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Simple Summary: The hypothalamus plays a critical role in the regulation of autonomic functions, acting as a central integrator of various physiological processes. Among its many regions, the dorsomedial hypothalamus and the perifornical region are particularly significant in the control of autonomic responses. This review highlights the critical roles of the dorsomedial hypothalamus and the perifornical region in autonomic control, emphasizing their importance in cardiorespiratory function. The dorsomedial hypothalamus nucleus (DMH) plays a pivotal role in the orchestration of sympathetic nervous system activities. Through its projections to the brainstem and pontomedullary nuclei, it controls heart rate, contractility, blood pressure, and respiratory activity, such as timing and volumes. The DMH integrates inputs from higher brain centers and processes these signals in order to modulate autonomic outflow accordingly. It has been demonstrated to be of particular significance in the context of stress responses, where it orchestrates the physiological adaptations that are necessary for all adaptative responses. The perifornical region (PeF), which is closely associated with the DMH, also makes a contribution to autonomic regulation. The involvement of the PeF region in autonomic control is evidenced by its function in coordinating the autonomic and endocrine responses to stress, frequently in conjunction with the DMH. The DMH and the PeF do not function in an isolated manner; rather, they are components of a comprehensive hypothalamic network that integrates several autonomic responses. This neural network could serve as a target for developing therapeutic strategies in cardiovascular diseases. [ABSTRACT FROM AUTHOR]

The dorsomedial hypothalamus nucleus (DMH) plays a pivotal role in the orchestration of sympathetic nervous system activities. Through its projections to the brainstem and pontomedullary nuclei, it controls heart rate, contractility, blood pressure, and respiratory activity, such as timing and volumes. The DMH integrates inputs from higher brain centers and processes these signals in order to modulate autonomic outflow accordingly. It has been demonstrated to be of particular significance in the context of stress responses, where it orchestrates the physiological adaptations that are necessary for all adaptative responses. The perifornical region (PeF), which is closely associated with the DMH, also makes a contribution to autonomic regulation. The involvement of the PeF region in autonomic control is evidenced by its function in coordinating the autonomic and endocrine responses to stress, frequently in conjunction with the DMH. The DMH and the PeF do not function in an isolated manner; rather, they are components of a comprehensive hypothalamic network that integrates several autonomic responses. This neural network could serve as a target for developing therapeutic strategies in cardiovascular diseases.

Abstract Sleep‐disordered breathing is a respiratory disorder commonly experienced by pregnant women. The recurrent hypoxaemic events associated with sleep‐disordered breathing have deleterious consequences for the mother and fetus. Adult male (but not female) rats born to dams subjected to gestational intermittent hypoxia (GIH) have a higher resting blood pressure than control animals and show behavioural/neurodevelopmental disorders. The origin of this persistent, sex‐specific effect of GIH in offspring is unknown, but disruption of the neuroendocrine stress pathways is a key mechanism by which gestational stress increases disease risk in progeny. Using FosB immunolabelling as a chronic marker of neuronal activation, we determined whether GIH augments basal expression of FosB in the perikaryas of cells in the paraventricular nucleus of the hypothalamus (PVN), a key structure in the regulation of the stress response and blood pressure. From gestational day 10, female rats were subjected to GIH for 8 h/day (light phase) until the day before delivery (gestational day 21); GIH consisted of 2 min hypoxic bouts (10.5% O2) alternating with normoxia. Control rats were exposed to intermittent normoxia over the same period (GNX). At adulthood (10–15 weeks), the brains of male and female rats were harvested for FosB immunohistochemistry. In males, GIH augmented PVN FosB labelling density by 30%. Conversely, PVN FosB density in GIH females was 28% lower than that of GNX females. We conclude that GIH has persistent and sex‐specific impacts on the development of stress pathways, thereby offering a plausible mechanism by which GIH can disturb neural development and blood pressure homeostasis in adulthood.

Sleep‐disordered breathing is a respiratory disorder commonly experienced by pregnant women. The recurrent hypoxaemic events associated with sleep‐disordered breathing have deleterious consequences for the mother and fetus. Adult male (but not female) rats born to dams subjected to gestational intermittent hypoxia (GIH) have a higher resting blood pressure than control animals and show behavioural/neurodevelopmental disorders. The origin of this persistent, sex‐specific effect of GIH in offspring is unknown, but disruption of the neuroendocrine stress pathways is a key mechanism by which gestational stress increases disease risk in progeny. Using FosB immunolabelling as a chronic marker of neuronal activation, we determined whether GIH augments basal expression of FosB in the perikaryas of cells in the paraventricular nucleus of the hypothalamus (PVN), a key structure in the regulation of the stress response and blood pressure. From gestational day 10, female rats were subjected to GIH for 8 h/day (light phase) until the day before delivery (gestational day 21); GIH consisted of 2 min hypoxic bouts (10.5% O2) alternating with normoxia. Control rats were exposed to intermittent normoxia over the same period (GNX). At adulthood (10–15 weeks), the brains of male and female rats were harvested for FosB immunohistochemistry. In males, GIH augmented PVN FosB labelling density by 30%. Conversely, PVN FosB density in GIH females was 28% lower than that of GNX females. We conclude that GIH has persistent and sex‐specific impacts on the development of stress pathways, thereby offering a plausible mechanism by which GIH can disturb neural development and blood pressure homeostasis in adulthood. New Findings: What is the central question of this study? In pregnant women, sleep apnoea increases the risk of disease for the offspring at various life stages. Given that gestational stress disrupts the programming of the stress pathways, we determined whether exposing female rats to gestational intermittent hypoxia (GIH) activates hypothalamic neurons regulating the stress response in adult rats. What is the main finding and its importance? Using FosB immunolabelling as a marker of marker of neuronal activation, we showed that GIH augmented basal activation of the paraventricular nucleus of the hypothalamus in males, but not females. Disruption of the stress pathways is a new hypothesis to explain the persistent and sex‐specific impacts of GIH on offspring health. [ABSTRACT FROM AUTHOR]

