Single-axon tracing of the corticosubthalamic hyperdirect pathway in primates
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Individual axons that form the hyperdirect pathway in Macaca fascicularis were visualized following microiontophoretic injections of biotinylated dextran amine in layer V of the primary motor cortex (M1). Twenty-eight singly labeled axons were reconstructed in 3D from serial sections. The M1 innervation of the subthalamic nucleus (STN) arises essentially from collaterals of long-ranged corticofugal axons en route to lower brainstem regions. Typically, after leaving M1, these large caliber axons (2–3 µm) enter the internal capsule and travel between caudate nucleus and putamen without providing any collateral to the striatum. More ventrally, they emit a thin collateral (0.5–1.5 µm) that runs lateromedially within the dorsal region of the STN, providing boutons en passant in the sensorimotor territory of the nucleus. In some cases, the medial tip of the collateral enters the lenticular fasciculus dorsally and yields a few beaded axonal branches in the zona incerta. In other cases, the collateral runs caudally and innervates the ventrolateral region of the red nucleus where large axon varicosities (up to 1.7 µm in diameter) are observed, many displaying perisomatic arrangements. Our ultrastructural analysis reveals a high synaptic incidence (141%) of cortical VGluT1-immunoreactive axon varicosities on distal dendrites of STN neurons, and on various afferent axons. Our single-axon reconstructions demonstrate that the so-called hyperdirect pathway derives essentially from collaterals of long-ranged corticofugal axons that are rarely exclusively devoted to the STN, as they also innervate the red nucleus and/or the zona incerta.
KeywordsBasal ganglia Subthalamic nucleus Primary motor cortex Single-axon reconstruction Corticosubthalamic projection Monkey
Biotinylated dextran amine
Deep brain stimulation
External segment of the globus pallidus (external pallidum)
Internal segment of the globus pallidus (internal pallidum)
Forel’s field H1 (thalamic fasciculus)
Forel’s field H2 (lenticular fasciculus)
Primary motor cortex
Phosphate buffer saline
Reticular thalamic nucleus
Substantia nigra pars reticulata
Superior pontine nucleus
The study was supported by research grants from the Canadian Institutes of Health Research (CIHR MOP-153068) and the Natural Sciences and Engineering Research Council of Canada (NSERC 2018-06264 and 2018-522690) to M.P. who also benefited from a Junior II career award from the Fonds de Recherche du Québec-Santé (FRQ-S). D.C. was the recipient of MSc fellowship from FRQ-S.
Compliance with ethical standards
All experimental procedures were approved by the Comité de Protection des Animaux de l’Université Laval, in accordance with the Canadian Council on Animal Care’s Guide to the Care and Use of Experimental Animals (Ed2). Maximum efforts were made to minimize the number of animals used.
Conflict of interest
The authors declare that they have no conflict of interest.
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