The Study Of Thalamic Striatum Pathway In Dyskinesia Of Parkinson's Disease Rats

Parkinson's disease(PD)is a complex neurodegenerative disorder with both non-motor and motor symptoms,such as dyskinesia,rigidity,resting tremor and postural instability.The distinguishing pathological feature of PD is a progressive loss of dopamine(DA)in the nigrostriatal pathway.The DA deficiency results in abnormal neuronal activity and increased synchrony in the basal ganglia-thalamocortical circuits,which may be correlated with the motor symptoms.The centromedian-parafascicular complex(CM/PF,or the parafascicular thalamic nucleus(PF)in rodents),intralaminar thalamic nuclei,has been reported to be the main non-dopaminergic neuron loss nucleus in the thalamic nuclei.Recently,high-frequency deep brain stimulation(DBS)PF can alleviate symptoms such as tremor and cognitive disorders that are difficult to treat by DBS other nuclei or by drugs.Therefore,PF has been used as a target for DBS to treat some of the motor symptoms of PD.Alterations of firing rate and oscillatory activity in the PF have also been recorded in PD patients and anesthetized animal models of the disease.Therefore,exploring the effects of DA depletion on neuronal activity in the PF in different behavioral states remains of interest.Recently,the thalamostriatal pathway has received increasing attention in PD research.For example,electrophysiological slice studies consistently have shown that PF-striatum synaptic transmission is dysregulated after DA depletion.However,PD-related changes in the relationship between neuronal activity in the PF and dorsal striatum has not yet been investigated.In addition,although the CM/PF has been used as a target for DBS to treat some of the motor symptoms of PD,the underlying mechanisms are still unclear.PF-DBS may exert its effects through the complex regulation of striatal neuronal activity and consequently influence some of the motor symptoms of PD.This study aimed to investigate the effects of 6-OHDA lesioning on neural activities in the PF and striatum and importantly on their relationship in awake,behaving animals.Therefore,Spikes and local field potential(LFP)were simultaneously recorded from chronically implanted electrodes in both the PF and striatum during rest or treadmill walking in the DA depleted hemisphere of hemiparkinsonian and neurologically intact rats.Moreover,with the immunofluorescence and laser scanning confocal,we distinguished the types of neurons in the PF and observed the damage condition of the PF neuron subtypes in lesioned rats.In this study,we first classified the PF neurons into two predominant substypes based on their electrophysiological characteristics: PF I and PF II.What's more,three types of neurons were collected in the striatum: medium spiny neuron(MSN),fast spiking interneurons(FSI)and cholinergic interneuron(CIN).Finding from this study,6-OHDA lesions extensively modified the activity of PF and striatum neurons and were accompanied by alteration of electrophysiological activity in the thalamostriatal circuit.After 6-OHDA lesion,we found changes in the neuronal firing rate and pattern in the PF of hemi-Parkinsonian rats.The LFP of the PF also emerged alteration in the 6-OHDA lesioned rats.During the treadmill walking period,both the small-amplitude PF I population and large-amplitude PF II neuron had decreased spike firing rates,but only PF II neurons had altered firing patterns.During rest,only PF I neuronal firing patterns were changed,and no firing rate changes in the two neuron subtypes was observed.We confirmed that DA loss induced increases in the relative LFP power in both the ? and low-? bands in the PF during both states,but a decrease of power in the ? band only during rest states.During the inattentive rest states,the Spike-LFP coherence of PF I increased in the ? and low-? bands in the PD rats relative to control rats.However,during the moving states,the Spike-LFP coherence of PF II in PD rats increased in the 1-12 Hz and ? bands compared to control rats.After 6-OHDA lesion,in the striatum of PD rats,the fring rates of MSNs were elevated most prominently and firing more irregular during the attentive rest or the treadmill walking states.The effects of the DA depletion on the FSI and CIN were very small.In the striatum,both an increase of LFP power in the ? band and a decrease of LFP power in the ? band were found in the lesioned rats during both states.Importantly,we found increased synchronization of LFP oscillations between PF and dorsal striatum after DA lesion.During the rest epochs,significant increases were found in both the ? and ? bands for the mean coherence,but only in the ? band for the phase coherence.During the treadmill walking epochs,significant increases were found in both ? and ? bands for the two coherence measures.PD was accompanied by increases in synchronization between PF spikes and striatum ?-frequency LFP.PF I neuronal spikes synchronized with the striatum ?-frequency band during the rest epoch,whereas PF II neuronal spikes had dramatically increased coherence with the striatum ? range during the treadmill walking epoch.The anatomic experimentals revealed that the neurons in 6-OHDA lesioned side of PF were damaged not only in the quantity but also in the morphology,compared with the normal side.However,by immunofluorescence experiment,two subtype neurons in PF were identified as glutamatergic neurons and ?-aminobutyric neurons.The number of ?-aminobutyric neurons was not affected but the number of glutamatergic neurons was significantly decreased after PD.In conclusion,the most notable finding was that the alteration of the electrophysiological activity in the thalamostriatal circuit and the two nuclei were state-dependent.And different PF and striatum neuron subtypes may be responsible for varying symptoms in different behaviour states after DA loss.These changes may be the cause of different pathological symptoms in different behavioral states.Hopefully,further investigations of the abnormalities along the thalamostriatal pathway in different behavioural states of PD will provide better insights into the fundamental mechanisms underlying the motor symptoms of PD and its therapeutic treatment.