Neuromodulation and the orchestration of the respiratory rhythm

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Abstract

The respiratory system is continuously modulated by numerous aminergic and peptidergic substances that act at all levels of integration: from the sensory level to the level of central networks and motor nuclei. The same neuronal networks receive inputs from multiple modulators released locally as well as from distal nuclei. All parameters of respiratory control are controlled by multiple neuromodulators. By partly converging onto similar G-proteins and second messenger systems, acetylcholine, norepinephrine, histamine, serotonin (5-HT), dopamine, ATP, substance P, cholecystokinin (CCK) can increase frequency, regularity and amplitude of respiratory activity. Yet, the same modulator can also exert differential effects on respiratory activity by acting on different receptors partly in the same neurons. In the pre-Bötzinger complex (pre-BötC) modulators can differentially modulate frequency and amplitude in different types of pacemaker neurons. Similarly motoneurons located in different motor nuclei receive differential amplitude modulation from different modulators. Thus, modulators are capable of orchestrating and modulating different parameters of respiratory activity by differentially targeting different cellular targets. A disturbance in modulatory control may lead to Sudden Infant Death Syndrome (SIDS) and erratic breathing.

Introduction

Neuromodulators have multiple functions in controlling respiratory rhythmic activity. They differentially regulate the amplitude and frequency of respiratory activity. They act at the level of motoneurons, sensory neurons and neurons located in various CNS nuclei. They are involved in the reconfiguration of the respiratory network during different forms of breathing. Thus, understanding how neuromodulators control the respiratory system will provide not only important insights into principles of neuromodulation, but also into how respiratory rhythmic activity is generated and regulated.

There is increasing evidence that the respiratory rhythm is generated by neuronal networks located within the ventral respiratory column (VRC) and the parafacial respiratory group (pFRG) (Alheid et al., 2002, Feldman and Del Negro, 2006). Although, still uncertain how these regions interact to generate the breathing rhythm, it is well established that a particular area within the VRC, the so called pre-Boetzinger complex (pre-BötC) is critical for generating inspiratory activity (Gray et al., 2001). Multiple studies have demonstrated that lesioning of the pre-BötC leads to the cessation of breathing (Wenninger et al., 2004, McKay et al., 2005). Isolated in medullary slices, the pre-BötC continues to generate three distinct types of activity patterns that appear to provide the basic rhythmic drive for the generation of three distinct forms of respiratory activity patterns: normal respiratory activity (sometimes referred to as eupnea), sighs and gasps (Lieske et al., 2000). The fact that the pre-BötC can be isolated in vitro has facilitated our understanding of the role of neuromodulators in regulating respiratory rhythm generation. This neuronal network exhibits an unprecedented degree of plasticity. Synaptic and intrinsic membrane properties are under the continuous control of neuromodulators that can differently regulate amplitude and frequency of respiratory activity, as well transitions between the different types of respiratory activities.

Although we are far from understanding all aspects of neuromodulation, it is obvious that neuromodulation is an integral part of the rhythm and pattern generating process itself. This review will highlight insights gained from experiments performed in transverse medullary slices. We will focus on the discussion of only a few modulators that best exemplify certain aspects of neuromodulatory control. Hence, it must be emphasized that neuromodulation is an even more complex process and that it will play a more versatile role in governing and orchestrating respiratory network activity in the intact animal. Indeed the locally modulated pre-BötC is connected with many other neuronal networks that are themselves under continuous modulatory control and in turn modulate the pre-BötC as will be discussed in the first paragraph.

Section snippets

Neuromodulators affect respiratory activity from numerous areas distributed throughout the nervous system

Respiratory rhythm generating areas, such as the pre-BötC receive multiple modulatory inputs from many areas outside (Fig. 1A) and within the vicinity of the pre-BötC. The pre-BötC projects to various respiratory-related areas that contain neuromodulators and are in turn modulated by multiple other areas. Most areas contain multiple neuromodulators that are partly co-released from the same neurons. Thus, neuromodulation occurs at all levels of integration, and it can be assumed that all

