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Harry G. Goshgarian - One of the best experts on this subject based on the ideXlab platform.
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Diaphragmatic recovery in rats with cervical spinal cord injury induced by a theophylline nanoconjugate: Challenges for clinical use
Journal of Spinal Cord Medicine, 2019Co-Authors: Yanhua Zhang, Janelle Schafer, Harry G. GoshgarianAbstract:Context: Following a spinal cord hemisection at the second cervical segment the ipsilateral hemidiaphragm is paralyzed due to the disruption of the rostral Ventral Respiratory Group (rVRG) axons de...
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Diaphragmatic recovery in rats with cervical spinal cord injury induced by a theophylline nanoconjugate: Challenges for clinical use
2019Co-Authors: Fangchao Liu, Janelle Schafer, Yanhua Zhang, Guangzhao Mao, Harry G. GoshgarianAbstract:Context: Following a spinal cord hemisection at the second cervical segment the ipsilateral hemidiaphragm is paralyzed due to the disruption of the rostral Ventral Respiratory Group (rVRG) axons descending to the ipsilateral phrenic motoneurons (PN). Systemically administered theophylline activates a functionally latent crossed phrenic pathway (CPP) which decussates caudal to the hemisection and activates phrenic motoneurons ipsilateral to the hemisection. The result is return of function to the paralyzed hemidiaphragm. Unfortunately, in humans, systemically administered theophylline at a therapeutic dose produces many unwanted side effects. Design and setting: A tripartite nanoconjugate was synthesized in which theophylline was coupled to a neuronal tracer, wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP), using gold nanoparticles as the coupler. Following intradiaphragmatic injection of the nanoconjugate, WGA-HRP selectively targets the theophylline-bound nanoconjugate to phrenic motoneurons initially, followed by neurons in the rVRG by retrograde transsynaptic transport. Participants: (N/A) Interventions: (N/A) Outcome Measures: Immunostaining, Electromyography (EMG). Results: Delivery of the theophylline-coupled nanoconjugate to the nuclei involved in respiration induces a return of Respiratory activity as detected by EMG of the diaphragm and a modest return of phrenic nerve activity. Conclusion: In addition to the modest return of phrenic nerve activity, there were many difficulties using the theophylline nanoconjugate because of its chemical instability, which suggests that the theophylline nanoconjugate should not be developed for clinical use as explained herein.
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bulbospinal Respiratory neurons are a source of double synapses onto phrenic motoneurons following cervical spinal cord hemisection in adult rats
Brain Research, 1993Co-Authors: Harry G. Goshgarian, Howard H. Ellenberger, Jack L FeldmanAbstract:Abstract The purpose of this study was to determine if the medullary neurons that provide the primary excitatiry drive to phrenic motoneurons (i.e., rostral Ventral Respiratory Group, rVRG) are a source of double synapse formation in the phrenic nucleus after spinal cord hemisection. The axons of rVRG neurons either ipsilateral or contralateral to the hemisection were labeled by injection of a mixture of HRP and WGA-HRP into the rostral Ventral Respiratory Group. Phrenic motoneurons ipsilateral and caudal to the hemisection were labeled by the retrograde transport of HRP. The ultrastructural results indicated that after hemisection, rVRG neurons from both sides of the medulla formed labelled double synapses in the phrenic nucleus.
