Heterogeneity of brainstem blood flow response to hypoxia in the anesthetized rat

Cerebral blood flow is strictly regulated during hypoxic stress. Because of the preponderant role of the brainstem in cardiorespiratory controls, blood flow response to hypoxia is stronger in this region than in the cortex. However, the brainstem is made up of various regions, which differ in their responsiveness to chemical stimuli. The objective of this study was to evaluate the distribution of blood flow during hypoxia using microsphere deposition methods in three brainstem regions containing key structures in cardiorespiratory controls: the nucleus tractus solitarus (NTS), the ventral respiratory groups (VRG) and the pontine respiratory groups (PRG). Microsphere injections were made during normoxia (FIO2 = 0.21) and after 15 min of hypoxia (FIO2 = 0.10). Based on this index, blood flow increase during hypoxia was higher in the VRG than in the dorsal part of the brainstem, containing the NTS and the PRG (P = 0.002, n = 10). These results suggest that blood flow response to hypoxia favours O2 delivery in brainstem regions involved in respiratory rhythm generation.     

The effects of hypoxia on the metabolic and cardiorespiratory responses to shivering produced by external and central cooling in the pigeon

Respiratory, cardiovascular and blood gas responses of pigeons to spinal cord cooling (36 +/- 1 degrees C), to ambient cooling (Ta = 5 degrees C) and to simultaneous spinal cord and ambient cooling were measured at three different levels of fractional inspired oxygen concentration (FIO2 = 0.209, 0.10 and 0.07). Shivering and the 'extra' VO2 provoked by ambient and/or spinal cord cooling were more or less reduced during hypoxic exposure depending on the intensity of cold stress and hypoxic states. At FIO2 = 0.10 shivering was markedly reduced and sometimes inhibited, whereas at FIO2 = 0.07 any pattern of cold tremor was inhibited. The accompanying cardiorespiratory responses were similar to those of thermoneutral controls exposed to the same FIO2. The amount by which VO2 was reduced in the pigeons exposed to hypoxia during ambient and/or spinal cord cooling was correlated, at both levels of hypoxia, to the thermoregulatory VO2 (viz. the 'extra' VO2 produced by cooling) prior to exposure to the hypoxic gas. The effect of hypoxia on shivering and associated cardiorespiratory adjustments was rapid and was completely reversible on return to air. We conclude that the thermoregulatory system in pigeons is sensitive to hypoxia, as is the case for mammals. The FIO2 that begins to inhibit thermoregulatory and metabolic responses to cold is lower in birds, perhaps as a result of the better ability of the bird to increase intrapulmonary gas and blood O2 convective transports when exposed to hypoxic gas.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adenosine release in nucleus tractus solitarii does not appear to mediate hypoxia-induced respiratory depression in rats

The time course of adenosine release in the nucleus tractus solitarii (NTS) and ventrolateral medulla (VLM) during acute systemic hypoxia was investigated in the anaesthetised rat by means of amperometric enzymatic sensors. It was found that acute hypoxia induced a significant delayed increase in adenosine level (reaching levels as high as 5 μM) in the NTS and that hypoxia-induced release of adenosine was similar at various regions of the NTS along its rostro-caudal axis. Significantly smaller or no increases in adenosine levels at all in response to hypoxia were observed in the VLM. The increase in adenosine level in the NTS occurred during reoxygenation after the termination of the hypoxic challenge and was accompanied by a smaller increase in inosine concentration. At the dorsal surface of the brainstem, only release of inosine was detected following acute hypoxia. Addition of the ecto-5'-nucleotidase inhibitor α,β-methylene ADP (200 μM) to the dorsal surface of the brainstem completely abolished the signal evoked by hypoxia, suggesting that the inosine arose from adenosine that was produced in the extracellular space by the prior release of ATP. This study indicates that following systemic hypoxia, adenosine levels in the NTS increase to a significantly greater extent than in the VLM. However, the increase in adenosine concentration in the NTS occurs too late to be responsible for the hypoxia-induced depression of the respiratory activity.     

