Neurokinin-1 receptor-expressing neurons in the ventral medulla are essential for normal central and peripheral chemoreception in the conscious rat.

Neurokinin-1 receptor immunoreactive (NK1R-ir) neurons and processes are widely distributed within the medulla, prominently at central chemoreceptor sites. Focal lesions of NK1R-ir neurons in the medullary raphe or the retrotrapezoid nucleus partially reduced the CO(2) response in conscious rats. We ask if NK1R-ir cells and processes over a wide region of the ventral medulla are essential for central and peripheral chemoreception by cisterna magna injection of SSP-SAP, a high-affinity version of substance P-saporin. After 22 days, NK1R-ir cell loss was -79% in the retrotrapezoid nucleus and -65% in the A5 region, which lie close to the ventral surface, and -38% in the medullary raphe and -49% in the pre-B?tzinger complex/rostral ventral respiratory group, which lie deeper. Dorsal chemoreceptor sites, the caudal nucleus tractus solitarius and the A6 region, were unaffected. At 8 and 22 days, these lesions produced 1) hypoventilation during air breathing in wakefulness ( approximately 8%) and in non-rapid eye movement (NREM) ( approximately 9%) and rapid eye movement ( approximately 14%) sleep, as measured over a 4-h period; 2) a substantially reduced ventilatory response to 7% CO(2) by 61% in wakefulness and 46-57% in NREM sleep; and 3) a decreased ventilatory response to 12% O(2) by 40% in wakefulness and 35% in NREM sleep at 8 days, with partial recovery by 22 days. NK1R-ir neurons in the ventral medulla are essential for normal central chemoreception, provide a drive to breathe, and modulate the peripheral chemoreceptor responses. These effects are not state dependent.     

Effects of disinhibition of neurons in the dorsomedial hypothalamus on central respiratory drive

Neurons within the dorsomedial hypothalamus (DMH) play a critical role in subserving the cardiovascular and neuroendocrine response to psychological stress. An increase in respiratory activity is also a characteristic feature of the physiological response to psychological stress, but there have been few studies of the role of DMH neurons in regulating respiratory activity. In this study we determined the effects of activation of DMH neurons on respiratory activity (assessed by measuring phrenic nerve activity, PNA) and the relationship between evoked changes in respiratory activity and changes in sympathetic vasomotor activity in spontaneously breathing urethane-anesthetized rats. Microinjections of bicuculline (4-40 pmol in 20 nl) into the DMH evoked dose-dependent increases in PNA burst frequency and amplitude. These were accompanied by dose-dependent decreases in mean tracheal CO(2) levels, indicative of hyperventilation. In control experiments, microinjections of bicuculline into sites adjacent to the DMH evoked much smaller or no changes in PNA. In experiments where renal sympathetic nerve activity (RSNA) was also measured, cycle-triggered averaging revealed that RSNA under resting conditions was partly correlated with the PNA, but in response to DMH disinhibition there was no consistent change in the amplitude of the respiratory-related variations in RSNA. The results indicate that DMH neurons can exert a powerful stimulatory effect on respiratory activity, causing hyperventilation. This is not associated with an increase in the degree of coupling between PNA and RSNA, indicating that the DMH-evoked increase in RSNA is not a consequence of increased central respiratory drive.     

Arginine vasopressin produces inhibition upon respiration without pressor effect in the rat

The purpose of the current study was to examine where arginine vasopressin (AVP) inhibits respiration by direct action on the areas of the ventrolateral medulla (VLM) in the rat. The animal was anesthetized by urethane (1.2 g/kg, i.p.), paralyzed with gallamine triethiodide, and artificially ventilated. Catheterization of the femoral artery and vein, and bilateral vagotomy were performed. The rat was then placed upon a stereotaxic instrument in a prone position. The phrenic nerve was separated and cut peripherally. Phrenic nerve activity (PNA) was monitored at normocapnia and hypercapnia in hyperoxia. Microinjection of AVP into various subregions of the VLM was then performed. In response to AVP microinjection, a transient period of apnea and then a significant decrease in PNA amplitude were observed. Arterial blood pressure was unchanged. This inhibition of PNA with AVP treatment was site-specific, attenuated by raising CO2 concentration, and totally abolished by pretreatment with AVP V1A receptor antagonist. Data of the present study indicate that endogenous resource of AVP may produce an inhibitory effect upon respiration via AVP receptors presented on neurons within the VLM.     

