Showing papers in "The Journal of Physiology in 2005"
TL;DR: Roles for specific interneurone types are suggested in structuring the activity of pyramidal cells via their respective target domains, and accurately timing and synchronizingPyramidal cell discharge, rather than providing generalized inhibition.
Abstract: The cerebral cortex encodes, stores and combines information about the internal and external environment in rhythmic activity of multiple frequency ranges. Neurones of the cortex can be defined, recognized and compared on the comprehensive application of the following measures: (i) brain area- and cell domain-specific distribution of input and output synapses, (ii) expression of molecules involved in cell signalling, (iii) membrane and synaptic properties reflecting the expression of membrane proteins, (iv) temporal structure of firing in vivo, resulting from (i)–(iii). Spatial and temporal measures of neurones in the network reflect an indivisible unity of evolutionary design, i.e. neurones do not have separate structure or function. The blueprint of this design is most easily accessible in the CA1 area of the hippocampus, where a relatively uniform population of pyramidal cells and their inputs follow an instantly recognizable laminated pattern and act within stereotyped network activity patterns. Reviewing the cell types and their spatio-temporal interactions, we suggest that CA1 pyramidal cells are supported by at least 16 distinct types of GABAergic neurone. During a given behaviour-contingent network oscillation, interneurones of a given type exhibit similar firing patterns. During different network oscillations representing two distinct brain states, interneurones of the same class show different firing patterns modulating their postsynaptic target-domain in a brain-state-dependent manner. These results suggest roles for specific interneurone types in structuring the activity of pyramidal cells via their respective target domains, and accurately timing and synchronizing pyramidal cell discharge, rather than providing generalized inhibition. Finally, interneurones belonging to different classes may fire preferentially at distinct time points during a given oscillation. As different interneurones innervate distinct domains of the pyramidal cells, the different compartments will receive GABAergic input differentiated in time. Such a dynamic, spatio-temporal, GABAergic control, which evolves distinct patterns during different brain states, is ideally suited to regulating the input integration of individual pyramidal cells contributing to the formation of cell assemblies and representations in the hippocampus and, probably, throughout the cerebral cortex.
918 citations
TL;DR: The results suggest that the effect of tDCS on cortico‐spinal excitability during a short period of stimulation (which does not induce after‐effects) primarily depends on subthreshold resting membrane potential changes, which are able to modulate the input‐output curve, but not motor thresholds.
Abstract: Weak transcranial direct current stimulation (tDCS) of the human motor cortex results in excitability shifts which occur during and after stimulation. These excitability shifts are polarity-specific with anodal tDCS enhancing excitability, and cathodal reducing it. To explore the origin of this excitability modulation in more detail, we measured the input–output curve and motor thresholds as global parameters of cortico-spinal excitability, and determined intracortical inhibition and facilitation, as well as facilitatory indirect wave (I-wave) interactions. Measurements were performed during short-term tDCS, which elicits no after-effects, and during other tDCS protocols which do elicit short- and long-lasting after-effects. Resting and active motor thresholds remained stable during and after tDCS. The slope of the input–output curve was increased by anodal tDCS and decreased by cathodal tDCS. Anodal tDCS of the primary motor cortex reduced intracortical inhibition and enhanced facilitation after tDCS but not during tDCS. Cathodal tDCS reduced facilitation during, and additionally increased inhibition after its administration. During tDCS, I-wave facilitation was not influenced but, for the after-effects, anodal tDCS increased I-wave facilitation, while cathodal tDCS had only minor effects. These results suggest that the effect of tDCS on cortico-spinal excitability during a short period of stimulation (which does not induce after-effects) primarily depends on subthreshold resting membrane potential changes, which are able to modulate the input-output curve, but not motor thresholds. In contrast, the after-effects of tDCS are due to shifts in intracortical inhibition and facilitation, and at least partly also to facilitatory I-wave interaction, which is controlled by synaptic activity.
643 citations
TL;DR: The mechanisms of FMD depend on the nature of the shear stress stimulus (stimulus response specificity), an update to the current guidelines for FMD assessment is provided, and the issues that surround the clinical utility of measuring both NO‐ and non‐NO‐mediated FMD are summarized.
Abstract: Endothelium-dependent flow-mediated dilatation (FMD) describes the vasodilatory response of a vessel to elevations in blood flow-associated shear stress. Nitric oxide (NO), one of many vasoactive substances released by the endothelium in response to shear stress, is of particular interest to researchers as it is an antiatherogenic molecule, and a reduction in its bioavailability may play a role in the pathogenesis of vascular disease. The goal of many human studies is to create a shear stress stimulus that produces an NO-dependent response in order to use the FMD measurements as an assay of NO bioavailability. The most common non-invasive technique is the 'reactive hyperaemia test' which produces a large, transient shear stress profile and a corresponding FMD. Importantly, not all FMD is NO mediated and the stimulus creation technique is a critical determinant of NO dependence. The purpose of this review is to (1) explain that the mechanisms of FMD depend on the nature of the shear stress stimulus (stimulus response specificity), (2) provide an update to the current guidelines for FMD assessment, and (3) summarize the issues that surround the clinical utility of measuring both NO- and non-NO-mediated FMD. Future research should include (1) the identification and partitioning of mechanisms responsible for FMD in response to various shear stress profiles, (2) investigation of stimulus response specificity in coronary arteries, and (3) investigation of non-NO FMD mechanisms and their connection to the development of vascular disease and occurrence of cardiovascular events.
613 citations
TL;DR: There is a rapid increase in collagen synthesis after strenuous exercise in human tendon and muscle, and the similar time course of changes of protein synthetic rates in different cell types supports the idea of coordinated musculotendinous adaptation.
Abstract: We hypothesized that an acute bout of strenuous, non-damaging exercise would increase rates of protein synthesis of collagen in tendon and skeletal muscle but these would be less than those of muscle myofibrillar and sarcoplasmic proteins. Two groups (n = 8 and 6) of healthy young men were studied over 72 h after 1 h of one-legged kicking exercise at 67% of maximum workload (W(max)). To label tissue proteins in muscle and tendon primed, constant infusions of [1-(13)C]leucine or [1-(13)C]valine and flooding doses of [(15)N] or [(13)C]proline were given intravenously, with estimation of labelling in target proteins by gas chromatography-mass spectrometry. Patellar tendon and quadriceps biopsies were taken in exercised and rested legs at 6, 24, 42 or 48 and 72 h after exercise. The fractional synthetic rates of all proteins were elevated at 6 h and rose rapidly to peak at 24 h post exercise (tendon collagen (0.077% h(-1)), muscle collagen (0.054% h(-1)), myofibrillar protein (0.121% h(-1)), and sarcoplasmic protein (0.134% h(-1))). The rates decreased toward basal values by 72 h although rates of tendon collagen and myofibrillar protein synthesis remained elevated. There was no tissue damage of muscle visible on histological evaluation. Neither tissue microdialysate nor serum concentrations of IGF-I and IGF binding proteins (IGFBP-3 and IGFBP-4) or procollagen type I N-terminal propeptide changed from resting values. Thus, there is a rapid increase in collagen synthesis after strenuous exercise in human tendon and muscle. The similar time course of changes of protein synthetic rates in different cell types supports the idea of coordinated musculotendinous adaptation.
