| Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. It is characterized pathologically by the selective and progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and the consequent deficiency of dopamine in the striatum. The dopaminergic deficit causes most of the motor manifestations associated with the disease, including resting tremor, rigidity, bradykinesia, gait disturbance and postural instability. The disease is mostly treated using dopamine replace therapy and surgery.High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN-HFS) is the preferred surgical treatment for advanced Parkinson’s disease. STN-DBS signifi cantly improves tremor, rigidity, and bradykinesia in patients with advanced Parkinson’s disease. DBS of different new brain targets is under investigation. New experimental brain targets for PD include the pedunculopontine nucleus (PPN),the caudal zona incerta (cZi), the thalamic centromedian-parafascicular (CM-Pf) complex and the substantia nigra pars reticulate (SNr). The ventromedial thalamic nucleus (VM) is an important thalamic motor nucleus. VM receive inputs from SNr and GPi. The projections from the ventromedial nucleus reach widespread cortical areas. Studies found that the neuronal activities in motor thalamic nuclues altered in primate PD model and PD patients. The ventromedial thalamic nucleus may play an important role in PD pathophysiology, and might be an effective target for PD treatment.The unilateral6-hydroxydopamine (6-OHDA) rat model has been widely used in PD research for decades. The model reproduces the major symptoms of PD, including akinesia, posture abnormality, tremor and dyskinesia. Many of motor deficits in this model can be measured using various behavioral tests, such as paw retraction test, apomorphine-induced rotations, locomotor activity, treadmill locomotion task and forelimb use asymmetry test. In rodents, voluntary wheel running task was used to monitor both the absolute levels of motor activity and the circadian rhythmicity of this activity in many studies. Numerous factors can influence voluntary wheel running behavior in animals. Recently, Leng et al. used voluntary wheel running task to evaluate motor dysfunctions in the1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. By blocking the de novo DA biosynthesis, they found a reduction of voluntary wheel running activity in MPTP-treated mice, which suggested that voluntary wheel running task might provide a useful tool to assess motor deficits in rodent model of PD.In the present study, the unilateral6-OHDA rat model was induced by injection of6-OHDA into unilateral medial forebrain bundle (MFB) using a stereotaxic instrument. We investigated voluntary wheel running behavior and the effect of STN-DBS and VM-DBS in this model. We also investigated the neuronal activities of the ventromedial thalamic nucleus in the model. The study includes four chapters:Chapter1Impaired voluntary wheel running behavior in the unilateral 6-hydroxydopamine rat model of Parkinson’s diseaseObjective:To investigate voluntary wheel running behavior in the unilateral6-hydroxydopamine (6-OHDA) rat model.Methods:Male Sprague-Dawley rats were assigned to2groups:6-OHDA group (n=17) and control group (n=8). The unilateral6-OHDA rat model was induced by injection of6-OHDA into unilateral medial forebrain bundle (MFB) using a stereotaxic instrument. Voluntary wheel running activity was assessed per day in successfully lesioned rats (n=10) and control rats. Each behavioral test lasted an hour. The following parameters were investigated during behavioral tests:the number of running bouts, the distance moved in the wheel, average peak speed in running bouts and average duration from the running start to the peak speed.Results:The number of running bouts and the distance moved in the wheel were significantly decreased in successfully lesioned rats compared with control rats. In addition, average peak speed in running bouts was decreased, and average duration from the running start to the peak speed was increased in lesioned animals, which might indicate motor deficits in these rats. These behavioral changes were still observed42days after lesion.Conclusion:Voluntary wheel running behavior is impaired in the unilateral6-OHDA rat model and may represent a useful tool to quantify motor deficits in this model.Chapter2High-frequency stimulation of the subthalamic nucleus improves impaired voluntary wheel running behavior in hemiparkinsonian ratsObjective:To investigate whether high-frequency stimulation of the subthalamic nucleus can improve impaired voluntary wheel running behavior in rats with unilateral6-hydroxydopamine lesions. Methods:Male Sprague-Dawley rats were assigned to2groups:6-OHDA group (n=24) and control group (n=11). A stimulation electrode was implanted into the right subthalamic nucleus. A microinjection cannula was also implanted ipsilateral to the electrode. The tip of the cannula was2mm above the medial forebrain bundle (MFB). The unilateral6-OHDA rat model was induced by injection of6-OHDA into unilateral medial forebrain bundle. Voluntary wheel running activity was assessed in successfully lesioned rats (n=17) and control rats. Limb-use asymmetry assessment also has been used to detect functional capacity. HFS of the STN (130Hz, pulse width60μs,50-175μA) was delivered during behavioral tests.Results:Seventeen out of the24rats were successfully