Published online before print January 4, 2007, doi: 10.1161/01.RES.0000257370.63694.73
© 2007 American Heart Association, Inc.
Integrative Physiology |
Central Command Regulation of Circulatory Function Mediated by Descending Pontine Cholinergic Inputs to Sympathoexcitatory Rostral Ventrolateral Medulla Neurons
From the Hypertension and Stroke Research Laboratories, Kolling Institute of Medical Research, Royal North Shore Hospital and School of Medical Sciences, University of Sydney, Australia.
Correspondence to Ann K. Goodchild, Hypertension and Stroke Research Labs, Building 10, Royal North Shore Hospital, St Leonards NSW 2065, Australia. E-mail anng{at}physiol.usyd.edu.au
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Abstract |
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Central command is a feedforward neural mechanism that evokes parallel modifications of motor and cardiovascular function during arousal and exercise. The neural circuitry involved has not been elucidated. We have identified a cholinergic neural circuit that, when activated, mimics effects on tonic and reflex control of circulation similar to those evoked at the onset of and during exercise. Central muscarinic cholinergic receptor (mAChR) activation increased splanchnic sympathetic nerve activity (SNA) as well as the range and gain of the sympathetic baroreflex via activation of mAChR in the rostral ventrolateral medulla (RVLM) in anesthetized artificially ventilated Sprague–Dawley rats. RVLM mAChR activation also attenuated and inhibited the peripheral chemoreflex and somatosympathetic reflex, respectively. Cholinergic terminals made close appositions with a subpopulation of sympathoexcitatory RVLM neurons containing either preproenkephalin mRNA or tyrosine hydroxylase immunoreactivity. M2 and M3 receptor mRNA was present postsynaptically in only non–tyrosine hydroxylase neurons. Cholinergic inputs to the RVLM arise only from the pedunculopontine tegmental nucleus. Chemical activation of this region produced increases in muscle activity, SNA, and blood pressure and enhanced the SNA baroreflex; the latter effect was attenuated by mAChR blockade. These findings indicate a novel role for cholinergic input from the pedunculopontine tegmental nucleus to the RVLM in central cardiovascular command. This pathway is likely to be important during exercise where a centrally evoked facilitation of baroreflex control of the circulation is required to maintain blood flow to active muscle.
Key Words: baroreflex • exercise • chemoreflex • somatosympathetic
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Introduction |
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A distinct pattern of tonic and reflex cardiovascular adjustments is mediated by central command to ensure appropriate muscle and organ perfusion during different arousal or behavioral states, such as sleep and exercise.1–3 Limited evidence implicates some regions within the pons and hypothalamus that could provide descending input to cardiovascular control sites4–6; however, the neural circuitry and neurotransmitters involved are yet to be elucidated.
Activation of the central cholinergic system has a profound effect on cardiovascular and other autonomic functions.7–18 Systemic or central administration of acetylcholinesterase inhibitors or muscarinic agonists increases blood pressure,7–11 lowers body temperature,12 and alters respiration.13,14 Pressor responses can be evoked via activation of muscarinic receptors (mAChR) within several cardiovascular nuclei, including the posterior hypothalamus,7 nucleus of the solitary tract,15 and rostral ventrolateral medulla (RVLM).10,11 Effects of central mAChR activation on cardiovascular reflexes are less well understood.8,16,17
Sympathoexcitatory and hypertensive effects of intravenously administered physostigmine are largely mediated by excitation of RVLM neurons.10,11,18 The RVLM generates basal sympathetic vasomotor activity and is a critical synaptic relay in cardiovascular reflexes.19,20 Descending cholinergic projections to the RVLM arise from neurons in the pedunculopontine tegmental nucleus (PPT),21 although local medullary neurons may also be a source of cholinergic input.22 The function of this input into the RVLM is unknown. A dense cholinergic terminal field is present within the RVLM,11,22,23 although supportive anatomical evidence that cholinergic terminals provide input to C1 or non-C1 spinally projecting neurons is lacking. Activation of the inhibitory M2 mAChR subtype in the RVLM is thought to mediate pressor responses,10,11 but its cellular location or that of other mAChR subtypes within the RVLM is unknown.
