The dorsomedial hypothalamic nucleus (DMH) is believed to play a key role in mediating vasomotor and cardiac responses evoked by an acute stress. Inhibition of neurons in the rostral ventrolateral medulla (RVLM) greatly reduces the increase in renal sympathetic nerve activity (RSNA) evoked by activation of the DMH, indicating that RVLM neurons mediate, at least in part, the vasomotor component of the DMH-evoked response. In this study, the first aim was to determine whether neurons in the medullary raphe pallidus (RP) region also contribute to the DMH-evoked vasomotor response, because it has been shown that the DMH-evoked tachycardia is mediated by the RP region. The second aim was to directly assess the effect of DMH activation on the firing rate of RVLM sympathetic premotor neurons. In urethane-anesthetized rats, injection of the GABAA receptor agonist muscimol (but not vehicle solution) in the RP region caused a modest (∼25%) but significant reduction in the increase in RSNA evoked by DMH disinhibition (by microinjection of bicuculline). In other experiments, disinhibition of the DMH resulted in a powerful excitation (increase in firing rate of ∼400%) of 5 out of 6 spinally projecting barosensitive neurons in the RVLM. The results indicate that neurons in the RP region make a modest contribution to the renal sympathoexcitatory response evoked from the DMH and also that sympathetic premotor neurons in the RVLM receive strong excitatory inputs from DMH neurons, consistent with the view that the RVLM plays a key role in mediating sympathetic vasomotor responses arising from the DMH.
- renal sympathetic nerve activity
- raphe pallidus
studies in both conscious and anesthetized rats have demonstrated that the dorsomedial hypothalamic nucleus (DMH) plays a critical role in mediating the autonomic, neuroendocrine, and behavioral response to an acute psychological stress such as air jet stress (9). Activation of neurons in the DMH evokes anxiety-like behavior, with concomitant increases in arterial pressure, heart rate (HR), renal sympathetic nerve activity (RSNA), gastrointestinal motility, and secretion of ACTH (1, 9, 11, 12, 29). Conversely, inhibition of the DMH, by bilateral microinjections of the GABAA receptor agonist muscimol, reduces the pressor response and tachycardia, as well as the increase in ACTH secretion and anxiety-like behavior normally evoked by air jet stress (29, 31, 32).
Recent studies have indicated that neurons in the rostral ventrolateral medulla (RVLM) and in the region of the raphe pallidus (RP) in the midline medulla are important components of the descending pathways that mediate the cardiovascular response to activation of the DMH. Bilateral injections of muscimol in the RVLM result in a large reduction in the renal sympathoexcitatory response evoked by disinhibition of the DMH but have no effect on the evoked tachycardia (11). On the other hand, Samuels et al. (26) found that injection of muscimol in the RP greatly reduced the tachycardia evoked by DMH disinhibition. These findings therefore indicate that the sympathetic vasomotor component of the DMH-evoked response is largely relayed via the RVLM, whereas the cardiac component is relayed via the RP region.
It is possible, however, that RP neurons may mediate a part of the sympathetic vasomotor response evoked from the DMH. First, it has been shown that activation of neurons in the RP region can increase the activity of splanchnic and renal sympathetic nerves that are believed to have a vasoconstrictor function (18, 24). Second, Fontes et al. (11) found that, even after bilateral inhibition of the RVLM, DMH activation still resulted in a significant increase in RSNA that was ∼25% of the response observed before bilateral inhibition of the RVLM. Third, unlike inhibition of the RP, bilateral inhibition of the RVLM results in a profound decrease in the tonic excitatory input to sympathetic vasomotor preganglionic neurons (8, 11). This could therefore reduce the excitability of renal sympathetic preganglionic neurons to inputs arising from all other sources, including the RP region. Thus, under normal conditions, a descending pathway that includes a relay in the RP region may make a significant contribution to the vasomotor response evoked from the DMH, even though this is not apparent when RVLM neurons are inhibited bilaterally. Finally, there are neurons in the RP that project to the RVLM (17), so it is conceivable that such neurons may relay inputs from the DMH to RVLM renal sympathoexcitatory neurons.
