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The carotid body (CB) is a bilateral arterial chemoreceptor located in the carotid artery bifurcation with an essential role in cardiorespiratory homeostasis. It is composed of highly perfused cell clusters, or glomeruli, innervated by sensory fibers. Glomus cells, the most abundant in each glomerulus, are neuron-like multimodal sensory elements able to detect and integrate changes in several physical and chemical parameters of the blood, in particular O2 tension, CO2 and pH, as well as glucose, lactate, or blood flow. Activation of glomus cells (e.g., during hypoxia or hypercapnia) stimulates the afferent fibers which impinge on brainstem neurons to elicit rapid compensatory responses (hyperventilation and sympathetic activation). This chapter presents an updated view of the structural organization of the CB and the mechanisms underlying the chemosensory responses of glomus cells, with special emphasis on the molecular processes responsible for acute O2 sensing. The properties of the glomus cell-sensory fiber synapse as well as the organization of CB output are discussed. The chapter includes the description of recently discovered CB stem cells and progenitor cells, and their role in CB growth during acclimatization to hypoxemia. Finally, the participation of the CB in the mechanisms of disease is briefly discussed.Widespread appreciation that neuroplasticity is an essential feature of the neural system controlling breathing has emerged only in recent years. In this chapter, we focus on respiratory motor plasticity, with emphasis on the phrenic motor system. First, we define related but distinct concepts neuromodulation and neuroplasticity. We then focus on mechanisms underlying two well-studied models of phrenic motor plasticity (1) phrenic long-term facilitation following brief exposure to acute intermittent hypoxia; and (2) phrenic motor facilitation after prolonged or recurrent bouts of diminished respiratory neural activity. Advances in our understanding of these novel and important forms of plasticity have been rapid and have already inspired translation in multiple respects (1) development of novel therapeutic strategies to preserve/restore breathing function in humans with severe neurological disorders, such as spinal cord injury and amyotrophic lateral sclerosis; and (2) the discovery that similar plasticity also occurs in nonrespiratory motor systems. Indeed, the realization that similar plasticity occurs in respiratory and nonrespiratory motor neurons inspired clinical trials to restore leg/walking and hand/arm function in people living with chronic, incomplete spinal cord injury. Similar application may be possible to other clinical disorders that compromise respiratory and non-respiratory movements.The phrenic neuromuscular system consists of the phrenic motor nucleus in the mid-cervical spinal cord, the phrenic nerve, and the diaphragm muscle. This motor system helps sustain breathing throughout life, while also contributing to posture, coughing, swallowing, and speaking. The phrenic nerve contains primarily efferent phrenic axons and afferent axons from diaphragm sensory receptors but is also a conduit for autonomic fibers. On a breath-by-breath basis, rhythmic (inspiratory) depolarization of phrenic motoneurons occurs due to excitatory bulbospinal synaptic pathways. Further, a complex propriospinal network innervates phrenic motoneurons and may serve to coordinate postural, locomotor, and respiratory movements. The phrenic neuromuscular system is impacted in a wide range of neuromuscular diseases and injuries. Contemporary research is focused on understanding how neuromuscular plasticity occurs in the phrenic neuromuscular system and using this information to optimize treatments and rehabilitation strategies to improve breathing and related behaviors.Airway function is under constant neurophysiological control, in order to maximize airflow and gas exchange and to protect the airways from aspiration, damage, and infection. There are multiple sensory nerve subtypes, whose disparate functions provide a wide array of sensory information into the CNS. Activation of these subtypes triggers specific reflexes, including cough and alterations in autonomic efferent control of airway smooth muscle, secretory cells, and vasculature. Importantly, every aspect of these reflex arcs can be impacted and altered by local inflammation caused by chronic lung disease such as asthma, bronchitis, and infections. Excessive and inappropriate activity in sensory and autonomic nerves within the airways is thought to contribute to the morbidity and symptoms associated with lung disease.Brain PCO2 is sensed primarily via changes in [H+]. Small pH changes are detected in the medulla oblongata and trigger breathing adjustments that help maintain arterial PCO2 constant. Larger perturbations of brain CO2/H+, possibly also sensed elsewhere in the CNS, elicit arousal, dyspnea, and stress, and cause additional breathing modifications. The retrotrapezoid nucleus (RTN), a rostral medullary cluster of glutamatergic neurons identified by coexpression of Phoxb and Nmb transcripts, is the lynchpin of the central respiratory chemoreflex. RTN regulates breathing frequency, inspiratory amplitude, and active expiration. It is exquisitely responsive to acidosis in vivo and maintains breathing autorhythmicity during quiet waking, slow-wave sleep, and anesthesia. The RTN response to [H+] is partly an intrinsic neuronal property mediated by proton sensors TASK-2 and GPR4 and partly a paracrine effect mediated by astrocytes and the vasculature. The RTN also receives myriad excitatory or inhibitory