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Journal of Applied Physiology... Sep 2018Spinal cord injury (SCI) at the level of cervical segments often results in life-threatening respiratory complications and requires long-term mechanical ventilator...
Spinal cord injury (SCI) at the level of cervical segments often results in life-threatening respiratory complications and requires long-term mechanical ventilator assistance. Thus restoring diaphragm activity and regaining voluntary control of breathing are the primary clinical goals for patients with respiratory dysfunction following cervical SCI. Epidural stimulation (EDS) is a promising strategy that has been explored extensively for nonrespiratory functions and to a limited extent within the respiratory system. The goal of the present study is to assess the potential for EDS at the location of the phrenic nucleus (C-C) innervating the diaphragm: the main inspiratory muscle following complete C cervical transection. To avoid the suppressive effect of anesthesia, all experiments were performed in decerebrate, C cervical transection, unanesthetized, nonparalyzed ( n = 13) and paralyzed ( n = 7) animals. Our results show that C segment was the most responsive to EDS and required the lowest threshold of current intensity, affecting tracheal pressure and phrenic nerve responses. High-frequency (200-300 Hz) EDS applied over C segment (C-EDS) was able to maintain breathing with normal end-tidal CO level and raise blood pressure. In addition, 100-300 Hz of C-EDS showed time- and frequency-dependent changes (short-term facilitation) of evoked phrenic nerve responses that may serve as a target mechanism for pacing of phrenic motor circuits. The present work provides the first report of successful EDS at the level of phrenic nucleus in a complete SCI animal model and offers insight into the potential therapeutic application in patients with high cervical SCI. NEW & NOTEWORTHY The present work offers the first demonstration of successful life-supporting breathing paced by epidural stimulation (EDS) at the level of the phrenic nucleus, following a complete spinal cord injury in unanesthetized, decerebrate rats. Moreover, our experiments showed time- and frequency-dependent changes of evoked phrenic nerve activity during EDS that may serve as a target mechanism for pacing spinal phrenic motor networks.
Topics: Animals; Blood Pressure; Carbon Dioxide; Cervical Cord; Decerebrate State; Electric Stimulation; Epidural Space; Heart Rate; Male; Phrenic Nerve; Rats; Rats, Sprague-Dawley; Recovery of Function; Respiration; Respiratory Muscles; Spinal Cord Injuries
PubMed: 29771608
DOI: 10.1152/japplphysiol.00895.2017 -
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 -
Journal of Neurophysiology Mar 2017The role of the dorsolateral pons in the control of expiratory duration (Te) and breathing frequency is incompletely understood. A subregion of the pontine...
The role of the dorsolateral pons in the control of expiratory duration (Te) and breathing frequency is incompletely understood. A subregion of the pontine parabrachial-Kölliker-Fuse (PB-KF) complex of dogs was identified via microinjections, in which localized pharmacologically induced increases in neuronal activity produced increases in breathing rate while decreases in neuronal activity produced decreases in breathing rate. This subregion is also very sensitive to local and systemic opioids. The purpose of this study was to precisely characterize the relationship between the PB-KF subregion pattern of altered neuronal activity and the control of respiratory phase timing as well as the time course of the phrenic nerve activity/neurogram (PNG). Pulse train electrical stimulation patterns synchronized with the onset of the expiratory (E) and/or phrenic inspiratory (I) phase were delivered via a small concentric bipolar electrode while the PNG was recorded in decerebrate, vagotomized dogs. Step frequency patterns during the E phase produced a marked frequency-dependent decrease in Te, while similar step inputs during the I phase increased inspiratory duration (Ti) by 14 ± 3%. Delayed pulse trains were capable of pacing the breathing rate by terminating the E phase and also of triggering a consistent stereotypical inspiratory PNG pattern, even when evoked during apnea. This property suggests that the I-phase pattern generator functions in a monostable circuit mode with a stable E phase and a transient I phase. Thus the I-pattern generator must contain neurons with nonlinear pacemaker-like properties, which allow the network to rapidly obtain a full on-state followed by relatively slow inactivation. The activated network can be further modulated and supplies excitatory drive to the neurons involved with pattern generation. A circumscribed subregion of the pontine medial parabrachial nucleus plays a key role in the control of breathing frequency primarily via changes in expiratory duration. Excitation of this subregion triggers the onset of the inspiratory phase, resulting in a stereotypical ramplike phrenic activity pattern independent of time within the expiratory phase. The ability to pace the I-burst rate suggests that the in vivo I-pattern generating network must contain functioning pacemaker neurons.
