Optimal interaction of respiratory and thermal regulation at rest and during exercise: Role of a serotonin-gated spinoparabrachial thermoafferent pathway

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Abstract

Recent evidence indicates that the lateral parabrachial nucleus (LPBN) in dorsolateral pons is pivotal in mediating the feedback control of inspiratory drive by central chemoreceptor input and feedforward control of body temperature by cutaneous thermoreceptor input. The latter is subject to descending serotonergic inhibition which gates the transmission of ascending thermoafferent information from spinal dorsal horn to the LPBN. Here, a model is proposed which suggests that the LPBN may be important in balancing respiratory and thermal homeostasis, two conflicting goals that are heightened by environmental heat/cold stress or exercise where the effects of respiratory thermolysis become prominent. This optimization model of respiratory–thermoregulatory interaction is supported by a host of recent studies which demonstrate that animals with serotonin (5-HT) dysfunction at the spinal dorsal horn – due to 5-HT antagonism, genetic 5-HT defects or spinal cord injury – all display similar respiratory abnormalities that are consistent with hyperactivity of the spinoparabrachial thermoafferent (and pain) pathway.

Introduction

Monoamines such as serotonin (5-HT) are thought to modulate many state-dependent changes in cardiorespiratory, thermoregulatory and pain/nociception physiology (Lydic, 1987, Audero et al., 2008, Gargaglioni et al., 2008). Recently, the effects of 5-HT on control of breathing and thermoregulation have received much attention (Hodges and Richerson, 2008a, Hodges and Richerson, 2008b, Hodges et al., 2008, Li and Nattie, 2008, Mitchell et al., 2008). Less well appreciated, however, is the interplay between these regulatory processes in balancing respiratory and thermal homeostasis through ventilatory CO2 elimination and respiratory thermolysis, two conflicting goals that are heightened by environmental heat/cold stress or muscular exercise particularly in panting animals. Such unaccounted-for confounding factors have led to many ambiguities in the interpretation of these previous data.

At the same time, other recent studies (Morrison et al., 2008, Nakamura and Morrison, 2008, Song and Poon, 2009a, Song and Poon, 2009b) have identified a critical area in the dorsolateral pons – the lateral parabrachial nucleus (LPBN) – as a pivotal relay for both central and peripheral chemoreceptor afferents and cutaneous thermoreceptor afferent. These findings indicate that the LPBN may be important in coordinating respiratory and thermal regulation. Here, I show that this hypothesis is consistent with a host of recent studies demonstrating the effects of 5-HT on control of breathing at rest and during exercise or following spinal cord injury (SCI). Of particular significance is the emergent respiratory-modulating effect of a serotonin-gated thermoafferent (and pain) pathway from spinal dorsal horn to the LPBN, which proves to be a possible missing link that may resolve many of the ambiguities in recent studies of 5-HT modulation of breathing (Hodges and Richerson, 2008a, Hodges and Richerson, 2008b, Hodges et al., 2008, Li and Nattie, 2008, Mitchell et al., 2008). The resultant model suggests a neural mechanism whereby respiratory and thermoregulatory pathways may interact to reconcile conflicting demands for respiratory homeostasis and thermal homeostasis during increased metabolic and/or thermal challenges.

Section snippets

Characteristics of ventilatory optimization during exercise

In humans, ventilatory output (V˙E) is tightly geared to metabolic CO2 production (V˙CO2) from rest to moderate exercise and this exercise ventilatory response is potentiated (with a steeper linear V˙EV˙CO2 relationship) when the normal isocapnic state is made hypercapnic at a constant elevated arterial PCO2 (PaCO2) level by breathing varying CO2-enriched mixtures (Poon and Greene, 1985). The potentiation effect is even more pronounced when the hypercapnia is caused by breathing through an

Limitations of the short-term modulation model

Another limitation of the “STM” model is the assumption that changes in VT/TI necessarily reflects similar changes in spinal respiratory motoneuron excitability. It is important to recognize that a decreased VT/TI response to exercise following spinal (intrathecal) methysergide may also result from decreased descending respiratory (inspiratory and/or expiratory) drive.2

Interplay of ventilatory CO2 elimination and thermolysis during panting

To address this dilemma (Q2), it is paramount to point out that exercise hyperpnea in many furry mammalian species (but not humans; Whipp and Wasserman, 1970) is important not only for respiratory regulation through pulmonary gas exchange, but also thermoregulation through respiratory evaporative heat loss as well (Gautier, 2000, Robertshaw, 2006, White, 2006). The latter has been extensively documented in many animal models (including goats, sheep, and dogs) that are traditionally used in

Abnormal ventilatory pattern in mice with genetic 5-HT deficiency or excess

The above-postulated effect of 5-HT on respiratory–thermoregulatory interaction is supported by several lines of evidence. Recently, Hodges and Richerson (2008b) reported that mutant mice with near-complete absence of central 5-HT neurons due to conditional knockout of the transcription factor Lmx1b displayed decreased core temperature (at an ambient temperature of 25 °C) and blunted hypercapnic ventilatory response compared with wild-type mice, whereas the hypoxic ventilatory response was not

Possible role of LPBN in respiratory–thermoregulatory interaction

Sensation of ambient temperature is traditionally thought to be mediated primarily by a spinothalamocortical pathway in which afferent signals from cutaneous and spinal warm/cold receptors are projected from the spinal and trigeminal dorsal horns to the thalamus and then relayed to the primary somatosensory cortex (Craig et al., 1994). The spinothalamic projections also have extensive collaterals to the LPBN (Hylden et al., 1989) before going to the thalamus (Romanovsky, 2007). Recently,

Dorsal horn 5-HT1A receptor activation restores respiratory drive after spinal cord injury

Another instance of spinal 5-HT dysfunction where the proposed model of respiratory–thermoregulatory interaction (Fig. 1) may prove instructive is SCI. In a series of recent studies, conscious rats recovering from incomplete contusion SCI at the T8 or C5 level were found to display a rapid and shallow breathing pattern at rest as well as depressed ventilatory response to hypercapnia (Teng et al., 1999, Teng et al., 2003, Choi et al., 2005), abnormalities that can be attributed in part to

Conclusion

The foregoing systematic review provides strong evidence that the LPBN plays a critical role in mediating respiratory–thermoregulatory interaction at rest and during exercise via a spinoparabrachial thermoafferent feedforward pathway. The latter is normally gated at the spinal dorsal horn by descending serotonergic inhibition presumably via the 5-HT1A receptor subtype. Disruption of the serotonergic inhibition by spinal 5-HT antagonism, genetic 5-HT defects or SCI unleashes the thermoafferent

Acknowledgments

I thank Drs. N.S. Cherniack, S. Morrison, G. Somjen, G. Song, and K. Wasserman for useful discussions. This work was supported by National Institutes of Health grants HL067966, HL072849 and HL079503.

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