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Plasticity and stability in neuronal output via changes in intrinsic excitability: it's what's inside that counts.

The nervous system faces an extremely difficult task. It must be flexible, both during development and in adult life, so that it can respond to a variety of environmental demands and produce adaptive behavior. At the same time the nervous system must be stable, so that the neural circuits that produce behavior function throughout the lifetime of the animal and that changes produced by learning endure. We are only beginning to understand how neural networks strike a balance between altering individual neurons in the name of plasticity, while maintaining long-term stability in neural system function. The balance of this plasticity and stability in neural networks undoubtedly plays a critical role in the normal functioning of the nervous system. While mechanisms of synaptic plasticity have garnered extensive study over the past three decades, it is only recently that more attention has been turned to plasticity of intrinsic excitability as a key player in neural network function. This review will focus on this emerging area of research that undoubtedly will contribute a great deal to our understanding of the functionality of the nervous system.

Animals↗

Additives in plastics.

The polymers used in plastics are generally harmless. However, they are rarely used in pure form. In almost all commercial plastics, they are "compounded" with monomeric ingredients to improve their processing and end-use performance. In order of total volume used, these monomeric additives may be classified as follows: reinforcing fibers, fillers, and coupling agents; plasticizers; colorants; stabilizers (halogen stabilizers, antioxidants, ultraviolet absorbers, and biological preservatives); processing aids (lubricants, others, and flow controls); flame retardants, peroxides; and antistats. Some information is already available, and much more is needed, on potential toxicity and safe handling of these additives during processing and manufacture of plastics products.

Antioxidants↗

Variations in clinical audit collection: a survey of plastic surgery units across the British Isles.

INTRODUCTION: Clinical audit is a requirement of good medical and surgical practice and is central to the UK Government's plans to modernise the NHS. MATERIALS AND METHODS: A survey was conducted to assess clinical audit data collection and collation within plastic surgery departments across the UK. The survey identified a variety of different data collection and collation methods, with extensive differences between plastic surgery departments. Those responsible for data collection and its funding were also identified by the survey. RESULTS: Results were obtained from 45 plastic surgery departments. Of the 45 departments surveyed, 12 collect data prospectively, whereas 26 units collect data retrospectively. The remaining departments collect data using a combination of methods. Of the units surveyed, 28 collect data on paper-based systems, with only 13 units using electronic applications. The personnel responsible for data collection were identified as being junior doctors. Departments collecting data prospectively do so from a greater number of sources than those collecting data retrospectively. CONCLUSIONS: This survey has focused on plastic surgery. The authors believe that similar results would be obtained from a survey of other surgical specialties. A huge variation in all parameters relating to the collection and collation of clinical audit data is seen. There are few standards within this specialty for data collection. Much work must be done in order to reach targets set by the UK Government.

Data Collection↗

Telemedicine in acute plastic surgical trauma and burns.

BACKGROUND: Telemedicine is a relatively new development within the UK, but is increasingly useful in many areas of medicine including plastic surgery. Plastic surgery centres often work on a hub-and-spoke basis with many district hospitals referring to one tertiary centre. The Queen Victoria Hospital is one such centre receiving calls from more than 28 hospitals in the Southeast of England resulting in approximately 20 referrals a day. OBJECTIVE: A telemedicine system was developed to improve trauma management. This study was designed to establish whether digital images were sufficiently accurate enough to aid decision-making. A store-and-forward telemedicine system was devised and the images of 150 trauma referrals evaluated in terms of injury severity and operative priority by each member of the plastic surgical team. RESULTS: Correlation scores for assessed images were high. Accuracy of "transmitted image" in comparison to injury on examination scored > 97%. Operative priority scores tended to be higher than injury severity. CONCLUSIONS: Telemedicine is an accurate method by which to transfer information on plastic surgical trauma including burns.

Burns↗

Signaling from cAMP/PKA to MAPK and synaptic plasticity.

The facilitation of hippocampus-based, long-lasting synaptic plasticity, which is frequently investigated in model systems such as long-term potentiation (LTP) and in learning paradigms such as the Morris water maze, is associated with several cellular key events: Ca(2+) influx through the N-methyl-D-aspartate (NMDA) receptor, generation of cyclic AMP (cAMP) and activation of protein kinase A (PKA), phosphorylation of mitogen-associated protein kinase (MAPK) and cAMP-response element-binding protein (CREB), and subsequent transcription of plasticity-associated genes. Recently, a signal-transduction cascade from cAMP/PKA to MAPK was discovered, which seems to be neuron-specific and comprises the critical events of hippocampus-based long-term plasticity described here into one single cascade. A major alternative to cAMP/PKA-MAPK signaling are the cascades from Ca(2+) to MAPK via Ras. However, Ras is inhibited by PKA. This article reviews the studies that argue for the existence of two competing pathways, and discusses their implication for the molecular mechanisms underlying synaptic plasticity.

