Download Reply: The cuneiform nucleus may be involved in the regulation of

doi:10.1093/brain/awt125
Brain 2013: 136; 1–2
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BRAIN
A JOURNAL OF NEUROLOGY
LETTER TO THE EDITOR
Reply: The cuneiform nucleus may be involved in the regulation of skeletal muscle tone
by motor pathway: a virally mediated trans-synaptic tracing study in surgically
sympathectomized mice
Mesbah Alam, Kerstin Schwabe and Joachim K. Krauss
Department of Neurosurgery, Medical University of Hannover, Hannover, Germany
Correspondence to: Mesbah Alam,
Neurosurgery, Medical School Hannover,
Carl-Neuberg-Str. 1 Hannover 30625,
Germany
E-mail: [email protected]
Sir, We appreciate the opportunity to respond to the comment by
Xiang et al. (2013) on our review on interspecies differences in the
pedunculopontine nucleus area. As exemplified by the data of
Xiang et al. (2013) it is evident that the mesencephalic locomotor
region compromises several distinct structures that are involved in
initiation and inhibition of gait, and certainly the implications of
both the cuneiform nucleus and the subcuneiform nucleus need to
be studied in more detail. Also, as mentioned in our review, there
is a paucity of data on the downstream mechanisms mediating
neuronal activity in the mesencephalic locomotor region.
The role of the pedunculopontine nucleus area as a target site
for deep brain stimulation for treatment of medically refractory
gait and postural abnormalities in late stage Parkinson’s disease
and progressive supranuclear palsy still needs further clarification.
Because post-mortem studies in Parkinson’s disease and progressive supranuclear palsy show 60% loss of cholinergic neurons
in the pedunculopontine nucleus (Jellinger, 1988) it should also
be considered that stimulation of the pedunculopontine nucleus
area may involve activation of adjacent structures in the mesencephalic locomotor region, especially the cuneiform nucleus
through neuronal modulation of efferents to motor neurons
(Milner and Mogensen, 1988). The pedunculopontine nucleus
and the cuneiform nucleus are diffusely intermingled and topographically
and
neurochemically
not
well
defined.
Cytoarchitecturally the pedunculopontine nucleus consists of a
dorsolateral compact part, the ‘pars compacta’, with a higher
density of cholinergic neurons and a diffuse part, the ‘pars dissipata’ with glutamatergic, cholinergic and other neuron types,
situated at the rostrocaudal axis. The cuneiform nucleus consists
of GABAergic and nitrergic neurons (reviewed in Inglis and Winn,
1995; Alam et al., 2011).
Both pedunculopontine nucleus and cuneiform nucleus have
been suggested to facilitate muscle tone during the initiation of
locomotion (Mori et al., 1987; Alam et al., 2011). Lesion within
the pedunculopontine tegmental area pars dissipata in rats resulted
in motor deEcits, which is consistent with the hypothesis that the
anterior pedunculopontine nucleus (the homologue to the pedunculopontine tegmental area pars dissipata in rodents), has functions related primarily to motor control, whereas the posterior
pedunculopontine nucleus (the pedunculopontine tegmental area
pars compacta) is less involved in motor activity (Alderson et al.,
2008). More recent studies, however, have shown that specific
lesions of cholinergic neurons in the pedunculopontine tegmental
area pars compacta result in motor dysfunction (Aziz and Stein,
1997; Karachi et al., 2010). So far, an anatomical connection between pedunculopontine nucleus and spinal cord has been
demonstrated in humans by using diffusion tractography
(Muthusamy et al., 2007) but not for the cuneiform nucleus.
Xiang et al. (2013) aimed to elucidate the motor neuronal circuitry between the skeletal muscle and cuneiform nucleus. They
found that neurons in the cuneiform nucleus and the caudal pars
compacta of the pedunculopontine tegmental area, which were
retrograde labelled after injection of the pseudorabies virus in the
gastrocnemius muscle, were not double-labelled for tyrosine hydroxylase and serotonin, whereas neurons in the pars dissipata of
the pedunculopontine tegmental area were double-labelled.
Advance Access publication June 13, 2013
ß The Author (2013). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
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| Brain 2013: 136; 1–2
The authors concluded that neuronal populations in the cuneiform
nucleus and caudal pars compacta of the pedunculopontine tegmental area differ from those of the pars dissipata of the pedunculopontine tegmental area, and suggested that the cuneiform
nucleus and the caudal pars compacta of the pedunculopontine
tegmental area regulate motor pathways by a direct neuronal circuit
from the caudal pars compacta of the pedunculopontine tegmental
area and cuneiform nucleus to skeletal muscle. Based on these findings the authors propose that neurons within the cuneiform nucleus
send projections to the medullary reticular formation, which in turn
projects to the central horn motor neurons, which control skeletal
muscle tone regulated by both and motor neurons.
Although the findings of Xiang et al. (2013) are certainly of
interest, we think that it is premature to suggest the cuneiform
nucleus directly as a target for deep brain stimulation in humans.
One should also keep in mind that the caudal pars compacta of
the pedunculopontine tegmental area and the cuneiform nucleus
differ with regard to their predominant neurotransmitters. In
Parkinson’s disease or progressive supranuclear palsy the loss of
cholinergic neurons in the pedunculopontine tegmental area might
be pivotal for disturbances of gait and posture (Warren et al.,
2005). Further experiments would be needed to elucidate if and
how stimulation of the cuneiform nucleus would affect muscle
tone when cholinergic neurons of the pedunculopontine tegmental
area are lost. Additionally, with regard to the interspecies differences considered in our review (Alam et al., 2011), the question
remains whether the findings shown in mice would also apply to
humans. Although the topography and morphological structure
are probably similar in most mammals, the distribution of cholinergic, glutamatergic or GABAergic neurons within these regions
and the degree of afferent and efferent Ebres may vary, which
could account for species-dependent outcome of behaviour in experimental settings.
Letter to the Editor
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