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: 8940110
• 负责人: JUDITH RICHMOND WALTERS
• 金额: $ 73.32万
• 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/8940110
• 关键词: Affect; Aftercare; Amantadine; Animal Model; Animals; Area; Automobile Driving; Basal Ganglia; Behavior; Behavioral; Bradykinesia; Brain Stem; Cell Death; Cell Nucleus; Cells; Cerebellum; Chronic; Clinical; Data; Data Reporting; Deep Brain Stimulation; Denervation; Dopamine; Dose; Dyskinetic syndrome; Electrodes; Excitatory Amino Acid Antagonists; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Future; GABA Agonists; GABA Antagonists; Goals; Human; Individual; Infusion procedures; Injection of therapeutic agent; Laboratories; Lesion; Levodopa; Literature; Maintenance; Manuscripts; Medial; Midbrain structure; Modeling; Motor; Motor Activity; Motor Cortex; Muscimol; N-Methylaspartate; National Institute of Neurological Disorders and Stroke; Neurons; Output; Parkinson Disease; Patients; Peripheral nerve injury; Pharmaceutical Preparations; Phase; Picrotoxin; Play; Rattus; Relative (related person); Rodent Model; Role; Sensory; Series; Site; Spike Potential; Spinal Cord; Staging; Substantia nigra structure; Symptoms; System; Techniques; Thalamic Nuclei; Thalamic structure; Therapeutic Effect; Time; Training; Walking; Work; cell injury; dopaminergic neuron; drug testing; insight; interest; limb movement; molecular imaging; optogenetics; research study; response; sensory system; tool; treatment effect

In the past year, we have continued to make progress in assessing changes in thalamo-cortical relationships in the rodent model of Parkinsons disease. Both bradykinetic and dyskinetic states have been shown to be associated with dramatic increases in oscillatory and synchronized activity in the motor cortex. Current results support the idea that these changes in motor cortex LFP activity are driven by alterations in the activity of thalamic input to cortex. However, our data to date does not support the view that the increases in LFP oscillations in the motor cortex are necessarily causing the motor symptoms. The emergence of dyskinesia in this animal model of Parkinsons disease can be disassociated from increases in high gamma range LFP activity in the motor thalamus and motor cortex. The role of the high beta/ low gamma oscillatory activity observed in the ventromedial thalamocortical projection during periods of bradykinesia in these animals is still under debate. While we are unsure of the actual consequences of the high beta/low LFP oscillations in the motor cortex, the thalamic component of the basal ganglia- thalamo-cortical loop does seem critical to the emergence of these LFP oscillations after loss of dopamine. We are working on the near-final draft of a manuscript reporting 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. We cannot draw conclusions from the behavioral effects of this treatment on treadmill walking, however, as inhibiting the activity in this nucleus with muscimol infusion reduces walking in the circular treadmill in both the unilaterally lesioned rat and the normal rat. Some form of thalamocortical activity appears critical for normal treadmill walking. In contrast, the GABA antagonist, picrotoxin, infused into the ventral medial thalamus, mimics the impact of L-dopa on treadmill walking. Presumably, by blocking the oscillatory inhibitory input from the SNpr to the ventral medial thalamus, this drug reduces beta range activity in the ventral medial thalamus, and facilitates treadmill walking. 