lesioned after the injection of6-OHDA into MFB. A significant main effect of time was found in the limb-use asymmetry score in successfully lesioned rats (F=53.542, P=0.000). Compared with the score before lesion, the limb-use asymmetry score increased significantly (P=0.000) after lesion. Compared with the score without STN-DBS, the limb-use asymmetry score during STN-DBS decreased significantly (P=0.038). A significant main effect of time was also found in the number of running bouts (F=4.522, P=0.028)and the distance moved in the wheel (F=6.382, P=0.009)in successfully lesioned rats. Compared with the tests without STN-DBS, the both parameters during STN-DBS decreased significantly. A significant main effect of time was also found in average peak speed in running bouts (F=7.973, P=0.004) and average duration from the running start to the peak speed (F=31.053, P=0.000). Compared with the tests without STN-DBS, the former decreased and the later increased significantly during STN-DBS.Conclusion:High-frequency stimulation of the subthalamic nucleus improves impaired voluntary wheel running behavior in rats with unilateral6-hydroxydopamine lesions. Voluntary wheel running test may represent a useful tool to quantify motor deficits in this model.Chapter3Alterations in neuronal activities of the ventromedial thalamic nucleus following nigrostriatal dopamine depletionObjective:To investigate neuronal activities of the ventromedial thalamic nucleus in rats with unilateral6-hydroxydopamine lesions.Methods:Twelve Male Sprague-Dawley rats were used in the experiment. Two recording electrodes were implanted into the bilateral ventromedial thalamic nucleus (VM). A microinjection cannula was also implanted. The tip of the cannula was2mm above the right medial forebrain bundle (MFB). The unilateral6-OHDA rat model was induced by injection of6-OHDA into unilateral medial forebrain bundle. Extracellular signals in the bilateral VM were acquired using in vivo multi-channel recording methods before or after lesion.Results:Nine out of the12rats were successfully lesioned after the injection of6-OHDA into MFB. From the12successfully lesioned rats, forty-six neurons and fifty-four neurons were recorded in the left VM and the right VM, respectively. The mean firing rates in the left VM and the right VM were15.5287±0.57269Hz and5.6981±0.2791Hz, respectively. The difference between them is significant (t=15.431, P=0.000). Compared with the mean firing rate before leison, the mean firing rate in the right VM decreased significantly after lesion (F=306.701, P=0.000). Compared with the proportion of burst neurons befor lesion, the proportion of burst neurons in the right VM increased significantly after lesion (P=0.001). After lesion, compared with the left VM, the proportion of burst neurons in the right VM also increased significantly (χ2=8.355, P=0.004).Conclusion:The mean firing rate in the VM decreased in the unilateral6-OHDA rat model. The proportion of burst neurons in the VM increased after lesion. The VM may play an important role in the PD pathophysiology.Chapter4High-frequency stimulation of the ventromedial thalamic nucleus improves impaired voluntary wheel running behavior in hemiparkinsonian ratsObjective:To investigate whether high-frequency stimulation of the ventromedial thalamic nucleus can improve impaired voluntary wheel running behavior in rats with unilateral6-hydroxydopamine lesions.Methods:Male Sprague-Dawley rats were assigned to2groups:6-OHDA group (n=22) and control group (n=11). A stimulation electrode was implanted into the right ventromedial thalamic nucleus (VM). A microinjection cannula was also implanted ipsilateral to the electrode. The tip of the cannula was2mm above the medial forebrain bundle (MFB). The unilateral6-OHDA rat model was induced by injection of6-OHDA into unilateral medial forebrain bundle. Voluntary wheel running activity was assessed in successfully lesioned rats (n=15) and control rats. Limb-use asymmetry assessment also has been used to detect functional capacity. Low (25Hz) or high (130Hz) stimulation of the VM (pulse width60μs,50-175μA) was delivered during behavioral tests.Results:Fifteen out of the22rats were successfully lesioned after the injection of6-OHDA into MFB. A significant main effect of time was found in the limb-use asymmetry score in successfully lesioned rats (F=19.392, P=0.000). Compared with the score before lesion, the limb-use asymmetry score increased significantly (P=0.000) after lesion. Compared with the score without DBS-VM, the limb-use asymmetry score during HFS-VM decreased significantly (P=0.009). However, the score during LFS-VM show no difference (P=0.4). A significant main effect of time was also found in the number of running bouts (F=5.932, P=0.004) in successfully lesioned rats. Compared with the tests without DBS-VM, the parameter during HFS-VM increased significantly (P=0.017). A significant main effect of time was found in average peak speed in running bouts (F=13.416, P=0.000). Compared with the tests without DBS-VM, the speed increased significantly during HFS-VM (P=0.008).Conclusion:High-frequency stimulation of the ventromedial thalamic nucleus improves impaired voluntary wheel running behavior in rats with unilateral6-hydroxydopamine lesions. The ventromedial thalamic nucleus might be an effective target for PD treatment. |
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