Hypoxia‐induced phrenic long‐term facilitation: emergent properties

Abstract

Just as in other neural systems, plasticity is a hallmark of the neural system controlling breathing. One spinal mechanism of respiratory plasticity is phrenic long-term facilitation (pLTF) following acute intermittent hypoxia. Although cellular mechanisms giving rise to pLTF occur within the phrenic motor nucleus, different signaling cascades elicit pLTF in different conditions. These cascades, referred to as “Q” and “S" pathways to phrenic motor facilitation (pMF), interact via cross-talk inhibition. Whereas the Q pathway dominates pLTF after mild to moderate hypoxic episodes, the S pathway dominates after severe hypoxic episodes. The biological significance of multiple pathways to pMF is not known. We discuss the possibility that interactions between pathways confer emergent properties to pLTF, including: 1) pattern sensitivity and 2) metaplasticity. Understanding these mechanisms and their interactions may enable us to optimize intermittent hypoxia induced plasticity as a treatment for patients that suffer from ventilatory impairment or other motor deficits.

Spinal 5-HT7 receptors induce phrenic motor facilitation via EPAC-mTORC1 signaling

“…While the S and Q pathways elicit pMF through distinct signaling cascades, they interact via mutual "cross-talk inhibition" (Dale-Nagle et al 2010;Devinney et al 2013;Hoffman and Mitchell 2013). One manifestation of cross-talk inhibition is the bell-shaped dose-response curve of pMF in response to intermittent intrathecal serotonin injections (MacFarlane and Mitchell 2009).…”

“…In ways similar to sensory motor facilitation in Aplysia, episodic serotonin receptor activation is necessary and sufficient for important forms of spinal respiratory motor plasticity, such as long-lasting (Ͼ90 min) phrenic motor facilitation (pMF) following acute intermittent hypoxia (AIH; reviewed by Mahamed and Mitchell 2007;Dale-Nagle et al 2010;Devinney et al 2013) or direct injections of serotonin or serotonin receptor agonists into the cervical spinal cord of rats (Hoffman…”

“…For example, episodic serotonin presentations enhance sensory motor synaptic transmission, giving rise to the gill withdrawal reflex (Brunelli et al 1976). This well-studied form of plasticity in an invertebrate model system relies on multiple serotonin receptor subtypes, each activating unique kinase signaling cascades (Barbas et al 2003).In ways similar to sensory motor facilitation in Aplysia, episodic serotonin receptor activation is necessary and sufficient for important forms of spinal respiratory motor plasticity, such as long-lasting (Ͼ90 min) phrenic motor facilitation (pMF) following acute intermittent hypoxia (AIH; reviewed by Mahamed and Mitchell 2007;Dale-Nagle et al 2010;Devinney et al 2013) or direct injections of serotonin or serotonin receptor agonists into the cervical spinal cord of rats (Hoffman …”

“…In ways similar to sensory motor facilitation in Aplysia, episodic serotonin receptor activation is necessary and sufficient for important forms of spinal respiratory motor plasticity, such as long-lasting (Ͼ90 min) phrenic motor facilitation (pMF) following acute intermittent hypoxia (AIH; reviewed by Mahamed and Mitchell 2007;Dale-Nagle et al 2010;Devinney et al 2013) or direct injections of serotonin or serotonin receptor agonists into the cervical spinal cord of rats (Hoffman and Mitchell 2011;MacFarlane et al 2009MacFarlane et al , 2011. Indeed, multiple serotonin receptor subtypes elicit pMF via mechanistically distinct signaling cascades named for the G proteins most often coupled with the initiating metabotropic serotonin receptor (Dale-Nagle et al 2010).…”

Clinical Use of Loop Gain Measures to Determine Continuous Positive Airway Pressure Efficacy in Patients with Complex Sleep Apnea. A Pilot Study

“…Possible mechanisms include the following: 1. Improved oxygenation may reverse the effects of apnea-induced intermittent hypoxia on chemoreflex sensitivity (25,26).…”