554 citations
TL;DR: Evidence is reported that decreasing RONS formation prevents activation of important signalling pathways, predominantly the MAPK–NF‐κB pathway; consequently the practice of taking antioxidants before exercise may have to be re‐evaluated.
Abstract: Reactive oxygen or nitrogen species (RONS) are produced during exercise due, at least in part, to the activation of xanthine oxidase. When exercise is exhaustive they cause tissue damage; however, they may also act as signals inducing specific cellular adaptations to exercise. We have tested this hypothesis by studying the effects of allopurinol-induced inhibition of RONS production on cell signalling pathways in rats submitted to exhaustive exercise. Exercise caused an activation of mitogen-activated protein kinases (MAPKs: p38, ERK 1 and ERK 2), which in turn activated nuclear factor κB (NF-κB) in rat gastrocnemius muscle. This up-regulated the expression of important enzymes associated with cell defence (superoxide dismutase) and adaptation to exercise (eNOS and iNOS). All these changes were abolished when RONS production was prevented by allopurinol. Thus we report, for the first time, evidence that decreasing RONS formation prevents activation of important signalling pathways, predominantly the MAPK–NF-κB pathway; consequently the practice of taking antioxidants before exercise may have to be re-evaluated.
456 citations
TL;DR: Exogenously applied H2S significantly increased whole‐cell KATP channel currents at concentrations equal to or lower than 100 μm and markedly increased open probability by more than 2‐fold of single KATp channels (inside‐out recording) in native INS‐1E cells.
Abstract: H2S is an important gasotransmitter, generated in mammalian cells from L-cysteine metabolism. As it stimulates K(ATP) channels in vascular smooth muscle cells, H2S may also function as an endogenous opener of K(ATP) channels in INS-1E cells, an insulin-secreting cell line. In the present study, K(ATP) channel currents in INS-1E cells were recorded using the whole-cell and single-channel recording configurations of the patch-clamp technique. K(ATP) channels in INS-1E cells have a single-channel conductance of 78 pS. These channels were activated by diazoxide and inhibited by gliclazide. ATP (3 mm) in the pipette solution inhibited K(ATP) channels in INS-1E cells. Significant amount of H2S was produced from INS-1E cells in which the expression of cystathinonie gamma-lyase (CSE) was confirmed. After INS-1E cells were transfected with CSE-targeted short interfering RNA (CSE-siRNA) or treated with DL-propargylglycine (PPG; 1-5 mm) to inhibit CSE, endogenous production of H2S was abolished. Increase in extracellular glucose concentration significantly decreased endogenous production of H2S in INS-1E cells, and increased insulin secretion. After transfection of INS-1E cells with adenovirus containing the CSE gene (Ad-CSE) to overexpress CSE, high glucose-stimulated insulin secretion was virtually abolished. Basal K(ATP) channel currents were significantly reduced after incubating INS-1E cells with a high glucose concentration (16 mm) or lowering endogenous H2S level by CSE-siRNA transfection. Under these conditions, exogenously applied H2S significantly increased whole-cell K(ATP) channel currents at concentrations equal to or lower than 100 microm. H2S (100 microm) markedly increased open probability by more than 2-fold of single K(ATP) channels (inside-out recording) in native INS-1E cells (n = 4, P < 0.05). Single-channel conductance and ATP sensitivity of K(ATP) channels were not changed by H2S. In conclusion, endogenous H2S production from INS-1E cells varies with in vivo conditions, which significantly affects insulin secretion from INS-1E cells. H2S stimulates K(ATP) channels in INS-1E cells, independent of activation of cytosolic second messengers, which may underlie H2S-inhibited insulin secretion from these cells. Interaction among H2S, glucose and the K(ATP) channel may constitute an important and novel mechanism for the fine control of insulin secretion from pancreatic beta-cells.
449 citations
TL;DR: Analysis of the sequence of single‐channel open and closed intervals shows that both NR2A‐ and NR2B‐containing receptors undergo multiple conformational changes prior to opening of the channel, with at least one of these steps being faster for NR1/NR2A thanNR2B.
Abstract: NR2A and NR2B are the predominant NR2 NMDA receptor subunits expressed in cortex and hippocampus. The relative expression level of NR2A and NR2B is regulated developmentally and these two subunits have been suggested to play distinct roles in long-term synaptic plasticity. We have used patch-clamp recording of recombinant NMDA receptors expressed in HEK293 cells to characterize the activation properties of both NR1/NR2A and NR1/NR2B receptors. Recordings from outside-out patches that contain a single active channel show that NR2A-containing receptors have a higher probability of opening at least once in response to a brief synaptic-like pulse of glutamate than NR2B-containing receptors (NR2A, 0.80; NR2B, 0.56), a higher peak open probability (NR2A, 0.50; NR2B, 0.12), and a higher open probability within an activation (NR2A, 0.67; NR2B, 0.37). Analysis of the sequence of single-channel open and closed intervals shows that both NR2A- and NR2B-containing receptors undergo multiple conformational changes prior to opening of the channel, with at least one of these steps being faster for NR2A than NR2B. These distinct properties produce profoundly different temporal signalling profiles for NR2A- and NR2B-containing receptors. Simulations of synaptic responses demonstrate that at low frequencies typically used to induce long-term depression (LTD; 1 Hz), NR1/NR2B makes a larger contribution to total charge transfer and therefore calcium influx than NR1/NR2A. However, under high-frequency tetanic stimulation (100 Hz; > 100 ms) typically used to induce long-term potentiation (LTP), the charge transfer mediated by NR1/NR2A considerably exceeds that of NR1/NR2B.
422 citations
TL;DR: The down‐regulation of KCC2 under pathophysiological conditions (epilepsy, damage) in mature neurones seems to reflect a ‘recapitulation’ of early developmental mechanisms, which may be a prerequisite for the re‐establishment of connectivity in damaged brain tissue.
