Showing papers in "The Journal of Physiology in 2008"

Similar metabolic adaptations during exercise after low volume sprint interval and traditional endurance training in humans

Abstract: Low-volume ‘sprint’ interval training (SIT) stimulates rapid improvements in muscle oxidative capacity that are comparable to levels reached following traditional endurance training (ET) but no study has examined metabolic adaptations during exercise after these different training strategies. We hypothesized that SIT and ET would induce similar adaptations in markers of skeletal muscle carbohydrate (CHO) and lipid metabolism and metabolic control during exercise despite large differences in training volume and time commitment. Active but untrained subjects (23 ± 1 years) performed a constant-load cycling challenge (1 h at 65% of peak oxygen uptake ( ˙ VO2peak) before and after 6 weeks of either SIT or ET (n = 5 men and 5 women per group). SIT consisted of four to six repeats of a 30 s ‘all out’ Wingate Test (mean power output ∼500 W) with 4.5 min recovery between repeats, 3 days per week. ET consisted of 40‐60 min of continuous cycling at a workload that elicited ∼65% ˙ VO2peak (mean power output ∼150 W) per day, 5 days per week. Weekly time commitment (∼1.5 versus ∼4.5 h) and total training volume (∼225 versus ∼2250 kJ week −1 ) were substantially lower in SIT versus ET. Despite these differences, both protocols induced similar increases (P < 0.05) in mitochondrial markers for skeletal muscle CHO (pyruvate dehydrogenase E1α protein content) and lipid oxidation (3-hydroxyacyl CoA dehydrogenase maximal activity) and protein content of peroxisome proliferator-activated receptor-γ coactivator-1α. Glycogen and phosphocreatine utilization during exercise were reduced after training, and calculated rates of whole-body CHO and lipid oxidation were decreased and increased, respectively, with no differences between groups (all main effects, P < 0.05). Given the markedly lower training volume in the SIT group, these data suggest that high-intensity interval training is a time-efficient strategy to increase skeletal muscle oxidative capacity and induce specific metabolic adaptations during exercise that are comparable to traditional ET.

Muscle fatigue: what, why and how it influences muscle function

Abstract: Much is known about the physiological impairments that can cause muscle fatigue. It is known that fatigue can be caused by many different mechanisms, ranging from the accumulation of metabolites within muscle fibres to the generation of an inadequate motor command in the motor cortex, and that there is no global mechanism responsible for muscle fatigue. Rather, the mechanisms that cause fatigue are specific to the task being performed. The development of muscle fatigue is typically quantified as a decline in the maximal force or power capacity of muscle, which means that submaximal contractions can be sustained after the onset of muscle fatigue. There is even evidence that the duration of some sustained tasks is not limited by fatigue of the principal muscles. Here we review experimental approaches that focus on identifying the mechanisms that limit task failure rather than those that cause muscle fatigue. Selected comparisons of tasks, groups of individuals and interventions with the task-failure approach can provide insight into the rate-limiting adjustments that constrain muscle function during fatiguing contractions.

Endurance exercise performance: the physiology of champions

Abstract: Efforts to understand human physiology through the study of champion athletes and record performances have been ongoing for about a century. For endurance sports three main factors – maximal oxygen consumption , the so-called ‘lactate threshold’ and efficiency (i.e. the oxygen cost to generate a give running speed or cycling power output) – appear to play key roles in endurance performance. and lactate threshold interact to determine the ‘performance ‘ which is the oxygen consumption that can be sustained for a given period of time. Efficiency interacts with the performance to establish the speed or power that can be generated at this oxygen consumption. This review focuses on what is currently known about how these factors interact, their utility as predictors of elite performance, and areas where there is relatively less information to guide current thinking. In this context, definitive ideas about the physiological determinants of running and cycling efficiency is relatively lacking in comparison with and the lactate threshold, and there is surprisingly limited and clear information about the genetic factors that might pre-dispose for elite performance. It should also be cautioned that complex motivational and sociological factors also play important roles in who does or does not become a champion and these factors go far beyond simple physiological explanations. Therefore, the performance of elite athletes is likely to defy the types of easy explanations sought by scientific reductionism and remain an important puzzle for those interested in physiological integration well into the future.

A common polymorphism in the brain‐derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS

Abstract: The brain-derived neurotrophic factor gene (BDNF) is one of many genes thought to influence synaptic plasticity in the adult brain and shows a common single nucleotide polymorphism (BDNF Val66Met) in the normal population that is associated with differences in hippocampal volume and episodic memory. It is also thought to influence possible synaptic changes in motor cortex following a simple motor learning task. Here we extend these studies by using new non-invasive transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (TDCS) techniques that directly test the excitability and plasticity of neuronal circuits in human motor cortex in subjects at rest. We investigated whether the susceptibility to TMS probes of plasticity is significantly influenced by the BDNF polymorphism. Val66Met carriers were matched with Val66Val individuals and tested on the following protocols: continuous and intermittent theta burst TMS; median nerve paired associative stimulation; and homeostatic plasticity in the TDCS/1 Hz rTMS model. The response of Met allele carriers differed significantly in all protocols compared with the response of Val66Val individuals. We suggest that this is due to the effect of BNDF on the susceptibility of synapses to undergo LTP/LTD. The circuits tested here are implicated in the pathophysiology of movement disorders such as dystonia and are being assessed as potential new targets in the treatment of stroke. Thus the polymorphism may be one factor that influences the natural response of the brain to injury and disease.