Neuromodulators, receptors, subtypes and second messenger systems

The previous paragraph described that multiple neuromodulators originate from many different regions of the CNS. At the cellular level modulators act on a variety of receptor subtypes exerting inhibitory and excitatory effects on the respiratory network via different second messenger systems. In this paragraph we will discuss these cellular mechanisms for some of the key neuromodulators including acetylcholine, 5-HT, substance P and norepinephrine, but the reader is referred to Table 1, Table 2

Inhibitory and excitatory control of respiratory frequency

Endogenously released neuromodulators provide continuous, excitatory and inhibitory drive onto the respiratory network (Fig. 2). Some of the known modulators exert either excitatory or inhibitory effects, while others have inhibitory as well as excitatory effects on respiratory functions. Substance P is an example for a modulator with primarily excitatory effects. This peptide exerts its excitatory effects by acting on NK1 receptors within the pre-BötC, but studies obtained in the

Medullary control of respiratory frequency

Insights gained into locally released neuromodulators were gained by manipulating endogenous, excitatory drive in spontaneously active medullary slices that contain the pre-BötC. Unilateral microinjection of the acetylcholinesterase inhibitor physostigmine into the pre-BötC increases the frequency of respiratory rhythmic activity, an effect that is partially blocked by either M3 mACh receptor antagonists or α4β2 nACh receptor antagonists (Shao and Feldman, 2005). The frequency of respiratory

Neuromodulatory control of regularity of rhythmic activity

From existing experiments there seems to be a tight correlation between modulatory control of frequency and regularity of respiratory rhythmic activity. Blockade of endogenous, excitatory drive decreases, while increasing endogenous excitatory drive increases respiratory frequency as well as regularity of the rhythm. The regularity of respiratory activity in transverse rhythmic slices is for example increased by 5-HT uptake blockers that mimic the “regularizing” effect of exogenously applied

Cadmium-insensitive pacemakers and the control of frequency and regulatory of rhythmic activity

Inspiratory neurons located within the pre-BötC exhibit two types of pacemaker properties (Thoby-Brisson and Ramirez, 2001). Pacemaker bursting in one population of inspiratory neurons seems to depend on the calcium-activated non-selective cation (CAN) current (Pena et al., 2004). These neurons are referred to as “cadmium-sensitive” pacemaker neurons, because bursting in these neurons is abolished following blockade of calcium influx with extracellularly applied cadmium. Pacemaker bursting in

Neuromodulation and the neuronal control of the amplitude of inspiratory activity

Exogenously applied agonists for alpha-1 adrenergic receptors, 5-HT2A receptors and NK1 receptors as well as 5-HT uptake blockers increase not only the frequency, but also the amplitude of respiratory activity at the level of the pre-BötC (Pena and Ramirez, 2002, Pena and Ramirez, 2004, Viemari and Ramirez, 2006a). Interestingly, these excitatory neuromodulators caused predominantly an increase in the amplitude of the depolarizing drive potential in cadmium-sensitive pacemaker neurons. An

The modulatory control of gasps and sighs, and the association with Sudden Infant Death Syndrome

In vitro preparations containing the pre-BötC show a distinct activity pattern during severe hypoxia. This activity pattern has been referred to as “fictive gasping” (Lieske et al., 2000). Like in vivo gasping this activity pattern is characterized by a faster rise time, shorter burst duration and lower frequency under hypoxic conditions (Ramirez and Garcia, 2007). The transition from normal respiratory activity into gasping activity is associated with a reconfiguration in network activity.

Neuromodulation and respiratory disorders

Because of the important role of neuromodulators in regulating frequency, regularity and amplitude of respiratory activity it should not surprise that a disturbance in any aspect of modulatory control may also lead to breathing disorders. A neurological disorder that has been linked to a disturbance in modulatory control is Rett syndrome. These patients have X-linked mutations in the methyl-CpG binding protein 2 gene (Mecp2), and typically suffer from severe breathing abnormalities that include

Concluding remarks

The examples discussed in this review illustrate that neuromodulators play critical roles in the neuronal control of breathing regularity, frequency and amplitude. Disturbances in the modulatory milieu seem to have severe clinical consequences that are possibly amenable to therapeutic treatments aimed at reestablishing normal levels of modulatory control. However, given the complexity of modulatory control as described in the first part of this review, it is probably difficult to predict how a

Acknowledgement

This manuscript was supported by NIH 68860.

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