

Cerebral Cortex↗

Roles for NF-kappaB in nerve cell survival, plasticity, and disease.

Here we review evidence of roles for NF-kappaB in the regulation of developmental and synaptic plasticity, and cell survival in physiological and pathological settings. Signaling pathways modulating NF-kappaB activity include those engaged by neurotrophic factors, neurotransmitters, electrical activity, cytokines, and oxidative stress. Emerging findings support a pivotal role for NF-kappaB as a mediator of transcription-dependent enduring changes in the structure and function of neuronal circuits. Distinct subunits of NF-kappaB may uniquely affect cognition and behavior by regulating specific target genes. NF-kappaB activation can prevent the death of neurons by inducing the production of antiapoptotic proteins such as Bcl-2, IAPs and manganese superoxide dismutase (Mn-SOD). Recent findings indicate that NF-kappaB plays important roles in disorders such as epilepsy, stroke, Alzheimer's and Parkinson's diseases, as well as oncogenesis. Molecular pathways upstream and downstream of NF-kappaB in neurons are being elucidated and may provide novel targets for therapeutic intervention in various neurological disorders.

Cell Survival↗

[IP3 receptor, a Ca2+ oscilator--role of IP3 receptor in development and neural plasticity].

IP3 is an important second messenger to release Ca2+ from internal store. IP3receptor (IP3R) works as an IP3 induced Ca2+ release channel and requires IP3 and Ca2+ as coagoinist. We found IP3R is involved in fertilization, meiosis and mitosis by using a specific antibody. We further found that IICR is essential for determination of dorsoventral axis formation. Neuronal type 1 IP3R-deficient mice generated by a gene-targeting technique exhibit a significant reduction of birth rate and abnormal behavior (ataxia and seizure). Long-term depression of the cerebellum was blocked in the type 1 IP3R-deficient mice. Long-term potentiation (LTP) of CA1 hippocampus was enhanced but depotentiation and LTP suppression was reduced in IP3R1-deficient mice. These evidences suggest that IICR is involved in neuronal plasticity. The coupling mechanism between ER Ca2+ stores and plasma membrane store-operated channels is crucial to Ca2+ signaling. Recently we found that IP3R interacts with the TRP3 Ca2+ channel on the plasma membrane and functional coupling of IP3R to TRP3 channel is important for store operated Ca2+ entry. Recently we found that IP3R is involved in determination of polarity and input specificity of activity-induced synaptic modification.

Animals↗

Delayed and remote effects of focal cortical infarctions: secondary damage and reactive plasticity.

Following cortical ischemia, several processes have been identified that occur in remote brain areas: (i) At the lesion border, in partially ischemic areas, inflammatory reactions with invasion of polymorphonuclear leukocytes and T lymphocytes, an immediate activation of microglia, and a delayed invasion of macrophages occur, and neurons in close contact to inflammatory cells show apoptotic cell death. These factors may affect the extent of the ensuing lesion. Leukocytes adhering to the endothelium after expression of cell adhesion molecules have a detrimental effect on reperfusion. (ii) In nonischemic brain areas remote from the lesion, alterations can be caused by electrical or chemical signals emanating from the infarct. Thus activation of astrocytes by spreading depressions probably initiate a partial resistance for further ischemia. (iii) In nonischemic, structurally connected brain areas, diaschisis effects are observed. Both ipsilateral to the lesion as well as contralateral to it an increase of neuronal excitability and a decrease of GABAergic inhibition are observed. This is associated with a down-regulation of GABA receptor binding, and an altered composition of GABA receptors by different subunits. These alterations may favor functional adaptive processes, but may also cause postischemic seizures and neuronal dysfunction. (iv) Adaptive changes in remote brain areas can be influenced by ischemia-induced remote alterations of brain functions. Furthermore, experimentally observed differential activation of NMDA responses may contribute to a differential propensity for adaptive processes in different brain areas. The investigations indicate potential new targets for therapeutic interventions after the first few hours following onset of stroke.

Animals↗

Nuclear calcium-activated gene expression: possible roles in neuronal plasticity and epileptogenesis.

