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In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus constitutes the central circadian pacemaker. The SCN receives light signals from the retina and controls peripheral circadian clocks (located in the cortex, the pineal gland, the liver, the kidney, the heart, etc.). This hierarchical organization of the circadian system ensures the proper timing of physiological processes. In each SCN neuron, interconnected transcriptional and translational feedback loops enable the circadian expression of the clock genes. Although all the neurons have the same genotype, the oscillations of individual cells are highly heterogeneous in dispersed cell culture: many cells present damped oscillations and the period of the oscillations varies from cell to cell. In addition, the neurotransmitters that ensure the intercellular coupling, and thereby the synchronization of the cellular rhythms, differ between the two main regions of the SCN. In this work, a mathematical model that accounts for this heterogeneous organization of the SCN is presented and used to study the implication of the SCN network topology on synchronization and entrainment properties. The results show that oscillations with larger amplitude can be obtained with scale-free networks, in contrast to random and local connections. Networks with the small-world property such as the scale-free networks used in this work can adapt faster to a delay or advance in the light/dark cycle (jet lag). Interestingly a certain level of cellular heterogeneity is not detrimental to synchronization performances, but on the contrary helps resynchronization after jet lag. When coupling two networks with different topologies that mimic the two regions of the SCN, efficient filtering of pulse-like perturbations in the entrainment pattern is observed. These results suggest that the complex and heterogeneous architecture of the SCN decreases the sensitivity of the network to short entrainment perturbations while, at the same time, i, Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

The purpose of this study was to record the discharge characteristics of tibialis anterior motor units over a range of target forces and to import these data, along with previously reported observations, into a computational model to compare experimental and simulated measures of torque variability during isometric contractions with the dorsiflexor muscles. The discharge characteristics of 44 motor units were quantified during brief isometric contractions at torques that ranged from recruitment threshold to an average of 22 ± 14.4% maximal voluntary contraction (MVC) torque above recruitment threshold. The minimal [range: 5.8-19.8 pulses per second (pps)] and peak (range: 8.6-37.5 pps) discharge rates of motor units were positively related to the recruitment threshold torque (R(2) ≥ 0.266; P < 0.001). The coefficient of variation for interspike interval at recruitment was positively associated with recruitment threshold torque (R(2) = 0.443; P < 0.001) and either decreased exponentially or remained constant as target torque increased above recruitment threshold torque. The variability in the simulated torque did not differ from the experimental values once the recruitment range was set to ∼85% MVC torque, and the association between motor twitch contraction times and peak twitch torque was defined as a weak linear association (R(2) = 0.096; P < 0.001). These results indicate that the steadiness of isometric contractions performed with the dorsiflexor muscle depended more on the distributions of mechanical properties than discharge properties across the population of motor units in the tibialis anterior., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, IF 2012: 3.48, info:eu-repo/semantics/published

The potassium channel tetramerization domain-containing protein 7 (KCTD7) was named after the structural homology of its predicted N-terminal broad complex, tramtrack and bric à brac/poxvirus and zinc finger domain with the T1 domain of the Kv potassium channel, but its expression profile and cellular function are still largely unknown. We have recently reported a homozygous nonsense mutation of KCTD7 in patients with a novel form of autosomal recessive progressive myoclonic epilepsy. Here, we show that KCTD7 expression hyperpolarizes the cell membrane and reduces the excitability of transfected neurons in patch clamp experiments. We found the expression of KCTD7 in the hippocampal and Purkinje cells of the murine brain, an expression profile consistent with our patients' phenotype. The effect on the plasma membrane resting potential is possibly mediated by Cullin-3, as we demonstrated direct molecular interaction of KCTD7 with Cullin-3 in co-immunoprecipitation assays. Our data link progressive myoclonic epilepsy to an inherited defect of the neuron plasma membrane's resting potential in the brain., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Neural circuits controlling fast movements are inherently unsteady as a result of their reciprocal innervation. This instability is enhanced by increased membrane excitability. Recent studies indicate that the loss of external inhibition is an important factor in the pathogenesis of several tremor disorders such as essential tremor, cerebellar kinetic tremor or parkinsonian tremor. Shaikh and colleagues propose a new conceptual scheme to analyze tremor disorders. Oscillations are simulated by changing the intrinsic membrane properties of burst neurons. The authors use a model neuron of Hodgkin-Huxley type with added hyperpolarization activated cation current (Ih), low threshold calcium current (It), and GABA/glycine mediated chloride currents. Post-inhibitory rebound is taken into account. The model includes a reciprocally innervated circuit of neurons projecting to pairs of agonist and antagonist muscles. A set of four burst neurons has been simulated: inhibitory agonist, inhibitory antagonist, excitatory agonist, and excitatory antagonist. The model fits well with the known anatomical organization of neural circuits for limb movements in premotor/motor areas, and, interestingly, this model does not require any structural modification in the anatomical organization or connectivity of the constituent neurons. The authors simulate essential tremor when Ih is increased. Membrane excitability is augmented by up-regulating Ih and It. A high level of congruence with the recordings made in patients exhibiting essential tremor is reached. These simulations support the hypothesis that increased membrane excitability in potentially unsteady circuits generate oscillations mimicking tremor disorders encountered in daily practice. This new approach opens new perspectives for both the understanding and the treatment of neurological tremor. It provides the rationale for decreasing membrane excitability by acting on a normal ion channel in a context of impaired external inhibition, Journal Article, SCOPUS: ed.j, info:eu-repo/semantics/published