Animals↗

The desirability of using radiopaque plastics in dentistry: a status report. Council on Dental Materials, Instruments, and Equipment.

Radiopacity in dental plastic materials is desirable. Currently, only radiopaque composite restorative materials and one temporary crown material are commercially available. Developments in incorporating radiopacity in other dental polymeric materials should be encouraged. Also, research should be conducted to quantify and standardize radiopacity both in materials and their clinical utilization. No requirement of radiopacity is currently included in any ANSI/ADA Specification applicable to dental plastic materials. However, standard test methods (ASTM Standard F640-79) have been established for radiopacity of plastics for medical use. The Council on Dental Materials, Instruments, and Equipment recommends that appropriate subcommittees of the American National Standards Committee MD156 develop, as quickly as possible, requirements and appropriate test methods to be placed in future revisions of standards covering plastics in dentistry.

Contrast Media↗

Coexistence of reactive plasticity and neurodegeneration in Alzheimer diseased brains.

Alzheimer's disease (AD) is a pathological process characterized by neuron degeneration and, as recently suggested, brain plasticity. In this work, we compared the reactive plasticity in AD brains associated to O-glycosydically linked glycans, recognized by lectins from Amaranthus leucocarpus (ALL) and Macrobrachium rosenbergii (MRL), and the tau neuritic degeneration. The neuritic degenerative process was evaluated by the quantification of aggregated neuritic structures. Lesions were determined using antibodies against hyperphosphorylated-tau (AD2), amyloid-beta, and synaptophysin. In these conditions, we classified and quantified three pathological structures associated to the neuritic degenerative process: 1) Amyloid-beta deposits (AbetaDs), 2) Classic neuritic plaques (NPs), and 3) Dystrophic neurites clusters (DNCs) lacking amyloid-beta deposits. Reactive plasticity structures were constituted by meganeuritic clusters (MCs) and peri-neuronal sprouting in neurons of the CA4 region of the hippocampus, immunoreactive to synaptophysin (exclusively in AD brains) and GAP-43. Besides, MCs were associated to sialylated O-glycosydically linked glycans as determined by positive labeling with ALL and MRL. Considering that these lectins are specific for the synaptic sprouting process in AD, our results suggest the co-occurrence of of several areas of reactive plasticity and neuron degeneration in AD.

Aged↗

Aging and motor learning: a possible role for norepinephrine in cerebellar plasticity.

Norepinephrine is known to act as a neuromodulator in the cerebellar cortex because it can increase the effect of neurotransmitters such as GABA. This neuromodulatory effect of NE is a possible substrate for an effect of NE on cerebellar plasticity. Cerebellar plasticity can be examined by studying the learning of motor skills. A rod walking paradigm is used in our laboratory for such investigations. Learning of this rod walking task is impaired in rats that are depleted of central stores of NE and in rats that have received the beta-adrenergic antagonist propranolol. In addition, in aged rats there is a correlation between the loss of beta-adrenergic receptor mediated neuromodulatory actions of NE in the cerebellum with a decreased ability to learn the rod walking task. Taken together this information supports a role for NE in cerebellar plasticity and suggest that the beta-adrenergic receptor is important for this plasticity.

Aging↗

Potential circuit mechanisms underlying concurrent thalamic and cortical plasticity.

During the last two decades, plastic reorganization of both sensory and motor representations in the adult central nervous system has been demonstrated following a large variety of manipulations, ranging from partial lesions of the sensory receptor surface to modifications in sensory experience (see /14/ for review). Yet, little is known about the neural circuit mechanisms underlying such reorganization process. Despite the difficulty in addressing this issue, recent studies have provided some insights into this fundamental question. Altogether, these studies suggest that the process of plastic reorganization is a system-wide phenomenon, involving both cortical and subcortical representations. Contrary to classical beliefs, recent work also suggests that the final outcome of the reorganization process is not necessarily beneficial, since it can lead to abnormal perceptual experiences /31/, such as the phantom limb sensation, and even pain /31,32/. In this review, we focus on recent insights into the possible circuit mechanisms underlying sensory plasticity and discuss the potential implications of these findings. We then present physiological evidence supporting the view that the process of plasticity observed at the cortical level may reflect simultaneous changes in many subcortical structures.

