Red nucleus structure and function: from anatomy to clinical neurosciences

Abstract

The red nucleus (RN) is a large subcortical structure located in the ventral midbrain. Although it originated as a primitive relay between the cerebellum and the spinal cord, during its phylogenesis the RN shows a progressive segregation between a magnocellular part, involved in the rubrospinal system, and a parvocellular part, involved in the olivocerebellar system. Despite exhibiting distinct evolutionary trajectories, these two regions are strictly tied together and play a prominent role in motor and non-motor behavior in different animal species. However, little is known about their function in the human brain. This lack of knowledge may have been conditioned both by the notable differences between human and non-human RN and by inherent difficulties in studying this structure directly in the human brain, leading to a general decrease of interest in the last decades. In the present review, we identify the crucial issues in the current knowledge and summarize the results of several decades of research about the RN, ranging from animal models to human diseases. Connecting the dots between morphology, experimental physiology and neuroimaging, we try to draw a comprehensive overview on RN functional anatomy and bridge the gap between basic and translational research.

Keywords: Locomotion; Neuroimaging; Pain; Phylogenesis; Review; Skilled movements.

Fig. 1

Evolution of the RN circuitry. The scheme highlights the increasing complexity of rubral circuitry, and the evolutionary trend towards gradual segregation of the rubrospinal (red) and rubro-olivo-cerebellar (green) systems. a Primitive RN (anurans) is a small, ill-delimited group of neurons in the ventral midbrain (dashed borders), representing a rather simple relay station between the cerebellum and the spinal cord. b In quadrupedal reptiles, a rubro-olivary pathway appears. c In quadrupedal mammals, a partial segregation between rubrospinal and rubro-olivo-cerebellar systems occurs, with distinct cerebellar output channels and a gradual differentiation between parvocellular and magnocellular RN. d In primates, complete anatomical segregation and functional specialization of rubrospinal and rubro-olivo-cerebellar systems can be observed. RN red nucleus, mRN magnocellular red nucleus, pRN parvocellular red nucleus, Ln lateral nucleus (dentate), In interposed nucleus, IO inferior olive, Thal thalamus

Fig. 2

The RN circuitry in detail. 3D rendering of the cerebellum, mRN (edges), pRN (red), dentate nucleus (light blue), interposed nucleus (yellow), inferior olive (green) and thalamus (white). a The rubrospinal system. Descending motor cortical output (red arrows) is relayed by the mRN through the rubrospinal tract. Sensory afferents from the spinal (blue arrows) cord reach both the IN and the paravermal cerebellum through the spinocerebellar tracts; cortical cerebellar output converges on the interposed nucleus through Purkinje fibers (purple arrow). Cerebellar output from IN (orange arrow) in turn is relayed on mRN forming a feedback loop. b The rubro-olivo-cerebellar system. The pRN receives excitatory afferent fibers (red arrows) from a larger set of cortical regions and from the dentate nucleus, while its main projection output is the rubro-olivary pathway. The inferior olive is connected to the cerebellar cortex via the climbing fibers (green arrow) that synapse directly on Purkinje cells directed to the DN (purple arrow), modulating cerebellar plasticity. Excitatory projections from the inferior olive (red arrows) reach also the dentate nucleus, that in turn sends inhibitory descending projections (blue arrows) forming a feedback loop. RST rubro-spinal tract, CST cortico-spinal tract, CTT central tegmental tract, ICP inferior cerebellar peduncle, SCP superior cerebellar peduncle, VA ventral anterior, VL ventral lateral

Fig. 3

Anatomy of the human RN. a Macrophotograph of human autoptic upper midbrain from an adult male of 81 years. b Schematic transverse sections of normal human upper midbrain illustrating territorial delineations (adapted from Nieuwenhuys et al. 1980). c Right half of a midbrain section from an adult male of 81 years, counterstained with Luxol Fast Blue. 3 nucleus of oculomotor nerve, 3n oculomotor nerve, bic brachium of inferior colliculus, CC cerebral crus, CG central grey substance, CNF cuneiform nucleus, ctg central tegmental tract, ml medial lemniscus, mlf medial longitudinal fasciculus, PN paranigral nucleus, R red nucleus, SC superior colliculus, scp superior cerebellar peduncle, SNC substantia nigra, compact part, SNL substantia nigra, lateral part, SNR substantia nigra, reticular part. Scale bar = 2.5 mm

Fig. 4

BDNF expression in adult human RN. Human adult midbrain from an adult female of 67 years immunostained for BDNF. a Low-power view photomontage of the right red nucleus. b Higher magnification of the area framed in (a). 3 nucleus of oculomotor nerve, SNC substantia nigra, compact part. Scale bars: a = 250 μm; b = 50 μm