Nigrostriatal dopamine mechanisms of cognitive control
黑质纹状体多巴胺认知控制机制
基本信息
- 批准号:10639280
- 负责人:
- 金额:$ 7.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAreaAttentionAwardBasal GangliaBasic ScienceBehavioralCodeCognitionCognitiveCorpus striatum structureDataDementiaDevelopmentDiagnosisDiseaseDopamineDorsalElectrophysiology (science)EventExhibitsFiberFoundationsGoalsImpaired cognitionImpairmentInstitutionKnowledgeLaboratoriesLearningLesionLinkMemoryModelingMusNerve DegenerationNeurobehavioral ManifestationsNeuronsParkinson DiseaseParkinson&aposs DementiaPatientsPerformancePhotometryPrefrontal CortexPrincipal InvestigatorQuality of lifeRampReportingResearchResolutionRodentRunningShort-Term MemorySignal TransductionSubstantia nigra structureSymptomsTechnical ExpertiseTechniquesTestingTimeTrainingTransgenic MiceWorkcareercognitive controlcognitive functioncognitive impairment in Parkinson&aposscognitive processcognitive taskdopaminergic neuroneffective therapyexecutive functionexperienceexperimental studyimprovedmild cognitive impairmentmillisecondmotor symptomneurobiological mechanismneurophysiologyneurotransmissionnigrostriatal pathwaynovelnovel therapeuticsoptogeneticspars compactapreventprogramsskill acquisitionskillssocietal coststargeted treatmenttemporal measurementtherapeutic developmenttherapy developmenttime interval
项目摘要
Project Summary/Abstract
Cognitive impairments, which affect memory, executive functioning, and timing, are experienced by the
majority of Parkinson’s disease patients at some point during their disease. For many patients, mild cognitive
impairments eventually devolve into Parkinson’s disease dementia. Despite the negative impact on quality of
life caused by these symptoms, there are currently no effective therapies to treat cognitive impairment in these
patients. Thus, there is an unmet need to develop new treatments for Parkinson’s disease-related cognitive
decline. This requires identifying the fundamental neurobiological mechanisms underlying cognitive dysfunction
in Parkinson’s disease.
Dopamine neuron degeneration in the nigrostriatal pathway is associated not only with the motor
symptoms of Parkinson’s disease, but also with cognitive symptoms. Parkinson’s disease patients have
reliably impaired performance on interval timing tasks and lesioning or manipulating dopamine neurons in
rodents also impairs performance on interval timing tasks. Furthermore, striatal neurons encode temporally
relevant information by ramping their activity across timed intervals. The overall goal of my proposed research
is to identify how nigrostriatal dopamine signals influence striatal microcircuitry during a cognitive task. My
overall hypothesis is that striatal temporal encoding depends on dopamine.
I will test this overall hypothesis with two distinct experiments. First, I will test the hypothesis that task-
modulated striatal dopamine activity predicts temporal encoding by striatal projection neurons during an
interval timing task. I will test this by recording local dopamine dynamics with striatal dLight and fiber
photometry while simultaneously recording striatal neuronal ensembles. Second, I will test the hypothesis that
dopamine neurons control striatal time-related ramping activity. I will optogenetically silence or stimulate
dopamine neurons at key behavioral events during the task while recording striatal neuronal ensemble activity.
Together, the proposed experiments will contribute to a model establishing how nigrostriatal dopamine
neurons regulate striatal cognitive processing. This knowledge will inform development of novel therapies for
cognitive impairments in Parkinson’s disease by identifying where and how to target treatments. This is highly
relevant for Parkinson’s disease and other dopamine-linked disorders, as this work will reveal foundational
basic science mechanisms of dopamine. Completion of the proposed work will not only expand my technical
and research skillset, but also enhance my professional development skills. Therefore, this award will advance
me towards my career goal of running an independent laboratory at a competitive research institution, focused
on dopamine and basal ganglia circuitry mechanisms of cognitively-guided action.
项目总结/摘要
认知障碍,影响记忆,执行功能和时间,是经历了由
大多数帕金森病患者在疾病期间的某个时候。对于许多患者来说,轻度认知障碍
最终会发展成帕金森氏症痴呆尽管对质量产生了负面影响,
由于这些症状引起的认知障碍,目前还没有有效的治疗方法来治疗这些症状。
患者因此,开发用于帕金森病相关认知功能障碍的新疗法的需求尚未得到满足。
下降这需要确定认知功能障碍的基本神经生物学机制
帕金森氏症的症状。
黑质纹状体通路中的多巴胺神经元变性不仅与运动相关,
帕金森病的症状,但也有认知症状。帕金森病患者有
在间隔计时任务上的表现可靠受损,
啮齿类动物也会损害间隔计时任务的表现。此外,纹状体神经元编码时间
通过在时间间隔内增加他们的活动来获得相关信息。我提出的研究的总体目标是
是确定黑质纹状体多巴胺信号如何影响纹状体微电路在认知任务。我
总的假设是纹状体的时间编码依赖于多巴胺。
我将用两个不同的实验来检验这个总体假设。首先,我将测试这个假设,即任务-
调制的纹状体多巴胺活性预测纹状体投射神经元在脑缺血期间的时间编码。
间隔计时任务。我将通过记录纹状体dLight和纤维的局部多巴胺动力学来测试这一点
光度测定,同时记录纹状体神经元系综。第二,我将检验一个假设,
多巴胺神经元控制纹状体时间相关的斜坡活动。我会通过光遗传学的方法
多巴胺神经元在关键行为事件的任务,同时记录纹状体神经元的整体活动。
总之,拟议的实验将有助于建立一个模型,建立黑质纹状体多巴胺
神经元调节纹状体的认知过程。这些知识将为开发新的治疗方法提供信息,
帕金森病的认知障碍,通过确定在哪里以及如何靶向治疗。这是高度
与帕金森病和其他多巴胺相关的疾病有关,因为这项工作将揭示
多巴胺的基础科学机制完成拟议的工作不仅将扩大我的技术
和研究技能,而且还提高了我的专业发展技能。因此,该奖项将推动
我朝着我的职业目标,在一个有竞争力的研究机构运行一个独立的实验室,专注于
多巴胺和基底神经节回路机制的认知引导的行动。
项目成果
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