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identification of the axon pathways which mediate functional recovery of a paralyzed hemidiaphragm following spinal cord hemisection in the adult rat
Experimental Neurology, 1992Co-Authors: Dale E Moreno, Xiao-jun Yu, Harry G. GoshgarianAbstract:Abstract Despite extensive neurophysiological work carried out to characterize the crossed phrenic phenomenon, relatively little is known about the morphological substrate of this reflex which restores function to a hemidiaphragm paralyzed by spinal cord injury. In the present study WGA-HRP was injected into normal and functionally recovered hemidiaphragm muscle in rats during the crossed phrenic phenomenon. The retrograde transynaptic transport characteristics of WGA-HRP was utilized to delineate the source of the neurons which mediate the crossed phrenic phenomenon. The results indicated that the neurons which drive phrenic motoneurons in spinal hemisected rats during the crossed phrenic phenomenon are located bilaterally in the rostral Ventral Respiratory Group (rVRG) of the medulla. No transneuronal labeling of propriospinal neurons was noted in either normal or spinal-hemisected rats. Thus, propriospinal neurons do not relay Respiratory drive to phrenic motoneurons. The neurons of the rVRG project monosynaptically to phrenic motoneurons. The present results suggest that both crossed and uncrossed bulbospinal pathways from the rVRG collateralize to both the left and right phrenic nucleic and functional recovery of a hemidiaphragm paralyzed by ipsilateral spinal cord hemisection is mediated by supraspinal neurons from both sides of the brain stem. These results are important to our complete understanding of the mechanisms which govern motor recovery in mammals following spinal cord injury.
Donald R Mccrimmon - One of the best experts on this subject based on the ideXlab platform.
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activation of astrocytic par1 receptors in the rat nucleus of the solitary tract regulates breathing through modulation of presynaptic trpv1
The Journal of Physiology, 2018Co-Authors: Rafiq Huda, Donald R Mccrimmon, Zheng Chang, Jeehaeh Do, Marco MartinaAbstract:KEY POINTS: In the rat nucleus of the solitary tract (NTS), activation of astrocytic proteinase-activated receptor 1 (PAR1) receptors leads to potentiation of neuronal synaptic activity by two mechanisms, one TRPV1-dependent and one TRPV1-independent. PAR1-dependent activation of presynaptic TRPV1 receptors facilitates glutamate release onto NTS neurons. The TRPV1-dependent mechanism appears to rely on astrocytic release of endovanilloid-like molecules. A subset of NTS neurons excited by PAR1 directly project to the rostral Ventral Respiratory Group. The PAR1 initiated, TRPV1-dependent modulation of synaptic transmission in the NTS contributes to regulation of breathing. ABSTRACT: Many of the cellular and molecular mechanisms underlying astrocytic modulation of synaptic function remain poorly understood. Recent studies show that G-protein coupled receptor-mediated astrocyte activation modulates synaptic transmission in the nucleus of the solitary tract (NTS), a brainstem nucleus that regulates crucial physiological processes including cardioRespiratory activity. By using calcium imaging and patch clamp recordings in acute brain slices of wild-type and TRPV1-/- rats, we show that activation of proteinase-activated receptor 1 (PAR1) in NTS astrocytes potentiates presynaptic glutamate release on NTS neurons. This potentiation is mediated by both a TRPV1-dependent and a TRPV1-independent mechanism. The TRPV1-dependent mechanism appears to require release of endovanilloid-like molecules from astrocytes, which leads to subsequent potentiation of presynaptic glutamate release via activation of presynaptic TRPV1 channels. Activation of NTS astrocytic PAR1 receptors elicits cFOS expression in neurons that project to Respiratory premotor neurons and inhibits Respiratory activity in control, but not in TRPV1-/- rats. Thus, activation of astrocytic PAR1 receptor in the NTS leads to a TRPV1-dependent excitation of NTS neurons causing a potent modulation of Respiratory motor output.
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caudal nuclei of the rat nucleus of the solitary tract differentially innervate Respiratory compartments within the ventrolateral medulla
Neuroscience, 2011Co-Authors: George F. Alheid, Weijie Jiao, Donald R MccrimmonAbstract:Abstract A substantial array of Respiratory, cardiovascular, visceral and somatic afferents are relayed via the nucleus of the solitary tract (NTS) to the brainstem (and forebrain). Despite some degree of overlap within the NTS, specificity is maintained in central Respiratory reflexes driven by second order afferent relay neurons in the NTS. While the topographic arrangement of Respiratory-related afferents targeting the NTS has been extensively investigated, their higher order brainstem targets beyond the NTS has only rarely been defined with any precision. Nonetheless, the various brainstem circuits serving blood gas homeostasis and airway protective reflexes must clearly receive a differential innervation from the NTS in order to evoke stimulus appropriate behavioral responses. Accordingly, we have examined the question of which specific NTS nuclei project to particular compartments within the Ventral Respiratory column (VRC) of the ventrolateral medulla. Our analyses of NTS labeling after retrograde tracer injections in the VRC and the nearby neuronal Groups controlling autonomic function indicate a significant distinction between projections to the Botzinger complex and preBotzinger complex compared to the remainder of the VRC. Specifically, the caudomedial NTS, including caudal portions of the medial solitary nucleus and the commissural division of NTS project relatively densely to the region of the retrotrapezoid nucleus and rostral ventrolateral medullary nucleus as well as to the rostral Ventral Respiratory Group while avoiding the intervening Botzinger and preBotzinger complexes. Area postrema appears to demonstrate a pattern of projections similar to that of caudal medial and commissural NTS nuclei. Other, less pronounced differential projections of lateral NTS nuclei to the various VRC compartments are additionally noted.
