Tract Targeting in the Primate Brain: Selective Elimination of the
Cortico-Subthalamic “Hyperdirect” Pathway
Inoue, Daisuke Koketsu, Shigeki Kato, Kazuto Kobayashi, Atsushi Nambu,
a neuron-specific retrograde gene-transfer vector (NeuRet vector), we
established immunotoxin (IT)-mediated tract targeting in the primate brain
that allows ablation of a neuronal population constituting a particular
pathway. Here, we attempted selective removal of the cortico-subthalamic
“hyperdirect” pathway. In conjunction with the direct and
indirect pathways, the hyperdirect pathway plays a crucial role in motor
information processing in the basal ganglia. This pathway links the
motor-related areas of the frontal lobe directly to the subthalamic
nucleus (STN) without relay at the striatum. After electrical stimulation
in the motor-related areas such as the supplementary motor area (SMA),
triphasic responses consisting of an early excitation, an inhibition, and
a late excitation are usually detected in the internal segment of the
globus pallidus (GPi). Several lines of pharmacophysiological evidence
suggest that the early excitation may be derived from the hyperdirect
pathway. In the present study, the NeuRet vector expressing human
interleukin-2 receptor α-subunit was injected into the STN of macaque
monkeys. Then, IT injections were made into the SMA. In these monkeys,
single-neuron activity in the GPi was recorded in response to the SMA
stimulation. We found that the early excitation was largely reduced, with
neither the inhibition nor the late excitation affected. The spontaneous
firing rate and pattern of GPi neurons remained unchanged. This indicates
that IT-mediated tract targeting successfully eliminated the hyperdirect
pathway selectively from the basal ganglia circuitry without affecting
spontaneous activity of STN neurons. The electrophysiological finding was
confirmed with anatomical data obtained from retrograde and anterograde
neural tracings. The present results define that the cortically-driven
early excitation in GPi neurons is mediated by the hyperdirect pathway.
The IT-mediated tract targeting technique will provide us with novel
strategies for elucidating various neural network functions.
ONE 6/25 doi:10.1371/journal.pone.0039149.g001
1. Schematic representation of the experimental setup and time-course.
A: Experimental setup. A pair of bipolar stimulating electrodes was
placed in the forelimb region of the supplementary motor area (SMA). A
glass-coated Elgiloy-alloy microelectrode was inserted obliquely into the
internal segment of the globus pallidus (GPi) for extracellular
single-unit recording. The NeuRet-IL-2Rα-GFP vector was injected into
the SMA-recipient territory of the subthalamic nucleus (STN) according to
the mapping of cortically evoked responses therein. Four-to-six weeks
later, immunotoxin (IT) was injected into the SMA forelimb region. Cd,
caudate nucleus; GPe, external segment of the globus pallidus; Put,
putamen. B: Experimental time-course. Neuronal recordings from the GPi in
a control condition were performed before the IT injections into the SMA.
Later than two weeks (wks) after the IT injections, GPi recordings were
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