Abstract: GABAergic signalling has the unique property of ‘ionic plasticity’, which is based on short-term and long-term changes in the Cl− and HCO3− ion concentrations in the postsynaptic neurones. While short-term ionic plasticity is caused by activity-dependent, channel-mediated anion shifts, long-term ionic plasticity depends on changes in the expression patterns and kinetic regulation of molecules involved in anion homeostasis. During development the efficacy and also the qualitative nature (depolarization/excitation versus hyperpolarization/inhibition) of GABAergic transmission is influenced by the neuronal expression of two key molecules: the chloride-extruding K+–Cl− cotransporter KCC2, and the cytosolic carbonic anhydrase (CA) isoform CAVII. In rat hippocampal pyramidal neurones, a steep up-regulation of KCC2 accounts for the ‘developmental switch’, which converts depolarizing and excitatory GABA responses of immature neurones to classical hyperpolarizing inhibition by the end of the second postnatal week. The immature hippocampus generates large-scale network activity, which is abolished in parallel by the up-regulation of KCC2 and the consequent increase in the efficacy of neuronal Cl− extrusion. At around postnatal day 12 (P12), an abrupt, steep increase in intrapyramidal CAVII expression takes place, promoting excitatory responses evoked by intense GABAergic activity. This is largely caused by a GABAergic potassium transient resulting in spatially widespread neuronal depolarization and synchronous spike discharges. These facts point to CAVII as a putative target of CA inhibitors that are used as antiepileptic drugs. KCC2 expression in adult rat neurones is down-regulated following epileptiform activity and/or neuronal damage by BDNF/TrkB signalling. The lifetime of membrane-associated KCC2 is very short, in the range of tens of minutes, which makes KCC2 ideally suited for mediating GABAergic ionic plasticity. In addition, factors influencing the trafficking and kinetic modulation of KCC2 as well as activation/deactivation of CAVII are obvious candidates in the ionic modulation of GABAergic responses. The down-regulation of KCC2 under pathophysiological conditions (epilepsy, damage) in mature neurones seems to reflect a ‘recapitulation’ of early developmental mechanisms, which may be a prerequisite for the re-establishment of connectivity in damaged brain tissue.
416 citations
TL;DR: This review explores the limitations of current proteomics protein discovery platforms, and proposes an alternative approach, applicable to a range of biological/physiological problems, in which quantitative mass spectrometric methods developed for analytical chemistry are employed to measure limited sets of candidate markers in large sets of clinical samples.
Abstract: The key concept of proteomics (looking at many proteins at once) opens new avenues in the search for clinically useful biomarkers of disease, treatment response and ageing. As the number of proteins that can be detected in plasma or serum (the primary clinical diagnostic samples) increases towards 1000, a paradoxical decline has occurred in the number of new protein markers approved for diagnostic use in clinical laboratories. This review explores the limitations of current proteomics protein discovery platforms, and proposes an alternative approach, applicable to a range of biological/physiological problems, in which quantitative mass spectrometric methods developed for analytical chemistry are employed to measure limited sets of candidate markers in large sets of clinical samples. A set of 177 candidate biomarker proteins with reported associations to cardiovascular disease and stroke are presented as a starting point for such a ‘directed proteomics’ approach.
409 citations
TL;DR: The findings demonstrate that the after‐effects of tDCS have a non‐synaptic mechanism of action based upon changes in neural membrane function and could arise from alterations in transmembrane proteins and from electrolysis‐related changes in [H+] induced by exposure to constant electric field.
Abstract: Although cathodal transcranial direct current stimulation (tDCS) decreases cortical excitability, the mechanisms underlying DC-induced changes remain largely unclear. In this study we investigated the effect of cathodal DC stimulation on spontaneous neural activity and on motor responses evoked by stimulation of the central and peripheral nervous system. We studied 17 healthy volunteers. Transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES) of the motor area were used to study the effects of cathodal tDCS (1.5 mA, 10 min) on resting motor threshold and motor evoked potentials (MEPs) recorded from the contralateral first dorsal interosseous muscle (FDI). The electroencephalographic (EEG) activity in response to cathodal tDCS was analysed by power spectral density (PSD). Motor axonal excitability changes in response to transcutaneous DC stimulation of the ulnar nerve (0.3 mA, 10 min) were assessed by testing changes in the size of the compound muscle action potential (CMAP) elicited by submaximal nerve stimulation. Cathodal tDCS over the motor area for 10 min increased the motor threshold and decreased the size of MEPs evoked by TMS for at least 60 min after current offset (t0 71.7 ± 5%, t20 50.8 ± 11%, t40 47.7 ± 7.7%, and t60 39.7 ± 6.4%, P < 0.01). The tDCS also significantly decreased the size of MEPs elicited by TES (t0 64 ± 16.4%, P= 0.09; t20 67.6 ± 10.8%, P= 0.06; and t40 58.3 ± 9.9%, P < 0.05). At the same time in the EEG the power of delta (2–4 Hz) and theta (4–7 Hz) rhythms increased (delta 181.1 ± 40.2, P < 0.05; and theta 138.7 ± 27.6, P= 0.07). At the peripheral level cathodal DC stimulation increased the size of the ulnar nerve CMAP (175 ± 34.3%, P < 0.05). Our findings demonstrate that the after-effects of tDCS have a non-synaptic mechanism of action based upon changes in neural membrane function. These changes apart from reflecting local changes in ionic concentrations, could arise from alterations in transmembrane proteins and from electrolysis-related changes in [H+] induced by exposure to constant electric field.
398 citations
TL;DR: Findings from a range of nutritional studies examining maternal and/or postnatal nutritional excess suggest that maternal over‐nutrition is deleterious to the health of offspring and can result in a phenotype of the offspring that is characteristic of metabolic syndrome.
Abstract: Studies in both humans and experimental animals addressing the ‘Fetal Origins of Adult Disease’ hypothesis have established a relationship between an adverse intrauterine environment and offspring disease in adult life. This phenomenon, termed ‘fetal programming’ describes a process whereby a stimulus in utero establishes a permanent response in the fetus leading to enhanced susceptibility to later disease. However, the environment, during periods of developmental plasticity in postnatal life, can also ‘programme’ function. Thus, the terms ‘developmental programming’ and the ‘Developmental Origins of Adult Health and Disease’ are preferentially utilized. The ‘Thrifty Phenotype’ hypothesis explained the association between insufficient in utero nutrition and the later development of Type 2 diabetes. Most recently the ‘Predictive Adaptive Response’ hypothesis proposes that the degree of mismatch between the pre- and postnatal environments is an important determinant of subsequent disease. Epidemiological studies have indicated that fetal growth restriction correlates with later disease, implying that fetal nutritional deprivation is a strong programming stimulus. This prompted the development of experimental animal models using controlled maternal calorie, protein or macronutrient deficiency during key periods of gestation. However, in many societies, maternal and postnatal nutrition are either sufficient or excessive. Here, we examine findings from a range of nutritional studies examining maternal and/or postnatal nutritional excess. There is supportive evidence from a limited number of studies to test the ‘Predictive Adaptive Response’ hypothesis. These suggest that maternal over-nutrition is deleterious to the health of offspring and can result in a phenotype of the offspring that is characteristic of metabolic syndrome.
