Invited Review: Intermittent hypoxia and respiratory plasticity

Abstract

Intermittent hypoxia elicits long-term facilitation (LTF), a persistent augmentation (hours) of respiratory motor output. Considerable recent progress has been made toward an understanding of the mechanisms and manifestations of this potentially important model of respiratory plasticity. LTF is elicited by intermittent but not sustained hypoxia, indicating profound pattern sensitivity in its underlying mechanism. During intermittent hypoxia, episodic spinal serotonin receptor activation initiates cell signaling events, increasing spinal protein synthesis. One associated protein is brain-derived neurotrophic factor, a neurotrophin implicated in several forms of synaptic plasticity. Our working hypothesis is that increased brain-derived neurotrophic factor enhances glutamatergic synaptic currents in phrenic motoneurons, increasing their responsiveness to bulbospinal inspiratory inputs. LTF is heterogeneous among respiratory outputs, differs among experimental preparations, and is influenced by age, gender, and genetics. Furthermore, LTF is enhanced following chronic intermittent hypoxia, indicating a degree of metaplasticity. Although the physiological relevance of LTF remains unclear, it may reflect a general mechanism whereby intermittent serotonin receptor activation elicits respiratory plasticity, adapting system performance to the ever-changing requirements of life.

Central and peripheral chemoreceptors evoke distinct responses in simultaneously recorded neurons of the raphé-pontomedullary respiratory network

“…State-dependent changes in ventilation in response to local perturbations of raphé neurons support the hypothesis that midline neurons are elements of a distributed brainstem system of central chemoreceptors (Nattie & Li 2009), as well as modulators of central chemoreceptors at other sites, including the retrotrapezoid nucleus (Mulkey et al 2004;Dias et al 2008). Stimulation of peripheral chemoreceptors also evokes changes in raphé neuron activity (Morris et al 1996a, and repeated intermittent stimulation of peripheral carotid body chemoreceptors or medullary raphé neurons can induce a long-term facilitation of phrenic nerve amplitude and cycling frequency (Millhorn et al 1980;Morris et al 1996aMorris et al ,b, 2001Mitchell et al 2001). Similar patterns of central chemoreceptor stimulation do not produce this respiratory memory (Millhorn 1986).…”

Invited Review: Neuroplasticity in respiratory motor control

“…This simple, functional definition is similar to the working definition used by the Society for Neuroscience (218). Phrenic long-term facilitation (LTF) following intermittent hypoxia qualifies as an example of plasticity in respiratory motor control because it reflects an enhanced respiratory motor output that outlasts the stimulus (episodic hypoxia) (166).…”

“…Thus sensory receptors provide negative feedback, adjusting breathing to meet changing conditions. Less widely appreciated functions of sensory receptors in respiratory control include their effects on neuromodulatory systems (101,157), on cortical areas associated with arousal and respiratory sensation (13,99), and their actions as guides to respiratory plasticity (166,167,193).…”

“…Serotonin-dependent plasticity is also important in respiratory motor control (Ref. 166; see Serotonin-Dependent Respiratory Plasticity below), although the detailed cellular and/or synaptic mechanisms may differ. Other neurochemicals such as norepinephrine (8,117) or trophic factors such as brain-derived neurotrophic factor (BDNF) may initiate or regulate synaptic plasticity (124,147,191,214,231).…”

“…Other reviews are available on selected aspects of respiratory plasticity [e.g., developmental plasticity (80,133), respiratory "memories" (46), time-dependent mechanisms of the hypoxic ventilatory response (8,21,60,117,166,197), serotonergic modulation and plasticity (157), plasticity in the exercise ventilatory response (157,236), and activity-dependent synaptic plasticity (105,193,194)]. Comprehensive reviews focused on selected aspects of respiratory plasticity will appear as a part of this Highlighted Topics series in the Journal of Applied Physiology.…”