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American Journal of Physiology.... Sep 2019Passive limb movement and limb muscle stretch in humans and animals are common experimental strategies used to investigate activation of the muscle mechanoreflex...
Passive limb movement and limb muscle stretch in humans and animals are common experimental strategies used to investigate activation of the muscle mechanoreflex independent of contraction-induced metabolite production. Cyclooxygenase (COX) metabolites, however, are produced by skeletal muscle stretch in vitro and have been found to impact various models of mechanoreflex activation. Whether COX metabolites influence the decerebrate rat triceps surae muscle stretch mechanoreflex model remains unknown. We examined the effect of rat triceps surae muscle stretch on the interstitial concentration of the COX metabolite prostaglandin E (PGE). Interstitial PGE concentration was increased above baseline values by 4 min of both static (38% increase, = 0.01) and dynamic (56% increase, < 0.01) triceps surae muscle stretch ( = 10). The 4-min protocol was required to collect enough microdialysis fluid for PGE detection. The finding that skeletal muscle stretch in vivo was capable of producing COX metabolites prompted the hypothesis that intra-arterial administration of the COX inhibitor indomethacin (1 mg/kg) would reduce the pressor and cardioaccelerator responses evoked during 30 s (the duration most commonly used in the rat mechanoreflex model) of static and dynamic rat triceps surae muscle stretch. We found that indomethacin had no effect ( > 0.05, = 9) on the pressor or cardioaccelerator response during 30 s of either static or dynamic stretch. We conclude that, despite the possibility of increased COX metabolite concentration, COX metabolites do not activate or sensitize thin-fiber muscle afferents stimulated during 30 s of static or dynamic hindlimb skeletal muscle stretch in healthy rats.
Topics: Animals; Blood Pressure; Cyclooxygenase Inhibitors; Decerebrate State; Dinoprostone; Heart Rate; Indomethacin; Male; Mechanoreceptors; Rats; Rats, Sprague-Dawley; Reflex, Stretch
PubMed: 31241976
DOI: 10.1152/ajpregu.00080.2019 -
Physiological Reports Jan 2019Mechanical signals within contracting skeletal muscles contribute to the generation of the exercise pressor reflex; an important autonomic and cardiovascular control...
Mechanical signals within contracting skeletal muscles contribute to the generation of the exercise pressor reflex; an important autonomic and cardiovascular control mechanism. In decerebrate rats, the mechanically activated channel inhibitor GsMTx4 was found to reduce the pressor response during static hindlimb muscle stretch; a maneuver used to investigate specifically the mechanical component of the exercise pressor reflex (i.e., the mechanoreflex). However, the effect was found only during the initial phase of the stretch when muscle length was changing and not during the later phase of stretch when muscle length was relatively constant. We tested the hypothesis that in decerebrate, unanesthetized rats, GsMTx4 would reduce the pressor response throughout the duration of a 30 sec, 1 Hz dynamic hindlimb muscle stretch protocol that produced repetitive changes in muscle length. We found that the injection of 10 μg of GsMTx4 into the arterial supply of a hindlimb reduced the peak pressor response (control: 15 ± 4, GsMTx4: 5 ± 2 mmHg, P < 0.05, n = 8) and the pressor response at multiple time points throughout the duration of the stretch. GsMTx4 had no effect on the pressor response to the hindlimb arterial injection of lactic acid which indicates the lack of local off-target effects. Combined with the recent finding that GsMTx4 reduced the pressor response only initially during static stretch in decerebrate rats, the present findings suggest that GsMTx4-sensitive channels respond primarily to mechanical signals associated with changes in muscle length. The findings add to our currently limited understanding of the channels that contribute to the activation of the mechanoreflex.
Topics: Animals; Blood Pressure; Decerebrate State; Hindlimb; Intercellular Signaling Peptides and Proteins; Male; Muscle Contraction; Muscle, Skeletal; Rats; Rats, Sprague-Dawley; Reflex; Spider Venoms
PubMed: 30632294
DOI: 10.14814/phy2.13974 -
The Journal of Neuroscience : the... Nov 2014Neural encoding of the passage of time to produce temporally precise movements remains an open question. Neurons in several brain regions across different experimental...