We hypothesized that cholinergic input to the RVLM from the PPT is involved in central command–mediated effects on cardiovascular function. Previous studies have shown that the PPT is involved in initiation of movement and modulation of muscle tone during locomotion, exercise, and arousal.4,24,25 Additionally, the PPT connects albeit indirectly with both motor and sympathetic outflows.5
We aimed, firstly, to determine the role of the RVLM in the autonomic responses and effects on reflex control of the circulation evoked by central mAChR activation. Secondly, we identified the mAChR subtypes involved by examining gene expression within phenotypically identified RVLM neurons and determined the exact sources of cholinergic input to the RVLM. Finally, we determined the tonic and reflex cardiovascular effects generated by chemical stimulation of the PPT.
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Materials and Methods |
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An expanded Materials and Methods section is available in the online data supplement at http://circres.ahajournals.org.
Studies were approved by the Animal Care and Ethics Committee of Royal North Shore Hospital/University of Technology, Sydney. Following experimentation, rats were euthanized while under surgical anesthesia by KCl (3 mol/L, 1 mL IV).
Male Sprague–Dawley rats (n=17) were anesthetized (urethane, 1.2 g/kg, 10% IP; Sigma-Aldrich) and maintained at surgical depth throughout experiments. Rats were intubated and arterial (femoral or carotid) and intravenous catheters inserted for arterial pressure (AP) measurement or drug administration. Splanchnic sympathetic activity (SNA) and phrenic nerve activity (PNA) were recorded using bipolar electrodes and in four rats tail blood flow (TBF) was also recorded using a laser Doppler flow probe (Oxford Optronics, Oxford, UK). In 2 rats electromyographic (EMG) activity from the left biceps femoris was also recorded. All signals were acquired online using Spike 2 software (CED Ltd, Cambridge, UK) as described previously.26,27 Microinjections were made into the RVLM as described previously26,27 in paralyzed (pancuronium dibromide, 0.8 mg), nonvagotomized animals (n=13), or into the pons using coordinates of Paxinos and Watson28 in bilaterally vagotomized animals before and after paralysis (n=4).
Cardiovascular reflexes were evoked as described previously26,27 using sequential injection of sodium nitroprusside (SNP) and phenylephrine (PE) (10 µg/kg), or intermittent electrical stimulation (0.5 Hz, 100 sweeps; twin pulses at 2.5-ms intervals; pulse width, 1 ms) of a somatic tibial nerve (TN, 15 to 20 V) or the barosensory aortic nerve (5 to 10 V). Carotid chemoreceptors were activated by brief hypoxia (100% N2 for 15 seconds).
Intravenous drugs were dissolved in saline: atropine methylnitrate (mATR) (peripheral mAChR blocker; t1/2, 4 hours; 5 mg/mL; Sigma); oxotremorine sesquifumarate salt (OXO) (broad spectrum mAChR agonist; t1/2, 1.6 hours; 0.5 mg/mL; Sigma); (-)scopolamine hydrobromide (SCOP) (broad spectrum mAChR antagonist; t1/2, 8 hours; 5 mg/mL); SNP (Faulding); and PE (ICN Biomedicals Inc). Drugs for microinjection were dissolved in 10 mmol/L PBS: L-glutamic acid (monosodium salt; 100 mmol/L [5 nmol/50 nL]; Sigma); (-)SCOP (60 mmol/L [3 nmol/50 nL]; Sigma); DL-homocysteic acid (DLH) (an excitatory amino acid; 100 mmol/L; MP Biomedicals); and (-)-bicuculline methiodide (a selective GABA-A receptor antagonist; 4 mmol/L; Sigma).
