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Richard C Rogers

Publications and source records attributed to Richard C Rogers.

At least 19 recordsLinked to original sources
PubMed2006

Tumor necrosis factor potentiates central vagal afferent signaling by modulating ryanodine channels.

Disease processes such as infection, leukemia, and autoimmune disorders are often associated with nausea, emesis, and anorexia. A common denominator of these rather disparate states is the production of the early, proinflammatory cytokine tumor necrosis factor-alpha (TNF) in significant quantities. Recent studies have shown that TNF may act as a neuromodulator in the hindbrain to produce malaise by potentiating visceral afferent signaling at the central processes of the vagus nerve. However, the mechanism by which TNF produces this signal amplification is not known. Our time-lapse calcium imaging studies of individual central vagal afferent varicosities in the caudal brainstem slice preparation show that, although TNF has minimal direct effects to elevate terminal intracellular calcium levels, TNF does potentiate the terminal afferent responses to other stimuli through a ryanodine-based, calcium-induced calcium release mechanism. Such a scheme may explain how TNF sensitizes visceral as well as somatosensory primary afferents.

Afferent Pathways↗
PubMed2006

Leptin and thyrotropin-releasing hormone: cooperative action in the hindbrain to activate brown adipose thermogenesis.

Explanations of leptin induction of thermogenesis typically involve primary detection elements in the hypothalamus. In turn, these circuits control medullary raphe neurons that regulate spinal efferent sympathetic projections to heat-producing brown adipose tissue (BAT). The hindbrain may be capable of considerable thermoregulatory capacity independent of the hypothalamus, though little is known about the site(s), mechanism(s) of action, or the physiological consequences of leptin action in the hindbrain. Several reports describe the presence of leptin receptor in the solitary nucleus, and there is functional evidence that leptin can act in the dorsal medulla to suppress feeding. We examined the effects of leptin, applied to the dorsal medulla, on BAT thermogenesis. Leptin alone (< or =25 microg) had no independent effect on BAT thermogenesis. We hypothesized that, while leptin may not be capable of activating thermocontrol mechanisms in the hindbrain directly, it may modulate the efficacy of other neural signals involved in the control of thermogenesis such as thyrotropin-releasing hormone (TRH). We tested the hypothesis that leptin and TRH, acting in the hindbrain, co-regulate thermogenesis. As expected, TRH (0.1 microg), alone, produces a small increase (+0.75 degrees C) in BAT temperature. Co-application of leptin (5 mug) and TRH (0.1 microg) to the dorsal medulla produces an increase in BAT and core temperature more than 300% greater than TRH alone (+3.5 degrees C). This effect is undiminished in the acute decerebrate rat, suggesting that the effect is mediated entirely by the hindbrain.

Adipose Tissue, Brown↗
PubMed2006

Differential coupling of beta3A- and beta3B-adrenergic receptors to endogenous and chimeric Galphas and Galphai.

Chimeric G proteins made by replacing the COOH-terminal heptapeptide of G(alpha)q with the COOH-terminal heptapeptide of G(alpha)s or G(alpha)i were used to assess the relative coupling of beta(3)-adrenergic receptor (beta(3)-AR) splice variants (beta(3A) and beta(3B)) to G(alpha)s and G(alpha)i. The G(alpha)q/s and G(alpha)q/i chimeras transformed the response to receptor activation from regulation of adenylyl cyclase to mobilization of intracellular calcium (Ca(2+)(i)). Complementary high-throughput and single-cell approaches were used to evaluate agonist-induced coupling of the receptor to the G protein chimeras. In cells stably transformed with rat beta(3)-AR, transfected with the G protein chimeras, and evaluated using a scanning fluorometer, beta(3)-AR-induced coupling to G(alpha)q/s produced a rapid eightfold increase in Ca(2+)(i) followed by a slow decay to levels 25% above baseline. G(alpha)q/i also linked rat beta(3)-AR to mobilization of Ca(2+)(i) in a similar time- and agonist-dependent manner, but the net 2.5-fold increase in Ca(2+)(i) was only 30% of the response obtained with G(alpha)q/s. Activation of the rat beta(3)-AR also increased GTP binding to endogenous G(alpha)i threefold in membranes from CHO cells stably transformed with the receptor. A complementary single-cell imaging approach was used to assess the relative coupling of mouse beta(3A)- and beta(3B)-AR to G(alpha)i under conditions established to produce equivalent agonist-dependent coupling of the receptor splice variants to G(alpha)q/s and to increases in intracellular cAMP through endogenous G(alpha)s. The beta(3A)- and beta(3B)-AR coupled equivalently to G(alpha)q/i, but the temporal patterns of Ca(2+)(i) mobilization indicated that coupling was significantly less efficient than coupling to G(alpha)q/s. Collectively, these findings indicate less efficient but equivalent coupling of beta(3A)- and beta(3B)-AR to G(alpha)i vs. G(alpha)s and suggest that differential expression of the splice variants would not produce local differences in signaling networks linked to beta(3)-AR activation.