Substance P in the ventrolateral medulla oblongata regulates ventilatory responses.

Local injection of substance P (SP) into the ventral portion of the nucleus gigantocellularis, nucleus reticularis lateralis, and nucleus retrofacialis of the ventrolateral medulla oblongata (VLM) or direct application on the ventral surface of the medulla oblongata caused marked stimulation of tidal volume (VT) and/or minute ventilation (VE). The ventilatory response to hypoxia was significantly blunted after SP in the VLM but not in the dorsal medulla oblongata (DM) (nucleus tractus solitarius). The SP antagonist [D-Pro2,D-Trp7,9]SP almost completely inhibited this response when applied locally to a wide area of the superficial layer of the VLM but not of the DM. Unilateral or bilateral application of 0.3-1.5 nmol of the SP antagonist in the VLM (corpus trapezoideum and the caudal region extending from the rootlets of the nucleus hypoglossus to the first cervical segment) markedly attenuated the response to a 5% CO2 inhalation. The inhibition of the CO2 response was seen after [D-Pro2,D-Trp7,9]SP in the rostral areas of the medulla oblongata corresponding to the corpus trapezoideum and the caudal region extending from the rootlets of the nucleus hypoglossus to the first cervical segment of the cervical cord. Electric somatosensory-induced ventilatory stimulation could be depressed by approximately 70% by [D-Pro2,D-Trp7,9]SP locally applied on the surface of the VLM. We conclude that SP is involved in the hypoxic, hypercapnic, and somatosensory ventilatory responses in the rat. However, these respiratory reflexes are mediated via different neuronal pools in the medulla oblongata, mainly the VLM.     

Fluorescence location of RVLM kainate microinjections that alter the control of breathing

Kainic acid (4.7 mM) applied to the rostral ventrolateral medulla (RVLM) surface decreases phrenic output, CO2 sensitivity, and blood pressure in chloralose-urethan-anesthetized, vagotomized, paralyzed, glomectomized, servoventilated cats. In this study using the same preparation, bilateral 50- to 100-nl kainate injections just below the RVLM surface better localized these responses topographically. The physiological responses to unilateral 10-nl kainate injections were then correlated with anatomic location determined by fluorescent microbeads (0.5 micron diam). Many sites were associated with no effect, a few rostral and caudal sites with increased phrenic activity, and cluster of sites with decreased phrenic activity often to apnea, decreased CO2 sensitivity, and decreased responses to carotid sinus nerve stimulation. Blood pressure was unaffected. These sites, within 400 microns of the surface, were ventral to the facial nucleus, ventrolateral to the nucleus paragigantocellularis lateralis, caudal to the superior olive, and rostral to the retrofacial nucleus. They appeared to be within the recently described retrotrapezoid nucleus, which contains cells with respiratory-related activity and projections to the dorsal and ventral respiratory groups. Cells within this site appear able to provide tonic input to respiration and to affect peripheral and central chemoreception.     

Lesions in retrotrapezoid nucleus decrease ventilatory output in anesthetized or decerebrate cats.

