CGRP infusion in unanesthetized rats increases expression of c-Fos in the nucleus tractus solitarius and caudal ventrolateral medulla, but not in the trigeminal nucleus caudalis

Cephalalgia ◽  
2014 ◽  
Vol 35 (3) ◽  
pp. 220-233 ◽  
Author(s):  
Deepak K Bhatt ◽  
Roshni Ramachandran ◽  
Sarah LT Christensen ◽  
Saurabh Gupta ◽  
Inger Jansen-Olesen ◽  
...  
Keyword(s):  
Protein Expression ◽  
Brain Stem ◽  
Dura Mater ◽  
Nucleus Tractus Solitarius ◽  
Early Gene ◽  
Ventrolateral Medulla ◽  
Trigeminal Nucleus ◽  
Caudal Ventrolateral Medulla ◽  
Trigeminal Nucleus Caudalis ◽  
The Brain

Background and aims Calcitonin gene-related peptide (CGRP) and glyceryl trinitrate (GTN) infusion in migraineurs provokes headache resembling spontaneous migraine, and CGRP receptor antagonists are effective in the treatment of acute migraine. We hypothesized that CGRP infusion would increase molecular markers of neuronal activation in migraine-relevant tissues of the rat. Methods CGRP was infused intravenously (i.v.) in freely moving rats to circumvent factors like anesthesia, acute surgery and severe hypotension, the three confounding factors for c-Fos expression. The trigeminal nucleus caudalis (TNC) was isolated at different time points after CGRP infusion. The level of c-Fos mRNA and protein expression in TNC were analyzed by qPCR and immunohistochemistry. c-Fos-stained nuclei were also counted in the nucleus tractus solitarius (NTS) and caudal ventrolateral medulla (CVLM), integrative sites in the brain stem for processing cardiovascular signals. We also investigated Zif268 protein expression (another immediate early gene) in TNC. The protein expression of p-ERK, p-CREB and c-Fos was analyzed in dura mater, trigeminal ganglion (TG) and TNC samples using Western blot. Results CGRP infusion caused a significant dose-dependent fall in mean arterial blood pressure. No significant activation of c-Fos in the TNC at mRNA and protein levels was observed after CGRP infusion. A significant increase in c-Fos protein was observed in the NTS and CVLM in the brain stem. Zif268 expression in the TNC was also not changed after CGRP infusion. p-ERK was increased in the dura mater 30 minutes after CGRP infusion. Conclusion CGRP infusion increased the early expression of p-ERK in the dura mater but did not increase c-Fos and Zif268 expression in the TNC. The rats may, thus, differ from migraine patients, in whom infusion of CGRP caused headache and a delayed migraine attack. The rat CGRP infusion model with c-Fos or Zif268 as neuronal pain markers in TNC is unsuitable for antimigraine drug testing.

scholarly journals Altered regulation of the rostral ventrolateral medulla in hypertensive obese Zucker rats

2011 ◽  
Vol 301 (1) ◽  
pp. H230-H240 ◽  
Author(s):  
Domitila A. Huber ◽  
Ann M. Schreihofer
Keyword(s):  
Sympathetic Nerve Activity ◽  
Nucleus Tractus Solitarius ◽  
Excitatory Input ◽  
Rostral Ventrolateral Medulla ◽  
Male Rats ◽  
Ventrolateral Medulla ◽  
Zucker Rats ◽  
Caudal Ventrolateral Medulla ◽  
Obese Zucker Rats ◽  
Altered Regulation

Obese Zucker rats (OZR) have elevated sympathetic nerve activity (SNA) and mean arterial pressure (MAP) compared with lean Zucker rats (LZR). We examined whether altered tonic glutamatergic, angiotensinergic, or GABAergic inputs to the rostral ventrolateral medulla (RVLM) contribute to elevated SNA and MAP in OZR. Male rats (14–18 wk) were anesthetized with urethane (1.5 g/kg iv), ventilated, and paralyzed to record splanchnic SNA, heart rate (HR), and MAP. Inhibition of the RVLM by microinjections of muscimol eliminated SNA and evoked greater decreases in MAP in OZR vs. LZR ( P < 0.05). Antagonism of angiotensin AT1 receptors in RVLM with losartan yielded modest decreases in SNA and MAP in OZR but not LZR ( P < 0.05). However, antagonism of ionotropic glutamate receptors in RVLM with kynurenate produced comparable decreases in SNA, HR, and MAP in OZR and LZR. Antagonism of GABAA receptors in RVLM with gabazine evoked smaller rises in SNA, HR, and MAP in OZR vs. LZR ( P < 0.05), whereas responses to microinjections of GABA into RVLM were comparable. Inhibition of the caudal ventrolateral medulla, a major source of GABA to the RVLM, evoked attenuated rises in SNA and HR in OZR ( P <0.05). Likewise, inhibition of nucleus tractus solitarius, the major excitatory input to caudal ventrolateral medulla, produced smaller rises in SNA and HR in OZR. These results suggest the elevated SNA and MAP in OZR is derived from the RVLM and that enhanced angiotensinergic activation and reduced GABAergic inhibition of the RVLM may contribute to the elevated SNA and MAP in the OZR.

