Molecular Basis of Deviance Detection and Stimulus Encoding

偏差检测和刺激编码的分子基础

• 批准号: 7478778
• 负责人: Raquel E Gur
• 金额: $ 23.53万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7478778
• 关键词: Auditory; Autopsy; Brain region; Cognitive deficits; Detection; Disease; Dopamine Receptor; Electroencephalography; ErbB4 gene; Event-Related Potentials; Functional Magnetic Resonance Imaging; Functional disorder; Glutamates; Hippocampus (Brain); Human; Interneurons; Lead; Molecular; Monitor; Mus; Mutant Strains Mice; N-Methyl-D-Aspartate Receptors; Neocortex; Neuregulin 1; Neurons; Parahippocampal Gyrus; Process; Protein Overexpression; Reporting; Retrieval; Schizophrenia; Short-Term Memory; Signal Pathway; Stimulus; Superior temporal gyrus; Symptoms; Testing; Theta Rhythm; Tissues; base; blood oxygenation level dependent response; neural circuit; neurochemistry; neurotransmission; novel; presynaptic; receptor function; transmission process

Cognitive deficits as well as positive and negative symptoms in schizophrenia may arise from abnormalities in very basic processes of detecting and encoding stimuli in appropriate neural circuitry. Those processes can be monitored with event-related potentials (ERPs), EEG oscillations and fMRI activation. Abnormalities have been reported repeatedly in schizophrenia in multiple auditory cortical ERPs and in theta and gamma EEG rhythms associated with deviance and novelty detection, as well as with encoding and retrieval of episodic and working memory. As described in Subprojects 0001 and 0003, our CCNMD has found that in schizophrenia gamma oscillatory abnormalities correlate with abnormal fMRI BOLD responses, including those in superior temporal gyrus and hippocampus. The microcircuits generating gamma and theta rhythms in neocortex and hippocampus have been elucidated in recent years. In both brain regions, the microcircuits are similar and consist of glutamatergic projection neurons reciprocally connected with one or more types of GABAergic interneurons. We propose that in schizophrenia hypofunction of glutamatergic input to GABAergic interneurons occurs in theta and gamma microcircuits with consequent GABAergic hypofunction leading to abnormal oscillations in the circuits. Our studies have identified factors in schizophrenia that could lead to glutamatergic and GABAergic dysfunction in hippocampal and cortical brain regions, including abnormal dysbindin expression and abnormal activation of NMDA receptors and the neuregulin 1-erbB4 signaling pathway. Subproject 0007 will test hypotheses related to these findings and potential consequences for glutamatergic-GABAergic neurotransmission. Aim 1 will examine whether or not presynaptic factors that contribute to glutamatergic function of theta and gamma microcircuits are abnormal in schizophrenia and a dysbindin mutant mouse (sandy). Aim 2 will use a novel neurochemical stimulation paradigm in human postmortem tissue and a Gsa overexpressing mouse to examine NMDA receptor function and NMDAR-dopamine receptor interactions that may contribute to theta and gamma microcircuit dysfunction in schizophrenia. Aim 3 will examine whether markers of GABAergic transmission are in fact altered in the gamma and theta microcircuits in that disorder.

精神分裂症患者的认知缺陷以及阳性和阴性症状可能源于异常 在适当的神经回路中检测和编码刺激的非常基本的过程中。这些进程 可以通过事件相关电位（ERP），EEG振荡和fMRI激活进行监测。异常 在精神分裂症的多个听觉皮层ERPs和θ和γ中反复报道 EEG节律与异常和新奇检测相关，以及与编码和检索 情景记忆和工作记忆如子项目0001和0003所述，我们的CCNMD发现，在精神分裂症中， γ振荡异常与异常fMRI BOLD反应相关，包括上级 颞回和海马。大脑皮层中产生伽马和θ节律的微电路， 海马近年来已被阐明。在这两个大脑区域，微电路是相似的， 由与一种或多种类型的GABA能神经元连接的多巴胺能投射神经元组成。 中间神经元我们认为，在精神分裂症中，γ-氨基丁酸能神经递质输入功能减退， 中间神经元发生在θ和γ微电路中，随后GABA能功能减退，导致 电路中的异常振荡 我们的研究已经确定了精神分裂症中可能导致多巴胺能和GABA能的因素， 海马和皮质脑区域的功能障碍，包括异常的dysbindin表达， NMDA受体和神经调节蛋白1-erbB 4信号通路的异常激活。子项目0007将测试 与这些发现相关的假设和对代谢能-GABA能 神经传递目的1将研究是否突触前因素，有助于突触能 θ和γ微电路功能在精神分裂症和dysbindin突变小鼠中异常 （桑迪）。目的2将在人类死后组织中使用一种新的神经化学刺激范例， 过表达小鼠以检查NMDA受体功能和NMDAR-多巴胺受体相互作用， 可能会导致精神分裂症患者的θ和γ微电路功能障碍。目标3将审查是否 GABA能传递的标记物实际上在该疾病中的γ和θ微电路中被改变。