Targeted Cortical Circuit Manipulation in Parkinson's Disease

项目总结/摘要 这个探索性项目是帕金森病（PD）研究人员和BRAIN工具之间的合作 开发人员，并将利用新的干预工具，改变神经回路动力学，以改善运动和 PD的非运动缺陷。在帕金森病中，中脑多巴胺神经元的变性过度促进了 皮质-基底神经节-丘脑皮质回路中的同步爆发放电，破坏其正常功能， 导致运动和情感功能障碍在该回路的不同入口点进行有针对性的神经调制 是改善PD症状治疗的一种有前途的策略。来自患者和小鼠的新发现 PD模型证明皮质是神经调节的潜在靶点，对PD产生有益作用 患者初级运动皮层（M1）表现出适应性变化，在产生异常运动中起着关键作用。 PD的皮质输出我们的研究确定了四个电路元件，可以有助于出现异常 M1活性：（1）锥体束（PT）神经元兴奋性降低，（2）M1小清蛋白兴奋性增加。 表达中间神经元（PV-IN），（3）增加M1 PV-IN的丘脑兴奋，和（4）同步 黑质丘脑突触活动该项目将探索调制特定的M1微电路在PD大脑使用 在BRAIN倡议下开发的工具。我们的中心假设是， M1微回路中关键神经元群体的突触驱动使网络活动正常化， 改善运动和非运动缺陷。我们将在两个特定目标（SA）中测试我们的假设，反映了 确定入口点。SA 1将定义调节内在兴奋性的生理和行为影响 通过降低和增加PT神经元（SA1.1）和PV-IN的兴奋性， （SA1.2）。SA 2将通过以下方式探测调节丘脑皮层回路的突触活动的影响： 确定丘脑输入到M1 PV-IN（SA2.1）和黑丘脑突触（SA2.2）的操作是否 拯救PD小鼠的病理生理学和行为表型。我们的主要目标是确定 这些关键的进入点提供了减轻小鼠行为缺陷的最有效策略 先进的PD模型。为了操纵神经元活动，该项目将利用生物发光 光遗传学（BL-OG）平台，其采用发光酶来激活光感测视蛋白，包括 最近开发的“内发光”方法， 分别在突触前和突触后配偶体中表达光发射器和传感器。为了实现我们的目标， 我们正在结合电路操作工具开发和PD小鼠模型行为研究方面的专业知识， 对复杂行为背后的大脑机制有更深入的了解。与此同时 我们的项目将推动潜在的新型治疗目的的转化进展。除了影响 在PD研究中，我们的研究结果有望对研究其他神经退行性疾病产生重大影响。 显示电路不平衡的疾病。

PROJECT SUMMARY/ABSTRACT This exploratory project is a collaboration between Parkinson's disease (PD) researchers and BRAIN tool developers and will utilize novel interventional tools for changing neural circuit dynamics to ameliorate motor and nonmotor deficits in PD. In PD, degeneration of midbrain dopamine neurons promotes an exaggeratedly synchronized burst firing in the cortico-basal ganglia-thalamocortical circuitry, disrupts its normal function, and causes both motor and affective dysfunction. Targeted neural modulation at different entry points in this circuitry is a promising strategy for improving the treatment of PD symptoms. Emerging findings from patients and mouse models of PD demonstrate the cortex as a potential target for neuromodulation yielding beneficial effects for PD patients. The primary motor cortex (M1) exhibits adaptive changes that play a critical role in generating aberrant cortical output in PD. Our studies identified four circuit elements that can contribute to the emergence of aberrant M1 activity: (1) decreased pyramidal tract (PT) neuron excitability, (2) increased excitability of M1 parvalbumin- expressing interneurons (PV-INs), (3) increased thalamic excitation of M1 PV-INs, and (4) synchronized nigrothalamic synaptic activity. This project will explore modulating specific M1 microcircuits in the PD brain using tools developed under the BRAIN initiative. Our central hypothesis is that manipulation of the firing activity within and the synaptic drive towards key neuron populations in the M1 microcircuit normalizes network activity and ameliorates motor and nonmotor deficits. We will test our hypothesis in two Specific Aims (SA), reflecting the identified entry points. SA1 will define the physiological and behavioral impact of modulating intrinsic excitability of cortical neuron populations by decreasing and increasing excitability of PT neurons (SA1.1) and PV-INs (SA1.2), respectively. SA2 will probe the impact of modulating synaptic activity of thalamocortical circuits by determining whether manipulations of thalamic inputs to M1 PV-INs (SA2.1) and nigrothalamic synapses (SA2.2) rescue pathophysiological and behavioral phenotypes of PD mice. Our major goal will be to determine which of these key entry points provides the most efficacious strategy for mitigating the behavioral deficits in a mouse model of advanced PD. For manipulation of neuronal activity this project will utilize the bioluminescent optogenetic (BL-OG) platform that employs light emitting luciferases to activate light sensing opsins, including the recently developed ‘interluminescence’ approach that enables controlling synaptic transmission by expressing the light emitter and sensor in pre- and post-synaptic partners, respectively. To achieve our goals, we are combining expertise in circuit manipulation tool development and PD mouse model behavioral research towards a more refined understanding of the brain mechanisms underlying complex behaviors. At the same time our project will drive translational progress toward potential novel therapeutic purposes. In addition to the impact on PD research our results are expected to have a significant impact on approaching other neurodegenerative diseases that show circuit imbalances.