The first aim of this study, therefore, was to test the possibility that neurons in the RP region contribute to the renal sympathoexcitation evoked from the DMH. For this purpose, we have determined the effect of inhibition of the RP region on the increase in HR and RSNA evoked by disinhibition of the DMH. Second, to determine the extent to which inputs from the DMH can influence the firing rate of sympathetic premotor vasomotor neurons in the RVLM, we have also determined the effect of disinhibition of the DMH on the activity of identified single barosensitive spinally projecting neurons in the RVLM.
Experiments were performed on male Sprague Dawley rats (body wt 280–460 g). All experiments were carried out in accordance with the guidelines for the Australian National Health and Medical Research Council Code of Practice. Two separate series of experiments were performed. In the first series, the effects of activation of the DMH on arterial pressure, HR, and RSNA were tested before and after injections of the GABAA receptor agonist muscimol in the RP. In the second series of experiments, the effect of activation of the DMH on the activity of single barosensitive spinally projecting neurons in the RVLM was determined.
Series 1: Microinjection experiments.
In these experiments the rats were anesthetized with urethane (1.4 g/kg ip). Body temperature was maintained in the range of 37–38°C with a heating pad. The trachea was cannulated, and catheters were placed in a femoral artery and a femoral vein for the recording of pulsatile arterial pressure and drug injection, respectively. The mean arterial pressure (MAP) and HR were derived from the pulsatile arterial pressure signal by means of a low-pass filter and rate meter, respectively. The renal sympathetic nerve on the left side was isolated from surrounding connective tissue, and its activity was recorded as described previously (34). The signal from the electrodes was amplified, passed through a band pass filter (50–1,000 Hz), and then rectified and integrated (resetting every 5 s). After completion of all surgical procedures, neuromuscular blockade was induced with alcuronium chloride (0.2 mg/kg iv every 1–2 h), and all animals were ventilated artificially with a respiratory pump at a level that maintained end-tidal CO2
The head was fixed in a stereotaxic apparatus, and the incisor bar was lowered to a level of 19 mm below the interaural line. The dorsal surfaces of the medulla and the cortex were exposed. Microinjections were made in the RP and the DMH, using a glass micropipette held in a micromanipulator at an angle of 20° (tip rostral) for the RP and at an angle of 28° (tip caudal) for the DMH. The compounds injected were bicuculline methochloride (20 nl of 5–2,000 μM solution for injections in the DMH, and 75 nl of 400 μM solution in the RP; Tocris) and muscimol hydrochloride (100 nl of 800 μM solution in the RP; Sigma). The vehicle solution was artificial cerebrospinal fluid (aCSF) adjusted to pH 7.4, and all drug solutions contained 1% Fast Blue fluorescence dye or 0.5% fluorescent microspheres to allow later histological determination of the injection sites. Microinjections were made by pressure, and the volume injected was measured by the displacement of the meniscus in the pipette with respect to a horizontal grid viewed through an operating microscope.
For microinjections in the DMH, the tip of the micropipette was positioned stereotaxically (3.14–3.60 mm caudal to bregma, 0.5–0.7 mm lateral to the midline, and 8.4–8.8 mm from the surface of the cortex), as previously described (11). For the dose-response experiment, injections of different doses of bicuculline (ranging from 0.1 to 40 pmol) or the aCSF vehicle solution were injected unilaterally in the DMH in random order, with a time interval of 20–45 min between injections.
