Circuit-Inspired Strategies to Restore Basal Ganglia Function in Mouse Models of Parkinson’s Disease

项目摘要 苍白球外段(GPE)是一个神经元多样性和高度相互连接的核。 在基底节内。在低多巴胺的条件下，GPE的可塑性促进了 导致广泛的基底节功能障碍的病理性放电模式。在帕金森氏病(PD)中， GPE中的脑深部刺激(DBS)可以缓解运动症状，这表明两者之间存在机制联系。 GPE中神经元功能障碍与帕金森病运动症状之间的关系。利用光遗传学靶向神经元 在GPE的亚群中，我们发现持续的行为救援可以通过干预来诱导 激活表达小白蛋白的GPE神经元(PV-GPE)并抑制LIM Homeobox 6表达的GPE 神经元(Lhhx6-GPE)。这些神经元亚群的突触输入的差异使我们能够 开发一种人类可翻译的电子DBS方案，该方案可以实现相同的细胞类型特异性 光遗传学。在帕金森病小鼠中，这些电路激发的猝发DBS方案提供了优越的治疗效果 优于传统方案，将治疗持续时间延长至活动期以外的几个小时 刺激。我们现在正在与匹兹堡阿勒格尼综合医院的神经外科医生合作，测试 电路激发的DBS方案在人类中的治疗效果。来自活体生理记录的结果 显示GPE干预逆转了帕金森病患者基底节的病理生理学数小时 刺激，增加了GPE干预诱导治疗可塑性恢复的有趣可能性 电路在疾病中的作用。这将代表着帕金森病疗法的变革性进步。但有一些人 关于GPE中的短暂干预如何转化为长期治疗效果的问题仍然存在 在行为层面上。这项提议将使用电生理、光遗传学和行为学方法来 通过实现三个主要目标确定持续性行为救援的治疗机制：(1)我们将 绘制持续行为救援所需的神经路径图，包括检验创新假说 运动和唤醒回路都涉及(2)我们将确定GPE的短期和长期影响 对基底节生理学的干预，检验GPE干预推动治疗的假设 多巴胺耗竭小鼠的可塑性，以及(3)我们将评估GPE干预的治疗效果 在多巴胺耗竭的不同阶段给药对运动和非运动症状的影响 神经回路参与，以及推进GPE干预的临床前测试以继续治疗 发展。这些研究将推动电路启发的方法的发展，修复而不是 掩蔽电路功能障碍可长期恢复疾病的脑功能。

Project Summary The external segment of the globus pallidus (GPe) is a neuronally diverse and highly interconnected nucleus within the basal ganglia. Under conditions of low dopamine, plasticity in the GPe promotes the emergence of pathological firing patterns that contribute to widespread basal ganglia dysfunction. In Parkinson’s disease (PD), deep brain stimulation (DBS) in the GPe can alleviate motor symptoms, suggesting there is a mechanistic link between neuronal dysfunction in the GPe and motor symptoms of PD. Using optogenetics to target neuronal subpopulations in the GPe, we discovered that persistent behavioral rescue could be induced by interventions that excited parvalbumin-expressing GPe neurons (PV-GPe) and inhibited Lim homeobox 6-expressing GPe neurons (Lhhx6-GPe). Differences in the synaptic inputs onto these neuronal subpopulations enabled us to develop a human-translatable electrical DBS protocol that could achieve the same cell-type specificity of optogenetics. In parkinsonian mice, these circuit-inspired burst DBS protocols provided superior therapeutic benefit over conventional protocols, extending the therapeutic duration for hours beyond the period of active stimulation. We are now collaborating with neurosurgeons at Allegheny General in Pittsburgh to test the therapeutic efficacy of circuit-inspired DBS protocols in humans. Results from in vivo physiological recordings revealed that GPe interventions reverse parkinsonian pathophysiology in the basal ganglia for hours following stimulation, raising the intriguing possibility that GPe interventions induce therapeutic plasticity that restores circuit function in disease. This would represent a transformative advance in PD therapeutics. But a number of questions still remain about how transient interventions in the GPe translate into long-lasting therapeutic effects at the behavioral level. This proposal will use electrophysiological, optogenetic, and behavioral approaches to identify the therapeutic mechanisms of persistent behavioral rescue by achieving three main goals: (1) We will map the neural pathways required for persistent behavioral rescue, including testing an innovative hypothesis that both motor and arousal circuits are involved (2) We will identify short-term and long-term effects of GPe interventions on basal ganglia physiology, testing the hypothesis that GPe interventions drive therapeutic plasticity in dopamine depleted mice, and (3) We will assess the therapeutic efficacy of GPe interventions delivered at different stages of dopamine depletion on both motor and non-motor symptoms to further study the neural circuits involved, as well as to advance preclinical testing of GPe interventions for continued therapeutic development. These studies will advance the development of circuit-inspired approaches that repair, rather than mask circuit dysfunction for long-term recovery of brain function in disease.