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Acetylcholine-dependent induction and expression of functional plasticity in the barrel cortex of the adult rat.

The involvement of acetylcholine (ACh) in the induction of neuronal sensory plasticity is well documented. Recently we demonstrated in the somatosensory cortex of the anesthetized rat that ACh is also involved in the expression of neuronal plasticity. Pairing stimulation of the principal whisker at a fixed temporal frequency with ACh iontophoresis induced potentiations of response that required re-application of ACh to be expressed. Here we fully characterize this phenomenon and extend it to stimulation of adjacent whiskers. We show that these ACh-dependent potentiations are cumulative and reversible. When several sensori-cholinergic pairings were applied consecutively with stimulation of the principal whisker, the response at the paired frequency was further increased, demonstrating a cumulative process that could reach saturation levels. The potentiations were specific to the stimulus frequency: if the successive pairings were done at different frequencies, then the potentiation caused by the first pairing was depotentiated, whereas the response to the newly paired frequency was potentiated. During testing, the potentiation of response did not develop immediately on the presentation of the paired frequency during application of ACh: the analysis of the kinetics of the effect indicates that this process requires the sequential presentation of several trains of stimulation at the paired frequency to be expressed. We present evidence that a plasticity with similar characteristics can be induced for responses to stimulation of an adjacent whisker, suggesting that this potentiation could participate in receptive field spatial reorganizations. The spatial and temporal properties of the ACh-dependent plasticity presented here impose specific constraints on the underlying cellular and molecular mechanisms.

Acetylcholine↗

Synaptic plasticity in vitro and in silico: insights into an intracellular signaling maze.

Synaptic plasticity provides a record of neuronal activity and is a likely basis for memory. The early apparent simplicity of the process of synaptic plasticity has been lost in a flood of experimental data that now implicates some 200 signaling molecules in cellular memory. It is now clear that these signaling networks perform surprisingly sophisticated cellular decisions that weigh factors such as input patterns, location of stimulus, history of activity, and context. Computer models have followed experiments into this maze of molecular detail, often matching closely with their experimental counterparts, but perhaps losing simplicity in the process. Here, we suggest that the merger of models and experiment have begun to restore the earlier simplicity by outlining a few key functional roles for signaling networks in synaptic plasticity. In this review, we discuss the current state of understanding of synaptic plasticity in terms of models and experiments.

Animals↗

Neuronal responses across cortical field A1 in plasticity induced by peripheral auditory organ damage.

The adult auditory cortex is capable of a plastic reorganization of its tonotopic map after damage to restricted parts of the cochlear sensory epithelium. We examine the precise conditions of cochlear damage required to demonstrate such plasticity in the primary auditory cortex (A1) of the cat and the changes observed in neuronal responses in the A1 which has reorganized in plasticity of the tonotopic map. From these data we attempt to predict the conditions required for similar plasticity to occur in humans after cochlear damage.

Animals↗

Injury- and use-related plasticity in adult auditory cortex.

After restricted cochlear lesions in adult animals the frequency selectivity of neurons in the cortical region deprived of its normal input by the lesion is changed such that the region is occupied by expanded representations of adjacent (perilesion) frequencies. These changes reflect a dynamic process of reorganization (plasticity) and are not explicable as passive consequences of the lesion. Analogous plasticity of cortical frequency selectivity and organization is seen following behavioural training that enhances the significance of particular acoustic stimuli. The occurrence of injury- and use-related auditory cortical plasticity gives rise to a number of questions relating to the mechanisms involved, the perceptual consequences and functional significance of such plastic changes, and their implications for the central processing of input from prosthetic devices. Evidence relating to these issues is briefly summarized in this review, and the directions of future research are considered.

Auditory Cortex↗

Activity-dependent plasticity in the adult auditory brainstem.

Over the past few years we have studied the plasticity of the adult auditory brainstem in the rat following unilateral changes to the pattern of sensory activation, either by intracochlear electrical stimulation or by deafening. We discovered that modifications to afferent activity induced changes in the molecular composition and cellular morphology throughout the auditory brainstem, including its major centers: the cochlear nucleus complex, the superior olivary complex, and the inferior colliculus. The time window studied ranged from 2 h to over 1 year following induction of changes to afferent activity. The molecular markers employed include the NMDA receptor subunit type 1, the cAMP response element binding protein (CREB), the immediate early gene products c-Fos, c-Jun and Egr-1, the growth and plasticity-associated protein GAP-43 and its mRNA, the calcium binding protein calbindin, the cell adhesion molecule integrin-alpha(1), the microtubule-associated protein MAP-1b, and the neurofilament light chain (NF-L). As a consequence of the specific electrical stimulation of the auditory afferents or the loss of hearing, a cascade of events is triggered that apparently modifies the integrative action and computational abilities of the central auditory system. An attempt is made to relate the diverse phenomena observed to a common molecular signaling network that is suspected to bridge sensory experience to changes in the structure and function of the brain. Eventually, a thorough understanding of these events will be essential for the specific diagnosis of patients, optimal timing for implantation, and suitable parameters for running of a cochlear implant or an auditory brainstem implant in humans. In this report an overview of the results obtained in the past years in our lab is presented, flanked by an introduction into the history of plasticity research and a model proposed for intracellular signal cascades related to activity-dependent plasticity.

