| Background Parkinson's disease(PD)is a degenerative disease of the nervous system more common in middle-aged and elderly people.It is mainly characterized by resting tremor,bradykinesia,myotonia,and posture disorders,and olfactory disorders,sleep disorders,mental and emotional disorders,autonomic dysfunction and cognitive dysfunction and other non-motor symptoms.The pathogenesis of PD is caused by oxidative stress,mitochondrial dysfunction,inflammatory response,and abnormal immune function due to a variety of pathogenic factors,resulting in massive degeneration of dopamine(DA)neurons in the substantia nigra.In spite of the continuous introduction of treatment programs and the launch of new drugs in the past decades,so far there is still no therapy can cure or slow the disease progression.Until now,Parkinson's disease remains an incurable disease.Non-human primates have many physiological characteristics that are similar to humans.The monkey Parkinson's disease model induced by MPTP is a typically representative,including clinical symptoms,pathological and biochemical changes..It becomes a widely accepted experimental model for PD study.Objective In this study,we established the cognitive behavioral DMTS method,evaluated the movement and non-kinematical changes of chronic lateral cynomolgus monkey PD model 7 years after the MPTP induction,and assessed the movement and non-motor activity of cynomolgus monkeys after intervention with levodopa and donepezil.Method1.To establish a cognitive behavioral DMTS assessment method and apply it to the training of cognition and behavior of macaque monkeys to explore the learning differences of different groups of cynomolgus monkeys.2.Behavioral changes after 7 years of modeling of lateral PD cynomolgus monkeys were examined through clinical scores,total body movement monitoring,fine arm movement with PUT feeding test and MAP feeding test,20-minute moving distance and activity amount,and circling counting Behavior.3.Non-motor behavior changes after 7 years of modeling of hemilateral PD cynomolgus monkeys were examined by means of DMTS cognitive evaluation and nighttime sleep activity.4.Effects of levodopa and donepezil on PD and non-kinesis behaviors after7 years of modeling in PD and control groups were investigated.Result1.The overall training success rate of cynomolgus monkey for DMTS test was 52.0%,of which male training success rate(82.0%)was higher than female(34.0%).The success rate of cynomolgus monkeys aged ? 20 years old was 63.0%,higher than that of younger cynomolgus monkeys(11 to 19 years old,40.9%).The training success rate of T2 DM animals(67.0%)was the same as that of obese monkeys,higher than that of the pre-diabetes(56.0%)and normal cynomolgus monkeys(33.0%).The length of time required for training females of cynomolgus monkeys was slightly higher than that of male cynomolgus monkeys.The length of time required for normal cynomolgus monkeys was significantly higher than that of general training,diabetes models,pre-diabetes models,and obesity models(P<0.05).2.The PD clinical score of cynomolgus monkeys was(3.86±0.56)after 7years of MPTP modeling,and the time required for PUT of non-lesioned left hand of the PD group was higher(23.14±3.56 s)than of the control group(P=0.003),but the lesioned right upper limb of the PD group could not perform the feeding test.The total daily activity counts of the PD group was lower than that of the control group during 24 hours and 12 hours but was not statistically significantly,so was the 12 hour night activity.The total daily travel distance and corresponding activity counts in the 20 minutes video recording was slight higher in the PD group than those in the control group,but there was no statistical significance.The rotation number of the PD group was(30.50±7.33),and no rotation was found in the control animals.The correct rate of 5s,10 s,15s,30 s delay for DMTS cognitive evaluation was significantly lower than that of control group(P<0.01).3.The clinical score of the PD group was significantly lower than that of the baseline after Levodopa intervention significantly decreased the total PD clinical score(2.43±0.23)(P=0.022),and the improvement of the lesioned right upper limb movement was much more significantly(P=0.011).The time required to pick up the food in the PUT test was significantly shorten in the left non-lesioned upper extremity after levodopa treatment(P=0.020),so was the FMPT(0.28±0.04 s)in the MAP test(P=0.049),but the lesioned right upper limb was still unable to perform the feeding operations.The total daily activity counts was significantly higher(improved)than that of the baseline both at 24 h cycle and the 12 h cycle after levodopa treatment(P<0.01).The number of rotation in the PD group animals after levodopa administration(19.25±7.77)was significantly lower than before the administration(P=0.001).In the DMTS cognition evaluation,there was no significant difference in the accuracy after 5s,10 s,15s,30 s delay for the PD group as compared with baseline.4.There was no significant improvement for the PD clinical scores before and after donepezil intervention.In the fine arm movement test,the time required for the non-lesioned left upper limb was also not statistically significant different before and after drug treatment.The lesioned right upper limb was still unable to perform fine motor testing.The total daily activity counts was slightly higher but not significantly different after drug treatment both at 24 h and 12 h period.The number of rotations after drug administration(9.50±3.91)was significantly lower than before the treatment(P=0.042).For the DMTS cognition evaluation,the correct rate after 5s,10 s,15s,and 30 s delay was not significantly different before and after drug administration.Conclusion The DMTS cognitive behavioral device and voluntary movement evaluation methods constructed based on WGTA are valided for behavioral evaluation of MPTP-induced PD model.The chronic clinical symptoms of MPTP in cynomolgus monkeys were improved after 7 years but still failed to fully recover.Bradykinesia and cognitive impairments still exist,which proves animals are still in the chronic PD state.Administration of levodopa can improve their clinical symptoms,including bradykinesia.Donepezil did not improve cognitive performance of the MPTP-induced PD animals,suggesting that changes in the long-term PD-cognitive-related neural circuits are not limited to acetylcholine neurons. |
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