TL;DR: Results show that cTBS preferentially decreases the amplitude of the corticospinal I1 wave, with approximately the same time course as other protocols that lead to MEP suppression, such as short‐interval intracortical inhibition.
Abstract: Previous studies have shown that low-frequency repetitive transcranial magnetic stimulation (rTMS) suppresses motor-evoked potentials (MEPs) evoked by single pulse TMS. The aim of the present paper was to investigate the central nervous system level at which rTMS produces a suppression of MEP amplitude. We recorded corticospinal volleys evoked by single pulse TMS of the motor cortex before and after 1 Hz rTMS in five conscious subjects who had an electrode implanted in the cervical epidural space for the control of pain. One of the patients had Parkinson's disease and was studied on medication. Repetitive TMS significantly suppressed the amplitude of later I-waves, and reduced the amplitude of concomitantly recorded MEPs. The earliest I-wave was not significantly modified by rTMS. The present results show that 1 Hz rTMS may decrease the amplitude of later descending waves, consistent with a cortical origin of the effect of 1 Hz rTMS on MEPs.
TL;DR: Evidence is provided that PGC‐1α not only mediates the increased expression of oxidative phosphorylation genes but also mediates alterations in mitochondrial architecture in response to aerobic exercise in humans.
Abstract: Mitochondrial impairment is hypothesized to contribute to the pathogenesis of insulin resistance Mitofusin (Mfn) proteins regulate the biogenesis and maintenance of the mitochondrial network, and when inactivated, cause a failure in the mitochondrial architecture and decreases in oxidative capacity and glucose oxidation Exercise increases muscle mitochondrial content, size, oxidative capacity and aerobic glucose oxidation To address if Mfn proteins are implicated in these exercise-induced responses, we measured Mfn1 and Mfn2 mRNA levels, pre-, post-, 2 and 24 h post-exercise Additionally, we measured the expression levels of transcriptional regulators that control mitochondrial biogenesis and functions, including PGC-1α, NRF-1, NRF-2 and the recently implicated ERRα We show that Mfn1, Mfn2, NRF-2 and COX IV mRNA were increased 24 h post-exercise, while PGC-1α and ERRα mRNA increased 2 h post-exercise Finally, using in vitro cellular assays, we demonstrate that Mfn2 gene expression is driven by a PGC-1α programme dependent on ERRα The PGC-1α/ERRα-mediated induction of Mfn2 suggests a role of these two factors in mitochondrial fusion Our results provide evidence that PGC-1α not only mediates the increased expression of oxidative phosphorylation genes but also mediates alterations in mitochondrial architecture in response to aerobic exercise in humans
TL;DR: An important contribution of heteromeric P2X2/3 receptors to nociceptive responses and mechanosensory transduction within the urinary bladder is revealed.
Abstract: Extracellular ATP plays a role in nociceptive signalling and sensory regulation of visceral function through ionotropic receptors variably composed of P2X2 and P2X3 subunits. P2X2 and P2X3 subunits can form homomultimeric P2X2, homomultimeric P2X3, or heteromultimeric P2X2/3 receptors. However, the relative contribution of these receptor subtypes to afferent functions of ATP in vivo is poorly understood. Here we describe null mutant mice lacking the P2X2 receptor subunit (P2X2−/−) and double mutant mice lacking both P2X2 and P2X3 subunits (P2X2/P2X3Dbl−/−), and compare these with previously characterized P2X3−/− mice. In patch-clamp studies, nodose, coeliac and superior cervical ganglia (SCG) neurones from wild-type mice responded to ATP with sustained inward currents, while dorsal root ganglia (DRG) neurones gave predominantly transient currents. Sensory neurones from P2X2−/− mice responded to ATP with only transient inward currents, while sympathetic neurones had barely detectable responses. Neurones from P2X2/P2X3Dbl−/− mice had minimal to no response to ATP. These data indicate that P2X receptors on sensory and sympathetic ganglion neurones involve almost exclusively P2X2 and P2X3 subunits. P2X2−/− and P2X2/P2X3Dbl−/− mice had reduced pain-related behaviours in response to intraplantar injection of formalin. Significantly, P2X3−/−, P2X2−/−, and P2X2/P2X3Dbl−/− mice had reduced urinary bladder reflexes and decreased pelvic afferent nerve activity in response to bladder distension. No deficits in a wide variety of CNS behavioural tests were observed in P2X2−/− mice. Taken together, these data extend our findings for P2X3−/− mice, and reveal an important contribution of heteromeric P2X2/3 receptors to nociceptive responses and mechanosensory transduction within the urinary bladder.
TL;DR: A computational model of a CA1 pyramidal cell predicted that M and h‐channels will generate mAHPs in a voltage‐dependent manner, as indicated by the experiments, and it is concluded that M‐ and h-channels generate the somatic mAHP in hippocampal pyramid cells, with little or no net contribution from SK channels.
Abstract: In hippocampal pyramidal cells, a single action potential (AP) or a burst of APs is followed by a medium afterhyperpolarization (mAHP, lasting ∼0.1 s). The currents underlying the mAHP are considered to regulate excitability and cause early spike frequency adaptation, thus dampening the response to sustained excitatory input relative to responses to abrupt excitation. The mAHP was originally suggested to be primarily caused by M-channels (at depolarized potentials) and h-channels (at more negative potentials), but not SK channels. In recent reports, however, the mAHP was suggested to be generated mainly by SK channels or only by h-channels. We have now re-examined the mechanisms underlying the mAHP and early spike frequency adaptation in CA1 pyramidal cells by using sharp electrode and whole-cell recording in rat hippocampal slices. The specific M-channel blocker XE991 (10 μm) suppressed the mAHP following 1–5 APs evoked by current injection at −60 mV. XE991 also enhanced the excitability of the cell, i.e. increased the number of APs evoked by a constant depolarizing current pulse, reduced their rate of adaptation, enhanced the afterdepolarization and promoted bursting. Conversely, the M-channel opener retigabine reduced excitability. The h-channel blocker ZD7288 (4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride; 10 μm) fully suppressed the mAHP at −80 mV, but had little effect at −60 mV, whereas XE991 did not measurably affect the mAHP at −80 mV. Likewise, ZD7288 had little or no effect on excitability or adaptation during current pulses injected from −60 mV, but changed the initial discharge during depolarizing pulses injected from −80 mV. In contrast to previous reports, we found that blockade of Ca2+-activated K+ channels of the SK/KCa type by apamin (100–400 nm) failed to affect the mAHP or adaptation. A computational model of a CA1 pyramidal cell predicted that M- and h-channels will generate mAHPs in a voltage-dependent manner, as indicated by the experiments. We conclude that M- and h-channels generate the somatic mAHP in hippocampal pyramidal cells, with little or no net contribution from SK channels.