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. The data also shows that neuronal activity in the ventral medial thalamus promotes increased coherence within the larger basal ganglia thalamo-cortical network after loss of dopamine. Future experiments will attempt to gain insight into the relationship between these oscillations in the cortex and the dysfunction evident during treadmill walking in the direction contraversive to the unilateral dopamine cell lesion. We are currently developing new electrodes to allow us to record locally as we infuse test drugs and as we apply optogenetic techniques to modify spiking activity to more selectively probe the different nodes of this circuit, and the manner in which thalamocortical activity ultimately impacts downstream systems regulating limb movement. We have also made progress on a series of studies examining the changes in thalamic and thalamo-cortical activity associated with chronic treatment of L-dopa. The therapeutic effect of treatment of Parkinsons disease 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 high gamma oscillations in the motor cortex of hemiparkinsonian rats and LID expression. This is especially interesting because high gamma has been observed in human PD patients in recordings through deep brain stimulation electrodes, and the role of this activity in generating dyskinesia is unclear. This activity has been referred to in the clinical literature as finely tuned gamma or FTG . As with the high beta/low gamma activity in the 30 36 hz range, our studies have shown that the motor thalamus is critical for the emergence of the 80-100 Hz activity evident in the motor cortex during LID in the hemiparkinsonian rat after priming with L-dopa. We are also examining the time course and correlations between the LID and the changes in cortical activity. A number of results show that dyskinetic behaviors and FTG emerge together. For example, pre-treatment with amantadine, a weak NMDA glutamate receptor antagonist used clinically to treat dyskinesia, mildly reduced both 100 Hz LFP power and LID. A manuscript is in final stages reporting this data. Other results show the FTG and the dyskinetic behavior can be disassociated. While a 0.3 mg/kg dose of MK-801, the NMDA GluR antagonist, eliminated both FTG and dyskinesia, a lower 0.15 mg/kg dose of the MK-801 administered i.p. abolished 100 Hz band oscillations without affecting LID. Results show that suppression of ventromedial thalamic 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 both motor thalamus and motor cortex is evident during LID, this aberrant thalamocortical synchronization does not appear to be requisite for the expression of dyskinesia. Most recently, we have focused on the role of the motor thalamus in inducing the cortical FTG. We are also 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. Further evidence that the motor thalamus is driving the FTG in the cortex emerges from studies of rate and spike-LFP phase-locking in the motor thalamus during LID. Treatments that induce or block the availability of L-dopa modulate the high gamma LFP activity in both motor