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pattern formation and rhythm generation in the Ventral Respiratory Group
Clinical and Experimental Pharmacology and Physiology, 2000Co-Authors: Donald R Mccrimmon, Fumiaki Hayashi, Armelle Monnier, Edward J ZuperkuAbstract:1. There is increasing evidence that the kernel of the rhythm-generating circuitry for breathing is located within a discrete subregion of a column of Respiratory neurons within the ventrolateral medulla referred to as the Ventral Respiratory Group (VRG). It is less clear how this rhythm is transformed into the precise patterns appearing on the varied motor outflows. 2. Two different approaches were used to test whether subregions of the VRG have distinct roles in rhythm or pattern generation. In one, clusters of VRG neurons were activated or inactivated by pressure injection of small volumes of neuroactive agents to activate or inactivate Groups of Respiratory neurons and the resulting effects on Respiratory rhythm and pattern were determined. The underlying assumption was that if rhythm and pattern are generated by neurons in different VRG subregions, then we should be able to identify regions where activation of neurons predominantly alters rhythm with little effect on pattern and other regions where pattern is altered with little effect on rhythm. 3. Based on the pattern of phrenic nerve responses to injection of an excitatory amino acid (DL-homocysteate), the VRG was divided into four subdivisions arranged along the rostrocaudal axis. Injections into the three rostral regions elicited changes in both Respiratory rhythm and pattern. From rostral to caudal the regions included: (i) a rostral bradypnoea region, roughly associated with the Botzinger complex; (ii) a dysrhythmia/tachypnoea area, roughly associated with the pre-Botzinger complex (PBC); (iii) a second caudal bradypnoea area; and, most caudally, (iv) a region from which no detectable change in Respiratory motor output was elicited. 4. In a second approach, the effect of unilateral lesions of one subregion, the PBC, on the Breuer-Hering reflex changes in rhythm were determined. Activation of this reflex by lung inflation shortens inspiration and lengthens expiration (TE). 5. Unilateral lesions in the PBC attenuated the reflex lengthening of TE, but did not change baseline Respiratory rhythm. 6. These findings are consistent with the concept that the VRG is not functionally homogenous, but consists of rostrocaudally arranged subregions. Neurons within the so-called PBC appear to have a dominant role in rhythm generation. Nevertheless, neurons within other subregions contribute to both rhythm and pattern generation. Thus, at least at an anatomical level resolvable by pressure injection, there appears to be a significant overlap in the circuitry generating Respiratory rhythm and pattern.