Animals↗

Imaging plasticity in cochlear implant patients.

Auditory re-afferentation by cochlear implants (CI) offers a unique opportunity to study directly from within the auditory modality plastic changes taking place at organisational levels up to the supra- or polymodal level. These plastic changes resulting from deafness and chronic electrical stimulation can be studied using modern neuroimaging techniques. In this paper, we review the available techniques and the experimental approaches to human studies of plasticity, we discuss the different forms of plasticity that are associated with cochlear implantation and we point to the interest of imaging studies for providing a prognosis of functional outcome after implantation.

Brain↗

Role of Cdk5 in neuronal signaling, plasticity, and drug abuse.

Functional and structural neuronal plasticity are mediated by a complex network of biochemical signal transduction pathways that control the strength of specific synapses and the formation of new synapses de novo. The neuronal protein kinase Cdk5 has been implicated as being involved in numerous aspects of both functional and structural plasticity through its regulation of signal transduction pathways. In this review the findings of a number of studies are summarized that have advanced our understanding of how Cdk5 may be involved in these processes. We focus on the modulation of protein phosphatase activity in both the hippocampus and basal ganglia, and review findings that indicate Cdk5 is likely to regulate neuronal plasticity in these brain regions. Studies showing involvement of Cdk5 in reward and motor-based plasticity, which are thought to underlie drug abuse, are discussed.

Animals↗

Brain plasticity under cochlear implant stimulation.

The benefit of cochlear implantation crucially depends on the ability of the brain to learn to classify neural activity evoked by the cochlear implant. Brain plasticity is a complex property with massive developmental changes after birth. The present paper reviews the experimental work on auditory plasticity and focuses on the plasticity required for adaptation to cochlear implant stimulation. It reviews the data on developmental sensitive periods in auditory plasticity of hearing, hearing-impaired and deaf, cochlear-implanted, animals. Based on the analysis of the above findings in animals and comparable data from humans, a cochlear implantation within the first 2 years of age is recommended.

Animals↗

Pathophysiology of stroke rehabilitation: the natural course of clinical recovery, use-dependent plasticity and rehabilitative outcome.

Even though the disruption of motor activity and function caused by stroke is at times severe, recovery is often highly dynamic. Recuperation reflects the ability of the neuronal network to adapt. Next to an unmasking of latent network representations, other adaptive processes, such as excitatory metabolic stress, an imbalance in activating and inhibiting transmission, leading to salient hyperexcitability, or the consolidation of novel connections, prime the plastic capabilities of the system. Rehabilitative interventions may modulate mechanisms of neurofunctional plasticity and influence the natural course after stroke, both positively, but potentially also acting detrimentally. Though routine rehabilitative procedures are an integral part of stroke care, evidence as to their effectiveness remains equivocal. The present review describes the natural course of motor recovery, focusing on ischemic stroke, and discusses use- and training-dependent adaptive effects. It complements a prior article which highlighted the pathophysiology of plasticity. Though the interaction between rehabilitation and plasticity remains elusive, an attempt is made to clarify how and to what extent rehabilitative therapy shapes motor recovery.

Brain↗

Synaptic and temporal ensemble interpretation of spike-timing-dependent plasticity.

We postulate that a simple, three-state synaptic switch governs changes in synaptic strength at individual synapses. Under this switch rule, we show that a variety of experimental results on timing-dependent plasticity can emerge from temporal and spatial averaging over multiple synapses and multiple spike pairings. In particular, we show that a critical window for the interaction of pre- and postsynaptic spikes emerges as an ensemble property of the collective system, with individual synapses exhibiting only a minimal form of spike coincidence detection. In addition, we show that a Bienenstock-Cooper-Munro-like, rate-based plasticity rule emerges directly from such a model. This demonstrates that two apparently separate forms of neuronal plasticity can emerge from a much simpler rule governing the plasticity of individual synapses.

Action Potentials↗

Plastics in medical applications.

