Dissecting Neural Circuit Mechanisms Underlying Pallidal Deep Brain Stimulation

摘要 脑深部电刺激（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 疾病为了治疗PD，DBS电极通常被放置到内部苍白球（GPi）或 丘脑底核（subthalamic nucleus，简称TH）。DBS的合理靶点选择是提供有效治疗的关键步骤 对于PD。GPi-DBS和STN-DBS均已被证明可显著降低主要PD 症状包括静止性震颤、僵硬、运动迟缓和运动不能。然而，越来越多的观察到， STN-DBS难以治疗的认知和行为副作用以及运动症状恶化， 人们对STN-DBS的关注，并促使人们对GPi-DBS越来越感兴趣。目前，缺乏对 治疗性DBS的电路机制阻碍了GPi-DBS的开发和优化， 提高治疗效果和最小化副作用。本研究建议的目的是确定 神经元和神经回路对GPi-DBS治疗效果的必要性 在定量评估帕金森病运动症状的过程中，我们将联合收割机 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对帕金森病运动功能影响的神经元和神经回路的必要性 （2）量化GPi DBS期间GPi神经回路中神经活动的变化， 光遗传抑制电刺激和光遗传学抑制的组合将提供一种新的治疗方法。 创新和强大的战略，电路功能分析，这样的方法将确定有效的 和GPi-DBS中的无效电路。我们假设选择性抑制治疗有效的 DBS神经回路会破坏DBS症状改善效果，减少神经活动并减弱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。

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.