Aim: Sympathoexcitation and sleep‐disordered breathing are common contributors for disease progression. Catecholaminergic neurons from the rostral ventrolateral medulla (RVLM‐C1) modulate sympathetic outflow and have anatomical projections to respiratory neurons; however, the contribution of highly selective activation of RVLM‐C1 neurons on long‐term autonomic and breathing (dys)regulation remains to be understood. Methods: To explore this relationship, a lentiviral vector carrying the light‐sensitive cation channel channelrhodopsin‐2 (LVV‐PRSX8‐ChR2‐YFP) was unilaterally injected into the RVLM of healthy rats. On the contralateral side, LVV‐PRSX8‐ChR2‐YFP was co‐injected with a specific immunotoxin (DβH‐SAP) targeted to eliminate C1 neurons. Results: Intermittent photostimulation of RVLM‐C1 in vivo, in unrestrained freely moving rats, elicited long‐term facilitation of the sympathetic drive, a rise in blood pressure and sympatho‐respiratory coupling. In addition, photoactivation of RVLM‐C1 induced long‐lasting ventilatory instability, characterized by oscillations in tidal volume and increased breathing variability, but only during non‐rapid eye movement sleep. These effects were not observed when photostimulation of the RVLM was performed in the presence of DβH‐SAP toxin. Conclusions: The finding that intermittent activation of RVLM‐C1 neurons induces autonomic and breathing dysfunction suggest that episodic stimulation of RVLM‐C1 may serve as a pathological substrate for the long‐term development of cardiorespiratory disorders. [ABSTRACT FROM AUTHOR]

We investigated the extent to which the facultative air‐breathing fish, the striped catfish (Pangasianodon hypophthalmus), uses air‐breathing to cope with aquatic hypercarbia, and how air‐breathing is influenced by the experimental exposure protocol and level of hypercarbia. We exposed individuals to severe aquatic hypercarbia (up to PwCO2 = 81 mmHg) using step‐wise and progressive exposure protocols while measuring gill ventilation rate, heart rate, mean arterial blood pressure, and air‐breathing frequency, as well as arterial blood pH and PCO2. We confirm that P. hypophthalmus is tolerant of hypercarbia. Under both protocols gill ventilation rate, heart rate, and mean arterial blood pressure were maintained near control levels even at very high CO2 levels. We observed a marked amount of individual variation in the PwCO2 at which air‐breathing was elicited, with some individuals not responding at all. The experimental protocol also influenced the onset of air‐breathing. Air‐breathing began at lower PwCO2 in the step‐wise protocol (23 ± 4.1 mmHg) compared with the progressive protocol (46 ± 7.8 mmHg). Air‐breathing was often followed by aquatic surface respiration, at higher PCO2 (71 ± 5.2 mmHg) levels. On average, the blood PCO2 was approximately 43% lower (46 ± 2.5 mmHg) than water PwCO2 (~81 mmHg) at our highest tested CO2 level. While this suggests that aerial CO2 elimination is an effective, and perhaps critical, respiratory strategy used by P. hypophthalmus to cope with severe hypercarbia, this observation may also be explained by a long lag time required for equilibration. Research Highlights: Pangasianodon hypophthalmus are tolerant of high aquatic CO2 (hypercarbia) but use air‐breathing and aquatic surface respiration to cope with severe levels.The onset of hypercarbia induced air‐breathing depends on the level and, importantly, the rate of PCO2 increase. [ABSTRACT FROM AUTHOR]

