Disordered Cellular Interactions in Prefrontal Local Circuits: a New Mechanistic Theory of Schizophrenia with Convergent Evidence across Animal Models

项目总结 精神分裂症是一种令人衰弱的神经精神疾病，是十大健康负担之一。 在世界范围内，然而目前的治疗方案对许多患者并不有效。为了开发新的治疗方法， 我们必须更好地了解这种疾病是如何改变大脑的生理的。这将需要 在突触传递水平上发生的病理生理过程之间建立联系， 神经元活动模式、电路动力学、信息处理，最后是认知表现。我们的 目前的知识体系是基于这一光谱的两个极端：导致功能障碍的基因缺陷 在细胞功能的一端，全球大脑激活模式和认知表现的变化 其他的。我们缺少的是神经回路层面的中间环节，或者更具体地说， 对精神分裂症患者神经活动时空模式扭曲的理解 最终导致网络执行的计算脱轨，导致认知失败。 一种被广泛接受的精神分裂症理论模型称为断线假说，它假设 这种疾病是由于大脑各区域之间的功能连接紊乱造成的。虽然有些功能成像 证据支持这一理论，它从未在神经元电路水平上进行过测试，因此 框架还没有开发出来。在这里，我们建议检验精神分裂症是一种疾病这一中心假设 在这种情况下，前额叶电路中异常的动作电位计时导致突触连接减弱 时间，通过建立的尖峰时间依赖的可塑性机制。 在具体目标1中，我们建议分析先前收集的神经元活动数据集，该数据集从 非人灵长类动物在接受一种模仿大脑功能的药物后执行工作记忆任务 精神分裂症。对这一数据的初步分析表明，尖峰活动是无序的，以至于细胞在 相同的本地电路不同步，细胞对之间的功能连接减少；这些发现 与我们的假设一致，即尖峰时序中断会导致脑功能中断 精神分裂症。我们将进一步发展这些分析，并将它们与认知过程的中断联系起来 这与人类精神分裂症患者的情况相似。在具体目标2中，我们建议进行大规模的 转基因小鼠的神经记录，以调查增加精神分裂症风险的突变 改变神经元相互作用的性质。我们将对神经数据应用类似的分析技术。 从目标1和目标2开始，以最大限度地发挥两种动物模型的翻译能力。最后，在具体目标上 3、为了建立理论框架，我们提出进行计算神经网络仿真。 这将无序的尖峰时序与功能性断开联系在一起。通过这些信息获得的信息 研究将为精神分裂症发病机制的新理论框架奠定基础，并可用于 引导理性地寻找新的治疗方法。

PROJECT SUMMARY Schizophrenia is a debilitating neuropsychiatric disorder that ranks among the top 10 health burdens worldwide, yet current treatment options are not effective for many patients. In order to develop new therapies, we must gain a better understanding of how the physiology of the brain is altered in the disease. This will require links to be established between pathophysiological processes that occur at the levels of synaptic transmission, neuronal activity patterns, circuit dynamics, information processing, and finally cognitive performance. Our current body of knowledge is based on the two extremes of this spectrum: genetic defects that lead to dysfunction in cellular function on one end, changes in global brain activation patterns and cognitive performance on the other. What we are missing is an intermediate link at the level of neural circuits, or more specifically, an understanding of how distortions of the spatial and temporal patterns of neural activity in schizophrenia ultimately derail the computations performed by the networks, leading to cognitive failure. A widely-accepted theoretical model of schizophrenia called the disconnection hypothesis posits that the disease results from disordered functional connectivity between brain regions. While some functional imaging evidence supports this theory, it has never been tested at the neuronal circuit level and thus a mechanistic framework has not been developed. Here we propose to test the central hypothesis that schizophrenia is a disease in which aberrant action potential timing in prefrontal circuits leads to weakening of synaptic connections over time, through established mechanisms of spike-timing-dependent plasticity. In the Specific Aim 1, we propose to analyze a previously collected dataset of neuronal activity obtained from nonhuman primates performing a working memory task after receiving a drug that mimics features of schizophrenia. Preliminary analysis of this data suggests that spiking activity is disordered such that cells in the same local circuits are desynchronized and functional connectivity between cell pairs is reduced; these findings are consistent with our hypothesis that spike timing disruption leads to functional disconnection in schizophrenia. We will further develop these analyses and relate them to the disruptions in cognitive processing that parallel those seen in human schizophrenic patients. In Specific Aim 2, we propose to conduct large-scale neural recordings in transgenic mice in order to investigate how a mutation that increases risk for schizophrenia changes the properties of neuronal interactions. We will apply similar analytical techniques to the neural data from Aims 1 and 2 in order to maximize the translational power of both animal models. Lastly, in Specific Aim 3, we propose to perform computational neural network simulations in order to establish a theoretical framework that causally links disordered spike timing to functional disconnection. The information gained through these studies will form a basis for a new theoretical framework of the pathogenesis of schizophrenia which can be used to guide a rational search for new treatments.