Pathological striatopallidal neuronalensembles in learned motor impairment in PD

PD 习得性运动障碍中的病理性纹状体苍白球神经元群

• 批准号: 10395604
• 负责人: Un Jung Kang
• 金额: $ 37.08万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395604
• 关键词: Antiparkinson Agents; Basal Ganglia; Brain region; Clinical Data; Corpus striatum structure; Deep Brain Stimulation; Development; Dopamine D2 Receptor; Dose; Doxycycline; Drug Prescriptions; Effectiveness; Electrophysiology (science); Etiology; Exposure to; Future; Hour; Impairment; Knock-out; Label; Lead; Learning; Levodopa; Long-Term Potentiation; Maintenance; Mediating; Motor; Motor output; Movement; Mus; Neuronal Plasticity; Neurons; Opsin; Parkinson Disease; Pathologic; Pathway interactions; Patients; Performance; Pharmacology; Plasma; Quality of life; Role; Slice; Synapses; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; Withdrawal; base; classical conditioning; cost; dopaminergic neuron; effective therapy; experience; experimental study; fluorophore; improved; motor control; motor impairment; motor symptom; mouse model; novel; optogenetics; postsynaptic; pre-clinical; prevent; promoter; recruit; response; social; success

ABSTRACT In Parkinson's disease (PD), degeneration of dopaminergic (DA) neurons leads to profound motor impairment. Although motor symptom is initially treatable by the DA precursor levodopa (L-DOPA), patients experience dis- abling motor fluctuations, including a shortened duration of action for L-DOPA, only partially treated with pharmacological means and deep brain stimulation. Preventing L-DOPA's declining effectiveness will greatly improve patients' quality of life and reduce social cost. Emergence of disabling motor fluctuation is associated with the decline of a component of L-DOPA's antiparkinsonian response, known as the long duration response (LDR). The LDR is a long-lasting motor improvement that persists long after L-DOPA plasma level has re- turned to baseline, gradually decaying over many hours to days after discontinuation of L-DOPA. Motor fluctuation may be caused by LDR declining too rapidly, and treatments that halt LDR decay may prevent mo- tor fluctuations. However, the mechanism underlying LDR is currently unknown. Using two distinct motor tasks, we recently found that both induction and decay of LDR is task-specific, requiring the pairing of task exposure with L-DOPA (for LDR induction) or with L-DOPA withdrawal (for LDR decay). These results point to associa- tive learning and neuroplasticity as the underlying mechanism. Furthermore, indirect pathway medium spiny neurons (iMSNs) are activated by LDR decay, and D2 receptor (D2R) knockout greatly slowed LDR decay. Based on the above results and previous findings that i) iMSN activation suppresses movement and may nor- mally function to inhibit competing responses; ii) iMSNs undergo aberrant long-term potentiation (LTP) when DA depleted, we will test the hypothesis that gradual motor impairment during LDR decay results from aberrant LTP in specific ensembles of iMSNs that are normally suppressed during normal movement by D2R stimula- tion, but become pathologically active during task exposure if DA is depleted. Using Drd2-EGFP mice to label iMSNs, we will first examine whether L-DOPA-rescued motor performance vs. LDR decay activate different iMSN ensembles in the same mouse: we will tag task-activated iMSN ensemble at the 1st time point using a Fos-promoter driven, doxycycline-gated fluorophore, then tag task-activated iMSN ensemble at the 2nd time point using endogenous Fos labeling, and compare their co-localization. We will then examine whether this “incorrect” iMSN ensemble activated during LDR decay (visualized by a Fos-driven fluorophore) has synaptic input changes that are consistent with the occurrence of LTP. Finally, we will use Fos-driven opsins to bi- directionally modulate this “incorrect” iMSN ensemble to show its causal, pathological role: that its activation leads to task-specific motor impairment, and its inhibition recues impairment task-specifically. By demonstrat- ing the existence of, and the role of, pathological iMSN ensembles in task-specific motor impairment in PD, and by identifying the form of aberrant neuroplasticity that leads to their recruitment during movement, these experiments will form a basis for future studies to develop novel treatments to halt or reverse LDR decay and motor fluctuation.

抽象的 在帕金森氏病（PD）中，多巴胺能（DA）神经元的变性导致了严重的运动障碍。 尽管最初可以通过DA前体左旋多巴（L-DOPA）治疗运动症状，但患者经历了疾病 阿布电动机波动，包括​​L-DOPA的作用缩短，仅部分处理 药理手段和深脑刺激。防止L-DOPA的效力下降将极大地 改善患者的生活质量并降低社会成本。禁用电动机波动的出现与 随着L-Dopa的反帕金森氏反应的一部分的下降，称为长时间响应 （LDR）。 LDR是一种持久的电动机改进 转向基线，逐渐衰减在L-DOPA中断后的几个小时到几天。发动机 波动可能是由于LDR的下降而引起的 Tor波动。但是，LDR的基础机制目前尚不清楚。使用两个不同的电机任务， 我们最近发现，LDR的诱导和衰减都是特定于任务的，需要任务曝光配对 使用L-DOPA（用于LDR诱导）或L-DOPA撤回（用于LDR衰减）。这些结果指向联想 作为基本机制，学习和神经可塑性。此外，间接途径中刺 神经元（IMSN）被LDR衰减激活，D2受体（D2R）敲除非常缓慢的LDR衰变。 基于上述结果和以前的发现，i）IMSN激活抑制运动，并且可能不可能 mally功能抑制竞争反应； ii）IMSNS经历异常长期增强（LTP） DA耗尽，我们将测试以下假设：LDR衰变期间的级运动障碍导致异常 LTP在IMSN的特定集合中通常在正常运动过程中被D2R刺激抑制 - tion，但如果DA耗尽，则在任务暴露期间变得有病理活跃。使用DRD2-EGFP小鼠标记 IMSNS，我们将首先检查L-DOPA验证的电动机性能与LDR衰减是否激活不同 同一鼠标中的IMSN合奏：我们将使用一个时间点标记任务激活的IMSN集​​合 FOS促销驱动器，强力霉素门控荧光团，然后在第二次标记任务激活的IMSN合奏 使用内源性FOS标记点，并比较其共定位。然后，我们将检查是否 在LDR衰减期间激活的“不正确” IMSN集​​合（由FOS驱动的荧光团可视化）具有突触 与LTP的发生一致的输入变化。最后，我们将使用FOS驱动的Opsins进行双向 定向调节这种“不正确”的IMSN合奏，以显示其因果关系的病理作用：它的激活 导致特定于任务的运动障碍，其抑制作用降低了任务。通过证明 病理IMSN合奏在PD中特定于任务的运动障碍中的存在和作用 通过确定导致其运动过程中招募的异常神经可塑性的形式，这些 实验将为将来的研究构成基础，以开发新的治疗方法以阻止或逆转LDR衰减，并 电动机波动。