Computational Modeling of Hippocampus in Schizophrenia

精神分裂症海马的计算模型

• 批准号: 7487297
• 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/7487297
• 关键词: Affinity; Antipsychotic Agents; Area; Behavior; Behavioral; Binding; Biochemical; Biological; Brain; Brain region; Cell Surface Receptors; Cells; Characteristics; Chromosome Pairing; 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; Numbers; 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; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; 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(申请人提供)：尽管在过去的几年里，研究人员已经在细胞和分子水平上了解了大量关于大脑功能的知识，但我们仍然对这些现象引发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缺乏了解。对于精神分裂症来说尤其如此：虽然大量研究表明海马体与精神分裂症的病因有关，并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单独或结合起来如何导致临床综合征。计算建模是一种研究工具，它允许人们在细胞或细胞集合水平上提供关于紧急特性如何产生的见解，从而在细胞现象和临床行为之间建立联系。我们已经开发了一个包含452个细胞的海马区CA1的计算机模拟。每个细胞都是一个生物真实的神经元模型，具有广泛的树突分支和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的特定假说。具体地说，我们将通过单独和联合使用(A)改变GABA系统的各个方面，(B)扰乱谷氨酸能系统，以及(C)增加多巴胺能张力，以精神分裂症的方式对模型进行“损伤”。我们将检查两个结果指标：振荡活动和上下文相关记忆任务的表现；这两个指标都与精神分裂症有临床相关性。最后，我们将应用一些药物，包括典型和非典型的抗精神病药物，并检查它们对系统功能的影响。我们希望这些研究1)提供对疾病神经病理基础的机械性和系统水平的洞察；2)产生假说，随后可以进行实验测试；以及3)确定潜在有效的抗精神病药物。此外，我们希望这项研究能够从方法论的角度做出贡献：虽然它只涉及一个大脑区域为特定的精神疾病执行离散的心理任务，但它是一种潜在的方法，可以应用于其他大脑区域和神经精神疾病。