The purpose of the study was to examine the influence of practice on time to failure of a submaximal contraction with the elbow flexor muscles and on reflex inhibition from brachioradialis afferents onto biceps brachii motor neurons. Fifteen subjects practiced sustaining an isometric contraction (20% of maximum) with the elbow flexors until failure. Spike-triggered stimulation was used to assess the influence of radial nerve stimulation on the discharge of single motor units in biceps brachii before and after three practice sessions. Time to failure increased from 760 +/- 333 s in session 1 to 1,103 +/- 415 s in session 3 (P < 0.03) and was accompanied by a slower rate of increase in electromyographic (EMG) activity of the short head of biceps brachii (P < 0.05). Stimulation of the radial nerve prolonged the interspike interval before practice (n = 56; 7.2 +/- 6.8 ms; P < 0.001), and this effect was reduced after practice (n = 62; 2.3 +/- 3.6 ms; P < 0.01). The reduction was greater for motor units in the short head of biceps brachii than for those in the long head (P < 0.05) and was associated with a slower rate of increase in EMG (r = 0.57, P = 0.03). The decrease in reflex inhibition was the main predictor of the increase in time to failure (r(2) = 0.60, P = 0.001). These results demonstrate that practice reduced an antagonistic inhibition and improved the ability of the muscles to perform a synergistic action of elbow flexion., Journal Article, Research Support, N.I.H. Extramural, info:eu-repo/semantics/published

The purpose of this study was to examine the effects of postactivation potentiation (PAP) on the torque and rate of torque development for contractions evoked by short trains of stimuli at different frequencies, in young and elderly adults. Individual mechanical contributions to each electrical stimulus within trains were also analysed. Single pulse, and two- (PT2) and three-pulse trains (PT3) delivered at 20, 50, 80 and 100 Hz were evoked before and during a 10 min period after a 6-s conditioning MVC. The results show that PAP of the torque for PT2 decreased with the increase of the stimulation frequency for young (from 184.5 to 140.4% of control values) and elderly (from 140.5 to 109.6%). Regardless of the stimulation frequency, the peak of PAP was greater in young than in elderly and occurred immediately after the conditioning MVC but was delayed for the 100 Hz condition in elderly adults. For PT3, the results were similar although the extent of PAP was less. The PAP of the mechanical contributions within the trains also decreased with the augmentation of the stimulation frequency. For most of the frequencies above 20 Hz, the peak of PAP for each mechanical contribution was delayed by 1 min after the conditioning MVC. These results indicate an age- and frequency-related PAP saturation of the successive mechanical contributions within a train of stimuli that decrease with time. The functional implication of the findings is that PAP effect is lower and delayed at high compared with low activation rate., Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, IF 2008: 1.75, info:eu-repo/semantics/published

OBJECTIVE: To investigate the dynamics of the synchronization between heart rate variability and sleep electroencephalogram power spectra and the effect of sleep apnea-hypopnea syndrome. METHODS: Heart rate and sleep electroencephalogram signals were recorded in controls and patients with sleep apnea-hypopnea syndrome that were matched for age, gender, sleep parameters, and blood pressure. Spectral analysis was applied to electrocardiogram and electroencephalogram sleep recordings to obtain power values every 20s. Synchronization likelihood was computed between time series of the normalized high frequency spectral component of RR-intervals and all electroencephalographic frequency bands. Detrended fluctuation analysis was applied to the synchronizations in order to qualify their dynamic behaviors. RESULTS: For all sleep bands, the fluctuations of the synchronization between sleep EEG and heart activity appear scale free and the scaling exponent is close to one as for 1/f noise. We could not detect any effect due to sleep apnea-hypopnea syndrome. CONCLUSIONS: The synchronizations between the high frequency component of heart rate variability and all sleep power bands exhibited robust fluctuations characterized by self-similar temporal behavior of 1/f noise type. No effects of sleep apnea-hypopnea syndrome were observed in these synchronizations. SIGNIFICANCE: Sleep apnea-hypopnea syndrome does not affect the interdependence between the high frequency component of heart rate variability and all sleep power bands as measured by synchronization likelihood., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