Although it is well known that neonatal sepsis can induce important alterations in cardiorespiratory control, their detailed early features and the mechanisms involved remain poorly understood. As a first step in resolving this issue, the main goal of this study was to characterize these alterations more extensively by setting up a full-term newborn lamb model of systemic inflammation using lipopolysaccharide (LPS) injection. Two 6-h polysomnographic recordings were performed on two consecutive days on eight full-term lambs: the first after an IV saline injection (control condition, CTRL); the second, after an IV injection of 2.5 μg/kg Escherichia coli LPS 0127:B8 (LPS condition). Rectal temperature, locomotor activity, state of alertness, arterial blood gases, respiratory frequency and heart rate, mean arterial blood pressure, apneas and cardiac decelerations, and heart-rate and respiratory-rate variability (HRV and RRV) were assessed. LPS injection decreased locomotor activity (p = 0.03) and active wakefulness (p = 0.01) compared to the CTRL. In addition, LPS injection led to a biphasic increase in rectal temperature (p = 0.01 at ∼30 and 180 min) and in respiratory frequency and heart rate (p = 0.0005 and 0.005, respectively), and to an increase in cardiac decelerations (p = 0.05). An overall decrease in HRV and RRV was also observed. Interestingly, the novel analysis of the representations of the horizontal and vertical visibility network yielded the most statistically significant alterations in HRV structure, suggesting its potential clinical importance for providing an earlier diagnosis of neonatal bacterial sepsis. A second goal was to assess whether the reflexivity of the autonomic nervous system was altered after LPS injection by studying the cardiorespiratory components of the laryngeal and pulmonary chemoreflexes. No difference was found. Lastly, preliminary results provide proof of principle that brainstem inflammation (increased IL-8 and TNF-α mRNA expression) can be shown 6 h after LPS injection. In conclusion, this full-term lamb model of systemic inflammation reproduces several important aspects of neonatal bacterial sepsis and paves the way for studies in preterm lambs aiming to assess both the effect of prematurity and the central neural mechanisms of cardiorespiratory control alterations observed during neonatal sepsis.

Heart rate and blood pressure oscillate in phase with respiratory activity. A component of these oscillations is generated centrally, with respiratory neurons entraining the activity of pre-sympathetic and parasympathetic cardiovascular neurons. Using a combination of optogenetic inhibition and excitation in vivo and in situ in rats, as well as neuronal tracing, we demonstrate that preBötzinger Complex (preBötC) neurons, which form the kernel for inspiratory rhythm generation, directly modulate cardiovascular activity. Specifically, inhibitory preBötC neurons modulate cardiac parasympathetic neuron activity whilst excitatory preBötC neurons modulate sympathetic vasomotor neuron activity, generating heart rate and blood pressure oscillations in phase with respiration. Our data reveal yet more functions entrained to the activity of the preBötC, with a role in generating cardiorespiratory oscillations. The findings have implications for cardiovascular pathologies, such as hypertension and heart failure, where respiratory entrainment of heart rate is diminished and respiratory entrainment of blood pressure exaggerated.

There is clear evidence of physiological effects of the gut microbiota on whole‐body function in health and disease. Microbiota–gut–brain axis signalling is recognised as a key player in behavioural disorders such as depression and anxiety. Recent evidence suggests that the gut microbiota affects neurocontrol networks responsible for homeostatic functions that are essential for life. We consider the evidence suggesting the potential for the gut microbiota to shape cardiorespiratory homeostasis. In various animal models of disease, there is an association between cardiorespiratory morbidity and perturbed gut microbiota, with strong evidence in support of a role of the gut microbiota in the control of blood pressure. Interventions that target the gut microbiota or manipulate the gut–brain axis, such as short‐chain fatty acid supplementation, prevent hypertension in models of obstructive sleep apnoea. Emerging evidence points to a role for the microbiota–gut–brain axis in the control of breathing and ventilatory responsiveness, relevant to cardiorespiratory disease. There is also evidence for an association between the gut microbiota and disease severity in people with asthma and cystic fibrosis. There are many gaps in the knowledge base and an urgent need to better understand the mechanisms by which gut health and dysbiosis contribute to cardiorespiratory control. Nevertheless, there is a growing consensus that manipulation of the gut microbiota could prove an efficacious adjunctive strategy in the treatment of common cardiorespiratory diseases, which are the leading causes of morbidity and mortality. [ABSTRACT FROM AUTHOR]