Neural encoding of the passage of time to produce temporally precise movements remains an open question. Neurons in several brain regions across different experimental contexts encode estimates of temporal intervals by scaling their activity in proportion to the interval duration. In motor cortex the degree to which this scaled activity relies upon afferent feedback and is guided by motor output remains unclear. Using a neural reward paradigm to dissociate neural activity from motor output before and after complete spinal transection, we show that temporally scaled activity occurs in the rat hindlimb motor cortex in the absence of motor output and after transection. Context-dependent changes in the encoding are plastic, reversible, and re-established following injury. Therefore, in the absence of motor output and despite a loss of afferent feedback, thought necessary for timed movements, the rat motor cortex displays scaled activity during a broad range of temporally demanding tasks similar to that identified in other brain regions.
Topics: Animals; Decerebrate State; Electromyography; Hindlimb; Male; Motor Cortex; Movement; Neurons; Rats; Rats, Long-Evans; Reward; Stereotyped Behavior
PubMed: 25411486
DOI: 10.1523/JNEUROSCI.1816-14.2014 -
American Journal of Physiology. Heart... May 2016Mechanical and metabolic stimuli arising from contracting muscles evoke the exercise pressor reflex. This reflex is greater in a rat model of simulated peripheral... (Comparative Study)
Comparative Study
Mechanical and metabolic stimuli arising from contracting muscles evoke the exercise pressor reflex. This reflex is greater in a rat model of simulated peripheral arterial disease in which a femoral artery is chronically ligated than it is in rats with freely perfused femoral arteries. The role played by the mechanically sensitive component of the exaggerated exercise pressor reflex in ligated rats is unknown. We tested the hypothesis that the mechano-gated channel inhibitor GsMTx4, a relatively selective inhibitor of mechano-gated Piezo channels, reduces the exercise pressor reflex in decerebrate rats with ligated femoral arteries. Injection of 10 μg of GsMTx4 into the arterial supply of the hindlimb reduced the pressor response to Achilles tendon stretch (a purely mechanical stimulus) but had no effect on the pressor responses to intra-arterial injection of α,β-methylene ATP or lactic acid (purely metabolic stimuli). Moreover, injection of 10 μg of GsMTx4 into the arterial supply of the hindlimb reduced both the integrated pressor area (control 535 ± 21, GsMTx4 218 ± 24 mmHg·s; P < 0.01), peak pressor (control 29 ± 2, GsMTx4 14 ± 3 mmHg; P < 0.01), and renal sympathetic nerve responses to electrically induced intermittent hindlimb muscle contraction (a mixed mechanical and metabolic stimulus). The reduction of the integrated pressor area during contraction caused by GsMTx4 was greater in rats with ligated femoral arteries than it was in rats with freely perfused femoral arteries. We conclude that the mechanically sensitive component of the reflex contributes to the exaggerated exercise pressor reflex during intermittent hindlimb muscle contractions in rats with ligated femoral arteries.
Topics: Achilles Tendon; Animals; Chemoreceptor Cells; Decerebrate State; Disease Models, Animal; Electric Stimulation; Femoral Artery; Hindlimb; Injections, Intra-Arterial; Intercellular Signaling Peptides and Proteins; Ion Channels; Ligation; Male; Mechanotransduction, Cellular; Membrane Transport Modulators; Muscle Contraction; Muscle, Skeletal; Peptides; Peripheral Arterial Disease; Rats, Sprague-Dawley; Reflex, Stretch; Spider Venoms; Sympathetic Nervous System; Time Factors
PubMed: 26921442
DOI: 10.1152/ajpheart.00974.2015 -
The Journal of Physiology May 2015This study examined motoneurone properties during fictive locomotion in the adult rat for the first time. Fictive locomotion was induced via electrical stimulation of... (Comparative Study)
Comparative Study
This study examined motoneurone properties during fictive locomotion in the adult rat for the first time. Fictive locomotion was induced via electrical stimulation of the mesencephalic locomotor region in decerebrate adult rats under neuromuscular blockade to compare basic and rhythmic motoneurone properties in antidromically identified extensor motoneurones during: (1) quiescence, before and after fictive locomotion; (2) the 'tonic' period immediately preceding locomotor-like activity, whereby the amplitude of peripheral flexor (peroneal) and extensor (tibial) nerves are increased but alternation has not yet occurred; and (3) locomotor-like episodes. Locomotion was identified by alternating flexor-extensor nerve activity, where the motoneurone either produced membrane oscillations consistent with a locomotor drive potential (LDP) or did not display membrane oscillation during alternating nerve activity. Cells producing LDPs were referred to as such, while those that did not were referred to as 'idle' motoneurones. LDP and idle motoneurones during locomotion had hyperpolarized spike threshold (Vth ; LDP: 3.8 mV; idle: 5.8 mV), decreased rheobase and an increased discharge rate (LDP: 64%; idle: 41%) during triangular ramp current injection even though the frequency-current slope was reduced by 70% and 55%, respectively. Modulation began in the tonic period immediately preceding locomotion, with a hyperpolarized Vth and reduced rheobase. Spike frequency adaptation did not occur in spiking LDPs or firing generated from sinusoidal current injection, but occurred during a sustained current pulse during locomotion. Input conductance showed no change. Results suggest motoneurone modulation occurs across the pool and is not restricted to motoneurones engaged in locomotion.