In the RP blocking experiment, the first step was to identify a site in the midline RP in which a microinjection of bicuculline (30 pmol in 75 nl) evoked a tachycardia of at least 40 beats/min. It has been demonstrated previously that microinjection of this dose of bicuculline in the RP evokes a significant increase in HR (18, 26). In all experiments, no more than two (and usually only 1) microinjections were required to identify such a site in the RP. Next, microinjections of bicuculline (10 pmol in 20 nl) were made in the DMH to identify a site at which an increase in HR of at least 50 beats/min and in RSNA of at least 40% was evoked. Again, in all experiments, no more than two (and usually only 1) microinjections were required to identify such a site. After recovery from this control injection, muscimol (80 pmol in 100 nl) was injected in the physiologically identified site in the RP, and a second microinjection of bicuculline was made in the DMH site. In control experiments, the procedure was the same except that the vehicle solution, instead of the muscimol solution, was injected in the RP site.
At the end of each experiment, the rat was killed with an overdose of pentobarbital sodium. The brain was then removed and placed in 50 ml of 4% paraformaldehyde solution for 1–3 days, after which coronal sections (50 μm) were cut on a freezing microtome and mounted on glass slides. Injection sites were determined using a fluorescence microscope.
Series 2: Single-unit recording experiments.
The surgical procedures for experiments in which extracellular single-unit recording was performed were the same as described previously (3). In brief, the rats were first anesthetized with pentobarbital sodium (40 mg/kg ip). The trachea was then cannulated, and the rat was ventilated artificially with 2% isoflurane in oxygen. Body temperature was maintained in the range of 37–38°C with a heating pad. Catheters were placed in a femoral artery and a femoral vein for the recording of pulsatile arterial pressure and drug injection, respectively. The tip of the arterial catheter was positioned in the lower thoracic aorta. A pneumatic cuff was placed around the lower thoracic aorta, via a left intercostal incision. The rat was then mounted prone in a stereotaxic frame with the head mildly ventroflexed (incisor bar at 19 mm below the interaural line). The dorsal surfaces of the medulla and the cortex were exposed for the recording of extracellular activity from the RVLM and for the microinjection of bicuculline in the DMH, respectively. The cervical spine was held horizontal by a thoracic spinal clamp. The lower cervical cord segment at the level of T1 was exposed, and a concentric bipolar stimulating electrode was positioned by a micromanipulator to stimulate the left dorsolateral funiculus. The mandibular branch of the right facial nerve was exposed via a small incision, and a second concentric bipolar stimulating electrode was positioned to stimulate it.
After the surgery, the isoflurane anesthesia was gradually withdrawn while being replaced by urethane (given intravenously as a 50% solution). The amount of urethane administered (1.0–1.4 g/kg) was the dose necessary to abolish withdrawal reflexes to noxious pinching of a hindpaw. After ensuring that the level of anesthesia had stabilized under urethane, the animal was then paralyzed with alcuronium chloride (0.2 mg/kg iv every 1–2 h). The adequacy of anesthesia with and without neuromuscular blockade was confirmed as described above for the first series of experiments.
Glass recording micropipettes (1.5-mm borosilicate tube) with a long shank were pulled to a tip size of 5 μm (for field potentials) or 1–3 μm (for single units). They were filled with either 2 M NaCl or 2% Pontamine sky blue dye in 0.5 M sodium acetate. Pipettes were inserted at an angle of 20° (tip rostral) in the right RVLM with a micromanipulator. Single-unit activity was amplified and filtered (high pass 100–500 Hz, low pass 3 kHz). A time window discriminator detected a unitary spike potential, whereas spike waveform and discrimination were monitored continuously. The filtered signals were stored on an instrumentation tape recorder together with the arterial blood pressure signal. Discriminated spike pulses and blood pressure were also recorded and analyzed by using the Spike2 system (Cambridge Electronic Design).