Although it is well known that neonatal sepsis can induce important alterations in cardiorespiratory control, their detailed early features and the mechanisms involved remain poorly understood. As a first step in resolving this issue, the main goal of this study was to characterize these alterations more extensively by setting up a full-term newborn lamb model of systemic inflammation using lipopolysaccharide (LPS) injection. Two 6-h polysomnographic recordings were performed on two consecutive days on eight full-term lambs: the first after an IV saline injection (control condition, CTRL); the second, after an IV injection of 2.5 μg/kg Escherichia coli LPS 0127:B8 (LPS condition). Rectal temperature, locomotor activity, state of alertness, arterial blood gases, respiratory frequency and heart rate, mean arterial blood pressure, apneas and cardiac decelerations, and heart-rate and respiratory-rate variability (HRV and RRV) were assessed. LPS injection decreased locomotor activity (p = 0.03) and active wakefulness (p = 0.01) compared to the CTRL. In addition, LPS injection led to a biphasic increase in rectal temperature (p = 0.01 at ∼30 and 180 min) and in respiratory frequency and heart rate (p = 0.0005 and 0.005, respectively), and to an increase in cardiac decelerations (p = 0.05). An overall decrease in HRV and RRV was also observed. Interestingly, the novel analysis of the representations of the horizontal and vertical visibility network yielded the most statistically significant alterations in HRV structure, suggesting its potential clinical importance for providing an earlier diagnosis of neonatal bacterial sepsis. A second goal was to assess whether the reflexivity of the autonomic nervous system was altered after LPS injection by studying the cardiorespiratory components of the laryngeal and pulmonary chemoreflexes. No difference was found. Lastly, preliminary results provide proof of principle that brainstem inflammation (increased IL-8 and TNF-α mRNA expression) can be shown 6 h after LPS injection. In conclusion, this full-term lamb model of systemic inflammation reproduces several important aspects of neonatal bacterial sepsis and paves the way for studies in preterm lambs aiming to assess both the effect of prematurity and the central neural mechanisms of cardiorespiratory control alterations observed during neonatal sepsis. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a major public health issue affecting more than 26 million people worldwide. HF is the most common cardiovascular disease in elder population; and it is associated with neurocognitive function decline, which represent underlying brain pathology diminishing learning and memory faculties. Both HF and neurocognitive impairment are associated with recurrent hospitalization episodes and increased mortality rate in older people, but particularly when they occur simultaneously. Overall, the published studies seem to confirm that HF patients display functional impairments relating to attention, memory, concentration, learning, and executive functioning compared with age-matched controls. However, little is known about the molecular mechanisms underpinning neurocognitive decline in HF. The present review round step recent evidence related to the possible molecular mechanism involved in the establishment of neurocognitive disorders during HF. We will make a special focus on cerebral ischemia, neuroinflammation and oxidative stress, Wnt signaling, and mitochondrial DNA alterations as possible mechanisms associated with cognitive decline in HF. Also, we provide an integrative mechanism linking pathophysiological hallmarks of altered cardiorespiratory control and the development of cognitive dysfunction in HF patients. [ABSTRACT FROM AUTHOR]

This review aimed to better understand the underlying physiology of the risks and benefits of bed-sharing. Eight databases were searched using terms relating to adult-infant/baby, bed-sharing/co-sleeping combined with outcome terms for physiology, sleep, cardiovascular, respiratory, temperature and behaviour. Of 836 papers identified, 59 papers representing 48 cohorts met inclusion criteria. Objective data using various methodologies were available in 27 papers and subjective data in 32 papers. Diverse measures were reported using variable definitions of bed-sharing. Identified physiological and behavioural differences between bed-sharing and cot-sleeping included increased behavioural arousals, warmer in-bed temperatures and increased breastfeeding duration in bedshare infants as well as differences in infant overnight sleep architecture, cardiorespiratory control and cortisol responses to stress. We concluded that many differences are context-specific, and dependent on the subjective view of the parents and their cultural values. Objective risk arises if the infant is unable to mount an appropriate physiological or behavioural response to their micro-environment. More studies in the bed-sharing setting are needed to identify infant risk, the potential benefits of a safer environment, and how bed-sharing interacts with infant care practices other than sleep. [ABSTRACT FROM AUTHOR]

This study was designed to determine the manner in which metabolism is suppressed during dormancy in black and white tegu lizards ( Tupinambis merianae). To this end, heart rate ( f), respiration rate ( f), and deep body temperature ( T) were continuously monitored in outdoor enclosures by radio-telemetry for nine months. There was a continuous decline in nighttime breathing and heart rate, at constant T, throughout the late summer and fall suggestive of an active metabolic suppression that developed progressively at night preceding the entrance into dormancy. During the day, however, the tegus still emerged to bask. In May, when the tegus made a behavioural commitment to dormancy, T (day and night) fell to match burrow temperature, accompanied by a further reduction in f and f. Tegus, under the conditions of this study, did arouse periodically during dormancy. There was a complex interplay between changes in f and T associated with the direct effects of temperature and the indirect effects of thermoregulation, activity, and changes in metabolism. This interplay gave rise to a daily hysteresis in the f/ T relationship reflective of the physiological changes associated with warming and cooling as preferred T alternated between daytime and nighttime levels. The shape of the hysteresis curve varied with season along with changes in metabolic state and daytime and nighttime body temperature preferences. [ABSTRACT FROM AUTHOR]

This study aimed to review available published reports concerning sudden unexpected postnatal collapse (SUPC) of apparently healthy infants within the first days of postnatal life, establish a structured presentation and delineate recommendations for preventive measures. All published reports of SUPC cases were retrospectively analyzed, and three not previously published SUPC cases at Karolinska University Hospital were detailed to exemplify the varying presentations and outcomes of SUPC. We found 398 published cases of SUPC occurring during first postnatal week. Estimated incidence of the SUPC of a presumably healthy infant after birth differs widely, ranging from 2.6 cases to 133 cases/100,000. However, definition, inclusion, and exclusion criteria vary substantially between reports. Our summary indicates that reported SUPC occurs more frequently than expected from recent surveys. About half of the infants die, and of the remaining survivors, half have neurological sequela. Of the 233 cases of sudden unexpected death described, no etiology was found in 153 cases. When a defined time for the SUPC event is described, approximately one third of reported events occur during the first 2 h, between 2 and 24 h and between 1 and 7 days after birth, respectively. Adequate education of caregivers and appropriate surveillance during the first days of newborns should enable us to save hundreds of lives. [ABSTRACT FROM AUTHOR]