Nuclear calcium signals associated with electrical activation of neurons are critical regulators of gene expression and may cause changes in neuronal structure and function. Recent studies have identified a key component of the transcriptional machinery, the coactivator CREB binding protein (CBP), as a target for a nuclear calcium signalling pathway. Because the regulation of many genes involves transcription factors that function through their interaction with CBP, this mechanism, termed 'the coactivator control model', may modulate the expression of a large number of genes. During normal working of the brain, nuclear calcium increases may be transient and initiate transcriptional responses that are important for learning and memory. However, more intense or sustained stimulations of neurons (for example those used in the kindling model) may overactivate nuclear calcium-regulated processes. This may initiate inappropriate gene expression responses and could lead to the formation of epileptic neuronal circuits and disorders of neuronal excitability.

Animals↗

Actin cytoskeletal dynamics in smooth muscle contraction.

Smooth muscles develop isometric force over a very wide range of cell lengths. The molecular mechanisms of this phenomenon are undefined, but are described as reflecting "mechanical plasticity" of smooth muscle cells. Plasticity is defined here as a persistent change in cell structure or function in response to a change in the environment. Important environmental stimuli that trigger muscle plasticity include chemical (e.g., neurotransmitters, autacoids, and cytokines) and external mechanical signals (e.g., applied stress and strain). Both kinds of signals are probably transduced by ionic and protein kinase signaling cascades to alter gene expression patterns and changes in the cytoskeleton and contractile system. Defining the signaling mechanisms and effector proteins mediating phenotypic and mechanical plasticity of smooth muscles is a major goal in muscle cell biology. Some of the signaling cascades likely to be important include calcium-dependent protein kinases, small GTPases (Rho, Rac, cdc42), Rho kinase, protein kinase C (PKC), Src family tyrosine kinases, mitogen-activated protein (MAP) kinases, and p21 activated protein kinases (PAK). There are many potential targets for these signaling cascades including nuclear processes, metabolic pathways, and structural components of the cytoskeleton. There is growing appreciation of the dynamic nature of the actin cytoskeleton in smooth muscles and the necessity for actin remodeling to occur during contraction. The actin cytoskeleton serves many functions that are probably critical for muscle plasticity including generation and transmission of force vectors, determination of cell shape, and assembly of signal transduction machinery. Evidence is presented showing that actin filaments are dynamic and that actin-associated proteins comprising the contractile element and actin attachment sites are necessary for smooth muscle contraction.

Actins↗

CELISA for rapid screening of monoclonal islet cell surface antibodies using living rat insulinoma cells as target.

An improved rapid cell enzyme-linked immunosorbent assay (CELISA) is described which is suitable for the large scale screening of monoclonal antibodies to islet cell surface antigens. 5 x 10(4) insulin-producing rat insulinoma (RIN) cells were seeded per well in a 96-well flat-bottomed polystyrene plate coated one day before a 0.01% poly-D-lysine solution in PBS. After culture for 4 days in 200 microliters/well RPMI 1640 supplemented with 7.5% heat-inactivated fetal calf serum, the cell number per well was up to 2.1 x 10(5). These monolayer RIN cell cultures were used as a target for the detection of islet cell surface antibodies (ICSA) in the supernatants of hybridomas. The cells were used without fixation to avoid modification of sensitive surface antigens. Poly-D-lysine did not cause non-specific binding of immunoglobulins to the plastic wells as tested with irrelevant monoclonals. The specificity and sensitivity of the method is comparable to indirect immunofluorescence. All mc-ICSA primary screened by indirect immunofluorescence using viable RIN cell suspensions were positive in this CELISA. There was a correlation (r = 0.7; n = 44) between the antibody binding measured by CELISA and the indirect immunofluorescence technique. The advantage of this CELISA is that cell surface structures are well preserved in a viable cell monolayer used as target without chemical fixation. This assay procedure should be generally suitable for the initial screening of monoclonal antibodies to cell surface antigens of cells growing under culture conditions.

Animals↗

A new approach to treatment of resistant gram-positive infections: potential impact of targeted IV to oral switch on length of stay.