The caudal pole of the facial nucleus (CP7) was located from its antidromic field potential evoked by facial nerve stimulation, as described by Brown and Guyenet (2). Recordings were made from neurons in the region 0–400 μm caudal to CP7 and 1.6–1.9 mm lateral to the midline. Recording sites were later marked by passing 10 nA of negative current for 10 min through the recording electrode to deposit Pontamine sky blue dye. Spinally projecting neurons were demonstrated by antidromic stimulation from the spinal cord (bipolar, 0.2-ms stimuli of amplitude 50–300 μA), by application of the criteria described previously (3). In addition, an aortic cuff was inflated to test that the neurons were barosensitive (confirmed by a pronounced decrease in firing rate during the pressor response to brief aortic constriction).
The procedures for microinjections of bicuculline (bicuculline methiodide, 20 nl of 1 mM solution; Sigma) in the DMH and for marking of injection sites in the DMH were the same as described above, for the first series of experiments.
Comparisons between responses evoked by microinjection of drugs were made using the paired or unpaired t-test, with application of Holm's step-down procedure (28) for multiple comparisons. The significance of correlation between paired measurements was determined by calculating the correlation coefficient r and then determining whether this value was significantly different from zero. A P value of <0.05 was regarded as statistically significant. All values are presented as means ± SE.
x ± 0.3 Hz, where x represents the frequency at which this peak occurred. In addition, the total power over the frequency range 0–12 Hz was also determined by determining the area under the autospectrum curve over this frequency range.
Responses evoked by different doses of bicuculline in the DMH.
As a first step, the dose-response relationship was determined in 10 barointact rats. In these rats, the baseline levels of MAP and HR were 85 ± 3 mmHg and 373 ± 10 beats/min, respectively. Microinjections of different doses of bicuculline (0.1–40 pmol) in the DMH produced dose-dependent increases in MAP, HR, and RSNA (Fig. 1). The minimum dose that produced statistically significant increases (P < 0.01 in all cases) in HR, MAP, and RSNA, compared with that evoked by the vehicle solution alone, was 0.4 pmol. The centers of the injection sites were all confirmed to be within the DMH (Fig. 2A).
Effects of muscimol in the RP on the responses evoked by disinhibition of the DMH.
As described in methods, in 10 experiments, bicuculline was injected in the DMH before and after injection of muscimol in a physiologically identified site within the RP (i.e., at which an increase in HR of at least 40 beats/min was evoked). The centers of these injection sites were confirmed to be within the RP (Fig. 2B). At these sites in the RP, bicuculline (30 pmol) evoked an increase in HR of 75 ± 10 beats/min, accompanied by an increase in MAP of 13 ± 3 mmHg, and a variable effect on RSNA, ranging from no effect to an increase of 85% (mean 20 ± 9%).
The dose of bicuculline selected for microinjection in the DMH (10 pmol in 20 nl) was one that produced a large but submaximal response (Fig. 1). The centers of the injections were confirmed to be located in the DMH (Fig. 2A). As previously described (11), the MAP, HR, and RSNA began to increase within 10–20 s after injection of bicuculline in the DMH, reached a peak after 5–10 min, and then declined gradually, returning to baseline levels after ∼30 min (Fig. 3). After injection of muscimol in the RP, the tachycardia and pressor response evoked by DMH disinhibition was greatly reduced (by 50–60%) after muscimol injection in the RP (Figs. 3 and 4A). There was also a reduction in the evoked increase in RSNA in 9 of 10 experiments, but the magnitude of this reduction (∼25% on average) was much less than the reduction in the evoked tachycardia and pressor response (Figs. 3 and 4A).
Muscimol injection in the RP had little effect on the baseline levels of MAP and HR but did result in a modest increase in RSNA (Table 1). To test whether the effect of muscimol in reducing the DMH-evoked increase in RSNA may have been dependent on the muscimol-evoked increase in baseline RSNA, the correlation coefficient between baseline RSNA and the postmuscimol reduction in the DMH-evoked increase in RSNA (expressed as a percentage of the premuscimol DMH-evoked increase) was determined. This was calculated to be −0.4, which was not significantly different from zero (P > 0.2).
