[show abstract][hide abstract] ABSTRACT: The prevailing view at present is that postsynaptic expression of the classical NMDA receptor-dependent long-term potentiation relies on an increase in the numbers of local AMPA receptors (AMPARs). This is thought to parallel an expansion of postsynaptic cell specializations, for instance dendritic spine heads, which accommodate synaptic receptor proteins. However, glutamate released into the synaptic cleft can normally activate only a hotspot of low-affinity AMPARs that occur in the vicinity of the release site. How the enlargement of the AMPAR pool is causally related to the potentiated AMPAR current remains therefore poorly understood. To understand possible scenarios of postsynaptic potentiation, here we explore a detailed Monte Carlo model of the typical small excitatory synapse. Simulations suggest that approximately 50% increase in the synaptic AMPAR current could be provided by expanding the existing AMPAR pool at the expense of 100-200% new AMPARs added at the same packing density. Alternatively, reducing the inter-receptor distances by only 30-35% could achieve a similar level of current potentiation without any changes in the receptor numbers. The NMDA receptor current also appears sensitive to the NMDA receptor crowding. Our observations provide a quantitative framework for understanding the 'resource-efficient' ways to enact use-dependent changes in the architecture of central synapses.
Philosophical Transactions of The Royal Society B Biological Sciences 01/2014; 369(1633):20130167.
[show abstract][hide abstract] ABSTRACT: Introduction
In order to define the pathophysiology underlying development of peripheral neuropathies, it is important to understand the excitability effects produced by alterations in membrane potential. Sensory and motor axons display different biophysical properties which are likely to affect their responsiveness to membrane potential changes.
To provide a template for the effects of membrane potential changes on sensory and motor axonal excitability.
Sensory and motor nerve excitability studies were recorded using threshold tracking techniques and QTracS software in six participants (mean age 31 ± 2 years). The median nerve was stimulated at the wrist, with both CMAPs and CSAPs recorded. A standard axonal excitability protocol was conducted, including assessment of strength–duration properties, threshold electrotonus, recovery cycle and current-threshold relationship. DC currents set to ±50% of the baseline rheobasic current were utilised to ensure comparability between motor and sensory axons.
As previously reported for motor axons, polarization had significant effects on axonal excitability. The overall pattern of excitability change was similar between motor and sensory axons – with depolarizing currents producing reduced threshold change in threshold electrotonus, upwards shift of the recovery cycle and reduced inward rectification in the current-threshold relationship. Effects on threshold electrotonus were more prominent in motor axons, with more significant reduction in threshold change to depolarizing and hyperpolarizing currents (TEd90ms; Depolarization: Motor: 46 ± 5%; Sensory: 23 ± 3%; P < .01; Hyperpolarization: Motor: −31 ± 2%; Sensory: −24 ± 2%; P < .05). By contrast, effects of hyperpolarization on measures associated with the hyperpolarization-activated cation conductance Ih were similar for motor and sensory axons (TEh70%peak: Motor: 18 ± 6%; Sensory 20 ± 4%; Hyperpolarizing IV drift – Motor: −4 ± 2%; Sensory: 7 ± 4%).
These findings provide a template for the differential interpretation of excitability changes associated with membrane potential change in sensory and motor neuropathies.
[show abstract][hide abstract] ABSTRACT: Decision-making involves two fundamental axes of control namely valence, spanning reward and punishment, and action, spanning invigoration and inhibition. We recently exploited a go/no-go task whose contingencies explicitly decouple valence and action to show that these axes are inextricably coupled during learning. This results in a disadvantage in learning to go to avoid punishment and in learning to no-go to obtain a reward. The neuromodulators dopamine and serotonin are likely to play a role in these asymmetries: Dopamine signals anticipation of future rewards and is also involved in an invigoration of motor responses leading to reward, but it also arbitrates between different forms of control. Conversely, serotonin is implicated in motor inhibition and punishment processing.
To investigate the role of dopamine and serotonin in the interaction between action and valence during learning.
We combined computational modeling with pharmacological manipulation in 90 healthy human volunteers, using levodopa and citalopram to affect dopamine and serotonin, respectively.
We found that, after administration of levodopa, action learning was less affected by outcome valence when compared with the placebo and citalopram groups. This highlights in this context a predominant effect of levodopa in controlling the balance between different forms of control. Citalopram had distinct effects, increasing participants' tendency to perform active responses independent of outcome valence, consistent with a role in decreasing motor inhibition.
Our findings highlight the rich complexities of the roles played by dopamine and serotonin during instrumental learning.