The aim of the present study was to determine the roles that externally versus internally oriented CO2/H+-sensitive chemoreceptors might play in promoting cardiorespiratory responses to environmental hypercarbia in the air-breathing fish, Hoplerythrinus unitaeniatus (jeju). Fish were exposed to graded hypercarbia (1, 2.5, 5, 10 and 20% CO2) and also to graded levels of environmental acidosis (pH -7.0, 6.0, 5.8, 5.6, 5.3 and 4.7) equal to the pH levels of the hypercarbic water to distinguish the relative roles of CO2 versus H+. We also injected boluses of CO2-equilibrated solutions (5, 10 and 20% CO2) and acid solutions equilibrated to the same pH as the CO2 boluses into the caudal vein (internal) and buccal cavity (external) to distinguish between internal and external stimuli. The putative location of the chemoreceptors was determined by bilateral denervation of branches of cranial nerves IX (glossopharyngeal) and X (vagus) to the gills. The data indicate that the chemoreceptors eliciting bradycardia, hypertension and gill ventilatory responses (increased frequency and amplitude) to hypercarbia are exclusively branchial, externally oriented and respond specifically to changes in CO2 and not H+. Those involved in producing the cardiovascular responses appeared to be distributed across all gill arches while those involved in the gill ventilatory responses were located primarily on the first gill arch. Higher levels of aquatic CO2 depressed gill ventilation and stimulated air breathing. The chemoreceptors involved in producing air breathing in response to hypercarbia also appeared to be branchial, distributed across all gill arches and responded specifically to changes in aquatic CO2. This would suggest that chemoreceptor groups with different orientations (blood versus water) are involved in eliciting air-breathing responses to hypercarbia in jeju. [ABSTRACT FROM AUTHOR]

In one series of experiments, heart frequency ( fH), blood pressure ( Pa), gill ventilation frequency ( f R), ventilation amplitude ( VAMP) and total gill ventilation ( VTOT) were measured in intact jeju ( Hoplerythrinus unitaeniatus) and jeju with progressive denervation of the branchial branches of cranial nerves IX (glossopharyngeal) and X (vagus) without access to air. When these fish were submitted to graded hypoxia (water PO2 ~140, normoxia to 17 mmHg, severe hypoxia), they increased f R, VAMP, VTOT and Pa and decreased fH. In a second series of experiments, air-breathing frequency ( fRA), measured in fish with access to the surface, increased with graded hypoxia. In both series, bilateral denervation of all gill arches eliminated the responses to graded hypoxia. Based on the effects of internal (caudal vein, 150 μg NaCN in 0.2 mL saline) and external (buccal) injections of NaCN (500 μg NaCN in 1.0 mL water) on f R, VAMP, VTOT, Pa and fH we conclude that the O2 receptors involved in eliciting changes in gill ventilation and associated cardiovascular responses are present on all gill arches and monitor the O2 levels of both inspired water and blood perfusing the gills. We also conclude that air breathing arises solely from stimulation of branchial chemoreceptors and support the hypothesis that internal hypoxaemia is the primary drive to air breathing. [ABSTRACT FROM AUTHOR]

Abstract: The localization, distribution and orientation of O2 chemoreceptors associated with the control of cardio-respiratory responses were investigated in the neotropical, Hoplias lacerdae. Selective denervation of the cranial nerves (IX and X) was combined with chemical stimulation (NaCN) to characterize the gill O2 chemoreceptors, and the fish were then exposed to gradual hypoxia to examine the extent of each cardio-respiratory response. Changes in heart rate (f H) and ventilation amplitude (V amp) were allied with chemoreceptors distributed on both internal and external surfaces of all gill arches, while ventilation rate (f R) was allied to the O2 chemoreceptors located only in the internal surface of the first gill arch. H. lacerdae exposed to gradual hypoxia produced a marked bradycardia (45%) and 50% increase in V amp, but only a relatively small change in f R (32%). Thus, the low f R response yet high V amp were in accord with the characterization of the O2 chemoreceptors. Comparing these results from H. lacerdae with hypoxia-tolerant species revealed a relationship existent between general oxygenation of the individual species environment, its cardio-respiratory response to hypoxia and the characterization of O2 chemoreceptors. [Copyright &y& Elsevier]