Pulmonary response to 3 h of hypoxia in prone pigs

Studies in whole animals, isolated lungs and pulmonary tissue strips have shown that the pulmonary vascular resistance (PVR) to hypoxia is temporally biphasic in nature. We studied the regional temporal response to hypoxia in prone pigs. The animals were ventilated with an FIO2 of 0.21 (control), followed by an FIO2 of 0.12 for 180 min. A biphasic response in P(pa) to hypoxia was seen with the first peak between 10 and 20 min and a second rise in P(pa) starting after 30 min, which was due to an increase in cardiac output. Regional blood flow (Q ) and ventilation (V (A)) were measured using i.v. infusion of 15 microm and inhalation of 1 microm fluorescent microspheres, respectively. We grouped the lung pieces according to their temporal relative flow response to hypoxia. The five groups were each spatially distributed similarly, but not identically, among the animals. The corresponding relative ventilation to each group did not vary much. We conclude that in the prone pig, the PVR response to sustained hypoxia varies among regions of the lungs. Following an initial rise in PVR in most lung pieces, we found unexpectedly that some regions continue to increase PVR progressively and while other regions decrease PVR after the initial increase. The net effect is little change of overall PVR to hypoxia with time. Normoxic control animals had little change in their hemodynamics and the large majority of the lung pieces did not change their resistance over 3h. We speculate that the differential response of regions may be due to a differential role of nitric oxide, endothelin-1 release or K(+) channels.     

Enhanced erythropoietin expression in the brainstem of newborn rats at high altitude

In addition to its role in elevating red blood cell number, erythropoietin (Epo) exerts protective functions against acute and delayed degenerative diseases of the brain. Moreover, we have recently demonstrated that endogenously synthesized Epo and soluble Epo receptor (a negative regulator of Epo binding to the Epo receptor) in the central nervous system play a crucial role in facilitating the ventilatory response and acclimatization to hypoxia. Here we hypothesized that cerebral Epo in the brainstem is implicated in the process that allows cardiorespiratory acclimatization to high altitude hypoxia during the postnatal period. Thus, we evaluated the postnatal ontogeny of cerebral Epo concentration of Sprague-Dawley rats living and reproducing at high altitude for longer than 19 years (3600 m in La Paz, Bolivia). Our results show that postnatal Epo concentration in high-altitude rats is higher in the brainstem than in the forebrain. Moreover, although Epo concentration in the forebrain of high-altitude rats is similar to sea-level controls, Epo level in the brainstem is surprisingly 2-fold higher in high-altitude rats than in sea-level controls. These findings strongly suggest that brainstem Epo plays an important role in tolerance to high altitude hypoxia after birth. From a clinical perspective, a better understanding of the role of Epo in the postnatal development of cardiorespiratory responses in neonates exposed to acute or chronic hypoxia might be useful.     

Effects of acute hypoxia on ventilatory response at the onset of cycle exercise in man.

In order to examine whether or not there are initial changes in ventilation at the start of bicycle exercise having work loads of differing intensities are affected with regard to normoxia and to hypoxia accompanying hypocapnia, six healthy male subjects performed submaximal exercise of 30 and 120 W at 60 rpm under normoxic (FIO2 = 0.21) and hypoxic (FIO2 = 0.11) conditions. Resting ventilation was significantly higher in hypoxia than in normoxia. However, no statistically significant differences in the initial change in ventilation at the start of exercise (delta VI assessed breath-by-breath) were found between eucapnic normoxia and hypocapnic hypoxia in both 30 and 120 W exercise. Moreover, blood lactate after exercise did not increase in any conditions as compared with rest. These observations suggest that the neurogenic ventilatory response immediately after submaximal exercise at a work load below the subject's anaerobic threshold is independent from PO2.     