Topics: Action Potentials; Adaptation, Physiological; Animals; Cats; Decerebrate State; Electric Stimulation; Female; Hindlimb; Locomotion; Models, Animal; Motor Neurons; Rats; Rats, Sprague-Dawley
PubMed: 25809835
DOI: 10.1113/JP270239 -
American Journal of Physiology. Heart... Nov 2019Mechanical and metabolic stimuli within contracting skeletal muscles reflexly increase sympathetic nervous system activity and blood pressure. That reflex, termed the...
Mechanical and metabolic stimuli within contracting skeletal muscles reflexly increase sympathetic nervous system activity and blood pressure. That reflex, termed the exercise pressor reflex, is exaggerated in patients with peripheral artery disease (PAD) and in a rat PAD model with a chronically ligated femoral artery. The cyclooxygenase (COX) pathway contributes to the exaggerated pressor response during rhythmic skeletal muscle contractions in patients with PAD, but the specific mechanism(s) of the COX-mediated exaggeration are not known. In decerebrate, unanesthetized rats with a chronically ligated femoral artery ("ligated" rats), we hypothesized that hindlimb arterial injection of the COX inhibitor indomethacin would reduce the pressor response during 1-Hz dynamic hindlimb skeletal muscle stretch; a model of the activation of the mechanical component of the exercise pressor reflex (i.e., the mechanoreflex). In ligated rats ( = 7), indomethacin reduced the pressor response during stretch (control: 30 ± 4; indomethacin: 12 ± 3 mmHg; < 0.01), whereas there was no effect in rats with "freely perfused" femoral arteries ( = 6, control: 18 ± 5; indomethacin: 17 ± 5 mmHg; = 0.87). In ligated rats ( = 4), systemic indomethacin injection had no effect on the pressor response during stretch. Femoral artery ligation had no effect on skeletal muscle COX protein expression or activity or concentration of the COX metabolite prostaglandin E. Conversely, femoral artery ligation increased expression of the COX metabolite receptors endoperoxide 4 and thromboxane A-R in dorsal root ganglia tissue. We conclude that, in ligated rats, the COX pathway sensitizes the peripheral endings of mechanoreflex afferents, which occurs principally as a result of increased expression of COX metabolite receptors. We demonstrate that the mechanoreflex is sensitized by the cyclooxygenase (COX) pathway within hindlimb skeletal muscles in the rat chronic femoral artery ligation model of simulated peripheral artery disease (PAD). The mechanism of sensitization appears attributable to increased receptors for COX metabolites on sensory neurons and not increased concentration of COX metabolites. Our data may carry important clinical implications for patients with PAD who demonstrate exaggerated increases in blood pressure during exercise compared with healthy counterparts.
Topics: Animals; Cyclooxygenase Inhibitors; Dinoprostone; Disease Models, Animal; Femoral Artery; Ganglia, Spinal; Hindlimb; Indomethacin; Ligation; Male; Mechanoreceptors; Mechanotransduction, Cellular; Muscle Contraction; Muscle, Skeletal; Peripheral Arterial Disease; Prostaglandin-Endoperoxide Synthases; Rats, Sprague-Dawley; Receptors, Prostaglandin E, EP4 Subtype; Receptors, Thromboxane A2, Prostaglandin H2; Reflex
PubMed: 31469294
DOI: 10.1152/ajpheart.00399.2019 -
American Journal of Physiology.... Mar 2020The vestibular system contributes to regulating sympathetic nerve activity and blood pressure. Initial studies in decerebrate animals showed that neurons in the rostral...