The suprachiasmatic nuclei (SCN) host a robust, self-sustained circadian pacemaker that coordinates physiological rhythms with the daily changes in the environment. Neuronal clocks within the SCN form a heterogeneous network that must synchronize to maintain timekeeping activity. Coherent circadian output of the SCN tissue is established by intercellular signaling factors, such as vasointestinal polypeptide. It was recently shown that besides coordinating cells, the synchronization factors play a crucial role in the sustenance of intrinsic cellular rhythmicity. Disruption of intercellular signaling abolishes sustained rhythmicity in a majority of neurons and desynchronizes the remaining rhythmic neurons. Based on these observations, the authors propose a model for the synchronization of circadian oscillators that combines intracellular and intercellular dynamics at the single-cell level. The model is a heterogeneous network of circadian neuronal oscillators where individual oscillators are damped rather than self-sustained. The authors simulated different experimental conditions and found that: (1) in normal, constant conditions, coupled circadian oscillators quickly synchronize and produce a coherent output; (2) in large populations, such oscillators either synchronize or gradually lose rhythmicity, but do not run out of phase, demonstrating that rhythmicity and synchrony are codependent; (3) the number of oscillators and connectivity are important for these synchronization properties; (4) slow oscillators have a higher impact on the period in mixed populations; and (5) coupled circadian oscillators can be efficiently entrained by light-dark cycles. Based on these results, it is predicted that: (1) a majority of SCN neurons needs periodic synchronization signal to be rhythmic; (2) a small number of neurons or a low connectivity results in desynchrony; and (3) amplitudes and phases of neurons are negatively correlated. The authors conclude that to understand the orc, Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

OBJECTIVE: The aim of the present study is to investigate the scaling properties of the sleep electroencephalogram (EEG) in remitted depressed men, and to evaluate if a past history of major depressive disorder (MDD) could modify significantly and definitively, as a "scar marker," the dynamics of the sleep EEG time series. METHODOLOGY: Whole night sleep electroencephalogram signals were recorded in 24 men: 10 untreated depressed men in full to partial remission (42.43+/-5.62 years) and 14 healthy subjects (42.8+/-8.55 years). Scaling properties in these time series were investigated with detrended fluctuation analysis (DFA) (time range: 0.16-2.00 s). The scaling exponent alpha was determined in stage 2, in slow wave sleep (stages 3 and 4), and during rapid eye movement (REM) sleep. Forty-five epochs of 20 s were chosen randomly in each of these stages for each subject in both groups. RESULTS: We did not observe a significant difference and deviation of the scaling exponents between the two groups during the three sleep stages of interest. CONCLUSION: In this study, we do not observe any functional sequelae of a past history of one or more unipolar major depressive episode on the fluctuation properties of the sleep EEG. This finding is a sign of similar underlying neuronal dynamics in healthy controls and patients with a lifetime history of MDD. This study gives an additional argument to the theory that depression does not modify definitively the dynamics of the neuronal networks and is therefore against the "depressive scar hypothesis," in which permanent residual deficit is created by the acute state of the depressive disease., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

This study compares the fatigability of the ankle dorsiflexors during five sets of 30 maximal concentric and eccentric contractions in young and elderly adults. The torque produced by the ankle dorsiflexors and the average surface electromyogram (aEMG) of the tibialis anterior were continuously recorded. The contribution of central and peripheral mechanisms to muscle fatigue was tested before, after each set of contractions, and during a 30 min recovery period by the superimposed electrical stimulation method. The compound muscle action potential (M-wave), the mechanical response to single (twitch) and paired (doublet) stimulation, and the postactivation potentiation were also recorded. Compared with young subjects, elderly adults exhibited a greater loss of torque for concentric (50.2 vs. 40.9%; P<0.05) and eccentric (42.1 vs. 27.1%; P < 0.01) contractions. Although young subjects showed a lesser decrease in torque during the eccentric compared with concentric contractions, elderly adults experienced similar fatigability for the two types of contractions despite a comparable depression in the EMG activity of both groups and contraction types (10-20%). As tested by the interpolated-twitch method and aEMG/M-wave ratio, voluntary activation was not altered during either type of contraction or for either age group. During the two fatigue tasks, only elderly adults experienced a decrease in M-wave area (26.4-35.4%; P < 0.05). All together, our results suggest that the fatigue exhibited by both young and elderly adults during maximal concentric and eccentric contractions mainly involved peripheral alterations and that elderly adults may also have experienced a decline in neuromuscular propagation., Journal Article, Research Support, Non-U.S. Gov't, IF 2007: 3.63, info:eu-repo/semantics/published

