Computational Modeling of Hippocampus in Schizophrenia

精神分裂症海马的计算模型

• 批准号: 7609102
• 负责人: PETER JOHN SIEKMEIER
• 金额: $ 17.55万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-21 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7609102
• 关键词: AMPA Receptors; Affinity; Antipsychotic Agents; Area; Behavior; Behavioral; Binding; Biochemical; Biological; Brain; Brain region; Cell Surface Receptors; Cells; Characteristics; Clinical; Complex; Computer Simulation; Data; Databases; Disease; Dopamine; Etiology; Exhibits; Frequencies; Functional disorder; Gap Junctions; Glutamates; Goals; Hippocampus (Brain); Impairment; Interneurons; Ion Channel; Kinetics; Lead; Learning; Lesion; Link; Literature; Memory; Modeling; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurobiology; Neurons; Neurotransmitters; Outcome; Outcome Measure; Outcome Study; Patients; Pattern; Performance; Pharmaceutical Preparations; Property; Research; Research Personnel; Running; Schizophrenia; Sensory Receptors; Simulate; Symptoms; Synapses; Syndrome; System; Testing; Time; atypical antipsychotic; base; density; gamma-Aminobutyric Acid; insight; neuropathology; neuropsychiatry; programs; psychologic; psychopharmacologic; receptor; receptor density; receptor function; research study; simulation; theories; tool

DESCRIPTION (provided by applicant): While researchers have learned vast amounts about brain function at a cellular and molecular level over the past several years, we still have a poor understanding of the manner in which these phenomena give rise to behavior, and the way that neurobiological dysfunction creates psychiatric symptoms. This is particularly true for schizophrenia: while a large number of research studies have implicated hippocampus in the etiology of schizophrenia, and several possible neuroanatomic and biochemical abnormalities have been identified in this region, we still do not know how these findings, alone or in combination, lead to the clinical syndrome. Computational modeling is a research tool that allows one to make links between cellular phenomena and clinical behaviors by offering insights at the level of cells or cell ensembles as to how emergent properties arise. We have developed a computer simulation of a subsection of hippocampus CA1 incorporating 452 cells. Each cell is a biologically realistic model of a neuron, featuring an extensive dendritic arborization and Na+, Ca++, K+DR, K*AHp, K+c, and K+A channels, as well as AMPA, NMDA, and GABA synapses. We will use an elaborated version of this computational model as a tool to examine particular hypothesis regarding the hippocampal neuropathology of schizophrenia. Specifically, we will "lesion" the model in a schizophrenogenic way by separately and in combination (a) altering aspects of the GABA system, (b) disrupting the glutamatergic system, and (c) increasing dopaminergic tone. We will examine two outcome measures: oscillatory activity and performance on context-dependent memory tasks; both of these have clinical correlations with schizophrenia. Finally, we will apply a number medications, including typical and atypical antipsychotics, and examine their effects on system functioning. We expect these studies to 1) offer mechanistic and system-level insights into the neuropathological basis of the illness; 2) generate hypotheses that can subsequently be tested experimentally; and 3) identify potentially effective antipsychotic medications. Also, we hope that this study can make a contribution from a methodological point of view: though it involves only one brain area performing a discrete psychological task for a particular psychiatric illness, it is an approach that potentially can be applied to other brain regions and neuropsychiatric diseases.

描述（由申请人提供）：虽然在过去的几年里，研究人员在细胞和分子水平上对大脑功能有了大量的了解，但我们对这些现象产生行为的方式以及神经生物学功能障碍产生精神症状的方式仍然知之甚少。精神分裂症尤其如此：虽然大量的研究表明海马体与精神分裂症的病因有关，并且在该区域发现了几种可能的神经解剖和生化异常，但我们仍然不知道这些发现是如何单独或联合导致临床综合征的。计算建模是一种研究工具，它允许人们在细胞或细胞集合体的水平上提供关于涌现特性如何产生的见解，从而建立细胞现象和临床行为之间的联系。我们开发了一个包含452个细胞的海马CA1分段的计算机模拟。每个细胞都是一个生物学上真实的神经元模型，具有广泛的树突树突化和Na+、Ca++、K+DR、K*AHp、K+c和K+ a通道，以及AMPA、NMDA和GABA突触。我们将使用这个计算模型的一个详细版本作为工具来检验关于精神分裂症的海马神经病理学的特定假设。具体来说，我们将通过单独和组合(a)改变GABA系统的各个方面，(b)破坏谷氨酸系统，(c)增加多巴胺能张力，以精神分裂症的方式“损害”模型。我们将检查两个结果测量：振荡活动和在情境依赖的记忆任务的表现；这两种症状都与精神分裂症有临床相关性。最后，我们将应用一些药物，包括典型和非典型抗精神病药物，并检查它们对系统功能的影响。我们希望这些研究能够：(1)为疾病的神经病理学基础提供机制和系统层面的见解；2)产生可以随后通过实验验证的假设；3)确定潜在有效的抗精神病药物。此外，我们希望这项研究可以从方法学的角度做出贡献：尽管它只涉及一个大脑区域执行特定精神疾病的离散心理任务，但它是一种潜在的可以应用于其他大脑区域和神经精神疾病的方法。