Project II: Circuit Mechanisms of Attentional-Motor Interface Dysfunction in PD Falls
Project II: Circuit Mechanisms of Attentional-Motor Interface Dysfunction in PD Falls
批准号:
10282006
负责人:
MARTIN F SARTER
金额:
$43.54万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-09-30 至 2026-06-30
关键词:
5-HT6 receptorAddressAdmission activityAnimal ModelAttentionAttenuatedBasic ScienceBehavioralBehavioral ParadigmBiosensorClinicalCodeComplementComplexCorpus striatum structureCouplingCuesDataDeafferentation procedureDenervationDetectionDisease ResistanceDopamineElementsEnvironmentEquilibriumExcisionExhibitsFall preventionFreezingFrequenciesFunctional disorderFundingGaitGait abnormalityGait speedGap JunctionsGenerationsGlutamatesHospitalizationHumanImmobilizationImpairmentInterneuronsInterventionLevodopaLimb structureLinkMeasuresMediatingMichiganModelingMotorMovementNational Institute of Neurological Disorders and StrokeNeuronsNicotinic ReceptorsNodalNursing HomesOxidasesParkinson DiseasePathway interactionsPatientsPerformancePersonsPharmacologyPhasePositron-Emission TomographyPre-Clinical ModelRattusRecommendationReportingResearchResearch Project GrantsResistanceResourcesRisk FactorsRodent ModelRoleSignal TransductionSymptomsSynapsesSystemTaxesTestingVirusWorkacetylcholine receptor agonistattenuationbasal forebrainbasal forebrain cholinergic neuronsbasecholinergicdesigner receptors exclusively activated by designer drugsdopamine replacement therapyeffective therapyequilibration disorderexperienceexperimental studyfallsglutamatergic signalingin vivoinhibitor/antagonistinsightkinematicsmotor controlneural circuitneuronal circuitryneurotransmissionnoveloptogeneticsresearch and developmentsynergismtherapeutic developmenttherapy developmenttranslational modeltranslational studytreadmill
中文摘要
项目二:摘要/摘要
大约三分之二的帕金森病(PD)患者经历过跌倒;这是
住院和养老院入院。帕金森病的这些衰弱特征对多巴胺具有抵抗力。
替代疗法,强调迫切需要以基础研究和治疗开发为重点
帕金森病患者非多巴胺能系统变性。我们之前建立了帕金森病跌倒的啮齿动物模型
开发了新的行为范式,反映了帕金森病跌倒的关键因素。我们的工作发现了
注意-运动接口网络是步态和平衡受损的主要病理生理基础
在警局。新型密歇根复杂运动控制任务(MCMCT)评估急性心肌梗死受损导致的跌倒
在大鼠体内的功能。我们还证明了皮质胆碱能和纹状体多巴胺(DL)双重缺失的大鼠
(大鼠),反映了帕金森病患者基于PET的发现,在MCMCT上显示出较高的跌倒发生率。就像PD Flowers一样,
DL大鼠的注意力障碍预示着跌倒的几率。α-4-β-2*烟碱型乙酰胆碱受体治疗
激动剂、AChase抑制剂和5-HT6受体拮抗剂(Idalopirdine)的联合治疗可减少跌倒
费率,表明我们系统的转换价值。我们现在建议进行严格的机械论研究,以确定
急性心肌梗死关键结节内的严重突触功能障碍。我们将评估基底前脑胆碱能信号的作用
在福尔斯(目标1),胆碱驱动的皮质-纹状体信息传递(目标2),以及纹状体的作用
胆碱能中间神经元(目标3)。这项工作将直接补充项目I和项目III的研究。
提出的研究得到了广泛的初步证据的支持,这些证据表明:1)光遗传的影响
基底前脑胆碱能信号对复杂运动控制的操纵;2)提示引导
复杂的运动通过皮质-纹状体谷氨酸能活动“输入”到纹状体;3)DREADD-
抑制或刺激纹状体胆碱能神经元间活动分别引起和预防跌倒;
4)这些中间神经元广泛地编码用于执行动作的线索。拟议的研究将确定
结节性和突触性急性心肌梗死功能障碍的机制,确定新的干预靶点,扩展了有价值的
用于治疗发展的临床前模型,以及作为研究有用的行为终点的实证性下降
AMI的关键节点。
英文摘要
PROJECT II: SUMMARY/ABSTRACT
Approximately two thirds of patients with Parkinson’s disease (PD) experience falls; a primary cause of
hospitalization and nursing home admission. These debilitating features of PD are resistant to dopamine
replacement therapy, emphasizing the urgent need for basic research and therapeutic development focused on
non-dopaminergic systems degenerating in PD. We previously established a rodent model of PD falls and
developed novel behavioral paradigms that reflect critical elements of PD falls. Our work identified disruptions of
the Attentional-Motor Interface (AMI) network as a major pathophysiologic substrate of impaired gait and balance
in PD. The novel Michigan Complex Motor Control Task (MCMCT) assesses falls resulting from impaired AMI
function in rats. We also demonstrated that rats with dual losses of cortical cholinergic and striatal dopamine (DL
rats), reflecting PET-based findings in PD fallers, exhibit high rates of falls on the MCMCT. As in PD fallers,
impairments in attention of DL rats predict fall rates. Treatment with an α4β2* nicotinic acetylcholine receptor
agonist, combination treatments of AChase inhibitors and a 5-HT6 receptor antagonist (idalopirdine) reduce fall
rates, indicating translational value of our system. We now propose rigorous mechanistic studies identifying
critical synaptic dysfunction within key AMI nodes. We will assess the role of basal forebrain cholinergic signaling
in falls (Aim 1), of cholinergically-driven cortico-striatal information transfer (Aim 2), and of the role of striatal
cholinergic interneurons (Aim 3). This work will directly complement the research of Projects I and III. The
proposed research is supported by extensive preliminary evidence demonstrating: 1) the impact of optogenetic
manipulations of basal forebrain cholinergic signaling on complex movement control; 2) that cues guiding
complex movements are “imported’ into the striatum via cortico-striatal glutamatergic activity; 3) that DREADD-
based inhibition or stimulation of striatal cholinergic interneuronal activity cause and prevent falls, respectively;
4) that these interneurons broadly code cues utilized to execute movements. The proposed research will identify
mechanisms of nodal and synaptic AMI dysfunctions, identify novel intervention targets, extend a valuable
preclinical model for therapy development, and substantiate falls as a useful behavioral endpoint for studying
key nodes of the AMI.