The vestibular system contributes to regulating sympathetic nerve activity and blood pressure. Initial studies in decerebrate animals showed that neurons in the rostral ventrolateral medulla (RVLM) respond to small-amplitude (<10°) rotations of the body, as in other brain areas that process vestibular signals, although such movements do not affect blood distribution in the body. However, a subsequent experiment in conscious animals showed that few RVLM neurons respond to small-amplitude movements. This study tested the hypothesis that RVLM neurons in conscious animals respond to signals from the vestibular otolith organs elicited by large-amplitude static tilts. The activity of approximately one-third of RVLM neurons whose firing rate was related to the cardiac cycle, and thus likely received baroreceptor inputs, was modulated by vestibular inputs elicited by 40° head-up tilts in conscious cats, but not during 10° sinusoidal rotations in the pitch plane that affected the activity of neurons in brain regions providing inputs to the RVLM. These data suggest the existence of brain circuitry that suppresses vestibular influences on the activity of RVLM neurons and the sympathetic nervous system unless these inputs are physiologically warranted. We also determined that RVLM neurons failed to respond to a light cue signaling the movement, suggesting that feedforward cardiovascular responses do not occur before passive movements that require cardiovascular adjustments.
Topics: Action Potentials; Animals; Cats; Consciousness; Medulla Oblongata; Neurons; Pressoreceptors; Sympathetic Nervous System; Vestibule, Labyrinth
PubMed: 31940234
DOI: 10.1152/ajpregu.00205.2019 -
American Journal of Physiology.... Jan 2020The exercise pressor reflex is composed of two components, namely the muscle mechanoreflex and the muscle metaboreflex. The afferents evoking the two components are...
The exercise pressor reflex is composed of two components, namely the muscle mechanoreflex and the muscle metaboreflex. The afferents evoking the two components are either thinly myelinated (group III) or unmyelinated (group IV); in combination they are termed "thin fiber afferents." The exercise pressor reflex is often studied in unanesthetized, decerebrate rats. However, the relationship between the magnitude of this reflex and the number of thin fiber afferents stimulated by muscle contraction is unknown. This lack of knowledge prompted us to test the hypothesis that the magnitude of the exercise pressor reflex was directly proportional to the amount of muscle mass activated. Muscle mechanoreceptors were stimulated by stretching the calcaneal tendon. Likewise, muscle metaboreceptors were stimulated by injecting lactic acid into the arterial supply of the hindlimb muscles. In addition, both muscle mechanoreceptors and metaboreceptors were stimulated by statically contracting the hindlimb muscles. We found that simultaneous bilateral (both hindlimbs) stimulation of thin fiber afferents with stretch, lactic acid, and static contraction evoked significantly greater pressor responses than did unilateral (one hindlimb) stimulation of these afferents. In addition, the magnitude of the pressor responses to bilateral simultaneous stimulation of thin fiber afferents evoked by stretch, lactic acid, and contraction was not significantly different from the magnitude of the sum of the pressor responses evoked by unilateral stimulation of these afferents by stretch, lactic acid, and contraction. We conclude that the magnitude of the exercise pressor reflex and its two components is dependent on the number of afferents stimulated.
Topics: Animals; Blood Pressure; Decerebrate State; Hindlimb; Male; Muscle Contraction; Muscle, Skeletal; Rats; Rats, Sprague-Dawley; Reflex
PubMed: 31664869
DOI: 10.1152/ajpregu.00263.2019 -
The Journal of Physiology Aug 2020Epidural electrical stimulation (ES) of the spinal cord restores/improves locomotion in patients. ES-evoked locomotor movements differ to some extent from the normal...
KEY POINTS
Epidural electrical stimulation (ES) of the spinal cord restores/improves locomotion in patients. ES-evoked locomotor movements differ to some extent from the normal ones. Operation of the locomotor network during ES is unknown. We compared the activity of individual spinal neurons during locomotion initiated by signals from the brainstem and by ES. We demonstrated that the spinal network generating locomotion under each of the two conditions is formed by the same neurons. A part of this network operates similarly under the two conditions, suggesting that it is essential for generation of locomotion under both conditions. Another part of this network operates differently under the two conditions, suggesting that it is responsible for differences in the movement kinematics observed under the two conditions.
