Limbic pallidal circuits linked to apathy in Parkinson’s disease during subthalamic deep brain stimulation
边缘苍白球回路与丘脑深部脑刺激期间帕金森病的冷漠有关
基本信息
- 批准号:10592985
- 负责人:
- 金额:$ 43.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdverse effectsAffectAmygdaloid structureAnatomyBehaviorBehavior assessmentBehavioralBiological MarkersBrainBrain DiseasesBrain regionChronicClinicalCognitionCognitiveDeep Brain StimulationDevelopmentDisease modelElectric StimulationElectricityElectrodesElectrophysiology (science)FDA approvedFOS geneFundingFutureGlobus PallidusGlutamatesGoalsGrantGrowthHumanHyperactivityImpairmentImplanted ElectrodesInjectionsInvestigationKnowledgeLaboratoriesLeadLesionLightLinkMaintenanceMeasuresMediatingModelingModernizationMood DisordersMoodsMotivationMotorMovementNeurodegenerative DisordersNeuronal PlasticityNeuronsOpsinOutcomeOutcome StudyOutputParkinson DiseasePathogenicityPatientsPharmaceutical PreparationsProtocols documentationQuality of lifeRattusResearchResearch Project GrantsRodentRoleSTN stimulationSleepStructureStructure of subthalamic nucleusSymptomsTechniquesTechnologyTestingThinkingTimeTissuesUnited States National Institutes of HealthWorkbehavior testclinical careclinically relevantdesigneffective therapyimprovedimproved outcomeinnovationmotor behaviormotor symptomnon-motor symptomnoveloptogeneticsparkinsonian rodentprogramsside effecttransmission process
项目摘要
PROJECT SUMMARY/ABSTARCT
Parkinson’s disease (PD) is a neurodegenerative disease that presents both motor and non-motor
disturbances. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is efficacious in treating cardinal
motor features of PD. In contrast, non-motor symptoms typically do not improve and may even worsen with
DBS. Electrode placement in the STN is targeted to the motor subregion, but off-target activation of limbic and
associative circuits, and the resultant adaptations in circuit activity after DBS, likely lead to non-motor adverse
effects. The long-term goals of our Research Program are to i) identify biomarkers that can be used to predict
when DBS may result in disorders of mood and cognition, and ii) improve DBS stimulation paradigms to reduce
non-motor adverse effects. Apathy is a prevalent non-motor symptom of PD that frequently worsens after STN-
DBS to significantly impair quality of life. Thus, the current R21 Study will focus on apathy. Accordingly, the
overall objective of the Study is to determine the mechanism(s) and anatomical substrate(s) of apathy after
STN-DBS in a rat model of PD. Highly selective optogenetic stimulation approaches will be used to isolate the
contribution of STN outputs known to regulate apathy; i.e., STN glutamatergic efferents to the ventral pallidum
(VP). The Study central hypotheses are that i) apathy-like behaviors during STN-DBS treatments in a rat model
of PD reflect neuroplasticity in downstream limbic structures that regulate motivation, and ii) activation of STN-
VP glutamatergic efferents in a rat model of PD is sufficient to mediate apathy-like behaviors and circuit
changes. Specific Aim 1 will assess the temporal development and persistence of apathy-like and motor
behaviors in chronic optogenetic STN-DBS. Specific Aim 2 will assess whether selective activation of
glutamatergic STN-VP projections during STN-DBS is sufficient to produce apathy-like behaviors.
Comprehensive behavioral assessments will include PD-like motor and apathy profiles. Circuit consequences
will be revealed by measuring post mortem markers of neuronal activity. The proposed research is innovative
as these studies will combine established techniques to decipher a currently undescribed pathogenic circuit
that likely underpins non-motor behaviors associated with STN-DBS. The research is significant for outcomes
are expected to i) determine the role of specific STN glutamatergic projections to the VP in PD-like behaviors,
ii) indicate the potential of STN-VP circuits to serve as biomarkers for apathy during DBS, and iii) form the
basis for future NIH-funded projects that will lead to the design of novel DBS protocols that improve outcomes.