[show abstract][hide abstract] ABSTRACT: Action inhibition can globally prevent all motor output or selectively cancel specific actions during concurrent motor output. Here we examine the behavioral and neural basis of selective inhibition focusing on the role of preparation. In 18 healthy human participants we manipulated the extent to which they could prepare for selective inhibition by providing or withholding information on what actions might need to be stopped. We show that, on average, information improves both speed and selectivity of inhibition. Functional magnetic resonance imaging data show that preparation for selective inhibition engages the inferior frontal gyrus, supplementary motor area, and striatum. Examining interindividual differences, we find the benefit of proactive control to speed and selectivity of inhibition trade off against each other, such that an improvement in stopping speed leads to a deterioration of selectivity of inhibition, and vice versa. This trade-off is implemented through engagement of the dorsolateral prefrontal cortex and putamen. Our results suggest proactive selective inhibition is implemented within frontostriatal structures, and we provide evidence that a speed-selectivity trade-off might underlie a range of findings reported previously.
[show abstract][hide abstract] ABSTRACT: Amnesic patients with bilateral hippocampal damage sustained in adulthood are generally unable to construct scenes in their imagination. By contrast, patients with developmental amnesia (DA), where hippocampal damage was acquired early in life, have preserved performance on this task, although the reason for this sparing is unclear. One possibility is that residual function in remnant hippocampal tissue is sufficient to support basic scene construction in DA. Such a situation was found in the one amnesic patient with adult-acquired hippocampal damage (P01) who could also construct scenes. Alternatively, DA patients' scene construction might not depend on the hippocampus, perhaps being instead reliant on non-hippocampal regions and mediated by semantic knowledge. To adjudicate between these two possibilities, we examined scene construction during functional MRI (fMRI) in Jon, a well-characterised patient with DA who has previously been shown to have preserved scene construction. We found that when Jon constructed scenes he activated many of the regions known to be associated with imagining scenes in control participants including ventromedial prefrontal cortex, posterior cingulate, retrosplenial and posterior parietal cortices. Critically, however, activity was not increased in Jon's remnant hippocampal tissue. Direct comparisons with a group of control participants and patient P01, confirmed that they activated their right hippocampus more than Jon. Our results show that a type of non-hippocampal dependent scene construction is possible and occurs in DA, perhaps mediated by semantic memory, which does not appear to involve the vivid visualisation of imagined scenes.
[show abstract][hide abstract] ABSTRACT: In progressive Multiple Sclerosis (MS), there is no proven therapy for preventing accumulation of irreversible disability. The pathological substrate of irreversible disability in MS is neuroaxonal loss, and brain tissue volume loss on MRI can infer such pathology. There is experimental evidence to suggest that cannabinoids may have a neuroprotective and anti-inflammatory effect, although in a recent UK clinical trial (CUPID), oral cannabinoid did not slow the development of disability in progressive MS compared with placebo.
Using serial MRI brain scans obtained during the CUPID trial, we compared oral Delta 9-tetrahydrocannabinol (Δ9-THC) versus placebo for the following: (i) rates of new T2 hyperintense and new T1 hypointense lesions, and (ii) rate of brain atrophy.
A subset of progressive MS patients from the CUPID trial, who were randomised to either Δ9-THC or placebo, were followed up for 3 years with MRI scans at 4 time points: baseline, and years 1, 2 and 3. MRI sequences included axial dual echo, fast (turbo) spin echo proton density and T2 weighted scans, as well as a conventional T1 weighted spin echo scan. 46 contiguous 3 mm thick axial slices were performed for each acquisition. Scans from each time point were compared with the immediately preceding scan. New T2 lesions and new T1 lesions were marked by review of the electronic data using imaging software application JIM 6.0. If a scan had been missed, comparison was made with the last scan performed. Normalised brain volume (NBV) was estimated with SIENAX. Two-time-point percentage brain volume change (PBVC) was estimated with SIENA for three time-point pairs: baseline to year 1, year 1 to year 2, and year 2 to year 3.
273 patients were entered into the sub-study. 182 (67%) received active treatment, and 91 (33%) received placebo. 45 subjects missed one or more scan. Those that only had the baseline scan were excluded from all further analyses. Losses to follow up were 27 at 1 year, 18 at 2 years, and 18 at 3 years. 32 patients did not have a baseline NBV. There was no evidence of an association between treatment group and number of new T1 lesions or T2 lesions, at any of the three time-point pairs (new T1 lesions: baseline to year 1 p=0.99, year 1 to year 2 p=0.17, year 2 to year 3 p=0.90; new T2 lesions: baseline to year 1 p=0.55, year 1 to year 2 p=0.076, year 2 to year 3 p=0.90). Mean baseline NBV was 1420ml (SD 89.02) for all subjects, with no significant difference between the arms (p=0.7). At each of the three time-point pairs, there was no evidence of a difference in mean PBVC between active and placebo arms (baseline to year 1: active -0.60%, placebo -0.59%, p=0.93; year 1 to year 2: active -0.58%, placebo -0.65%, p=0.62; year 2 to year 3: active -0.88%, placebo -0.76%, p=0.39).
