gms | German Medical Science

Objective: Rat models of Parkinson's disease are commonly based on unilateral lesioning of the substantia nigra, pars compacta (SNc), resulting in only a hemiparkinson-like phenotype. In contrast, bilateral lesioning often leads to a parkinsonian phenotype where motor symptoms (hypokinesia and bradykinesia) can be observed. Bilaterally lesioned animals are therefore better suited to study pathophysiology and potential treatments. Here, we assessed locomotor activity during high-frequency stimulation (HFS) of the subthalamic nucleus (STN) and electrophysiological changes in animals lesioned bilaterally using microelectrode targeting.

Methods: Microelectrode recordings were performed in both hemispheres of anaesthesized Brown Norway rats to identify the borders of the substantia nigra pars reticulata (SNr) under stereotactic guidance. The lesion was placed at the anterior and dorsal margin of the SNr with relative sparing of cell groups in the ventral tegmental area. After ~4 months, 6-OHDA and sham-animals were bilaterally implanted in the STN with bipolar platin-iridium electrodes and frontal cortical screws were used to record LFP and ECoG activity, respectively. Bipolar HFS (130 Hz, 60µsec) was performed on the STN of one hemisphere, using stimulation amplitudes below the threshold of producing dyskinetic side effects. Experiments were conducted in an open-field arena and locomotor activity (overall covered distance; locomotion and resting time; movement velocity) was quantified using a specially designed video-tracking system.

Results: Microrecording-guided targeting produced a high percentage of successful lesions as revealed by histological and behavioural quantification. Over 24hrs, lesioned animals displayed >70% reduction of the covered distance, >50% reduction in total time of activity and >25% reduction of speed. In contrast, ineffective or sham lesioning resulted in reductions of only 10-20% in these parameters. Electrophysiological signals showed evidence of changes in the low frequency range.

Conclusions: Together, these results provide a multi-axis behavioural and electrophysiological investigation in a rarely used, but arguably more accurate, rodent model of Parkinson's disease.