Kainic acid (KA) injections into the retrotrapezoid nucleus (RTN) of anesthetized deafferented cats profoundly decreased phrenic activity (PA) and CO2 sensitivity (J. Appl. Physiol. 68: 1157-1166, 1990). In this study small electrolytic lesions of the RTN produced the same results, indicating that the KA destroyed cells. We then asked whether anesthetic depression or the absence of peripheral chemoreceptors could explain the degree of respiratory depression observed. In decerebrate cats electrolytic lesions of the RTN resulted in a decrease in PA similar to that seen under anesthesia. CO2 sensitivity was decreased by RTN lesions that extended into the caudal RTN but less so than under anesthesia. KA injections resulted in an initial increase in PA followed by a continuous decrease, a pattern similar to that seen under anesthesia but with a slower time course. CO2 sensitivity was essentially absent. Peripheral chemodenervation produced a small further decrease in PA and a downward shift of the CO2 response without change in slope. Blood pressure was unaffected by RTN lesions but was decreased by more-caudal lesions without respiratory effects. The RTN appears to be necessary for the maintenance of eupneic phrenic activity and CO2 sensitivity even in decerebrate cats with intact peripheral chemoreceptors.     

Cardiopulmonary response to vasopressin-induced activation on V1A receptors in the lateral ventrolateral medulla in the rat

The aim of the study was to examine whether or not arginine vasopressin (AVP) might modulate cardiopulmonary functions by acting on the lateral area of the ventrolateral medulla (VLM) in the rat. The rat was anesthetized, bilaterally vagotomized, paralyzed, ventilated, and then placed on a stereotaxic instrument in a prone position. Activity of the phrenic nerve (PNA) was monitored at normocapnia and hypercapnia in hyperoxia. Microinjection of AVP into the lateral region of the VLM resulted in a brief apnea followed by a significant decrease in PNA amplitude and a concomitant significant increase in blood pressure. The inhibition of PNA with AVP treatment could be partly attenuated by hypercapnia but not by phentolamine. Both inhibition of PNA and pressor response with AVP microinjection into the lateral VLM were totally abolished after pretreatment with AVP V1A receptor antagonist. These results suggest that a vasopressinergic pathway projects to the lateral VLM and modulates cardiopulmonary functions via AVP V1A receptors on neurons within the lateral VLM.     

Neurokinin-1 receptor-expressing cells regulate depressor region of rat ventrolateral medulla

Intraparenchymal injection of the saporin conjugate [Sar9, Met (O2)11] substance P-saporin (SSP-SAP) into the ventrolateral medulla (VLM) destroys neurokinin-1 receptor-immunoreactivity (NK1R-ir) neurons selectively. This treatment attenuates the hypotension caused by injection of DL-homocysteic acid (DLH) into the caudal VLM (CVLM). Here we ask whether SSP-SAP creates this deficit by destroying the CVLM GABAergic interneurons that mediate the sympathetic baroreflex (baroactivated depressor neurons) or by destroying other VLM neurons. Two weeks after unilateral SSP-SAP treatment (97% loss of VLM NK1R-ir neurons) DLH-induced hypotension and sympathetic tone inhibition were blunted on the lesioned side. Unlesioned or unilaterally lesioned rats received phenylephrine (PE) while awake to identify CVLM baroactivated depressor neurons by the presence of Fos-ir nuclei. Although CVLM Fos-ir cells were not NK1R-ir, their number was reduced approximately 60-70% on the SSP-SAP-injected side. SSP-SAP spared VLM neurons devoid of NK1R-ir, such as the catecholaminergic cells and the precerebellar glutamatergic neurons. In the pre-B?tzinger region of the VLM the toxin killed glutamatergic neurons while sparing glycinergic and GABAergic inhibitory neurons. In the CVLM region approximately 26% of the inhibitory cells were destroyed. In conclusion, the baroactivated depressor neurons of the CVLM do not appear to express NK1Rs but their activity is probably modulated by a population of excitatory NK1R-ir cells located in the VLM. The results also suggest that a region located below the CVLM (subCVLM) may contain an unrelated population of GABAergic depressor neurons that are NK1R-ir but are either not barosensitive or do not express Fos during baroreceptor stimulation.     