Plastics are fulfilling a number of critical roles in a variety of medical applications. While some of these are low-technology, throw-away products, many of the applications impose critical requirements as to mechanical performance, chemical resistance, biocompatibility, ability to be sterilized and to remain sterile. By performing capably and reliably in these applications, plastics have found a major outlet, one that offers good opportunities for the present materials as well as for future developments. Numerous challenges remain. The present materials perform, though barely adequately, and superior performance over longer periods of time is an important goal. While off-the-shelf plastics have been used in most medical applications, it is likely that development work will focus on the needs of specific important medical applications. In addition to the usual need for ever decreasing costs and prices, there is the opportunity for materials that possess improved blood compatibility, radiation resistance, and/or in vivo compatibility for improved degradable sutures, coatings for pacemakers, phthalate-free plastics, bags with improved gas impermeability and disposables with controlled degradability.

Biocompatible Materials↗

The use of metal or plastic needles in continuous subcutaneous infusion in a hospice setting.

OBJECTIVES: Battery-driven portable syringe drivers are a convenient method for administering many drugs by continuous subcutaneous infusion (CSCI) to patients who cannot swallow medications. At the St. Clare Hospice, nurses usually use plastic needles to minimize needlestick injury but sometimes have patients transferred to metal needles. This study retrospectively examines this practice and its effectiveness. METHODS: The duration of audit was four months. During this period, there were 40 patients (23 women, 17 men), who required their medications delivered by CSCI. A total number of 74 sites were used. Metal or plastic needle CSCIs connected with one-hour release Graseby Syringe Drivers were used. The syringes were set to deliver 2 mm/hour. The maximum volume syringe used was 50 ml. The data were collected retrospectively. Analysis and results. Sixteen patients (21.6 percent) developed minor complications (13 plastic, three metal). Among them, 16 showed inflammation. Two patients (3.5 percent) showed slight bleeding. Only one patient (1.7 percent) showed local infection (metal). In 14 patients (18.9 percent), the needle was reinserted due to various reasons, including needles pulled out by patients or needles falling out due to unknown reasons. There were no needlestick injuries reported, and the staff members reported that all problems encountered were easy to identify and resolve. CONCLUSION: Plastic needle CSCI prevents needlestick injury and gives minimum distress to the patients. More research is needed to determine the local side effects of drugs used and the strategies to resolve these problems.

Adult↗

Drug interactions with medical plastics.

Knowledge about drug interactions with plastic materials used in medical and surgical practice is at an elementary stage. Information that has appeared so far on the sorption of drugs to intravenous fluid containers, delivery sets, syringes, or other plastic apparatus has highlighted that polyvinyl chloride (PVC) is the major offender in this respect. Fortunately, in only a few cases is this sorption phenomenon and loss of drug from fluid likely to present a clinical hazard; in most instances, methods are available to prevent or overcome the problem, providing it is recognized. Current information suggests that the following drugs may exhibit clinically significant sorption to plastic materials: insulin, glyceryl trinitrate (nitroglycerin), diazepam, chlormethiazole, vitamin A acetate, isosorbide dinitrate, and a miscellaneous group of drugs including some phenothiazines, warfarin sodium, hydralazine hydrochloride, and thiopentone sodium. In addition, chloroquine binds strongly to glass and to cellulose acetate, but seemingly not to plastics. Brief details of these interactions and their management are given, together with some preliminary information and warnings on drug interactions (e.g., epinephrine, rifampicin) with hydrophilic contact lenses. The latter interactions may cause irreversible coloration of the lenses.

Adsorption↗

In vitro evaluation of bleomycin-induced cell lethality from plastic and glass containers.

To optimize cancer chemotherapy, a considerable amount of research has been expended to study pharmacologic, pharmacokinetic, biochemical, and pharmaceutic properties of antineoplastic agents. However, published data on the stability and compatibility of these agents in various administration fluids and containers are few in number. Evidence of a significant decrease in stability as shown by high-performance liquid chromatography has been reported when bleomycin was infused in plastic containers for prolonged periods (over 24 hours) as compared with the same procedure with glass containers. Because administration of bleomycin is usually given as a continuous infusion, we undertook this study to determine whether the drug loss of stability that occurs in plastic containers results in a therapeutic loss of efficacy (cytotoxicity). By using a tumor stem-cell assay we compared the quantitative effects of bleomycin in plastic and glass containers on cell lethality. The results from our assay showed no significant difference in cell lethality by bleomycin from its aqueous solution stored in glass and plastic containers over the time periods observed. If these results had been statistically significant, the tumor stem-cell assay may have been shown to be a more sensitive means of determining the clinical significance of these stability studies.

