[Selective ablation of certain neural pathways by gene transfer using viral vectors: analysis of primate basal...

Using a neuron-specific retrograde gene-transfer vector based on the lentivirus, we established immunotoxin (IT)-mediated tract targeting in the primate brain; this technique allows ablation of a neuronal population constituting a certain pathway. Here, we introduce a recent study on selective removal of the cortico-subthalamic "hyperdirect" pathway. Together 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 of 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 evidence suggest that the early excitation may be derived from the hyperdirect pathway. We injected the lentiviral vector expressing human interleukin-2 receptor α-subunit into the monkey STN. IT was then injected into the SMA. We recorded GPi neuron responses to SMA stimulation. We found that the early excitation was reduced neither with the inhibition nor with the late excitation. The spontaneous firing rate and pattern of GPi neurons remained unchanged. This indicated that IT-mediated tract targeting successfully and selectively eliminated the hyperdirect pathway from the basal ganglia circuitry without affecting the spontaneous activity of STN neurons. This electrophysiological finding was confirmed using anatomical data obtained from retrograde and anterograde neural tracings. The present results show 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.