L-DOPA-induced dyskinesias (LID) are debilitating motor symptoms of dopamine-replacement therapy for Parkinson’s disease (PD) that emerge after years of L-DOPA treatment. While there is an abundance of research into the cellular and synaptic origins of LID, less is known about how LID impacts systems-level circuits and neural synchrony, how synchrony is affected by the dose and duration of L-DOPA exposure, or how potential novel treatments for LID, such as sub-anesthetic ketamine, alter this activity. Sub-anesthetic ketamine treatments have recently been shown to reduce LID, and ketamine is known to affect neural synchrony. To investigate these questions, we measured movement and local-field potential (LFP) activity from the motor cortex (M1) and the striatum of preclinical rodent models of PD and LID. In the first experiment, we investigated the effect of the LID priming procedures and L-DOPA dose on neural signatures of LID. Two common priming procedures were compared: a high-dose procedure that exposed unilateral 6-hydroxydopamine-lesioned rats to 12 mg/kg L-DOPA for 7 days, and a low-dose procedure that exposed rats to 7 mg/kg L-DOPA for 21 days. Consistent with reports from other groups, 12 mg/kg L-DOPA triggered LID and 80-Hz oscillations; however, these 80-Hz oscillations were not observed after 7 mg/kg administration despite clear evidence of LID, indicating that 80-Hz oscillations are not an exclusive signature of LID. We also found that weeks-long low-dose priming resulted in the emergence of non-oscillatory broadband gamma activity (> 30 Hz) in the striatum and theta-to-high-gamma cross-frequency coupling (CFC) in M1. In a second set of experiments, we investigated how ketamine exposure affects spectral signatures of low-dose L-DOPA priming. During each neural recording session, ketamine was delivered through 5 injections (20 mg/kg, i.p.) administered every 2 hours. We found that ketamine exposure suppressed striatal broadband gamma associated with LID but enhanced M1 broadband activity. We also found that M1 theta-to-high-gamma CFC associated with the LID on-state was suppressed by ketamine. These results suggest that ketamine’s therapeutic effects are region specific. Our findings also have clinical implications, as we are the first to report novel oscillatory signatures of the common low-dose LID priming procedure that more closely models dopamine replacement therapy in individuals with PD. We also identify neural correlates of the anti-dyskinetic activity of sub-anesthetic ketamine treatment.

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L-DOPA引起的运动障碍的光谱特征取决于L-DOPA剂量，并被氯胺酮抑制

L-DOPA引起的运动障碍（LID）使帕金森氏病（PD）的多巴胺替代疗法的运动症状恶化，这种症状在L-DOPA治疗多年后出现。尽管关于LID的细胞和突触起源的研究很多，但是关于LID如何影响系统级电路和神经同步性，L-DOPA暴露的剂量和持续时间如何影响同步性或潜在的新颖性知之甚少LID的治疗（例如亚麻醉的氯胺酮）会改变这种活性。近来已证明亚麻醉的氯胺酮治疗可降低LID，已知氯胺酮会影响神经同步性。为了调查这些问题，我们测量了运动皮层（M1）和PD和LID临床前啮齿动物模型的纹状体的运动和局部场电位（LFP）活动。在第一个实验中 我们研究了LID启动程序和L-DOPA剂量对LID神经信号的影响。比较了两种常见的启动程序：将单侧6-羟基多巴胺损伤的大鼠暴露于12 mg / kg L-DOPA 7天的高剂量程序，以及将大鼠暴露于7 mg / kg L-DOPA的低剂量程序。持续21天。与其他组的报告一致，12 mg / kg L-DOPA触发了LID和80 Hz振荡；然而，尽管有明确的LID证据，但在7 mg / kg的给药后仍未观察到这些80 Hz振荡，这表明80 Hz振荡并非LID的专有标志。我们还发现，长达数周的低剂量启动导致纹状体中出现非振荡性宽带伽马活性（> 30 Hz），并且在M1中出现了theta至高伽马交叉频率耦合（CFC）。在第二组实验中 我们研究了氯胺酮暴露如何影响低剂量L-DOPA引发的光谱特征。在每次神经记录期间，通过5次注射（20 mg / kg，我。第2页）。我们发现氯胺酮暴露抑制了与LID相关的纹状体宽带伽玛，但增强了M1宽带活性。我们还发现，氯胺酮抑制了与LID接通状态相关的M1到高伽马CFC。这些结果表明氯胺酮的治疗作用是区域特异性的。我们的发现也具有临床意义，因为我们是第一个报告常见的低剂量LID引发程序的新颖振荡信号的方法，该信号可以更紧密地模拟PD患者的多巴胺替代疗法。我们还确定了亚麻醉氯胺酮治疗的抗运动障碍活性的神经相关性。