Topics: Animals; Dogs; Electric Stimulation; Excitatory Amino Acid Agonists; Exhalation; Female; Male; Parabrachial Nucleus; Phrenic Nerve; Respiration; Respiratory Rate; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
PubMed: 27974449
DOI: 10.1152/jn.00591.2016 -
Stimulation of spinal δ-opioid receptors attenuates the exercise pressor reflex in decerebrate rats.American Journal of Physiology.... Jun 2019A reflex arising from contracting hindlimb muscle is responsible in part for the increases in arterial pressure and heart rate evoked by exercise. The afferent arm of...
A reflex arising from contracting hindlimb muscle is responsible in part for the increases in arterial pressure and heart rate evoked by exercise. The afferent arm of this reflex comprises group III and IV afferents. δ-Opioid receptors are expressed predominately on the spinal endings of group III afferents, whereas μ-opioid receptors are expressed predominately on the spinal endings of group IV afferents. Using stimuli that activated group III afferents, namely static contraction, calcaneal tendon stretch, and lactic acid injection into the superficial epigastric artery, we tested the hypothesis that, in rats with either patent or ligated femoral arteries, activation of pre- and postsynaptic δ-opioid receptors in the dorsal horn attenuated pressor reflex responses to these stimuli. In rats with patent arteries or ligated femoral arteries, [d-Pen]enkephalin (DPDPE), a δ-opioid agonist injected intrathecally (10 μg in 10 μl), significantly attenuated the pressor responses to contraction, stretch, and lactic acid (all < 0.05). Naltrindole, a δ-opioid receptor antagonist, prevented the attenuation. In contrast, DPDPE did not attenuate the pressor response to capsaicin injection into the superficial epigastric artery in either group of rats (both > 0.05). Intrathecal injection of saline (10 μl), the vehicle for DPDPE, had no effect on the pressor responses in either group of rats. We conclude that activation of spinal δ-opioid receptors attenuates reflexes evoked by group III afferents in both freely perfused and ligated rats.
Topics: Animals; Decerebrate State; Enkephalin, D-Penicillamine (2,5)-; Femoral Artery; Heart Rate; Male; Muscle Contraction; Muscle, Skeletal; Physical Conditioning, Animal; Physical Exertion; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, mu; Reflex
PubMed: 30943058
DOI: 10.1152/ajpregu.00013.2019 -
Neuroscience Mar 2015A fundamental problem in neurophysiology is the understanding of neuronal mechanisms by which the central nervous system produces a sequence of voluntary or involuntary...
A fundamental problem in neurophysiology is the understanding of neuronal mechanisms by which the central nervous system produces a sequence of voluntary or involuntary motor acts from a diverse repertory of movements. These kinds of transitions between motor acts are extremely complex; however, they could be analyzed in a more simple form in decerebrate animals in the context of spinal central pattern generation. Here, we present for the first time a physiological phenomenon of post-scratching locomotion in which decerebrate cats exhibit a compulsory locomotor activity after an episode of scratching. We found flexor, extensor and intermediate single interneurons rhythmically firing in the same phase during both scratching and the subsequent post-scratching locomotion. Because no changes in phase of these neurons from scratching to post-scratching locomotion were found, we suggest that in the lumbar spinal cord there are neurons associated with both motor tasks. Moreover, because of its high reproducibility we suggest that the study of post-scratching fictive locomotion, together with the unitary recording of neurons, could become a useful tool to study neuronal mechanisms underlying transitions from one rhythmic motor task to another, and to study in more detail the central pattern generator circuitry in the spinal cord.
Topics: Animals; Behavior, Animal; Cats; Central Pattern Generators; Decerebrate State; Ear; Locomotion; Lumbar Vertebrae; Methyltransferases; Motor Activity; Motor Neurons; Spinal Cord; Tibial Nerve
PubMed: 25556832
DOI: 10.1016/j.neuroscience.2014.12.038 -
Neuroscience Jan 2019People with Rett Syndrome (RTT), a neurodevelopmental disorder caused by mutations in the MECP2 gene, have breathing abnormalities manifested as periodical...
People with Rett Syndrome (RTT), a neurodevelopmental disorder caused by mutations in the MECP2 gene, have breathing abnormalities manifested as periodical hypoventilation with compensatory hyperventilation, which are attributable to a high incidence of sudden death. Similar breathing abnormalities have been found in animal models with Mecp2 disruptions. Although RTT-type hypoventilation is believed to be due to depressed central inspiratory activity, whether this is true remains unknown. Here we show evidence for reshaping in firing activity and patterns of medullary respiratory neurons in RTT-type hypoventilation without evident depression in inspiratory neuronal activity. Experiments were performed in decerebrate rats in vivo. In Mecp2-null rats, abnormalities in breathing patterns were apparent in both decerebrate rats and awake animals, suggesting that RTT-type breathing abnormalities take place in the brainstem without forebrain input. In comparison to their wild-type counterparts, both inspiratory and expiratory neurons in Mecp2-null rats extended their firing duration, and fired more action potentials during each burst. No changes in inspiratory or expiratory neuronal distributions were found. Most inspiratory neurons started firing in the middle of expiration and changed their firing pattern to a phase-spanning type. The proportion of post-inspiratory neurons was reduced in the Mecp2-null rats. With the increased firing activity of both inspiratory and expiratory neurons in null rats, phrenic discharges shifted to a slow and deep breathing pattern. Thus, the RTT-type hypoventilation appears to result from reshaping of firing activity of both inspiratory and expiratory neurons without evident depression in central inspiratory activity.
