Metabolic activity of excitatory parafascicular and pedunculopontine inputs to the subthalamic nucleus in a rat model of Parkinson's disease

Using a combination of metabolic measurement and retrograde tracing, we sho w that the neurons in the pedunculopontine nucleus and parafascicular nucle us of the thalamus that project to the subthalamic nucleus are hyperactive after nigrostriatal dopaminergic denervation in rats. In Parkinson's diseas e, the loss of dopaminergic neurons induces a cascade of functional changes in the basal ganglia circuitry including a hyperactivity of the subthalami c nucleus. This hyperactivity is thought to be due to a diminution of the i nhibitory pallidal influence. However, recent studies have suggested that o ther cerebral structures are involved in the subthalamic neuronal hyperacti vity. This study was undertaken to identify these cerebral structures. Neur ons projecting to the subthalamic nucleus were identified by retrograde tra nsport of wheat germ agglutinin conjugated to horseradish peroxidase, injec ted into the subthalamic nucleus of rats with 6-hydroxydopamine unilateral lesion of the substantia nigra pars compacta and sham-lesioned animals. Met abolic activity was determined in the same neurons using in situ hybridizat ion for the first subunit of cytochrome oxidase messenger RNA, a metabolic marker, and image analysis. Horseradish peroxidase-labeled neurons were fou nd in the globus pallidus, parafascicular and pedunculopontine nucleus and sometimes in raphe nuclei and the substantia nigra pars compacta. Measureme nt of metabolic activity was performed for the globus pallidus, the peduncu lopontine and parafascicular nuclei. The expression level of the first subu nit of cytochrome oxidase messenger RNA in neurons projecting to the subtha lamic nucleus was 62% higher in parafascicular neurons and 123% higher in p edunculopontine neurons in 6-hydroxydopamine-lesioned rats, compared to sha m-lesioned animals. An increase was also observed in the globus pallidus, b ut did not reach significance. Our results suggest that hyperactivity of subthalamic neurons could be due, at least in part, to an increase of excitatory input arising from the pedu nculopontine and parafascicular nuclei. These data also suggest that the la tter structures may play an important role in the physiopathology of Parkin son's disease. (C) 2000 IBRO. Published by Elsevier Science Ltd.