Neuroscience_topics
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Neuroscience: CNS disease, pain, brain research, ion channels, synaptic transmission, channelopathies, neuronal network
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Gap Junctions Compensate for Sublinear Dendritic Integration in an Inhibitory Network

Electrically coupled inhibitory interneurons dynamically control network excitability. Yet little is known about how chemical and electrical synapses regulate their activity. Using two-photon glutamate uncaging and dendritic patch-clamp recordings, we found that the dendrites of cerebellar Golgi interneurons acted as passive cables. They conferred distance-dependent sublinear synaptic integration and weakened distal excitatory inputs. Gap junctions were present at a higher density on distal dendrites and contributed substantially to membrane conductance. Depolarization of one Golgi cell increased firing in its neighbors and inclusion of dendritic gap junctions in interneuron network models enabled distal excitatory synapses to drive network activity more effectively. Our results suggest that dendritic gap junctions counteract sublinear dendritic integration by enabling excitatory synaptic charge to spread into the dendrites of neighboring inhibitory interneurons. - Science 2012/03/08

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Calcium-based plasticity model explains sensitivity of synaptic changes to spike pattern, rate, and dendritic location

Calcium-based plasticity model explains sensitivity of synaptic changes to spike pattern, rate, and dendritic location | Neuroscience_topics | Scoop.it

Multiple stimulation protocols have been found to be effective in changing synaptic efficacy by inducing long-term potentiation or depression. In many of those protocols, increases in postsynaptic calcium concentration have been shown to play a crucial role. However, it is still unclear whether and how the dynamics of the postsynaptic calcium alone determine the outcome of synaptic plasticity. Here, we propose a calcium-based model of a synapse in which potentiation and depression are activated above calcium thresholds. We show that this model gives rise to a large diversity of spike timing-dependent plasticity curves, most of which have been observed experimentally in different systems. It accounts quantitatively for plasticity outcomes evoked by protocols involving patterns with variable spike timing and firing rate in hippocampus and neocortex. Furthermore, it allows us to predict that differences in plasticity outcomes in different studies are due to differences in parameters defining the calcium dynamics. The model provides a mechanistic understanding of how various stimulation protocols provoke specific synaptic changes through the dynamics of calcium concentration and thresholds implementing in simplified fashion protein signaling cascades, leading to long-term potentiation and long-term depression. The combination of biophysical realism and analytical tractability makes it the ideal candidate to study plasticity at the synapse, neuron, and network levels. PNAS 109(10), 2012

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Lithium enhances remyelination of peripheral nerves

Lithium enhances remyelination of peripheral nerves | Neuroscience_topics | Scoop.it

Glycogen synthase kinase 3β (GSK3β) inhibitors, especially the mood stabilizer lithium chloride, are also used as neuroprotective or anti-inflammatory agents. We studied the influence of LiCl on the remyelination of peripheral nerves. We showed that the treatment of adult mice with LiCl after facial nerve crush injury stimulated the expression of myelin genes, restored the myelin structure, and accelerated the recovery of whisker movements. LiCl treatment also promoted remyelination of the sciatic nerve after crush. We also demonstrated that peripheral myelin gene MPZ and PMP22 promoter activities, transcripts, and protein levels are stimulated by GSK3β inhibitors (LiCl and SB216763) in Schwann cells as well as in sciatic and facial nerves. LiCl exerts its action in Schwann cells by increasing the amount of β-catenin and provoking its nuclear localization. We showed by ChIP experiments that LiCl treatment drives β-catenin to bind to T-cell factor/lymphoid-enhancer factor response elements identified in myelin genes. Taken together, our findings open perspectives in the treatment of nerve demyelination by administering GSK3β inhibitors such as lithium. - PNAS 109(10), 2012

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Unified quantitative model of AMPA receptor trafficking at synapses

Unified quantitative model of AMPA receptor trafficking at synapses | Neuroscience_topics | Scoop.it

