DBS Protocols for Long-Lasting Therapeutic Benefit in Mouse and Primate Models of Parkinson's Disease
DBS 方案可在帕金森病小鼠和灵长类动物模型中获得持久治疗效果
基本信息
- 批准号:10582684
- 负责人:
- 金额:$ 61.01万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-15 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AcuteAnatomyAnimal ModelBasal GangliaBehavioralBiological AssayBrainCell NucleusCellsClinicalComplexConsumptionDataDeep Brain StimulationDevicesDissociationDopamineElectric StimulationEnsureFrequenciesFunctional disorderGlobus PallidusHomeoboxHourHumanImmobilizationInterventionKnowledgeMachine LearningMapsMasksMediatingModelingMotorMovementMusNatureNervous SystemNeuronsOutputOxidopamineParkinson DiseaseParkinsonian DisordersParvalbuminsPathologicPatientsPatternPhasePhysiologicalPhysiologyPopulationPrimatesProtocols documentationResearchResolutionRiskSTN stimulationSiteSliceSolidStructure of subthalamic nucleusSymptomsSynapsesTestingTherapeuticTherapeutic EffectTimeTranslatingTreatment EfficacyWhole-Cell Recordingsattenuationbattery lifecell typeclinical applicationcostdesigneffective therapyefficacy testingexperimental studyextracellularhigh dimensionalityin vivoinsightmotor deficitmotor recoverymotor symptommouse modelneural patterningneuroregulationnonhuman primatenovelnovel therapeutic interventionoptogeneticspre-clinicalpredictive modelingrational designrecruitreduce symptomsresponseside effecttherapeutic evaluationtranslation to humans
项目摘要
Abstract
Deep brain stimulation (DBS) is one of the most effective treatments for patients with advanced Parkinson's
disease (PD). Delivery of high frequency electrical stimulation to the subthalamic nucleus (STN) ameliorates
parkinsonian motor symptoms, often within seconds, but therapeutic effects wear off quickly if stimulation is
stopped, often within minutes. This transient nature of symptomatic relief underscores the fact that existing DBS
protocols mask symptoms but do not alleviate underlying circuit dysfunction. A modified DBS protocol, called
coordinated reset (CR-DBS), has shown potential to provide long-lasting therapeutic benefits for days to weeks
after stimulation, but this protocol has been slow to translate into widespread clinical use because (1) the multi-
site, pseudorandom stimulation patterns required to implement it cannot be delivered with existing devices and
(2) its mechanisms of action remain obscure, hindering insights into what parameters of CR-DBS should be
tuned to ensure engagement of long-lasting effects. Recently, in a mouse model of PD, we discovered a cellular-
based strategy to induce long-lasting motor recovery, by using optogenetics to target interventions to specific
neuronal subpopulations in the external globus pallidus (GPe), an anatomical neighbor of the STN. Long-lasting
motor rescue was induced by interventions that simultaneously increased the firing rates of GPe neurons
enriched in parvalbumin (PV-GPe) and decreased the firing rates of GPe neurons enriched in lim homeobox 6
(Lhx6-GPe). Interestingly, at the physiological level, these cell-type specific interventions in the GPe converged
upon a similar mechanism as CR-DBS, by ameliorating pathological patterns of neural activity in basal ganglia
output nuclei that have been associated with parkinsonian motor deficits. This proposal will use knowledge
gained from our discovery of long-lasting rescue through cell-type directed interventions in GPe to guide
rational design and interrogation of human-applicable forms of DBS that may yield similarly long-lasting
therapeutic benefit. Our experiments will test a novel, mechanistic hypothesis, based on supporting preliminary
data, that the pattern of electrical DBS can be tuned to drive cell-type specific responses in the GPe that mirror
those previously found to be sufficient to induce of long-lasting motor rescue with optogenetics. Experiments in
Aim 1 will investigate the cellular mechanisms through which phasic stimulation in the STN evokes cell-type
specific responses in the GPe (Aim 1.1) and use a machine learning approach to identify stimulation protocols
that maximize this cell-type specific response (Aim 1.2). Experiments in Aim 2 will test the therapeutic efficacy
of phasic stimulation protocols compared to conventional DBS, using behavioral and physiological assays in
mouse (Aim 2.1) and primate (Aim 2.2) models of PD. Taken together, these experiments will advance our
understanding of the fundamental differences between how conventional vs. phasic stimulation impacts
the nervous system, with cell-type specific and synapse-specific resolution, and could provide novel
therapeutic strategies that can be rapidly translated into humans.