BACKGROUND: Patients prescribed intravenous (IV) glycopeptides usually remain in hospital until completion of this treatment. Some of these patients could be discharged earlier if a switch to an oral antibiotic was made. This study was designed to identify the percentage of inpatients currently prescribed IV glycopeptides who could be discharged earlier if a switch to an oral agent was used, and to estimate the number of bed days that could be saved. We also aimed to identify the patient group(s) most likely to benefit, and to estimate the number of days of IV therapy that could be prevented in patients who remained in hospital. METHODS: Patients were included if they were prescribed an IV glycopeptide for 5 days or more. Predetermined IV to oral antibiotic switch criteria and discharge criteria were applied. A multiple logistic regression model was used to identify the characteristics of the patients most likely to be suitable for earlier discharge. RESULTS: Of 211 patients, 62 (29%) could have had a reduced length of stay if they were treated with a suitable oral antibiotic. This would have saved a total of 649 inpatient days (median 5 per patient; range 1-54). A further 31 patients (15%) could have switched to oral therapy as an inpatient thus avoiding IV line use. The patients most likely to be suitable for early discharge were those with skin and soft tissue infection, under the cardiology, cardiothoracic surgery, orthopaedics, general medical, plastic surgery and vascular specialities, with no high risk comorbidity and less than five other regularly prescribed drugs. CONCLUSION: The need for glycopeptide therapy has a significant impact on length of stay. Effective targeting of oral antimicrobials could reduce the need for IV access, allow outpatient treatment and thus reduce the length of stay in patients with infections caused by antibiotic resistant gram-positive bacteria.

Administration, Oral↗

Role of neurotrophins in synapse development and plasticity.

Neurotrophic factors are traditionally viewed as secretory proteins that regulate long-term survival and differentiation of neurons. The role of neurotrophic factors in the structural integrity of the nervous system makes them attractive candidates as therapeutic agents for neurodegenerative diseases. However, the fact that expression of many neurotrophic factors in the central nervous system is rapidly enhanced by neuronal activity suggests a new role for these factors in activity-dependent processes, such as synaptic development and plasticity. A series of recent studies has provided strong evidence for this novel function of neurotrophic factors. The neurotrophin family of proteins has been shown to acutely potentiate synaptic transmission at the neuromuscular junction and in the brain. These factors are also involved in the maturation of the neuromuscular synapses and in the development of synapses in the visual system. Gene targeting and physiological experiments demonstrate that brain-derived neurotrophic factor (BDNF) plays an important role in long-term potentiation (LTP), a cellular model for learning and memory. These findings have brought together two hotly pursued areas of neuroscience, namely, the function of neurotrophic factors and the mechanisms for synaptic plasticity. Continuous studies in this new field will help understand how synapses develop and function in the brain, and may have significant implications in treating learning disorders in both children and adults.

Adult↗

Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression.

There is growing evidence from neuroimaging and ostmortem studies that severe mood disorders, which have traditionally been conceptualized as neurochemical disorders, are associated with impairments of structural plasticity and cellular resilience. It is thus noteworthy that recent preclinical studies have shown that critical molecules in neurotrophic signaling cascades (most notably cyclic adenosine monophosphate [cAMP] response element binding protein, brain-derived neurotrophic factor, bcl-2, and mitogen activated protein [MAP] kinases) are long-term targets for antidepressant agents and antidepressant potentiating modalities. This suggests that effective treatments provide both trophic and neurochemical support, which serves to enhance and maintainnormal synaptic connectivity, thereby allowing the chemical signal to reinstate the optimal functioning of critical circuits necessary for normal affective functioning. For many refractory patients, drugs mimicking "traditional" strategies, which directly or indirectly alter monoaminergic levels, may be of limited benefit. Newer "plasticity enhancing" strategies that may have utility in the treatment of refractory depression include N-methyl-D-aspartate antagonists, alpha-amino-3-hydroxy-5-methylisoxazole propionate (AMPA) potentiators, cAMP phosphodiesterase inhibitors, and glucocorticoid receptor antagonists. Small-molecule agents that regulate the activity f growth factors, MAP kinases cascades, and the bcl-2 family of proteins are also promising future avenues. The development of novel, nonaminergic-based therapeutics holds much promise for improved treatment of severe, refractory mood disorders.

Animals↗

GPR3 in neuro-metabolic-immune-reproductive nexus - a potential therapeutic target for Multi-System diseases.

