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: 8596683
• 负责人: Steven Michael Graves
• 金额: $ 4.92万
• 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/8596683
• 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; 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; public health relevance; 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(申请人提供)：本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，以及在帕金森氏病(PD)和L-多巴诱发的运动障碍(LID)中使用由设计药物(DREADD)独家激活的设计受体。帕金森病的原因是黑质多巴胺能神经元的进行性丧失，导致纹状体多巴胺耗竭，纹状体是控制运动活动和动作选择的基础神经节回路的一部分。PD是最多的 常见的神经退行性运动障碍，用L多巴治疗效果显著。然而，慢性L-多巴治疗会导致无法控制的运动副作用，如舞蹈症、肌张力障碍和/或手动症，即眼睑。纹状体主要由GABA能棘突投射神经元组成，根据受体的表达和投射可分为两个亚群。多条证据表明，LID的神经病理过程中涉及直接通路、表达D2受体的纹状体黑质棘突投射神经元，但对间接通路、表达D2受体的纹状体黑质投射神经元(ISPN)的参与知之甚少。我们的初步证据表明，在帕金森病小鼠模型中，运动障碍小鼠的iSPN脊柱密度降低并恢复，这种脊柱缺陷反映了与运动障碍重新连接的皮质纹状体回路的丢失。我们寻求完善和扩展我们的初步数据，以更好地了解iSPN在LIDs中的病理。为此，我们将使用前波技术来评估神经解剖/形态、功能和电路。我们的工作假设是，iSPN皮质纹状体回路的恢复会导致iSPN中错误连接，导致iSPN中不适当的时间和规模的活动，导致无法抑制不想要的、运动障碍的运动。此外，我们假设皮质纹状体的重新连接是在L-多巴治疗期间D2介导的iSPN活性抑制所产生的动态平衡适应，在L-多巴治疗期间增加iSPN的兴奋性(使用在iSPN中表达的hM3D DREADD)将防止这种动态平衡适应并减少LID。计划中的研究将有助于我的整个NRSA目标，以获得在神经成像、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、形态和功能的变化(AIM I)、LID诱导的iSPN电路动力学(AIM II)以及增加iSPN的兴奋性(使用DREADD技术)对LID的发育和表达的影响(AIM III)。这项研究的结果将增进我们对iSPN和LIDs中的皮质纹状体回路的理解，同时扩大我的技术能力，推进我成为一名独立的学术神经科学家的职业目标。