Adenylyl Cyclases↗
PubMed2006

Esophageal-gastric relaxation reflex in rat: dual control of peripheral nitrergic and cholinergic transmission.

It has long been known that the esophageal distension produced by swallowing elicits a powerful proximal gastric relaxation. Gastroinhibitory control by the esophagus involves neural pathways from esophageal distension-sensitive neurons in the nucleus tractus solitarius centralis (cNTS) with connections to virtually all levels of the dorsal motor nucleus of the vagus (DMV). We have shown recently that cNTS responses are excitatory and primarily involve tyrosine hydroxylase-immunoreactive cells, whereas the DMV response involves both an alpha1 excitatory and an alpha2 inhibitory response. In the present study, using an esophageal balloon distension to evoke gastric relaxation (esophageal-gastric reflex, EGR), we investigated the peripheral pharmacological basis responsible for this reflex. Systemic administration of atropine methyl nitrate reduced the amplitude of the gastric relaxation to 52.0+/-4.4% of the original EGR, whereas NG-nitro-L-arginine methyl ester (L-NAME) reduced it to 26.3+/-7.2% of the original EGR. Concomitant administration of atropine methyl nitrate and L-NAME reduced the amplitude of the gastric relaxation to 4.0+/-2.5% of control. This reduction in the amplitude of induced EGR is quite comparable (4.3+/-2.6%) to that seen when the animal was pretreated with the nicotinic ganglionic blocker hexamethonium. In the presence of bethanechol, the amplitude of the esophageal distension-induced gastric relaxation was increased to 177.0+/-10.0% of control; administration of L-NAME reduced this amplitude to 19.9+/-9.5%. Our data provide a clear demonstration that the gastroinhibitory control by the esophagus is mediated via a dual vagal innervation consisting of inhibitory nitrergic and excitatory cholinergic transmission.

Animals↗
PubMed2006

Brainstem circuits regulating gastric function.

Brainstem parasympathetic circuits that modulate digestive functions of the stomach are comprised of afferent vagal fibers, neurons of the nucleus tractus solitarius (NTS), and the efferent fibers originating in the dorsal motor nucleus of the vagus (DMV). A large body of evidence has shown that neuronal communications between the NTS and the DMV are plastic and are regulated by the presence of a variety of neurotransmitters and circulating hormones as well as the presence, or absence, of afferent input to the NTS. These data suggest that descending central nervous system inputs as well as hormonal and afferent feedback resulting from the digestive process can powerfully regulate vago-vagal reflex sensitivity. This paper first reviews the essential "static" organization and function of vago-vagal gastric control neurocircuitry. We then present data on the opioidergic modulation of NTS connections with the DMV as an example of the "gating" of these reflexes, i.e., how neurotransmitters, hormones, and vagal afferent traffic can make an otherwise static autonomic reflex highly plastic.

Animals↗
PubMed2005

Live-cell imaging methods for the study of vagal afferents within the nucleus of the solitary tract.