Coexistence of neurons integrating urinary bladder activity and pelvic nerve activity in the same cardiovascular areas of the pontomedulla in cats

The present study examines the coexistence of neurons in the same cardiovascular point of the pontomedulla that integrates urinary bladder (UB) motility, and pelvic nerve activity (PNA). Microinjection of monosodium L-glutamate (Glu) into the locus coeruleus (LC), the gigantocellular tegmental field (FTG), the rostral ventrolateral medulla (RVLM), and the dorsomedial medulla (DM) produced pressor responses, whereas injection into the lateral tegmental field (FTL), the nucleus of tractus solitarii (NTS), and the caudal ventrolateral medulla (CVLM) produced depressor responses. However, microinjection of Glu into the dorsomotor nucleus of the vagus (DMV) and the ambiguus nucleus (AN), where the vagus nerve originates, produced marked bradycardia. Many of these cardiovascular responses were accompanied by increased, or decreased parasympathetic PNA. In six animals, sympathetic renal nerve activity (RNA) and PNA also increased simultaneously during the pressor response. The present study also examines the connection between the DMV-AN and the sacral intermediolateral column (IML), where parasympathetic preganglionic neurons (PGNs) of the pelvic nerve located. Biotinylated dextran amine (BDA), an anterograde tracer, was iontophoretically injected into the DMV or AN. No labelled terminal or neuron was detected in the sacral IML, but labelled terminals were observed in the bilateral LC, and also in the bilateral sides of the FTG, FTL, RVLM, DM, and CVLM. These results suggest that neurons of the DMV and/or AN may indirectly regulate the sacral parasympathetic PGNs through the LC for supraspinal control of the pelvic nerve. Furthermore, these results also suggest the coexistence of multiple autonomic integrating mechanisms of different kinds within various cardiovascular areas of the pontomedulla.     

Muscimol dialysis in the retrotrapezoid nucleus region inhibits breathing in the awake rat.

Under anesthesia, inactivation of the retrotrapezoid nucleus (RTN) region markedly inhibits breathing and chemoreception. In conscious rats, we dialyzed muscimol for 30 min to inhibit neurons of the RTN region reversibly. Dialysis of artificial cerebrospinal fluid had no effect. Muscimol (1 or 10 mM) significantly decreased tidal volume (VT) (by 16-17%) within 15 min. VT remained decreased for 50 min or more, with recovery by 90 min. Ventilation (VE) decreased significantly (by 15-20%) within 15 min and then returned to baseline within 40 min as a result of an increase in frequency. This, we suggest, is a compensatory physiological response to the reduced VT. Oxygen consumption was unchanged. In response to 7% CO(2) in the 1 mM group, absolute VE and change in VE were significantly reduced (by 19-22%). In the 10 mM group, the response to dialysis included a time-related increase in frequency and decrease in body temperature, which may reflect greater spread of muscimol. In the awake rat, the RTN region provides a portion of the tonic drive to breathe, as well as a portion of the response to hypercapnia.     

Activation of ventrolateral medulla neurons by arginine vasopressin via V1A receptors produces inhibition on respiratory-related hypoglossal nerve discharge in the rat

Arginine vasopressin (AVP) is an important neurohormone in the regulation of many aspects of central nervous system, yet its modulation on the respiratory function remains largely unknown. The aims of this study were to investigate the modulation of phrenic (PNA) and hypoglossal nerve activity (HNA) by central administration of AVP and to identify the involvement of AVP V1A receptors in this modulation. Animals were anesthetized with urethane (1.2 g/kg, i.p.), paralyzed with gallamine triethiodide (5 mg/kg, i.v.), and artificially ventilated. The rat was then placed on a stereotaxic apparatus in a prone position. PNA and HNA were monitored at normocapnia in hyperoxia. Microinjection of AVP into the medial ventrolateral medulla (VLM) and/or rostral ventral respiratory group (rVRG) produced a dose-dependent inhibition on both PNA and HNA, whereas the microinjection of AVP into the region of lateral VLM resulted in a similar inhibition of these nerve activities and a pressor response. Systemic administration of phentolamine abolished the pressor effect but did not affect the inhibition of PNA and HNA evoked by AVP injection into the lateral VLM and/or rVRG, suggesting that AVP-induced inhibition of PNA and HNA was not due to the side effect of pressor response. These cardiopulmonary modulations were totally abolished by the central pretreatment of AVP V1A receptor antagonist. Our results suggested that AVP may activate neurons located at the VLM and/or rVRG via the AVP V1A receptor to inhibit respiratory-related HNA and thus to regulate upper airway aperture.     