Role of the brain stem in generating the 2- to 6-Hz oscillation in sympathetic nerve discharge

1993 ◽  
Vol 265 (5) ◽  
pp. R1026-R1035 ◽  
Author(s):  
S. Zhong ◽  
Z. S. Huang ◽  
G. L. Gebber ◽  
S. M. Barman
Keyword(s):  
Brain Stem ◽  
Sympathetic Nerve ◽  
Cervical Spinal Cord ◽  
Ventrolateral Medulla ◽  
Population Activity ◽  
A Value ◽  
Decerebrate Cats ◽  
The Brain ◽  
Nerve Discharge

We tested the hypothesis that brain stem circuits normally generate a 2- to 6-Hz oscillation in sympathetic nerve discharge (SND). Experiments were performed on baroreceptor-denervated decerebrate cats and urethan-anesthetized rats in which renal or splanchnic SND was recorded along with field potentials (population activity) from sites in the rostral ventrolateral medulla, medullary raphe, or medullary lateral tegmental field. Our major findings were as follows. 1) Population activity recorded from the three medullary regions contained a 2- to 6-Hz oscillation. 2) The 2- to 6-Hz oscillation in population activity recorded from some medullary sites was correlated to that in SND. Peak coherence in the 2- to 6-Hz band approached a value of 1 in some cases. 3) Whereas cervical spinal cord transection abolished or markedly reduced SND, the 2- to 6-Hz oscillation in medullary activity was essentially unchanged. These results support the view that the 2- to 6-Hz oscillation in SND can be generated in the brain stem of cats and rats.

Effects of insulin on the cardiovascular integrating mechanisms of brain stem in cats

1993 ◽  
Vol 265 (4) ◽  
pp. E609-E616 ◽  
Author(s):  
S. W. Kuo ◽  
J. H. Hsieh ◽  
W. C. Wu ◽  
H. T. Horng ◽  
L. R. Shian ◽  
...  
Keyword(s):  
Brain Stem ◽  
Cardiovascular Responses ◽  
Serum Glucose ◽  
Ventrolateral Medulla ◽  
Reticular Nucleus ◽  
Motor Nucleus ◽  
Renal Nerve ◽  
Pressor Responses ◽  
The Brain ◽  
Stimulation Of

In 65 cats anesthetized with alpha-chloralose and urethane, the effects of insulin on cardiovascular responses to stimulation of various structures in the brain stem were studied. The threshold dose of insulin injected intravenously that produced systemic hypoglycemia was 5-10 U/kg. Subthreshold hypoglycemic doses of insulin were used intracerebroventricularly (0.25 U/kg) or intracerebrally (2 mU in 200 nl). Sixty minutes after intravenous insulin, when serum glucose concentrations decreased from 158 to 43 mg/100 ml, pressor responses to stimulation of the periaqueductal gray of midbrain (PAG), locus coeruleus (LC), dorsal medulla (DM), ventrolateral medulla (VLM), and parvocellular reticular nucleus (PVC) decreased significantly. Depressor and bradycardiac response to stimulation of paramedian reticular nucleus or dorsal motor nucleus of vagus (DMV) decreased significantly as well. Thirty minutes after intracerebroventricular insulin, pressor responses of PAG, DM, and the bradycardiac response of DMV decreased significantly. Thirty minutes after intracerebral insulin, pressor responses and renal nerve activities of LC (but not PAG), VLM, DM, and PVC decreased significantly. A similar but faster onset (5 min) of depression of cardiovascular responses on stimulating the LC, VLM, DM, and PVC was observed in another six acutely midcollicular-decerebrate cats recovered from halothane anesthesia. These findings suggest that insulin directly inhibits the vasomotor structures of the brain stem and decreases the pressor responses to stimulation.