Substantial evidence suggests that vagal afferent functions are modulated by agonists acting on afferent terminals in the solitary nucleus (NST). Actions of these agonists are implied through intracellular recordings from cultured nodose ganglion cells or second order NST neurons. While high-quality data have been obtained using these methods, techniques in which physiological measurements can be made directly on the afferent terminal fields, in situ, in the NST, would eliminate several potential interpretive problems inherent in these less direct approaches. This paper describes methods developed to directly measure changes in presynaptic cytoplasmic calcium in vagal afferents using time-lapse laser confocal microscopy on the in vitro brainstem slice. Calcium green dextran (CG) transported from the nodose ganglion clearly demonstrates vagal afferent fibers ramifying throughout the NST in the in vitro brainstem slice. CG-labeled vagal afferents can be repeatedly activated by focal electrical stimulation, by agonists acting on presynaptic ligand-gated ion channels, and by molecules that are presumed to act directly on vagal afferents based on previous physiological and immunocytochemical studies. Image and preparation stability are a challenge to the success of the experiment; however, methods described here should assist direct studies of transduction events within other afferent terminal fields in the CNS.

Animals↗
PubMed2004

Alpha-1 adrenergic input to solitary nucleus neurones: calcium oscillations, excitation and gastric reflex control.

The nucleus of the solitary tract (NST) processes substantial visceral afferent input and sends divergent projections to a wide array of CNS targets. The NST is essential to the maintenance of behavioural and autonomic homeostasis and is the source, as well as the recipient, of considerable noradrenergic (NE) projections. The significance of NE projections from the NST to other CNS regions has long been appreciated, but the nature of NE action on NST neurones themselves, especially on the alpha-1 receptor subtype, is controversial. We used a combination of methodologies to establish, systematically, the effects and cellular basis of action of the alpha-1 agonist, phenylephrine (PHE), to control NST neurones responsible for vago-vagal reflex regulation of the stomach. Immunocytochemical and retrograde tracing studies verified that the area postrema, A2, A5, ventrolateral medulla and locus coeruleus regions are sources of catecholaminergic input to the NST. In vivo electrophysiological recordings showed that PHE activates physiologically identified, second-order gastric sensory NST neurones. In vivo microinjection of PHE onto NST neurones caused a significant reduction in gastric tone. Finally, in vitro calcium imaging studies revealed that PHE caused dramatic cytosolic calcium oscillations in NST neurones. These oscillations are probably the result of an interplay between agonist-induced and inositol 1,4,5-trisphosphate (IP(3))-mediated intracellular calcium release and Ca(2+)-ATPase control of intracellular calcium storage pumps. The oscillations persisted even in perfusions of zero calcium-EGTA Krebs solution suggesting that the calcium oscillation is mediated principally by intracellular calcium release-reuptake mechanisms. Cyclical activation of the NST may function to increase the responsiveness of these neurones to incoming afferent input (i.e., elevate the "gain"). An increase in gain of afferent input may cause an amplification of the response part of the reflex and help explain the powerful effects that alpha-1 agonists have in suppressing gastric motility and producing anorexia.

Adrenergic alpha-Agonists↗
PubMed2004

Immunocytochemical localization of TNF type 1 and type 2 receptors in the rat spinal cord.

Tumor necrosis factor-alpha (TNF-alpha) is secreted in numerous pathophysiological situations by a variety of cell types. Tactile hypersensitivity (allodynia) is one component of a constellation of "illness behaviors" triggered by TNF-alpha. TNF-alpha is also implicated in neuropathic pain after peripheral nerve injury and apoptosis after spinal cord injury (SCI). It is possible that SCI, illness- and peripheral injury-induced hypersensitivity may share a similar spinal mediated etiology. These studies identify the locus of type-1 TNF (TNFR1 or p55) and type-2 TNF (TNFR2 or p75) receptors within the spinal cord. At all spinal levels, TNFR1 receptor immunoreactivity (TNFR1-ir) was constitutively expressed on cells and afferent fibers within the dorsal root ganglia, afferent fibers of the dorsal root, dorsal root entry zone (REZ) and within lamina I and II of the dorsal horn. Unilateral dorsal rhizotomy eliminated the characteristic pattern of TNFR1-ir at the rhizotomized REZ. In contrast, TNFR2-ir was consistently absent from dorsal root fibers and the region of the root entry zone. Consistent with our previous report, medullary afferent fibers in the solitary tract and spinal trigeminal tract labelled for TNF1-ir, but did not express TNFR2-ir. The presence TNFR1-ir on dorsal horn afferents, suggests that TNF-alpha may be a mechanism responsible for tactile hypersensitivity during illness. The presence of TNFR1 receptors, and perhaps their long-term activation or plasticity, may also play a critical role in the chronic allodynia and hyperreflexia observed after SCI or peripheral nerve damage.