Ventilatory response to acute hypoxia in transgenic mice over-expressing erythropoietin: effect of acclimation to 3-week hypobaric hypoxia

We used transgenic mice constitutively over-expressing erythropoietin ("tg6" mice) and wild-type (wt) mice to investigate whether the high hematocrit (hct), consequence of Epo over-expression affected: (1) the normoxic ventilation (V (E)) and the acute hypoxic ventilatory response (HVR) and decline (HVD), (2) the increase in ventilation observed after chronic exposure to hypobaric hypoxia (430mmHg for 21 days), (3) the respiratory "blunting", and (4) the erythrocythemic response induced by chronic hypoxia exposure. V (E) was found to be similar in tg6 and wt mice in normoxia (FIO2=0.21). Post-acclimation V (E) was significantly elevated in every time point in wt mice at FIO2=0.10 when compared to pre-acclimation values. In contrast, tg6 mice exhibited a non-significant increase in V (E) throughout acute hypoxia exposure. Changes in V (E) are associated with adjustments in tidal volume (V(T)). HVR and HVD were independent of EE in tg6 and wt mice before chornic hypoxia exposure. HVR was significantly greater in wt than in tg6 mice after chronic hypoxia. After acclimation, HVD decreased in tg6 mice. Chronic hypoxia exposure caused hct to increase significantly in wt mice, while only a marginal increase occurred in the tg6 group. Although pre-existent EE does not appear to have an effect on HVR, the observation of alterations on V(T) suggests that it may contribute to time-dependent changes in ventilation and in the acute HVR during exposure to chronic hypoxia. In addition, our results suggest that EE may lead to an early "blunting" of the ventilatory response.     

Effects of acute hypoxia on ventilatory response at the onset of submaximal exercise

In order to investigate the effects of acute hypoxia and accompanying hypocapnia on the ventilatory response at the onset of dynamic exercise, four healthy adult men performed 50W rectangular loads on a cycle-ergometer in normoxic (FIO2 = 0.21) and hypoxic (FIO2 = 0.11) conditions. No statistically significant differences in the initial ventilatory responses to exercise (both delta VI and delta VE assessed on a breath-by-breath basis) were found between eucapnic normoxia (PETO2 approximately 95, PETCO2 approximately 42 Torr) and hypocapnic hypoxia (PETO2 approximately 45, PETCO2 approximately 35 Torr). The present findings support the contention that the neurogenic ventilatory drive at the onset of early exercise is independent from PO2 and PCO2.     

Basilar artery blood flow velocity and the ventilatory response to acute hypoxia in mountaineers

Hypoxic ventilatory response is higher in successful extreme-altitude climbers than in controls. We hypothesized that these climbers have lower brainstem blood flow secondary to hypoxia which may possibly cause retention of medullary CO(2) and greater ventilatory drive. Using transcranial Doppler, basilar artery blood flow velocity (Vba) was measured at sea level in 7 extreme-altitude climbers and 10 controls in response to 10 min sequential exposures to inspired oxygen fractions (FI(O(2))) of 0.21 (baseline), 0.13, 0.11, 0.10, 0.09, 0.08 and 0.07. Sa(O(2)) was higher in climbers at FI(O(2)) of 0.11 (P<0.05), 0.08 and 0.07 (both P<0.0001). Expired ventilation (VE) increased more (n.s.), and PET(CO(2)) decreased more (n.s.) in the climbers than in controls. Vba did not significantly change in both groups at FI(O(2)) of 0.13-0.09. At FI(O(2)) of 0.08 and 0.07, Vba decreased 21% (P<0.03) and 27% (P<0.01), respectively, in climbers, and increased 29% (P<0.01) and 27% (P<0.01), respectively, in controls. The conflicting effects of hypoxia and hypocapnia on both medullary blood flow and ventilatory drive thus balance out, giving climbers a greater drive and higher Sa(O(2)), despite lower PET(CO(2)) and lower brain stem blood flow.     