synaptic inputs including from [H+]-responsive neurons (e.g., serotonergic). RTN is silenced by moderate hypoxia. RTN inactivity (periodic or sustained) contributes to periodic breathing and, likely, to central sleep apnea. RTN development relies on transcription factors Egr2, Phox2b, Lbx1, and Atoh1. PHOX2B mutations cause congenital central hypoventilation syndrome; they impair RTN development and consequently the central respiratory chemoreflex.Breathing is a critical, complex, and highly integrated behavior. Normal rhythmic breathing, also referred to as eupnea, is interspersed with different breathing related behaviors. Sighing is one of such behaviors, essential for maintaining effective gas exchange by preventing the gradual collapse of alveoli in the lungs, known as atelectasis. Critical for the generation of both sighing and eupneic breathing is a region of the medulla known as the preBötzinger Complex (preBötC). Efforts are underway to identify the cellular pathways that link sighing as well as sneezing, yawning, and hiccupping with other brain regions to better understand how they are integrated and regulated in the context of other behaviors including chemosensation, olfaction, and cognition. Unraveling these interactions may provide important insights into the diverse roles of these behaviors in the initiation of arousal, stimulation of vigilance, and the relay of certain behavioral states. This chapter focuses primarily on the function of the sigh, how it is locally generated within the preBötC, and what the functional implications are for a potential link between sighing and cognitive regulation. Furthermore, we discuss recent insights gained into the pathways and mechanisms that control yawning, sneezing, and hiccupping.Opiates, such as morphine, and synthetic opioids, such as fentanyl, constitute a class of drugs acting on opioid receptors which have been used therapeutically and recreationally for centuries. Opioid drugs have strong analgesic properties and are used to treat moderate to severe pain, but also present side effects including opioid dependence, tolerance, addiction, and respiratory depression, which can lead to lethal overdose if not treated. This chapter explores the pathophysiology, the neural circuits, and the cellular mechanisms underlying opioid-induced respiratory depression and provides a translational perspective of the most recent research. The pathophysiology discussed includes the effects of opioid drugs on the respiratory system in patients, as well as the animal models used to identify underlying mechanisms. Using a combination of gene editing and pharmacology, the neural circuits and molecular pathways mediating neuronal inhibition by opioids are examined. [https://www.selleckchem.com/products/ABT-888.html ABT-888] By using pharmacology and neuroscience approaches, new therapies to prevent or reverse respiratory depression by opioid drugs have been identified and are currently being developed. Considering the health and economic burden associated with the current opioid epidemic, innovative research is needed to better understand the side effects of opioid drugs and to discover new therapeutic solutions to reduce the incidence of lethal overdoses.The clinical term dyspnea (a.k.a. breathlessness or shortness of breath) encompasses at least three qualitatively distinct sensations that warn of threats to breathing air hunger, effort to breathe, and chest tightness. Air hunger is a primal homeostatic warning signal of insufficient alveolar ventilation that can produce fear and anxiety and severely impacts the lives of patients with cardiopulmonary, neuromuscular, psychological, and end-stage disease. The sense of effort to breathe informs of increased respiratory muscle activity and warns of potential impediments to breathing. Most frequently associated with bronchoconstriction, chest tightness may warn of airway inflammation and constriction through activation of airway sensory nerves. This chapter reviews human and functional brain imaging studies with comparison to pertinent neurorespiratory studies in animals to propose the interoceptive networks underlying each sensation. The neural origins of their distinct sensory and affective dimensions are discussed, and areas for future research are proposed. Despite dyspnea's clinical prevalence and impact, management of dyspnea languishes decades behind the treatment of pain. The neurophysiological bases of current therapeutic approaches are reviewed; however, a better understanding of the neural mechanisms of dyspnea may lead to development of novel therapies and improved patient care.Much of biology is rhythmical and comprises oscillators that can couple. These have optimized energy efficiency and have been preserved during evolution. The respiratory and cardiovascular systems contain numerous oscillators, and importantly, they couple. This coupling is dynamic but essential for an efficient transmission of neural information critical for the precise linking of breathing and oxygen delivery while permitting adaptive responses to changes in state. The respiratory pattern generator and the neural network responsible for sympathetic and cardiovagal (parasympathetic) tone generation interact at many levels ensuring that cardiac output and regional blood flow match oxygen delivery to the lungs and tissues efficiently. The most classic manifestations of these interactions are respiratory sinus arrhythmia and the respiratory modulation of sympathetic nerve activity. These interactions derive from shared somatic and cardiopulmonary afferent inputs, reciprocal interactions between brainstem networks and inputs from supra-pontine regions.