Activation of pro-survival Akt and ERK1/2 signalling pathways underlie the anti-apoptotic effects of flavanones in cortical neurons

There is growing interest in the potential beneficial effects of flavonoids in the aging and diseased brain. We have investigated the potential of the flavanone hesperetin and two of its metabolites, hesperetin-7-O-beta-D-glucuronide and 5-nitro-hesperetin, to inhibit oxidative stress-induced neuronal apoptosis. Exposure of cortical neurons to hydrogen peroxide led to the activation of apoptosis signal-regulating kinase 1 via its de-phosphorylation at Ser963, the phosphorylation of c-jun N-terminal kinase and c-Jun (Ser73) and the activation of caspase 3 and caspase 9. Whilst hesperetin glucuronide failed to exert protection, both hesperetin and 5-nitro-hesperetin were effective at preventing neuronal apoptosis via a mechanism involving the activation/phosphorylation of both Akt/protein kinase B and extracellular signal-regulated kinase 1 and 2 (ERK1/2). Protection against oxidative injury and the activation of Akt and ERK1/2 followed a bell-shaped response and was most apparent at 100 nmol/L concentrations. The activation of ERK1/2 and Akt by flavanones led to the inhibition of the pro-apoptotic proteins, apoptosis signal-regulating kinase 1, by phosphorylation at Ser83 and Bad, by phosphorylation at both Ser136 and Ser112 and to the inhibition of peroxide-induced caspase 9 and caspase 3 activation. Thus, flavanones may protect neurons against oxidative insults via the modulation of neuronal apoptotic machinery.

Champagne wine polyphenols protect primary cortical neurons against peroxynitrite-induced injury

White wines are generally low in polyphenol content as compared to red wines. However, Champagne wines have been shown to contain relatively high amounts of phenolic acids that may exert protective cellular actions in vivo. In this study, we have investigated the potential neuroprotective effects of Champagne wine extracts, and individual phenolics present in these extracts, against peroxynitrite-induced injury. Organic and aqueous Champagne wine extracts exhibited potent neuroprotective activity against peroxynitrite-induced injury at low concentrations (0.1 mu g/mL). This protection appeared to be in part due to the cellular actions of individual components found in the organic extracts, notably tyrosol, caffeic acid, and gallic acid. These phenolics were observed to exert potent neuroprotection at concentrations between 0.1 and 10 mu M. Together, these data suggest that polyphenols present in Champagne wine may induce a neuroprotective effect against oxidative neuronal injury.

(-)Epicatechin stimulates ERK-dependent cyclic AMP response element activity and up-regulates GluR2 in cortical neurons

Emerging evidence suggests that the cellular actions of flavonoids relate not simply to their antioxidant potential but also to the modulation of protein kinase signalling pathways. We investigated in primary cortical neurons, the ability of the flavan-3-ol, (-)epicatechin, and its human metabolites at physiologically relevant concentrations, to stimulate phosphorylation of the transcription factor cAMP-response element binding protein (CREB), a regulator of neuronal viability and synaptic plasticity. (-)Epicatechin at 100-300 nmol/L stimulated a rapid, extracellular signal-regulated kinase (ERK)- and PI3K-dependent, increase in CREB phosphorylation. At micromolar concentrations, stimulation was no longer apparent and at the highest concentration tested (30 mu mol/L) (-)epicatechin was inhibitory. (-)Epicatechin also stimulated ERK and Akt phosphorylation with similar bell-shaped concentration-response characteristics. The human metabolite 3 '-O-methyl-(-)epicatechin was as effective as (-)epicatechin at stimulating ERK phosphorylation, but (-)epicatechin glucuronide was inactive. (-)Epicatechin and 3 '-O-methyl-(-)epicatechin treatments (100 nmol/L) increased CRE-luciferase activity in cortical neurons in a partially ERK-dependent manner, suggesting the potential to increase CREB-mediated gene expression. mRNA levels of the glutamate receptor subunit GluR2 increased by 60%, measured 18 h after a 15 min exposure to (-)epicatechin and this translated into an increase in GluR2 protein. Thus, (-)epicatechin has the potential to increase CREB-regulated gene expression and increase GluR2 levels and thus modulate neurotransmission, plasticity and synaptogenesis.

Coding of visual space during motor preparation: approaching objects rapidly modulate corticospinal excitability in hand-centered coordinates

Defensive behaviors, such as withdrawing your hand to avoid potentially harmful approaching objects, rely on rapid sensorimotor transformations between visual and motor coordinates. We examined the reference frame for coding visual information about objects approaching the hand during motor preparation. Subjects performed a simple visuomanual task while a task-irrelevant distractor ball rapidly approached a location either near to or far from their hand. After the distractor ball appearance, single pulses of transcranial magnetic stimulation were delivered over the subject's primary motor cortex, eliciting motor evoked potentials (MEPs) in their responding hand. MEP amplitude was reduced when the ball approached near the responding hand, both when the hand was on the left and the right of the midline. Strikingly, this suppression occurred very early, at 70-80ms after ball appearance, and was not modified by visual fixation location. Furthermore, it was selective for approaching balls, since static visual distractors did not modulate MEP amplitude. Together with additional behavioral measurements, we provide converging evidence for automatic hand-centered coding of visual space in the human brain.