Differential effects of resistance and endurance exercise in the fed state on signalling molecule phosphorylation and protein synthesis in human muscle

Abstract: Resistance (RE) and endurance (EE) exercise stimulate mixed skeletal muscle protein synthesis. The phenotypes induced by RE (myofibrillar protein accretion) and EE (mitochondrial expansion) training must result from differential stimulation of myofibrillar and mitochondrial protein synthesis. We measured the synthetic rates of myofibrillar and mitochondrial proteins and the activation of signalling proteins (Akt-mTOR-p70S6K) at rest and after an acute bout of RE or EE in the untrained state and after 10 weeks of RE or EE training in young healthy men. While untrained, RE stimulated both myofibrillar and mitochondrial protein synthesis, 67% and 69% (P < 0.02), respectively. After training, only myofibrillar protein synthesis increased with RE (36%, P = 0.05). EE stimulated mitochondrial protein synthesis in both the untrained, 154%, and trained, 105% (both P < 0.05), but not myofibrillar protein synthesis. Acute RE and EE increased the phosphorylation of proteins in the Akt-mTOR-p70S6K pathway with comparatively minor differences between two exercise stimuli. Phosphorylation of Akt-mTOR-p70S6K proteins was increased after 10 weeks of RE training but not by EE training. Chronic RE or EE training modifies the protein synthetic response of functional protein fractions, with a shift toward exercise phenotype-specific responses, without an obvious explanatory change in the phosphorylation of regulatory signalling pathway proteins.

Contribution of transcranial magnetic stimulation to the understanding of cortical mechanisms involved in motor control

Abstract: Transcranial magnetic stimulation (TMS) was initially used to evaluate the integrity of the corticospinal tract in humans non-invasively. Since these early studies, the development of paired-pulse and repetitive TMS protocols allowed investigators to explore inhibitory and excitatory interactions of various motor and non-motor cortical regions within and across cerebral hemispheres. These applications have provided insight into the intracortical physiological processes underlying the functional role of different brain regions in various cognitive processes, motor control in health and disease and neuroplastic changes during recovery of function after brain lesions. Used in combination with neuroimaging tools, TMS provides valuable information on functional connectivity between different brain regions, and on the relationship between physiological processes and the anatomical configuration of specific brain areas and connected pathways. More recently, there has been increasing interest in the extent to which these physiological processes are modulated depending on the behavioural setting. The purpose of this paper is (a) to present an up-to-date review of the available electrophysiological data and the impact on our understanding of human motor behaviour and (b) to discuss some of the gaps in our present knowledge as well as future directions of research in a format accessible to new students and/or investigators. Finally, areas of uncertainty and limitations in the interpretation of TMS studies are discussed in some detail.

Endurance exercise performance in Masters athletes: age-associated changes and underlying physiological mechanisms

Abstract: Older (‘Masters’) athletes strive to maintain or even improve upon the performance they achieved at younger ages, but declines in athletic performance are inevitable with ageing. In this review, we describe changes in peak endurance exercise performance with advancing age as well as physiological factors responsible for those changes. Peak endurance performance is maintained until ∼35 years of age, followed by modest decreases until 50–60 years of age, with progressively steeper declines thereafter. Among the three main physiological determinants of endurance exercise performance (i.e. maximal oxygen consumption , lactate threshold and exercise economy), a progressive reduction in appears to be the primary mechanism associated with declines in endurance performance with age. A reduction in lactate threshold, i.e. the exercise intensity at which blood lactate concentration increases significantly above baseline, also contributes to the reduction in endurance performance with ageing, although this may be secondary to decreases in . In contrast, exercise economy (i.e. metabolic cost of sustained submaximal exercise) does not change with age in endurance-trained adults. Decreases in maximal stroke volume, heart rate and arterio-venous O2 difference all appear to contribute to the age-related reductions in in endurance-trained athletes. Declines in endurance exercise performance and its physiological determinants with ageing appear to be mediated in large part by a reduction in the intensity (velocity) and volume of the exercise that can be performed during training sessions. Given their impressive peak performance capability and physiological function capacity, Masters athletes remain a fascinating model of ‘exceptionally successful ageing’ and therefore are highly deserving of our continued scientific attention as physiologists.

Retinal ganglion cells in diabetes

Abstract: Diabetic retinopathy has long been recognized as a vascular disease that develops in most patients, and it was believed that the visual dysfunction that develops in some diabetics was due to the vascular lesions used to characterize the disease. It is becoming increasingly clear that neuronal cells of the retina also are affected by diabetes, resulting in dysfunction and even degeneration of some neuronal cells. Retinal ganglion cells (RGCs) are the best studied of the retinal neurons with respect to the effect of diabetes. Although investigations are providing new information about RGCs in diabetes, including therapies to inhibit the neurodegeneration, critical information about the function, anatomy and response properties of these cells is yet needed to understand the relationship between RGC changes and visual dysfunction in diabetes.