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Respiratory neurons mediating the breuer hering reflex prolongation of expiration in rat
The Journal of Neuroscience, 1996Co-Authors: Fumiaki Hayashi, Sharon K Coles, Donald R MccrimmonAbstract:Afferent input from pulmonary stretch receptors is important in the control of the timing of inspiratory and expiratory phases of the Respiratory cycle. The current study was undertaken to identify neurons within a column of Respiratory neurons in the ventrolateral medulla (termed the Ventral Respiratory Group, VRG) that, when activated by lung inflation, produce the Breuer–Hering (BH) reflex in which lung inflation causes inspiratory termination and expiratory prolongation. Intracellular recordings of VRG neurons revealed three Groups of inspiratory (I) and two Groups of expiratory (E) neurons similar to previous descriptions: I-augmenting (I-Aug), I-decrementing (I-Dec), I-plateau (I-All), E-augmenting (E-Aug), and E-decrementing (E-Dec) neurons. Low-intensity, low-frequency stimulation of a vagus nerve elicited paucisynaptic EPSPs in E-Dec, I-Aug, and I-All neurons that could be divided into two Groups on the basis of latency (2.8 ± 0.1 msec, n = 10; 4.0 ± 0.1 msec, n = 17). IPSPs were elicited in I-Aug and I-All neurons (4.8 ± 0.1 msec, n = 12). However, only E-Dec neurons were depolarized when the BH reflex was activated by lung inflation (7.5 cm H 2 O) or mimicked by vagus nerve stimulation (50 Hz). All other neurons were hyperpolarized and ceased firing during BH reflex-mediated expiratory prolongation. A subset of E-Dec neurons (termed E-Dec early ) discharged before inspiratory termination and could contribute to inspiratory termination. The findings are consistent with the hypothesis that a Group of E-Dec neurons receives a paucisynaptic (probably disynaptic) input from pulmonary afferents and, in turn, inhibits inspiratory neurons, thereby lengthening expiration.
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Respiratory neurons mediating the breuer hering reflex prolongation of expiration in rat
The Journal of Neuroscience, 1996Co-Authors: Fumiaki Hayashi, Sharon K Coles, Donald R MccrimmonAbstract:Afferent input from pulmonary stretch receptors is important in the control of the timing of inspiratory and expiratory phases of the Respiratory cycle. The current study was undertaken to identify neurons within a column of Respiratory neurons in the ventrolateral medulla (termed the Ventral Respiratory Group, VRG) that, when activated by lung inflation, produce the Breuer–Hering (BH) reflex in which lung inflation causes inspiratory termination and expiratory prolongation. Intracellular recordings of VRG neurons revealed three Groups of inspiratory (I) and two Groups of expiratory (E) neurons similar to previous descriptions: I-augmenting (I-Aug), I-decrementing (I-Dec), I-plateau (I-All), E-augmenting (E-Aug), and E-decrementing (E-Dec) neurons. Low-intensity, low-frequency stimulation of a vagus nerve elicited paucisynaptic EPSPs in E-Dec, I-Aug, and I-All neurons that could be divided into two Groups on the basis of latency (2.8 ± 0.1 msec, n = 10; 4.0 ± 0.1 msec, n = 17). IPSPs were elicited in I-Aug and I-All neurons (4.8 ± 0.1 msec, n = 12). However, only E-Dec neurons were depolarized when the BH reflex was activated by lung inflation (7.5 cm H 2 O) or mimicked by vagus nerve stimulation (50 Hz). All other neurons were hyperpolarized and ceased firing during BH reflex-mediated expiratory prolongation. A subset of E-Dec neurons (termed E-Dec early ) discharged before inspiratory termination and could contribute to inspiratory termination. The findings are consistent with the hypothesis that a Group of E-Dec neurons receives a paucisynaptic (probably disynaptic) input from pulmonary afferents and, in turn, inhibits inspiratory neurons, thereby lengthening expiration.
Patrice G Guyenet - One of the best experts on this subject based on the ideXlab platform.
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Central chemoreceptors and sympathetic vasomotor outflow.