Motor brain regions are involved in the encoding of delayed intentions: a fMRI study

In studies of prospective memory, recall of the content of delayed intentions is normally excellent, probably because they contain actions that have to be enacted at a later time. Action words encoded for later enactment are more accessible from memory than those encoded for later verbal report [Freeman, J.E., and Ellis, J.A. 2003a. The representation of delayed intentions: A prospective subject-performed task? Journal of Experimental Psychology: Learning, Memory, and Cognition, 29, 976-992.]. As this higher assessibility is lost when the intended actions have to be enacted during encoding, or when a motor interference task is introduced concurrent to intention encoding, Freeman and Ellis suggested that the advantage of to-be-enacted actions is due to additional preparatory motor operations during encoding. Accordingly, in a fMRI study with 10 healthy young participants, we investigated whether motor brain regions are differentially activated during verbal encoding of actions for later enactment with the right hand in contrast to verbal encoding of actions for later verbal report. We included an additional condition of verbal encoding of abstract verbs for later verbal report to investigate whether the semantic motor information inherent in action verbs in contrast to abstract verbs activates motor brain regions different from those involved in the verbal encoding of actions for later enactment. Differential activation for the verbal encoding of to-be-enacted actions in contrast to to-be-reported actions was found in brain regions known to be involved in covert motor preparation for hand movements, i.e. the postcentral gyrus, the precuneus, the dorsal and ventral premotor cortex, the posterior middle temporal gyrus and the inferior parietal lobule. There was no overlap between these brain regions and those differentially activated during the verbal encoding of actions in contrast to abstract verbs for later verbal report. Consequently, the results of this fMRI study suggest the presence of preparatory motor operations during the encoding of delayed intentions requiring a future motor response, which cannot be attributed to semantic information inherent to action verbs. (c) 2006 Elsevier B.V. All rights reserved.

Changing patterns of cognitive-motor interference (CMI) over time during recovery from stroke

Objective: To explore the extent and nature of change in cognitive-motor interference (CMI) among rehabilitating stroke patients who showed dual-task gait decrement at initial assessment. Design: Experimental, with in-subjects, repeated measures design. Setting: Rehabilitation centre for adults with acquired, nonprogressive brain injury. Subjects: Ten patients with unilateral stroke, available for reassessment 1-9 months following their participation in a study of CMI after brain injury. Measures: Median stride duration; mean word generation. Methods: Two x one-minute walking trials, two x one-minute word generation trials, two x one-minute trials of simultaneous walking and word generation; 10-metre walking time; Barthel ADL Scale score. Results: Seven out of ten patients showed reduction over time in dual-task gait decrement. Three out of ten showed reduction in cognitive decrement. Only one showed concomitant reduction in gait and word generation decrement. Conclusion: Extent of CMI during relearning to walk after a stroke reduced over time in the majority of patients. Effects were more evident in improved stride duration than improved cognitive performance. Measures of multiple task performance should be included in assessment for functional recovery.

Determining feature relevance for the grouping of motor unit action potentials through generative topographic mapping

The study of motor unit action potential (MUAP) activity from electrornyographic signals is an important stage on neurological investigations that aim to understand the state of the neuromuscular system. In this context, the identification and clustering of MUAPs that exhibit common characteristics, and the assessment of which data features are most relevant for the definition of such cluster structure are central issues. In this paper, we propose the application of an unsupervised Feature Relevance Determination (FRD) method to the analysis of experimental MUAPs obtained from healthy human subjects. In contrast to approaches that require the knowledge of a priori information from the data, this FRD method is embedded on a constrained mixture model, known as Generative Topographic Mapping, which simultaneously performs clustering and visualization of MUAPs. The experimental results of the analysis of a data set consisting of MUAPs measured from the surface of the First Dorsal Interosseous, a hand muscle, indicate that the MUAP features corresponding to the hyperpolarization period in the physisiological process of generation of muscle fibre action potentials are consistently estimated as the most relevant and, therefore, as those that should be paid preferential attention for the interpretation of the MUAP groupings.

Architecture for neuronal cell control of a mobile robot

It is usually expected that the intelligent controlling mechanism of a robot is a computer system. Research is however now ongoing in which biological neural networks are being cultured and trained to act as the brain of an interactive real world robot - thereby either completely replacing or operating in a cooperative fashion with a computer system. Studying such neural systems can give a distinct insight into biological neural structures and therefore such research has immediate medical implications. In particular, the use of rodent primary dissociated cultured neuronal networks for the control of mobile `animals' (artificial animals, a contraction of animal and materials) is a novel approach to discovering the computational capabilities of networks of biological neurones. A dissociated culture of this nature requires appropriate embodiment in some form, to enable appropriate development in a controlled environment within which appropriate stimuli may be received via sensory data but ultimate influence over motor actions retained. The principal aims of the present research are to assess the computational and learning capacity of dissociated cultured neuronal networks with a view to advancing network level processing of artificial neural networks. This will be approached by the creation of an artificial hybrid system (animal) involving closed loop control of a mobile robot by a dissociated culture of rat neurons. This 'closed loop' interaction with the environment through both sensing and effecting will enable investigation of its learning capacity This paper details the components of the overall animat closed loop system and reports on the evaluation of the results from the experiments being carried out with regard to robot behaviour.

Generative topographic mapping applied to clustering and visualization of motor unit action potentials

The identification and visualization of clusters formed by motor unit action potentials (MUAPs) is an essential step in investigations seeking to explain the control of the neuromuscular system. This work introduces the generative topographic mapping (GTM), a novel machine learning tool, for clustering of MUAPs, and also it extends the GTM technique to provide a way of visualizing MUAPs. The performance of GTM was compared to that of three other clustering methods: the self-organizing map (SOM), a Gaussian mixture model (GMM), and the neural-gas network (NGN). The results, based on the study of experimental MUAPs, showed that the rate of success of both GTM and SOM outperformed that of GMM and NGN, and also that GTM may in practice be used as a principled alternative to the SOM in the study of MUAPs. A visualization tool, which we called GTM grid, was devised for visualization of MUAPs lying in a high-dimensional space. The visualization provided by the GTM grid was compared to that obtained from principal component analysis (PCA). (c) 2005 Elsevier Ireland Ltd. All rights reserved.