The authors propose to define the epileptic syndromes with continuous spikes and waves during slow sleep (CSWS) as a cognitive or behavioral impairment acquired during childhood, associated with a strong activation of the interictal epileptiform discharges during NREM sleep--whatever focal or generalized--and not related to another factor than the presence of CSWS. The type of syndrome will be defined according to the neurological and neuropsychological deficit. These syndromes have to be classified among the localization-related epileptic syndromes. Some cases are idiopathic and others are symptomatic. Guidelines for work-up and treatment are proposed., Journal Article, Review, SCOPUS: ar.j, info:eu-repo/semantics/published

The purpose of this brief review is to examine the neural adaptations associated with training, by focusing on the behavior of single motor units. The review synthesizes current understanding on motor unit recruitment and rate coding during voluntary contractions, briefly describes the techniques used to record motor unit activity, and then evaluates the adaptations that have been observed in motor unit activity during maximal and submaximal contractions. Relatively few studies have directly compared motor unit behavior before and after training. Although some studies suggest that the voluntary activation of muscle can increase slightly with strength training, it is not known how the discharge of motor units changes to produce this increase in activation. The evidence indicates that the increase is not attributable to changes in motor unit synchronization. It has been demonstrated, however, that training can increase both the rate of torque development and the discharge rate of motor units. Furthermore, both strength training and practice of a force-matching task can evoke adaptations in the discharge characteristics of motor units. Because the variability in discharge rate has a significant influence on the fluctuations in force during submaximal contractions, the changes produced with training can influence motor performance during activities of daily living. Little is known, however, about the relative contributions of the descending drive, afferent feedback, spinal circuitry, and motor neuron properties to the observed adaptations in motor unit activity., Journal Article, Research Support, N.I.H. Extramural, Research Support, Non-U.S. Gov't, Review, info:eu-repo/semantics/published

In the small intestine, interstitial cells of Cajal (ICC) surrounding the myenteric plexus generate the pacemaking slow waves that are essential for an efficient intestinal transit. The underlying molecular mechanisms of the slow wave are poorly known. Our aim was to identify ICC-specific genes and their function in the mouse jejunum. Suppression subtractive hybridization using two independent ICC-deficient mouse models identified 56 genes putatively downregulated in the muscularis propria compared with wild-type littermates. Differential expression was confirmed by real-time quantitative PCR for the tyrosine kinase receptor KIT, the established marker for ICC, and for the Na(+)-K(+)-2Cl(-) cotransporter (NKCC1). Immunoreactivity for NKCC1 was detected in myenteric ICC but not in the ICC population located at the deep muscular plexus. NKCC1 was also expressed in enteric neurons and mucosal crypts. Bumetanide, an NKCC1 inhibitor, reversibly affected the shape, amplitude, and frequency of the slow waves. Similar alterations were observed in NKCC1 knockout mice. These data support the hypothesis that NKCC1 expressed in myenteric ICC is involved in the mechanism of slow waves in the murine jejunum., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Variations in intracellular calcium concentration ([Ca2+]i) provide a critical signal for synaptic plasticity. In accordance with Hebb's postulate (Hebb, 1949), an increase in postsynaptic [Ca2+]i can induce bidirectional changes in synaptic strength depending on activation of specific biochemical pathways (Bienenstock et al. 1982; Lisman, 1989; Stanton and Sejnowski, 1989). Despite its strategic location for signal processing, spatiotemporal dynamics of [Ca2+]i changes and their relationship with synaptic plasticity at the cerebellar mossy fiber (mf)-granule cell (GrC) relay were unknown. In this paper, we report the plasticity/[Ca2+]i relationship for GrCs, which are typically activated by mf bursts (Chadderton et al. 2004). Mf bursts caused a remarkable [Ca2+]i increase in GrC dendritic terminals through the activation of NMDA receptors, metabotropic glutamate receptors (probably acting through IP3-sensitive stores), voltage-dependent calcium channels, and Ca2+-induced Ca2+ release. Although [Ca2+]i increased with the duration of mf bursts, long-term depression was found with a small [Ca2+]i increase (bursts <250 ms), and long-term potentiation (LTP) was found with a large [Ca2+]i increase (bursts >250 ms). LTP and [Ca2+]i saturated for bursts >500 ms and with theta-burst stimulation. Thus, bursting enabled a Ca2+-dependent bidirectional Bienenstock-Cooper-Munro-like learning mechanism providing the cellular basis for effective learning of burst patterns at the input stage of the cerebellum., Comparative Study, In Vitro, Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Regulation of voltage-gated sodium channels is crucial to firing patterns that constitute the output of medium spiny neurons (MSN), projecting neurons of the striatum. This modulation is thus critical for the final integration of information processed within the striatum. It has been shown that the adenylate cyclase pathway reduces sodium currents in MSN through channel phosphorylation by cAMP-dependent protein kinase. However, it is unknown whether a phospholipase C (PLC)-mediated signaling cascade could also modulate voltage-gated sodium channels within MSN. Using the whole-cell patch clamp technique, we investigated the effects of activation of two key components in PLC-mediated signaling cascades: protein kinase C (PKC) and inositol-1,4,5-triphosphate (IP(3)) receptors on voltage-dependent sodium current. Cellular dialysis with phorbol 12-myristate 13-acetate, an activator of PKC, significantly reduced peak sodium current amplitude, while adenophostin A, an activator of IP(3) receptors, significantly increased peak sodium current amplitude. This effect of adenophostin was abolished by calcium chelation or by FK506, an inhibitor of calcineurin. These results suggest an antagonistic role of PKC and IP(3) in the modulation of striatal voltage-gated sodium channels, peak current amplitude being decreased through phosphorylation by PKC and increased through dephosphorylation by calcineurin., Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