As described previously,29,30 injections of cholera toxin B subunit (CTB) (1%, retrograde tracer) were made centered in the intermediolateral cell column (n=10) or RVLM (n=3) under anesthesia and animals were recovered for 36 to 72 hours. Rats were transcardially perfused and brains processed for light and fluorescence immunohistochemistry30,31 or combined in situ hybridization and immunohistochemistry as described previously.32 Briefly, 50-µm sections were incubated with species-specific primary antibodies to detect CTB (goat; List OR rabbit; Virostat), vesicular acetylcholine transporter (vAChT) (Chemicon), tyrosine hydroxylase (TH) (Sigma, Australia), or neuron-specific nuclear protein (NeuN) (Chemicon). For detection of mRNA sections were hybridized with digoxigenin (DIG)-labeled antisense riboprobe specific to preproenkephalin (PPE), M2 or M3 receptor (see the online data supplement) followed by incubation with DIG primary antibodies. For detection of protein sections were incubated with biotinylated- or fluorophore-conjugated secondary antisera (1:500; Jackson ImmunoResearch Laboratories, Inc). For light microscopy, vAChT and CTB were detected using enhanced diaminobenzidine reactions (nickel and imidazole).30
Protocols
Animals were pretreated with mATR (2 mg/kg), and OXO was injected intravenously (0.2 mg/kg); SCOP was then injected bilaterally into the RVLM (9 nmol per side). Reflexes were tested before and after OXO in the absence or presence of SCOP. Injections of DLH or bicuculline were made into the PPT and effects of SNP injection and TN stimulation were tested before and after SCOP intravenous injection (2 mg/kg).
Close appositions between vAChT immunoreactivity (vAChT-IR) and CTB/TH-IR or non–TH-IR neurons in the RVLM were examined at x100 magnification; serial cell counts of vAChT-IR appositions or M2 receptor/CTB/TH were made from every fourth section. For detailed data and statistical analysis, see the online data supplement.
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Results |
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RVLM mAChR Mediate Sympathoexcitatory but Not Other Autonomic Effects Evoked by Central mAChR Activation
Central mAChR activation (OXO) significantly increased AP, mean and postinspiratory-related discharge of SNA, heart rate (HR) and TBF and reduced PNA amplitude (Figure 1A, 1B, and 1D). Bilateral injection of SCOP into the RVLM (Figure 1C) significantly attenuated the increase in AP (n=8, P<0.01), SNA (n=8, P<0.01), HR (n=8, P<0.05) and post-inspiratory activation of SNA (n=4, P<0.05) but had no effect on changes in TBF (n=4; P=NS) or PNA amplitude (n=4; P=NS) evoked by OXO (Figure 1D).
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Spectral analysis of systolic AP (SAP) and SNA revealed an increase in low frequency (LF, 
0.4 Hz) oscillations following OXO (0.3±0.1 versus 36.5±15.1 mm Hg2, P<0.05; 4.6±1.4 versus 47.5±17.9 SNA%2, P<0.05). Respiratory-related oscillations of SNA also tended to be increased (P=0.051). SCOP injected bilaterally into the RVLM had no effect on baseline parameters but prevented the increase in LF oscillations evoked by OXO (0.3±0.1 versus 0.4±0.1 mm Hg2; 3.3±1.0 versus 7.3±2.5 SNA%,2 n=7, P<0.05) (Figure II in the online data supplement).
Activation of RVLM mAChR Facilitates the Sympathetic Baroreflex and Inhibits the Somatosympathetic and Chemoreflexes
OXO significantly enhanced the reflex sympathoexcitatory and inhibitory responses evoked by equipotent doses of SNP and PE (Figure 2). This effect was reproducible following repeat injection of OXO (Figure 2A). OXO significantly increased the maximum plateau (146±4 versus 321±12%, P<0.01) and maximum gain of the SNA baroreflex (4.4±0.5 versus 8.2±0.6%/mm Hg, P<0.05) (Figure 2B and 2C). The operating point (resting MAP) also shifted closer to the point of maximum gain (Figure 2C).
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Figure 3 shows the effects of OXO on cardiovascular reflexes before and after blockade of mAChR bilaterally in the RVLM. OXO increased the magnitude of SNA inhibition evoked by aortic nerve stimulation (166±13% control, n=6, P<0.01) or excitation following SNP administration (4±1 versus 17±2% SNA/50 mmHg, n=4, P<0.01). In contrast, OXO inhibited both excitatory peaks of SNA evoked by TN stimulation (early peak 37±3% control, P<0.01, late peak 41±5% control, n=9, P<0.01). Sympathoexcitatory and pressor responses to brief hypoxia were attenuated and inhibited, respectively (53±6% control, P<0.01; +33±2 mm Hg versus –17±5 mm Hg, n=7, P<0.01). Bilateral injection of SCOP into the RVLM reversed effects of OXO on reflexes, such that they were mostly indistinguishable from controls. The early peak of the somatosympathetic reflex was only partially restored (66±4% control, P<0.01). A repeat injection of OXO 30 minutes following SCOP failed to elicit effects on any reflex similar to its initial robust effects (n
4 per group). The pressor response to brief hypoxia did not return to normal after the initial dose of OXO. Grouped data are illustrated in supplemental Figure I.