Trafficking of AMPA receptors (AMPARs) plays a key role in synaptic transmission. However, a general framework integrating the two major mechanisms regulating AMPAR delivery at postsynapses (i.e., surface diffusion and internal recycling) is lacking. To this aim, we built a model based on numerical trajectories of individual AMPARs, including free diffusion in the extrasynaptic space, confinement in the synapse, and trapping at the postsynaptic density (PSD) through reversible interactions with scaffold proteins. The AMPAR/scaffold kinetic rates were adjusted by comparing computer simulations to single-particle tracking and fluorescence recovery after photobleaching experiments in primary neurons, in different conditions of synapse density and maturation. The model predicts that the steady-state AMPAR number at synapses is bidirectionally controlled by AMPAR/scaffold binding affinity and PSD size. To reveal the impact of recycling processes in basal conditions and upon synaptic potentiation or depression, spatially and temporally defined exocytic and endocytic events were introduced. The model predicts that local recycling of AMPARs close to the PSD, coupled to short-range surface diffusion, provides rapid control of AMPAR number at synapses. In contrast, because of long-range diffusion limitations, extrasynaptic recycling is intrinsically slower and less synapse-specific. Thus, by discriminating the relative contributions of AMPAR diffusion, trapping, and recycling events on spatial and temporal bases, this model provides unique insights on the dynamic regulation of synaptic strength. - PNAS 109(9)

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A deadly solution

A deadly solution | Neuroscience_topics | Scoop.it

As Big Pharma struggles to find the next blockbuster drug, could nature have some clues? One company thinks so – and they think the key lay in some of the world’s most deadly animals - Laboratory News

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Molecular and biophysical basis of glutamate and trace metal modulation of voltage-gated Cav2.3 calcium channels

Molecular and biophysical basis of glutamate and trace metal modulation of voltage-gated Cav2.3 calcium channels | Neuroscience_topics | Scoop.it

Here, we describe a new mechanism by which glutamate (Glu) and trace metals reciprocally modulate activity of the Cav2.3 channel by profoundly shifting its voltage-dependent gating. We show that zinc and copper, at physiologically relevant concentrations, occupy an extracellular binding site on the surface of Cav2.3 and hold the threshold for activation of these channels in a depolarized voltage range. Abolishing this binding by chelation or the substitution of key amino acid residues in IS1–IS2 (H111) and IS2–IS3 (H179 and H183) loops potentiates Cav2.3 by shifting the voltage dependence of activation toward more negative membrane potentials. We demonstrate that copper regulates the voltage dependence of Cav2.3 by affecting gating charge movements. Thus, in the presence of copper, gating charges transition into the “ON” position slower, delaying activation and reducing the voltage sensitivity of the channel. Overall, our results suggest a new mechanism by which Glu and trace metals transiently modulate voltage-dependent gating of Cav2.3, potentially affecting synaptic transmission and plasticity in the brain. JGP 139(3), 2012

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Autisme: des différences cérébrales visibles dès 6 mois

Autisme: des différences cérébrales visibles dès 6 mois | Neuroscience_topics | Scoop.it
Des différences de développement dans le cerveau d'enfants autistes se manifestent très tôt, révèle une étude, entre 6 mois et 2 ans.
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Grey matter in our brains is increasing – are we evolving?

Grey matter in our brains is increasing – are we evolving? | Neuroscience_topics | Scoop.it
Scientists are finding consistent changes in the amount of grey matter in one specific area of the brain – that responsible for conforming to social pressures.
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Regulation of the ATP-sensitive Potassium Channel Subunit, Kir6.2, by a Ca2+-dependent Protein Kinase C

The activity of ATP-sensitive potassium (KATP) channels is governed by the concentration of intracellular ATP and ADP and is thus responsive to the metabolic status of the cell. Phosphorylation of KATP channels by protein kinase A (PKA) or protein kinase C (PKC) results in the modulation of channel activity and is particularly important in regulating smooth muscle tone. At the molecular level the smooth muscle channel is composed of a sulfonylurea subunit (SUR2B) and a pore-forming subunit Kir6.1 and/or Kir6.2. Previously, Kir6.1/SUR2B channels have been shown to be inhibited by PKC, and Kir6.2/SUR2B channels have been shown to be activated or have no response to PKC. In this study we have examined the modulation of channel complexes formed of the inward rectifier subunit, Kir6.2, and the sulfonylurea subunit, SUR2B. Using a combination of biochemical and electrophysiological techniques we show that this complex can be inhibited by protein kinase C in a Ca2+-dependent manner and that this inhibition is likely to be as a result of internalization. We identify a residue in the distal C terminus of Kir6.2 (Ser-372) whose phosphorylation leads to down-regulation of the channel complex. This inhibitory effect is distinct from activation which is seen with low levels of channel activity. (JBC)

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Two new structures of the human muscarinic acetylcholine receptors (M2, M3)