Animals↗

Plasticity of the hippocampal place cell representation.

The role of the hippocampus in the representation of 'place' has been attributed to the place cells, whose spatially localised firing suggests their participation in forming a cognitive map of the environment. That this map is necessary for spatial memory formation is indicated by the propensity of almost all navigational tasks to be disrupted by hippocampal damage. The hippocampus has also long been implicated in the formation of episodic memories, and the unusually plastic nature of hippocampal synapses testifies to its probable mnemonic role. Arguably, the place cell representation should, if it is to support spatial learning, be modifiable according to known principles of synaptic reorganization. The present article reviews evidence that the place cell representation is indeed plastic, and that its plasticity depends on the same neurobiological mechanisms known to underlie experimentally induced synaptic plasticity. Inferences are drawn regarding the architecture of the spatial representation and the principles by which it is modified. Spatial learning is promising to be the first kind of memory which is completely understood at all levels, from molecular through circuitry to behaviour and beyond.

Animals↗

Optimising plasticity: environmental and training associated factors in transplant-mediated brain repair.

With progressively ageing populations, degeneration of nerve cells of the brain, due to accident or disease, represents one of the major problems for health and welfare in the developed world. The molecular environment in the adult brain promotes stability limiting its ability to regenerate or to repair itself following injury. Cell transplantation aims to repair the nervous system by introducing new cells that can replace the function of the compromised or lost cells. Alternatives to primary embryonic tissue are actively being sought but this is at present the only source that has been shown reliably to survive grafting into the adult brain and spinal cord, connect with the host nervous system, and influence behaviour. Based on animal studies, several clinical trials have now shown that embryonic tissue grafts can partially alleviate symptoms in Parkinson's disease, and related strategies are under evaluation for Huntington's disease, spinal cord injury, stroke and other CNS disorders. The adult brain is at its most plastic in the period following injury, offering a window of opportunity for therapeutic intervention. Enriched environment, behavioural experience and grafting can each separately influence neuronal plasticity and recovery of function after brain damage, but the extent to which these factors interact is at present unknown. To improve the outcome following brain damage, transplantation must make use of the endogenous potential for plasticity of both the host and the graft and optimise the external circumstances associated with graft-mediated recovery. Our understanding of mechanisms of brain plasticity subsequent to brain damage needs to be associated with what we know about enhancing intrinsic recovery processes in order to improve neurobiological and surgical strategies for repair at the clinical level. With the proof of principle beginning to emerge from clinical trials, a rich area for innovative research with profound therapeutic application, even broader than the specific context of transplantation, is now opening for investigation.

Animals↗

Chronic oral nicotine normalizes dopaminergic function and synaptic plasticity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned primates.

Our recent studies show that chronic oral nicotine partially protects against striatal damage in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primates. To identify the cellular changes associated with this protective action, we investigated the effects of nicotine treatment on stimulus-evoked dopamine release, dopamine turnover, and synaptic plasticity in striatum from lesioned and unlesioned animals. Monkeys were chronically (6 months) treated with nicotine in the drinking water and subsequently lesioned with the dopaminergic neurotoxin MPTP (6 months) while nicotine was continued. Nigrostriatal damage increased nicotinic acetylcholine receptor (nAChR)-mediated fractional dopamine release from residual terminals, primarily through changes in alpha3*/alpha6* nAChRs. In contrast, fractional receptor-evoked dopamine release was similar to control in unlesioned and lesioned animals with chronic oral nicotine. Long-term nicotine administration also attenuated the enhanced K(+)-evoked fractional dopamine release from synaptosomes of MPTP-lesioned animals, suggesting that nicotine treatment had a generalized effect on dopaminergic function. This premise was further supported by experiments showing that nicotine dosing decreased the elevated dopamine turnover that occurs after nigrostriatal damage. We next investigated changes in synaptic plasticity with lesioning and nicotine treatment. Nicotine treatment alone enhanced synaptic plasticity by lowering the threshold for long-term depression (LTD) in the corticostriatal pathway. MPTP lesioning led to a loss of LTD, a measure of short-term synaptic plasticity. In contrast, LTD was preserved in nicotine-treated lesioned animals. Thus, the present data show that the disruptions in striatal dopaminergic function after nigrostriatal damage were attenuated with chronic nicotine administration. These cellular alterations may underlie the ability of nicotine to maintain/restore normal function with nigrostriatal damage.