项目摘要/ABSTARCT
帕金森病(PD)是一种神经退行性疾病,同时表现为运动和非运动
骚乱。丘脑底核脑深部电刺激治疗红斑狼疮
帕金森病的运动特征。相比之下,非运动性症状通常不会改善,甚至可能会随着
星展银行。在STN中电极的放置是针对运动区的,但边缘和
联合回路,以及由此产生的DBS后回路活动的适应,可能会导致非运动性不利
效果。我们研究计划的长期目标是:i)确定可用于预测的生物标志物
当DBS可能导致情绪和认知障碍时,以及II)改进DBS刺激范式以减少
非运动性不良反应。冷漠是帕金森病的一种普遍的非运动症状,在STN后经常恶化-
星展银行会显著降低生活质量。因此,目前的R21研究将集中在冷漠上。因此,
本研究的总体目标是确定冷漠的机制(S)和解剖学基础(S)后
STN-DBS在帕金森病大鼠模型中的作用。将使用高选择性的光遗传刺激方法来分离
已知的调节冷漠的STN输出的贡献;即STN谷氨酸能传出到腹侧苍白球
(副总裁)。研究的中心假设是:i)在STN-DBS治疗期间的大鼠模型中的冷漠样行为
帕金森病的发生反映了下游边缘结构中调节动机的神经可塑性,以及ii)STN-
帕金森病大鼠模型中VP谷氨酸能传出足以调节冷漠样行为和回路
改变。具体目标1将评估冷漠和运动的时间发展和持续性
慢性光遗传STN-DBS的行为。特定目标2将评估选择性激活
STN-DBS期间的谷氨酸能STN-VP投射足以产生冷漠样行为。
全面的行为评估将包括类似帕金森病的运动和冷漠特征。巡回后果
将通过测量神经元活动的死后标记来揭示。建议的研究具有创新性。
因为这些研究将结合已有的技术来破译目前未描述的致病电路
这可能是与STN-DBS相关的非运动行为的基础。这项研究对结果具有重要意义
预计将:1)确定特定的STN谷氨酸能投射到VP在PD样行为中的作用,
Ii)指出STN-VP回路作为DBS期间冷漠的生物标志物的潜力,以及iii)表格
为未来NIH资助的项目奠定基础,这些项目将导致设计新的DBS协议,以改善结果。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Alana E. Kirby其他文献
Cognitive Decline in a Case of Poorly Controlled Bipolar Disorder: A Diagnostic and Therapeutic Challenge.
控制不良的双相情感障碍病例中的认知下降:诊断和治疗的挑战。
- DOI:
- 发表时间:
2017 - 期刊:
- 影响因子:3.8
- 作者:
R. Thom;Polina Teslyar;Alana E. Kirby;T. Fong;R. Friedman;R. Brady;K. Bloomingdale - 通讯作者:
K. Bloomingdale
TABLE 1. CHARACTERISTICS OF PATIENTS WITH ABRUPT ONSET TIC-LIKE MOVEMENTS VS TIC-LIKE MOVEMENTS OF TIKTOK “TIC-” RELATED CONTENT
表 1. 突发性抽动样运动患者的特征与 TikTok“TIC-”相关内容的抽动样运动患者的特征
- DOI:
- 发表时间:
2022 - 期刊:
- 影响因子:0
- 作者:
C. Olvera;Alana E. Kirby - 通讯作者:
Alana E. Kirby
Transmission of Temporal Information Through the Auditory Pathway Measured with Cochlear-Implant Stimulation
- DOI:
- 发表时间:
2011 - 期刊:
- 影响因子:0
- 作者:
Alana E. Kirby - 通讯作者:
Alana E. Kirby
Level of Satisfaction with the Intervention
对干预的满意度
- DOI:
- 发表时间:
2019 - 期刊:
- 影响因子:0
- 作者:
R. Thom;Polina Teslyar;Alana E. Kirby;T. Fong;R. Friedman;R. Brady;K. Bloomingdale - 通讯作者:
K. Bloomingdale
Alana E. Kirby的其他文献
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