REGULATION OF BREATHING IN A WIDE RANGE OF PHYSICAL ACTIVITIES

In modern physiology, very simplified perceptions of such an essential system for the body as the respiratory system have taken root. The system analysis showed that at a physical load of more than 50 W, the tissue respiratory subsystem is activated, providing a volume blood flow rate adequate to the amount of oxygen consumed, and in the external respiratory subsystem the regulation on oxygen voltage in arterial blood is activated, and the regulation on carbon dioxide voltage is deactivated. The role of respiratory frequency in increasing the rate of diffusion through the alveolar capillary membrane is shown. For physiologists, medical professionals and trainers.

Respiratory and cardiovascular systems

‘Respiratory and cardiovascular systems’ begins with the anatomy of the thoracic cavity, including the lungs, skeletal tissue, and soft tissue, before consideration of the two main physiological components of the thorax: the pulmonary and cardiovascular systems. The main structures of the pulmonary system are discussed (pleura and pleural cavities, the upper and lower airways), together with respiratory mechanics, the principles of gaseous exchange and gas transport in the blood, the relationships between ventilation and perfusion, and the regulation of breathing. Major respiratory conditions and diseases are also covered, such as cystic fibrosis, pulmonary embolism, asthma, and the effect of altitude. The cardiovascular system topics includes blood physiology (haematology and haemostasis) and the heart in terms of anatomy, its function as a pump, and the nature of the heart as an electrical tissue (the electrocardiogram). The function of the heart is discussed, including during exercise and in diseases such as heart failure and hypertension.

CO 2 sensing by connexin26 and its role in the control of breathing

Breathing is essential to provide the O 2 required for metabolism and to remove its inevitable CO 2 by-product. The rate and depth of breathing is controlled to regulate the excretion of CO 2 to maintain the pH of arterial blood at physiological values. A widespread consensus is that chemosensory cells in the carotid body and brainstem measure blood and tissue pH and adjust the rate of breathing to ensure its homeostatic regulation. In this review, I shall consider the evidence that underlies this consensus and highlight historical data indicating that direct sensing of CO 2 also plays a significant role in the regulation of breathing. I shall then review work from my laboratory that provides a molecular mechanism for the direct detection of CO 2 via the gap junction protein connexin26 (Cx26) and demonstrates the contribution of this mechanism to the chemosensory regulation of breathing. As there are many pathological mutations of Cx26 in humans, I shall discuss which of these alter the CO 2 sensitivity of Cx26 and the extent to which these mutations could affect human breathing. I finish by discussing the evolution of the CO 2 sensitivity of Cx26 and its link to the evolution of amniotes.

A Panting Consciousness: Beckett, Breath, and Biocognitive Feedback

Booming Western interest in mindfulness and meditation has significantly mainstreamed breath and breathing practices, where focussed breathing is taken to be conducive to novel psychological states. Thanks to the regulation of breathing patterns, patterns in our thinking are not just affected but revealed, together with their entanglement with respiration (in a variety of looping effects here considered as ‘biocognitive feedback’). What makes this reciprocal feedback possible is the structural intimacy and co-dependency of breath and consciousness—a dyadic and dynamic relationship already conceptualised by William James, and today reappraised by contemporary, Buddhist-inspired cognitive sciences. Critically integrating psychological, cognitive, phenomenological, and narratological frameworks, this essay investigates the co-dependent intimacy between breath and cognition as represented, explored, and complicated in the narrative work of Samuel Beckett.

REGULATION OF BREATHING IN THE EXTENDED RANGE

In modern physiology, very simplified perceptions of such an essential system for the body as the respiratory system have taken root. The system analysis showed that at a physical load of more than 50 W, the tissue respiratory subsystem is activated, providing a volume blood flow rate adequate to the amount of oxygen consumed, and in the external respiratory subsystem the regulation on oxygen voltage in arterial blood is activated, and the regulation on carbon dioxide voltage is deactivated. The role of respiratory frequency in increasing the rate of diffusion through the alveolar capillary membrane is shown.

