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: 8557086
• 负责人: JUDITH RICHMOND WALTERS
• 金额: $ 73.23万
• 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/8557086
• 关键词: Acute; Address; Affect; Animal Model; Basal Ganglia; Bilateral; Brain; Cell Death; Cell Nucleus; Cells; Characteristics; Chronic; Collaborations; Complement; Contralateral; Data; Data Analyses; Deep Brain Stimulation; Denervation; Disease; Dopamine; Electrophysiology (science); Frequencies; Functional Magnetic Resonance Imaging; Future; GABA Agonists; Gait; Goals; Image; Infusion procedures; Interneurons; Investigation; Ipsilateral; Lead; Lesion; Levodopa; Link; Maintenance; Manuscripts; Medial; Modeling; Motor; Motor Cortex; Motor output; Mus; Muscimol; Neurons; Output; Parkinson Disease; Parkinsonian Disorders; Patients; Peripheral Nerves; Peripheral nerve injury; Population; Preparation; Rattus; Relative (related person); Research Personnel; Role; Sample Size; Sensory; Series; Site; Slice; Spike Potential; Substantia nigra structure; Symptoms; Synapses; Techniques; Thalamic Nuclei; Thalamic structure; Time; Training; Vibrissae; Walking; awake; barrel cortex; base; hippocampal pyramidal neuron; in vivo; insight; motor control; motor deficit; nerve supply; neurophysiology; optogenetics; postsynaptic; research study; response; sensory cortex; somatosensory; stellate cell; treatment strategy

In the past year, progress has been made in assessing changes in thalamo-cortical relationships in association with two types of neuronal damage: peripheral nerve injury and dopamine cell death. Both insults are thought to lead to alterations in the activity of thalamic input to cortex - the sensory cortex in the case of peripheral nerve injury, and the motor cortex in the case of dopamine cell death - and both appear to induce changes in cortical function as a result of the changes in thalamic activity. Our recent studies of the effects of dopamine cell death on thalamo-cortical plasticity have addressed the question of how loss of dopamine affects activity in this network in awake behaving rats. Increases in synchronized and oscillatory activity in the basal ganglia have been linked to motor deficits in Parkinsonss disease (PD). To examine the role of thalamo-cortical component of the basal ganglia- thalamo-cortical loop in the emergence of this activity, we have been increasing our sample size and analyzing data from recordings of spike/LFP relationships between basal ganglia output, motor thalamus and motor cortex in hemiparkinsonian rats trained to walk on a circular treadmill. These recordings of LFP activity from multiple sites within the motor network show correlated increases in coherence between motor cortex and basal ganglia output, between motor cortex and ventral medial thalamus, and between basal ganglia output and ventral medial thalamus in the 30-35 Hz range after dopamine cell lesion during treadmill walking. These effects are reversed by treatment of the rats with L-dopa to compensate for dopamine cell loss. We find power in this frequency range and coherence between the different nodes in this basal ganglia thalamocortical loop are significantly reduced by this treatment. Collectively, these data show that spiking activity becomes synchronized and, at the population level, rhythmic in this high beta/low gamma frequency range throughout the basal ganglia thalamocortical network during walking in the rat model of Parkinsons disease. These results have led to the hypothesis that neuronal activity in the ventral medial thalamus promotes increased coherence within the larger network after loss of dopamine. To further examine this, we have extended our series of experiments using infusion of the GABA agonist muscimol into the ventral medial nucleus to show reduced power in both motor cortex and substantia nigra LFP and reduced coherence between these two sites in the high beta/low gamma range during treadmill walking during muscimol infusion. Results support the view that neuronal activity in the thalamocortical projections contributes to the emergence of high beta/low gamma synchronization throughout the basal ganglia thalamocortical network in the awake behaving parkinsonian rat. We have also found that muscimol infusion in both the unilaterally lesioned rat and the normal rat reduce walking in the circular treadmill. This data supports a role for the ventral medial thalamus in maintenance of normal motor function and the manuscript is in preparation. Most recently we have explored the time course of these changes in basal ganglia thalamocortical network resonance after dopamine cell lesion in awake behaving rats. Data show that the increases in coherence evolve over the first week after dopamine cell lesion. Moreover, between week 1 and week three, the dominant frequency of the synchronous oscillation becomes slightly but significantly higher, suggesting that some degree of plasticity occurs over time in this network. Future plans include strategies for gaining insight into the potential significance of evolving plasticity basal ganglia thalamocortical loops in both non-lesioned and lesioned hemispheres of the hemiparkinsonian rat after loss of dopamine. The long term goal is to develop a better understanding of the significance and mechanisms underlying these network changes with respect to strategies for 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 anesthetized rats. Neurophysiological recordings of spiking and LFP response in the barrel cortex both ipsilateral and contralateral to the unilateral infraorbital denervation have shown increased response of neurons in the barrel cortex contralateral to stimulation of the intact whisker pad in rat with unilateral infraorbital denervation. Most of the neurons responding to contralateral stimulation have the extacellular waveforms characteristic of pyramidal neurons. In contrast, increases in neuronal response in the ipsilateral cortex have the waveform characteristics of interneurons. As the contralateral responses are thought to reflect thalamic input, and the ipsilateral responses may be more likely to reflect transcortical input, these results point to different types of post-lesion plasticity in somatosensory circuits after the unilateral lesion of whisker pad innervation. Interestingly, both types of change are associated with increased fMRI response. Recent related studies carried out in the Mouse Imaging Facility have utilized brain slice electrophysiology to demonstrate thalamocortical input strengthening onto the cortical L4 stellate cells which appears to be due to an increase in postsynaptic strength and the number of functional synapses. A future goal is to extend the in vivo studies to explore the neurophysiological response in the thalamic nuclei relaying the activity to the barrel cortex to obtain further 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. An additional goal is to incorporate optogenetic techniques into the imaging and neurophysiological studies.