The Journal of physiology, 2006Co-Authors: Thiago S Moreira, Ana C Takakura, Eduardo Colombari, Patrice G GuyenetAbstract:The present study explores how elevations in brain P(CO(2)) increase the sympathetic nerve discharge (SND). SND, phrenic nerve discharge (PND) and putative sympathoexcitatory vasomotor neurons of the rostral ventrolateral medulla (RVLM) were recorded in anaesthetized sino-aortic denervated and vagotomized rats. Hypercapnia (end-expiratory CO(2) from 5% to 10%) increased SND (97 +/- 6%) and the activity of RVLM neurons (67 +/- 4%). Injection of kynurenic acid (Kyn, ionotropic glutamate receptor antagonist) into RVLM or the retrotrapezoid nucleus (RTN) eliminated or reduced PND, respectively, but did not change the effect of CO(2) on SND. Bilateral injection of Kyn or muscimol into the rostral Ventral Respiratory Group (rVRG-pre-Bötzinger region, also called CVLM) eliminated PND while increasing the stimulatory effect of CO(2) on SND. Muscimol injection into commissural part of the solitary tract nucleus (commNTS) had no effect on PND or SND activation by CO(2). As expected, injection of Kyn into RVLM or muscimol into commNTS virtually blocked the effect of carotid body stimulation on SND in rats with intact carotid sinus nerves. In conclusion, CO(2) increases SND by activating RVLM sympathoexcitatory neurons. The relevant central chemoreceptors are probably located within or close to RVLM and not in the NTS or in the rVRG-pre-Bötzinger/CVLM region. RVLM sympathoexcitatory neurons may be intrinsically pH-sensitive and/or receive excitatory synaptic inputs from RTN chemoreceptors. Activation of the central Respiratory network reduces the overall sympathetic response to CO(2), presumably by activating barosensitive CVLM neurons and inhibiting RTN chemoreceptors.
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a Group of glutamatergic interneurons expressing high levels of both neurokinin 1 receptors and somatostatin identifies the region of the pre botzinger complex
The Journal of Comparative Neurology, 2003Co-Authors: Hong Wang, Ruth L Stornetta, Diane L Rosin, Charles P Sevigny, Matthew C Weston, Patrice G GuyenetAbstract:The pre-Botzinger complex (pre-BotC) is a physiologically defined Group of ventrolateral medullary neurons that plays a central role in Respiratory rhythm generation. These cells are located in a portion of the rostral ventrolateral medulla (RVLM) that is difficult to identify precisely for lack of a specific marker. We sought to determine whether somatostatin (SST) might be a marker for this region. The rat pre-BotC area was defined as a 500-μm-long segment of ventrolateral medulla coextensive with the Ventral Respiratory Group. This region was identified by juxtacellular labeling of neurons with Respiratory-related activity and by its location rostral to the phrenic premotor neurons. It contained most of the SST-ir neuronal somata of the RVLM. These cells were small (107 μm2) and expressed high levels of preprosomatostatin mRNA. They were strongly neurokinin 1 receptor (NK1R)-ir and were selectively destroyed by saporin conjugated with an NK1R agonist (SSP-SAP). Most SST-ir neurons (>90%) contained vesicular glutamate transporter 2 (VGLUT2) mRNA, and terminals immunoreactive for SST and VGLUT2 protein were found in their midst. Few SST-ir neurons contained GAD-67 mRNA (<1%) or preproenkephalin mRNA (6%). Retrograde labeling experiments demonstrated that over 75% of the SST-ir neurons project to the contralateral pre-BotC area, but none projects to the spinal cord. In conclusion, the RVLM contains many neurons that express preprosomatostatin mRNA. A subGroup of these cells contains high levels of SST and NK1R immunoreactivity in their somata. These glutamatergic interneurons identify a narrow region of the RVLM that appears to be coextensive with the pre-BotC of adult rats. J. Comp. Neurol. 455:499–512, 2003. © 2002 Wiley-Liss, Inc.
