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.

项目总结 帕金森氏病(PD)是一种使人衰弱的神经疾病，全世界有多达1000万人患有帕金森氏症 严重限制患者生活质量的震颤、运动迟缓和僵硬的症状。脑深部 刺激(DBS)是一种有效的治疗方法，用于表现出症状不充分的患者。 由药物控制。这种治疗包括将持续的高频刺激传递给 丘脑底核(STN)或苍白球内核(GPI)是基底节中的两个调制核 (BG)。DBS能显著改善运动症状，但不区分神经元回路及其影响 当刺激关闭时，它会迅速腐烂。对持续刺激的需要增加了副作用的风险 以及更换电池的频率。因此，对可选刺激模式的研究 实现持久的复苏至关重要。这样的刺激模式可以最大限度地减少由此产生的不良后果 通过恒流输送，同时还以逆转异常的形式诱导治疗可塑性 帕金森病患者的血糖同步活动。由于DBS的细胞作用机制尚不清楚， 识别这些模式的临床进展一直是有限的。Gittis实验室的最新发现表明 光遗传学操作不同的神经元亚群(具体地说，激活PV神经元和 抑制BG中央核--苍白球外核(GPE)中的Lhx6神经元)可提供长时间的 减少在基线时表现为运动迟缓或运动迟缓的多巴胺耗竭小鼠的不动状态。为了努力 利用对这些细胞类型的突触特征的洞察，使这一发现可翻译，我们发现 电刺激在丘脑内侧核(EPN，啮齿动物GPI的同源物)中传递，因为爆发可以 产生与上述相同的信元类型调制。这样的DBS方案在体内测试时产生 刺激停止后持续数小时的运动恢复。这些发现可能会极大地影响 治疗窗口狭窄的帕金森氏病患者的标准护理，通过最大限度地提高他们的 治疗持续时间，最大限度地减少副作用，并可能改变其病理电路。这样做的目的是 建议演示一种临床可翻译的优化突发DBS协议，该协议可以产生长效的 通过逆转BG中潜在的病理活动来恢复运动。为了优化突发DBS 从翻译的角度来看，目标1将建立刺激频率和持续时间的组合 需要看到持久的治疗效果。潜在地加速向患有DBS的PD患者的转换 在STN中植入突发DBS的效果将与在EPN中的突发DBS的效果进行比较。因为病人 在疾病的不同阶段显示运动和非运动症状，Aim 2将描述行为 突发性DBS对不同程度多巴胺耗竭症状的影响。最后，为了努力理解 持久汽车救援的潜在机制，目标3将评估爆裂DBS是否会导致 通过减弱黑质网状部(SNR)神经元的病理性放电来治疗可塑性。