Δ9-THC was not better than placebo at reducing the rates of new T1 or T2 lesions or brain atrophy in patients with progressive MS.
Journal of neurology, neurosurgery, and psychiatry 11/2013; 84(11):e2.
[show abstract][hide abstract] ABSTRACT: Neuropeptides play an important role in modulating seizures and epilepsy. Unlike neurotransmitters which operate on a millisecond time-scale, neuropeptides have longer half lives; this leads to modulation of neuronal and network activity over prolonged periods, so contributing to setting the seizure threshold. Most neuropeptides are stored in large dense vesicles and co-localize with inhibitory interneurons. They are released upon high frequency stimulation making them attractive targets for modulation of seizures, during which high frequency discharges occur. Numerous neuropeptides have been implicated in epilepsy; one, ACTH, is already used in clinical practice to suppress seizures. Here, we concentrate on neuropeptides that have a direct effect on seizures, and for which therapeutic interventions are being developed. We have thus reviewed the abundant reports that support a role for neuropeptide Y (NPY), galanin, ghrelin, somatostatin and dynorphin in suppressing seizures and epileptogenesis, and for tachykinins having pro-epileptic effects. Most in vitro and in vivo studies are performed in hippocampal tissue in which receptor expression is usually high, making translation to other brain areas less clear. We highlight recent therapeutic strategies to treat epilepsy with neuropeptides, which are based on viral vector technology, and outline how such interventions need to be refined in order to address human disease.
[show abstract][hide abstract] ABSTRACT: The agranular architecture of motor cortex lacks a functional interpretation. Here, we consider a 'predictive coding' account of this unique feature based on asymmetries in hierarchical cortical connections. In sensory cortex, layer 4 (the granular layer) is the target of ascending pathways. We theorise that the operation of predictive coding in the motor system (a process termed 'active inference') provides a principled rationale for the apparent recession of the ascending pathway in motor cortex. The extension of this theory to interlaminar circuitry also accounts for a sub-class of 'mirror neuron' in motor cortex - whose activity is suppressed when observing an action -explaining how predictive coding can gate hierarchical processing to switch between perception and action.
[show abstract][hide abstract] ABSTRACT: Introduction: Skeletal muscle channelopathies are rare disorders of muscle membrane excitability. Their episodic nature may result in diagnostic difficulty and delays in diagnosis. Advances in diagnostic clinical electrophysiology combined with DNA-based diagnosis have improved diagnostic accuracy and efficiency. Ascribing pathogenic status to identified genetic variants in muscle channel genes may be complex and functional analysis, including molecular expression, may help with this. Accurate clinical and genetic diagnosis enables genetic counselling, advice regarding prognosis and aids treatment selection. Areas covered: An approach to accurate and efficient diagnosis is outlined. The importance of detailed clinical evaluation including careful history, examination and family history is emphasised. The role of specialised electrodiagnostics combined with DNA testing and molecular expression is considered. New potential biomarkers including muscle MRI using MRC Centre protocols are discussed. Expert opinion: A combined diagnostic approach using careful clinical assessment, specialised neurophysiology and DNA testing will now achieve a clear diagnosis in most patients with muscle channelopathies. An accurate diagnosis enables genetic counselling and provides information regarding prognosis and treatment selection. Genetic analysis often identifies new variants of uncertain significance. In this situation, functional expression studies as part of a diagnostic service will enable determination of pathogenic status of novel genetic variants.
[show abstract][hide abstract] ABSTRACT: Prior experience is critical for decision-making. It enables explicit representation of potential outcomes and provides training to valuation mechanisms. However, we can also make choices in the absence of prior experience by merely imagining the consequences of a new experience. Using functional magnetic resonance imaging repetition suppression in humans, we examined how neuronal representations of novel rewards can be constructed and evaluated. A likely novel experience was constructed by invoking multiple independent memories in hippocampus and medial prefrontal cortex. This construction persisted for only a short time period, during which new associations were observed between the memories for component items. Together, these findings suggest that, in the absence of direct experience, coactivation of multiple relevant memories can provide a training signal to the valuation system that allows the consequences of new experiences to be imagined and acted on.
Nature Neuroscience 09/2013;
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