Administration, Oral↗

Transcriptional signatures of cellular plasticity in mice lacking the alpha1 subunit of GABAA receptors.

GABAA receptors mediate the majority of inhibitory neurotransmission in the CNS. Genetic deletion of the alpha1 subunit of GABAA receptors results in a loss of alpha1-mediated fast inhibitory currents and a marked reduction in density of GABAA receptors. A grossly normal phenotype of alpha1-deficient mice suggests the presence of neuronal adaptation to these drastic changes at the GABA synapse. We used cDNA microarrays to identify transcriptional fingerprints of cellular plasticity in response to altered GABAergic inhibition in the cerebral cortex and cerebellum of alpha1 mutants. In silico analysis of 982 mutation-regulated transcripts highlighted genes and functional groups involved in regulation of neuronal excitability and synaptic transmission, suggesting an adaptive response of the brain to an altered inhibitory tone. Public gene expression databases permitted identification of subsets of transcripts enriched in excitatory and inhibitory neurons as well as some glial cells, providing evidence for cellular plasticity in individual cell types. Additional analysis linked some transcriptional changes to cellular phenotypes observed in the knock-out mice and suggested several genes, such as the early growth response 1 (Egr1), small GTP binding protein Rac1 (Rac1), neurogranin (Nrgn), sodium channel beta4 subunit (Scn4b), and potassium voltage-gated Kv4.2 channel (Kcnd2) as cell type-specific markers of neuronal plasticity. Furthermore, transcriptional activation of genes enriched in Bergman glia suggests an active role of these astrocytes in synaptic plasticity. Overall, our results suggest that the loss of alpha1-mediated fast inhibition produces diverse transcriptional responses that act to regulate neuronal excitability of individual neurons and stabilize neuronal networks, which may account for the lack of severe abnormalities in alpha1 null mutants.

Animals↗

N-cadherin transsynaptically regulates short-term plasticity at glutamatergic synapses in embryonic stem cell-derived neurons.

The cell adhesion molecule N-cadherin has been proposed to regulate synapse formation in mammalian central neurons. This is based on its synaptic localization enabling alignment of presynaptic and postsynaptic specializations by an adhesion mechanism. However, a potential role of N-cadherin in regulating synaptic transmission has remained elusive. In this paper, a functional analysis of N-cadherin knock-out synapses was enabled by in vitro neuronal differentiation of mouse embryonic stem cells circumventing the early embryonic lethality of mice genetically null for N-cadherin. In our in vitro system, initial synapse formation was not altered in the absence of N-cadherin, which might be attributable to compensatory mechanisms. Here, we demonstrate that N-cadherin is required for regulating presynaptic function at glutamatergic synapses. An impairment in the availability of vesicles for exocytosis became apparent selectively during high activity. Short-term plasticity was strongly altered with synaptic depression enhanced in the absence of N-cadherin. Most intriguingly, facilitation was converted to depression under specific stimulation conditions. This indicates an important role of N-cadherin in the control of short-term plasticity. To analyze, whether N-cadherin regulates presynaptic function by a transsynaptic mechanism, we studied chimeric cultures consisting of wild-type neocortical neurons and ES cell-derived neurons. With N-cadherin absent only postsynaptically, we observed a similar increase in short-term synaptic depression as found in its complete absence. This indicates a retrograde control of short-term plasticity by N-cadherin. In summary, our results revealed an unexpected involvement of a synaptic adhesion molecule in the regulation of short-term plasticity at glutamatergic synapses.

Animals↗

Nogo receptor antagonism promotes stroke recovery by enhancing axonal plasticity.

After ischemic stroke, partial recovery of function frequently occurs and may depend on the plasticity of axonal connections. Here, we examine whether blockade of the Nogo-NogoReceptor (NgR) pathway might enhance axonal sprouting and thereby recovery after focal brain infarction. Mutant mice lacking NgR or Nogo-AB recover complex motor function after stroke more completely than do control animals. After a stroke, greater numbers of axons emanating from the undamaged cortex cross the midline to innervate the contralateral red nucleus and the ipsilateral cervical spinal cord; this axonal plasticity is enhanced in ngr -/- or nogo-ab -/- mice. In rats with middle cerebral artery occlusion, both the recovery of motor skills and corticofugal axonal plasticity are promoted by intracerebroventricular administration of a function-blocking NgR fragment. Behavioral improvement occurs when therapy is initiated 1 week after arterial occlusion. Thus, delayed pharmacological blockade of the NgR promotes subacute stroke recovery by facilitating axonal plasticity.

