A latent serotonin-1A receptor-gated spinal afferent pathway inhibiting breathing

Spinal afferents such as nociceptive afferents and group III–IV muscle afferents are known to exert an acute excitatory effect on breathing when activated. Here, we report the surprising existence of latent spinal afferents which exerted tonic inhibitory influence on breathing subliminally in anesthetized rats, an effect which was reversed upon activation of serotonin-1A receptors (5-HT[subscript 1A]Rs) in lumbar spinal cord, lesion of pontine lateral parabrachial nucleus or suppression of the adjacent Kölliker-Fuse nucleus with NMDA receptor blockade. Small-interfering RNA knockdown of 5-HT[subscript 1A]Rs in lumbar spinal cord unequivocally localized the site of 5-HT[subscript 1A]R-mediated gating of these respiratory-inhibiting interoceptive afferents to relay neurons in the spinal superficial dorsal horn at the lumbar level and not cervical spinal or supraspinal levels. Our results reveal a novel somatosensory/viscerosensory mechanism which exerts tonic inhibitory influence on homeostatic regulation of breathing independent from the classical chemoreflex excitatory pathways, and suggest a hitherto unrecognized therapeutic target in spinal dorsal horn for 5-HT[subscript 1A]R-based treatment of a variety of respiratory abnormalities.National Institutes of Health (U.S.) (Grants HL093225 and HL067966

Activation of Brainstem Neurons by Underwater Diving in the Rat

The mammalian diving response is a powerful autonomic adjustment to underwater submersion greatly affecting heart rate, arterial blood pressure, and ventilation. The bradycardia is mediated by the parasympathetic nervous system, arterial blood pressure is mediated via the sympathetic system and still other circuits mediate the respiratory changes. In the present study we investigate the cardiorespiratory responses and the brainstem neurons activated by voluntary diving of trained rats, and, compare them to control and swimming animals which did not dive. We show that the bradycardia and increase in arterial blood pressure induced by diving were significantly different than that induced by swimming. Neuronal activation was calculated after immunohistochemical processing of brainstem sections for Fos protein. Labeled neurons were counted in the caudal pressor area, the medullary dorsal horn, subnuclei of the nucleus tractus solitarii (NTS), the nucleus raphe pallidus (RPa), the rostroventrolateral medulla, the A5 area, the nucleus locus coeruleus, the Kölliker–Fuse area, and the external lateral and superior lateral subnuclei of the parabrachial nucleus. All these areas showed significant increases in Fos labeling when data from voluntary diving rats were compared to control rats and all but the commissural subnucleus of the NTS, A5 area, and RPa were significantly different from swimming rats. These data provide a substrate for more precise experiments to determine the role of these nuclei in the reflex circuits driving the diving response

Glutamatergic Receptors Modulate Normoxic but Not Hypoxic Ventilation and Metabolism in Naked Mole Rats

Naked mole rats (Heterocephalus glaber) are among the most hypoxia-tolerant mammals, but their physiological responses to acute and chronic sustained hypoxia (CSH), and the molecular underpinnings of these responses, are poorly understood. In the present study we evaluated the acute hypoxic ventilatory response and the occurrence of ventilatory acclimatization to hypoxia following CSH exposure (8–10 days in 8% O2) of naked mole rats. We also investigated the role of excitatory glutamatergic signaling in the control of ventilation and metabolism in these conditions. Animals acclimated to normoxia (control) or CSH and then exposed to acute hypoxia (7% O2 for 1 h) exhibited elevated tidal volume (VT), but decreased breathing frequency (fR). As a result, total ventilation (V.E) remained unchanged. Conversely, VT was lower in CSH animals relative to controls, suggesting that there is ventilatory plasticity following acclimatization to chronic hypoxia. Both control and CSH-acclimated naked mole rats exhibited similar 60–65% decreases in O2 consumption rate during acute hypoxia, and as a result their air convection requirement (ACR) increased ∼2.4 to 3-fold. Glutamatergic receptor inhibition decreased fR, V.E, and the rate of O2 consumption in normoxia but did not alter these ventilatory or metabolic responses to acute hypoxia in either the control or CSH groups. Taken together, these findings indicate that ventilatory acclimatization to hypoxia is atypical in naked mole rats, and glutamatergic signaling is not involved in their hypoxic ventilatory or metabolic responses to acute or chronic hypoxia

Neural Circuitry Underlying Waking Up to Hypercapnia

Obstructive sleep apnea is a sleep and breathing disorder, in which, patients suffer from cycles of atonia of airway dilator muscles during sleep, resulting in airway collapse, followed by brief arousals that help re-establish the airway patency. These repetitive arousals which can occur hundreds of times during the course of a night are the cause of the sleep-disruption, which in turn causes cognitive impairment as well as cardiovascular and metabolic morbidities. To prevent this potential outcome, it is important to target preventing the arousal from sleep while preserving or augmenting the increase in respiratory drive that reinitiates breathing, but will require understanding of the neural circuits that regulate the cortical and respiratory responses to apnea. The parabrachial nucleus (PB) is located in rostral pons. It receives chemosensory information from medullary nuclei that sense increase in CO2 (hypercapnia), decrease in O2 (hypoxia) and mechanosensory inputs from airway negative pressure during apneas. The PB area also exerts powerful control over cortical arousal and respiration, and therefore, is an excellent candidate for mediating the EEG arousal and restoration of the airway during sleep apneas. Using various genetic tools, we dissected the neuronal sub-types responsible for relaying the stimulus for cortical arousal to forebrain arousal circuits. The present review will focus on the circuitries that regulate waking-up from sleep in response to hypercapnia