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Cholinergic Terminals Closely Appose Sympathoexcitatory RVLM Neurons
vAChT-IR terminals were found throughout the VLM and in cell bodies within the facial and ambigual motor nuclei, consistent with previous reports.33,34 A choline acetyltransferase–positive cell group previously identified in the ventromedial medulla22 was not present using vAChT labeling (supplemental Figure IV). vAChT-IR terminals were closely apposed to CTB-labeled spinally projecting cells in the RVLM; 32.6±7.4% (379/1118 cells, n=3) of all CTB-IR neurons and 31.1±5.6% (66/206 cells, n=3) of TH-positive CTB-IR cells (Figure 4A and 4B). vAChT-IR varicosities also formed perisomatic appositions with NeuN-positive non-TH RVLM neurons that expressed PPE, as well as other PPE-negative NeuN-positive cells (Figure 4C).
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M2 and M3 Receptor mRNA Is Expressed in Spinally Projecting Non-TH Neurons in the RVLM
All mAChR subtypes were expressed in an RVLM tissue punch (supplemental Figure III). We analyzed the cellular distribution of M2 receptor expression in the RVLM and found that no spinally projecting TH neurons contained M2 receptor mRNA (0/310, n=5) (Figure 5A). In contrast, 23±4% of spinally projecting non-TH RVLM neurons did express M2 receptor mRNA (78/367, n=5) (Figure 5C). M3 receptor mRNA was also expressed in some TH-IR/non-CTB-IR and some CTB-IR/non-TH neurons (Figure 5B and 5D).
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Direct Cholinergic Projections to the RVLM From the PPT
To determine the source of cholinergic input to the RVLM, discrete injections of CTB were made unilaterally into the RVLM (Figure 6A) and cholinergic neurons were identified by vAChT-IR. CTB-IR neurons were found in regions previously described, including the parabrachial nucleus, the paraventricular nucleus of the hypothalamus (Figure 6B), central nucleus of the amygdala, and the cortex.21,35 vAChT-IR neurons were also found in regions previously described33,34 (Figure 6C and 6D). Neurons that were double-labeled for CTB and vAChT had a restricted distribution and were confined within the PPT (Figure 6C and 6D).
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Chemical Stimulation of the PPT Increases Muscle Activity and SNA and Facilitates the Sympathetic Baroreflex via mAChR Activation
Bilateral injection of bicuculline into the PPT evoked increases in AP and EMG activity (Figure 7A). EMG activity but not the increase in AP was abolished by subsequent neuromuscular (NM) blockade (Figure 7A). Injection of DLH into the PPT produced an increase in SNA and AP and increased the magnitude of SNA excitation produced by injection of SNP (Figure 7B). These effects could be evoked throughout the rostrocaudal extent of the PPT (7 to 9 mm caudal to Bregma). Smaller increases in SNA were evoked at sites dorsal or ventral but facilitation of baroreflex-evoked SNA responses was restricted to the PPT (6.5 to 7.5 mm ventral) (Figure 7B). Transient alterations in PNA frequency were observed following stimulation of the PPT and surrounding brain areas, whereas the somatosympathetic reflex was unaffected. Prior blockade of central mAChR receptors with SCOP intravenous injection prevented the facilitation of baroreflex-evoked SNA responses (n=3, P<0.05) but did not abolish sympathoexcitation produced by DLH injection into the PPT (Figure 7C).
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Discussion |
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The novel findings of this study are (1) mAChR activation in the RVLM facilitates the sympathetic baroreflex and attenuates and inhibits the sympathetic chemoreflex and somatosympathetic reflex, respectively; (2) identified sympathoexcitatory neurons in the RVLM receive cholinergic input and differentially express M2 and M3 receptor subtypes; (3) chemical stimulation of the PPT, which provides the only direct cholinergic input to the RVLM, evokes a similar pattern of tonic and baroreflex SNA responses to that seen following RVLM mAChR activation. Neurons in the PPT control muscle tone during locomotion, exercise, and arousal.4,24,25 Our findings indicate that tonic and reflex cardiovascular adjustments are also evoked from the PPT via direct cholinergic projections to the RVLM. These data support our hypothesis that cholinergic input to the RVLM is involved in central command.