Hyperalaninaemia during acute hypoxia in the anesthetized rabbit (author's transl)]

Blood alanine (Ala), an important glucose precursor, has been demonstrated to result mainly from the transamination of pyruvate derived from glucose in muscle [10]. A positive relationship between blood pyruvate and blood alanine was reported during muscular exercise and fasting. The alanine/pyruvate relationship in arterial blood has been studied in male fasted anesthetized rabbits before, during and after a short term hypoxic stress (50 minutes). Three groups of animals were studied : normoxic control (FIO2 = 0.28 ; n = 3) (C), hypoxic hypoxia (FIO2 = 0.10 ; n = 4) (HH) and hypoxia induced by respiring the animals with a carbon monoxide containing gas mixture (FIO2 = 0.28, FICO = 0.002 ; n = 6) (HCO). The hypoxic stress was of similar magnitude in HH and HCO groups. During the hypoxic periods an increase of [Ala] was observed along with hyperlactatemia and hyperpyruvatemia. Hyperalaninemia and hyperlactatemia was higher in HH than in HCO groups and hyperglycemia was observed only in HH group (adrenergic stimulation). In normoxic conditions [Ala] correlates positively with pyruvate. This relationship vanishes during the hypoxic and post hypoxic periods. The percentage increase of [Ala] during hypoxia was larger than that of pyruvate. These data, as well as recent reports in the literature, suggest that elevated [Ala] during hypoxia may result from increased muscular production from glycolytic pyruvate and other amino acids and decreased hepatic utilization (gluconeogenesis).     

Cardiorespiratory responses to shivering in vagotomized pigeons during normoxia and hypoxia

We measured respiratory, cardiovascular and blood gas responses to shivering during normoxia and hypoxia in five bilaterally, cervically vagotomized pigeons and compared these data with those previously reported in pigeons with intact vagi (Gleeson et al. 1986). Such neural section in birds denervates, among other receptors, the carotid bodies and intrapulmonary chemoreceptors. Normoxic breathing frequency (fR) and ventilation (VE) were decreased after vagotomy. Intact pigeons showed increases in oxygen consumption (VO2), tidal volume (VT), fR and VE during shivering. Vagotomized pigeons showed similar though slightly smaller increases in fR, VO2 and VE during shivering, but VT did not change. Normoxic heart rate was greater after vagotomy and was increased during shivering as in intact pigeons. Mean arterial blood pressure (MBPa) and stroke volume were not affected by vagotomy or shivering. At the onset of shivering both intact and vagotomized pigeons exhibited immediate increases in ventilation and heart rate. Exposure of vagotomized pigeons to hypoxic gas (fractional inspired oxygen concentration, FIO2 = 0.12) during cooling completely abolished shivering electromyogram (EMG) activity. In contrast, shivering in intact pigeons was not completely inhibited until the FIO2 fell below 0.10. We conclude that bilateral, cervical vagotomy in the pigeon causes hypoventilation and tachycardia during normoxia, but that these denervated birds are still able to rapidly effect cardiorespiratory adjustments to shivering. It is suggested that these responses are mediated mainly via afferent feedback from the shivering muscles. Hypoxia inhibits shivering in both intact and vagotomized birds and the mechanism is probably related to the reduced O2 delivery to the central structures that integrate thermoregulatory demand and coordinate appropriate responses.     

Exercise limb blood flow response to acute and chronic hypoxia in Danish lowlanders and Aymara natives