摘要
脑深部电刺激(DBS)是治疗晚期帕金森病患者最有效的方法之一
疾病(PD)。向丘脑底核(subthalamic nucleus,简称STN)递送高频电刺激改善了
帕金森氏症的运动症状,往往在几秒钟内,但治疗效果磨损迅速,如果刺激是
通常在几分钟内就停止了。这种症状缓解的短暂性强调了现有DBS
治疗方案掩盖了症状,但不能减轻潜在的回路功能障碍。一种改进的DBS协议,称为
协调复位(CR-DBS)已显示出提供数天至数周持久治疗益处的潜力
刺激后,但该方案转化为广泛的临床应用很慢,因为(1)多-
现场,实现它所需的伪随机刺激模式不能用现有的设备提供,
(2)它的作用机制仍然模糊,阻碍了对CR-DBS参数的深入了解。
调整以确保长期效果的参与。最近,在帕金森病小鼠模型中,我们发现了一种细胞-
基于策略,以诱导持久的运动恢复,通过使用光遗传学针对特定的干预措施,
外苍白球(GPe)中的神经元亚群,GPe在解剖学上与苍白球相邻。持久
通过同时增加GPe神经元的放电率的干预来诱导运动拯救
富含小清蛋白(PV-GPe)的神经元放电频率降低,富含lim同源框6的GPe神经元放电频率降低
(Lhx6-GPe)。有趣的是,在生理水平上,GPe中这些细胞类型特异性干预措施
与CR-DBS相似的机制,通过改善基底神经节神经活动的病理模式,
与帕金森氏症运动缺陷有关的输出核团。这份提案将利用知识
从我们发现通过GPe中的细胞类型定向干预来指导
合理设计和询问人类适用的DBS形式,可能产生类似的持久性
治疗益处。我们的实验将测试一个新的,机械的假设,基于支持初步
数据,电DBS的模式可以被调谐以驱动GPe中的细胞类型特异性反应,
先前发现足以诱导光遗传学的持久运动拯救的那些。实验
目的1将探讨通过相位刺激在海马引起细胞类型的细胞机制
GPe中的特定反应(目标1.1),并使用机器学习方法来识别刺激方案
使这种细胞类型特异性反应最大化(目标1.2)。目标2中的实验将测试治疗效果
与传统DBS相比,使用行为和生理分析,
小鼠(目标2.1)和灵长类动物(目标2.2)PD模型。综合起来,这些实验将推动我们的
了解常规刺激与阶段性刺激影响之间的根本差异
神经系统,具有细胞类型特异性和突触特异性分辨率,并可以提供新的
可以迅速转化为人类的治疗策略。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Aryn Hilary Gittis其他文献
Aryn Hilary Gittis的其他文献
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{{ truncateString('Aryn Hilary Gittis', 18)}}的其他基金
Circuit-Inspired Strategies to Restore Basal Ganglia Function in Mouse Models of Parkinson’s Disease
恢复帕金森病小鼠模型基底神经节功能的受电路启发的策略
- 批准号:
10665167 - 财政年份:2023
- 资助金额:
$ 61.01万 - 项目类别:
Training Program in Big Data Systems Neuroscience
大数据系统神经科学培训计划
- 批准号:
10630961 - 财政年份:2022
- 资助金额:
$ 61.01万 - 项目类别:
Training Program in Big Data Systems Neuroscience
大数据系统神经科学培训计划
- 批准号:
10411631 - 财政年份:2022
- 资助金额:
$ 61.01万 - 项目类别:
CRCNS: Diverse effects of GABAergic inputs on a basal ganglia output center
CRCNS:GABA 能输入对基底神经节输出中心的多种影响
- 批准号:
10685556 - 财政年份:2021
- 资助金额:
$ 61.01万 - 项目类别:
CRCNS: Diverse effects of GABAergic inputs on a basal ganglia output center
CRCNS:GABA 能输入对基底神经节输出中心的多种影响
- 批准号:
10395793 - 财政年份:2021
- 资助金额:
$ 61.01万 - 项目类别:
DBS Protocols for Long-Lasting Therapeutic Benefit in Mouse and Primate Models of Parkinson's Disease
DBS 方案可在帕金森病小鼠和灵长类动物模型中获得持久治疗效果
- 批准号:
10362570 - 财政年份:2020
- 资助金额:
$ 61.01万 - 项目类别:
CIRCUIT MECHANISMS UNDERLYING LONG-LASTING RECOVERY OF MOVEMENT IN DOPAMINE DPELETED MICE INDUCED BY OPTOGENETIC INTERVENTION IN THE GPe
GPe 光遗传学干预引起的多巴胺缺乏小鼠运动持久恢复的电路机制
- 批准号:
10316994 - 财政年份:2018
- 资助金额:
$ 61.01万 - 项目类别:
DELINEATING CELL-SPECIFIC OUTPUT PATHWAYS OF THE GPe THAT SUPPORT LONG-LASTING BEHAVIORAL RECOVERY IN DOPAMINE DEPLETED MICE
描绘支持多巴胺耗尽小鼠长期行为恢复的 GPe 细胞特异性输出途径
- 批准号:
10317096 - 财政年份:2017
- 资助金额:
$ 61.01万 - 项目类别:
DELINEATING CELL-SPECIFIC OUTPUT PATHWAYS OF THE GPe THAT SUPPORT LONG-LASTING BEHAVIORAL RECOVERY IN DOPAMINE DEPLETED MICE
描绘支持多巴胺耗尽小鼠长期行为恢复的 GPe 细胞特异性输出途径
- 批准号:
10063586 - 财政年份:2017
- 资助金额:
$ 61.01万 - 项目类别:
NOVEL EXPERIMENTAL PLATFORM FOR PRODOMAL PARKINSON'S DISEASE
前发性帕金森病的新型实验平台
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9112176 - 财政年份:2016
- 资助金额:
$ 61.01万 - 项目类别:
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