This study examines the effect of fascicle length change on motor-unit recruitment and discharge rate in the human tibialis anterior (TA) during isometric contractions of various intensities. The torque produced during dorsiflexion and the surface and intramuscular electromyograms (EMGs) from the TA were recorded in eight subjects. The behavior of the same motor unit (n = 59) was compared at two ankle joint angles (+10 and -10 degrees around the ankle neutral position). Muscle fascicle length of the TA was measured noninvasively using ultrasonography recordings. When the ankle angle was moved from 10 degrees plantarflexion to 10 degrees dorsiflexion, the torque produced during maximal voluntary contraction (MVC) was significantly reduced [35.2 +/- 3.3 vs. 44.3 +/- 4.2 (SD) Nm; P < 0.001] and the average surface EMG increased (0.47 +/- 0.08 vs. 0.43 +/- 0.06 mV; P < 0.05). At reduced ankle joint angle, muscle fascicle length declined by 12.7% (P < 0.01) at rest and by 18.9% (P < 0.001) during MVC. Motor units were activated at a lower recruitment threshold for short compared with long muscle fascicle length, either when expressed in absolute values (2.1 +/- 2.5 vs. 3.6 +/- 3.7 Nm; P < 0.001) or relative to their respective MVC (5.2 +/- 6.1 vs. 8.8 +/- 9.0%). Higher discharge rate and additional motor-unit recruitment were observed at a given absolute or relative torque when muscle fascicles were shortened. However, the data indicate that increased rate coding was mainly present at low torque level (<10% MVC), when the muscle-tendon complex was compliant, whereas recruitment of additional motor units played a dominant role at higher torque level and decreased compliance (10-35% MVC). Taken together, the results suggest that the central command is modulated by the afferent proprioceptive information during submaximal contractions performed at different muscle fascicle lengths., Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Calbindin is a fast Ca2+-binding protein expressed by Purkinje cells and involved in their firing regulation. Its deletion produced approximately 160-Hz oscillation sustained by synchronous, rhythmic Purkinje cells in the cerebellar cortex of mice. Parvalbumin is a slow-onset Ca2+-binding protein expressed in Purkinje cells and interneurons. In order to assess its function in Purkinje cell firing regulation, we studied the firing behavior of Purkinje cells in alert mice lacking parvalbumin (PV-/-), calbindin (CB-/-) or both (PV-/- CB-/-) and in wild-type controls. The absence of either protein resulted in Purkinje cell firing alterations (decreased complex spike duration and pause, increased simple spike firing rate) that were more pronounced in CB-/- than in PV-/- mice. Cumulative effects were found in complex spike alterations in PV-/- CB-/- mice. PV-/- and CB-/- mice manifested approximately 160-Hz oscillation that was sustained by Purkinje cells firing rhythmically and synchronously along the parallel fiber axis. This oscillation was dependent on GABA(A), N-methyl-D-aspartate and gap junction transmission. PV-/- CB-/- mice exhibited a dual-frequency (110 and 240 Hz) oscillation. The instantaneous spectral densities of both components were inversely correlated. Simple and complex spikes of Purkinje cells were phase-locked to one of the two oscillation frequencies. Mono- and dual-frequency oscillations presented similar pharmacological properties. These results demonstrate that the absence of the Ca2+ buffers parvalbumin and calbindin disrupts the regulation of Purkinje cell firing rate and rhythmicity in vivo and suggest that precise Ca2+ transient control is required to maintain the normal spontaneous arrhythmic and asynchronous firing pattern of the Purkinje cells., Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, FLWIN, info:eu-repo/semantics/published