Abstract: Encoding of sensory information by nucleus of the solitary tract (NTS) neurons is incompletely understood. Using extracellular single-unit recording in α-chloralose-urethane anesthetized cats, we have examined the discharge characteristics of NTS neurons to activation of somatic Aδ and C fiber afferents by skeletal muscle contraction evoked by electrical stimulation of lower lumbar/upper sacral ventral roots. Generally, somatic afferent stimulation evoked two distinct firing patterns. The first population (36/43 cells) increased their firing rate to brief somatic stimuli. A subset (21/27 cells) exhibited a rapid decay of their firing rate during sustained somatic stimulation. Peak instantaneous firing frequency (F p) increased proportionally with the intensity of somatic stimulation (105±4 vs. 119±4 vs. 139±4 Hz, 10, 20 and 40 Hz, respectively, P<0.0001), whereas steady-state firing frequency (F ss) was not altered (25±2 vs. 27±2 vs. 27±2 Hz, 10, 20 and 40 Hz, respectively, P=0.72). Two indices were derived to quantify the decay properties. The decay rate constant (obtained from exponential curve fitting) was not altered by stimulation frequency (461±10 vs. 442±14 vs. 429±26 ms, 10, 20 and 40 Hz, respectively, P=0.415), nor was the decay index (derived to express the percent reduction in firing rate with respect to the initial peak firing rate; 76±2 vs. 77±2 vs. 81±2%, 10, 20 and 40 Hz, respectively, P=0.187). In contrast, the second population (seven of 43 cells) decreased their firing rate to stimulation. Of the NTS neurons tested for barosensitivity (29/36), none responded to pressure stimulation. These results have identified a population of somatosensitive NTS neurons that exhibit rapid firing rate decay properties during sustained stimulation. However, this population could faithfully encode phasic excitation during rhythmic somatosensory input. These results are discussed in relation to the role of somatosensory input on baroreflex function. [Copyright &y& Elsevier]

Heart rate variability (HRV) at rest and heart rate recovery after exercise reflect cardiac vagal activity. The aim of this study was to determine whether increasing HRV during involuntary respiratory training induced by rebreathing air using a Hepburn heart and lung exerciser (HHALE) could, like exercise, improve vagal tone. Eighteen subjects (36–88 years) underwent a 6-week control period, then a 6-week training period with the HHALE following which half continued training for 6 weeks and half ceased training. Measurements were made of HRV, work at 60% predicted heart rate max for 15 min, heart rate recovery after exercise, resting blood pressure, heart rate, vital capacity and forced expiratory volume. After the first 6-week HHALE training, there was a significant increase of 13.2±5.7 ν in the high frequency peak of the power spectrum of HRV at rest, whereas, the low frequency peak decreased. Similarly, exercise performance showed a significant improvement of 0.031±0.012 J per heartbeat from a pre-training 0.128±0.022. Also, heart rate recovery after exercise significantly faster (drop in the first 20 s improving by 3.3±1.5 beats from a pre-training 12.9±1.6). The subgroup that continued training maintained or slightly improved these values. In those that ceased training the speed of heart rate recovery at the end of the exercise test returned to pre-trained levels, whereas, other responses were either maintained or decreased slightly. We conclude that training with the HHALE can, without additional exercise, increase cardiac vagal tone and exercise performance. [ABSTRACT FROM AUTHOR]

Despite being obligate air breathers, many species of marine mammal are capable of spending most of their lives submerged in water. How they do this has been a subject of intense interest to physiologists for over a century, yet we still do not have a detailed understanding of the physiological mechanisms underlying this behaviour. What are the proximate mechanisms that trigger the ‘decisions’ to submerge and return to the surface? The present study proposes a model intended to address this question, based on fundamental concepts of cardiorespiratory control. Two basic hypotheses are examined by computer simulation, using a mathematical model of the mammalian cardiorespiratory control system with parameter values for an adult Weddell seal: (1) that the control of diving can be considered to be a respiratory control problem, and (2) that dives are initiated and maintained by disfacilitation of respiratory drive, not inhibition. Computer simulations confirmed the plausibility of these hypotheses. Simulated diving behaviour and physiological responses (ventilation, cardiac output, blood and tissue gas tensions) were consistent with published data from freely diving Weddell seals. Dives up to the estimated aerobic dive limit (ADL, 18–25 min) could be simulated without the need for active inhibition of breathing in this model. This theoretical analysis suggests that the most important physiological adjustments occur during the surface interval phase of the dive cycle and include hyperventilation accompanied by high cardiac output, appropriate regulation of cerebral blood flow and central chemoreceptor threshold shifts. During dives, cardiac output, distribution of peripheral blood flow, splenic contraction and peripheral chemoreflex drives were found to modulate physiological and behavioural responses, but were not essential for simulated dives to occur. The main conclusion from this study is that the central chemoreceptor may be an important mechanism involved in the regulation of diving behaviour, implying that CO2, not O2, is the key regulatory variable in this model. This model includes and extends the ADL concept and suggests an explicit mechanism by which the respiratory control system may play a central role in the regulation of diving behaviour. It is likely that respiratory mechanisms are an important component of a hierarchical behavioural control system and further studies are required to test the qualitative and quantitative validity of the model. [ABSTRACT FROM AUTHOR]

During the nursing period seals undergo several physiological and behavioural changes. A key component of development is increased cardiorespiratory control, fundamental for breath-holding and thus diving. This study focused on the ontogenetic changes in cardiac responses to respiration in quietly resting, pre-weaned harbour seal pups (Phoca vitulina). During periods of quiet rest, breathing became episodic, eupnoea interspersed with periods of apnoea. Little change was observed in respiration (∼35 breaths min-1) and eupnoeic heart rate (∼160 beats min-1) throughout the nursing period. However, apnoea duration increased (from ∼20 to 40 s), while apnoeic heart rate decreased with age (from ∼150 to 90 beats min-1). The observed decline in apnoeic heart rate resulted from an increase in cardiorespiratory control as pups approached weaning, evident by the ability to maintain a lower heart rate more consistently. Similar changes in cardiorespiratory patterns have been reported for elephant and Weddell seals. Due to the early onset of independent foraging, however, the rate of cardiorespiratory control development was more rapid in harbour seals. Our findings suggest that by 1 month of age, harbour seal pups possess the cardiorespiratory control necessary to sustain long-duration apnoeas, fundamental for proficient diving and successful foraging upon weaning. [ABSTRACT FROM AUTHOR]