Immobilization induces anabolic resistance in human myofibrillar protein synthesis with low and high dose amino acid infusion

Abstract: We tested the hypothesis that increasing blood amino acid (AA) availability would counter the physical inactivity-induced reduction in muscle protein synthesis We determined how 14 days of unilateral knee immobilization affected quadriceps myofibrillar protein synthesis (MPS) in young healthy subjects (10 men, 2 women, 21 ± 1 years; 802 ± 40 kg, mean ±sem) in the post-absorptive state and after infusing AA (10% Primene) at low or high doses (43 and 261 mg kg−1 h−1) Muscle cross-sectional area (MRI) and peak isometric torque declined in the immobilized leg (−50 ± 12% and −25 ± 3%, respectively, both P 06) in the non-immobilized leg Immobilization induced a 27% decline in the rate of post-absorptive MPS (immobilized, 0027 ± 0003: non-immobilized, 0037 ± 0003% h−1; P < 0001) Regardless of dose, AA infusion stimulated a greater rise in MPS in the non-immobilized legs; at 4 h MPS was greater by +54 ± 12% with low dose and +68 ± 17% with high dose AA infusion (both P < 0001) There was some evidence of delayed responsiveness of phosphorylation of Akt to high doses of AA and p70S6k at both doses but no marked differences in that of mTOR, GSK3β or eEF2 Phosphorylation of focal adhesion kinase (Tyr576/577) was reduced (P < 005) with immobilization We observed no change in polyubiquitinated protein content after immobilization We confirm that 14 days of immobilization reduces MPS in the post-absorptive state and this diminution is reduced but not abolished by increased provision of AA, even at high rates The immobilization-induced decline in post-absorptive MPS with the ‘anabolic resistance’ to amino acids can account for much of immobilization-induced muscle atrophy

Elevation in cerebral blood flow velocity with aerobic fitness throughout healthy human ageing.

Abstract: It is known that cerebral blood flow declines with age in sedentary adults, although previous studies have involved small sample sizes, making the exact estimate of decline imprecise and the effects of possible moderator variables unknown. Animal studies indicate that aerobic exercise can elevate cerebral blood flow; however, this possibility has not been examined in humans. We examined how regular aerobic exercise affects the age-related decline in blood flow velocity in the middle cerebral artery (MCAv) in healthy humans. Maximal oxygen consumption, body mass index (BMI), blood pressure and MCAv were measured in healthy sedentary (n = 153) and endurance-trained (n = 154) men aged between 18 and 79 years. The relationships between age, training status, BMI and MCAv were examined using analysis of covariance methods. Mean +/- s.e.m. estimates of regression coefficients and 95% confidence intervals (95% CI) were calculated. The age-related decline in MCAv was -0.76 +/- 0.04 cm s(-1) year(-1) (95% CI = -0.69 to -0.83, r(2) = 0.66, P < 0.0005) and was independent of training status (P = 0.65). Nevertheless, MCAv was consistently elevated by 9.1 +/- 3.3 cm s(-1) (CI = 2.7-15.6, P = 0.006) in endurance-trained men throughout the age range. This approximately 17% difference between trained and sedentary men amounted to an approximate 10 year reduction in MCAv 'age' and was robust to between-group differences in BMI and blood pressure. Regular aerobic-endurance exercise is associated with higher MCAv in men aged 18-79 years. The persistence of this finding in older endurance-trained men may therefore help explain why there is a lower risk of cerebrovascular disease in this population.

The acute effect of stretching on the passive stiffness of the human gastrocnemius muscle tendon unit.

Abstract: Passive stretching is commonly used to increase limb range of movement prior to athletic performance but it is unclear which component of the muscle-tendon unit (MTU) is affected by this procedure. Movement of the myotendinous junction (MTJ) of the gastrocnemius medialis muscle was measured by ultrasonography in eight male participants (20.5 +/- 0.9 years) during a standard stretch in which the ankle was passively dorsiflexed at 1 deg s(-1) from 0 deg (the foot at right angles to the tibia) to the participants' volitional end range of motion (ROM). Passive torque, muscle fascicle length and pennation angle were also measured. Standard stretch measurements were made before (pre-) and after (post-) five passive conditioning stretches. During each conditioning stretch the MTU was taken to the end ROM and held for 1 min. Pre-conditioning the extension of the MTU during stretch was taken up almost equally by muscle and tendon. Following conditioning, ROM increased by 4.6 +/- 1.5 deg (17%) and the passive stiffness of the MTU was reduced (between 20 and 25 deg) by 47% from 16.0 +/- 3.6 to 10.2 +/- 2.0 Nm deg(-1). Distal MTJ displacement (between 0 and 25 deg) increased from 0.92 +/- 0.06 to 1.16 +/- 0.05 cm, accounting for all the additional MTU elongation and indicating that there was no change in tendon properties. Muscle extension pre-conditioning was explicable by change in length and pennation angle of the fascicles but post-conditioning this was not the case suggesting that at least part of the change in muscle with conditioning stretches was due to altered properties of connective tissue.