TL;DR: It is concluded that maternal protein restriction adversely affects glucose and insulin metabolism of male and female F2 offspring in a manner specific to sex and developmental time window during their mother's fetal and neonatal development.
Abstract: Compelling epidemiological and experimental evidence indicates that a suboptimal environment during fetal and neonatal development in both humans and animals may programme offspring susceptibility to later development of several chronic diseases including obesity and diabetes in which altered carbohydrate metabolism plays a central role. One of the most interesting and significant features of developmental programming is the evidence from several studies that the adverse consequences of altered intrauterine environments can be passed transgenerationally from mother (F0) to daughter (F1) to second generation offspring (F2). We determined whether when F0 female rats are exposed to protein restriction during pregnancy and/or lactation their F1 female pups deliver F2 offspring with in vivo evidence of altered glucose and insulin metabolism. We fed F0 virgin Wistar rats a normal control 20% casein diet (C) or a protein restricted isocaloric diet (R) containing 10% casein during pregnancy. F1 female R pups weighed less than C at birth. After delivery, mothers received C or R diet during lactation to provide four F1 offspring groups CC (first letter pregnancy diet and second lactation diet), RR, CR and RC. All F1 female offspring were fed ad libitum with C diet after weaning and during their first pregnancy and lactation. As they grew female offspring (F1) of RR and CR mothers exhibited low body weight and food intake with increased sensitivity to insulin during a glucose tolerance test at 110 days of postnatal life. Male F2 CR offspring showed evidence of insulin resistance. In contrast RC F2 females showed evidence of insulin resistance. Sex differences were also observed in F2 offspring in resting glucose and insulin and insulin: glucose ratios. These sex differences also showed differences specific to stage of development time window. We conclude that maternal protein restriction adversely affects glucose and insulin metabolism of male and female F2 offspring in a manner specific to sex and developmental time window during their mother's (the F1) fetal and neonatal development.
TL;DR: The present study provides the first genome‐scale regional ionic channel expression profile in the mouse heart by using large‐scale real‐time RT‐PCR and two‐way hierarchical clustering analysis of the 71 genes successfully classified the six pools from the four distinct regions.
Abstract: Even though sequencing of the mammalian genome has led to the discovery of a large number of ionic channel genes, identification of the molecular determinants of cellular electrical properties in different regions of the heart has been rarely obtained. We developed a high-throughput approach capable of simultaneously assessing the expression pattern of ionic channel repertoires from different regions of the mouse heart. By using large-scale real-time RT-PCR, we have profiled 71 channels and related genes in the sinoatrial node (SAN), atrioventricular node (AVN), the atria (A) and ventricles (V). Hearts from 30 adult male C57BL/6 mice were microdissected and RNA was isolated from six pools of five mice each. TaqMan data were analysed using the threshold cycle (C(t)) relative quantification method. Cross-contamination of each region was checked with expression of the atrial and ventricular myosin light chains. Two-way hierarchical clustering analysis of the 71 genes successfully classified the six pools from the four distinct regions. In comparison with the A, the SAN and AVN were characterized by higher expression of Nav beta 1, Nav beta 3, Cav1.3, Cav3.1 and Cav alpha 2 delta 2, and lower expression of Kv4.2, Cx40, Cx43 and Kir3.1. In addition, the SAN was characterized by higher expression of HCN1 and HCN4, and lower expression of RYR2, Kir6.2, Cav beta 2 and Cav gamma 4. The AVN was characterized by higher expression of Nav1.1, Nav1.7, Kv1.6, Kvbeta1, MinK and Cav gamma 7. Other gene expression profiles discriminate between the ventricular and the atrial myocardium. The present study provides the first genome-scale regional ionic channel expression profile in the mouse heart.
TL;DR: It is reported that extracellular dihydrostreptomycin not only blocks the mechano‐electrical transducer channels of mouse outer hair cells at negative membrane potentials, but also enters the cells through these channels, which are located in the cells' mechanosensory hair bundles.
Abstract: The most serious side-effect of the widely used aminoglycoside antibiotics is irreversible intracellular damage to the auditory and vestibular hair cells of the inner ear. The mechanism of entry into the hair cells has not been unequivocally resolved. Here we report that extracellular dihydrostreptomycin not only blocks the mechano-electrical transducer channels of mouse outer hair cells at negative membrane potentials, as previously shown, but also enters the cells through these channels, which are located in the cells' mechanosensory hair bundles. The voltage-dependent blocking kinetics indicate an open-channel block mechanism, which can be well described by a two barrier–one binding site model, quantifying the antibiotic's block of the channel as well as its permeation in terms of the associated rate constants. The results identify the open transducer channels as the main route for aminoglycoside entry. Intracellularly applied dihydrostreptomycin also blocks the transducer channels, but at positive membrane potentials. However, the potency of the block was two orders of magnitude lower than that due to extracellular dihydrostreptomycin. Extracellular Ca2+ increases the free energy of the barrier nearest the extracellular side and of the binding site for dihydrostreptomycin. This reduces both the entry of dihydrostreptomycin into the channel and the channel's affinity for the drug. In vivo, where the extracellular Ca2+ concentration in the endolymph surrounding the hair bundles is < 100 μm, we predict that some 9000 dihydrostreptomycin molecules per second enter each hair cell at therapeutic drug concentrations.
TL;DR: It is suggested that standing is a skilled, trial and error activity that improves with experience and is automated (possibly by the cerebellum), complement and extend the recent demonstration that paradoxical muscle movements are the norm in human standing.