Bleomycin↗

Symptoms and signs caused by neural plasticity.

Plastic changes in the central nervous system are associated with hyperactivity, hypersensitivity, and spread of activity including activation of brain regions that are not typically involved. Symptoms and signs such as neuropathic pain and tinnitus and hyperactive disorders such as muscle spasm and synkinesis may result from such changes in function. Plastic changes that cause symptoms of diseases can be initiated by novel stimulations, overstimulation, or deprivation of input and the induced changes in the function of central nervous system structures may persist and aggravate after these events have ceased if the condition is not reversed. Disorders that are caused by neural plasticity are potentially reversible with treatment. However, the absence of morphologic abnormalities makes diagnosis of these conditions difficult and their treatment has been hampered by lack of understanding of their pathophysiology. Here the role of neural plasticity in the pathophysiology of several disorders is reviewed.

Animals↗

Pain-related synaptic plasticity in spinal dorsal horn neurons: role of CGRP.

BACKGROUND: The synaptic and cellular mechanisms of pain-related central sensitization in the spinal cord are not fully understood yet. Calcitonin gene-related peptide (CGRP) has been identified as an important molecule in spinal nociceptive processing and ensuing behavioral responses, but its contribution to synaptic plasticity, cellular mechanisms and site of action in the spinal cord remain to be determined. Here we address the role of CGRP in synaptic plasticity in the spinal dorsal horn in a model of arthritic pain. RESULTS: Whole-cell current- and voltage-clamp recordings were made from substantia gelatinosa (SG) neurons in spinal cord slices from control rats and arthritic rats (> 6 h postinjection of kaolin/carrageenan into the knee). Monosynaptic excitatory postsynaptic currents (EPSCs) were evoked by electrical stimulation of afferents in the dorsal root near the dorsal root entry zone. Neurons in slices from arthritic rats showed increased synaptic transmission and excitability compared to controls. A selective CGRP1 receptor antagonist (CGRP8-37) reversed synaptic plasticity in neurons from arthritic rats but had no significant effect on normal transmission. CGRP facilitated synaptic transmission in the arthritis pain model more strongly than under normal conditions where both facilitatory and inhibitory effects were observed. CGRP also increased neuronal excitability. Miniature EPSC analysis suggested a post- rather than pre-synaptic mechanism of CGRP action. CONCLUSION: This study is the first to show synaptic plasticity in the spinal dorsal horn in a model of arthritic pain that involves a postsynaptic action of CGRP on SG neurons.

Action Potentials↗

PVC-plasticizer DEHP in medical products: do thin coatings really reduce DEHP leaching into blood?

The hemocompatibility of artificial surfaces in extracorporeal blood circulation systems can be improved by coatings. According to the literature, heparin coatings should avoid the leaching of the plasticizer di(2-ethylhexyl) phthalate (DEHP) into the blood from components made from plasticized polyvinyl chloride (PVC). DEHP and its metabolites are known to impair the fertility of male rodents; effects on human fertility are assumed. Three different surface coatings with and without heparin were examined in a Chandler Loop model at 37 degrees C using fresh human blood to evaluate their hemocompatibility and barrier property to plasticizer. The levels of toxic oxidation products of DEHP generated in the blood, particularly, were found as high as in the uncoated tubing. The coatings improved the hemocompatibility, but are not safe protection against the hazardous metabolites of DEHP. For pregnant women, neonates and children, we would recommend using the available surface-coated plasticized PVC tubing sets, but free of DEHP.

Anticoagulants↗

Plastic control of striatal glutamatergic transmission by ensemble actions of several neurotransmitters and targets for drugs of abuse.

Long-lasting alterations in the efficacy of glutamatergic synapses, such as long-term potentiation (LTP) and long-term depression (LTD), are prominent models for mechanisms of information storage in the brain. It has been suggested that exposure to drugs of abuse produces synaptic plasticity at glutamatergic synapses that shares many features with LTP and LTD, and that these synaptic changes may play roles in addiction. We have examined the involvement of particular neurotransmitters in synaptic plasticity at glutamatergic synapses within the striatum, a brain region with prominent roles in initiation and sequencing of actions, as well as habit formation. Our studies indicate that multiple neurotransmitters interact to produce striatal synaptic plasticity, and that the relative strength and patterning of the afferent inputs that release the various neurotransmitters determines whether LTP or LTD is activated. Drugs of abuse interact with glutamatergic synaptic plasticity in multiple ways, including alterations in dopamine release and more direct effects on glutamate release and glutamate receptors. We hypothesize that these effects contribute to addiction by facilitating the formation of new, drug-centered habits, and by disruption of more adaptive behaviors.

Animals↗