Noradrenergic modulation of the respiratory neural network

Abstract

Noradrenergic dysregulation has been reported in human pathologies affecting the control of breathing, such as sudden infant death syndrome, congenital central hypoventilation syndrome and Rett syndrome. Noradrenergic neurons, located predominantly in pontine nuclei, are among the earliest to arise within the hindbrain and play an essential role in the maturation of the respiratory network. Noradrenergic neurons also play a major role in the modulation of the respiratory motor pattern from birth through adulthood. The critical importance of this signaling system in respiratory control is illustrated by the severe respiratory disturbances associated with gene mutations affecting noradrenergic neurons (Phox2 and Mecp2). Here, the role of catecholaminergic pontine nuclei in the control of breathing, the cellular effects of norepinephrine on the respiratory network and the pathological consequence to breathing of abnormalities in this signaling system will be discussed.

Introduction

Catecholamines (CA), and norepinephrine (NE) in particular, play important roles in the maturation and modulation of many rhythmic behaviors including respiration (Viemari et al., 2004, Viemari and Ramirez, 2006a). Catecholamines are also involved in several autonomic functions that strongly influence the respiratory system, including cardiovascular control and sleep cycle regulation (Byrum and Guyenet, 1987, Guyenet et al., 1993, Ouyang et al., 2004, Li and Nattie, 2006). The critical role played by CA in many autonomic functions is largely orchestrated by modulation of brainstem circuits. Thus, while this review focuses on the role of NE in respiration, a brief, general overview of catecholamine synthesis and distribution within the brainstem is provided to help the reader understand the influence of various nuclei on breathing. Briefly, catecholaminergic neurons produce NE, adrenaline or dopamine. NE and adrenaline cell groups within the brainstem are numbered in a caudal to rostral direction. A1–A7 groups contain NE and C1–C3 are adrenergic. NE neurons are generally defined as neurons that express tyrosine hydroxylase (TH) and dopamine-β-hydroxylase (DBH), whereas adrenergic neurons specifically express phenylethanolamine N-methyltransferase (PNMT, Fig. 1A).

Catecholaminergic neurons have powerful modulatory effects on the respiratory network, the hypothesized kernel of which is located in the Pre-Bötzinger complex, a small bilaterally repeated nucleus in the ventrolateral medulla (Smith et al., 1991). When isolated in transverse slice preparations, the Pre-Bötzinger complex is capable of generating multiple rhythmic inspiratory-like motor-bursts defined by Lieske et al. (2000) as resembling eupnea, sighs and gasps. These respiratory-related rhythms emerge through a combination of synaptic and intrinsic membrane properties that include bursting pacemaker properties (Butera et al., 1999, Del Negro et al., 2005, Ramirez et al., 2004, Ramirez and Viemari, 2005). Neuromodulators differentially alter fictive eupnea, sighs and gasping activities, not only by acting through different cellular signaling mechanisms, but also through their unique impact on different inspiratory cell types (Viemari and Ramirez, 2006a, Tryba et al., 2006, Tryba et al., 2008).

Recent studies have described an additional kernel for respiratory rhythm generation: the parafacial nucleus located rostral to the Pre-Bötzinger complex (Ballanyi et al., 1999, Janczewski et al., 2002, Onimaru and Homma, 2003, Mellen et al., 2003) although its role has been questioned in adult rats (Fortuna et al., 2008).

This review will describe the role of CA and the effects of gene mutations affecting noradrenergic neurons on the neural network that control breathing. Then, it will cover the role of the pons in mediating CA/NE modulation and the cellular effects of CA/NE on the reduced respiratory network in vitro. Finally, this review will identify the essential role of NE in the development of the respiratory network.