Connexin26 mediates CO2-dependent regulation of breathing via glial cells of the medulla oblongata

Breathing is highly sensitive to the PCO2 of arterial blood. Although CO2 is detected via the proxy of pH, CO2 acting directly via Cx26 may also contribute to the regulation of breathing. Here we exploit our knowledge of the structural motif of CO2-binding to Cx26 to devise a dominant negative subunit (Cx26DN) that removes the CO2-sensitivity from endogenously expressed wild type Cx26. Expression of Cx26DN in glial cells of a circumscribed region of the mouse medulla - the caudal parapyramidal area – reduced the adaptive change in tidal volume and minute ventilation by approximately 30% at 6% inspired CO2. As central chemosensors mediate about 70% of the total response to hypercapnia, CO2-sensing via Cx26 in the caudal parapyramidal area contributed about 45% of the centrally-mediated ventilatory response to CO2. Our data unequivocally link the direct sensing of CO2 to the chemosensory control of breathing and demonstrates that CO2-binding to Cx26 is a key transduction step in this fundamental process.

Connexin26 mediates CO2-dependent regulation of breathing via glial cells of the medulla oblongata

Breathing is highly sensitive to the PCO2 of arterial blood. Although CO2 is detected via the proxy of pH, CO2 acting directly via Cx26 may also contribute to the regulation of breathing. Here we exploit our knowledge of the structural motif of CO2-binding to Cx26 to devise a dominant negative subunit (Cx26DN) that removes the CO2-sensitivity from endogenously expressed wild type Cx26. Expression of Cx26DN in glial cells of a circumscribed region of the medulla - the caudal parapyramidal area – reduced the adaptive change in tidal volume and minute ventilation by approximately 30% at 6% inspired CO2. As central chemosensors mediate about 70% of the total response to hypercapnia, CO2-sensing via Cx26 in the caudal parapyramidal area contributed about 45% of the centrally-mediated ventilatory response to CO2. Our data unequivocally links the direct sensing of CO2 to the chemosensory control of breathing and demonstrates that CO2-binding to Cx26 is a key transduction step in this fundamental process.

Identification of a novel breathing circuit that controls pain and anxiety

Alleviating pain with controlled breathing has been practiced throughout human history. Despite its wide use and long history, a neural circuit-based understanding of the pain-breathing interaction is largely lacking. Here we report a novel breathing circuit that regulates non-homeostatic breathing rhythm, as well as pain and anxiety. We identify that a cluster of neurons expressing the Oprm1 gene, which encodes the μ-opioid receptor (MOR) in the lateral subdivision of parabrachial nucleus (PBLOprm1), directly regulates breathing rate in mice by conveying signals from the limbic areas to respiratory rhythm generating neurons in the medullary preBötzinger Complex (preBötC). In addition, we found that pain signals rapidly increase breathing rate by activating these neurons in both awake and anesthetized mice. Inactivating these neurons not only decreases the breathing rate, but it also substantially decreases anxiety-like behaviors and induces strong appetitive behaviors. Furthermore, PBLOprm1 inactivation alleviates pain by attenuating the perception of the affective-motivational aspect of pain. These results suggest that PBLOprm1 neurons play a critical role in the non-homeostatic regulation of breathing and in the regulation of pain and anxiety through breathing.

Acute O2 sensing through HIF2α-dependent expression of atypical cytochrome oxidase subunits in arterial chemoreceptors

Acute cardiorespiratory responses to O2 deficiency are essential for physiological homeostasis. The prototypical acute O2-sensing organ is the carotid body, which contains glomus cells expressing K+ channels whose inhibition by hypoxia leads to transmitter release and activation of nerve fibers terminating in the brainstem respiratory center. The mechanism by which changes in O2 tension modulate ion channels has remained elusive. Glomus cells express genes encoding HIF2α (Epas1) and atypical mitochondrial subunits at high levels, and mitochondrial NADH and reactive oxygen species (ROS) accumulation during hypoxia provides the signal that regulates ion channels. We report that inactivation of Epas1 in adult mice resulted in selective abolition of glomus cell responsiveness to acute hypoxia and the hypoxic ventilatory response. Epas1 deficiency led to the decreased expression of atypical mitochondrial subunits in the carotid body, and genetic deletion of Cox4i2 mimicked the defective hypoxic responses of Epas1-null mice. These findings provide a mechanistic explanation for the acute O2 regulation of breathing, reveal an unanticipated role of HIF2α, and link acute and chronic adaptive responses to hypoxia.