Early Defects of GABAergic Synapses in the Brain Stem of a MeCP2 Mouse Model of Rett Syndrome

2008 ◽  
Vol 99 (1) ◽  
pp. 112-121 ◽  
Author(s):  
L. Medrihan ◽  
E. Tantalaki ◽  
G. Aramuni ◽  
V. Sargsyan ◽  
I. Dudanova ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Brain Stem ◽  
Rett Syndrome ◽  
Time Course ◽  
Molecular Mechanisms ◽  
Neurodevelopmental Disorder ◽  
Therapeutic Interventions ◽  
Ventrolateral Medulla ◽  
Diagnostic Tools ◽  
The Brain

Rett syndrome is a neurodevelopmental disorder caused by mutations in the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2) and represents the leading genetic cause for mental retardation in girls. MeCP2-mutant mice have been generated to study the molecular mechanisms of the disease. It was suggested that an imbalance between excitatory and inhibitory neurotransmission is responsible for the behavioral abnormalities, although it remained largely unclear which synaptic components are affected and how cellular impairments relate to the time course of the disease. Here, we report that MeCP2 KO mice present an imbalance between inhibitory and excitatory synaptic transmission in the ventrolateral medulla already at postnatal day 7. Focusing on the inhibitory synaptic transmission we show that GABAergic, but not glycinergic, synaptic transmission is strongly depressed in MeCP2 KO mice. These alterations are presumably due to both decreased presynaptic γ-aminobutyric acid (GABA) release with reduced levels of the vesicular inhibitory transmitter transporter and reduced levels of postsynaptic GABAA-receptor subunits α2 and α4. Our data indicate that in the MeCP2 −/y mice specific synaptic molecules and signaling pathways are impaired in the brain stem during early postnatal development. These observations mandate the search for more refined diagnostic tools and may provide a rationale for the timing of future therapeutic interventions in Rett patients.

PACAP is expressed in sympathoexcitatory bulbospinal C1 neurons of the brain stem and increases sympathetic nerve activity in vivo

2008 ◽  
Vol 294 (4) ◽  
pp. R1304-R1311 ◽  
Author(s):  
Melissa M. J. Farnham ◽  
Qun Li ◽  
Ann K. Goodchild ◽  
Paul M. Pilowsky
Keyword(s):  
Blood Pressure ◽  
Brain Stem ◽  
Sympathetic Nerve ◽  
Sympathetic Nerve Activity ◽  
Intrathecal Administration ◽  
Ventrolateral Medulla ◽  
Cell Group ◽  
Nerve Activity ◽  
The Brain

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neuropeptide present in the rat brain stem. The extent of its localization within catecholaminergic groups and bulbospinal sympathoexcitatory neurons is not established. Using immunohistochemistry and in situ hybridization, we determined the extent of any colocalization with catecholaminergic and/or bulbospinal projections from the brain stem was determined. PACAP mRNA was found in tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the C1-C3 cell groups. In the rostral ventrolateral medulla (RVLM), PACAP mRNA was found in 84% of the TH-ir neurons and 82% of bulbospinal TH-ir neurons. The functional significance of these PACAP mRNA positive bulbospinal neurons was tested by intrathecal administration of PACAP-38 in anaesthetized rats. Splanchnic sympathetic nerve activity doubled (110%) and heart rate rose significantly (19%), although blood pressure was unaffected. In addition, as previously reported, PACAP was found in the A1 cell group but not in the A5 cell group or in the locus coeruleus. The RVLM is the primary site responsible for the tonic and reflex control of blood pressure through the activity of bulbospinal presympathetic neurons, the majority of which contain TH. The results indicate 1) that pontomedullary neurons containing both TH and PACAP that project to the intermediolateral cell column originate from C1-C3 and not A5, and 2) intrathecal PACAP-38 causes a prolonged, sympathoexcitatory effect.

scholarly journals Transneuronal tracing of neural pathways that regulate hindlimb muscle blood flow

2007 ◽  
Vol 292 (4) ◽  
pp. R1532-R1541 ◽  
Author(s):  
T.-K. Lee ◽  
J. H. Lois ◽  
J. H. Troupe ◽  
T. D. Wilson ◽  
B. J. Yates
Keyword(s):  
Blood Flow ◽  
Brain Stem ◽  
Pseudorabies Virus ◽  
Muscle Blood Flow ◽  
Ventrolateral Medulla ◽  
Cell Group ◽  
Sympathetic Outflow ◽  
Survival Times ◽  
Left And Right ◽  
The Brain

Despite considerable interest in the neural mechanisms that regulate muscle blood flow, the descending pathways that control sympathetic outflow to skeletal muscles are not adequately understood. The present study mapped these pathways through the transneuronal transport of two recombinant strains of pseudorabies virus (PRV) injected into the gastrocnemius muscles in the left and right hindlimbs of rats: PRV-152 and PRV-BaBlu. To prevent PRV from being transmitted to the brain stem via motor circuitry, a spinal transection was performed just below the L2 level. Infected neurons were observed bilaterally in all of the areas of the brain that have previously been shown to contribute to regulating sympathetic outflow: the medullary raphe nuclei, rostral ventrolateral medulla (RVLM), rostral ventromedial medulla, A5 adrenergic cell group region, locus coeruleus, nucleus subcoeruleus, and the paraventricular nucleus of the hypothalamus. The RVLM, the brain stem region typically considered to play the largest role in regulating muscle blood flow, contained neurons infected following the shortest postinoculation survival times. Approximately half of the infected RVLM neurons were immunopositive for tyrosine hydroxylase, indicating that they were catecholaminergic. Many (47%) of the RVLM neurons were dually infected by the recombinants of PRV injected into the left and right hindlimb, suggesting that the central nervous system has a limited capacity to independently regulate blood flow to left and right hindlimb muscles.