大鼠延髓至下丘脑腹内侧核的儿茶酚胺能投射神经元在胃伤害性刺激后的Fos表达

本实验用ＨＲＰ注入下丘脑腹内侧核结合逆行追踪与抗ＦＯＳ蛋白和抗酪氨酸羟化酶（ＴＨ）抗血清双重免疫细胞化学相结合的三重标记方法,对大鼠孤束核和延髓腹外侧区至下丘脑腹内侧核的儿茶酚胺能投射神经元在胃伤害性刺激后的ｃ－ｆｏｓ表达进行了观察。本文发现孤束核和延髓腹外侧区有七种不同的标记细胞：ＨＲＰ、Ｆｏｓ、ＴＨ单标细胞Ｆｏｓ／ＨＲＰ、Ｆｏｓ／ＴＨ、ＨＲＰ／ＴＨ双标细胞和Ｆｏｓ／ＨＲＰ／ＴＨ三标细胞。上述七种标记细胞主要分布在延髓中段和尾段孤束核的内侧亚核和延髓腹外侧区以及两者之间的网状结构。ＨＲＰ标记细胞以注射侧为主,对侧有少量分布。本文结果证明,大鼠孤束核、延髓腹外侧区和网状结构内儿茶酚胺能神经元有些至下丘脑腹内侧核的投射,其中一部分儿茶酚胺能神经元参与了胃伤害性刺激的传导和调控。     

Role of serotonergic input to the ventrolateral medulla in expression of the 10-Hz sympathetic nerve rhythm

We studied the changes in inferior cardiac sympathetic nerve discharge (SND) produced by unilateral microinjections of 5-hydroxytryptamine (5-HT) receptor agonists and antagonists into the ventrolateral medulla (VLM) of urethane-anesthetized, baroreceptor-denervated cats. Microinjection of the 5-HT2 receptor antagonist LY-53857 (10 mM) into either the rostral or caudal VLM significantly reduced (P < or = 0.05) the 10-Hz rhythmic component of basal SND without affecting its lower-frequency, aperiodic component. The selective depression of 10-Hz power was accompanied by a statistically significant decrease in mean arterial pressure (MAP). Microinjection of LY-53857 into the VLM also attenuated the increase in 10-Hz power that followed tetanic stimulation of depressor sites in the caudal medullary raphé nuclei. Microinjection of the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)2-amino-propane (DOI; 10 microM) into the VLM selectively enhanced 10-Hz SND, and intravenous DOI (1 mg/kg) partially reversed the reduction in 10-Hz SND produced by 5-HT2 receptor blockade in the VLM. Microinjection of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT; 10 mM), into either the rostral or caudal VLM also selectively attenuated 10-Hz SND and significantly reduced MAP. The reduction in 10-Hz SND produced by 8-OHDPAT was partially reversed by intravenous WAY-100635 (1 mg/kg), which selectively blocks 5-HT1A receptors. These results support the view that serotonergic inputs to the VLM play an important role in expression of the 10-Hz rhythm in SND.     

