Model of the Pathological Changes in the Thalamo-Cortical Motor Circuit in Parkinsonism

灵长类动物的运动在一定程度上是由涉及大脑三个部分的大脑回路控制的：运动皮质、基底节和丘脑。这些回路的活动变化导致了帕金森氏症等运动障碍的异常。虽然基底节的活动变化被很好地定义，但对灵长类动物基底节连接的运动丘脑和皮质中与帕金森病相关的变化知之甚少。为了了解人类的这些变化，重要的是研究灵长类动物的回路功能障碍，因为这些神经元区域在连接和组成上都不同于其他物种，如啮齿类动物。该项目旨在以常规建模方法无法实现的方式来增强对这些网络动力学的理解，因为传统建模方法通常使用大量笨重的耦合方程。一旦描述了动力学，针对帕金森患者丘脑活动正常化的新的治疗方法可能被开发和优化，以实现安全性和有效性。大脑回路的数学模型有助于理解基底神经节-丘脑皮质连接网络中的这些异常。该项目将生成一个新的基底节-丘脑-皮质通路的多尺度模型，该模型将反映单个神经元的非线性性质，同时利用每个核团的固有特征。第一个目标将是创建一个功能齐全的丘脑皮质环路模型，该模型可以定位和检查健康和疾病大脑活动状态之间的分叉。尤其令人感兴趣的是参数空间中的轨迹，它可能允许帕金森患者返回到稳定的健康状态，使研究人员能够确定新的治疗机会。下一步，由于灵长类特定的丘脑中间神经元目前还不能在体内确定靶点，该模型将用于检查这些中间神经元在系统中所起的作用。最后，该模型将使用来自健康和帕金森症非人类灵长类动物的神经元记录的广泛数据集进行验证。与记录数据的比较将把数学模型的分析限制在参数空间的生理上可信的区域。这一裁决反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Movement in primates is, in part, controlled by brain circuits that involve three parts of the brain: the motor cortex, basal ganglia, and thalamus. Activity changes in these circuits contribute to the abnormalities seen in movement disorders such Parkinson’s disease. While activity changes in the basal ganglia are well defined, little is known about parkinsonism-associated changes in the primate basal ganglia-connected motor thalamus and cortex. To understand these changes in humans it is important to study the circuit dysfunction in primates, as these neuronal regions differ in both connections and composition from other species such as rodents. This project aims to enhance understanding of these network dynamics in ways that cannot be accomplished with conventional modeling approaches that often use an unwieldy number of coupled equations. Once the dynamics are described, new treatment approaches directed at normalizing thalamic activity in parkinsonian subjects may be developed and optimized for safety and effectiveness.Mathematical models of brain circuits are helpful to understand these abnormalities within the basal ganglia-thalamocortical network of connections. This project will generate a new multiscale model of the basal ganglia-thalamo-cortical pathways that will reflect the nonlinear nature of individual neurons while taking advantage of the inherent features of each nucleus. The first objective will be to create a fully functional thalamocortical loop model that can locate and examine the bifurcations between healthy and diseased brain activity states. Of particular interest are the trajectories in parameter space that could allow a parkinsonian subject to return back to the stable healthy state, allowing possibilities for researchers to identify new therapeutic opportunities. Next, since the primate-specific thalamic interneurons cannot currently be targeted with certainty in vivo, the model will be used to examine the roles that these interneurons have on the system. Finally, the model will be validated using an extensive dataset of neuronal recordings from healthy and parkinsonian nonhuman primates. Comparison to the recorded data will restrict the analysis of the mathematical model to a physiologically plausible region of the parameter space.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.