Aim: The femoral artery blood flow response to submaximal, one‐legged, dynamic, knee‐extensor exercise was determined in acute and chronic hypoxia to investigate the hypotheses that with adaptation to chronic hypoxia blood haemoglobin increases, allowing preservation of blood flow as in normoxia. Methods: Sixteen Danish lowlanders participated, in groups of six to eight, in the experiments at sea level normoxia (FiO₂ ? 0.21) and acute hypoxia (FiO₂ ? 0.11), and chronic hypoxia after ～7 and 9–10 weeks at ～5260 m altitude breathing ambient air (FiO₂ ? 0.21) or a hyperoxic gas (FiO₂ ? 0.55). The response was compared with that in six Aymara natives. Results: The haemoglobin and haematocrit increased (P < 0.003) in the lowlanders at altitude vs. at sea level by ～39 and 27% respectively; i.e. to a similar (P = ns) level as in the natives. At rest, blood flow was the same (P = ns) in the lowlanders at sea level and altitude, as in the natives at altitude. During the onset of and incremental exercise, blood flow was the same (P = ns) in the lowlanders at sea level and altitude, as in the natives at altitude. Acute hypoxia increased (P < 0.05) blood flow by ～55% during exercise in the lowlanders at sea level. Acute hyperoxia decreased (P < 0.05) blood flow by ～22–29% during exercise in the lowlanders and natives at altitude. Conclusion: In chronic hypoxia, blood haemoglobin increases, allowing normalization of the elevated exercise blood flow response in acute hypoxia, and preservation of the kinetics and steady‐state exercise blood flow as in normoxia, being similar as in the natives at altitude.     

Differential responses of respiratory nuclei to anoxia in rhythmic brain stem slices of mice

The response of the neonatal respiratory system to hypoxia is characterized by an initial increase in ventilation, which is followed within a few minutes by a depression of ventilation below baseline levels. We used the transverse medullary slice of newborn mice as a model system for central respiratory control to investigate the effects of short-lasting periods of anoxia. Extracellular population activity was simultaneously recorded from the ventral respiratory group (VRG) and the hypoglossus (XII) nucleus (a respiration-related motor output nucleus). During anoxia, respiratory frequency was modulated in a biphasic manner and phase-locked in both the VRG and the XII. The amplitude of phasic respiratory bursts was increased only in the XII and not in the VRG. This increase in XII burst amplitude commenced approximately 1 min after the anoxic onset concomitant with a transient increase in tonic activity. The burst amplitude remained elevated throughout the entire 5 min of anoxia. Inspiratory burst amplitude in the VRG, in contrary, remained constant or even decreased during anoxia. These findings represent the first simultaneous extracellular cell population recordings of two respiratory nuclei. They provide important data indicating that rhythm generation is altered in the VRG without a concomitant alteration in the VRG burst amplitude, whereas the burst amplitude is modulated only in the XII nucleus. This has important implications because it suggests that rhythm generation and motor pattern generation are regulated separately within the respiratory network.     

Neurons in the preBötzinger complex and VRG are located in proximity to arterioles in newborn mice

The constant cyclic respiratory activity in the brainstem requires an un-interrupted blood flow providing glucose and O₂ to neurons generating respiratory rhythm. Here we used a combination of classical vascular visualization techniques, and calcium imaging, to compare the microvascular structure and localization of active respiratory neurons in the brainstem of newborn mice at the level of the preBötzinger complex (PBC) and ventral respiratory group. The brainstem is supplied with perforating arteries, which enter primarily in the midline and in a circumscribed region mid-laterally in the medulla. Presumed arterioles then pass dorso-medially with a high density immediately lateral to the midline, and mid-laterally at 60% of the midline-to-lateral edge distance. Calcium imaging, using Fluo-8, AM, showed that active PBC/VRG neurons are located in the same region where a high density of arterioles is found. We conclude that the striking co-localization of medullary arterioles and the PBC/VRG could imply that respiratory neurons may derive part of their glucose and oxygen consumption directly from arterioles, and that humoral factors affecting ventilation may reach respiratory neurons by precapillary transport mechanisms.     