The cardiovascular challenge of exercising in the heat

Abstract: Exercise in the heat can pose a severe challenge to human cardiovascular control, and thus the provision of oxygen to exercising muscles and vital organs, because of enhanced thermoregulatory demand for skin blood flow coupled with dehydration and hyperthermia Cardiovascular strain, typified by reductions in cardiac output, skin and locomotor muscle blood flow and systemic and muscle oxygen delivery accompanies marked dehydration and hyperthermia during prolonged and intense exercise characteristic of many summer Olympic events This review focuses on how the cardiovascular system is regulated when exercising in the heat and how restrictions in locomotor skeletal muscle and/or skin perfusion might limit athletic performance in hot environments

Smooth muscle cell calcium activation mechanisms

Abstract: Smooth muscle cell (SMC) contraction is controlled by the Ca2+ and Rho kinase signalling pathways. While the SMC Rho kinase system seems to be reasonably constant, there is enormous variation with regard to the mechanisms responsible for generating Ca2+ signals. One way of dealing with this diversity is to consider how this system has been adapted to control different SMC functions. Phasic SMCs (vas deferens, uterus and bladder) rely on membrane depolarization to drive Ca2+ influx across the plasma membrane. This depolarization can be induced by neurotransmitters or through the operation of a membrane oscillator. Many tonic SMCs (vascular, airway and corpus cavernosum) are driven by a cytosolic Ca2+ oscillator that generates periodic pulses of Ca2+. A similar oscillator is present in pacemaker cells such as the interstitial cells of Cajal (ICCs) and atypical SMCs that control other tonic SMCs (gastrointestinal, urethra, ureter). The changes in membrane potential induced by these cytosolic oscillators does not drive contraction directly but it functions to couple together individual oscillators to provide the synchronization that is a characteristic feature of many tonic SMCs.

Locomotor muscle fatigue modifies central motor drive in healthy humans and imposes a limitation to exercise performance

Abstract: We asked whether the central effects of fatiguing locomotor muscle fatigue exert an inhibitory influence on central motor drive to regulate the total degree of peripheral fatigue development. Eight cyclists performed constant-workload prefatigue trials (a) to exhaustion (83% of peak power output (Wpeak), 10 ± 1 min; PFT83%), and (b) for an identical duration but at 67%Wpeak (PFT67%). Exercise-induced peripheral quadriceps fatigue was assessed via changes in potentiated quadriceps twitch force (ΔQtw,pot) from pre- to post-exercise in response to supra-maximal femoral nerve stimulation (ΔQtw,pot). On different days, each subject randomly performed three 5 km time trials (TTs). First, subjects repeated PFT83% and the TT was started 4 min later with a known level of pre-existing locomotor muscle fatigue (ΔQtw,pot−36%) (PFT83%-TT). Second, subjects repeated PFT67% and the TT was started 4 min later with a known level of pre-existing locomotor muscle fatigue (ΔQtw,pot−20%) (PFT67%-TT). Finally, a control TT was performed without any pre-existing level of fatigue. Central neural drive during the three TTs was estimated via quadriceps EMG. Increases in pre-existing locomotor muscle fatigue from control TT to PFT83%-TT resulted in significant dose-dependent changes in central motor drive (−23%), power output (−14%), and performance time (+6%) during the TTs. However, the magnitude of locomotor muscle fatigue following various TTs was not different (ΔQtw,pot of −35 to −37%, P= 0.35). We suggest that feedback from fatiguing muscle plays an important role in the determination of central motor drive and force output, so that the development of peripheral muscle fatigue is confined to a certain level.

Interdependent roles for hypoxia inducible factor and nuclear factor-κB in hypoxic inflammation

Abstract: Decreased oxygen availability (hypoxia) is a hallmark feature of the microenvironment in a number of chronic inflammatory conditions including arthritis and inflammatory bowel disease (IBD). Recent advances in our understanding of oxygen-dependent cell signalling have uncovered several mechanisms by which hypoxia impacts upon the development of inflammation through the coordinated expression of adaptive, inflammatory and apoptotic genes. Two central transcription factors involved in the regulation of this response are hypoxia inducible factor (HIF) and nuclear factor-κB (NF-κB) which display different degrees of sensitivity to activation during hypoxia. Furthermore, HIF and NF-κB demonstrate an intimate interdependence at several mechanistic levels. Recent studies indicate that these pathways may represent important new therapeutic targets in diseases characterized by hypoxic inflammation.

: what do we know, and what do we still need to know?

Abstract: Maximal oxygen uptake is a physiological characteristic bounded by the parametric limits of the Fick equation: (left ventricular (LV) end-diastolic volume − LV end-systolic volume) × heart rate × arterio-venous oxygen difference. ‘Classical’ views of emphasize its critical dependence on convective oxygen transport to working skeletal muscle, and recent data are dispositive, proving convincingly that such limits must and do exist. ‘Contemporary’ investigations into the mechanisms underlying peripheral muscle fatigue due to energetic supply/demand mismatch are clarifying the local mediators of fatigue at the skeletal muscle level, though the afferent signalling pathways that communicate these environmental conditions to the brain and the sites of central integration of cardiovascular and neuromotor control are still being worked out. Elite endurance athletes have a high due primarily to a high cardiac output from a large compliant cardiac chamber (including the myocardium and pericardium) which relaxes quickly and fills to a large end-diastolic volume. This large capacity for LV filling and ejection allows preservation of blood pressure during extraordinary rates of muscle blood flow and oxygen transport which support high rates of sustained oxidative metabolism. The magnitude and mechanisms of cardiac phenotype plasticity remain uncertain and probably involve underlying genetic factors, as well as the length, duration, type, intensity and age of initiation of the training stimulus

Human tendon behaviour and adaptation, in vivo.