Postural impairment is one of the most consistent features of Angelman syndrome. Using multiple-channel electromyography, we studied a lower limb and an upper limb isometric postural task in 14 patients with Angelman syndrome and 18 unimpaired control subjects. Both tasks were associated with synchronous bursts of activity at frequencies of 6-8 s(-1) in all recorded muscles in all patients with Angelman syndrome and none of the control subjects. This pattern was not altered by extra-loading. Electroencephalogram recorded during the upper limb task showed no change in relation to the task. Burst-locked back-averaging of the electroencephalogram showed no spiking before or during the bursts. Various physiological and pathological rhythmic muscle activities have been proposed to be a manifestation of oscillations in the central nervous system and it has been suggested that such oscillations may have a role in the processing of motor commands. The mechanism of the rhythmic muscle bursting activity associated with maintaining posture in patients with Angelman syndrome is not clear, although it could be consistent with cerebellar Purkinje cell dysfunction, either as a pathological feature or as an adaptive process to overcome deficits in motor coordination., Journal Article, info:eu-repo/semantics/published

Cerebellar Purkinje cells receive two different excitatory inputs from parallel and climbing fibers, causing simple and complex spikes, respectively. Purkinje cells present three modes of simple spike firing, namely tonic, silent and bursting. The influence of complex spike firing on simple spike firing has been extensively studied. However, it is unknown whether and how the simple spike firing mode may influence complex spike waveform and firing rate in vivo. We studied complex spike firing during tonic and silent mode periods in non-anesthetized mice. We found that complex spike firing rate is not influenced by simple spike firing modes, but that the complex spike waveform is altered following high frequency simple spike firing. This alteration is a specific decrement of the second depolarizing component of the complex spike. We demonstrate that the amplitude of the second depolarizing component is inversely proportional to the simple spike firing rate preceding the complex spike and that this amplitude is independent of previous complex spike firing. This waveform modulation is different from previously reported modulation in paired-pulse depression and refractoriness., Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

In vertebrates, several groups of metabotropic glutamate receptors (mGluRs) are known to modulate synaptic properties. In contrast, the Drosophila genome encodes a single functional mGluR (DmGluRA), an ortholog of vertebrate group II mGluRs, greatly expediting the functional characterization of mGluR-mediated signaling in the nervous system. We show here that DmGluRA is expressed at the glutamatergic neuromuscular junction (NMJ), localized in periactive zones of presynaptic boutons but excluded from active sites. Null DmGluRA mutants are completely viable, and all of the basal NMJ synaptic transmission properties are normal. In contrast, DmGluRA mutants display approximately a threefold increase in synaptic facilitation during short stimulus trains. Prolonged stimulus trains result in very strongly increased ( approximately 10-fold) augmentation, including the appearance of asynchronous, bursting excitatory currents never observed in wild type. Both defects are rescued by expression of DmGluRA only in the neurons, indicating a specific presynaptic requirement. These phenotypes are reminiscent of hyperexcitable mutants, suggesting a role of DmGluRA signaling in the regulation of presynaptic excitability properties. The mutant phenotypes could not be replicated by acute application of mGluR antagonists, suggesting that DmGluRA regulates the development of presynaptic properties rather than directly controlling short-term modulation. DmGluRA mutants also display mild defects in NMJ architecture: a decreased number of synaptic boutons accompanied by an increase in mean bouton size. These morphological changes bidirectionally correlate with DmGluRA levels in the presynaptic terminal. These data reveal the following two roles for DmGluRA in presynaptic mechanisms: (1) modulation of presynaptic excitability properties important for the control of activity-dependent neurotransmitter release and (2) modulation of synaptic architecture., Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., info:eu-repo/semantics/published

Human brain function is regionally organised during paradoxical sleep (PS) in a very different way than during wakefulness or slow wave sleep. The important activity in the pons and in the limbic/paralimbic areas constitutes the key feature of the functional neuroanatomy of PS, together with a relative quiescence of prefrontal and parietal associative cortices. Two questions are still outstanding. What neurocognitive and neurophysiological mechanisms may explain this original organization of brain function during PS? How the pattern of regional brain function may relate to dream content? Although some clues are already available, the experimental answer to both questions is still pending., Journal Article, Review, info:eu-repo/semantics/published

The mechanical performance of a muscle can be enhanced by preceding contractile activity, such as occurs with postactivation potentiation. To investigate whether the type of contraction influences the extent of potentiation, the effects of 6-s maximal isometric (ISO), concentric (CON), and eccentric (ECC) maximal voluntary contractions (MVC) on the muscle twitch were compared in the tibialis anterior of nine subjects. The study also examined the effect of postactivation potentiation on the force evoked by the second (C2) and third (C3) responses of two-pulse (PT2) and three-pulse (PT3) trains that were delivered at a 10-ms interpulse interval. The results showed that immediately after the conditioning MVC, twitch torque (Pt) and its maximal rate of torque development (+dPt/dt) and relaxation (-dPt/dt) were significantly enhanced, without any change in contraction time (CT), half-relaxation time ((1/2)RT), and compound muscle action potential (M wave). The extent of Pt potentiation was similar for all MVC modalities, and the mean maximal values ranged from 150% to 180%. Furthermore, postactivation potentiation was greater for the single pulse compared with PT2 and PT3 responses. All parameters returned to initial values within 7-10 min. Although Pt (or C1) was potentiated more than was C2 and C3, its decline over time was proportionally more rapid than those for C2 and C3. We conclude that postactivation potentiation was not related to the type of conditioning MVC under these experimental conditions. The observation that postactivation potentiation increased C1 more than C2 and C3 indicates that a saturation process limits the extent of potentiation during the summation of successive responses to a train of stimuli. These results have practical application in the design of functional electrical stimulation protocols., Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, FLWIN, info:eu-repo/semantics/published