Altered responses of MeCP2-deficient mouse brain stem to severe hypoxia

Rett syndrome (RTT) patients suffer from respiratory arrhythmias with frequent apneas causing intermittent hypoxia. In a RTT mouse model (methyl-CpG-binding protein 2-deficient mice; Mecp2(-/y)) we recently discovered an enhanced hippocampal susceptibility to hypoxia and hypoxia-induced spreading depression (HSD). In the present study we investigated whether this also applies to infant Mecp2(-/y) brain stem, which could become life-threatening due to failure of cardiorespiratory control. HSD most reliably occurred in the nucleus of the solitary tract (NTS) and the spinal trigeminal nucleus (Sp5). HSD susceptibility of the Mecp2(-/y) NTS and Sp5 was increased on 8 mM K(+)-mediated conditioning. 5-HT(1A) receptor stimulation with 8-hydroxy-2-(di-propylamino)tetralin (8-OH-DPAT) postponed HSD by up to 40%, mediating genotype-independent protection. The deleterious impact of HSD on in vitro respiration became obvious in rhythmically active slices, where HSD propagation into the pre-B?tzinger complex (pre-B?tC) immediately arrested the respiratory rhythm. Compared with wild-type, the Mecp2(-/y) pre-B?tC was invaded less frequently by HSD, but if so, HSD occurred earlier. On reoxygenation, in vitro rhythms reappeared with increased frequency, which was less pronounced in Mecp2(-/y) slices. 8-OH-DPAT increased respiratory frequency but failed to postpone HSD in the pre-B?tC. Repetitive hypoxia facilitated posthypoxic recovery only if HSD occurred. In 57% of Mecp2(-/y) slices, however, HSD spared the pre-B?tC. Although this occasionally promoted residual hypoxic respiratory activity ("gasping"), it also prolonged the posthypoxic recovery, and thus the absence of central inspiratory drive, which in vivo would lengthen respiratory arrest. In view of the breathing disorders in RTTs, the increased hypoxia susceptibility of MeCP2-deficient brain stem potentially contributes to life-threatening disturbances of cardiorespiratory control.     

Prenatal nicotine exposure alters the response of the mouse in vitro respiratory rhythm to hypoxia

Prenatal nicotine exposure is associated with deficiencies in the ability to respond to life threatening stressors such as hypoxia. Although many of these deficiencies appear to originate from defects in the brainstem respiratory network, the specific effects of prenatal nicotine exposure on the brainstem respiratory network are not well understood. We have tested the effects of prenatal nicotine exposure on the respiratory rhythm using an in vitro mouse brainstem slice preparation containing the pre-Bötzinger Complex, a region of the ventral respiratory group that is the postulated site of inspiratory rhythm generation. We found that nicotine exposure during pre- and early postnatal development led to a lower frequency of baseline fictive respiratory discharges from rhythmic slices and a reduction in the ability of the slice to maintain a respiratory rhythm during exposure to severe hypoxia compared to controls. These impairments of the central respiratory rhythm could potentially affect the ability to survive a period of exposure to severe hypoxia in vivo.     

Reciprocal modulation of O2 and CO2 cardiorespiratory chemoreflexes in the tambaqui

This study examined the effect of acute hypoxic and hypercapnic cardiorespiratory stimuli, superimposed on existing cardiorespiratory disturbances in tambaqui. In their natural habitat, these fish often encounter periods of hypoxic hypercapnia that can be acutely exacerbated by water turnover. Tambaqui were exposed to periods of normoxia, hypoxia, hyperoxia and hypercapnia during which, externally oriented O2 and CO2 chemoreceptors were further stimulated, by administration into the inspired water of sodium cyanide and CO2-equilibrated water, respectively. Hyperoxic water increased the sensitivity of the NaCN-evoked increase in breathing frequency (f(R)) and decrease in heart rate. Hypoxia and hypercapnia attenuated the increase in f(R) but, aside from blood pressure, did not influence the magnitude of NaCN-evoked cardiovascular changes. Water PO2 influenced the magnitude of the CO2-evoked cardiorespiratory changes and the sensitivity of CO2-evoked changes in heart rate and blood flow. The results indicate that existing respiratory disturbances modulate cardiorespiratory responses to further respiratory challenges reflecting both changes in chemosensitivity and the capacity for further change.     