Abstract: It has been widely assumed for nearly a century, that postural muscles operate in a spring-like manner and that muscle length signals joint angle (the mechano-reflex mechanism). Here we employ automated analysis of ultrasound images to resolve calf muscle (soleus and gastrocnemius) length changes as small as 10 mum in standing subjects. Previously, we have used balancing of a real inverted pendulum to make predictions about human standing. Here we test and confirm these predictions on 10 subjects standing quietly. We show that on average the calf muscles are actively adjusted 2.6 times per second and 2.8 times per unidirectional sway of the body centre of mass (CoM). These alternating, small (30-300 microm) movements provide impulsive, ballistic regulation of CoM movement. The timing and pattern of these adjustments are consistent with multisensory integration of all information regarding motion of the CoM, pattern recognition, prediction and planning using internal models and are not consistent with control solely by local reflexes. Because the system is unstable, errors in stabilization provide a perturbation which grows into a sway which has to be reacted to and corrected. Sagittal sway results from this impulsive control of calf muscle activity rather than internal sources (e.g. the heart, breathing). This process is quite unlike the mechano-reflex paradigm. We suggest that standing is a skilled, trial and error activity that improves with experience and is automated (possibly by the cerebellum). These results complement and extend our recent demonstration that paradoxical muscle movements are the norm in human standing.
TL;DR: A thermodynamic principle is elaborated, which predicts that the small gating charge of TRP channels is a crucial factor for the large voltage shifts induced by various stimuli, and indicates that, although the voltage sensor is not yet known, the C‐terminus may substantially change the voltage dependence of these channels.
Abstract: TRP channels represent the main pathways for cation influx in non-excitable cells. Although TRP channels were for a long time considered to be voltage independent, several TRP channels now appear to be weakly voltage dependent with an activation curve extending mainly into the non-physiological positive voltage range. In connection with this voltage dependence, there is now abundant evidence that physical stimuli, such as temperature (TRPV1, TRPM8, TRPV3), or the binding of various ligands (TRPV1, TRPV3, TRPM8, TRPM4), shift this voltage dependence towards physiologically relevant potentials, a mechanism that may represent the main functional hallmark of these TRP channels. This review discusses some features of voltage-dependent gating of TRPV1, TRPM4 and TRPM8. A thermodynamic principle is elaborated, which predicts that the small gating charge of TRP channels is a crucial factor for the large voltage shifts induced by various stimuli. Some structural considerations will be given indicating that, although the voltage sensor is not yet known, the C-terminus may substantially change the voltage dependence of these channels.
TL;DR: It is demonstrated how the inhibitory microcircuitry of the cerebellar cortex orchestrates synaptic integration and precise timing of spikes in Purkinje cells, enabling them to act as coincidence detectors of parallel fibre input.
Abstract: Although the cerebellum is thought to play a key role in timing of movements on the time scale of milliseconds, it is unclear how such temporal fidelity is ensured at the cellular level. We have investigated the timing of feed-forward inhibition onto interneurons and Purkinje cells activated by parallel fibre stimulation in slices of cerebellar cortex from P18–25 rats. Feed-forward inhibition was activated within ∼1 ms after the onset of excitation in both cell types. The rapid onset of feed-forward inhibition sharply curtailed EPSPs and increased the precision of the resulting action potentials. The time window for summation of EPSPs was reduced to 1–2 ms in the presence of feed-forward inhibition, which could inhibit the efficacy of asynchronous EPSPs for up to 30 ms. Our findings demonstrate how the inhibitory microcircuitry of the cerebellar cortex orchestrates synaptic integration and precise timing of spikes in Purkinje cells, enabling them to act as coincidence detectors of parallel fibre input.
TL;DR: The novel hypothesis that non‐hybridized and possible hybridized forms of siRNA can move between mammalian cells through connexin‐specific gap junctions is supported.
Abstract: The purpose of this study was to determine whether oligonucleotides the size of siRNA are permeable to gap junctions and whether a specific siRNA for DNA polymerase β (pol β) can move from one cell to another via gap junctions, thus allowing one cell to inhibit gene expression in another cell directly. To test this hypothesis, fluorescently labelled oligonucleotides (morpholinos) 12, 16 and 24 nucleotides in length were synthesized and introduced into one cell of a pair using a patch pipette. These probes moved from cell to cell through gap junctions composed of connexin 43 (Cx43). Moreover, the rate of transfer declined with increasing length of the oligonucleotide. To test whether siRNA for pol β was permeable to gap junctions we used three cell lines: (1) NRK cells that endogenously express Cx43; (2) Mβ16tsA cells, which express Cx32 and Cx26 but not Cx43; and (3) connexin-deficient N2A cells. NRK and Mβ16tsA cells were each divided into two groups, one of which was stably transfected to express a small hairpin RNA (shRNA), which gives rise to siRNA that targets pol β. These two pol β knockdown cell lines (NRK-kcdc and Mβ16tsA-kcdc) were co-cultured with labelled wild type, NRK-wt or Mβ16tsA-wt cells or N2A cells. The levels of pol β mRNA and protein were determined by semiquantitative RT-PCR and immunoblotting. Co-culture of Mβ16tsA-kcdc cells with Mβ16tsA-wt, N2A or NRK-wt cells had no effect on pol β levels in these cells. Similarly, co-culture of NRK-kcdc with N2A cells had no effect on pol β levels in the N2A cells. In contrast, co-culture of NRK-kcdc with NRK-wt cells resulted in a significant reduction in pol β in the wt cells. The inability of Mβ16tsA-kcdc cells to transfer siRNA is consistent with the fact that oligonucleotides of the 12 nucleotide length were not permeable to Cx32/Cx26 channels. This suggested that Cx43 but not Cx32/Cx26 channels allowed the cell-to-cell movement of the siRNA. These results support the novel hypothesis that non-hybridized and possible hybridized forms of siRNA can move between mammalian cells through connexin-specific gap junctions.
TL;DR: The data suggest that the associated with the changes in central blood volume influence the MCA Vmean at rest and during exercise and its regulation is independent of cerebral autoregulation.
Abstract: Cerebral autoregulation maintains cerebral blood flow constant over a range of arterial pressures from 60 to 150 mmHg (Paulson et al. 1990). In humans, measurements of middle cerebral artery mean blood velocity (MCA Vmean) provide an index of the cerebral blood flow (Ide & Secher, 2000; Van Lieshout et al. 2003). In conditions where MCA Vmean was reduced or increased by 30 Torr lower body negative pressure (LBNP) (Zhang et al. 1998b) and head-up tilt (Jorgensen et al. 1993), or mild and moderate exercise (Brys et al. 2003; Ogoh et al. 2005b), respectively, central blood volume and cardiac output were also decreased or increased, respectively. These changes in MCA Vmean occurred without changes in arterial carbon dioxide tension (Pa,CO2) or cerebral autoregulation. Van Lieshout et al. (2001) confirmed the relationship between , MCA Vmean and central blood volume when they demonstrated that the MCA Vmean was decreased in association with the reduction in that occurs when changing postural positions from supine to standing. This reduction in MCA Vmean was present even though mean arterial pressure (MAP) was increased.