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neurokinin 1 receptor expressing cells of the Ventral Respiratory Group are functionally heterogeneous and predominantly glutamatergic
The Journal of Neuroscience, 2002Co-Authors: Patrice G Guyenet, Charles P Sevigny, Matthew C Weston, Ruth L StornettaAbstract:According to a recent theory (Gray et al., 1999) the neurokinin-1 receptor (NK1R)-immunoreactive (ir) neurons of the Ventral Respiratory Group (VRG) are confined to the pre-Botzinger complex (pre-BotC) and might be glutamatergic interneurons that drive Respiratory rhythmogenesis. In this study we tested whether the NK1R-ir neurons of the VRG are glutamatergic. We also examined whether different Groups of NK1R-ir neurons coexist in the VRG on the basis of whether these cells contain preproenkephalin (PPE) mRNA or project to the spinal cord. NK1R immunoreactivity was found in two populations of VRG neurons that are both predominantly glutamatergic because most of them contained vesicular glutamate transporter 2 mRNA (77 +/- 9%; n = 3). A Group of small fusiform neurons (somatic cross section: 91 +/- 3.6 microm2) that has neither PPE mRNA nor spinal projections is primarily restricted to the pre-BotC. These cells may be the interneurons the destruction of which produces massive disruptions of the Respiratory rhythm (Gray et al., 2001). The rest of the NK1R-ir neurons of the VRG are multipolar, are larger (somatic cross section: 252 +/- 15 microm2), and express high levels of PPE mRNA. Some of these cells located in the rostral half of the rostral VRG project to the spinal cord (C4 or T3). Using electrophysiological methods, we showed that these bulbospinal NK1R-ir neurons are slowly discharging inspiratory-augmenting neurons, suggesting that they may control phrenic or intercostal motor neurons. In summary, NK1R-expressing cells of the VRG are a heterogeneous Group of predominantly glutamatergic neurons that include subpopulations of Respiratory premotor neurons.
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depressor and tachypneic responses to chemical stimulation of the Ventral Respiratory Group are reduced by ablation of neurokinin 1 receptor expressing neurons
The Journal of Neuroscience, 2002Co-Authors: Hong Wang, Teresa P Germanson, Patrice G GuyenetAbstract:Our goal was to investigate whether the neurokinin-1 receptor (NK1R)-expressing cells of the rostral ventrolateral medulla (RVLM) regulate respiration and arterial pressure (AP). We examined the consequences of their ablation on the cardioRespiratory responses [phrenic nerve discharge (PND) and AP] caused by injectingdl-homocysteic acid (DLH) into the Ventral Respiratory Group (VRG). In intact rats, DLH produced tachypnea only when injected into the pre-Botzinger complex (pre-BotC). Injections into pre-BotC and rostral VRG (rVRG) caused hypotension, whereas injections into the Botzinger region elevated AP. Selective unilateral ablation of RVLM NK1R-immunoreactive cells (97% loss within the pre-BotC and rVRG without loss of catecholaminergic neurons) was done by injecting saporin (SAP) conjugated with a selective NK1R agonist [Sar9, Met(O2)11]-substance P (SSP). Free SAP produced no lesion. Resting AP was normal in SAP- and SSP-SAP-treated rats, but the PND rate was slightly elevated in SSP-SAP-treated rats. The response of SAP-treated rats to DLH injection into VRG was normal and identical on each side, but tachypnea could not be elicited in the pre-BotC of SSP-SAP-treated rats on the toxin-injected side, and DLH caused a long-lasting apnea on the untreated side. The hypotension produced by DLH injection into pre-BotC and rVRG of SSP-SAP-treated rats was reduced on the lesioned side only. In conclusion, NK1R-expressing cells of the rostral ventrolateral medulla control both Respiratory rhythm and blood pressure. However, there is no evidence yet that these two functions are regulated by the same NK1R-expressing neurons.