To investigate whether the intensity and duration of a sustained contraction influences reflex regulation, we compared sustained fatiguing contractions at 25 % and 50 % of maximal voluntary contraction (MVC) force in the human abductor pollicis brevis (APB) muscle. Because the activation of motoneurones during fatigue may be reflexively controlled by the metabolic status of the muscle, we also compared reflex activities during sustained and intermittent (6 s contraction, 4 s rest) contractions at 25 % MVC for an identical duration. The short-latency Hoffmann(H) reflex and the long-latency reflex (LLR) were recorded during voluntary contractions, before, during and after the fatigue tests, with each response normalised to the compound muscle action potential (M-wave). The results showed that fatigue during sustained contractions was inversely related to the intensity, and hence the duration, of the effort. The MVC force and associated surface electromyogram (EMG) declined by 26.2 % and 35.2 %, respectively, after the sustained contraction at 50 % MVC, and by 34.2 % and 44.2 % after the sustained contraction at 25 % MVC. Although the average EMG increased progressively with time during the two sustained fatiguing contractions, the amplitudes of the H and LLR reflexes decreased significantly. Combined with previous data (Duchateau & Hainaut, 1993), the results show that the effect on the H reflex is independent of the intensity of the sustained contraction, whereas the decline in the LLR is closely related to the duration of the contraction. Because there were no changes in the intermittent test at 25 % MVC, the results indicate that the net excitatory spinal and supraspinal reflex-mediated input to the motoneurone pool is reduced. This decline in excitation to the motoneurones, however, can be temporarily compensated by an enhancement of the central drive., Journal Article, Research Support, Non-U.S. Gov't, FLWIN, info:eu-repo/semantics/published

The effect of pre- versus postsynaptic mechanisms in the decrease in spinal reflex response during passive muscle stretching was studied. The change in the electromyographic (EMG) responses of two reflex pathways sharing a common pool of motoneurones, with (Hoffmann or H reflex) or without (exteroceptive or E reflex) a presynaptic inhibitory mechanism, was compared. The EMG activities were recorded in the soleus muscle in response to the electrical stimulation of the tibial nerve at the popliteal fossa (H reflex), and at the ankle (E reflex) for different dorsiflexion angles of the ankle. The compound muscle action potential (M wave) in the soleus and the abductor hallucis was recorded in order to control the stability of the electrical stimulation during stretching. The results indicate that in the case of small-amplitude muscle stretching (10 degrees of dorsiflexion), a significant reduction (-25%; P < 0.05) in the Hmax/Mmax ratio was present without any significant change in the Emax/Mmax ratio. At a greater stretching amplitude (20 degrees of dorsiflexion), the E reflex was found to be reduced (-54.6%; P < 0.001) to a similar extent as the H reflex (-54.2%). As soon as the ankle joint returned to the neutral position (ankle at 90 degrees), the two reflex responses recovered their initial values. In additional experiments, motor-evoked potential (MEP) induced by the magnetic stimulation of the motor cortex was recorded and showed a similar type of behaviour to that observed in the E reflex. These results indicate that reduced motoneurone excitation during stretching is caused by pre- and postsynaptic mechanisms. Whereas premotoneuronal mechanisms are mainly involved in the case of small stretching amplitude, postsynaptic ones play a dominant role in the reflex inhibition when larger stretching amplitude is performed., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Using a new antibody developed against the C-terminus of the cannabinoid receptor (CB1), the immunostaining in the hippocampus revealed additional axon terminals relative to the pattern reported previously with an N-terminus antibody. Due to a greater sensitivity of this antibody, a large proportion of boutons in the dendritic layers displaying symmetrical (GABAergic) synapses were also strongly immunoreactive for CB1 receptors, as were axon terminals of perisomatic inhibitory cells containing cholecystokinin. Asymmetrical (glutamatergic) synapses, however, were always negative for CB1. To investigate the effect of presynaptic CB1 receptor activation on hippocampal inhibition, we recorded inhibitory postsynaptic currents (IPSCs) from principal cells. Bath application of CB1 receptor agonists (WIN55,212-2 and CP55,940) suppressed IPSCs evoked by local electrical stimulation, which could be prevented or reversed by the CB1 receptor antagonist SR141716A. Action potential-driven IPSCs, evoked by pharmacological stimulation of a subset of interneurons, were also decreased by CB1 receptor activation. We also examined the effects of CB1 receptor agonists on Ca2+-independent miniature IPSCs (mIPSC). Both agonists were without significant effect on the frequency or amplitude of mIPSCs. Synchronous gamma oscillations induced by kainic acid in the CA3 region of hippocampal slices were reversibly reduced in amplitude by the CB1 receptor agonist CP 55,940, which is consistent with an action on IPSCs. We used CB1-/- knock-out mice to confirm the specificity of the antibody and of the agonist (WIN55,212-2) action. We conclude that activation of presynaptic CB1 receptors decreases Ca2+-dependent GABA release, and thereby reduces the power of hippocampal network oscillations., Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., FLWIN, info:eu-repo/semantics/published