Summary. The postnatal development of tyrosine hydroxylase activity has been studied in the brainstem catecholaminergic cell groups (A1C1, A2C2, A5, A6, A7), involved in cardiorespiratory control. In rat, at birth and at postnatal days P3, P7, P14, P21 ant P68, we used a microdissection technique followed by in vivo measurement of the tyrosine hydroxylase (TH) activity, the rate-limiting enzyme in catecholamine synthesis. There is two successive marked increases in TH activity: at P3 in every catecholaminergic cell groups (A1C1, +225%; A2C2, +300%; A5, +190%; A6, +205% compared to birth) and during the third postnatal week with a peak of TH activity at P14 (A6, +90% above the P7 level) or at P21 (A1C1, +715%; caudal A2C2, +585%; rostral A2C2, +15%; A5, +445%; A7, +180% compared to P7). The data suggest the existence of two temporal windows during the neurochemical development of the catecholaminergic cell groups, which correspond to two metabolic transitions. The first one could be related to the intra-, extrauterine transition and the second one, to a deep energetic phase of maturation in the rat brain, closely related to the maturation of cardiorespiratory processes. [ABSTRACT FROM AUTHOR]

The present report describes a novel rhythmically active brainstem slice preparation that generates respiratory activity spontaneously in both mice and rats of varying maturational states. The brainstems of neonatal (0-4 days) and mature (3-8 weeks) mice and rats were isolated and a 600- to 750-μm thick slice cut to include the dorsomedial and the ventrolateral regions of the complete rostro-caudal extent of the medulla. This plane of section we have termed ' tilted-sagittal'. Rhythmically discharging neurones were recorded extracellularly from both the dorsal and ventral regions of the slice. The recording sites of these neurones were found in the hypoglossal motonucleus (XII) and in areas of the ventrolateral medulla that includes the ventral respiratory group (VRG) region. Histological examination revealed the preservation of neuronal structures important for cardiorespiratory regulation and reflex control including the nucleus of the solitary tract as well as the nucleus ambiguus. In addition, pontine structures including the A5 region were also preserved. Rhythmic activity was found only in slices where the ambiguual column was preserved in its entirety. The mean frequency of discharge of XII neurones was 20 and 10 bursts per minute in neonates and mature rodents respectively. In preparations of mature animals we demonstrate that this frequency increased significantly ( P<0.05) by either raising temperature from 29°C to 38°C (54%), elevating extracellular potassium concentration from 4 to 7.5 mM (52%), blocking potassium channels (20%) or decreasing pH from 7.4 to 7.0 (18%). The burst duration to frequency ratio of XII and VRG rhythmic neurones was similar and therefore indicative of a common brainstem oscillator. Consistent with this finding was that rhythmic activity in the VRG persisted despite removal of the dorsomedial region of the slice. In contrast, rhythmic XII neurones became tonic following mechanical disconnection of the VRG. [ABSTRACT FROM AUTHOR]

A comprehensive model of oxygen (O2) and carbon dioxide (CO2) exchange, transport, and storage in the adult human is presented, and its ability to provide realistic responses under different physiological conditions is evaluated. The model comprises three compartments ( i.e., lung, body tissue, and brain tissue) and incorporates a controller that adjusts alveolar ventilation and cardiac output dynamically integrating stimuli coming from peripheral and central chemoreceptors. A new realistic CO2 dissociation curve based on a two-buffer model of acid-base chemical regulation is included. In addition, the model explicitly considers relevant physiological factors such as buffer base, the nonlinear interaction between the O2 and CO2 chemoreceptor responses, pulmonary shunt, dead space, variable time delays, and Bohr and Haldane effects. Model simulations provide results consistent with both dynamic and steady-state responses measured in subjects undergoing inhalation of high CO2 (hypercapnia) or low O2 (hypoxia) and subsequent recovery. An analysis of the results indicates that the proposed model fits the experimental data of ventilation and gas partial pressures as some meaningful simulators now available and in a very large range of gas intake fractions. Moreover, it also provides values of blood concentrations of CO2, HCO− 3, and hydrogen ions in good agreement with more complex simulators characterized by an implicit formulation of the CO2 dissociation curve. In the experimental conditions analyzed, the model seems to represent a single theoretical framework able to appropriately describe the different phenomena involved in the control of respiration. [ABSTRACT FROM AUTHOR]

