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

前额叶局部回路中的细胞相互作用紊乱：精神分裂症的新机制理论与跨动物模型的趋同证据

• 批准号: 9190179
• 负责人: Jennifer Lyn Zick
• 金额: $ 3.8万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-06 至 2019-09-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9190179
• 关键词: Action Potentials; Address; Affect; American; Animal Disease Models; Animal Model; Automobile Driving; Behavior; Brain; Brain region; Cell physiology; Cells; Chronic; Cognitive; Cognitive deficits; Communication; Computer Simulation; Coupling; DNA Sequence Alteration; Data; Data Analyses; Data Set; Disease; Failure; Functional Imaging; Functional disorder; Genetic; Genetic Models; Genetic Risk; Health; Human; Impaired cognition; Intervention; Knock-out; Knowledge; Lead; Link; Modeling; Molecular; Monkeys; Mus; Mutation; N-Methyl-D-Aspartate Receptors; Neural Network Simulation; Neurons; Pathogenesis; Patients; Pattern; Pharmaceutical Preparations; Physiological; Physiology; Population; Prefrontal Cortex; Process; Property; Research; Risk; Schizophrenia; Short-Term Memory; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Testing; Theoretical model; Therapeutic Agents; Time; Training; Training Programs; Transgenic Mice; base; cognitive control; cognitive performance; cognitive process; developmental genetics; evidence base; foot; functional restoration; genome wide association study; information processing; neural circuit; neural patterning; neuronal circuitry; neurophysiology; neuropsychiatric disorder; nonhuman primate; novel; novel therapeutics; receptor function; relating to nervous system; severe mental illness; theories

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.

项目摘要 精神分裂症是一种使人衰弱的神经精神疾病，它是十大健康负担之一 然而，目前的治疗方案对许多患者无效。为了开发新的疗法， 我们必须更好地了解这种疾病如何改变大脑生理机能。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 目前的知识体系是基于这一谱系的两个极端：导致功能障碍的遗传缺陷 一方面是细胞功能的改变，另一方面是全球大脑激活模式和认知能力的改变。 其他.我们所缺少的是神经回路水平上的中间环节，或者更具体地说， 理解精神分裂症患者神经活动的时空模式的扭曲 最终使网络执行的计算脱轨，导致认知失败。 一个被广泛接受的精神分裂症理论模型，称为断开假说，认为 疾病是由大脑区域之间的功能连接紊乱引起的。虽然一些功能成像 证据支持这一理论，但它从未在神经元回路水平上进行过测试，因此是一种机械的 框架尚未建立。在这里，我们提出测试的中心假设，精神分裂症是一种疾病， 其中前额叶回路中的动作电位时序异常导致突触连接减弱， 时间，通过建立机制的尖峰时间依赖可塑性。 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， 非人灵长类动物在接受模拟工作记忆功能的药物后， 精神分裂症对该数据的初步分析表明，尖峰活动是无序的，使得细胞中的细胞 相同的局部电路被去极化，细胞对之间的功能连接减少;这些发现 与我们的假设一致，即尖峰时间中断导致功能性断开， 精神分裂症我们将进一步发展这些分析，并将其与认知过程中的干扰联系起来。 与人类精神分裂症患者相似在具体目标2中，我们建议进行大规模的 在转基因小鼠的神经记录，以研究如何突变，增加患精神分裂症的风险， 改变了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 为了最大化两种动物模型的转化能力，最后，具体目标 3、我们提出进行计算神经网络模拟，以建立一个理论框架， 将紊乱的尖峰时间与功能性断开联系起来。通过这些获得的信息 研究将为精神分裂症发病机制的新理论框架奠定基础， 来指导新疗法的合理探索