Two new structures of the human muscarinic acetylcholine receptors (M2, M3) | Neuroscience_topics | Scoop.it

- M2 muscarinic acetylcholine receptor bound to an antagonist http://www.nature.com/nature/journal/v482/n7386/full/nature10753.html 

- Structure and dynamics of the M3 muscarinic acetylcholine receptor http://www.nature.com/nature/journal/v482/n7386/full/nature10867.html

 

Both published in Nature 482 (23 February 2012)

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Anesthésies répétées et troubles de la mémoire

Anesthésies répétées et troubles de la mémoire | Neuroscience_topics | Scoop.it

Le sévoflurane, un agent anesthésique couramment utilisé chez l’homme, entraîne des troubles de la mémoire irréversibles chez la souris après plusieurs administrations. En outre, il déclenche des mécanismes associés à la survenue de la maladie d’Alzheimer. Des travaux publiés dans la revue Anesthesiology qui incitent à mener des études complémentaires chez l’homme, notamment auprès des patients les plus âgés. (INSERM)

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Pain: A new trick for opioids?

Pain: A new trick for opioids? | Neuroscience_topics | Scoop.it

Continuous low doses of opioids such as morphine are often prescribed for the management of severe pain symptoms, but this treatment does not undo the changes in pain signalling pathways that underlie chronic pain. In a new paper published in Science, a team led by Drdla-Schutting and Sandkühler reveals that these drugs have previously undiscovered potential for use in the treatment of chronic pain by showing that an acute high dose of an opioid agonist is able to reverse plasticity at pain-transmitting synapses in the rat spinal cord. (Nature Rev Neuroscience - http://www.nature.com/nrn/journal/v13/n3/full/nrn3190.html)

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Promising New Epilepsy Therapies Featured at 2012 Epilepsy Pipeline Update Conference

Promising New Epilepsy Therapies Featured at 2012 Epilepsy Pipeline Update Conference | Neuroscience_topics | Scoop.it

WASHINGTON, Feb. 21, 2012 /PRNewswire-USNewswire/ -- The Epilepsy Therapy Project (ETP), a non-profit organization whose mission is to accelerate new therapies for people living with epilepsy and seizures, and the parent organization of epilepsy.com, today released presentation highlights from its successful 2012 Epilepsy Pipeline Update Conference held in San Francisco and announced the winner of its "Shark Tank" competition for the most innovative new product idea in epilepsy treatment and care. This year's epilepsy pipeline conference featured a stellar line up of leading drug and device developers, investigators and industry leaders and showcased cutting-edge epilepsy therapies in development, including medical technology and therapeutic products. (...) - sacbee.com

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Discovery of hair-cell roots suggests the brain modulates sound sensitivity

Discovery of hair-cell roots suggests the brain modulates sound sensitivity | Neuroscience_topics | Scoop.it
The hair cells of the inner ear have a previously unknown "root" extension that may allow them to communicate with nerve cells and the brain to regulate sensitivity to sound vibrations and head position, researchers have discovered.
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Rat brains also have a default mode network

Rat brains also have a default mode network | Neuroscience_topics | Scoop.it

The default mode network (DMN) in humans has been suggested to support a variety of cognitive functions and has been implicated in an array of neuropsychological disorders. However, its function(s) remains poorly understood. We show that rats possess a DMN that is broadly similar to the DMNs of nonhuman primates and humans. Our data suggest that, despite the distinct evolutionary paths between rodent and primate brain, a well-organized, intrinsically coherent DMN appears to be a fundamental feature in the mammalian brain whose primary functions might be to integrate multimodal sensory and affective information to guide behavior in anticipation of changing environmental contingencies. - PNAS 109(10), 2012

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Molecular mechanism of pharmacological activation of BK channels

Molecular mechanism of pharmacological activation of BK channels | Neuroscience_topics | Scoop.it

