Subthalamic Nucleus Activity in the Awake Hemiparkinsonian Rat: Relationships with Motor and Cognitive Networks

Abstract

Oscillatory activity in both beta and gamma ranges has been recorded in the subthalamic nucleus (STN) of Parkinson's disease (PD) patients and linked to motor function, with beta activity considered antikinetic, and gamma activity, prokinetic. However, the extent to which nonmotor networks contribute to this activity is unclear. This study uses hemiparkinsonian rats performing a treadmill walking task to compare synchronized STN local field potential (LFP) activity with activity in motor cortex (MCx) and medial prefrontal cortex (mPFC), areas involved in motor and cognitive processes, respectively. Data show increases in STN and MCx 29 -36 Hz LFP spectral power and coherence after dopamine depletion, which are reduced by apomorphine and levodopa treatments. In contrast, recordings from mPFC 3 weeks after dopamine depletion failed to show peaks in 29 -36 Hz LFP power. However, mPFC and STN both showed peaks in the 45-55 Hz frequency range in LFP power and coherence during walking before and 21 days after dopamine depletion. Interestingly, power in this low gamma range was transiently reduced in both mPFC and STN after dopamine depletion but recovered by day 21. In contrast to the 45-55 Hz activity, the amplitude of the exaggerated 29 -36 Hz rhythm in the STN was modulated by paw movement. Furthermore, as in PD patients, after dopamine treatment a third band (high gamma) emerged in the lesioned hemisphere. The results suggest that STN integrates activity from both motor and cognitive networks in a manner that varies with frequency, behavioral state, and the integrity of the dopamine system.

Effects of L-dopa priming on cortical high beta and high gamma oscillatory activity in a rodent model of Parkinson's disease

“…1 for details). In agreement with previous data (Brazhnik et al, 2012; Delaville et al, 2015; Quiroga-Varela et al, 2013), high beta (25–35 Hz) LFP power in the motor cortex of the lesioned hemisphere in fully-lesioned rats was significantly increased during treadmill walking compared to both intact control and partially-lesioned rats (Fig. 2A, C and E).…”

“…Furthermore, high gamma LFP activity increased in power and L-dopa-induced dyskinesia increased in duration between the first and last day of L-dopa priming in fully-lesioned rats. These observations are consistent with recent studies showing high gamma activity in the motor cortex and striatum of rats with L-dopa-induced dyskinesia (Delaville et al, 2015; Halje et al, 2012) and may be relevant to clinical reports of finely-tuned gamma (FTG) activity in the motor cortex, globus pallidus internal segment (GPi), subthalamic nucleus (STN), and thalamus in PD patients following DA replacement therapy (Litvak et al, 2012; Lopez-Azcarate et al, 2010; Jenkinson et al, 2013; Alegre et al, 2005; Kempf et al, 2009; Trottenberg et al, 2006; Alegre et al, 2012). Although the direct pathway has been more highly implicated in the mechanisms underlying L-dopa-induced dyskinesia than the indirect pathway (Darmopil et al, 2009; Fieblinger et al, 2014; Mela et al, 2012; Westin et al, 2007), we show that both D1 and D2 receptor agonists independently induced both the 80 Hz cortical high gamma oscillations and dyskinetic behaviors in the L-dopa primed rat.…”

“…Results are reported from three distinct groups: fully DA-lesioned, partially DA-lesioned, and intact control rats. Our findings show that L-dopa priming attenuates the cortical high beta activity that is associated with parkinsonian bradykinesia in the fully-lesioned rats (Avila et al, 2010; Brazhnik et al, 2012, 2014; Delaville et al, 2015) and promotes the emergence of a relatively narrow band of high gamma LFP activity (70–110 Hz range with a peak frequency ~80 Hz) in the motor cortex in conjunction with L-dopa-induced dyskinesia. Furthermore, high gamma LFP activity increased in power and L-dopa-induced dyskinesia increased in duration between the first and last day of L-dopa priming in fully-lesioned rats.…”

“…Similar to our previous studies (Avila et al, 2010; Brazhnik et al, 2012, 2014; Delaville et al, 2015), shorter epochs of FFT-based power spectra (60 s epochs of total power, as presented in the bar graphs) were obtained using a custom written Spike2 script from LFP waveforms that were smoothed to 500 Hz from their original sampling frequency (1000 or 2000 Hz). Inspection of the data showed that there was relatively little variability in the raw voltage levels over frequencies of interest within each group of rats (i.e., signals were within 3 standard deviations of the mean) and little evidence of significant extraneous/instrumental fluctuations between groups, indicating that normalization procedures were not necessary for these data sets.…”

“…PD primarily affects the motor system, inducing rigidity, slowness of movement, tremors and lack of coordination. Development of these motor impairments has been associated with the emergence of synchronized and oscillatory activity in the beta frequency range (13–35 Hz) in the motor cortex and basal ganglia of PD patients (Brown, 2003; Brittain and Brown, 2014; Brown et al, 2001; Levy et al, 2002; Priori et al, 2004; Weinberger et al, 2006; Kuhn et al, 2005) and hemiparkinsonian rats (Sharott et al, 2005; Avila et al, 2010; Brazhnik et al, 2012, 2014; Delaville et al, 2015). Increased oscillatory activity has also been observed at lower frequencies in parkinsonian primates (Bergman et al, 1994; Gatev et al, 2006; Devergnas et al, 2014; Raz et al, 2000; Rivlin-Etzion et al, 2010).…”