Abstract: Tendon properties contribute to the complex interaction of the central nervous system, muscle-tendon unit and bony structures to produce joint movement. Until recently limited information on human tendon behaviour in vivo was available; however, novel methodological advancements have enabled new insights to be gained in this area. The present review summarizes the progress made with respect to human tendon and aponeurosis function in vivo, and how tendons adapt to ageing, loading and unloading conditions. During low tensile loading or with passive lengthening not only the muscle is elongated, but also the tendon undergoes significant length changes, which may have implications for reflex responses. During active loading, the length change of the tendon far exceeds that of the aponeurosis, indicating that the aponeurosis may more effectively transfer force onto the tendon, which lengthens and stores elastic energy subsequently released during unloading, in a spring-like manner. In fact, data recently obtained in vivo confirm that, during walking, the human Achilles tendon provides elastic strain energy that can decrease the energy cost of locomotion. Also, new experimental evidence shows that, contrary to earlier beliefs, the metabolic activity in human tendon is remarkably high and this affords the tendon the ability to adapt to changing demands. With ageing and disuse there is a reduction in tendon stiffness, which can be mitigated with resistance exercises. Such adaptations seem advantageous for maintaining movement rapidity, reducing tendon stress and risk of injury, and possibly, for enabling muscles to operate closer to the optimum region of the length-tension relationship.

Differential effects of hydrocortisone and TNFα on tight junction proteins in an in vitro model of the human blood-brain barrier

Abstract: Homeostasis of the central nervous system (CNS) microenvironment is maintained by the blood–brain barrier (BBB) which regulates the transport of molecules from blood into brain and back. Many disorders change the functionality and integrity of the BBB. Glucocorticoids are being used sucessfully in the treatment of some disorders while their effects on others are questionable. In addition, conflicting results between clinical and experimental experience using animal models has arisen, so that the results of molecular studies in animal models need to be revisited in an appropriate in vitro model of the human BBB for more effective treatment strategies. Using the human brain microvascular endothelial cell line hCMEC/D3, the influence of glucocorticoids on the expression of barrier constituting adherens junction and tight junction transmembrane proteins (VE-cadherin, occludin, claudins) was investigated and compared to other established BBB models. In hCMEC/D3 cells the administration of glucocorticoids induced expression of the targets occludin 2.75 ± 0.04-fold and claudin-5 up to 2.32 ± 0.11-fold, which is likely to contribute to the more than threefold enhancement of transendothelial electrical resistance reflecting barrier tightness. Our analyses further provide direct evidence that the GC hydrocortisone prevents endothelial barrier breakdown in response to pro-inflammatory stimuli (TNFα administration), which could be demonstrated to be partly based on maintenance of occludin levels. Our studies strongly suggest stabilization of BBB function as a mode of GC action on a molecular level in the human brain vasculature.

The physiological basis of the effects of intermittent theta burst stimulation of the human motor cortex.

Abstract: Theta burst stimulation (TBS) is a form of repetitive transcranial magnetic stimulation (TMS). When applied to motor cortex it leads to after-effects on corticospinal and corticocortical excitability that may reflect LTP/LTD-like synaptic effects. An inhibitory form of TBS (continuous, cTBS) suppresses MEPs, and spinal epidural recordings show this is due to suppression of the I1 volley evoked by TMS. Here we investigate whether the excitatory form of TBS (intermittent, iTBS) affects the same I-wave circuitry. We recorded corticospinal volleys evoked by single pulse TMS of the motor cortex before and after iTBS in three conscious patients who had an electrode implanted in the cervical epidural space for the control of pain. As in healthy subjects, iTBS increased MEPs, and this was accompanied by a significant increase in the amplitude of later I-waves, but not the I1 wave. In two of the patients we tested the excitability of the contralateral cortex and found a significant suppression of the late I-waves. The extent of the changes varied between the three patients, as did their age. To investigate whether age might be a significant contributor to the variability we examined the effect of iTBS on MEPs in 18 healthy subjects. iTBS facilitated MEPs evoked by TMS of the conditioned hemisphere and suppressed MEPs evoked by stimulation of the contralateral hemisphere. There was a slight but non-significant decline in MEP facilitation with age, suggesting that interindividual variability was more important than age in explaining our data. In a subgroup of 10 subjects we found that iTBS had no effect on the duration of the ipsilateral silent period suggesting that the reduction in contralateral MEPs was not due to an increase in ongoing transcallosal inhibition. In conclusion, iTBS affects the excitability of excitatory synaptic inputs to pyramidal tract neurones that are recruited by a TMS pulse, both in the stimulated hemisphere and in the contralateral hemisphere. However the circuits affected differ from those influenced by the inhibitory, cTBS, protocol. The implication is that cTBS and iTBS may have different therapeutic targets.

Expression and function of the ion channel TRPA1 in vagal afferent nerves innervating mouse lungs

Abstract: Transient receptor potential (TRP) A1 and TRPM8 are ion channels that have been localized to afferent nociceptive nerves. These TRP channels may be of particular relevance to respiratory nociceptors in that they can be activated by various inhaled irritants and/or cold air. We addressed the hypothesis that mouse vagal sensory nerves projecting to the airways express TRPA1 and TRPM8 and that they can be activated via these receptors. Single cell RT-PCR analysis revealed that TRPA1 mRNA, but not TRPM8, is uniformly expressed in lung-labelled TRPV1-expressing vagal sensory neurons. Neither TRPA1 nor TRPM8 mRNA was expressed in TRPV1-negative neurons. Capsaicin-sensitive, but not capsaicin-insensitive, lung-specific neurons responded to cinnamaldehyde, a TRPA1 agonist, with increases in intracellular calcium. Menthol, a TRPM8 agonist, was ineffective at increasing cellular calcium in lung-specific vagal sensory neurons. Cinnamaldehyde also induced TRPA1-like inward currents (as measured by means of whole cell patch clamp recordings) in capsaicin-sensitive neurons. In an ex vivo vagal innervated mouse lung preparation, cinnamaldehyde evoked action potential discharge in mouse vagal C-fibres with a peak frequency similar to that observed with capsaicin. Cinnamaldehyde inhalation in vivo mimicked capsaicin in eliciting strong central-reflex changes in breathing pattern. Taken together, our results support the hypothesis that TRPA1, but not TRPM8, is expressed in vagal sensory nerves innervating the airways. TRPA1 activation provides a mechanism by which certain environmental stimuli may elicit action potential discharge in airway afferent C-fibres and the consequent nocifensor reflexes.