去年，在评估与两种类型的神经元损伤相关的丘脑皮质关系变化方面取得了进展：周围神经损伤和多巴胺细胞死亡。这两种损伤都被认为会导致丘脑皮层输入活动的改变（周围神经损伤时为感觉皮层，多巴胺细胞死亡时为运动皮层），并且两者似乎都会引起皮层功能的变化，如丘脑活动变化的结果。 我们最近关于多巴胺细胞死亡对丘脑皮质可塑性影响的研究解决了多巴胺的丧失如何影响清醒行为大鼠的该网络活动的问题。 基底神经节同步和振荡活动的增加与帕金森病 (PD) 的运动缺陷有关。 为了研究基底神经节-丘脑-皮质环路的丘脑-皮质成分在这种活动出现中的作用，我们一直在增加样本量并分析基底神经节输出、运动丘脑和运动丘脑之间的尖峰/LFP关系记录的数据。训练在圆形跑步机上行走的偏侧帕金森病大鼠的运动皮层。这些运动网络内多个部位的 LFP 活动记录显示，在 30-35 Hz 范围内，运动皮层和基底神经节输出之间、运动皮层和腹内侧丘脑之间以及基底神经节输出和腹内侧丘脑之间的一致性相关性增加。跑步机行走期间多巴胺细胞损伤。通过用左旋多巴治疗大鼠以补偿多巴胺细胞的损失，可以逆转这些效应。我们发现该频率范围内的功率和基底神经节丘脑皮质环中不同节点之间的一致性通过这种治疗显着降低。总的来说，这些数据表明，在帕金森病大鼠模型中行走期间，在整个基底神经节丘脑皮质网络的高β/低γ频率范围内，尖峰活动变得同步，并且在群体水平上有节奏。 这些结果导致了这样的假设：在多巴胺丧失后，腹侧内侧丘脑的神经元活动促进了更大网络内的一致性增加。为了进一步研究这一点，我们扩展了我们的一系列实验，使用 GABA 激动剂蝇蕈醇注入腹侧内侧核，以显示运动皮层和黑质 LFP 的功率降低，以及这两个位点在高 β/低 γ 中的一致性降低输注蝇蕈醇期间在跑步机上行走时的范围。结果支持以下观点：在清醒行为的帕金森病大鼠中，丘脑皮质投射中的神经元活动有助于整个基底神经节丘脑皮质网络中高β/低γ同步的出现。我们还发现单侧病变大鼠和正常大鼠输注蝇蕈醇都会减少在圆形跑步机上的行走。 该数据支持腹侧内侧丘脑在维持正常运动功能中的作用，手稿正在准备中。 最近，我们探索了清醒行为大鼠多巴胺细胞损伤后基底节丘脑皮质网络共振的这些变化的时间过程。数据显示，在多巴胺细胞损伤后的第一周内，一致性增加。此外，在第一周和第三周之间，同步振荡的主频率变得稍微但显着较高，这表明该网络随着时间的推移出现了一定程度的可塑性。未来的计划包括深入了解多巴胺丧失后半侧帕金森病大鼠的非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的策略。长期目标是更好地理解这些网络变化的意义和机制，以制定治疗和改善帕金森病症状的策略。 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。单侧眶下去神经同侧和对侧的桶状皮层中的尖峰和 LFP 反应的神经生理学记录显示，单侧眶下去神经的大鼠对完整胡须垫的刺激对侧桶状皮层中的神经元的反应增加。大多数对对侧刺激做出反应的神经元具有锥体神经元的细胞外波形特征。相反，同侧皮层神经元反应的增加具有中间神经元的波形特征。 由于对侧反应被认为反映丘脑输入，而同侧反应可能更可能反映经皮层输入，这些结果表明在胡须垫神经支配的单侧损伤后体感回路中存在不同类型的损伤后可塑性。有趣的是，这两种类型的变化都与功能磁共振成像反应的增加有关。最近在小鼠成像设施中进行的相关研究利用脑切片电生理学来证明皮质 L4 星状细胞的丘脑皮质输入增强，这似乎是由于突触后强度和功能性突触数量的增加所致。 未来的目标是扩展体内研究，探索丘脑核团将活动传递到桶状皮层的神经生理学反应，以进一步了解经胼胝体与丘脑活动的变化在诱导对侧和同侧功能磁共振成像反应改变中的相对作用。单侧眶下去神经后刺激完整的胡须垫。另一个目标是将光遗传学技术纳入成像和神经生理学研究中。