BACKGROUND: GPR3(G-protein-coupled receptor 3), an orphan G-protein-coupled receptor (GPCR) with constitutive Gs activity, is expressed in the brain, liver, ovary, and other tissues, regulating cell proliferation, differentiation, and apoptosis across the nervous, reproductive, immune, and metabolic systems. This review synthesizes evidence on its integrated signaling and physiological functions to address the lack of a comprehensive multisystem pathophysiology overview. METHODS: A systematic literature search was conducted on PubMed and Web of Science, using keywords such as "GPR3", "GPCR", "neurodegeneration", "metabolism", "immune", "reproduction", "agonist", "inhibitor", and "therapeutic target". This search identified GPR3's roles in neurodegenerative diseases, immune inflammation, reproduction, and energy metabolism. The analysis focused on signaling pathways, ligand regulation, and therapeutic potential. RESULTS: The research indicates that GPR3 is involved in neuronal survival, synaptic plasticity, and microglial activity via the cAMP/PKA, PI3K/Akt, and β - arrestin pathways. It promotes amyloid - β formation in Alzheimer's disease (AD), yet provides neuroprotection in Parkinson's disease (PD) models. It may contribute to anxiety/depression - like states, maintain oocyte meiotic arrest in the ovary, and activate thermogenic genes in adipose tissue. GPR3 modulates immune responses. Using oleic acid (OA) and diphenyleneiodonium (DPI) as activators, and AF64394 and cannabidiol (CBD) as antagonists, it shows potential in disease models. CONCLUSION: GPR3 acts as a central molecular hub integrating neural, metabolic, immune, and reproductive signaling, highlighting its potential as a therapeutic target for chronic multisystem disorders. However, its dual roles in certain pathologies and translation challenges necessitate further research.

Humans↗

Functional requirement for class I MHC in CNS development and plasticity.

Class I major histocompatibility complex (class I MHC) molecules, known to be important for immune responses to antigen, are expressed also by neurons that undergo activity-dependent, long-term structural and synaptic modifications. Here, we show that in mice genetically deficient for cell surface class I MHC or for a class I MHC receptor component, CD3zeta, refinement of connections between retina and central targets during development is incomplete. In the hippocampus of adult mutants, N-methyl-D-aspartate receptor-dependent long-term potentiation (LTP) is enhanced, and long-term depression (LTD) is absent. Specific class I MHC messenger RNAs are expressed by distinct mosaics of neurons, reflecting a potential for diverse neuronal functions. These results demonstrate an important role for these molecules in the activity-dependent remodeling and plasticity of connections in the developing and mature mammalian central nervous system (CNS).

Animals↗

Experience-dependent plasticity without long-term depression by type 2 metabotropic glutamate receptors in developing visual cortex.

Synaptic depression is thought to underlie the loss of cortical responsiveness to an eye deprived of vision. Here, we establish a fundamental role for type 2 metabotropic glutamate receptors (mGluR2) in long-term depression (LTD) of synaptic transmission within primary visual cortex. Direct mGluR2 activation by (2S,2'R,3'R-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) persistently depressed layer 2/3 field potentials in slices of mouse binocular zone when stimulated concomitantly. Chemical LTD was independent of N-methyl-d-aspartate (NMDA) receptors but occluded conventional LTD by low-frequency stimulation, indicating shared downstream events. Antagonists or targeted disruption of mGluR2 conversely prevented LTD induction by electrical low-frequency stimulation to layer 4. In contrast, Schaeffer collateral synapses did not exhibit chemical LTD, revealing hippocampal area CA1, naturally devoid of mGluR2, to be an inappropriate model for neocortical plasticity. Moreover, monocular deprivation remained effective in mice lacking mGluR2, and receptor expression levels were unchanged during the critical period in wild-type mice, indicating that experience-dependent plasticity is independent of LTD induction in visual cortex. Short-term depression that was unaffected by mGluR2 deletion may better reflect circuit refinement in vivo.

Animals↗

B-50 (GAP-43) in the spinal cord caudal to hemisection: indication for lack of intraspinal sprouting in dorsal root axons.

