Respiratory activities are produced by medullary respiratory rhythm generators and are modulated from various sites in the lower brainstem, and which are then output as motor activities through premotor efferent networks in the brainstem and spinal cord. Over the past few decades, new knowledge has been accumulated on the anatomical and physiological mechanisms underlying the generation and regulation of respiratory rhythm. In this review, we focus on the recent findings and attempt to elucidate the anatomical and functional mechanisms underlying respiratory control in the lower brainstem and spinal cord.

The anatomical structure of central respiratory chemoreceptors in the superficial ventral medulla of rats was studied by using hypercapnia-induced c- foslabeling to identify cells directly stimulated by extracellular pH or Pco ₂. The distribution of c- fos-positive cells was found to be predominantly perivascular to surface vessels. In the superficial ventral medullary midline, parapyramidal, and ventrolateral regions where c- fos-positive cells were concentrated, we found a common, characteristic, anatomical architecture. The medullary surface showed an indentation covered by a surface vessel, and the marginal glial layer was thickened. We classified c- fos-positive cells into two types. One (type I cell) was small, was located inside the marginal glial layer and close to the medullary surface, and surrounded fine vessels. The other (type II cell) was large and located dorsal to the marginal glial layer. c- fos Expression under synaptic blockade suggested that type I cells are intrinsically chemosensitive. The chemosensitivity of surface cells (possible type I cells) surrounding vessels was confirmed electrophysiologically in slice preparations. We suggest that this characteristic anatomical structure may be the central chemoreceptor.

Key points: Autonomic respiratory rhythm is essential to maintain lives and is generated in the lower brainstem. The ventrolateral medullary region, called the pre‐Bötzinger complex (preBötC), is the kernel for respiratory rhythm generation. Despite previous extensive studies focusing on neurons, the mechanism of how respiratory rhythm is generated has not been fully understood. Here we show that non‐neuronal glial cells (a subset of putative astrocytes) in the preBötC are periodically activated preceding inspiratory neuronal activity, periodic activity of putative astrocytes persists during blockade of neuronal activity, and stimulation of astrocytes in the preBötC induces inspiratory neuronal firings. These findings together with the previous report that blockade of astrocytic metabolism abolishes inspiratory neural output suggest that astrocytes are functionally involved in respiratory rhythm generation. These results will help us better understand how respiratory rhythm is generated and how respiratory output is disturbed in various pathological conditions. Abstract  The neural inspiratory activity originates from a ventrolateral medullary region called the pre‐Bötzinger complex (preBötC), yet the mechanism underlying respiratory rhythmogenesis is not completely understood. Recently, the role of not only neurons but astrocytes in the central respiratory control has attracted considerable attention. Here we report our discovery that an intracellular calcium rise in a subset of putative astrocytes precedes inspiratory neuronal firing in rhythmically active slices. Functional calcium imaging from hundreds of preBötC cells revealed that a subset of putative astrocytes exhibited rhythmic calcium elevations preceding inspiratory neuronal activity with a time lag of approximately 2 s. These preinspiratory putative astrocytes maintained their rhythmic activities even during the blockade of neuronal activity with tetrodotoxin, whereas the rhythm frequency was lowered and the intercellular phases of these rhythms were decoupled. In addition, optogenetic stimulation of preBötC putative astrocytes induced firing of inspiratory neurons. These findings raise the possibility that astrocytes in the preBötC are actively involved in respiratory rhythm generation in rhythmically active slices.

In the field of respiratory clinical practice, the importance of measuring carbon dioxide (CO₂) concentrations cannot be overemphasized. Within the body, assessment of the arterial partial pressure of CO₂ (PaCO₂) has been the gold standard for many decades. Non-invasive assessments are usually predicated on the measurement of CO₂ concentrations in the air, usually using an infrared analyzer, and these data are clearly important regarding climate changes as well as regulations of air quality in buildings to ascertain adequate ventilation. Measurements of CO₂ production with oxygen consumption yield important indices such as the respiratory quotient and estimates of energy expenditure, which may be used for further investigation in the various fields of metabolism, obesity, sleep disorders, and lifestyle-related issues. Measures of PaCO₂ are nowadays performed using the Severinghaus electrode in arterial blood or in arterialized capillary blood, while the same electrode system has been modified to enable relatively accurate non-invasive monitoring of the transcutaneous partial pressure of CO₂ (PtcCO₂). PtcCO₂ monitoring during sleep can be helpful for evaluating sleep apnea syndrome, particularly in children. End-tidal PCO₂ is inferior to PtcCO₂ as far as accuracy, but it provides breath-by-breath estimates of respiratory gas exchange, while PtcCO₂ reflects temporal trends in alveolar ventilation. The frequency of monitoring end-tidal PCO₂ has markedly increased in light of its multiple applications (e.g., verify endotracheal intubation, anesthesia or mechanical ventilation, exercise testing, respiratory patterning during sleep, etc.).