It has been shown previously that disinhibition of the RP activates the sympathetic outflow to brown adipose tissue, as part of a thermoregulatory response (18). This raises the possibility that the increase in RSNA evoked by disinhibition of the DMH that is mediated by RP neurons is the result of activation of renal sympathetic fibers innervating brown adipose tissue located close to the kidney (30), rather than renal sympathetic vasomotor fibers. To test this possibility, we determined (see methods) the cardiac-related component of the power spectra of the RSNA at the frequency of the HR before and after disinhibition of the RP, since this component of the autospectrum reflects the baroreceptor reflex influence on RSNA, which is indicative of sympathetic vasomotor activity (18). This procedure was performed in six experiments in which bicuculline microinjection in the RP evoked the largest increases in RSNA (34–85% above the preinjection baseline level). In all six experiments, the magnitude of the cardiac-related component of the power spectrum was increased significantly (by 92 ± 25%, P < 0.05) at the time when the RSNA had increased to its peak level, compared with the magnitude of this component just before bicuculline microinjection (Fig. 5). The cardiac-related component also increased significantly when calculated as a proportion of the total power (from 6.0 ± 0.9 to 8.1 ± 0.8%, P < 0.05).
Extracellular single-unit recording in the RVLM.
Extracellular single-unit recordings were made from six individual barosensitive bulbospinal neurons. All six neurons showed a profound decrease in firing rate during the pressor response to brief aortic constriction (Fig. 6A), and all were antidromically activated from the lower cervical cord (Fig. 6B). Three of these neurons had basal firing rates in the range 0.5–1.9 spikes/s, whereas the other three had higher basal firing rates (8.6–34.6 spikes/s). The conduction velocities ranged from 1.3 to 5.0 m/s. Unilateral microinjections of bicuculline (10 pmol in 20 nl) in the DMH greatly increased the firing rate of five of six RVLM neurons, to 417 ± 125% above the preinjection level (range 84–663%; Fig. 7, A and B), accompanied by an increase in MAP of 23 ± 3 mmHg. The one unit that did not respond to DMH activation was the one with the highest basal firing rate (34.6 spikes/s). The locations of the centers of the bicuculline injection sites in the DMH, and of the recording sites in the RVLM, are shown in Fig. 8.
The results of this study show for the first time that inhibition of neurons in the region of the RP results in a modest although significant reduction in the activation of the renal sympathetic outflow evoked by disinhibition of the DMH. The results also clearly demonstrate that sympathetic premotor neurons in the RVLM are powerfully excited by disinhibition of the DMH. These findings, taken together with those of a previous study from our laboratory (11), clearly indicate that neurons in both the RVLM and RP region relay excitatory inputs to the renal sympathetic outflow that arise from activation of neurons in the DMH. We discuss below the physiological implications of these findings, after first considering some methodological issues.
Muscimol injection in the RP had very little effect on MAP and HR, as previously reported by Samuels et al. (26). On the other hand, there was a modest increase in the baseline RSNA (∼20%). It could be argued that this increase in basal RSNA may have by itself reduced the magnitude of the evoked increase in RSNA, even if RP neurons were not part of the pathway subserving the DMH-evoked increase in RSNA. If that were the case, one would expect a positive correlation between the effect of muscimol on baseline RSNA and its effect in reducing the DMH-evoked increase in RSNA. In fact, there was no such correlation, indicating that the reduction in the DMH-evoked increase in RSNA was not because of the change in the baseline level of RSNA.
