It takes your breath away – NK1R ablation in the pre-Bötzinger complex

Abstract

To a large extent, you owe the fact that you are alive to a small part of the ventral medulla oblongata. This region contains some of the neurons controlling respiration, intermingled with others that are thought to be involved in the control of blood pressure and heart rate. However, unlike other parts of the brain, such as the hippocampus, there is no rigid spatial organization of the neuronal types into discrete layers or, even, functional phenotypes. This has meant that identification of a neuron as belonging to a particular functional class has been dependent on its relationship to either cardiovascular or respiratory variables. Therefore, the most reliable identification is made in intact animals or preparations in which measurements of such variables can be made. In such preparations, neurons with properties that make them ideal candidates for a role in the rhythm generation necessary for respiration have been localized to the pre-Botzinger complex in the ventral medulla. The complex is a collection of functionally related neurons, rather than a pure anatomical nucleus. Therefore, the problem has been how to distinguish these neurons from others in the area with separate functions and determine the nature of their participation in the generation of respiration.Recent advances support strongly a proposal that the pre-Botzinger complex can be defined anatomically by neurokinin 1 receptor (NK1R)-containing neurons, and these neurons are crucial for respiratory rhythmogenesis. Wang et al.1xNeurokinin-1-receptor-immunoreactive neurons of the ventral respiratory group in the rat. Wang, H. et al. J. Comp. Neurol. 2001; 434: 128–146Crossref | PubMed | Scopus (111)See all References1 show that NK1R-containing cells in the ventral medulla meet several established criteria for the respiratory rhythm generators: (1) they are distinct from catecholaminergic (presumed to have cardiovascular function) and cholinergic (motor) neurons; (2) they are presumed to be excitatory as they do not contain mRNA for markers of GABAergic (GAD-67) or glycinergic (GlyT2) neurons; (3) the majority project to the contralateral pre-Botzinger complex.In a further step, Gray et al.2xNormal breathing requires pre-Botzinger complex neurokinin-1-receptor-expressing neurons. Gray, P.A. et al. Nat. Neurosci. 2001; 4: 927–930Crossref | PubMed | Scopus (342)See all References2 show that these NK1R-containing neurons are necessary for normal breathing. Selective destruction of the NK1R-containing neurons bilaterally, by injection of the ligand, substance P, conjugated to the toxin saporin, resulted in a profound change from eupneic to ataxic breathing patterns (characterized by shortened respiratory periods and an irregular sequence of inspiratory efforts, interspersed with prolonged periods of apnoea). Also, the lesioned rats were unable to maintain appropriate levels of blood gases and pH and had pathological responses to hypoxia or hyperoxia, although these deficits were not lethal.These studies show that an area crucial for normal breathing can be defined anatomically, an intact pre-Botzinger complex is necessary for normal breathing and neurons expressing NK1R, in particular, are necessary for this normal breathing. However, because breathing persists following the ablation of NK1R-containing neurons, other contributions might arise from the non-NK1R-containing neurons in the pre-Botzinger complex, as well as neurons in other ‘respiratory’ regions of the brainstem. Further experiments akin to those described here will provide a more complete understanding and could lead to new insights into failures of normal breathing, such as central sleep apnoea and, even, sudden infant death syndrome.