Circulatory control of phrenic motor plasticity

• Published in: Respiratory physiology & neurobiology Vol. 265; pp. 19 - 23
• Main Authors: Perim, Raphael R., Mitchell, Gordon S.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2019
• Subjects: Acute intermittent hypoxia; Adenosine; Adenosine - metabolism; Animals; Cervical Cord - physiology; Circulatory control; Humans; Hypoxia - metabolism; Hypoxia - physiopathology; Neuronal Plasticity - physiology; Oxygen - metabolism; Phrenic Nerve - physiology; Respiratory motor plasticity; Respiratory Physiological Phenomena; Serotonin; Serotonin - metabolism; Synaptic Potentials - physiology; Circulatory control; Adenosine; Acute intermittent hypoxia; Serotonin; Respiratory motor plasticity
• ISSN: 1569-9048; 1878-1519
• DOI: 10.1016/j.resp.2019.01.004

•Cardiovascular changes that compromise oxygen availability in spinal cord tissue might impact expression of respiratory motor plasticity.•Impaired circulatory control and local tissue oxygen availability lead to extracellular adenosine accumulation.•Increased adenosine can trigger cross-talk inhibition or shift the balance from serotonergic towards adenosinergic mechanisms to pLTF. Acute intermittent hypoxia (AIH) elicits distinct mechanisms of phrenic motor plasticity initiated by brainstem neural network activation versus local (spinal) tissue hypoxia. With moderate AIH (mAIH), hypoxemia activates the carotid body chemoreceptors and (subsequently) brainstem neural networks associated with the peripheral chemoreflex, including medullary raphe serotonergic neurons. Serotonin release and receptor activation in the phrenic motor nucleus then elicits phrenic long-term facilitation (pLTF). This mechanism is independent of tissue hypoxia, since electrical carotid sinus nerve stimulation elicits similar serotonin-dependent pLTF. In striking contrast, severe AIH (sAIH) evokes a spinal adenosine-dependent, serotonin-independent mechanism of pLTF. Spinal tissue hypoxia per se is the likely cause of sAIH-induced pLTF, since local tissue hypoxia elicits extracellular adenosine accumulation. Thus, any physiological condition exacerbating spinal tissue hypoxia is expected to shift the balance towards adenosinergic pLTF. However, since these mechanisms compete for dominance due to mutual cross-talk inhibition, the transition from serotonin to adenosine dominant pLTF is rather abrupt. Any factor that compromises spinal cord circulation will limit oxygen availability in spinal cord tissue, favoring a shift in the balance towards adenosinergic mechanisms. Such shifts may arise experimentally from treatments such as carotid denervation, or spontaneous hypotension or anemia. Many neurological disorders, such as spinal cord injury or stroke compromise local circulatory control, potentially modulating tissue oxygen, adenosine levels and, thus, phrenic motor plasticity. In this brief review, we discuss the concept that local (spinal) circulatory control and/or oxygen delivery regulates the relative contributions of distinct pathways to phrenic motor plasticity.