Large-conductance voltage- and Ca2+-activated K+ (Slo1 BK) channels serve numerous cellular functions, and their dysregulation is implicated in various diseases. Drugs activating BK channels therefore bear substantial therapeutic potential, but their deployment has been hindered in part because the mode of action remains obscure. Here we provide mechanistic insight into how the dehydroabietic acid derivative Cym04 activates BK channels. As a representative of NS1619-like BK openers, Cym04 reversibly left-shifts the half-activation voltage of Slo1 BK channels. Using an established allosteric BK gating model, the Cym04 effect can be simulated by a shift of the voltage sensor and the ion conduction gate equilibria toward the activated and open state, respectively. BK activation by Cym04 occurs in a splice variant-specific manner; it does not occur in such Slo1 BK channels using an alternative neuronal exon 9, which codes for the linker connecting the transmembrane segment S6 and the cytosolic RCK1 domain—the S6/RCK linker. In addition, Cym04 does not affect Slo1 BK channels with a two-residue deletion within this linker. Mutagenesis and model-based gating analysis revealed that BK openers, such as Cym04 and NS1619 but not mallotoxin, activate BK channels by functionally interacting with the S6/RCK linker, mimicking site-specific shortening of this purported passive spring, which transmits force from the cytosolic gating ring structure to open the channel's gate.

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Withania somnifera reverses Alzheimer's disease pathology by enhancing low-density lipoprotein receptor-related protein in liver

Withania somnifera reverses Alzheimer's disease pathology by enhancing low-density lipoprotein receptor-related protein in liver | Neuroscience_topics | Scoop.it

A 30-d course of oral administration of a semipurified extract of the root of Withania somnifera consisting predominantly of withanolides and withanosides reversed behavioral deficits, plaque pathology, accumulation of β-amyloid peptides (Aβ) and oligomers in the brains of middle-aged and old APP/PS1 Alzheimer's disease transgenic mice. It was similarly effective in reversing behavioral deficits and plaque load in APPSwInd mice (line J20). The temporal sequence involved an increase in plasma Aβ and a decrease in brain Aβ monomer after 7 d, indicating increased transport of Aβ from the brain to the periphery. Enhanced expression of low-density lipoprotein receptor-related protein (LRP) in brain microvessels and the Aβ-degrading protease neprilysin (NEP) occurred 14–21 d after a substantial decrease in brain Aβ levels. However, significant increase in liver LRP and NEP occurred much earlier, at 7 d, and were accompanied by a rise in plasma sLRP, a peripheral sink for brain Aβ. In WT mice, the extract induced liver, but not brain, LRP and NEP and decreased plasma and brain Aβ, indicating that increase in liver LRP and sLRP occurring independent of Aβ concentration could result in clearance of Aβ. Selective down-regulation of liver LRP, but not NEP, abrogated the therapeutic effects of the extract. The remarkable therapeutic effect of W. somnifera mediated through up-regulation of liver LRP indicates that targeting the periphery offers a unique mechanism for Aβ clearance and reverses the behavioral deficits and pathology seen in Alzheimer's disease models. - PNAS 109(9)

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Computer modelling: Brain in a box

Computer modelling: Brain in a box | Neuroscience_topics | Scoop.it

Henry Markram wants €1 billion to model the entire human brain. Sceptics don't think he should get it. - Nature

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Properties of Ca2+ sparks revealed by four-dimensional confocal imaging of cardiac muscle

Properties of Ca2+ sparks revealed by four-dimensional confocal imaging of cardiac muscle | Neuroscience_topics | Scoop.it

Parameters (amplitude, width, kinetics) of Ca2+ sparks imaged confocally are affected by errors when the spark source is not in focus. To identify sparks that were in focus, we used fast scanning (LSM 5 LIVE; Carl Zeiss) combined with fast piezoelectric focusing to acquire x–y images in three planes at 1-µm separation (x-y-z-t mode). In 3,000 x–y scans in each of 34 membrane-permeabilized cat atrial cardiomyocytes, 6,906 sparks were detected. 767 sparks were in focus. They had greater amplitude, but their spatial width and rise time were similar compared with all sparks recorded. Their distribution of amplitudes had a mode at ΔF/F0 = 0.7. The Ca2+ release current underlying in-focus sparks was 11 pA, requiring 20 to 30 open channels, a number at the high end of earlier estimates. Spark frequency was greater than in earlier imaging studies of permeabilized ventricular cells, suggesting a greater susceptibility to excitation, which could have functional relevance for atrial cells. Ca2+ release flux peaked earlier than the time of peak fluorescence and then decayed, consistent with significant sarcoplasmic reticulum (SR) depletion. The evolution of fluorescence and release flux were strikingly similar for in-focus sparks of different rise time (T). Spark termination involves both depletion of Ca2+ in the SR and channel closure, which may be synchronized by depletion. The observation of similar flux in sparks of different T requires either that channel closure and other termination processes be independent of the determinants of flux (including [Ca2+]SR) or that different channel clusters respond to [Ca2+]SR with different sensitivity.  - JGP 139(3)

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A single GluN2 subunit residue controls NMDA receptor channel properties via intersubunit interaction : Nature Neuroscience

A single GluN2 subunit residue controls NMDA receptor channel properties via intersubunit interaction : Nature Neuroscience | Neuroscience_topics | Scoop.it
The authors investigate the basis of the variations in the channel properties of NMDAR subtypes and report that the specificity of the Mg2+ block, the selective permeability to Ca2+ and the single-channel conductance are all primarily controlled by...
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Does your brain produce new cells?

