Thalamo-Cortical Plasticity: Sensory Denervation and Loss of Dopamine

在过去的一年中，在评估单侧多巴胺细胞损伤后丘脑皮质活动的变化方面取得了进展。在氨基甲酸乙酯麻醉大鼠帕金森病模型中，多巴胺细胞病变1-2周和3周后，在丘脑运动区、腹前核、腹外侧核和腹内核三个区域的记录与氨基甲酸乙酯麻醉大鼠运动皮质或SNpr的同时记录配对。我们之前的研究表明，在损伤后1周，经氨基甲酸乙酯麻醉的大鼠，多巴胺的丧失与基底节区输出以1hz节奏为主的携带有关。在我们最近的研究中，在多巴胺细胞损伤三周后，我们观察到腹侧内侧核在1hz范围内的记录功率下降，相对于腹侧前核/腹侧外侧核，腹侧内侧核接收很大比例的基底神经节输出。此外，多巴胺能损伤后，运动皮质皮质丘脑锥体输出神经元的第5层记录显示速率降低，而第4层神经元速率不受影响。多巴胺损伤大鼠VM的1hz活动减弱，运动皮层第5层活动减少，这一证据支持了一种假设，即抑制性基底节区和兴奋性运动皮层投射的同步振荡输入可以减少运动丘脑的1hz振荡活动，并限制基底节区丘脑皮层环路在该频率范围内的共振潜力。

In the past year, progress has been made in assessing changes in thalamocortical activity following unilateral dopamine cell lesion. In the urethane anesthetized rat model of Parkinsons disease, recordings in three areas in the motor thalamus, ventral anterior, ventral lateral and ventral medial nuclei, 1-2 and 3 weeks after dopamine cell lesion lesion were paired with simultaneous recordings in motor cortex or SNpr in urethane-anesthetized rats. We have previously shown that loss of dopamine is associated with entrainment of basal ganglia output to the 1 Hz rhythm dominate in the cortex in urethane anesthetized rats by 1 week after lesion. In our recent study, three weeks after dopamine cell lesion, we observed a reduction in power in the 1 Hz range in recordings from the ventral medial nucleus, which, relative to the ventral anterior/ventral lateral nuclei, receives a large proportion of the basal ganglia output. In addition, recordings in layer 5 of putative pyramidal corticothalamic output neurons in motor cortex showed rate decreases after dopaminergic lesion, whereas layer 4 neuronal rate was not affected. This evidence of a dampening of 1 Hz activity in the VM and reduced activity in layer 5 of the motor cortex in the dopamine lesioned rats support the hypothesis that coincident oscillatory input from inhibitory basal ganglia and excitatory motor cortex projections can reduce the 1 Hz oscillatory activity in the motor thalamus, and limit the potential for resonance in this frequency range in basal ganglia thalamocortical loops. Further efforts in the current review period have involved developing techniques for assessing spike/LFP relationships between motor cortex and motor thalamus bilaterally in hemiparkinsonian rats trained to walk on a circular treadmill. After unilateral dopamine cell lesions, the hemiparkinsonian rats can make reasonable progress on the circular treadmill if they are oriented in the direction ipsiversive to the unilateral lesion, with their affected paws on the outside of the circular path. If they were oriented in the opposite way, controversive to the lesion, with their affected paws on the inside of the circular path, they had considerable difficulty walking, and generally froze or reared and tried to turn around. This arrangement allows us to compare motor cortex and motor thalamus activity in the intact and lesioned hemispheres in the hemiparkinson rats as they walked ipsiversively on the treadmill, and perform identical experiments in control rats walking at the same speed. At the same time, the rats profound difficulty with contraversive walking provide an index of disability, as contraversive walking was notably improved by treatment with drugs such as l-dopa and apomorphine. This paradigm also provided a means for encouraging the rats to remain inactive for reasonably long epochs, as after a series of walk - rest cycles, they readily engaged in inattentive rest when the treadmill was turned off. In conjunction with spiking activity and LFPs, EMG activity was recorded bilaterally from the scapularis muscle and sessions were videotaped to provide further confirmation of the level of motor activity in the rats. In the hemiparkinson rat, dopamine loss is associated with dramatic increases in beta range activity (25 40 Hz) in basal ganglia output to the thalamus during treadmill walking. Moreover, results showed that high beta activity is, in fact, significantly increased in the motor cortex of the lesioned hemisphere, relative to the non-lesioned hemisphere during treadmill walking at 1 - 3 weeks after dopamine cell lesion, and is highly coherent with activity in both the substantia nigra pars reticulata, a basal ganglia output nucleus and the motor thalamus. Motor cortex power and coherence with SNpr activity in high beta ranges were reduced by L-dopa administration, and effects of L-dopa were reversed by 8-OHDPAT or a dopamine antagonist. The data also raise questions about the potential involvement of feedback to the cortex via thalamocortical loops and network resonance in contributing to increased beta range activity in the motor cortex. The data suggests that rhythms emerging in the basal ganglia after loss of dopamine do not simply reflect downstream entrainment to normally occurring cortical rhythms. Additional factors would appear to be playing a role, as the lesioned hemisphere in the cortex shows an increase in power in the high beta range as is evident in the SNpr and the motor thalamus. These could include resonance in the basal ganglia thalmocortical circuits, as suggested by the present results, as well as local changes in cortical network function and/or compensatory processes involving transcortical activity, in addition to changes in striatal network function and plasticity within the basal ganglia itself. The Future Plans address strategies for gaining insight into the potential significance of evolving plasticity basal ganglia thalamocortical loops in both non-lesioned and lesioned hemispheres after loss of dopamine. The long term goal is to translate this insight into better means of treatment and amelioration of Parkinsons disease symptoms. These studies have been complemented by investigation of bilateral changes in activity in the barrel cortex following unilateral denervation of the whiskers in collaboration with investigators in the Mouse Imaging Facility. These investigators have shown that unilateral infraorbital denervation, removing the innervation of the whiskers unilaterally, increases both contralateral and ipsilateral fMRI responses in association with stimulation of the intact whisker pad. In addition, fMRI response in thalamic whisker barrel nuclei providing input to the barrel cortex can be visualized in these anestheized rats. Neurophysiological recordings of spiking and LFP response in the barrel cortex both ipsilateral and contralateral to the unilateral infraorbital denervation are currently under way to provide insight into neurophysiological basis of the alterations in fMRI response in the barrel cortex. A future goal is to extend these studies to explore the neurophysiological response in the thalamic nuclei relaying the activity to the barrel cortex to obtain insight into the relative roles of changes in transcallosal vs thalamic activity in inducing altered contralateral and ipsilateral fMRI responses to stimulation of the intact whisker pad following unilateral infraorbital denervation.