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: 8746844
• 负责人: JUDITH RICHMOND WALTERS
• 金额: $ 72.97万
• 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/8746844
• 关键词: Affect; Amantadine; Animal Model; Area; Automobile Driving; Basal Ganglia; Bradykinesia; Cell Death; Cell Nucleus; Cells; Cerebellum; Chronic; Data; Data Analyses; Deep Brain Stimulation; Denervation; Disinhibition; Dopa; Dopamine; Dose; Dyskinetic syndrome; Electrodes; Excitatory Amino Acid Antagonists; Functional Magnetic Resonance Imaging; GABA Agonists; Gait; Goals; Human; Implant; Infusion procedures; Injection of therapeutic agent; Lead; Lesion; Levodopa; Link; Maintenance; Manuscripts; Medial; Modeling; Motor; Motor Cortex; Muscimol; N-Methylaspartate; Neurons; Output; Parkinson Disease; Pathway interactions; Patients; Play; Rattus; Relative (related person); Replacement Therapy; Rodent Model; Role; Sensory; Series; Site; Source; Spike Potential; Structure; Substantia nigra structure; Subthalamic structure; Techniques; Thalamic Nuclei; Thalamic structure; Therapeutic Effect; Time; Training; Walking; awake; base; dopaminergic neuron; insight; interest; neurophysiology; novel strategies; response

In the past year, progress has been made in assessing changes in thalamo-cortical relationships in the rodent model of Parkinsons disease in conjunction with bradykinesia associated with dopamine cell death and in conjunction with dyskinesia associated with chronic L-dopa treatment. Both bradykinetic and dyskinetic states have been shown to induce dramatic changes in oscillatory and synchronized activity in the motor cortex activity. We have been exploring the extent to which these changes in motor cortex activity may be linked, and potentially driven by, alterations in the activity of thalamic input to cortex. We are also examining the extent to which these changes in motor cortex activity correlate with the emergence of bradykinesia and dyskinesia in this animal model of Parkinsons disease. To examine the role of thalamo-cortical component of the basal ganglia- thalamo-cortical loop in the emergence of bradykinesia associated with loss of dopamine, we have been analyzing data from recordings of spike/local field potential (LFP) relationships between basal ganglia output (substantia nigra pars reticulata (SNpr), 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 SNpr, between motor cortex and ventral medial thalamus, and between SNpr and ventral medial thalamus in the 30-35 Hz range after dopamine cell lesion during treadmill walking. Infusion of the GABA agonist muscimol into the ventral medial nucleus to inhibit activity in this nucleus causes a reduction of power in both motor cortex and SNpr LFP and reduced coherence between these two sites in the high beta/low gamma range during treadmill walking during muscimol infusion. 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 is consistent with a role for the motor thalamus in induction of high beta/low gamma synchronization of LFP activity in the motor cortex and with the hypothesis that neuronal activity in the ventral medial thalamus promotes increased coherence within the larger network after loss of dopamine. We are currently using new approaches to assess more precisely the relationships between spiking activity in the LFP oscillations in these nuclei in order to further examine the relative roles of these different areas in driving spiking in the different nodes of this circuit. The manuscript is close to completion. A second series of studies has examined the changes in thalamic and thalamic-cortical activity associated with chronic treatment of L-dopa. The therapeutic effect of treatment of Parkinsons disease (PD) patients with the dopamine precursor L-dopa has been well established. However, over time, L-dopa therapy leads to severe motor complications referred as L-dopa-induced dyskinesias (LID). Recently, we have confirmed that there is a strong association between the presence of 80-100 Hz oscillations in the motor cortex of hemiparkinsonian rats and LID expression. This is especially interesting because high gamma activity resembling that observed in this rat model of PD has been observed in human PD patients in recordings throught deep brain stimulation electrodes, and the role of this activity in generating dyskinesia is unclear. As L-dopa administration is believed to lead to a reduction in basal ganglia output and disinhibition of the thalamocortical pathway in Parkinsons disease, we are currently investigating the role of the motor thalamus in contributing to the 80-100 Hz activity evident in the motor cortex during LID in the hemiparkinsonian rat primed for 7 days with L-dopa. We are also examining the time course and correlations between the LID and the changes in cortical activity. LFPs and neuronal activity recorded from electrodes chronically implanted in the motor cortex, ventral medial thalamic nucleus and SNpr show prominent increases in a strickingly focused band of 100 Hz gamma range in both the ventral thalamus and motor cortex LFP activity and in coherence between these two structures. This high gamma 100 Hz activity is strongly associated with the emergence of LID over 7 days of priming. Pre-treatment with amantadine, a weak NMDA glutamate receptor antagonist (GluR ant) used clinically to treat dyskinesia, mildly reduced both 100 Hz LFP power and LID, while a 0.3 mg/kg dose of MK-801, the NMDA GluR ant, eliminated them. These results support the idea of a causative association between LID and 100 Hz activity in the thalamocortical circuit. However, a lower 0.15 mg/kg dose of the MK-801 abolished 100 Hz band oscillations without affecting LID. Moreover, preliminary results show that suppression of Vm activity by local injection of the GABA receptor agonist muscimol completely eliminated aberrant 100 Hz synchronization within the motor cortex, but had nearly no effect on LID. The results suggest that while robust high gamma oscillatory activity in the VM and MCx is evident during LID, this aberrant thalamocortical synchronization does not appear to be requisite for the expression of dyskinesia. We are currently adding to the Ns in this study and exploring the possible role of the cerebellum in contributing to the dramatic changes in thalamocortical activity observed in this model of L-dopa induced dyskinesia.