Animals↗
PubMed2004

TNF alpha-p55 receptors: medullary brainstem immunocytochemical localization in normal and vagus nerve-transected rats.

Tumor necrosis factor alpha (TNF(alpha)) is a potent modulator of autonomic reflex mechanisms that control the stomach. Evidence suggests that TNF(alpha) action directly on vago-vagal reflex control circuits causes the autonomic misregulation of digestion manifested as gastrointestinal stasis, nausea, and emesis associated with illness. Neurophysiological studies indicated that TNF(alpha) may have effects on vagal afferents in the solitary nucleus, as well as neurons of the solitary nucleus (NST) and dorsal motor nucleus (DMN) of the vagus. The aim of this study was to determine the location of the TNFR1 receptor (p55) in the medulla using immunocytochemical methods. We devised a technique for localizing the p55 receptor using heat-induced antigen recovery in fixed tissue sections. This protocol allowed us to demonstrate that dense p55-immunoreactivity (p55-ir) is constitutively present on central (but not peripheral) vagal afferents in the solitary tract (ST) and nucleus; p55-ir is also present on afferents entering the spinal trigeminal nucleus. Unilateral supra-nodose vagotomy eliminated p55-ir from ipsilateral central vagal afferents. Virtually all neurons in the brainstem appeared to express p55-ir at a low level, i.e., just above background. However, vagotomy caused a dramatic up-regulation of p55-ir in vagal motor neurons. This increase in p55-ir in axotomized neurons may play a pivotal role in the connection between the occurrence of the injury and the initiation of apoptotic processes resulting in elimination of damaged neurons.

Animals↗
PubMed2003

Norepinephrine effects on identified neurons of the rat dorsal motor nucleus of the vagus.

The dorsal motor nucleus of the vagus (DMV) receives more noradrenergic terminals than any other medullary nucleus; few studies, however, have examined the effects of norepinephrine (NE) on DMV neurons. Using whole cell recordings in thin slices, we determined the effects of NE on identified gastric-projecting DMV neurons. Twenty-five percent of DMV neurons were unresponsive to NE, whereas the remaining 75% responded to NE with either an excitation (49%), an inhibition (26%), or an inhibition followed by an excitation (4%). Antrum/pylorus- and corpus-projecting neurons responded to NE with a similar percentage of excitatory (49 and 59%, respectively) and inhibitory (20% for both groups) responses. A lower percentage of excitatory (37%) and a higher percentage of inhibitory (36%) responses were, however, observed in fundus-projecting neurons. In all groups, pretreatment with prazosin or phenylephrine antagonized or mimicked the NE-induced excitation, respectively. Pretreatment with yohimbine or UK-14304 antagonized or mimicked the NE-induced inhibition, respectively. These data suggest that NE depolarization is mediated by alpha(1)-adrenoceptors, whereas NE hyperpolarization is mediated by alpha(2)-adrenoceptors. In 16 neurons depolarized by NE, amplitude of the action potential afterhyperpolarization (AHP) and its kinetics of decay (tau) were significantly reduced vs. control. No differences were found on the amplitude and tau of AHP in neurons hyperpolarized by NE. Using immunohistochemical techniques, we found that the distribution of tyrosine hydroxylase fibers within the DMV was significantly different within the mediolateral extent of DMV; however, distribution of cells responding to NE did not show a specific pattern of localization.

Adrenergic alpha-Agonists↗
PubMed2003

TNFalpha-stimulation of cFos-activation of neurons in the solitary nucleus is suppressed by TNFR:Fc adsorbant construct in the dorsal vagal complex.