No stress please! Mechanisms of stress hyporesponsiveness of the maternal brain

Abstract: The time around birth is accompanied by behavioural and physiological adaptations of the maternal brain, which ensure reproductive functions, maternal care and the survival of the offspring. In addition, profound neuroendocrine and neurobiological adaptations have been described with respect to behavioural and neuroendocrine stress responsiveness in rodents and human mothers. Thus, the hormonal response of the hypothalamo-pituitary-adrenal (HPA) axis and the response of the sympathetic nervous system to emotional and physical stressors are severely attenuated. Moreover, anxiety-related behaviour and emotional responsiveness to stressful stimuli are reduced with the result of general calmness. These complex adaptations of the maternal brain are likely to be a consequence of an increased activity of brain systems with inhibitory effects on the HPA axis (such as the oxytocin and prolactin systems) and of a reduced activity of excitatory pathways (noradrenaline (norepinephrine), corticotrophin-releasing factor and opioids). Experimental manipulation of these systems using complementary approaches indeed demonstrates their importance in these maternal brain adaptations. Maternal stress adaptations are not only important for the healthy prenatal development of the offspring by preventing excessive glucocorticoid responses and in the promotion of postnatal maternal behaviour, but are also vital for the well-being of the mother and her mental health.

Corticotropin-releasing factor increases mouse ventral tegmental area dopamine neuron firing through a protein kinase C-dependent enhancement of Ih

Abstract: Stress induces the release of the peptide corticotropin-releasing factor (CRF) into the ventral tegmental area (VTA), and also increases dopamine levels in brain regions receiving dense VTA input. Therefore, stress may activate the mesolimbic dopamine system in part through the actions of CRF in the VTA. Here, we explored the mechanism by which CRF affects VTA dopamine neuron firing. Using patch-clamp recordings from brain slices we first determined that the presence of Ih is an excellent predictor of dopamine content in mice. We next showed that CRF dose-dependently increased VTA dopamine neuron firing, which was prevented by antagonism of the CRF receptor-1 (CRF-R1), and was mimicked by CRF-R1 agonists. Inhibition of the phospholipase C (PLC)–protein kinase C (PKC) signalling pathway, but not the cAMP–protein kinase A (PKA) signalling pathway, prevented the increase in dopamine neuron firing by CRF. Furthermore, the effect of CRF on VTA dopamine neurons was not attenuated by blockade of IA, IK(Ca) or IKir, but was completely eliminated by inhibition of Ih. Although cAMP-dependent modulation of Ih through changes in the voltage dependence of activation is well established, we surprisingly found that CRF, through a PKC-dependent mechanism, enhanced Ih independent of changes in the voltage dependence of activation. Thus, our results demonstrated that CRF acted on the CRF-R1 to stimulate the PLC–PKC signalling pathway, which in turn enhanced Ih to increase VTA dopamine neuron firing. These findings provide a cellular mechanism of the interaction between CRF and dopamine, which can be involved in promoting the avoidance of threatening stimuli, the pursuit of appetitive behaviours, as well as various psychiatric conditions.

Role for metabotropic glutamate receptor 5 (mGluR5) in the pathogenesis of fragile X syndrome.

Abstract: Metabotropic glutamate receptors (mGluRs) have been implicated in a diverse variety of neuronal functions. Studies reviewed here indicate that exaggerated signalling through mGluR5 can account for multiple cognitive and syndromic features of fragile X syndrome, the most common inherited form of mental retardation and autism. Since a reduction of mGluR5 signalling can reverse fragile X phenotypes, these studies provide a compelling rationale for the use of mGluR5 antagonists for the treatment of fragile X and related disorders.

Time course of change in vasodilator function and capacity in response to exercise training in humans