The observation that muscimol injection in the RP evoked an increase in RSNA was unexpected, given that our results show that disinhibition of neurons in this region also tends to increase RSNA. It is known, however, that the RP region contains renal sympathoinhibitory (7, 23) and sympathoexcitatory neurons (Ref. 24 and the present study). We have previously shown (23) that the sites in the RP region from which renal sympathoinhibitory responses are most readily evoked are more caudal (close to the level 12.8 mm caudal to bregma) than the sites at which renal sympathoexcitatory responses were evoked in the present study (11.3–11.8 mm caudal to bregma). It is possible, however, that sympathoinhibitory neurons could also be located more rostrally and may intermingle with sympathoexcitatory neurons in the more rostral part of the RP region. Thus the muscimol injections in the RP may inhibit tonic activity in both sympathoexcitatory and sympathoinhibitory neurons, and the balance of these two opposing effects will determine the net effect on the level of RSNA. The fact that muscimol injection in this region of the RP resulted in an increase in RSNA therefore suggests that sympathoinhibitory neurons within this region make a greater contribution than sympathoexcitatory neurons to the tonic level of RSNA.
Comparison of the roles of the RP and RVLM in mediating cardiovascular responses evoked from the DMH.
Our findings indicate that neurons within the RP region make a modest contribution to the renal sympathoexcitatory response evoked from the DMH. It seems likely that the remaining component of the DMH-evoked response is mediated largely via neurons in the RVLM, since inhibition of RVLM neurons reduced the DMH-evoked response by ∼75% (11). With regard to the cardiac component of the response, our results confirm the finding by Samuels et al. (26) that muscimol in the RP greatly reduces the evoked tachycardia. This is also consistent with our previous observation that inhibition of the RVLM has no effect on the tachycardia evoked from the DMH (11). Thus, in summary, our results together with those of others lead to the conclusion that the tachycardia evoked from the DMH is mediated largely via the medullary raphe nuclei, whereas the renal sympathoexcitation is mediated predominantly via the RVLM and to a lesser extent via the medullary raphe.
An important question is whether the neurons within the medullary raphe that contribute to the renal sympathoexcitation evoked from the DMH have a vasomotor function, or else regulate renal sympathetic nerves innervating nonvascular targets. In this regard, it is known that the RP contains neurons that regulate the sympathetic outflow to brown adipose tissue (18, 19) and that there are deposits of brown adipose tissue located close to the kidney (30) that may be innervated by renal sympathetic nerves. Analysis of the autospectra of the RSNA showed that the cardiac-related component of the power spectrum increased, both in absolute magnitude and as a proportion of the total power, when the RSNA increased as a consequence of disinhibition of RP neurons. The cardiac-related component of the power spectrum reflects the baroreceptor reflex influence on RSNA, which is indicative of sympathetic vasomotor activity (18). Thus the increase in the magnitude of this component of the RSNA autospectrum indicates that the increase in RSNA evoked by activation of RP neurons reflects, at least in part, an increase in renal sympathetic vasomotor activity. At the same time, we cannot rule out the possibility that some of the DMH-evoked increase in RSNA that is mediated by the RP region is the result of activation of renal sympathetic nerves regulating thermogenesis, or other nonvasomotor functions such as renin release and sodium excretion (15). In any case, our results suggest that, in comparison with the RVLM, the RP region makes a much smaller contribution to renal vasomotor effects evoked from the DMH. This is consistent with the hypothesis, as proposed recently by Morrison (19), that sympathetic premotor neurons controlling visceral vasoconstriction are located predominantly within the RVLM rather than the medullary raphe nuclei.
Our observations do not address the question as to whether the neurons in the RP region and in the RVLM that mediate increases in RSNA evoked by disinhibition of the DMH are normally activated by the same inputs. Apart from its role in mediating the physiological response to acute psychological stress (9), recent evidence indicates that the DMH is also involved in thermoregulatory responses (5, 14, 35, 36). The RSNA is increased during heat stress (25), and it is conceivable that DMH neurons that increase RSNA in response to heat stress are distinct from those that increase RSNA in response to acute psychological stress. If that were the case, then the descending pathways arising from such neurons would also be separate and may project to different relay nuclei within the medulla. It should be noted, however, that stress can induce an increase in body temperature (21), and so both descending pathways could be activated by DMH neurons that subserve the cardiovascular and thermogenic components of a stress response.