Vagal interactions on brain stem neurons receiving input from the proximal stomach in cats

1990 ◽  
Vol 258 (2) ◽  
pp. G320-G327 ◽  
Author(s):  
William D. Barber ◽  
Chun-Su Yuan ◽  
Brian J. Cammarata
Keyword(s):  
Brain Stem ◽  
Nucleus Tractus Solitarius ◽  
Recording Site ◽  
Proximal Stomach ◽  
Neuronal Interactions ◽  
Afferent Fibers ◽  
Significant Difference ◽  
The Mean ◽  
Vagal Afferent ◽  
The Brain

Gastric vagal fibers on the proximal stomach that join the dorsal and ventral vagal trunks were electrically stimulated to localize and evaluate brain stem neuronal interactions in anesthetized cats. The brain stem responses were located in nucleus tractus solitarius in the dorsomedial, caudal region of the medulla oblongata. There was no significant difference in the mean latency of the gastric vagally evoked brain stem response between the dorsal and ventral vagal trunks. The responses consisted of single or multiple spikes with a mean latency of ap290 ± 50 (SD) ms. Forty-one percent, or 168 unitary responses of the 406 total responses recorded, showed convergence of proximal gastric vagal input from both the dorsal and ventral vagal trunks on the same recording site or on the same cell. Of those unitary responses that received convergent proximal gastric vagal input, 95 unitary responses (57%) showed convergence of input to the same area, on different cells at the same recording site during a single trial. Seventy-three single units (43%) received convergent input from proximal gastric vagal afferent fibers in both the dorsal and ventral trunks. Fifty-two, or 7l%, of the single unit convergent responses were excitatory in nature, whereas the remaining 29% were inhibitory. These data demonstrated that proximal gastric vagal afferent fibers that join the dorsal and ventral trunks converged on a significant number of single neurons in the brain stem. The convergent response was synaptically secure and exerted an identifiable biasing effect on the response of the brain stem neuron. These convergent interactions may play an important role in reflex mechanisms concerned with adaptive relaxation to accommodate the ingested content by the proximal stomach. gastric; proximal gastric vagal; ventral vagus; dorsal vagus; nucleus tractus solitarius; vagal brain stem interactions Submitted on March 14, 1988 Accepted on September 19, 1989

A1 cell group mediates solitary nucleus excitation of supraoptic vasopressin cells

1989 ◽  
Vol 257 (5) ◽  
pp. R1020-R1026 ◽  
Author(s):  
T. A. Day ◽  
J. R. Sibbald
Keyword(s):  
Nucleus Tractus Solitarius ◽  
Single Pulse ◽  
Neurosecretory Cells ◽  
Ventrolateral Medulla ◽  
Cell Group ◽  
Onset Latency ◽  
Unit Recording ◽  
Inhibitory Neurotransmitter ◽  
Caudal Ventrolateral Medulla ◽  
Electrolytic Lesions

Stimulation of the nucleus tractus solitarius (NTS) excites putative vasopressin-secreting cells of the supraoptic nucleus (SON) via a catecholaminergic projection to hypothalamus. Despite recent evidence of a direct catecholaminergic projection from NTS to SON, we have performed single-unit recording experiments in pentobarbital sodium-anesthetized rats to investigate the possibility that NTS stimulation effects on SON vasopressin cells are indirect, being relayed via the A1 noradrenergic cell group of the caudal ventrolateral medulla. The effects of single-pulse NTS and A1 region stimulation on the activity of antidromically identified SON neurosecretory cells that had been functionally characterized as vasopressin secreting were compared. NTS stimulation excited 81% of all putative vasopressin-secreting cells tested (n = 83), with a mean onset latency of 51 +/- 1 ms. A1 region stimulation excited 76% of all cells tested and 90% of units responsive to NTS stimulation, with a mean latency of 39 +/- 1 ms. Consistent with previous work NTS stimulation excited only a minority of oxytocin cells tested (3/13), and of these two-thirds also responded to A1 stimulation. Bilateral electrolytic lesions of the A1 region abolished the effects of NTS stimulation on putative vasopressin cells. Ipsilateral A1 region injections of the inhibitory neurotransmitter gamma-amino-butyric acid reversibly blocked NTS stimulation effects on putative vasopressin cells in animals where the contralateral A1 region had already been lesioned. These results support the proposal that excitation of SON vasopressin-secreting cells after NTS stimulation is due to activation of a relay projection through the A1 noradrenergic cell group of the caudal ventrolateral medulla.

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