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

项目摘要 帕金森病（PD）是一种使人衰弱的神经系统疾病，影响全球多达1000万人， 严重限制患者生活质量的震颤、运动迟缓和僵硬症状。深部脑 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。这种治疗包括对患者进行连续的高频刺激， 丘脑底核（subthalamic nucleus，简称NNNA）或苍白球（globus pallidus interna，简称GPi）是基底神经节中的两个调节核团 （BG）。DBS可急性改善运动症状，但不能区分神经元回路及其影响 当刺激关闭时迅速衰减。持续刺激的需要增加了副作用的风险 以及电池更换的频率。因此，对替代刺激模式的研究， 生产长期恢复至关重要。这样的刺激模式可以最大限度地减少不良后果， 通过恒定电流递送，同时还诱导以逆转异常的神经传导形式的治疗可塑性， 在PD患者中观察到BG的同步活动。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有限。Gittis实验室的最新发现表明， 光遗传学操纵不同的神经元亚群（具体地，激活PV神经元和 抑制外侧苍白球（GPe）（BG的中央核）中的Lhx6神经元）提供了持久的 在基线时表现出运动迟缓或运动不能的多巴胺耗尽小鼠中不动性的降低。为了努力 利用这些细胞类型的突触特征，我们发现， 在脚内核（EPN，GPi的啮齿动物同源物）中以爆发形式递送的电刺激可以 产生与上述相同的细胞类型调制。当在体内测试时，这种DBS方案产生 运动恢复持续数小时后停止刺激。这些发现可能会极大地影响 帕金森病患者的护理标准显示出狭窄的治疗窗口，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，并可能改变他们的病理电路。这个目标 一项提案是证明一种临床上可翻译的优化突发DBS协议，该协议可以产生持久的 通过逆转BG中的潜在病理活动来恢复运动。为了优化突发DBS， 从平移的角度来看，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。潜在加速向患有DBS的PD患者的转化 在EPN中的植入物中，将比较EPN中的突发DBS和EPN中的突发DBS的效果。由于患者 在疾病的不同阶段显示运动与非运动症状，目标2将描述行为 突发DBS对不同多巴胺耗竭水平下症状的影响。最后，为了理解 长期运动救援的潜在机制，目标3将评估突发DBS是否会诱导 通过减弱黑质网状部（SNr）神经元的病理性放电来增强治疗可塑性。

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.