Does your brain produce new cells? | Neuroscience_topics | Scoop.it

Everyone wants to believe the human brain continues to produce new cells throughout life, but the evidence is thin on the ground and several prominent researchers are sceptical... 

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Deconstructing the Neuropathic Pain Phenotype to Reveal Neural Mechanisms

After nerve injury maladaptive changes can occur in injured sensory neurons and along the entire nociceptive pathway within the CNS, which may lead to spontaneous pain or pain hypersensitivity. The resulting neuropathic pain syndromes present as a complex combination of negative and positive symptoms, which vary enormously from individual to individual. This variation depends on a diversity of underlying pathophysiological changes resulting from the convergence of etiological, genotypic, and environmental factors. The pain phenotype can serve therefore, as a window on underlying pathophysiological neural mechanisms and as a guide for developing personalized pain medicine. Neuron 73(4), 2012

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The neuroethics of non-invasive brain stimulation

The neuroethics of non-invasive brain stimulation | Neuroscience_topics | Scoop.it

Transcranial direct current stimulation (TDCS) is a brain stimulation tool that is portable, painless, inexpensive, apparently safe, and with potential long-term efficacy. Recent results obtained from TDCS experiments offer exciting possibilities for the enhancement and treatment of normal or impaired abilities, respectively. We discuss new neuroethical problems that have emerged from the usage of TDCS, and also focus on one of the most likely future applications of TDCS: enhancing learning and cognition in children with typical and atypical development. - Current Biology

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IRB feed for brain caps

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Opposite effects of fear conditioning and extinction on dendritic spine remodelling

It is generally believed that fear extinction is a form of new learning that inhibits rather than erases previously acquired fear memories. Although this view has gained much support from behavioural and electrophysiological studies the hypothesis that extinction causes the partial erasure of fear memories remains viable. Using transcranial two-photon microscopy, we investigated how neural circuits are modified by fear learning and extinction by examining the formation and elimination of postsynaptic dendritic spines of layer-V pyramidal neurons in the mouse frontal association cortex. Here we show that fear conditioning by pairing an auditory cue with a footshock increases the rate of spine elimination. By contrast, fear extinction by repeated presentation of the same auditory cue without a footshock increases the rate of spine formation. The degrees of spine remodelling induced by fear conditioning and extinction strongly correlate with the expression and extinction of conditioned fear responses, respectively. Notably, spine elimination and formation induced by fear conditioning and extinction occur on the same dendritic branches in a cue- and location-specific manner: cue-specific extinction causes formation of dendritic spines within a distance of two micrometres from spines that were eliminated after fear conditioning. Furthermore, reconditioning preferentially induces elimination of dendritic spines that were formed after extinction. Thus, within vastly complex neuronal networks, fear conditioning, extinction and reconditioning lead to opposing changes at the level of individual synapses. These findings also suggest that fear memory traces are partially erased after extinction. (Nature - http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10792.html?WT.ec_id=NATURE-20120223)

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Mechanisms of CaMKII action in long-term potentiation

Mechanisms of CaMKII action in long-term potentiation | Neuroscience_topics | Scoop.it

Long-term potentiation (LTP) of synaptic strength occurs during learning and can last for long periods, making it a probable mechanism for memory storage. LTP induction results in calcium entry, which activates calcium/calmodulin-dependent protein kinase II (CaMKII). CaMKII subsequently translocates to the synapse, where it binds to NMDA-type glutamate receptors and produces potentiation by phosphorylating principal and auxiliary subunits of AMPA-type glutamate receptors. These processes are all localized to stimulated spines and account for the synapse-specificity of LTP. In the later stages of LTP, CaMKII has a structural role in enlarging and strengthening the synapse. - Nature Reviews Neuroscience 13 (2012)

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