The cytokine tumor necrosis factor alpha (TNF(alpha)) may act within the neural circuitry of the medullary dorsal vagal complex (DVC) to affect changes in gastric function such as gastric stasis, loss of appetite, nausea, and vomiting. The definitive demonstration that endogenously generated TNF(alpha) is acting within the DVC circuitry to affect these changes has been impeded by the lack of an antagonist for TNF(alpha). The present studies used localized central nervous system microinjections of the TNF-adsorbant construct (TNFR:Fc) to specifically neutralize the ability of endogenously produced TNF(alpha) to activate NST neurons. Our studies reveal that TNFR:Fc suppresses induction of cFos normally evoked by TNF(alpha). These results validate our hypothesis that circulating TNF(alpha) may act directly within the DVC to affect gastric function in a variety of pathophysiological states.

Animals↗
PubMed2003

Descending spinal projections from the rostral gigantocellular reticular nuclei complex.

Electrophysiological and physiological studies have suggested that the ventral medullary gigantocellular reticular nuclei (composed of the gigantocellular ventralis and pars alpha nuclei as well as the adjacent lateral paragigantocellular nucleus; abbreviated Gi-LPGi complex) provide descending control of pelvic floor organs (Mackel [1979] J. Physiol. (Lond.) 294:105-122; Hubscher and Johnson [1996] J. Neurophysiol. 76:2474-2482; Hubscher and Johnson [1999] J. Neurophysiol. 82:1381-1389; Johnson and Hubscher [1998] Neuroreport 9:341-345). Specifically, this complex of paramedian reticular nuclei has been implicated in the inhibition of sexual reflexes. In the present study, an anterograde fluorescent tracer was used to investigate direct descending projections from the Gi-LPGi complex to retrogradely labeled pudendal motoneurons (MN) in the male rat. Our results demonstrated that, although a high density of arborizations from Gi-LPGi fibers appears to be in close apposition to pudendal MNs, this relationship also applies to other MNs throughout the entire spinal cord. The Gi-LPGi also projects to spinal autonomic regions, i.e., both the intermediolateral cell column and the sacral parasympathetic nucleus, as well as to regions of the intermediate gray, which contain interneurons involved in the organization of pelvic floor reflexes. Lastly, throughout the length of the spinal cord, numerous neurons located primarily in laminae VII-X, were retrogradely labeled with Fluoro-Ruby after injections into the Gi-LPGi. The diffuse descending projections and arborizations of this pathway throughout the spinal cord suggest that this brainstem area is involved in the direct, descending control of a variety of spinal activities. These results are in contrast with our observations of the discrete projections of the caudal nucleus raphe obscurus, which target the autonomic and somatic MNs involved specifically in sexual and eliminative functions (Hermann et al. [1998] J. Comp. Neurol. 397:458-474).

Animals↗
PubMed2003

Musings on the wanderer: what's new in our understanding of vago-vagal reflexes? III. Activity-dependent plasticity in vago-vagal reflexes controlling the stomach.

Vago-vagal reflex circuits modulate digestive functions from the oral cavity to the transverse colon. Previous articles in this series have described events at the level of the sensory receptors encoding the peripheral stimuli, the transmission of information in the afferent vagus, and the conversion of this data within the dorsal vagal complex (DVC) to impulses in the preganglionic efferents. The control by vagal efferents of the postganglionic neurons impinging on the glands and smooth muscles of the target organs has also been illustrated. Here we focus on some of the mechanisms by which these apparently static reflex circuits can be made quite plastic as a consequence of the action of modulatory inputs from other central nervous system sources. A large body of evidence has shown that the neuronal elements that constitute these brain stem circuits have nonuniform properties and function differently according to status of their target organs and the level of activity in critical modulatory inputs. We propose that DVC circuits undergo a certain amount of short-term plasticity that allows the brain stem neuronal elements to act in harmony with neural systems that control behavioral and physiological homeostasis.

Animals↗
PubMed2002

Tumor necrosis factor-alpha inhibits physiologically identified dorsal motor nucleus neurons in vivo.