Central neuropeptide systems and respiratory control during development

The substance P/neurotachykinin-1 (NK-1) and the mu-opioid G protein-coupled receptor systems endow brainstem respiratory regions and display discrete developmental patterns. Hypoxia-induced neuropeptide release may increase receptor endocytosis, reducing receptor accessibility to ligands. We wondered whether the attenuated respiratory response to hypoxia of developing piglets after single (Respir. Physiol. 92 (1993a) 115) or repeated daily hypoxic exposure (J. Appl. Physiol. 83 (1997) 522) is influenced by differential endocytosis of NK-1 vs mu-opioid receptors. Whereas the long-term (24 h) response of both receptors to recurrent hypoxia in piglet brainstem is similar, i.e. upregulation, the short-term (5 min) response to single or recurrent hypoxia, albeit in rats, is different: radiolabelled NK-1 receptors are greatly reduced, suggesting enhanced endocytosis, but mu-opioid receptors remain unchanged, implying unaltered endocytosis. If confirmed in piglet brainstem, this difference would produce relatively more available mu-opioid receptors to opioid peptides in hypoxia that might contribute to the attenuated respiratory responses to single and repeated hypoxia during development.     

Axonal projections from Bötzinger expiratory neurons to contralateral ventral and dorsal respiratory groups in the cat

Summary We studied projection patterns of the augmenting expiratory neurons of the Bötzinger complex (BÖT) in the contralateral brainstem. Three experimental approaches were used: 1) electrophysiological analysis using antidromic microstimulation, and morphological analyses using 2) intraaxonal injection of HRP, and 3) application of the anterograde tracer Phaseolus vulgaris leucoagglutinin (PHA-L). Taken together, the three methods revealed morphological details of the axonal arborizations of the expiratory neurons in the BÖT and the ventral respiratory group (VRG). The majority of augmenting expiratory neurons of the BÖT had axonal collaterals in the contralateral brainstem. The stem axons to the contralateral side crossed the midline almost at the level of the cell somata. They descended dorsomedial to the ventral spinocerebellar tract and gave off collateral branches directed dorsomedially. Terminal boutons were distributed abundantly in the caudal part of the BÖT and in the more caudally situated VRG. Axon collaterals sometimes ran to the dorsal respiratory group (DRG) and distributed terminal boutons there. Together with the fact of extensive ipsilateral arborizations shown previously, the present results indicate that the augmenting expiratory neurons of the BÖT have wide bilateral influence on the BÖT, VRG, DRG, and spinal cord.Abbreviations VII facial nucleus - XII hypoglossal nucleus - AMB nucleus ambiguus - AP area postrema - CX external cuneate nucleus - D descending vestibular nucleus - DX dorsal-motor nucleus of the vagus - M medial vestibular nucleus - NTS nucleus of the solitary tract - R nucleus of Roller - S solitary tract - RFN retrofacial nucleus This paper is dedicated to Professor Hajime Mannen on the occasion of his 65th birthdaySupported by grants-in-aid for Scientific Research nos. 60304044, 62570068, 62770043, and 63570027 from the Japan Ministry of Education, Science and Culture     

Functional and structural models of pontine modulation of mechanoreceptor and chemoreceptor reflexes

The dorsolateral and ventrolateral pons (dl-pons, vl-pons) are critical brainstem structures mediating the plasticity of the Hering-Breuer mechanoreflex (HBR) and carotid chemoreflex (CCR). Review of anatomical evidence indicates that dl-pons and vl-pons are connected reciprocally with one another and with medullary nucleus tractus solitarius (NTS) and ventral respiratory group (VRG). With this structural map, functional models of HBR and CCR are proposed in which the respiratory rhythm is modulated by short-term depression (STD) or potentiation (STP) of corresponding primary NTS-VRG and auxiliary pons-VRG excitatory or inhibitory pathways. Behaviorally, STD and STP of respiratory reflexes are akin to non-associative learning such as habituation, sensitization or desensitization to afferent inputs. Computationally, the STD and STP effects amount to signal differentiation and integration in the time domain, or high-pass and low-pass filtering in the frequency domain, respectively. These functional and structural models of pontomedullary signal processing provide a novel conceptual framework that unifies a wealth of experimental observations regarding mechanoreceptor and chemoreceptor reflex control of breathing.