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neurokinin 1 receptor immunoreactive neurons of the Ventral Respiratory Group in the rat
The Journal of Comparative Neurology, 2001Co-Authors: Hong Wang, Patrice G Guyenet, Ruth L Stornetta, Diane L RosinAbstract:The rostral end of the Ventral Respiratory Group (VRG) contains neurons that are intensely neurokinin-1 receptor (NK1R) immunoreactive (ir). It has been theorized that some of these cells might be critical to Respiratory rhythmogenesis (Gray et al. [1999] Science 286:1566–1568). In the present study we determined what major transmitter these NK1R-ir cells make and whether they are bulbospinal or propriomedullary. NK1R-ir neurons were found in the VRG between Bregma levels −11.7 and −13.6 mm. The highest concentration was found between Bregma −12.3 and −13.0 mm. This region overlaps with the pre-Botzinger complex (pre-BotC) as it was found to contain many pre-inspiratory neurons, few E2-expiratory neurons, and no I-incremental neurons. VRG NK1R-ir neurons contain neither tyrosine hydroxylase (TH) nor choline acetyl-transferase (ChAT) immunoreactivity, although dual-labeled neurons were found elsewhere within the rostral medulla. GAD67 mRNA was commonly detected in the ventrolateral medulla (VLM) but rarely in the NK1R-ir neurons of the pre-BotC region (6 % of somatic profiles). GlyT2 mRNA was commonly found in the pre-BotC region but rarely within NK1R-ir neurons (1.3 %). Up to 40% of VRG NK1R-ir neurons were retrogradely labeled by Fluoro-Gold (FG) injected in the contralateral pre-BotC region. Some NK1R-ir VRG neurons located caudal to Bregma −12.6 mm were retrogradely labeled by FG injected in the spinal cord (C4–C5, T2–T4). In sum, NK1R immunoreactivity is present in many types of Ventral medullary neurons. Within the VRG proper, NK1R-ir neurons are concentrated in an area that overlaps with the pre-BotC. Within this limited region of the VRG, NK1R-ir neurons are neither cholinergic nor catecholaminergic, and very few are γ-aminobutyric acid (GABA)ergic or glycinergic. The data suggest that most NK1R-ir neurons of the pre-BotC region are excitatory. Furthermore, the more rostral NK1R-ir cells are propriomedullary, whereas some of the caudal ones project to the spinal cord. J. Comp. Neurol. 434:128–146, 2001. © 2001 Wiley-Liss, Inc.
Miguel Goulao - One of the best experts on this subject based on the ideXlab platform.
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astrocyte progenitor transplantation promotes regeneration of bulbospinal Respiratory axons recovery of diaphragm function and a reduced macrophage response following cervical spinal cord injury
Glia, 2018Co-Authors: Miguel Goulao, Biswarup Ghosh, Mark W Urban, Malya Sahu, Christina Mercogliano, Brittany A Charsar, Sreeya Komaravolu, Cole G Block, George M SmithAbstract:Stem/progenitor cell transplantation delivery of astrocytes is a potentially powerful strategy for spinal cord injury (SCI). Axon extension into SCI lesions that occur spontaneously or in response to experimental manipulations is often observed along endogenous astrocyte "bridges," suggesting that augmenting this response via astrocyte lineage transplantation can enhance axon regrowth. Given the importance of Respiratory dysfunction post-SCI, we transplanted glial-restricted precursors (GRPs)-a class of lineage-restricted astrocyte progenitors-into the C2 hemisection model and evaluated effects on diaphragm function and the growth response of descending rostral Ventral Respiratory Group (rVRG) axons that innervate phrenic motor neurons (PhMNs). GRPs survived long term and efficiently differentiated into astrocytes in injured spinal cord. GRPs promoted significant recovery of diaphragm electromyography amplitudes and stimulated robust regeneration of injured rVRG axons. Although rVRG fibers extended across the lesion, no regrowing axons re-entered caudal spinal cord to reinnervate PhMNs, suggesting that this regeneration response-although impressive-was not responsible for recovery. Within ipsilateral C3-5 Ventral horn (PhMN location), GRPs induced substantial sprouting of spared fibers originating in contralateral rVRG and 5-HT axons that are important for regulating PhMN excitability; this sprouting was likely involved in functional effects of GRPs. Finally, GRPs reduced the macrophage response (which plays a key role in inducing axon retraction and limiting regrowth) both within the hemisection and at intact caudal spinal cord surrounding PhMNs. These findings demonstrate that astrocyte progenitor transplantation promotes significant plasticity of rVRG-PhMN circuitry and restoration of diaphragm function and suggest that these effects may be in part through immunomodulation.
George M Smith - One of the best experts on this subject based on the ideXlab platform.
