L-DOPA-induced dyskinesias and dysregulation of striatopallidal neurons

左旋多巴诱导的运动障碍和纹状体苍白球神经元失调

• 批准号: 8758664
• 负责人: Steven Michael Graves
• 金额: $ 2.64万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8758664
• 关键词: Achievement; Adverse effects; Anatomy; Athetosis; Attenuated; Basal Ganglia; Behavior; Cells; Chorea; Chronic; Corpus striatum structure; Coupled; Data; Designer Drugs; Development; Disease; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Dose; Dyskinetic syndrome; Dystonia; Exhibits; Failure; Figs - dietary; Frequencies; Functional disorder; Globus Pallidus; Glutamates; Goals; Health; Image; Imaging Techniques; Knowledge; L-DOPA induced dyskinesia; Laser Scanning Microscopy; Lesion; Levodopa; Mediating; Mission; Modeling; Morphology; Motor; Motor Activity; Movement; Movement Disorders; Mus; National Research Service Awards; Nerve Degeneration; Neuroanatomy; Neurons; Outcomes Research; Palliative Care; Parkinson Disease; Pathology; Pathway interactions; Physiology; Population; Public Health; Research; Role; Scientific Advances and Accomplishments; Structure of subthalamic nucleus; Substantia nigra structure; Synapses; Techniques; Technology; Testing; Time; Training; Vertebral column; Work; base; career; density; design; dopaminergic neuron; insight; mouse model; neuroimaging; neuropathology; novel; optogenetics; post-doctoral training; prevent; receptor; receptor expression; restoration; selective expression; two-photon

DESCRIPTION (provided by applicant): This NRSA application is submitted for support of post-doctoral training involving neuroanatomy/morphology, physiology, neurocircuitry, and use of designer receptors exclusively activated by designer drugs (DREADDs) in Parkinson's disease (PD) and L-DOPA-induced dyskinesias (LIDs). PD results from a progressive loss of dopaminergic neurons in the substantia nigra resulting in dopamine depletion of the striatum, part of the basal ganglia circuitry controlling motor activity and action selection. PD is the most common neurodegenerative movement disorder and is efficaciously treated with L-DOPA. However, chronic L-DOPA therapy leads to uncontrolled motor side effects such as chorea, dystonia, and/or athetosis, i.e. LIDs. The striatum consists primarily of GABAergic spiny projection neurons that can be divided into two subpopulations based on receptor expression and projections. Multiple lines of evidence indicate involvement of direct pathway, D1-expressing striatonigral spiny projection neurons in the neuropathology of LIDs, but less is known about the involvement of indirect pathway, D2 receptor-expressing striatopallidal spiny projection neurons (iSPNs). Our preliminary evidence indicates that in a mouse model of PD, iSPN spine density was decreased and recovered in dyskinetic mice and that this spine deficit reflected a loss of corticostriatal circuitry that rewired with dyskinesias. We seek to complete and expand our preliminary data to better understand iSPN pathology in LIDs. To do so we will use front-wave technologies to assess neuroanatomy/morphology, function, and circuitry. Our working hypothesis is that restoration of iSPN corticostriatal circuitry leads to mis-wiring with inappropriately timed and scaled activity in iSPNs resulting in the failure to suppress unwanted, dyskinetic movements. Moreover we hypothesize that the corticostriatal re-wiring is a homeostatic adaptation resultant from D2-mediated suppression of iSPN activity during L-DOPA therapy and that increasing iSPN excitability (using the hM3D DREADD expressed in iSPNs) during L-DOPA administration will prevent the homeostatic adaptations and decrease LIDs. The planned studies will contribute to my overall NRSA objective to acquire outstanding training in neuroimaging, physiology, optogenetics, and the use of DREADDS and will be used to determine LID-induced changes in iSPN anatomy, morphology and function (aim I), LID-induced circuit dynamics in iSPNs (aim II), and the effect of increasing iSPN excitability (using DREADD technology) on the development and expression of LIDs (aim III). Outcomes from this research will advance our understanding of iSPNs and corticostriatal circuitry in LIDs while expanding my technical abilities and advancing my career objective of becoming an independent academic neuroscientist.

描述（由申请人提供）：此NRSA申请是为了支持博士后培训，涉及神经解剖学/形态学，生理学，神经回路，以及在帕金森病（PD）和左旋多巴诱导的运动障碍（LID）中使用专门由设计药物（DREADDs）激活的设计受体。PD由黑质中多巴胺能神经元的进行性损失引起，导致纹状体的多巴胺耗竭，纹状体是控制运动活动和动作选择的基底神经节回路的一部分。PD是最 常见的神经退行性运动障碍，并有效地用左旋多巴治疗。然而，长期L-DOPA治疗导致不受控制的运动副作用，例如舞蹈病、肌张力障碍和/或手足徐动症，即LID。纹状体主要由GABA能多刺投射神经元组成，其可基于受体表达和投射分为两个亚群。多条证据表明直接通路，D1-表达纹状体黑质棘状投射神经元参与LIDS的神经病理学，但较少有人知道间接通路，D2受体表达纹状体锥体棘状投射神经元（iSPN）的参与。我们的初步证据表明，在PD的小鼠模型中，iSPN棘密度降低，并在运动障碍小鼠中恢复，并且这种棘缺陷反映了皮质纹状体回路的丢失，其与运动障碍重新连接。我们寻求完成和扩展我们的初步数据，以更好地了解LID中的iSPN病理。为此，我们将使用前波技术来评估神经解剖学/形态学、功能和电路。我们的工作假设是，iSPN皮质纹状体回路的恢复导致错误布线，iSPN中的活动时间和比例不当，导致无法抑制不必要的运动障碍运动。此外，我们假设皮质纹状体重新布线是在L-DOPA治疗期间由D2介导的iSPN活性抑制引起的稳态适应，并且在L-DOPA施用期间增加iSPN兴奋性（使用在iSPN中表达的hM 3D DREADD）将防止稳态适应并降低LID。计划中的研究将有助于我的总体NRSA目标，即获得神经影像学，生理学，光遗传学和DREADDS使用方面的出色培训，并将用于确定LID诱导的iSPN解剖学，形态学和功能变化（目的I），LID诱导的iSPN回路动力学（目的II），以及增加iSPN兴奋性（使用DREADD技术）对LID的发育和表达的影响（目的III）。这项研究的结果将促进我们对LID中iSPN和皮质纹状体回路的理解，同时扩大我的技术能力，并推进我成为独立学术神经科学家的职业目标。