Abstract: Studies of the impact of exercise training on arterial adaptation in healthy subjects have produced disparate results. It is possible that some studies failed to detect changes because functional and structural adaptations follow a different time course and may therefore not be detected at discrete time points. To gain insight into the time course of training-induced changes in artery function and structure, we examined conduit artery flow mediated dilatation (FMD), an index of nitric oxide (NO)-mediated artery function, and conduit dilator capacity (DC), a surrogate marker for arterial remodelling, in the brachial and popliteal arteries of 13 healthy male subjects (21.6 +/- 0.6 years) and seven non-active controls (22.8 +/- 0.2 years) studied at 2-week intervals across an 8-week cycle and treadmill exercise training programme. Brachial and popliteal artery FMD and DC did not change in control subjects at any time point. FMD increased from baseline (5.9 +/- 0.5%) at weeks 2 and 4 (9.1 +/- 0.6, 8.5 +/- 0.6%, respectively, P < 0.01), but returned towards baseline levels again by week 8 (6.9 +/- 0.7%). In contrast, brachial artery DC progressively increased from baseline (8.1 +/- 0.4%) at weeks 2, 4, 6 and 8 (9.2 +/- 0.6, 9.9 +/- 0.6, 10.0 +/- 0.5, 10.5 +/- 0.8%, P < 0.05). Similarly, popliteal artery FMD increased from baseline (6.2 +/- 0.7%) at weeks 2, 4 and 6 (9.1 +/- 0.6, 9.5 +/- 0.6, 7.8 +/- 0.5%, respectively, P < 0.05), but decreased again by week 8 (6.5 +/- 0.6%), whereas popliteal DC progressively increased from baseline (8.9 +/- 0.4%) at week 4 and 8 (10.5 +/- 0.7, 12.2 +/- 0.6%, respectively, P < 0.05). These data suggest that functional changes in conduit arteries occur rapidly and precede arterial remodelling in vivo. These data suggest that complimentary adaptations occur in arterial function and structure and future studies should adopt multiple time point assessments to comprehensively assess arterial adaptations to interventions such as exercise training in humans.

A functional insulin-like growth factor receptor is not necessary for load-induced skeletal muscle hypertrophy

Abstract: Increasing the mechanical load on skeletal muscle results in increased expression of insulin-like growth factor I (IGF-I), which is thought to be a critical step in the induction of muscle hypertrophy. To determine the role of the IGF-I receptor in load-induced skeletal muscle hypertrophy, we utilized a transgenic mouse model (MKR) that expresses a dominant negative IGF-I receptor specifically in skeletal muscle. Skeletal muscle hypertrophy was induced in the plantaris muscle using the functional overload (FO) model, a model which has previously been shown to induce significant elevations of IGF-I expression in skeletal muscle. Adult male wild-type (WT) and MKR mice were subjected to 0, 7 or 35 days of FO. In control or unchallenged animals, the plantaris mass was 11% greater in WT compared to the MKR mice (P < 0.05). After 7 days of FO, plantaris mass increased significantly by 26% and 62% in WT and MKR mice, respectively (P < 0.05). After 35 days of FO, WT and MKR mice demonstrated significant increases of 100% and 122%, respectively, in plantaris mass (P < 0.05). Further, at no time point was the degree of hypertrophy significantly different between the WT and MKR mice. Previous research suggests that IGF-I induces muscle growth through activation of the Akt-mTOR signalling pathway; therefore, we measured the phosphorylation status of Akt and p70(s6k) in the WT and MKR mice after 7 days of FO. Significant increases of approximately 100% and approximately 200% in Akt (Ser-473) and p70(s6k) (Thr-389) phosphorylation were measured in overloaded plantaris from both WT and MKR mice, respectively. Moreover, no differences were detected between the WT and MKR mice. These data suggest that increased mechanical load can induce muscle hypertrophy and activate the Akt and p70(s6k) independent of a functioning IGF-I receptor.

The regulation of dendritic arbor development and plasticity by glutamatergic synaptic input: a review of the synaptotrophic hypothesis.

Abstract: The synaptotropic hypothesis, which states that synaptic inputs control the elaboration of dendritic (and axonal) arbors was articulated by Vaughn in 1989. Today the role of synaptic inputs in controlling neuronal structural development remains an area of intense research activity. Several recent studies have applied modern molecular genetic, imaging and electrophysiological methods to this question and now provide strong evidence that maturation of excitatory synaptic inputs is required for the development of neuronal structure in the intact brain. Here we critically review data concerning the hypothesis with the expectation that understanding the circumstances when the data do and do not support the hypothesis will be most valuable. The synaptotrophic hypothesis contributes at both conceptual and mechanistic levels to our understanding of how relatively minor changes in levels or function of synaptic proteins may have profound effects on circuit development and plasticity.

Bidirectional long-term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation.

Abstract: Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising tool to induce plastic changes that are thought in some cases to reflect N-methyl-d-aspartate-sensitive changes in synaptic efficacy. As in animal experiments, there is some evidence that the sign of rTMS-induced plasticity depends on the prior history of cortical activity, conforming to the Bienenstock–Cooper–Munro (BCM) theory. However, experiments exploring these plastic changes have only examined priming-induced effects on a limited number of rTMS protocols, often using designs in which the priming alone had a larger effect than the principle conditioning protocol. The aim of this study was to introduce a new rTMS protocol that gives a broad range of after-effects from suppression to facilitation and then test how each of these is affected by a priming protocol that on its own has no effect on motor cortical excitability, as indexed by motor-evoked potential (MEP). Repeated trains of four monophasic TMS pulses (quadripulse stimulation: QPS) separated by interstimulus intervals of 1.5–1250 ms produced a range of after-effects that were compatible with changes in synaptic plasticity. Thus, QPS at short intervals facilitated MEPs for more than 75 min, whereas QPS at long intervals suppressed MEPs for more than 75 min. Paired-pulse TMS experiments exploring intracortical inhibition and facilitation after QPS revealed effects on excitatory but not inhibitory circuits of the primary motor cortex. Finally, the effect of priming protocols on QPS-induced plasticity was consistent with a BCM-like model of priming that shifts the crossover point at which synaptic plasticity reverses from depression to potentiation. The broad range of after-effects produced by the new rTMS protocol opens up new possibilities for detailed examination of theories of metaplasticity in humans.