Julius H. Comroe, Jr., distinguished lecture: central chemoreception: then ... and now

The 2010 Julius H. Comroe, Jr., Lecture of the American Physiological Society focuses on evolving ideas in chemoreception for CO?/pH in terms of what is "sensed," where it is sensed, and how the sensed information is used physiologically. Chemoreception is viewed as involving neurons (and glia) at many sites within the hindbrain, including, but not limited to, the retrotrapezoid nucleus, the medullary raphe, the locus ceruleus, the nucleus tractus solitarius, the lateral hypothalamus (orexin neurons), and the caudal ventrolateral medulla. Central chemoreception also has an important nonadditive interaction with afferent information arising at the carotid body. While ventilation has been viewed as the primary output variable, it appears that airway resistance, arousal, and blood pressure can also be significantly affected. Emphasis is placed on the importance of data derived from studies performed in the absence of anesthesia.     

Role of ventrolateral medulla in generating the 10-Hz rhythm in sympathetic nerve discharge

We recorded changes in right inferior cardiac and either left inferior cardiac or left vertebral sympathetic nerve discharge (SND) produced by unilateral microinjections of GABA-A and excitatory amino acid (EAA) receptor antagonists into the ventrolateral medulla (VLM) of urethane-anesthetized, baroreceptor-denervated cats. Unilateral microinjections of GABA-A receptor antagonists, SR-95531 or bicuculline, into single tracks in VLM anywhere between 1 and 5 mm rostral to the obex eliminated or markedly reduced 10-Hz power in SND on both sides of the body. Low-frequency components (<6 Hz) of SND were unaffected. Complete blockade of the 10-Hz rhythm occurred with a dose of SR-95531 as low as 6.25 pmol in a 50-nl volume. Unilateral microinjections of the nonselective EAA receptor antagonist, kynurenate (KYN; 7.5 nmol), into the caudal or rostral VLM significantly reduced, but did not eliminate, 10-Hz SND ipsilateral to the injection sites, while 10-Hz SND contralateral to the injection sites was not significantly changed. These observations suggest that 1) GABAergic transmission in VLM is critical for generation of the 10-Hz rhythm, 2) the caudal and rostral portions of VLM act together to generate the 10-Hz rhythm, and 3) 10-Hz rhythm generation depends, at least in part, on tonic or phasic excitatory drive to GABAergic interneurons in caudal VLM and presympathetic neurons in rostral VLM. The data also suggest that pathways interconnecting the two halves of the brain stem play an important role in promoting 10-Hz rhythm generation.     

Parvalbumin in respiratory neurons of the ventrolateral medulla of the adult rat

A column of parvalbumin immunoreactive neurons is closely associated with the location of respiratory neurons in the ventrolateral medulla of the rat. The majority (66%) of bulbospinal neurons in the medullary ventral respiratory column (VRC) that were retrogradely labeled by tracer injections in the phrenic nucleus were also positive for parvalbumin. In contrast, only 18.8% of VRC neurons retrogradely labeled after a tracer injection in the VRC, also expressed parvalbumin. The average cross-sectional area of VRC neurons retrogradely labeled after VRC injections was 193.8 μm² ± 6.6 SE. These were significantly smaller than VRC parvalbumin neurons (271.9 μm² ± 12.3 SE). Parvalbumin neurons were found in the Bötzinger Complex, the rostral ventral respiratory group (VRG), and the caudal VRG, areas which all contribute to the bulbospinal projection. In contrast, parvalbumin neurons were sparse or absent in the preBötzinger Complex and in the vicinity of the retrotrapezoid nucleus, areas that have few bulbospinal projections. Parvalbumin was rarely colocalized within Neurokinin-1 receptor positive (NK1R) VRC neurons, which are found in the preBötzinger complex and in the anteroventral part of the rostral VRG. Parvalbumin neurons in the Bötzinger Complex and rostral VRG help define the rostrocaudal extent of these regions. The absence of parvalbumin neurons from the intervening preBötzinger complex also helps establish the boundaries of this region. Regional boundaries described in this manner are in good agreement with earlier physiological and anatomical studies. Taken together, the distributions of parvalbumin, NK1R and bulbospinal neurons suggest that the rostral VRG may be subdivided into distinct, anterodorsal, anteroventral, and posterior subdivisions.     

