Abstract
Using 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.
Highlights
To define the framework of complex and elaborate neural networks, it is essential to systematically understand diverse brain functions acquired on network basis
The NeuRet-IL-2Ra-GFP vector was injected into the subthalamic nucleus (STN) of monkeys M, G, and U based on the results of the electrophysiological mapping
Together with the direct and indirect pathways, the hyperdirect pathway is known to be among the major pathways of the basal ganglia [9,10]
Summary
To define the framework of complex and elaborate neural networks, it is essential to systematically understand diverse brain functions acquired on network basis. We have found that the use of modified glycoprotein of rabies virus for a pseudotyped lentiviral vector based on human immunodeficiency virus type 1 (HIV-1) can enhance the efficiency of gene transfer through retrograde transport of the vector [4,5]. This property of the pseudotyped vector is greatly meritorious for gene transfer into cell bodies of neurons that are located remote from the injection site of the vector. In mice with the vector expressing IL-2Ra injected into the striatum, IT injection into the thalamus succeeded in selective removal of the thalamostriatal pathway [6]
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