RVLM mAChRs mediate the increase in SNA and HR evoked by centrally acting OXO, in agreement with previous studies.10,11 Postinspiratory-related discharge of SNA was also enhanced, indicating a direct effect on respiratory-related inputs to the RVLM36 that presumably contributes to the mean increase in SNA evoked by OXO. This effect was elicited independently of the OXO-evoked depression of phrenic amplitude, which is mediated by sites other than the RVLM.13,14 The OXO-evoked increase in TBF, presumably contributing to the well-described hypothermic effect of this drug,12 is also mediated via other central sites. These may include the preoptic area of the hypothalamus as it receives cholinergic input and carbachol microinjections here evoke hypothermia.37
We showed, for the first time, that the reflex responses of SNA to baroreceptor loading or unloading, demonstrated following vasoactive drug administration and by direct stimulation of baroreceptor afferents, were markedly enhanced by OXO and were mediated by RVLM mAChRs. Furthermore, baroreflex-related LF oscillations of both SAP and SNA38 were enhanced.
Our findings show that RVLM mAChR activation resets the SNA baroreflex to higher pressures and increases its range and gain. Earlier studies showed that the pressor effect of bilateral carotid occlusion was greater after central or systemic administration of physostigmine.8,17 Caputi et al demonstrated an upward shift in baroreflex HR responses without changes in range or gain following intracerebroventricular injection of physostigmine.16 A limitation of the present study was that pretreatment with mATR to block peripheral mAChR precluded analysis of vagally mediated HR responses. Our findings indicate that RVLM mAChR activation facilitates sympathetic vasomotor responses to baroreflex activation, whereas cholinergic effects at brain sites important in reflex vagal control, including the nucleus ambiguus,39 may evoke resetting of the HR baroreflex without changing its gain.
OXO evoked differential effects on cardiovascular reflexes via RVLM mAChR activation. Baroreflex SNA responses mediated by direct inhibition or disinhibition of RVLM neurons40 were enhanced. Somatosympathetic and chemoreflex SNA responses mediated by direct excitation of RVLM neurons36 were inhibited and attenuated, respectively. The clear inhibition of the somatosympathetic reflex suggests that these effects were not indirectly caused by raised sympathetic activity. To our knowledge, a study in anesthetized cats also showed that a somatosympathetic reflex evoked by intercostal nerve stimulation was inhibited by OXO.41 As single RVLM neurons receive largely convergent input from baroreceptors, peripheral chemoreceptors, somatic afferents, and central respiratory neurons,42–45 3 mechanisms are possible to explain our data: OXO activates inhibitory presynaptic mAChRs located on reflex inputs to RVLM neurons, postsynaptic excitatory mAChRs on RVLM neurons, or a combination of both. Pre- and postsynaptic effects of carbachol on RVLM neurons have been demonstrated in vitro.18
Phenotypically identified sympathoexcitatory (CTB+TH) and putative sympathoexcitatory (CTB+non-TH, or PPE+) neurons in the RVLM were closely apposed by vAChT-IR varicosities. This is the first anatomical evidence indicating that cholinergic terminals may synapse with sympathoexcitatory RVLM neurons. Milner et al23 showed that choline acetyltransferase IR terminals formed abundant synaptic contacts in the ventral medulla but these were rarely seen with TH-containing neurons. In the study by Milner et al, however, only caudal sections of the RVLM were examined (0.5 to 2.0 mm caudal to the facial nucleus); these contain few spinally projecting neurons.29 Furthermore, compared with choline acetyltransferase, immunoreactivity to vAChT as used here gives better cholinergic terminal labeling.33,34
Our results showed, for the first time, that the M2 receptor was not expressed in TH neurons but was expressed in a subpopulation of spinally projecting non-TH neurons. M2 receptor-preferring antagonists prevent pressor effects of RVLM mAChR activation.11 The ligands used, however, do not display high affinity for any 1 particular subtype.46 If M2 receptors do mediate OXO-evoked sympathoexcitatory responses, then they are most likely located presynaptically in the RVLM or this effect is mediated by non-TH spinally projecting neurons. Huangfu et al have shown in neonatal RVLM that both C1 and non-C1 cells depolarized in response to mAChR activation.18 Because vAChT-IR terminals apposed both classes of RVLM neurons, we sought evidence for expression of other receptor subtypes. A subpopulation of spinally projecting non-TH RVLM neurons also contain M3 receptor mRNA. We have further demonstrated that mRNA for all 5 mAChR subtypes was present in the RVLM, confirming earlier studies in WKY and SHR rats.47 Our results suggest that different or multiple mAChR subtypes may be expressed by sympathoexcitatory RVLM neurons.
