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

基本信息

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
项目类别：
财政年份：
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

项目摘要

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.

在过去的一年中，与两种类型的神经元损害相关的丘脑皮层关系的变化取得了进展：周围神经损伤和多巴胺细胞死亡。两种侮辱都被认为会导致丘脑输入对皮质的活性发生变化 - 在外周神经损伤的情况下，感觉皮质以及多巴胺细胞死亡的运动皮层 - 两者似乎都会导致皮层功能的变化，这是丘脑活性变化的结果。我们最近关于多巴胺细胞死亡对丘脑皮层可塑性的影响的研究已经解决了以下问题：多巴胺损失如何影响该网络中的活动。基底神经节中同步和振荡活性的增加与帕金森病（PD）的运动缺陷有关。为了研究基底神经节 - 丘脑 - 皮层环的丘脑 - 皮质成分在这项活动的出现中，我们一直在增加样本量，并分析了基底神经节输出，运动thalamus和Motor cortex in Hemiparkinsonian Rats in Hemiparkinson to parking to Wrage to Wragemult thaignular treadmill的峰值/LFP关系的数据。电动机网络中多个位点的LFP活性记录显示，运动皮层和基底神经节输出之间的相干性增加，运动皮层和腹侧内侧丘脑之间，以及在多巴胺细胞行走后的30--35 Hz范围内的基础神经节输出与腹侧神经内侧丘脑之间的相关性。通过用L-DOPA治疗大鼠以补偿多巴胺细胞损失，可以逆转这些作用。我们发现该频率范围内的功率和这种基础神经节丘脑皮层环中不同节点之间的相干性可显着降低。总的来说，这些数据表明，在帕金森氏病大鼠模型中行走期间，在整个基底丘脑皮层网络中，峰值活性变得同步，并且在人群水平上，在这个高β/低伽马频率范围内有节奏。这些结果导致了以下假设：腹侧丘脑中内侧丘脑的神经元活性促进了多巴胺丧失后较大网络内的相干性提高。为了进一步研究这一点，我们使用GABA激动剂麝香酚输注到腹侧内侧核中扩展了一系列实验，以显示运动皮层和质原LFP中的功率降低，并在肌肉摩尔菌输液期间在跑步型过程中步行期间这两个位点之间的相干性降低。结果支持这样的观点，即丘脑皮质预测中的神经元活性在整个基底神经节丘脑皮层网络中促进了高β/低γ同步的出现。我们还发现，单侧病变的大鼠和正常大鼠在圆形跑步机中的行走中的麝香酚输注。该数据支持腹侧丘脑在维持正常运动功能中的作用，并且手稿正在准备。最近，我们探索了多巴胺细胞病变后，在醒着的大鼠中，我们探索了基底神经节丘脑皮层网络共振的这些变化的时间过程。数据表明，在多巴胺细胞病变后的第一周，相干性的增加。此外，在第1周至第三周之间，同步振荡的主要频率变得略微但明显更高，这表明在该网络中会发生某种程度的可塑性。未来的计划包括了解多巴胺丧失后，洞察力基础神经节丘脑皮层环的潜在意义的策略。长期目标是更好地理解这些网络在治疗和改善帕金森氏病症状的策略方面的重要性和机制。通过研究小鼠成像设施中的研究人员，对晶须的单方面神经化作用后，对枪管皮层活性的双侧变化的研究得到了补充。这些研究人员表明，单侧眶下神经支配，单侧去除晶须的神经，同时增加对侧和同侧fMRI的反应，并与完整的晶须垫有关。此外，在这些麻醉大鼠中可以看到丘脑晶须桶核中的fMRI反应。枪管皮层中尖峰和LFP反应的神经生理记录在同侧和对侧与单侧肩肌肌脱落的对比，已经显示出对枪管皮层对对比的神经元的反应增加，而神经元的反应是刺激在刺激大鼠刺激大鼠刺激的一边质质量刺激的一边，而单位型在刺激的刺激的刺激性刺激的刺激性刺激的是单侧的触发性鞭毛垫。响应对侧刺激的大多数神经元具有锥体神经元的特征。相反，同侧皮质中神经元反应的增加具有中间神经元的波形特征。由于认为对侧反应反映了丘脑的输入，并且同侧反应可能更有可能反映皮层输入，这些结果表明，在单侧晶须垫中的单侧病变后，体感应电路中不同类型的静脉内可塑性。有趣的是，两种变化都与fMRI响应增加有关。在小鼠成像设施中进行的最新相关研究利用了脑切片电生理学，证明了丘脑皮质输入加强皮质L4星状细胞，这似乎是由于突触后强度的增加和功能突触的数量。未来的目标是扩展体内研究，以探索丘脑核中的神经生理反应，从而将活性传达到枪管皮层中，以进一步深入了解thallamic与丘脑活性的相对作用在诱导对侧和同侧FMRI反应刺激的刺激剂中的相对作用，以诱导变化。另一个目标是将光遗传技术纳入成像和神经生理学研究。