Autoresuscitation is an important cardiorespiratory protective mechanism that allows neonatal mammals to recover from primary apnea. It begins with hypoxia-induced gasping and ends, if successful, with the recovery of rhythmic breathing and normal heart rate. Many factors influence the efficacy of autoresuscitation, including the availability of serotonin (5-HT) in the brain. Since the early 2000's, there has been mounting interest in the role of 5-HT in promoting autoresuscitation, driven in large part by the recognition that both failed autoresuscitation and a deficiency of central 5-HT correlate with Sudden Infant Death Syndrome in humans. Within this timeframe, newly developed animal models with a central 5-HT deficiency have examined experimentally the role of 5-HT in autoresuscitation capability. The purpose of this review is to discuss some of the methodological considerations associated with 5-HT-deficient animal models, to summarize major findings arising from their use, and to highlight several key issues related to 5-HT involvement in gasping and the autoresuscitation response. [ABSTRACT FROM AUTHOR]

The article discuses a study which investigates the neural control of breathing and circulation in animal models. It highlights the major role of carotid chemoreflex to cardiorespiratory control in chronic obstructive pulmonary disease (COPD). Advanced pharmacotherapy for asthma and successful carotid chemoreceptor removal, is also emphasized.

Several studies demonstrate that, within the ventral medullary surface (VMS), excitatory amino acids are necessary components of the neural circuits involved in the tonic and reflex control of respiration and circulation. In the present study we investigated the cardiorespiratory effects of unilateral microinjections of the broad spectrum glutamate antagonist kynurenic acid (2 nmol/200 nl) along the VMS of urethane-anesthetized rats. Within the VMS only one region was responsive to this drug. This area includes most of the intermediate respiratory area, partially overlapping the rostral ventrolateral medulla (IA/RVL). When microinjected into the IA/RVL, kynurenic acid produced a respiratory depression, without changes in mean arterial pressure or heart rate. The respiratory depression observed was characterized by a decrease in ventilation, tidal volume and mean inspiratory flow and an increase in respiratory frequency. Therefore, the observed respiratory depression was entirely due to a reduction in the inspiratory drive. Microinjections of vehicle (200 nl of saline) into this area produced no significant changes in breathing pattern, blood pressure or heart rate. Respiratory depression in response to the blockade of glutamatergic receptors inside the rostral VMS suggests that neurons at this site have an endogenous glutamatergic input controlling the respiratory cycle duration and the inspiratory drive transmission.

Heart rate and blood pressure oscillate in phase with respiratory activity. A component of these oscillations is generated centrally, with respiratory neurons entraining the activity of pre-sympathetic and parasympathetic cardiovascular neurons. Using a combination of optogenetic inhibition and excitation in vivo and in situ in rats, as well as neuronal tracing, we demonstrate that preBötzinger Complex (preBötC) neurons, which form the kernel for inspiratory rhythm generation, directly modulate cardiovascular activity. Specifically, inhibitory preBötC neurons modulate cardiac parasympathetic neuron activity whilst excitatory preBötC neurons modulate sympathetic vasomotor neuron activity, generating heart rate and blood pressure oscillations in phase with respiration. Our data reveal yet more functions entrained to the activity of the preBötC, with a role in generating cardiorespiratory oscillations. The findings have implications for cardiovascular pathologies, such as hypertension and heart failure, where respiratory entrainment of heart rate is diminished and respiratory entrainment of blood pressure exaggerated., Competing Interests: CM, AC, JB, MM, SL, JK, NK, SM, SM, AA No competing interests declared, (© 2020, Menuet et al.)

Background: Carotid body (peripheral oxygen sensor) sensitisation is pivotal in the development of chronic intermittent hypoxia (CIH)-induced hypertension. We sought to determine if exposure to CIH, modelling human sleep apnoea, adversely affects cardiorespiratory control in guinea-pigs, a species with hypoxia-insensitive carotid bodies. We reasoned that CIH-induced disruption of gut microbiota would evoke cardiorespiratory morbidity., Methods: Adult male guinea-pigs were exposed to CIH (6.5% O 2 at nadir, 6 cycles.hour -1 ) for 8 h.day -1 for 12 consecutive days., Findings: CIH-exposed animals established reduced faecal microbiota species richness, with increased relative abundance of Bacteroidetes and reduced relative abundance of Firmicutes bacteria. Urinary corticosterone and noradrenaline levels were unchanged in CIH-exposed animals, but brainstem noradrenaline concentrations were lower compared with sham. Baseline ventilation was equivalent in CIH-exposed and sham animals; however, respiratory timing variability, sigh frequency and ventilation during hypoxic breathing were all lower in CIH-exposed animals. Baseline arterial blood pressure was unaffected by exposure to CIH, but β-adrenoceptor-dependent tachycardia and blunted bradycardia during phenylephrine-induced pressor responses was evident compared with sham controls., Interpretation: Increased carotid body chemo-afferent signalling appears obligatory for the development of CIH-induced hypertension and elevated chemoreflex control of breathing commonly reported in mammals, with hypoxia-sensitive carotid bodies. However, we reveal that exposure to modest CIH alters gut microbiota richness and composition, brainstem neurochemistry, and autonomic control of heart rate, independent of carotid body sensitisation, suggesting modulation of breathing and autonomic homeostasis via the microbiota-gut-brainstem axis. The findings have relevance to human sleep-disordered breathing., Funding: The Department of Physiology, and APC Microbiome Ireland, UCC., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)