During exercise the competition for perfusion between active and inactive skeletal muscle, brain and other organ beds is regulated by the sympathetic nervous system (Rowell, 1993). For example, during progressive changes in exercise workloads, from rest to maximal exercise, progressive sympathoexcitation occurs (Hartley et al. 1972) resulting in an increasing proportional distribution of the to the active skeletal muscles (Rowell, 1993). It was found that when healthy subjects performed one-legged exercise MCA Vmean was increased by 20% and was maintained when they performed two-legged exercise (Hellstrom et al. 1997). However, in patients with heart failure, one-legged exercise did not increase MCA Vmean and two-legged exercise resulted in a decreased MCA Vmean (Hellstrom et al. 1997). When the increase in was reduced by β1-blockade (Ide et al. 1998, 2000; Dalsgaard et al. 2004), or atrial fibrillation (Ide et al. 1999), the increase in MCA Vmean during bicycling exercise was reduced. These findings further indicate that is an important factor in establishing the MCA Vmean to be regulated by cerebral autoregulation.
We hypothesized that the MCA Vmean that is regulated by cerebral autoregulation is directly related to at rest and during exercise. We further hypothesized that the relationship established between MCA Vmean and at rest is reduced during exercise. To test these hypotheses, we manipulated at rest and during exercise by using LBNP of 8 and 16 Torr and infusions of albumin to decrease and increase central blood volume, respectively.
TL;DR: This study characterized and directly compared sodium channels Nav1.2 and Nav 1.6 in a mammalian neuronal cell background and demonstrated differences in their properties that may affect neuronal behaviour, including action potential electrogenesis and depolarization.
Abstract: Sodium channels Nav1.2 and Nav1.6 are both normally expressed along premyelinated and myelinated axons at different stages of maturation and are also expressed in a subset of demyelinated axons, where coexpression of Nav1.6 together with the Na+/Ca2+ exchanger is associated with axonal injury. It has been difficult to distinguish the currents produced by Nav1.2 and Nav1.6 in native neurones, and previous studies have not compared these channels within neuronal expression systems. In this study, we have characterized and directly compared Nav1.2 and Nav1.6 in a mammalian neuronal cell background and demonstrate differences in their properties that may affect neuronal behaviour. The Nav1.2 channel displays more depolarized activation and availability properties that may permit conduction of action potentials, even with depolarization. However, Nav1.2 channels show a greater accumulation of inactivation at higher frequencies of stimulation (20–100 Hz) than Nav1.6 and thus are likely to generate lower frequencies of firing. Nav1.6 channels produce a larger persistent current that may play a role in triggering reverse Na+/Ca2+ exchange, which can injure demyelinated axons where Nav1.6 and the Na+/Ca2+ exchanger are colocalized, while selective expression of Nav1.2 may support action potential electrogenesis, at least at lower frequencies, while producing a smaller persistent current.
TL;DR: In this article, the authors showed that blocking stretch-activated channels can ameliorate the force reduction following stretched contractions by reducing the influx of Ca2+ into the muscle.
Abstract: The mdx mouse lacks dystrophin and is a model of human Duchenne muscular dystrophy. Single mdx muscle fibres were isolated and subjected to a series of stretched (eccentric) contractions while measuring intracellular calcium concentration ([Ca2+]i) with fluo-3 and confocal microscopy. Following the stretched contractions there was a slow rise in resting [Ca2+]i and after 30 min both the [Ca2+]i during a tetanus (tetanic [Ca2+]i) and the tetanic force were reduced. Two blockers of stretch-activated channels, streptomycin and the spider venom toxin GsMTx4, prevented the rise of resting [Ca2+]i and partially prevented the decline of tetanic [Ca2+]i and force. Reducing extracellular calcium to zero also prevented the rise in resting [Ca2+]i and prevented some of the decline in tetanic [Ca2+]i and force. Patch-clamping experiments identified a stretch-activated channel in both wild-type and mdx myotubes which was blocked by GsMTx4. These data suggest that blockers of stretch-activated channels can ameliorate the force reduction following stretched contractions by reducing the influx of Ca2+ into the muscle. We therefore tested whether in intact mdx mice streptomycin, added to the drinking water, was capable of reducing muscle damage. mdx mice show a period of muscle damage from 20 to 40 days of life and fibres which regenerate from this damage display central nuclei. We measured the frequency of central nuclei in control mdx mice compared to streptomycin-treated mdx mice and showed that the incidence of central nuclei was significantly reduced by streptomycin treatment. This result suggests that blockers of stretch-activated channels may protect against muscle damage in the intact mdx mouse.
TL;DR: Results point to Kv4.2 as the major contributor to the A‐current in hippocampal CA1 neurones and suggest a prominent role for Kv 4.2 in regulating AP shape and dendritic signalling.
Abstract: A-type potassium channels regulate neuronal firing frequency and the back-propagation of action potentials (APs) into dendrites of hippocampal CA1 pyramidal neurones. Recent molecular cloning studies have found several families of voltage-gated K+ channel genes expressed in the mammalian brain. At present, information regarding the relationship between the protein products of these genes and the various neuronal functions performed by voltage-gated K+ channels is lacking. Here we used a combination of molecular, electrophysiological and imaging techniques to show that one such gene, Kv4.2, controls AP half-width, frequency-dependent AP broadening and dendritic action potential propagation. Using a modified Sindbis virus, we expressed either the enhanced green fluorescence protein (EGFP)-tagged Kv4.2 or an EGFP-tagged dominant negative mutant of Kv4.2 (Kv4.2gW362F) in CA1 pyramidal neurones of organotypic slice cultures. Neurones expressing Kv4.2gW362F displayed broader action potentials with an increase in frequency-dependent AP broadening during a train compared with control neurones. In addition, Ca2+ imaging of Kv4.2gW362F expressing dendrites revealed enhanced AP back-propagation compared to control neurones. Conversely, neurones expressing an increased A-type current through overexpression of Kv4.2 displayed narrower APs with less frequency dependent broadening and decreased dendritic propagation. These results point to Kv4.2 as the major contributor to the A-current in hippocampal CA1 neurones and suggest a prominent role for Kv4.2 in regulating AP shape and dendritic signalling. As Ca2+ influx occurs primarily during AP repolarization, Kv4.2 activity can regulate cellular processes involving Ca2+-dependent second messenger cascades such as gene expression and synaptic plasticity.