thalamus and motor cortex, and allow us to track how activity in the two areas changes with changes in LFP . Interestingly, changes in firing rate and phase-locking are highly correlated with the changes in power in the high gamma range in the ventromedial thalamus, but not in the motor cortex. It appears that power in this high gamma range can change dramatically in the motor cortex LFP without an associated changes in spike-LFP phase locking. Firing rate changes are not obvious either, in our analysis to date. More remains to be done, but studies to date raise interesting questions about the consequences of the high gamma range activity in the motor cortex. Gamma activity is generally considered an important modulator of cortical function, and we are hopeful that insight into the causes and consequences of expression of exaggerated levels of this activity, as occurs following chronic L-dopa treatment after loss of dopamine, will provide insight into both normal and pathological roles of this activity

在过去的一年里，我们在评估帕金森病啮齿动物模型中丘脑皮质关系的变化方面继续取得进展。 运动迟缓和运动障碍状态均已被证明与运动皮层振荡和同步活动的急剧增加有关。 目前的结果支持这样的观点，即运动皮层 LFP 活动的这些变化是由丘脑皮层输入活动的变化驱动的。 然而，我们迄今为止的数据并不支持运动皮层中 LFP 振荡的增加必然导致运动症状的观点。 这种帕金森病动物模型中运动障碍的出现与运动丘脑和运动皮层中高伽马范围 LFP 活性的增加无关。 在这些动物运动迟缓期间，在腹内侧丘脑皮质投射中观察到的高β/低γ振荡活动的作用仍在争论中。 虽然我们不确定运动皮层中高β/低LFP振荡的实际后果，但基底神经节-丘脑-皮质环路的丘脑成分似乎对于多巴胺丧失后这些LFP振荡的出现至关重要。 我们正在起草一份手稿的接近最终稿，该手稿报告了训练在圆形跑步机上行走的半帕金森病大鼠的基底神经节输出、黑质网状部（SNpr）、运动丘脑和运动皮层之间的尖峰/局部场电位（LFP）关系的记录数据。这些运动网络内多个部位的 LFP 活动记录显示，在跑步机行走过程中多巴胺细胞损伤后，运动皮层和 SNpr 之间、运动皮层和腹内侧丘脑之间以及 SNpr 和腹内侧丘脑之间在 30-35 Hz 范围内的一致性相关性增加。 将 GABA 激动剂蝇蕈醇注入腹侧内侧核以抑制该核的活动，导致运动皮层和 SNpr LFP 的功率降低，并降低跑步机行走期间这两个位点在高 β/低 γ 范围内的一致性。 然而，我们无法从这种治疗对跑步机行走的行为影响得出结论，因为用蝇蕈醇输注抑制该核的活动会减少单侧病变大鼠和正常大鼠在圆形跑步机上的行走。 某种形式的丘脑皮质活动对于正常的跑步机行走似乎至关重要。 相比之下，GABA 拮抗剂印防己毒素注入腹侧内侧丘脑，可模拟左旋多巴对跑步机行走的影响。据推测，该药物通过阻断从 SNpr 到腹侧内侧丘脑的振荡抑制输入，降低了腹侧内侧丘脑的 β 范围活动，并促进跑步机行走。 该数据支持腹侧内侧丘脑在维持正常运动功能中的作用，并且与运动丘脑在诱导运动皮质中 LFP 活动的高 β/低 γ 同步中的作用一致。数据还表明，在多巴胺缺失后，腹侧内侧丘脑的神经元活动促进了较大的基底神经节丘脑皮质网络内的一致性增加。 未来的实验将试图深入了解皮层中的这些振荡与在跑步机上沿与单侧多巴胺细胞损伤相反的方向行走时明显的功能障碍之间的关系。 我们目前正在开发新的电极，使我们能够在注入测试药物时进行本地记录，并应用光遗传学技术来修改尖峰活动，以更有选择性地探测该回路的不同节点，以及丘脑皮层活动最终影响调节肢体运动的下游系统的方式。 我们还在一系列研究中取得了进展，这些研究检查了与左旋多巴长期治疗相关的丘脑和丘脑皮质活动的变化。 使用多巴胺前体左旋多巴治疗帕金森病患者的疗效已得到充分证实。然而，随着时间的推移，左旋多巴治疗会导致严重的运动并发症，称为左旋多巴诱发的运动障碍（LID）。最近，我们证实偏侧帕金森病大鼠运动皮层中 80-100 Hz 高伽马振荡的存在与 LID 表达之间存在密切关联。这是特别有趣的，因为通过深部脑刺激电极的记录在人类帕金森病患者中观察到高伽马值，并且这种活动在产生运动障碍中的作用尚不清楚。 这种活性在临床文献中被称为微调伽马或 FTG。 与 30-36 Hz 范围内的高 β/低 γ 活动一样，我们的研究表明，运动丘脑对于左旋多巴启动后的偏侧帕金森病大鼠 LID 期间运动皮层中明显的 80-100 Hz 活动的出现至关重要。我们还在研究 LID 与皮质活动变化之间的时间进程和相关性。大量结果表明，运动障碍行为和 FTG 同时出现。例如，用金刚烷胺（一种临床上用于治疗运动障碍的弱 NMDA 谷氨酸受体拮抗剂）进行预处理，可轻微降低 100 Hz LFP 功率和 LID。 报告该数据的手稿已进入最后阶段。 其他结果表明 FTG 和运动障碍行为可以分离。虽然 0.3 mg/kg 剂量的 MK-801（NMDA GluR 拮抗剂）消除了 FTG 和运动障碍，但 0.15 mg/kg 剂量的 MK-801 腹腔注射给药。取消了 100 Hz 频带振荡而不影响 LID。 结果表明，通过局部注射 GABA 受体激动剂蝇蕈醇来抑制腹内侧丘脑活动，完全消除了运动皮层内异常的 100 Hz 同步，但对 LID 几乎没有影响。结果表明，虽然在 LID 期间运动丘脑和运动皮层均存在明显的强烈高伽马振荡活动，但这种异常的丘脑皮层同步似乎并不是运动障碍表达所必需的。 最近，我们重点关注运动丘脑在诱导皮质 FTG 中的作用。我们还在探索小脑在左旋多巴诱发的运动障碍模型中观察到的丘脑皮质活动的巨大变化中可能发挥的作用。对 LID 期间运动丘脑速率和尖峰 LFP 锁相的研究得出了运动丘脑驱动皮质中 FTG 的进一步证据。 诱导或阻断左旋多巴可用性的治疗可调节运动丘脑和运动皮层的高伽玛 LFP 活性，并使我们能够跟踪这两个区域的活动如何随 LFP 的变化而变化。 有趣的是，放电率和锁相的变化与腹内侧丘脑高伽玛范围内的功率变化高度相关，但与运动皮层中的功率变化无关。 看来，在这种高伽马范围内的功率可以在运动皮层 LFP 中发生巨大变化，而尖峰 LFP 锁相不会发生相关变化。 根据我们迄今为止的分析，发射率变化也不明显。 还有更多工作要做，但迄今为止的研究提出了关于运动皮层高伽马范围活动的后果的有趣问题。 伽玛活性通常被认为是皮质功能的重要调节剂，我们希望深入了解这种活性表达水平过高的原因和后果（如多巴胺丧失后长期左旋多巴治疗后发生的情况），将有助于深入了解这种活性的正常和病理作用