Dissecting Neural Circuit Mechanisms Underlying Pallidal Deep Brain Stimulation

剖析苍白球深部脑刺激背后的神经回路机制

• 批准号: 10730757
• 负责人: Chunxiu Yu
• 金额: $ 46.95万
• 依托单位: MICHIGAN TECHNOLOGICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730757
• 关键词: Adverse effects; Anatomy; Animal Behavior; Attenuated; Automobile Driving; Behavior; Behavioral; Behavioral Assay; Biology; Biomedical Engineering; Bradykinesia; Brain; Cells; Clinical; Clinical Research; Cognitive; Communities; Deep Brain Stimulation; Development; Discipline; Education; Electric Stimulation; Electrical Engineering; Electrodes; Electrophysiology (science); Elements; Engineering; Environment; Forelimb; Generations; Globus Pallidus; Lateral; Learning; Mental disorders; Michigan; Modeling; Monitor; Motor; Motor Cortex; Movement Disorders; Neurons; Neurosciences; Operative Surgical Procedures; Outcome; Parkinson Disease; Parkinsonian Disorders; Pathologic; Patients; Proton Pump; Rattus; Refractory; Reporting; Research; Research Infrastructure; Research Proposals; Rest Tremor; Site; Step Tests; Structure of subthalamic nucleus; Students; Symptoms; Techniques; Technology; Testing; Thalamic structure; Therapeutic; Therapeutic Effect; Training; Treatment Efficacy; Universities; Work; attenuation; computer science; effective therapy; graduate student; implantation; improved; innovation; insight; interest; light gated; motor symptom; nervous system disorder; neural; neural circuit; neuromechanism; neurosurgery; neurotransmission; novel; novel therapeutic intervention; optogenetics; reduce symptoms; side effect; signal processing; therapeutically effective; treatment optimization; undergraduate student

ABSTRACT Deep brain stimulation (DBS) is an effective therapy for various movement disorders including Parkinson’s disease. To treat PD, DBS electrodes are typically placed into either the internal globus pallidus (GPi) or the subthalamic nucleus (STN). Rational target selection for DBS is a critical step in delivering effective treatment for PD. Both GPi-DBS and STN-DBS have been proven to produce remarkable reductions in cardinal PD symptoms including resting tremor, rigidity, bradykinesia, and akinesia. However, increased observations of worsening cognitive and behavioral side effects and motor symptoms refractory to STN-DBS have raised concerns on STN-DBS and prompted growing interest in GPi-DBS. Currently, the lack of understanding of the circuit mechanisms underlying the therapeutic DBS hampers the development and optimization of GPi-DBS to improve therapeutic efficacy and minimize side effects. The objective of this research proposal is to identify the necessity of neural elements and circuits for the therapeutic effect of GPi-DBS by manipulating relevant neural circuits during the quantitative assessment of parkinsonian motor symptoms. We will combine electrical stimulation, optogenetic inhibition, simultaneous multisite recording, and quantitative behavioral assays in a rat model of PD to determine the functional relevance of GPi-DBS associated neural elements and circuits including GPi, primary motor cortex, and ventral lateral motor thalamus. Our specific aims are to (1) determine the necessity of neural elements and circuits for the effects of GPi-DBS and STN-DBS on parkinsonian motor symptoms; (2) quantify the changes of neural activity in GPi neural circuits during GPi-DBS with selective optogenetic inhibition. The combination of electrical stimulation and optogenetic inhibition will provide an innovative and powerful strategy for circuit function analyses, and such an approach will identify the effective and non-effective circuits in GPi-DBS. We hypothesize that selective suppression of therapeutically effective DBS neural circuits will disrupt DBS symptom amelioration efficacy, reduce neural activity and attenuate DBS effects on pathological neural oscillations and synchrony. The outcomes of the proposed research will provide novel insight into the neural mechanisms underlying GPi-DBS and ultimately establish a framework for developing novel therapeutic strategies to improve the efficacy and efficiency of DBS therapy in PD and other neurological and psychiatric disorders.

抽象的 深部脑刺激（DBS）是治疗包括帕金森氏症在内的各种运动障碍的有效疗法 为了治疗帕金森病，DBS 电极通常放置在苍白球内部 (GPi) 或苍白球内。 丘脑底核 (STN) 的合理选择是提供有效治疗的关键步骤。 GPi-DBS 和 STN-DBS 均已被证明可以显着减少基数 PD。 症状包括静止性震颤、强直、运动迟缓和运动不能。 STN-DBS 难治性的认知和行为副作用以及运动症状的进展有所增加 对 STN-DBS 的关注并促使人们对 GPi-DBS 的兴趣日益浓厚。目前，人们对 GPi-DBS 缺乏了解。 治疗性 DBS 背后的电路机制阻碍了 GPi-DBS 的开发和优化 提高治疗效果并最大限度地减少副作用本研究计划的目的是确定 通过操纵相关神经元和神经回路来实现 GPi-DBS 治疗效果的必要性 在定量评估帕金森运动症状时，我们将结合电气电路。 大鼠的刺激、光遗传学抑制、同时多位点记录和定量行为测定 PD 模型以确定 GPi-DBS 相关神经元件和回路的功能相关性，包括 GPi、初级运动皮层和腹侧运动丘脑 我们的具体目标是 (1) 确定 GPi-DBS 和 STN-DBS 对帕金森运动影响的神经元件和回路的必要性 (2) 选择性量化 GPi-DBS 期间 GPi 神经回路中神经活动的变化 光遗传学抑制的结合将提供电刺激和光遗传学抑制。 创新且强大的电路功能分析策略，这种方法将确定有效的 我们捕获了 GPi-DBS 中的选择性抑制治疗有效的回路。 DBS神经回路会破坏DBS症状改善功效，减少神经活动并减弱DBS 所提出的研究结果将提供对病理性神经振荡和同步性的影响。 对 GPi-DBS 神经机制的新颖见解，并最终建立一个框架 开发新的治疗策略以提高 DBS 治疗 PD 和其他疾病的疗效和效率 神经和精神疾病。