The Research On The Electrophysiological Change Of The Pedunculopontine Nucleus In Rat Models Of Parkinson's Disease

Parkinson's disease(PD)is a common progressive neurodegenerative disease.The main pathological change is the loss of dopaminergic(DA)neurons in the substantia nigra of the midbrain,which in turn triggers the disorder of the basal ganglia,and then causes some symptoms of PD.The symptoms are characterized by tremor at rest,rigidity,slowness of voluntary movement and freezing.The mainstay of PD treatment is dopamine replacement with levodopa or dopamine agonist.However,some side effects,such as dyskinesia and gait disturbances respond poorly to this treatment.Recently,low-frequency deep brain stimulation of the pedunculopontine nucleus(PPN)is emerging as an alternative treatment to improve the postural and gait disorders in clinical studies,which cause PPN attracting a great deal of interest.PPN is a neurochemical heterogeneous nucleus,which contains different neuronal population.However,in PD condition,the classification of the electrophysiological characteristics of PPN and the link between electrophysiological characteristics and neuronal morphology is controversial.Based on this,we implanted electrodes in the PPN and then recorded the spontaneous discharge of individual neuron in the PPN in control and rat models of PD groups.The immunofluorescence histochemical staining was used to detect the morphological characteristics.The present study showed the following results:Neurons in PPN are classified into three different types according to their electrophysiological characteristics.These neurons are identified as cholinergic,?-aminobutyric acid(GABA)and glutamatergic neurons by juxtacellular techniques accordingly.In PD condition,the discharge rate of all three types of neurons increased,in which glutamatergic neurons changed significantly.In the spike-local field potential(LFP)coherence analysis,after 6-hydroxydopamine(6-OHDA)lesion,the synchrony of cholinergic neurons did not change significantly,the synchronization of GABAergic neurons significantly increased in the low frequency band,the glutamatergic neurons had phase-locked in the beta(12-30 Hz)frequency band.Taken together,the electrophysiological characteristics of glutamatergic neurons changed significantly in PD conditions.Histological results showed the number and morphology of the three types of neurons in PPN have changed.On the lesioned side,the size of cell body of cholinergic neurons became smaller,the number of GABAergic neurons decreased,and decreased neuronal density and shrink cell body area size happened on glutamatergic neurons.Taken together,the morphology of glutamatergic neurons changed significantly in PD conditions.The experimental results in this part confirmed that the electrophysiological changes of neurons in PPN are related to morphological changes,but the electrophysiological changes may also be caused by changes in the projections received by PPN.It is known that the nucleus of direct and indirect pathways of PPN and the basal ganglia and the primary motor cortex(M1)have fiber projections.Therefore,abnormal activities of the basal ganglia and M1 are likely to cause the change of PPN.Baesd on this,the effect of the two pathways and M1 on the change of PPN activitied need to be further detected.The electrodes are implanted into PPN and M1 in control group and PD model group at the same time.The rats are treated with D1 receptor blocker SCH23390 and D2 receptor blocker Raclopride during the resting state and treadmill exercising state.The present study showed the following results:In the PD model of rats,the relative power of PPN increased in beta(12-30 Hz)frequency band.The elimination of D1 or D2 receptor could mimick the change of the beta power caused by the loss of dopamine in PPN during resting states not in locomotor states.It was worthy to mention that the increase of beta band power in PD condition would be worse by blocking the direct pathway,while corrected by blocking the indirect pathway when the rats were in the resting or locomotor states.In the PD model of rats,the relative power of M1 increased in beta(12-30 Hz)frequency band.The elimination of D1 or D2 receptor could mimick the change of the beta power caused by the loss of dopamine in PPN during resting states or locomotor states.It was worthy to mention that the increase of beta band power in PD condition would be worse by blocking the direct pathway,while corrected by blocking the indirect pathway when the rats were only in the resting states.The LFP synchronization in PPN and M1 was enhanced after 6-OHDA lesion when the rats were in the resting and locomotion states.Such alteration could be reversed by blocking the indirect pathway.To sum up,in the PD model of rats,the glutamatergic neurons showed dramatic change in the electrophysiological characteristics.In addition,strong beta synchrony is a key pathophysiological symptom of parkinsonian circuits.Meanwhile,dramatic morphological damage was also detected in glutamatergic neurons in the lesioned side,which indicated the close relationship between the electrophysiological and morphological properties.The LFP in the PPN and the coherence between PPN and M1 in the beta frequency band changed after the intervention of antagonist,which could be corrected by the intervention of D2 receptor antagonist.These result indicated that the indirect pathway mediated by D2 receptor plays a key role in the change of electrophysiological properties in PPN after 6-OHDA lesion,which provided a new view to detect the mechanism of PD.