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会议论文
Project II: Circuit Mechanisms of Attentional-Motor Interface Dysfunction in PD Falls
-
批准号:10493267
-
项目类别:
-
资助金额:$43.49万
-
财政年份:2021
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负责人:MARTIN F SARTER
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依托单位:
Addiction liability, poor attentional control, and cholinergic deficiency
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批准号:10440417
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项目类别:
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资助金额:$38.36万
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财政年份:2018
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负责人:MARTIN F SARTER
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依托单位:
Addiction liability, poor attentional control, and cholinergic deficiency
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批准号:9925194
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项目类别:
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资助金额:$38.64万
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财政年份:2018
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负责人:MARTIN F SARTER
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依托单位:
Addiction liability, poor attentional control, and cholinergic deficiency
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批准号:9593624
-
项目类别:
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资助金额:$40.11万
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财政年份:2018
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负责人:MARTIN F SARTER
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依托单位:
Addiction liability, poor attentional control, and cholinergic deficiency
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批准号:10197075
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项目类别:
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资助金额:$38.5万
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财政年份:2018
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负责人:MARTIN F SARTER
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依托单位:
Choline transporter capacity limits motivated behavior on mice, rats, and humans
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批准号:7984725
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项目类别:
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资助金额:$41.19万
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财政年份:2010
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负责人:MARTIN F SARTER
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依托单位:
Choline transporter capacity limits motivated behavior on mice, rats, and humans
-
批准号:8626443
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项目类别:
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资助金额:$38.12万
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财政年份:2010
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负责人:MARTIN F SARTER
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依托单位:
Choline transporter capacity limits motivated behavior on mice, rats, and humans
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批准号:8109385
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项目类别:
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资助金额:$38.11万
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财政年份:2010
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负责人:MARTIN F SARTER
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依托单位:
Choline transporter capacity limits motivated behavior on mice, rats, and humans
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批准号:8436265
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项目类别:
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资助金额:$36.6万
-
财政年份:2010
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负责人:MARTIN F SARTER
-
依托单位:
Choline transporter capacity limits motivated behavior on mice, rats, and humans
-
批准号:8267075
-
项目类别:
-
资助金额:$38.13万
-
财政年份:2010
-
负责人:MARTIN F SARTER
-
依托单位:
Nicotinic regulation of cortical ACh release and behavioral function
-
批准号:7649345
-
项目类别:
-
资助金额:$30.22万
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财政年份:2007
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负责人:MARTIN F SARTER
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依托单位:
In vivo screening of cholinergic cognition enhancers
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批准号:7492128
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项目类别:
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资助金额:$17.1万
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财政年份:2007
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负责人:MARTIN F SARTER
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依托单位:
Nicotinic regulation of cortical ACh release and behavioral function
-
批准号:7365409
-
项目类别:
-
资助金额:$29.39万
-
财政年份:2007
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负责人:MARTIN F SARTER
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依托单位:
In vivo screening of cholinergic cognition enhancers
-
批准号:7237792
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项目类别:
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资助金额:$19.63万
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财政年份:2007
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负责人:MARTIN F SARTER
-
依托单位:
Nicotinic regulation of cortical ACh release and behavioral function
-
批准号:7869388
-
项目类别:
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资助金额:$30.2万
-
财政年份:2007
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负责人:MARTIN F SARTER
-
依托单位:
Cholinergic plasticity in auditory input processing
-
批准号:7014075
-
项目类别:
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资助金额:$7.44万
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财政年份:2005
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负责人:MARTIN F SARTER
-
依托单位:
Cholinergic plasticity in auditory input processing
-
批准号:6899499
-
项目类别:
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资助金额:$7.65万
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财政年份:2005
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负责人:MARTIN F SARTER
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依托单位:
Regulation of cortical ACh and Cognition
-
批准号:6830188
-
项目类别:
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资助金额:$12.29万
-
财政年份:2003
-
负责人:MARTIN F SARTER
-
依托单位:
Regulation of cortical ACh and Cognition
-
批准号:6720594
-
项目类别:
-
资助金额:$12.29万
-
财政年份:2003
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负责人:MARTIN F SARTER
-
依托单位:
Regulation of cortical ACh and Cognition
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批准号:7156930
-
项目类别:
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资助金额:$12.29万
-
财政年份:2003
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负责人:MARTIN F SARTER
-
依托单位:
海外基金