We compared the contribution of central and peripheral processes to muscle fatigue induced in the ankle dorsiflexor muscles by tests performed during concentric (CON) and eccentric (ECC) conditions. Each fatigue test consisted of five sets of 30 maximum voluntary contractions at a constant speed of 50 degrees /s for a 30 degrees range of motion of the ankle joint. The torque produced by the dorsiflexors and the surface electromyogram (EMG) of the tibialis anterior muscle were recorded during the fatigue tests. Before, during, and after the tests, the compound muscle action potential (M wave) and the contractile properties in response to single and paired electrical stimuli, as well as the interpolated-twitch method and postactivation potentiation (PAP), were recorded during isometric conditions. Compared with ECC contractions, the CON ones resulted in a greater (P < 0.05) loss of force (-31.6% vs. -23.8%) and a decrease in EMG activity (-26.4% vs. -17.5%). This difference was most pronounced during the first four sets of contractions, but was reduced during the last set. Activation was not altered by the tests because neither the interpolated-twitch response nor the ratio of the voluntary EMG to the amplitude of the M wave was changed in the two fatigue tests. Although there was no significant difference in M-wave amplitude between the two tests, changes in the twitch parameters and in the PAP were found to be greater in the CON than ECC contractions. It is concluded that the greater alterations in the contractile properties observed during the CON contractions indicate that intracellular Ca(2+)-controlled excitation-contraction (E-C) coupling processes, possibly associated with a higher energy requirement, are affected to a much greater degree than during ECC contractions., Journal Article, Research Support, Non-U.S. Gov't, FLWIN, info:eu-repo/semantics/published

The electromechanical adaptations of the triceps surae muscle were examined in one subject confined to bed for 5 wk due to strong orthostatic headaches. The torque produced by the triceps surae and the electromyographic (EMG) activities of the slow soleus (Sol) and fast lateral gastrocnemius (LG) were studied in response to voluntary and electrically induced contractions. Bed rest caused a 46% decrease in the maximal voluntary contraction (MVC) torque. This loss of strength was associated with a deficit of 33% in central activation and 19% in the estimated muscle force-generating capacity. The EMG activity during MVC was found to be reduced in both muscles, but to a greater extent in the LG (-51%) than in the Sol (-32%). The decrease in amplitude of the maximal M wave (Mmax) recorded in response to supramaximal electrical stimulation was greater in Sol (-28%) than in LG (-12%). After bed rest, the twitch time to peak torque was slightly prolonged (+9%) and the maximal rate of tension development (dT/dt) was reduced by 31% in electrically induced and 24% in voluntary contractions. Although muscle fatigability during a 60-s sustained MVC was not affected by the bed rest period, the relative contributions of the two muscles differed from control. These results indicate that muscular adaptations were more prominent in Sol while neural adaptations were more significant in LG. Furthermore, the neural changes almost completely recovered within 2 wk, whereas the contractile alterations required at least 5 times longer to return to the control values., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

1. The contractile properties, recruitment and firing rates of motor units from the human adductor pollicis and the first dorsal interosseous were studied during voluntary isometric contractions after 6-8 weeks' immobilization of the corresponding limbs. 2. In both muscles, motor units of different force thresholds showed a proportionally identical twitch tension decrease and slowing of their time course after immobilization. 3. When expressed as a percentage of the maximal voluntary contraction, more high-threshold motor units were recorded in disused muscles than in control muscles, but the order of recruitment was maintained. 4. The motor unit firing rate at recruitment was identical in control and disused muscles, but the maximal firing rate decreased in all motor units after immobilization. This decrease of the maximal firing rate was greater in motor units of lower threshold than in those of higher threshold. 5. The results further document motoneuronal plasticity in human muscles of different fibre type composition., Journal Article, Research Support, Non-U.S. Gov't, FLWIN, info:eu-repo/semantics/published