A Comparative Neuroanatomical Study of the Red Nucleus of the Cat, Macaque and Human Satoru Onodera1*, T. Philip Hicks2 1 Department of Anatomy, School of Medicine, Iwate Medical University, Morioka, Japan, 2 Department of Biology, Faculty of Science and Environmental Studies, Lakehead University, Thunder Bay, Ontario, Canada Abstract Background: The human red nucleus (Nr) is comparatively less well-studied than that of cats or monkeys. Given the functional importance of reticular and midbrain structures in control of movement and locomotion as well as from an evolutionary perspective, we investigated the nature and extent of any differences in Nr projections to the olivary complex in quadrupedal and bipedal species. Using neuroanatomical tract-tracing techniques we developed a ‘‘neural sheet’’ hypothesis allowing us to propose how rubro-olivary relations differ among the three species. Methods and Findings: Wheat germ agglutinin-horseradish peroxidase staining supports findings that the cat’s nucleus accessories medialis of Bechtrew (NB) projects mainly to the lateral bend of the principal olive. We clarified boundaries among nucleus of Darkschewitsch (ND), NB and parvicellular red nucleus (pNr) of the cat’s neural sheet. The macaque’s ND- medial accessory olivary projection is rostro-caudally organized and the dorsomedial and ventrolateral parts of the macaque’s pNr may project to the principal olive’s rostral and caudal dorsal lamella; in cat it projects as well to pNr. Myelin- and Nissl-stained sections show that a well-developed dorsomedial part of the human Nr consists of densely packed cells, deriving small myelinated fibers that continue into the medial central tegmental tract. Conclusions: Based on these findings we suggest there are distinct bipedal-quadrupedal differences for Nr projections to the olivary complex. We propose the Nr of cats and monkeys comprise the ND, NB and pNr in a zonal sheet-like structure, retaining clear nuclear boundaries and an isolated, well-developed mNr. The human NB may be distinguished from its more specialised ND (ND lies alongside a well-developed pNr) in the human central gray. Phylogenetically, the NB may have been translocated into a roll-shaped Nr in the reticular formation, the dorsomedial portion of which might correspond to the cat’s and monkey’s NB. Citation: Onodera S, Hicks TP (2009) A Comparative Neuroanatomical Study of the Red Nucleus of the Cat, Macaque and Human. PLoS ONE 4(8): e6623. doi:10.1371/journal.pone.0006623 Editor: Hiroaki Matsunami, Duke Unviersity, United States of America Received February 25, 2009; Accepted July 8, 2009; Published August 13, 2009 Copyright: 2009 Onodera et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors have no support or funding to report. Competing Interests: The authors have declared that no competing interests exist. * E-mail: sonodera@iwate-med.ac.jp Introduction The structure and function of the mesodiencephalic region and possible homologies among experimental species used in neuro- anatomical and electrophysiological studies such as rat, cat and monkey has long been problematic. However the important role of many of the midbrain nuclei in locomotion especially, but also in many aspects of other forms of motor control, make a comparison of connectivity relationships involving this region between bipeds and quadrupeds of considerable interest. Such knowledge may lead for example to new insights into evolutionary processes which could have resulted in the advent of bipedalism. They also may cast new light on how fine-movement control likely emerged from more primitive forms of template-based motor functions. The aim of the present study was to identify area(s) corresponding to the human nucleus accessories medialis of Becheterew (NB) and its descending tract through comparisons of data from the cat, macaque and human, and to propose a new model for the human red nucleus. In humans, the red nucleus consists of the parvicellular red nucleus (pNr) and it derives the central tegmental tract (CTT), whereas the cat’s red nucleus contains the magnocellular red nucleus (mNr), the origin of the rubrospinal tract. In a pioneering study of this region in cats, Ogawa (1939) proposed that the cat’s pNr corresponded to a nuclear complex consisting of the nucleus of Darkschewitsch (ND), the interstitial nucleus of Cajal (Nint) and the nucleus of the fields of Forel, forming the medial tegmental tract (MTT) [1]. Mannen (1988) published a work entitled ‘‘A dendro-cyto-myeloarchitectonic atlas of the cat’s brain’’; his work was based on material stained by Golgi-, Weigert- and Nissl- prepared serial sections [2]. Individual Golgi-impregnated neurons (printed in eight published colours) clearly were identifiable throughout the entire brain. This excellently detailed atlas showed the cat’s mNr as being classified as ‘‘closed nuclei’’ in contrast to ‘‘open nuclei’’, since the extranuclear dendrites of its cells seldom were found in the neighboring reticular formation. In these normally stained sections, the poorly-developed feline pNr could not be clearly demarcated from among the diffusely distributed neurons of the reticular formation. Of course all anatomical studies, whether using tract-tracing with WGA-HRP or cytological in nature (e.g., Golgi-, Weigert- or Nissl-staining) particularly those done in earlier decades, will be limited by technical and PLoS ONE | www.plosone.org 1 August 2009 | Volume 4 | Issue 8 | e6623