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The human motor cortex microcircuit: insights for neurodegenerative disease

Abstract

The human motor cortex comprises a microcircuit of five interconnected layers with different cell types. In this Review, we use a layer-specific and cell-specific approach to integrate physiological accounts of this motor cortex microcircuit with the pathophysiology of neurodegenerative diseases affecting motor functions. In doing so we can begin to link motor microcircuit pathology to specific disease stages and clinical phenotypes. Based on microcircuit physiology, we can make future predictions of axonal loss and microcircuit dysfunction. With recent advances in high-resolution neuroimaging we can then test these predictions in humans in vivo, providing mechanistic insights into neurodegenerative disease.

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Fig. 1: Motor cortex cell type and connectivity between layers of the motor cortex (rodent).
Fig. 2: Layer-specific and cell-specific schematic of the M1 microcircuit.
Fig. 3: Effect of postsynaptic neuronal death on presynaptic axons and neurons (human).
Fig. 4: Layer-specific and cell-specific connectivity loss in human PD and LID.
Fig. 5: Layer-specific and cell-specific connectivity loss in human HD and human ALS.
Fig. 6: Average layer-dependent fMRI responses in the motor cortex of all participants in response to four different sensorimotor tasks (human).
Fig. 7: In vivo layer-specific and cell-specific high-resolution neuroimaging in humans.

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Acknowledgements

P.M. is supported by the National Institute for Health Research. G.R. and S.J.T. are supported by a Wellcome Trust Collaborative Award (grant code 200181/Z/15/Z). The authors thank A. Oswal, G. Maegherman, Y. Wu and S. Kaiser for helpful comments on the manuscript.

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P.M. and J.J. researched data for the article, and made a substantial contribution to the discussion of content and writing, reviewing and editing of the manuscript before submission. S.J.T. and G.R. made a substantial contribution to the discussion of content, and reviewing and editing of the manuscript before submission.

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Correspondence to Peter McColgan.

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Glossary

Antisense oligonucleotide therapies

(ASOs). Insertion of single-stranded DNA molecules that bind to target pre-mRNA and recruit RNAse H, causing degradation of the complex. This approach has already been applied to numerous neurodegenerative diseases, including Huntington disease, Parkinson disease, amyotrophic lateral sclerosis and Alzheimer disease.

Fusiform

A spindle shape, which is wide in the middle and tapers at both ends.

Piriform

A pear shape, from the Latin pirum (‘pear’) and forma (‘shape’).

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

(MPTP). A compound that can cross the blood–brain barrier, where it is then converted into 1-methyl-4-phenylpyridinium (MPP+), a neurotoxin, which causes selective and permanent destruction of dopaminergic neurons in the substania nigra.

Vibrotactile discrimination

An experimental design in which stimuli of two different frequencies are applied to the hand and the participant is asked to discriminate between the low-frequency and high-frequency stimuli.

Infragranular layers

Cortical layers 5 and 6, which are below the granular layer 4 in the neocortex.

Supragranular layers

Cortical layers 1–3, which are above the granular layer 4 in the neocortex.

Magnetic resonance spectroscopy

(MRS). A technique detecting radiofrequency electromagnetic signals that are produced by the atomic nuclei within molecules. It can be used to obtain measures of chemicals in the brain, such as N-acetylasparate, creatine, glutamate and GABA.

Hyperkinetic

Increased or excessive movement, such as tremor in Parkinson disease or chorea in Huntington disease.

Hypokinetic

Reduced or slowed movement, such as reduced fine finger movements and rigidity seen in Parkinson disease.

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McColgan, P., Joubert, J., Tabrizi, S.J. et al. The human motor cortex microcircuit: insights for neurodegenerative disease. Nat Rev Neurosci 21, 401–415 (2020). https://doi.org/10.1038/s41583-020-0315-1

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