Sprouting of dorsal root axons has been suggested to occur in the mature cat spinal cord caudal to a hemisection at a low thoracic level sparing the dorsal columns. The lesion interrupts supraspinal descending projections, while leaving ascending collaterals of dorsal root axons intact. This hypothesis was re-evaluated by comparing the light and electron microscopic immunoreactivity of B-50 (GAP-43) on both sides of the postulated target regions for sprouting, the intermediate gray and the dorsal horn. The neural-specific phosphoprotein B-50 is involved in regenerative and developmental axonal outgrowth and synaptic plasticity. The light microscopic distribution pattern and density of B-50 immunostaining, measured by quantitative densitometry, were bilaterally symmetrical in all segments below the hemisection 3.5, 8, 14, 21, and 56 days postoperatively, as they were in the intact animal. Ultrastructurally, growth cone-like profiles were not detectable during putative periods of sprouting in regions of interest. After removal of degenerated axon terminals, vacated postsynaptic places appeared to be covered by astrocytic processes. These results indicate that, under the present experimental conditions, sprouting of primary afferents in adult cats is unlikely to be involved in functional plasticity after removal of descending pathways.

Animals↗

cDNA gene expression profile of rat hippocampus after chronic treatment with antidepressant drugs.

BACKGROUND: Chronic antidepressant treatment causes alterations in several hippocampal genes, which participate in neuronal plasticity. However the full picture of their mechanism of action is not known. The advent of genomics enables to identify a broader mechanism of action and identify novel targets for antidepressant development. METHODS: The present study examined the cDNA microarray gene expression profile in the hippocampus induced by chronic antidepressant treatment, in rats exposed to the forced swim test. Animals were treated for 2 weeks with moclobemide, clorgyline and amitriptyline. RESULTS: The three antidepressants significantly reduced immobility in the forced swim test and initiated significant homologous changes in gene expressions. These include up regulation of cAMP response element binding protein and down regulation of corticotrophin releasing hormone. Other gene changes noted were those related to neuropeptides, neurogenesis and synaptogenesis, including synaptophysin and neogenin. Some 89 genes were changed by at least 2 drugs, out of which 53 were changed oppositely by forced swim test. Confirmation of gene changes, have come from real time RT-PCR. CONCLUSIONS: A significant number and homology in gene expression were observed with the three antidepressants. Many of the genes were associated with neurogenesis and synaptogenesis, including synaptophysin and neogenin.

Activating Transcription Factor 1↗

Human intestinal mucosal mononuclear cells exhibit lymphokine-activated killer cell activity.

Previous investigations have shown that mononuclear cells present in human intestinal mucosa possess cytotoxic properties that are unique and different from those of cells circulating in the peripheral blood. We have further explored the cytolytic capacity of human intestinal mucosal mononuclear cells using both phenotypic and functional criteria. Using an immunoperoxidase technique on gut frozen sections, we failed to identify cells bearing surface markers displayed by natural killer cells and recognized by the monoclonal antibodies Leu7, Leu11, and Leu15. Freshly isolated human lamina proprial mononuclear cells (LPMC) were unable to lyse K562 target cells, even after using a variety of experimental conditions which included depletion of adherent cells, fractionation by Percoll gradients or panning with monoclonal antibodies, and treatment with a prostaglandin synthetase inhibitor or interferon-gamma. In contrast, when LPMC were cultured in the presence of the lymphokine interleukin 2 (IL 2), they displayed high levels of cytotoxicity against both K562 and Daudi target cells. Such cytolytic activity appeared after 1 or 2 days of culture, was dependent on the amount of IL 2 added to the cultures, was independent of plastic adherent cells, and could be inhibited by agents that block proliferation. Interferon-gamma, when used under experimental conditions identical to those adopted for IL 2, was unable to induce any significant cytotoxicity by LPMC or enhance the level of killing obtained by stimulation with IL 2 alone. This IL 2-induced, nonspecific cytotoxicity of LPMC probably represents a form of lymphokine-activated killer cell function similar to that recently described for human peripheral blood lymphocytes. In view of the absence of morphologic and functional evidence for natural killer cells in human intestinal mucosa, the phenomenon of lymphokine-activated killer cell activity displayed by LPMC may represent an alternate cytotoxic function potentially relevant to intestinal mucosa immunity.

Adolescent↗