在过去的一年中，在评估帕金森氏病啮齿动物模型中丘脑 - 皮质关系的变化以及与多巴胺细胞死亡相关的铁肌疾病以及与慢性L-DOPA治疗相关的发射障碍有关的情况下取得了进展。 头部肌动态和运动障碍态都显示出诱导运动皮层活性中振荡和同步活性的急剧变化。我们一直在探索丘脑输入对皮质的活性的改变，并有可能将这些变化的运动皮质活性变化链接在一起。 我们还在研究这种运动皮层活性的这些变化与这种帕金森病动物模型中的易屈肌和运动障碍的出现有关。 To examine the role of thalamo-cortical component of the basal ganglia- thalamo-cortical loop in the emergence of bradykinesia associated with loss of dopamine, we have been analyzing data from recordings of spike/local field potential (LFP) relationships between basal ganglia output (substantia nigra pars reticulata (SNpr), motor thalamus and motor cortex in hemiparkinsonian rats经过训练的跑步机，从运动网络中的多个地点进行的LFP活动的录音与运动皮层和SNPR之间的相干性相关，在多巴胺范围内的30-35 Hz范围内，运动皮层和腹侧内侧丘脑之间腹侧内侧核抑制该核的活性会导致运动皮层和SNPR LFP的功率降低，并在输注过程中高β/低γ范围内这两个位点之间的相干性降低。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。该数据支持腹侧内侧丘脑在维持正常运动功能中的作用，并且与运动丘脑的运动在诱导高β/低γ同步运动皮层中的LFP活性以及与假设的假设中的作用是一致的。目前，我们正在使用新方法来更准确地评估这些核中LFP振荡中的峰值活性之间的关系，以便进一步研究这些不同区域在该电路不同节点中驱动尖峰的相对作用。手稿接近完成。 第二项研究研究了与L-DOPA慢性治疗有关的丘脑和丘脑皮层活性的变化。 多巴胺前体L-DOPA治疗帕金森氏病（PD）患者的治疗作用已得到充分确立。但是，随着时间的流逝，L-DOPA疗法导致严重的运动并发症，称为L-DOPA诱导的运动障碍（LID）。最近，我们已经证实，在半腺苷大鼠的运动皮层中存在80-100 Hz振荡与盖子表达之间存在很强的关联。这一点特别有趣，因为高γ活性类似于这种大鼠的PD模型中观察到的在人类PD患者中，在通过深脑刺激电极的记录中观察到，并且该活性在产生运动障碍中的作用尚不清楚。 As L-dopa administration is believed to lead to a reduction in basal ganglia output and disinhibition of the thalamocortical pathway in Parkinsons disease, we are currently investigating the role of the motor thalamus in contributing to the 80-100 Hz activity evident in the motor cortex during LID in the hemiparkinsonian rat primed for 7 days with L-dopa.我们还在研究盖子与皮质活动变化之间的时间过程和相关性。 LFP和神经元活性从慢性植入的电极记录在运动皮层，腹侧内侧丘脑核和SNPR中，在腹侧丘脑和运动皮层LFP的100 Hz Gamma范围内的焦点焦点中，在这些两个结构之间的100 Hz Gamma范围内显示出明显的增加。 这种高γ100Hz活性与7天启动的盖子出现密切相关。使用临床治疗运动障碍的NMDA谷氨酸受体拮抗剂（GLUR ANT）的Amantadine进行预处理，可用于治疗运动障碍，轻度降低100 Hz LFP和盖子，而MK-801的0.3 mg/kg剂量的MK-801，NMDA GLUR蚂蚁消除了它们。这些结果支持丘脑皮质回路中盖和100 Hz活性之间的因果关系的想法。但是，MK-801的0.15 mg/kg剂量降低了100 Hz带振荡而不会影响盖子。此外，初步结果表明，通过局部注入GABA受体激动剂肌酚对VM活性的抑制完全消除了运动皮质中的异常100 Hz同步，但对盖子几乎没有影响。结果表明，虽然在盖子期间，VM和MCX中有强大的高γ振荡活性是显而易见的，但这种异常的丘脑皮质同步似乎对于表达发育不良的表达并不是必需的。我们目前正在这项研究中的NS增加，并探讨小脑在这种L-DOPA诱导的运动障碍模型中观察到的丘脑皮质活性的急剧变化。