ABSTRACT
Locomotion is a vital motor function for both animals and humans. Epidural electrical stimulation (ES) of the spinal cord is used to restore/improve locomotor movements in patients. However, operation of locomotor networks during ES has never been studied. Here we compared the activity of individual spinal neurons recorded in decerebrate cats of either sex during locomotion initiated by supraspinal commands (caused by stimulation of the mesencephalic locomotor region, MLR) and by ES. We found that under both conditions, the same neurons had modulation of their activity related to the locomotor rhythm, suggesting that the network generating locomotion under the two conditions is formed by the same neurons. About 40% of these neurons had stable modulation (i.e. small dispersion of their activity phase in sequential cycles), as well as a similar phase and shape of activity burst in MLR- and ES-evoked locomotor cycles. We suggest that these neurons form a part of the locomotor network that operates similarly under the two conditions, and are critical for generation of locomotion. About 23% of the modulated neurons had stable modulation only during MLR-evoked locomotion. We suggest that these neurons are responsible for some differences in kinematics of MLR- and ES-evoked locomotor movements. Finally, 25% of the modulated neurons had unstable modulation during both MLR- and ES-evoked locomotion. One can assume that these neurons contribute to maintenance of the excitability level of locomotor networks necessary for generation of stepping, or belong to postural networks, activated simultaneously with locomotor networks by both MLR stimulation and ES.
Topics: Animals; Brain Stem; Cats; Decerebrate State; Electric Stimulation; Humans; Locomotion; Mesencephalon; Spinal Cord
PubMed: 32445488
DOI: 10.1113/JP279460 -
American Journal of Physiology. Heart... Feb 2018Mechanical and metabolic signals arising during skeletal muscle contraction reflexly increase sympathetic nerve activity and blood pressure (i.e., the exercise pressor... (Comparative Study)
Comparative Study
Mechanical and metabolic signals arising during skeletal muscle contraction reflexly increase sympathetic nerve activity and blood pressure (i.e., the exercise pressor reflex). In a rat model of simulated peripheral artery disease in which a femoral artery is chronically (~72 h) ligated, the mechanically sensitive component of the exercise pressor reflex during 1-Hz dynamic contraction is exaggerated compared with that found in normal rats. Whether this is due to an enhanced acute sensitization of mechanoreceptors by metabolites produced during contraction or involves a chronic sensitization of mechanoreceptors is unknown. To investigate this issue, in decerebrate, unanesthetized rats, we tested the hypothesis that the increases in mean arterial blood pressure and renal sympathetic nerve activity during 1-Hz dynamic stretch are larger when evoked from a previously "ligated" hindlimb compared with those evoked from the contralateral "freely perfused" hindlimb. Dynamic stretch provided a mechanical stimulus in the absence of contraction-induced metabolite production that closely replicated the pattern of the mechanical stimulus present during dynamic contraction. We found that the increases in mean arterial blood pressure (freely perfused: 14 ± 1 and ligated: 23 ± 3 mmHg, P = 0.02) and renal sympathetic nerve activity were significantly greater during dynamic stretch of the ligated hindlimb compared with the increases during dynamic stretch of the freely perfused hindlimb. These findings suggest that the exaggerated mechanically sensitive component of the exercise pressor reflex found during dynamic muscle contraction in this rat model of simulated peripheral artery disease involves a chronic sensitizing effect of ligation on muscle mechanoreceptors and cannot be attributed solely to acute contraction-induced metabolite sensitization. NEW & NOTEWORTHY We found that the pressor and sympathetic nerve responses during dynamic stretch were exaggerated in rats with a ligated femoral artery (a model of peripheral artery disease). Our findings provide mechanistic insights into the exaggerated exercise pressor reflex in this model and may have important implications for peripheral artery disease patients.
Topics: Animals; Arterial Pressure; Decerebrate State; Disease Models, Animal; Femoral Artery; Hindlimb; Kidney; Ligation; Male; Muscle Contraction; Muscle Spindles; Muscle, Skeletal; Peripheral Arterial Disease; Rats, Sprague-Dawley; Reflex; Sympathetic Nervous System; Time Factors
PubMed: 29054973
DOI: 10.1152/ajpheart.00498.2017