Long term facilitation of phrenic motor output
Introduction
After a brief hypoxic exposure (5 min), respiratory motor activity returns to pre-hypoxic levels within 10–15 min in anesthetized rats (Bach et al., 1999b). In contrast, episodic hypoxia at 5 min intervals leads to a long-lasting (>1 h) post-hypoxia enhancement of inspiratory motor output, referred to as long-term facilitation (LTF, Fig. 1) (Hayashi et al., 1993, Powell et al., 1998). Most investigators have concluded that LTF is expressed primarily as increased inspiratory motor output or tidal volume (McCrimmon et al., 1995), although breathing frequency may also be preferentially augmented in some circumstances (Turner and Mitchell, 1997). LTF arises from a central neural mechanism (Millhorn et al., 1980a) that requires serotonin receptor activation (Millhorn et al., 1980b, Fregosi and Mitchell, 1994, Bach and Mitchell, 1996, Kinkead and Mitchell, 1999).
Although the physiological significance of LTF in intact, unanesthetized animals is not yet understood, we believe that study of this phenomenon will have important implications from several perspectives. First, LTF is an intriguing example of plasticity in respiratory motor control, a neural control system traditionally thought of as fixed and immutable from birth. By investigations of the mechanisms leading to LTF, we may gain further insights concerning the mechanisms and prevalence of plasticity within this important homeostatic control system. On the other hand, LTF provides a unique experimental opportunity to examine serotonin-dependent plasticity in the mammalian central nervous system since clear functional significance (i.e. altered respiratory motor output) can be ascribed to the underlying neural mechanisms. Thus, studies of LTF may yield important insights concerning the mechanisms of neural plasticity beyond respiratory control, of relevance to the mammalian CNS in general. Finally, only through further investigations of LTF and its mechanisms and manifestations can we hope to understand its physiological relevance.
The role(s) of LTF may be relatively straightforward. One possibility is that it may contribute to stabilization of breathing during sleep. For example, episodic exposure to hypoxemia (as occurs in obstructive sleep apnea), could lead to LTF of upper airway motoneurons, and the associated increase in upper airway muscle activity could help to maintain upper airway patency. Consistent with this hypothesis, Veasey and colleagues have provided evidence that serotonergic modulation of upper airway motor output is important in the maintenance of upper airway patency in a bulldog model of obstructive sleep apnea (Veasey et al., 1996). This effect is presumably mediated by state-dependent serotonergic modulation of hypoglossal and other upper airway motoneurons (Kubin et al., 1994, Fenick et al., 1998).
On the other hand, LTF may be a reflection of a more generalized mechanism whereby serotonin dependent plasticity allows continual, life-long adjustments in respiratory motor control. For example, serotonin-dependent plasticity may allow refinements in the output of selected motor pools to accommodate development/age related changes in lung/chest wall mechanics, or to adjust respiratory motor output so that it remains appropriate in the face of changing body mass, injury or the onset of disease. An understanding of hypoxia-induced LTF and its significance is further complicated by recent indications that its manifestation within an individual is subject to genetic influences and is, in itself, plastic. Such ‘meta-plasticity’ suggests that LTF may assume greater or lesser roles in modifying respiratory motor output, depending on the specific history of an individual (e.g. disease, injury, changes in physiological circumstances).
It is hoped that the identification of network, cellular, and molecular mechanisms underlying hypoxia-induced LTF may enable the emergence of a comprehensive understanding of serotonin-dependent plasticity in respiratory motor control, and its overall significance in the control of breathing. Prior to the attainment of such a comprehensive understanding, it may be necessary to understand more completely the factors that influence the manifestation of phrenic LTF. Thus, the primary goals of this paper are to provide an updated literature review of LTF, to more clearly define the influence of selected variables on hypoxia-induced phrenic LTF in anesthetized rats via meta-analysis of a large data set, and to propose an updated mechanistic model of LTF. It is hoped that such a discussion will encourage the design and execution of experiments to fill the voids in our knowledge and, thereby, engender further insights concerning LTF and its physiological significance. In this manuscript, the discussion will focus on phrenic nerve responses, although LTF can be evoked in other respiratory motor outputs (e.g. hypoglossal and inspiratory intercostal nerves; Fregosi and Mitchell, 1994, Bach and Mitchell, 1996, Mateika and Fregosi, 1997), presumably by a common mechanism.
Section snippets
Review of LTF literature
This literature review will focus on recent findings. For a more comprehensive discussion, the reader is referred to earlier reviews (McCrimmon et al., 1995, Powell et al., 1998). LTF was described initially by Millhorn et al., 1980a, Millhorn et al., 1980b. These authors demonstrated that repeated electrical stimulation of the cut central end of the carotid sinus nerve augmented phrenic inspiratory activity for up to 90 min post-stimulation in anesthetized, vagotomized cats. The long-lasting
Meta-analysis of LTF in anesthetized rats
Numerous investigations have demonstrated that LTF is a robust and reproducible phenomenon (McCrimmon et al., 1995). However, substantial inter-animal variability is common. For example, in our laboratory, approximately 10% of experimental preparations fail to exhibit significant phrenic LTF. Accordingly, in an effort to better characterize the influence of selected variabiles on LTF in a single experimental model, we pooled data collected in our laboratory by four investigators using a common
Proposed mechanism of LTF
Our basic working model concerning the mechanism(s) of LTF has been described previously (McCrimmon et al., 1995, Bach and Mitchell, 1996). However, a number of extensions can be offered that merit further discussion. The basic model is shown in Fig. 5. In this schema, hypoxia activates carotid chemoafferent neurons that, in turn, activate medullary neurons involved with both rhythm generation and burst pattern formation. Chemoafferent neurons either directly or indirectly activate raphe
Acknowledgements
We thank Brad Hodgeman for his help preparing the figures. This work has been supported by the National Heart, Lung and Blood Institute (HL 36780 and 53319).
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