Spatiotemporal Features Of Gamma Oscillations Mediated By Dopamine D3 Receptors In Dyskinetic Rats

Background:Parkinson’s disease(PD)is a common neurodegenerative disease in the aged,and levodopa replacement therapy is the standard treatment for PD patients.Levodopa-induced dyskinesia(LID)is a common complication of Parkinson’s disease following chronic dopaminergic treatment.Excessive gamma oscillations have been reported in LID.However,the longitudinal alteration,spatial connectivity and regulatory mechanisms of gamma oscillations remain unclear.Here,we investigated the spatiotemporal features of gamma oscillations and the mechanism of dopamine D3 receptors’(D3Rs’)effects on gamma oscillations.Methods:For experiment 1,54 rats were divided randomly into six groups:Sham+saline(n=8),Sham+LB(n=8),PD+saline(n=10),PD+LB(n=19)and PD+PD 128907(n=9)groups.Unilateral 6-hydroxydopamine(6-OHDA;DR0610,HARVEYBIO,China)lesion were created in rats in the latter three groups,and sham lesions were created with saline in rats in the former two groups.Apomorphine-induced rotation test were conducted to detect successful PD induction on day 14.On day 15,microelectrodes were implanted into the Ml and DLS on the lesion side.On day 29,baseline LFP(5 min)was recorded for all rats.Subsequently,intraperitoneal injections of LB(8 mg/kg L-dopa plus 12 mg/kg benserazide;PD+LB and Sham+LB groups)or PD 128907(0.3mg/kg,a selective D3R agonist,PD+PD128907 group)or saline(Sham+saline and PD+saline)was administered for 14 consecutive days.The Abnormal Involuntary Movement Scale(AIMs)was administered on days 29,32,35,38,and 41 while LFP were recorded.After 14 days of LB injection,rats in the PD+LB group were injected with LB plus saline(LID+LB group,n=8)or the selective D3R antagonist PG01037(LID+PG01037 group,n=8;AOB5096 and AOBIOUS,8 mg/kg)for 7 consecutive days to further examine the potential role of D3R as a target for LID treatment.The AIMs was evaluated during LFP recording on days 43,46,and 49.All rats were sacrificed for histological analysis on day 50.Results:Time-dependent parabolic pattern of cortical aperiodic signals(exponent and offset shifts)and periodic components(peak frequency shift,power and bandwidth)correlated with corresponding Abnormal Involuntary Movement Scale scores after a single levodopa injection.Day-dependent increased manner of cortical aperiodic signals(exponent and offset shifts)and periodic components(peak frequency shift and power)at 80 min after repeated levodopa injection across recording days correlated with dyskinesia,with the peak frequency being the most sensitive parameter.Synchronized gamma oscillations with bidirectional motor cortex(?) dorsolateral striatum flow in LID was identified.Furthermore,targeting D3R with its selective agonist PD 128907 induced excessive gamma oscillations and dyskinesia.Conversely,PG01037,a selective D3R antagonist,normalized gamma oscillations and attenuated dyskinesia.Based on the extracted parameters,peak frequency of cortical gamma oscillations was a convenient and promising indicator to diagnose and classify LID.D3R,a potential target,mediated gamma oscillations to ameliorate dyskinesia.Conclusions:Day-dependent increased pattern and time-dependent parabolic trend of periodic and aperiodic activities were identified in this study which may contribute to optimize neuromodulatory stimulation parameters,guide non-invasive brain stimulation and design a promising feedback signal for closed-loop neuromodulation in future clinical applications of PD.OF note,among analyzed parameters,peak frequency of periodic gamma activities was a reliable and promising biomarker to diagnose and classify LID.Moreover,the role of D3R play in dyskinesia is explored at level of electrophysiology which provide compelling scientific evidence for the future clinical translation and application of D3R.