In agreement with Yasui et al,21 we found that the projection from the PPT to the RVLM is cholinergic. In addition, we showed that the PPT is the only cholinergic cell group that provides input to the RVLM. Local inputs from choline acetyltransferase–positive neurons in the ventromedial medulla22 are not functionally cholinergic, as we found that these cells did not contain vAChT.
We demonstrated for the first time that chemical stimulation of the PPT facilitates baroreflex-evoked excitation of SNA, mimicking effects of RVLM mAChR activation. Blockade of mAChR with SCOP prevented this effect but did not completely abolish sympathoexcitation generated by PPT activation. Electrical stimulation of the PPT increases AP, HR, and renal SNA (with a lesser increase in lumbar SNA) in decerebrate animals.48,49 Sympathoexcitatory responses are also evoked from surrounding brain areas including the cuneiform nucleus.50 At present, we cannot explain the lack of effect of stimulating the PPT on other reflex responses that are modified by activation of RVLM mAChR.
Disinhibition of the PPT increased EMG activity, consistent with studies that reported increases in muscle activity following electrical or chemical stimulation of the PPT in anesthetized or decerebrate animals.24,48,49 Single cholinergic neurons in the PPT have dual connections with the motor cortex and stellate ganglion, as revealed by polysynaptic viral tracing.5 The PPT may therefore be a key nodal point where changes in motor signals can be coordinated with descending modulation of sympathetic function. The simplest explanation of our data is that stimulation of the PPT evokes muscular activity and releases acetylcholine activating RVLM mAChR pre- and/or postsynaptically located on sympathoexcitatory neurons, causing an increase in AP and SNA as well as increasing the range and gain of the sympathetic baroreflex.
Functional Implications
The involvement of the PPT in initiating and modulating movement related to arousal and locomotion, including exercise, is well recognized.4,24,25 The present findings indicate that the cholinergic projection to the RVLM may be activated in parallel to elicit tonic and reflex cardiovascular adjustments that are appropriate to different behaviors. The pattern of effects bears a striking similarity to those evoked by central command during exercise.2,3,51
Exercise is accompanied by a resetting of baroreflex control of SNA and HR to higher AP.2,51–53 This is thought to be crucial to AP elevation at exercise onset and AP stabilization during exercise and can oppose other reflex influences on circulation, including nociceptive and peripheral chemoreflexes.3 In addition to an increase in AP and SNA, the increase in the range and gain of the sympathetic baroreflex as seen here strongly resembles that evoked during treadmill exercise in conscious rats.52 Studies showing complete sympathetic baroreflex function curves during exercise in humans are sparse, although some studies have demonstrated large increases in linear baroreflex gain of muscle SNA during static exercise53 or no change during moderate intensity arm cycling.54 In contrast, exercise appears to reset the cardiac component of the baroreflex to higher AP without changing its gain,51 also resembling effects on the HR baroreflex evoked by central administration of physostigmine.16 Recent evidence indicates that the cardiac baroreflex is transiently inhibited at exercise onset, which may facilitate immediate vagal withdrawal.55
In conclusion, our data indicate that the cholinergic projection from the PPT to the RVLM is an integral component of the central command pathway that regulates circulatory function during exercise and possibly other arousal or behavioral states.
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Acknowledgments |
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We thank Simon McMullan and Peter Burke for helpful discussions.
Sources of Funding
Supported by the National Health and Medical Research Council of Australia (211023, 211196), Garnett Passe and Rodney Williams Memorial Foundation, North Shore Heart Research Foundation (6-05/06), and Northern Sydney Central Coast Area Health (2006:03). J.R.P. and N.N.K. receive Australian Postgraduate awards.
Disclosures
None.
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Footnotes |
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Original received October 13, 2006; revision received November 29, 2006; accepted December 20, 2006.
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