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Respiratory axon regeneration in the chronically injured spinal cord
'Elsevier BV', 2021Co-Authors: Lan Cheng, Biswarup Ghosh, George M Smith, Armin Sami, Hannah J. Goudsward, Megan C. Wright, Angelo C. LeporeAbstract:Promoting the combination of robust regeneration of damaged axons and synaptic reconnection of these growing axon populations with appropriate neuronal targets represents a major therapeutic goal following spinal cord injury (SCI). A key impediment to achieving this important aim includes an intrinsic inability of neurons to extend axons in adult CNS, particularly in the context of the chronically-injured spinal cord. We tested whether an inhibitory peptide directed against phosphatase and tensin homolog (PTEN: a central inhibitor of neuron-intrinsic axon growth potential) could restore inspiratory diaphragm function by reconnecting critical Respiratory neural circuitry in a rat model of chronic cervical level 2 (C2) hemisection SCI. We found that systemic delivery of PTEN antagonist peptide 4 (PAP4) starting at 8 weeks after C2 hemisection promoted substantial, long-distance regeneration of injured bulbospinal rostral Ventral Respiratory Group (rVRG) axons into and through the lesion and back toward phrenic motor neurons (PhMNs) located in intact caudal C3-C5 spinal cord. Despite this robust rVRG axon regeneration, PAP4 stimulated only minimal recovery of diaphragm function. Furthermore, re-lesion through the hemisection site completely removed PAP4-induced functional improvement, demonstrating that axon regeneration through the lesion was responsible for this partial functional recovery. Interestingly, there was minimal formation of putative excitatory monosynaptic connections between regrowing rVRG axons and PhMN targets, suggesting that (1) limited rVRG-PhMN synaptic reconnectivity was responsible at least in part for the lack of a significant functional effect, (2) chronically-injured spinal cord presents an obstacle to achieving synaptogenesis between regenerating axons and post-synaptic targets, and (3) addressing this challenge is a potentially-powerful strategy to enhance therapeutic efficacy in the chronic SCI setting. In conclusion, our study demonstrates a non-invasive and transient pharmacological approach in chronic SCI to repair the critically-important neural circuitry controlling diaphragmatic Respiratory function, but also sheds light on obstacles to circuit plasticity presented by the chronically-injured spinal cord
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astrocyte progenitor transplantation promotes regeneration of bulbospinal Respiratory axons recovery of diaphragm function and a reduced macrophage response following cervical spinal cord injury
Glia, 2018Co-Authors: Miguel Goulao, Biswarup Ghosh, Mark W Urban, Malya Sahu, Christina Mercogliano, Brittany A Charsar, Sreeya Komaravolu, Cole G Block, George M SmithAbstract:Stem/progenitor cell transplantation delivery of astrocytes is a potentially powerful strategy for spinal cord injury (SCI). Axon extension into SCI lesions that occur spontaneously or in response to experimental manipulations is often observed along endogenous astrocyte "bridges," suggesting that augmenting this response via astrocyte lineage transplantation can enhance axon regrowth. Given the importance of Respiratory dysfunction post-SCI, we transplanted glial-restricted precursors (GRPs)-a class of lineage-restricted astrocyte progenitors-into the C2 hemisection model and evaluated effects on diaphragm function and the growth response of descending rostral Ventral Respiratory Group (rVRG) axons that innervate phrenic motor neurons (PhMNs). GRPs survived long term and efficiently differentiated into astrocytes in injured spinal cord. GRPs promoted significant recovery of diaphragm electromyography amplitudes and stimulated robust regeneration of injured rVRG axons. Although rVRG fibers extended across the lesion, no regrowing axons re-entered caudal spinal cord to reinnervate PhMNs, suggesting that this regeneration response-although impressive-was not responsible for recovery. Within ipsilateral C3-5 Ventral horn (PhMN location), GRPs induced substantial sprouting of spared fibers originating in contralateral rVRG and 5-HT axons that are important for regulating PhMN excitability; this sprouting was likely involved in functional effects of GRPs. Finally, GRPs reduced the macrophage response (which plays a key role in inducing axon retraction and limiting regrowth) both within the hemisection and at intact caudal spinal cord surrounding PhMNs. These findings demonstrate that astrocyte progenitor transplantation promotes significant plasticity of rVRG-PhMN circuitry and restoration of diaphragm function and suggest that these effects may be in part through immunomodulation.