Synchronized activation of sympathetic vasomotor, cardiac, and respiratory outputs by neurons in the midbrain colliculi

The superior and inferior colliculi are believed to generate immediate and highly coordinated defensive behavioral responses to threatening visual and auditory stimuli. Activation of neurons in the superior and inferior colliculi have been shown to evoke increases in cardiovascular and respiratory activity, which may be components of more generalized stereotyped behavioral responses. In this study, we examined the possibility that there are "command neurons" within the colliculi that can simultaneously drive sympathetic and respiratory outputs. In anesthetized rats, microinjections of bicuculline (a GABA(A) receptor antagonist) into sites within a circumscribed region in the deep layers of the superior colliculus and in the central and external nuclei of the inferior colliculus evoked a response characterized by intense and highly synchronized bursts of renal sympathetic nerve activity (RSNA) and phrenic nerve activity (PNA). Each burst of RSNA had a duration of ～300-400 ms and occurred slightly later (peak to peak latency of 41 ± 8 ms) than the corresponding burst of PNA. The bursts of RSNA and PNA were also accompanied by transient increases in arterial pressure and, in most cases, heart rate. Synchronized bursts of RSNA and PNA were also evoked after neuromuscular blockade, artificial ventilation, and vagotomy and so were not dependent on afferent feedback from the lungs. We propose that the synchronized sympathetic-respiratory responses are driven by a common population of neurons, which may normally be activated by an acute threatening stimulus.     

CO2 dialysis in nucleus tractus solitarius region of rat increases ventilation in sleep and wakefulness.

To evaluate the function of widely distributed central chemoreceptors during sleep and wakefulness in the rat, we focally stimulate single chemoreceptor sites during naturally occurring sleep-wake cycles by microdialysis of artificial cerebrospinal fluid equilibrated with 25% CO2. In retrotrapezoid nucleus, this increased ventilation (tidal volume) by 24% only in wakefulness (Li A, Randall M, and Nattie E. J Appl Physiol 87: 910-919, 1999). In caudal medullary raphé, it increased ventilation (frequency) by 15-20% only in sleep (Nattie EE and Li A. J Appl Physiol 90: 1247-1257, 2001). Here, in nucleus tractus solitarius (NTS), focal acidification significantly increased ventilation by 11% in sleep and 7% in wakefulness rostrally (n = 5) and by 16% in sleep and 28% in wakefulness caudally (n = 5). The sleep-wake cycle was unaltered. Dialysis with 5% CO2 had no effect. Dialysis with 50% CO2 caudally did not further stimulate ventilation but did disrupt sleep. Central chemoreceptors in the NTS affect breathing in both sleep and wakefulness. The threshold for arousal in caudal NTS is greater than that for the stimulation of breathing.     

Role of ventrolateral medulla in regulation of respiratory and cardiovascular systems

It is now widely accepted that the ventrolateral aspect of the medulla oblongata (VLM) plays an important role in regulation of the respiratory and cardiovascular systems. The VLM has been implicated as being involved in a number of different physiological functions, including central chemoreception, integration of afferent inputs from certain sense organs to the respiratory and cardiovascular controllers, the source of excitatory input to preganglionic sympathetic neurons in the spinal cord, and location of synaptic relay between the higher brain defense areas and spinal cord sympathetic elements. In recent years there have been a number of important findings concerning both the anatomical substrate and neurophysiological characteristics of VLM neurons involved in regulation of the respiratory and cardiovascular systems. New anatomical findings show that neuronal networks located in the VLM send projections to and receive projections from brain stem nuclei that have traditionally been associated with respiratory and cardiovascular regulation. Nevertheless, there are still many important questions concerning the role of the VLM in control of these vital systems that have yet to be answered. For instance, are the same VLM neurons involved in control of both systems? Is the VLM the only site for central respiratory chemoreception? This review will endeavor to examine new findings and to reexamine some older findings concerning the VLM.