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.

项目概要/摘要 帕金森病（PD）是一种神经退行性疾病，表现为运动性和非运动性两种疾病 干扰。丘脑底核 (STN) 的深部脑刺激 (DBS) 可有效治疗红斑狼疮 PD 的运动特征。相反，非运动症状通常不会改善，甚至可能恶化 星展银行。 STN 中的电极放置针对运动分区，但边缘系统和边缘系统的脱靶激活 DBS 后联想回路以及由此产生的回路活动适应可能会导致非运动不良 影响。我们研究计划的长期目标是 i) 识别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 非运动不良反应。冷漠是 PD 的一种常见非运动症状，在 STN 治疗后经常恶化。 DBS 会严重损害生活质量。因此，当前的 R21 研究将重点关注冷漠。据此， 该研究的总体目标是确定冷漠之后的机制和解剖学基础 PD 大鼠模型中的 STN-DBS。高度选择性的光遗传学刺激方法将用于分离 STN 输出的贡献已知可调节冷漠；即，STN 谷氨酸能传出到腹侧苍白球 （副总裁）。该研究的中心假设是 i) 大鼠模型 STN-DBS 治疗期间出现冷漠样行为 PD 的变化反映了调节动机的下游边缘结构的神经可塑性，以及 ii) STN- 的激活 PD大鼠模型中的VP谷氨酸传出足以介导冷漠样行为和回路 变化。具体目标 1 将评估冷漠样和运动性的时间发展和持续性 慢性光遗传学 STN-DBS 中的行为。具体目标 2 将评估是否选择性激​​活 STN-DBS 期间谷氨酸能 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 PD 的运动和冷漠特征。电路后果 将通过测量神经元活动的死后标记来揭示。所提出的研究具有创新性 因为这些研究将结合现有技术来破译目前未描述的致病回路 这可能是与 STN-DBS 相关的非运动行为的基础。该研究对于结果具有重要意义 预计 i) 确定特定 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 期间冷漠生物标志物的潜力，以及 iii) 形成 NIH 资助的未来项目的基础，这些项目将导致设计可改善结果的新型 DBS 方案。