In the single-unit recording experiments, the identified barosensitive neurons in the RVLM had conduction velocities that were within the same range as those identified in previous studies in rats (2, 20). Although only a relatively small sample (n = 6) was studied, it is noteworthy that five of these neurons were powerfully excited by disinhibition of the DMH. In a previous study, we found that the increase in RSNA evoked by disinhibition was greatly reduced by bilateral inhibition of the RVLM (11). As pointed out in the Introduction, however, a limitation of that previous study is that bilateral inhibition of the RVLM removes a major tonic excitatory input to sympathetic preganglionic vasomotor neurons (8), leaving open the possibility that, under such conditions, the excitability of renal sympathetic preganglionic neurons to inputs arising from all other sources, including the RP region, would be reduced. The results of the present study, however, provide direct evidence that sympathetic premotor neurons in the RVLM receive strong excitatory inputs from DMH neurons and support the conclusion that the RVLM plays a key role in mediating sympathetic vasomotor responses arising from activation of the DMH.
Output pathways from the RP and RVLM mediating cardiovascular responses evoked by DMH disinhibition.
Like the RVLM, the RP region projects to sympathetic preganglionic nuclei at all levels of the thoracolumbar spinal cord of the rat, including the segments that contain preganglionic neurons innervating the kidney (13, 33). Similarly, studies using viral transneuronal labeling in the rat and rabbit have also demonstrated the existence of renal sympathetic premotor neurons in the RP region, although to a much lesser extent than in the RVLM (10, 27). Thus the simplest interpretation of our results is that the DMH-evoked renal sympathoexcitation is mediated by separate parallel descending pathways originating from sympathetic premotor neurons in the RVLM and RP region. At the same time, the possibility should also be acknowledged that part of the renal sympathoexcitatory response relayed by the RP region could be dependent on a synapse within the RVLM, because there are neurons in the RP that project directly to the RVLM (17). Even if such a pathway is involved in the DMH-evoked response, however, it is unlikely to be a major factor driving renal sympathetic premotor neurons in the RVLM, since our results show that inhibition of the RP causes only a modest reduction in the DMH-evoked renal sympathoexcitation. Similarly, it has been shown recently that the tachycardia evoked by disinhibition of the RP is independent of the RVLM (6).
In recent years, much evidence has accumulated that indicates that the DMH plays a pivotal role in integrating the autonomic, neuroendocrine, and behavioral responses to acute stress (9), as well as in evoking autonomic responses associated with thermoregulatory responses (5, 14, 35, 36). The results of this study provide new information about the output pathways that mediate the large increase in RSNA that is evoked by activation of neurons within the DMH, but many important questions remain. For example, there is now good evidence that there are subsets of sympathetic premotor neurons within the RP and RVLM that selectively regulate different sympathetic outflows (16, 19), but it is not known whether, at the level of the DMH, there are also separate populations of neurons that selectively regulate these different outflows, or whether instead there are “command neurons” within the DMH that drive the different components of a response, such as that evoked by an acute psychological stress or thermal challenge, in an integrated and coordinated fashion. A recent study has identified neurons in the DMH that have collateral outputs to both kidneys (4) but whether such neurons also regulate the sympathetic outflows to other target organs involved in the response to acute stress or thermal challenge remains to be determined.
This study was supported by the National Health and Medical Research Council of Australia and the National Heart Foundation of Australia. M. A. P. Fontes was supported by a Fellowship from the Conselho Nacional de Desenvolvimento Científíco e Tecnológico of Brazil.
Current address of M. A. P. Fontes: Laboratório de Hipertensão, Departamento de Fisiologia e Biofísica, ICB-UFMG, Universidade Federal de Minas Gerais, Belo Horizonte, MG 31270 901, Brazil.
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- Copyright © 2004 the American Physiological Society