Abstract

The pre-Bötzinger complex has been identified as an essential part of the medullary respiratory network in mammals. Although well described in experimental animals, its localization in the human brain has remained elusive. Using serially sectioned brainstems from 19 normal individuals and patients suffering from neurodegenerative diseases (multiple system atrophy, n = 10; spinocerebellar ataxia type 3, n = 8), we have identified a circumscribed area of the ventrolateral medulla that represents the human homologue of the pre-Bötzinger complex and have mapped its longitudinal and horizontal extents. The presumed human pre-Bötzinger complex is characterized by an aggregation of loosely scattered, small and lipofuscin-rich neurons, which contain neurokinin 1 receptor as well as somatostatin, but are negative for markers of monoaminergic neurons and of motoneurons. In brains of patients suffering from multiple systems atrophy (with central respiratory deficits but without swallowing problems), pre-Bötzinger complex neurons were reduced, whereas pharyngeal motoneurons of the ambigual nucleus were not affected. In contrast, in brains of patients with spinocerebellar ataxia 3 (no reported central respiratory deficits but with dysphagia), pre-Bötzinger complex neurons were preserved, whereas ambigual motoneurons, which control swallowing, were diminished. These pathoanatomical findings support the view, that affection of the central respiratory network, including the pre-Bötzinger complex, contributes to breathing disorders in multiple system atrophy, whereas damage to ambigual motoneurons is important for pathogenesis of breathing disturbances and dysphagia in patients with spinocerebellar ataxia type 3. On the basis of these findings, the putative human homologue of the pre-Bötzinger complex can now be reliably delineated on pigment-Nissl-stained sections, making neuropathological investigations of central respiratory disturbances feasible.

Highlights

  • The pre-Botzinger complex was identified as an essential part of the medullary rhythm-generating network in experimental animals almost two decades ago (Smith et al, 1991)

  • Using serially sectioned brainstems from 19 normal individuals and patients suffering from neurodegenerative diseases, we have identified a circumscribed area of the ventrolateral medulla that represents the human homologue of the pre-Botzinger complex and have mapped its longitudinal and horizontal extents

  • The localization of the presumed pre-Botzinger complex was studied in human brain using three complementary approaches: (i) comparison of cytoarchitectonic landmarks within the medulla oblongata between experimental mammals and humans; (ii) immunocytochemical staining of putative pre-Botzinger complex neurons in human material based on data from laboratory animals; and (iii) systematic comparison between brainstems of normal human individuals and of patients suffering from neurodegenerative diseases associated with the occurrence of breathing deficits of different pathological origin (i.e. multiple system atrophy (MSA) and SCA3)

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Summary

Introduction

The pre-Botzinger complex was identified as an essential part of the medullary rhythm-generating network in experimental animals almost two decades ago (Smith et al, 1991). The pre-Botzinger complex is well characterized as part of the group of ventral medullary respiratory neurons that form a rostrocaudal column throughout the medulla oblongata from the facial nucleus (VII) to the pyramidal decussation. This column can be subdivided into four distinct groups: the rostral Botzinger complex, followed by the pre-Botzinger complex, the rostral ventral respiratory group and the caudal ventral respiratory group (for review see Feldman and Del Negro, 2006). As the preBotzinger complex and other medullary respiratory areas were primarily defined by functional criteria in experimental animals, any analysis in human tissue will depend on cytoarchitectonic and/or neurochemical homologies. Analogies between experimental animals, such as rats, mice or cats, and human tissue are further hampered by the enlargement of the human inferior olive that is accompanied by a rearrangement of all other areas of the ventrolateral medulla (Blessing, 2004)

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