TL;DR: The increased central fatigue during hyperthermia may represent a failure of descending voluntary drive to compensate for changed muscle properties, despite the availability of additional cortical output.
Abstract: Fatigue is increased during hyperthermia, and torque declines more rapidly in sustained maximal voluntary contractions (MVCs). This can be caused by a greater decline in voluntary activation of muscle (i.e. 'central fatigue'). The present study aimed to localize the site of failure of voluntary drive during hyperthermia. Seven subjects made brief (2-3 s) and sustained (2 min) MVCs of elbow flexor muscles in two experiments. Core temperature was normal (approximately 37 degrees C) in the first experiment, and elevated (approximately 38.5 degrees C) by passive heating in the second. During some MVCs, transcranial magnetic stimulation of the motor cortex (TMS) was delivered, and the evoked torque (superimposed twitch) and EMG responses were measured. During hyperthermia, voluntary torque was reduced by approximately 2.4% during brief MVCs (P = 0.03), and decreased further (approximately 12%) during sustained MVCs (P = 0.01). The superimposed twitch amplitude in the sustained MVC was approximately 50% larger (P = 0.01). Thus, the ability to drive the muscle maximally in a sustained fashion was decreased, and some motor cortical output, which could have increased torque, remained untapped by voluntary drive. The additional central fatigue was not associated with altered motor cortical 'excitability', as EMG responses produced by TMS were similar at the two temperatures. However, the peak relaxation rate of muscle increased by approximately 20% (P = 0.005) during hyperthermia. Hence, faster motor unit firing rates would be required to produce fusion of force. The increased central fatigue during hyperthermia may represent a failure of descending voluntary drive to compensate for changed muscle properties, despite the availability of additional cortical output.
TL;DR: A division of labour appears to exist whereby different frequencies and spatiotemporal properties of hippocampal rhythms are mediated by different interneurone subtypes.
Abstract: Using whole-cell patch-clamp recordings in conjunction with post hoc anatomy we investigated the physiological properties of hippocampal stratum oriens and stratum pyramidale inhibitory interneurones, before and following the induction of pharmacologically evoked gamma frequency network oscillations. Prior to kainate-induced transient epochs of gamma activity, two distinct classes of oriens interneurones, oriens lacunosum-moleculare (O-LM) and trilaminar cells, showed prominent differences in their membrane and firing properties, as well as in the amplitude and kinetics of their excitatory postsynaptic events. In the active network both types of neurone received a phasic barrage of gamma frequency excitatory inputs but, due to their differential functional integration, showed clear differences in their output patterns. While O-LM cells fired intermittently at theta frequency, trilaminar interneurones discharged on every gamma cycle and showed a propensity to fire spike doublets. Two other classes of fast spiking interneurones, perisomatic targeting basket and bistratified cells, in the active network discharged predominantly single action potentials on every gamma cycle. Thus, within a locally excited network, O-LM cells are likely to provide a theta-frequency patterned output to distal dendritic segments, whereas basket and bistratified cells are involved in the generation of locally synchronous gamma band oscillations. The anatomy and output profile of trilaminar cells suggest they are involved in the projection of locally generated gamma rhythms to distal sites. Therefore a division of labour appears to exist whereby different frequencies and spatiotemporal properties of hippocampal rhythms are mediated by different interneurone subtypes.
TL;DR: Rats born to mothers fed a cafeteria diet during gestation alone or during both gestation and lactation exhibited impaired skeletal muscle development and metabolic disorders normally associated with insulin resistance as early as the weaning stage.
Abstract: We examined the effects of a maternal cafeteria diet on skeletal muscle and adipose tissue development in the offspring at weaning. Rats born to mothers fed the cafeteria diet either during gestation alone or during both gestation and lactation exhibited a 25% reduction in muscle cross-sectional area with approximately 20% fewer fibres compared with pups fed a balanced chow diet. Maintaining the cafeteria diet during lactation increased intramuscular lipid content and fat pad weights characterized by adipocyte hypertrophy but not hyperplasia. These pups also had elevated muscle IGF-1, IGF-1 receptor, and PPARγ mRNA levels, which may indicate an attempt to maintain normal insulin sensitivity. The increased adiposity and elevated IGF-1, IGF-1 receptor and PPARγ mRNAs were not seen in the pups rehabilitated to the balanced diet during lactation. However, these pups exhibited reduced muscle cell proliferation (PCNA) with reduced insulin receptor and a trend towards reduced glucose transporter (GLUT)-4 mRNAs when compared with pups fed a balanced chow diet, indicating possible alterations in glucose uptake by muscle tissue. Therefore, rats born to mothers fed a cafeteria diet during gestation alone or during both gestation and lactation exhibited impaired skeletal muscle development and metabolic disorders normally associated with insulin resistance as early as the weaning stage.
TL;DR: It is suggested that reduced voluntary activation contributes to the early force loss after eccentric exercise, but that it is not due to muscle soreness.
Abstract: Muscle damage reduces voluntary force after eccentric exercise but impaired neural drive to the muscle may also contribute. To determine whether the delayed-onset muscle soreness, which develops approximately 1 day after exercise, reduces voluntary activation and to identify the possible site for any reduction, voluntary activation of elbow flexor muscles was examined with both motor cortex and motor nerve stimulation. We measured maximal voluntary isometric torque (MVC), twitch torque, muscle soreness and voluntary activation in eight subjects before, immediately after, 2 h after, 1, 2, 4 and 8 days after eccentric exercise. Motor nerve stimulation and motor cortex stimulation were used to derive twitch torques and measures of voluntary activation. Eccentric exercise immediately reduced the MVC by 38 +/- 3% (mean +/- s.d., n = 8). The resting twitch produced by motor nerve stimulation fell by 82 +/- 6%, and the estimated resting twitch by cortical stimulation fell by 47 +/- 15%. While voluntary torque recovered after 8 days, both measures of the resting twitch remained depressed. Muscle tenderness occurred 1-2 days after exercise, and pain during contractions on days 1-4, but changes in voluntary activation did not follow this time course. Voluntary activation assessed with nerve stimulation fell 19 +/- 6% immediately after exercise but was not different from control values after 2 days. Voluntary activation assessed by motor cortex stimulation was unchanged by eccentric exercise. During MVCs, absolute increments in torque evoked by nerve and cortical stimulation behaved differently. Those to cortical stimulation decreased whereas those to nerve stimulation tended to increase. These findings suggest that reduced voluntary activation contributes to the early force loss after eccentric exercise, but that it is not due to muscle soreness. The impairment of voluntary activation to nerve stimulation but not motor cortical stimulation suggests that the activation deficit lies in the motor cortex or at a spinal level.