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

• 批准号: 10592985
• 负责人: Alana E. Kirby
• 金额: $ 43.45万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10592985
• 关键词: Address; Adverse effects; Affect; Amygdaloid structure; Anatomy; Behavior; Behavior assessment; Behavioral; Biological Markers; Brain; Brain Diseases; Brain region; Chronic; Clinical; Cognition; Cognitive; Deep Brain Stimulation; Development; Disease model; Electric Stimulation; Electricity; Electrodes; Electrophysiology (science); FDA approved; FOS gene; Funding; Future; Globus Pallidus; Glutamates; Goals; Grant; Growth; Human; Hyperactivity; Impairment; Implanted Electrodes; Injections; Investigation; Knowledge; Laboratories; Lead; Lesion; Light; Link; Maintenance; Measures; Mediating; Modeling; Modernization; Mood Disorders; Moods; Motivation; Motor; Movement; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Opsin; Outcome; Outcome Study; Output; Parkinson Disease; Pathogenicity; Patients; Pharmaceutical Preparations; Protocols documentation; Quality of life; Rattus; Research; Research Project Grants; Rodent; Role; STN stimulation; Sleep; Structure; Structure of subthalamic nucleus; Symptoms; Techniques; Technology; Testing; Thinking; Time; Tissues; United States National Institutes of Health; Work; behavior test; clinical care; clinically relevant; design; effective therapy; improved; improved outcome; innovation; motor behavior; motor symptom; non-motor symptom; novel; optogenetics; parkinsonian rodent; programs; side effect; transmission process

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。