Animals↗

Enduring critical period plasticity visualized by transcranial flavoprotein imaging in mouse primary visual cortex.

Experience-dependent plasticity in the visual cortex was investigated using transcranial flavoprotein fluorescence imaging in mice anesthetized with urethane. On- and off-responses in the primary visual cortex were elicited by visual stimuli. Fluorescence responses and field potentials elicited by grating patterns decreased similarly as contrasts of visual stimuli were reduced. Fluorescence responses also decreased as spatial frequency of grating stimuli increased. Compared with intrinsic signal imaging in the same mice, fluorescence imaging showed faster responses with approximately 10 times larger signal changes. Retinotopic maps in the primary visual cortex and area LM were constructed using fluorescence imaging. After monocular deprivation (MD) of 4 d starting from postnatal day 28 (P28), deprived eye responses were suppressed compared with nondeprived eye responses in the binocular zone but not in the monocular zone. Imaging faithfully recapitulated a critical period for plasticity with maximal effects of MD observed around P28 and not in adulthood even under urethane anesthesia. Visual responses were compared before and after MD in the same mice, in which the skull was covered with clear acrylic dental resin. Deprived eye responses decreased after MD, whereas nondeprived eye responses increased. Effects of MD during a critical period were tested 2 weeks after reopening of the deprived eye. Significant ocular dominance plasticity was observed in responses elicited by moving grating patterns, but no long-lasting effect was found in visual responses elicited by light-emitting diode light stimuli. The present results indicate that transcranial flavoprotein fluorescence imaging is a powerful tool for investigating experience-dependent plasticity in the mouse visual cortex.

Animals↗

Requirement for the RIIbeta isoform of PKA, but not calcium-stimulated adenylyl cyclase, in visual cortical plasticity.

The cAMP-dependent protein kinase (PKA) signaling pathway plays a key role in visual cortical plasticity. Inhibitors that block activation of all PKA regulatory subunits (RIalpha,RIbeta, RIIalpha, RIIbeta) abolish long-term potentiation (LTP) and long-term depression (LTD) in vitro and ocular dominance plasticity (ODP) in vivo. The details of this signaling cascade, however, including the source of PKA signals and which PKA subunits are involved, are unknown. To investigate these issues we have examined LTP, LTD, and ODP in knock-out mice lacking either the two cortically expressed Ca2+-stimulated adenylyl cyclases (AC1 and AC8) or the predominant neocortical subunit of PKA (RIIbeta). Here we show that plasticity remains intact in AC1/AC8-/- mice, whereas ODP and LTD, but not LTP, are absent in RIIbeta-/- mice. We conclude that (1) plasticity in the visual cortex does not require the activity of known Ca2+-stimulated adenylyl cyclases, (2) the PKA dependence of ODP and LTD, but not LTP, is mediated by RIIbeta-PKA, and (3) multiple isoforms of PKA contribute to LTD.

Adenylyl Cyclases↗

Hunting increases adaptive auditory map plasticity in adult barn owls.

The optic tectum (OT) of barn owls contains topographic maps of auditory and visual space. Barn owls reared with horizontally displacing prismatic spectacles (prisms) acquire a novel auditory space map in the OT that restores alignment with the prismatically displaced visual map. Although juvenile owls readily acquire alternative maps of auditory space as a result of experience, this plasticity is reduced greatly in adults. We tested whether hunting live prey, a natural and critically important behavior for barn owls, increases auditory map plasticity in adult owls. Two groups of naive adult owls were fit with prisms. The first group was fed dead mice during 10 weeks of prism experience, while the second group was required to hunt live prey for an identical period of time. When the owls hunted live prey, auditory maps shifted substantially farther (five times farther, on average) and the consistency of tuning curve shifts within each map increased. Only a short period of time in each day, during which the two groups experienced different conditions, accounts for this effect. In addition, increased map plasticity correlated with behavioral improvements in the owls' ability to strike and capture prey. These results indicate that the experience of hunting dramatically increases adult adaptive plasticity in this pathway.

Acoustic Stimulation↗