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.

摘要 脑深部刺激(DBS)是治疗包括帕金森氏症在内的各种运动障碍的有效方法 疾病。为了治疗帕金森病，DBS电极通常被放置在内侧苍白球(GPI)或 丘脑底核(STN)。合理选择DBS的靶点是提供有效治疗的关键一步 对警局来说。GPI-DBS和STN-DBS都已被证明能显著降低基底性PD 症状包括静止性震颤、僵硬、运动迟缓和动作迟缓。然而，越来越多的观察到 对STN-DBS难以治愈的认知和行为副作用和运动症状的恶化引发了 对STN-DBS的担忧，并促使人们对GPI-DBS越来越感兴趣。目前，对这一问题缺乏了解 治疗性DBS的电路机制阻碍了GPI-DBS的发展和优化 提高治疗效果，最大限度减少副作用。这项研究建议的目标是确定 操纵相关神经对GPI-DBS疗效的神经元件和神经回路的必要性 帕金森病患者运动症状的定量评估过程中的回路。我们将结合电气设备 大鼠的刺激、光遗传抑制、同步多点记录和定量行为分析 PD模型用于确定GPI-DBS相关神经元件和电路的功能相关性，包括 GPI、初级运动皮质和腹侧运动丘脑。我们的具体目标是：(1)确定 GPI-DBS和STN-DBS对帕金森病运动影响的神经元和回路必要性 (2)对GPI-DBS过程中GPI神经环路神经活动的变化进行量化 光遗传抑制。电刺激和光遗传抑制的结合将提供一种 创新和强大的电路功能分析策略，这样的方法将识别有效的 和GPI-DBS中的无效电路。我们假设选择性抑制治疗有效 DBS神经回路会破坏DBS症状的改善效果，减少神经活动，减弱DBS 对病理性神经振荡和同步性的影响。拟议研究的结果将提供 对GPI-DBS背后的神经机制的新见解，并最终建立 开发新的治疗策略以提高DBS治疗帕金森病和其他疾病的疗效和效率 神经和精神障碍。