Preferential motor unit loss in the SOD1G93A transgenic mouse model of amyotrophic lateral sclerosis

Abstract: The present study investigated motor unit (MU) loss in a murine model of familial amyotrophic lateral sclerosis (ALS). The fast-twitch tibialis anterior (TA) and medial gastrocnemius (MG) muscles of transgenic SOD1G93A and SOD1WT mice were studied during the presymptomatic phase of disease progression at 60 days of age. Whole muscle maximum isometric twitch and tetanic forces were 80% lower (P < 0.01) in the TA muscles of SOD1G93A compared to SOD1WT mice. Enumeration of total MU numbers within TA muscles showed a 60% reduction (P < 0.01) within SOD1G93A mice (38 ± 7) compared with SOD1WT controls (95 ± 12); this was attributed to a lower proportion of the most forceful fast-fatigable (FF) MU in SOD1G93A mice, as seen by a significant (P < 0.01) leftward shift in the cumulative frequency histogram of single MU forces. Similar patterns of MU loss and corresponding decreases in isometric twitch force were observed in the MG. Immunocytochemical analyses of the entire cross-sectional area (CSA) of serial sections of TA muscles stained with anti-neural cell adhesion molecule (NCAM) and various monoclonal antibodies for myosin heavy chain (MHC) isoforms showed respective 65% (P < 0.01) and 28% (P < 0.05) decreases in the number of innervated IIB and IID/X muscle fibres in SOD1G93A, which paralleled the 60% decrease (P < 0.01) in the force generating capacity of individual fibres. The loss of fast MUs was partially compensated by activity-dependent fast-to-slower fibre type transitions, as determined by increases (P < 0.04) in the CSA and proportion of IIA fibres (from 4% to 14%) and IID/X fibres (from 31% to 39%), and decreases (P < 0.001) in the CSA and proportion of type IIB fibres (from 65% to 44%). We conclude that preferential loss of IIB fibres is incomplete at 60 days of age, and is consistent with a selective albeit gradual loss of FF MUs that is not fully compensated by sprouting of the remaining motoneurons that innervate type IIA or IID/X muscle fibres. Our findings indicate that disease progression in fast-twitch muscles of SOD1G93A mice involves parallel processes: (1) gradual selective motor axon die-back of the FF motor units that contain large type IIB muscle fibres, and of fatigue-intermediate motor units that innervate type IID/X muscle fibres, and (2) activity-dependent conversion of motor units to those innervated by smaller motor axons innervating type IIA fatigue-resistant muscle fibres.

Increased sympathetic outflow in juvenile rats submitted to chronic intermittent hypoxia correlates with enhanced expiratory activity

Abstract: Chronic intermittent hypoxia (CIH) in rats produces changes in the central regulation of cardiovascular and respiratory systems by unknown mechanisms. We hypothesized that CIH (6% O(2) for 40 s, every 9 min, 8 h day(-1)) for 10 days alters the central respiratory modulation of sympathetic activity. After CIH, awake rats (n = 14) exhibited higher levels of mean arterial pressure than controls (101 +/- 3 versus 89 +/- 3 mmHg, n = 15, P < 0.01). Recordings of phrenic, thoracic sympathetic, cervical vagus and abdominal nerves were performed in the in situ working heart-brainstem preparations of control and CIH juvenile rats. The data obtained in CIH rats revealed that: (i) abdominal (Abd) nerves exhibited an additional burst discharge in late expiration; (ii) thoracic sympathetic nerve activity (tSNA) was greater during late expiration than in controls (52 +/- 5 versus 40 +/- 3%; n = 11, P < 0.05; values expressed according to the maximal activity observed during inspiration and the noise level recorded at the end of each experiment), which was not dependent on peripheral chemoreceptors; (iii) the additional late expiratory activity in the Abd nerve correlated with the increased tSNA; (iv) the enhanced late expiratory activity in the Abd nerve unique to CIH rats was accompanied by reduced post-inspiratory activity in cervical vagus nerve compared to controls. The data indicate that CIH rats present an altered pattern of central sympathetic-respiratory coupling, with increased tSNA that correlates with enhanced late expiratory discharge in the Abd nerve. Thus, CIH alters the coupling between the central respiratory generator and sympathetic networks that may contribute to the induced hypertension in this experimental model.

Synaptic integration and plasticity of new neurons in the adult hippocampus

Abstract: Adult neurogenesis, a developmental process encompassing the birth of new neurons from adult neural stem cells and their integration into the existing neuronal circuitry, highlights the plasticity and regenerative capacity of the adult mammalian brain. Substantial evidence suggests essential roles of newborn neurons in specific brain functions; yet it remains unclear how these new neurons make their unique contribution. Recently, a series of studies have delineated the basic steps of the adult neurogenesis process and shown that many of the distinct steps are dynamically regulated by the activity of the existing circuitry. Here we review recent findings on the synaptic integration and plasticity of newborn neurons in the adult hippocampus, including the basic biological process, unique characteristics, critical periods, and activity-dependent regulation by the neurotransmitters GABA and glutamate. We propose that adult neurogenesis represents not merely a replacement mechanism for lost neurons, but also an ongoing developmental process in the adult brain that offers an expanded capacity for plasticity for shaping the existing circuitry in response to experience throughout life.