Topics: Action Potentials; Animals; Decerebrate State; Disease Models, Animal; Male; Medulla Oblongata; Methyl-CpG-Binding Protein 2; Neurons; Phrenic Nerve; Rats, Sprague-Dawley; Rats, Transgenic; Respiration; Rett Syndrome; Wakefulness
PubMed: 30458221
DOI: 10.1016/j.neuroscience.2018.11.011 -
Frontiers in Neural Circuits 2017Spinal cord neurons active during locomotion are innervated by descending axons that release the monoamines serotonin (5-HT) and norepinephrine (NE) and these neurons...
Spinal cord neurons active during locomotion are innervated by descending axons that release the monoamines serotonin (5-HT) and norepinephrine (NE) and these neurons express monoaminergic receptor subtypes implicated in the control of locomotion. The timing, level and spinal locations of release of these two substances during centrally-generated locomotor activity should therefore be critical to this control. These variables were measured in real time by fast-cyclic voltammetry in the decerebrate cat's lumbar spinal cord during fictive locomotion, which was evoked by electrical stimulation of the mesencephalic locomotor region (MLR) and registered as integrated activity in bilateral peripheral nerves to hindlimb muscles. Monoamine release was observed in dorsal horn (DH), intermediate zone/ventral horn (IZ/VH) and adjacent white matter (WM) during evoked locomotion. Extracellular peak levels (all sites) increased above baseline by 138 ± 232.5 nM and 35.6 ± 94.4 nM (mean ± SD) for NE and 5-HT, respectively. For both substances, release usually began prior to the onset of locomotion typically earliest in the IZ/VH and peaks were positively correlated with net activity in peripheral nerves. Monoamine levels gradually returned to baseline levels or below at the end of stimulation in most trials. Monoamine oxidase and uptake inhibitors increased the release magnitude, time-to-peak (TTP) and decline-to-baseline. These results demonstrate that spinal monoamine release is modulated on a timescale of seconds, in tandem with centrally-generated locomotion and indicate that MLR-evoked locomotor activity involves concurrent activation of descending monoaminergic and reticulospinal pathways. These gradual changes in space and time of monoamine concentrations high enough to strongly activate various receptors subtypes on locomotor activated neurons further suggest that during MLR-evoked locomotion, monoamine action is, in part, mediated by extrasynaptic neurotransmission in the spinal cord.
Topics: Analysis of Variance; Animals; Biogenic Monoamines; Biophysics; Cats; Decerebrate State; Dose-Response Relationship, Drug; Electric Stimulation; Electrochemistry; Evoked Potentials; Hindlimb; Locomotion; Mesencephalon; Muscles; Neural Pathways; Reaction Time; Spinal Cord
PubMed: 28912689
DOI: 10.3389/fncir.2017.00059 -
Experimental Brain Research Sep 2021Successful propagation throughout the step cycle is contingent on adequate regulation of whole-limb stiffness by proprioceptive feedback. Following spinal cord injury...
Successful propagation throughout the step cycle is contingent on adequate regulation of whole-limb stiffness by proprioceptive feedback. Following spinal cord injury (SCI), there are changes in the strength and organization of proprioceptive feedback that can result in altered joint stiffness. In this study, we measured changes in autogenic feedback of five hindlimb extensor muscles following chronic low thoracic lateral hemisection (LSH) in decerebrate cats. We present three features of the autogenic stretch reflex obtained using a mechanographic method. Stiffness was a measure of the resistance to stretch during the length change. The dynamic index documented the extent of adaptation or increase of the force response during the hold phase, and the impulse measured the integral of the response from initiation of a stretch to the return to the initial length. The changes took the form of variable and transient increases in the stiffness of vastus (VASTI) group, soleus (SOL), and flexor hallucis longus (FHL), and either increased (VASTI) or decreased adaptation (GAS and PLANT). The stiffness of the gastrocnemius group (GAS) was also variable over time but remained elevated at the final time point. An unexpected finding was that these effects were observed bilaterally. Potential reasons for this finding and possible sources of increased excitability to this muscle group are discussed.
