Thalamo-Cortical Plasticity: Sensory Denervation and Loss of Dopamine

丘脑皮质可塑性：感觉神经支配和多巴胺丧失

• 批准号: 8158248
• 负责人: JUDITH RICHMOND WALTERS
• 金额: $ 49.43万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8158248
• 关键词: Corpus striatum structure; Denervation; Dopamine; Sensory

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.

去年，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。 在帕金森病的乌拉坦麻醉大鼠模型中，多巴胺细胞损伤后 1-2 周和 3 周，运动丘脑、腹侧前部、腹侧外侧和腹侧内侧核三个区域的记录与乌拉坦麻醉大鼠运动皮层或 SNpr 的同步记录配对。我们之前已经表明，在病变后 1 周，氨基甲酸乙酯麻醉的大鼠的皮质中，多巴胺的丧失与基底神经节输出主导的 1 Hz 节律有关。在我们最近的研究中，多巴胺细胞损伤三周后，我们观察到腹侧内侧核记录的 1 Hz 范围内的功率降低，相对于腹侧前/腹外侧核，腹侧内侧核接收大部分基底神经节输出。此外，运动皮层中假定的锥体皮质丘脑输出神经元第 5 层的记录显示多巴胺能损伤后速率下降，而第 4 层神经元速率未受影响。在多巴胺损伤的大鼠中，VM 中 1 Hz 活动的减弱和运动皮层第 5 层活动减少的证据支持这样的假设：来自抑制性基底神经节和兴奋性运动皮层投射的一致振荡输入可以减少运动丘脑中的 1 Hz 振荡活动，并限制基底神经节丘脑皮质中在此频率范围内共振的可能性。 循环。 当前审查期间的进一步工作涉及开发技术，用于评估训练在圆形跑步机上行走的偏侧帕金森病大鼠的双侧运动皮层和运动丘脑之间的尖峰/LFP关系。 单侧多巴胺细胞损伤后，如果偏侧帕金森病大鼠的方向与单侧损伤相同，受影响的爪子位于圆形路径的外侧，则它们可以在圆形跑步机上取得合理的进展。 如果它们的方向相反，与病变有争议，受影响的爪子位于圆形路径的内侧，它们行走时就会遇到相当大的困难，并且通常会僵住或直立并试图转身。 这种安排使我们能够比较帕金森大鼠在跑步机上自由行走时完整和受损半球的运动皮层和运动丘脑活动，并在以相同速度行走的对照大鼠中进行相同的实验。 同时，患有反向行走的大鼠严重困难提供了残疾指数，因为通过左旋多巴和阿扑吗啡等药物治疗显着改善了反向行走。这种范例还提供了一种鼓励大鼠在相当长的时期内保持不活动的方法，因为在一系列步行-休息循环之后，当跑步机关闭时，它们很容易进行不专心的休息。 结合尖峰活动和 LFP，记录肩胛肌双侧的肌电图活动，并对过程进行录像，以进一步确认大鼠的运动活动水平。 在偏侧帕金森病大鼠中，多巴胺损失与跑步机行走期间基底神经节向丘脑输出的β范围活动（25-40Hz）的急剧增加有关。 此外，结果表明，多巴胺细胞损伤后 1-3 周在跑步机上行走时，相对于未损伤半球，损伤半球运动皮层的高 β 活性实际上显着增加，并且与黑质网状部、基底神经节输出核和运动丘脑的活动高度一致。左旋多巴给药降低了运动皮层的功率以及高β范围内SNpr活性的一致性，并且左旋多巴的作用被8-OHDPAT或多巴胺拮抗剂逆转。这些数据还提出了关于通过丘脑皮层环路和网络共振向皮层反馈是否可能参与运动皮层β范围活动增加的问题。 数据表明，多巴胺丧失后基底神经节中出现的节律不仅仅反映了正常发生的皮质节律的下游夹带。其他因素似乎也发挥了作用，因为皮质中受损的半球显示出高β范围内的功率增加，这在 SNpr 和运动丘脑中很明显。 正如目前的结果所表明的，这些可能包括基底神经节丘脑皮质回路的共振，以及皮质网络功能和/或涉及跨皮质活动的补偿过程的局部变化，此外还有纹状体网络功能和基底神经节本身可塑性的变化。 未来计划提出了一些策略，以深入了解多巴胺丧失后未病变和病变半球中基底神经节丘脑皮质环的可塑性演化的潜在意义。 长期目标是将这一见解转化为更好的治疗方法和改善帕金森病症状。 与小鼠成像设施的研究人员合作，对胡须单侧去神经支配后桶状皮层活动的双边变化进行了调查，对这些研究进行了补充。 这些研究人员表明，单侧眶下去神经，即单侧去除胡须的神经支配，会增加与刺激完整胡须垫相关的对侧和同侧功能磁共振成像反应。 此外，在这些麻醉的大鼠中，可以观察到丘脑须桶核向桶皮层提供输入的功能磁共振成像反应。目前正在对单侧眶下去神经的同侧和对侧桶状皮层中的尖峰和 LFP 反应进行神经生理学记录，以深入了解桶状皮层 fMRI 反应变化的神经生理学基础。 未来的目标是扩展这些研究，探索丘脑核团将活动传递到桶状皮层的神经生理学反应，以深入了解经胼胝体与丘脑活动变化在单侧眶下去神经后诱导对侧和同侧功能磁共振成像对完整胡须垫刺激反应改变的相对作用。