Cell-type Specific Neuromodulation Using Burst DBS Produces Long-lasting Behavioral and Physiological Rescue in a Parkinsonian Mouse Model

使用突发 DBS 进行细胞类型特异性神经调节可在帕金森病小鼠模型中产生持久的行为和生理救援

• 批准号: 10683099
• 负责人: Shruti Nanivadekar
• 金额: $ 4.43万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 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 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683099
• 关键词: Acceleration; Affect; Animals; Attenuated; Basal Ganglia; Behavior; Behavioral; Biological Markers; Bradykinesia; Cell Nucleus; Clinical; Coupled; Data; Deep Brain Stimulation; Disease; Dopamine; Dopamine Receptor; Dose; Electric Stimulation; Electrophysiology (science); Fiber; Foundations; Frequencies; Ganglia; Globus Pallidus; Goals; Histology; Homeobox; Homologous Gene; Hour; Human; Immobilization; Implant; In Vitro; Intervention; Investigation; Knowledge; Machine Learning; Methods; Modeling; Motor; Movement; Movement Disorders; Mus; Neurons; Neurosciences; Parkinson Disease; Parvalbumins; Pathologic; Patients; Pattern; Persons; Pharmaceutical Preparations; Physiological; Progressive Disease; Protocols documentation; Quality of life; Recovery; Research; Risk; Rodent; Role; Stimulus; Structure of subthalamic nucleus; Substantia nigra structure; Symptoms; Synapses; Testing; Therapeutic; Time; Translations; Treatment Efficacy; Tremor; Work; acute symptom; adverse outcome; battery replacement; cell type; clinical translation; effective therapy; endopeduncular nucleus; experience; improved; in vitro Model; in vivo; in vivo evaluation; insight; motor disorder; motor recovery; motor symptom; mouse model; nervous system disorder; neural; neuromechanism; neuronal circuitry; neuroregulation; neurotransmission; non-motor symptom; optimal treatments; optogenetics; parkinsonian rodent; power consumption; preclinical study; side effect; signal processing; skills; standard of care; symptom treatment

PROJECT SUMMARY Parkinson’s disease (PD) is a debilitating neurological disorder affecting up to 10 million people worldwide with symptoms of tremor, bradykinesia, and rigidity that severely limit the quality of life of patients. Deep brain stimulation (DBS) is an effective treatment used in patients who demonstrate symptoms that are inadequately controlled by medications. This treatment involves the delivery of continuous high frequency stimulation to either the subthalamic nucleus (STN) or the globus pallidus interna (GPi), two modulatory nuclei in the basal ganglia (BG). DBS improves motor symptoms acutely but does not differentiate between neuronal circuits, and its effects decay rapidly when stimulation is turned off. The need for constant stimulation increases the risk of side effects and the frequency of battery replacement. Hence the investigation of alternative patterns of stimulation that produce long-lasting recovery is critical. Such stimulation paradigms could minimize adverse outcomes caused by constant current delivery while also inducing therapeutic plasticity in the form of reversal of the aberrant synchronous activity of the BG seen in PD patients. Since the cellular mechanism of action of DBS is unknown, the clinical advances in identifying these patterns have been limited. Recent findings in the Gittis lab suggest that optogenetically manipulating distinct neuronal subpopulations (specifically, activating PV neurons and inhibiting Lhx6 neurons) in the external globus pallidus (GPe), a central nucleus of the BG, provides long-lasting reduction in immobility in dopamine-depleted mice that show bradykinesia or akinesia at baseline. In an effort to make this finding translatable, using insights from the synaptic features of these cell-types, we identified that electrical stimulation delivered in the entopeduncular nucleus (EPN, rodent homolog of the GPi) as bursts can produce the same cell-type modulation described above. Such a DBS protocol when tested in vivo produced motor recovery that lasted for hours after stimulation was stopped. These findings could hugely impact the standard of care for Parkinson’s disease patients that show a narrow therapeutic window, by maximizing their therapeutic duration, minimizing side effects, and potentially altering their pathological circuitry. The goal of this proposal is to demonstrate a clinically translatable optimized burst DBS protocol which can produce long-lasting motor recovery by reversing the underlying pathological activity in the BG. In an effort to optimize burst DBS from a translational standpoint, Aim 1 will establish the combination of stimulation frequency and duration required to see prolonged therapeutic benefits. To potentially accelerate the translation to PD patients with DBS implants in the STN, the effect of burst DBS in the STN will be compared to burst DBS in the EPN. Since patients show motor vs. non-motor symptoms at varying stages of the disease, Aim 2 will characterize the behavioral effects of burst DBS on symptoms at varying levels of dopamine depletion. Finally, in an effort to understand the underlying mechanism of the long-lasting motor rescue, Aim 3 will evaluate whether burst DBS induces therapeutic plasticity by attenuating the pathological firing of Substantia nigra pars reticulata (SNr) neurons.

项目概要 帕金森病 (PD) 是一种使人衰弱的神经系统疾病，影响着全球多达 1000 万人。 震颤、运动迟缓和强直等症状严重限制了患者的生活质量。 刺激（DBS）是一种有效的治疗方法，用于治疗症状不充分的患者 这种治疗包括向任一部位提供持续的高频刺激。 丘脑底核 (STN) 或苍白球内核 (GPi)，基底神经节中的两个调节核 (BG)。DBS 可以显着改善运动症状，但不能区分神经回路及其影响。 当刺激关闭时会迅速衰减，持续刺激的需要会增加副作用的风险。 以及电池更换的频率，因此研究了替代刺激模式。 产生持久的恢复至关重要。这种刺激模式可以最大限度地减少所造成的不良后果。 通过恒定电流传输，同时还以逆转异常的形式诱导治疗可塑性 PD 患者中 BG 的同步活动 由于 DBS 的细胞作用机制尚不清楚， Gittis 实验室的最新发现表明，识别这些模式的临床进展有限。 通过光遗传学操作不同的神经元亚群（具体来说，激活 PV 神经元和 抑制 Lhx6 神经元）位于外苍白球 (GPe)（BG 的中央核），提供持久的 多巴胺耗尽的小鼠在基线时表现出运动迟缓或运动不能的减少。 利用这些细胞类型突触特征的见解，使这一发现可转化，我们发现 电刺激在脚内核（EPN，啮齿类动物 GPi 的同源物）中传递，作为爆发可以 当进行体内测试时，产生与上述相同的细胞类型调节。 刺激停止后持续数小时的运动恢复可能会产生巨大影响。 通过最大限度地提高治疗窗口狭窄的帕金森病患者的护理标准 治疗持续时间，最大限度地减少副作用，并可能改变其病理回路。 该提案旨在展示一种可临床转化的优化突发 DBS 协议，该协议可以产生持久的效果 通过逆转 BG 中潜在的病理活动来恢复运动，以优化突发 DBS。 从转化的角度来看，目标 1 将建立刺激频率和持续时间的组合 需要看到长期的治疗效果，以潜在地加速向接受 DBS 的 PD 患者的转化。 STN 中的植入物，将 STN 中的突发 DBS 的效果与 EPN 中的突发 DBS 进行比较。 显示疾病不同阶段的运动症状与非运动症状，目标 2 将描述行为特征 最后，为了了解突发性 DBS 对不同多巴胺消耗水平的症状的影响。 持久运动救援的潜在机制，目标 3 将评估突发 DBS 是否会诱发 通过减弱黑质网状部（SNr）神经元的病理性放电来实现治疗可塑性。