Premature responding following bilateral stimulation of the rat subthalamic nucleus is amplitude and frequency dependent

The subthalamic nucleus (STN), a key component of the basal ganglia circuitry, functions as an internal clock that regulates the correct sequence of movements in a motor response. The importance of the STN in motor function is evidenced by its involvement in Parkinson disease (PD). This nucleus has also been associated with the attentional and emotional aspects of motor behavior through its connections with the limbic and prefrontal areas of the brain. As lesions of the STN have been shown to increase premature responding in a serial reaction time task in rats, indicative of its involvement in cognitive performance, the present study aimed to investigate whether bilateral deep brain stimulation (DBS) of the STN, in non-lesioned rats, affects cognitive functions and whether these are dependent on certain stimulation parameters. Rats were trained in a choice reaction time task and implanted bilaterally with electrodes. Stimulation parameters (amplitude, frequency and pulse width) were varied during the test procedure, after which rats were sacrificed and the brains processed for histochemical staining. Results show no change in reaction times or motor times during stimulation. However, a linear decrease in premature responses was observed with decreasing amplitudes and at high frequencies only. These results are the First to demonstrate that bilateral STN HFS has a positive effect on cognition in freely moving rats. This latter result is in contrast to findings following lesions of the STN, and suggests that current strength and frequency of stimulation are parameters that are integral to the mediation of stimulation effects. Furthermore, the overall effects of DBS on neuronal cells cannot be classified simply as being "inhibitory" and evidently mediates its effects by more complex mechanisms than lesions of the same brain area. (C) 2004 Elsevier B.V. All rights reserved.