Our previous studies have shown that tumor necrosis factor-alpha (TNF-alpha) activates solitary nucleus neurons involved in vago-vagal reflex control of gastric motility. Here, we describe the dual role of TNF-alpha as also modulating neurons in the dorsal motor nucleus of the vagus (DMN) that respond to gastric distention. A large majority of physiologically identified DMN neurons are rapidly and completely inhibited by exposure to TNF-alpha, suggesting that TNF-alpha may induce gastric stasis by functioning as a hormone that modulates both portions of this reflex pathway during illness.

Animals↗
PubMed2002

In vitro and in vivo analysis of the effects of corticotropin releasing factor on rat dorsal vagal complex.

In vivo and in vitro electrophysiological experiments were performed on the rat dorsal vagal complex (DVC, i.e. nucleus of the tractus solitarius, NTS, and dorsal motor nucleus of the vagus, DMV) to examine the effects of corticotropin releasing hormone (CRF) on the central components of the vago-vagal reflex control of gastric function. When applied to gastrointestinal projecting DMV neurones, CRF (10-300 nM) induced a concentration-dependent membrane depolarization, an increase in action potential firing rate and decrease in amplitude of the action potential afterhyperpolarization (P < 0.05). Pretreatment with the non-selective CRF antagonist, astressin (0.5-1 microM) or the selective CRF(2) receptor antagonist, astressin 2B (500 nM) attenuated the CRF-induced increase in firing rate but did not alter basal discharge rate. CRF (30-300 nM) increased the amplitude of excitatory postsynaptic currents (EPSCs) evoked by stimulation of the NTS (P < 0.05). An alteration in the paired pulse ratio indicated the EPSC's increase occurred due to actions at presynaptic sites. In the in vivo anaesthetized rat preparation, bilateral microinjections (20 fmol in 20 nl for each site) of CRF in the DVC decreased gastric motility in rats pretreated with the muscarinic agonist, bethanecol (P < 0.05). The effects of CRF were abolished by systemic administration of the NOS inhibitor, L-NAME, or by bilateral vagotomy. We concluded that CRF had both a direct and an indirect excitatory effect on DMV neurones via activation of CRF(2) receptors and the decrease in gastric motility observed following microinjection of CRF in the DVC is due to the activation of an inhibitory non-adrenergic non-cholinergic input to the gastrointestinal tract.

Action Potentials↗
PubMed2002

Cell death in models of spinal cord injury.

Current treatments for acute spinal cord injury are based on animal models of human spinal cord injury (SCI). These models have shown that the initial traumatic injury to cord tissue is followed by a long period of secondary injury that includes a number of cellular and biochemical cascades. These secondary injury processes are potential targets for therapies. Continued refinement of rat and mouse models of SCI, along with more detailed analyses of the biology of the lesion in these models, points to both necrotic and apoptotic mechanisms of cell death after SCI. In this chapter, we review recent evidence for long-term apoptotic death of oligodendrocytes in long tracts undergoing Wallerian degeneration following SCI. This process appears to be related closely to activation of microglial cells. It is has been thought that microglial cells might be the source of cytotoxic cytokines, such as tumor necrosis factor-alpha (TNF-alpha), that kill oligodendrocytes. However, more recent evidence in vivo suggests that TNF-alpha by itself may not induce necrosis or apoptosis in oligodendrocytes. We review data that suggests other possible pathways for apoptosis, such as the neurotrophin receptor p75 which is expressed in both neurons and oligodendrocytes after SCI in rats and mice. In addition, it appears that microglial activation and TNF-alpha may be important in acute SCI. Ninety minutes after a moderate contusion lesion, microglia are activated and surround dying neurons. In an 'atraumatic' model of SCI, we have now shown that TNF-alpha appears to greatly potentiate cell death mediated by glutamate receptors. These studies emphasize that multiple mechanisms and interactions contribute to secondary injury after SCI. Continued study of both contusion models and other new approaches to studying these mechanisms will be needed to maximize strategies for acute and chronic therapies, and for neural repair.

Animals↗