Topics: Animals; Decerebrate State; Hindlimb; Muscle, Skeletal; Reflex; Reflex, Stretch; Spinal Cord Injuries; Up-Regulation
PubMed: 34218298
DOI: 10.1007/s00221-020-06016-1 -
American Journal of Physiology.... Feb 2023We investigated the role played by bradykinin 2 (B2) receptors in the exaggerated exercise pressor reflex in rats with a femoral artery ligated for 72 h to induce...
We investigated the role played by bradykinin 2 (B2) receptors in the exaggerated exercise pressor reflex in rats with a femoral artery ligated for 72 h to induce simulated peripheral artery disease (PAD). We hypothesized that in decerebrate, unanesthetized rats with a ligated femoral artery, hindlimb arterial injection of HOE-140 (100 ng, B2 receptor antagonist) would reduce the pressor response to 30 s of electrically induced 1 Hz hindlimb skeletal muscle contraction, and 30 s of 1 Hz hindlimb skeletal muscle stretch (a model of mechanoreflex activation isolated from contraction-induced metabolite production). We hypothesized no effect of HOE-140 in sham-operated "freely perfused" rats. In both freely perfused ( = 4) and "ligated" ( = 4) rats, we first confirmed efficacious B2 receptor blockade by demonstrating that HOE-140 injection significantly reduced ( < 0.05) the peak increase in mean arterial pressure (peak ΔMAP) in response to hindlimb arterial injection of bradykinin. In subsequent experiments, we found that HOE-140 reduced the peak ΔMAP response to muscle contraction in ligated ( = 14; control: 23 ± 2; HOE-140: 17 ± 2 mmHg; = 0.03) but not freely perfused rats ( = 7; control: 17 ± 3; HOE-140: 18 ± 4 mmHg; = 0.65). Furthermore, HOE-140 had no effect on the peak ΔMAP response to stretch in ligated rats ( = 14; control: 37 ± 4; HOE-140: 32 ± 5 mmHg; = 0.13) but reduced the integrated area under the blood pressure signal over the final ∼20 s of the maneuver. The data suggest that B2 receptors contribute to the exaggerated exercise pressor reflex in rats with simulated PAD, and that contribution includes a modest role in the chronic sensitization of the mechanically activated channels/afferents that underlie mechanoreflex activation.
Topics: Rats; Animals; Reflex; Muscle, Skeletal; Receptors, Bradykinin; Rats, Sprague-Dawley; Bradykinin; Muscle Contraction; Peripheral Arterial Disease; Blood Pressure; Femoral Artery; Hindlimb
PubMed: 36534589
DOI: 10.1152/ajpregu.00274.2022 -
Journal of Applied Physiology... Oct 2019The spontaneous or self-sustained discharge of spinal motoneurons can be observed in both animals and humans. Although the origins of this self-sustained discharge are...
The spontaneous or self-sustained discharge of spinal motoneurons can be observed in both animals and humans. Although the origins of this self-sustained discharge are not fully known, it can be generated by activation of persistent inward currents intrinsic to the motoneuron. If self-sustained discharge is generated exclusively through this intrinsic mechanism, the discharge of individual motor units will be relatively independent of one another. Alternatively, if increased activation of premotor circuits underlies this prolonged discharge of spinal motoneurons, we would expect correlated activity among motoneurons. Our aim is to assess potential synaptic drive by quantifying coherence during self-sustained discharge of spinal motoneurons. Electromyographic activity was collected from 20 decerebrate animals using a 64-channel electrode grid placed on the isolated soleus muscle before and following intrathecal administration of methoxamine, a selective α-noradrenergic agonist. Sustained muscle activity was recorded and decomposed into the discharge times of ~10-30 concurrently active individual motor units. Consistent with previous reports, the self-sustained discharge of motor units occurred at low mean discharge rates with low-interspike variability. Before methoxamine administration, significant low-frequency coherence (<2 Hz) was observed, while minimal coherence was observed within higher frequency bands. Following intrathecal administration of methoxamine, increases in motor unit discharge rates and strong coherence in both the low-frequency and 15- to 30-Hz beta bands were observed. These data demonstrate beta-band coherence among motor units can be observed through noncortical mechanisms and that neuromodulation of spinal/brainstem neurons greatly influences coherent discharge within spinal motor pools. The correlated discharge of spinal motoneurons is often used to describe the input to the motor pool. We demonstrate spinal/brainstem neurons devoid of cortical input can generate correlated motor unit discharge in the 15- to 30-Hz beta band, which is amplified through neuromodulation. Activity in the beta band is often ascribed to cortical drive in humans; however, these data demonstrate the capability of the mammalian segmental motor system to generate and modulate this coherent state of motor unit discharge.
Topics: Animals; Cats; Female; Hindlimb; Male; Motor Neurons; Muscle, Skeletal; Spine
PubMed: 31318619
DOI: 10.1152/japplphysiol.00110.2019