Neural Oscillations in Schizophrenia and a Rat Model

描述(由申请人提供)：神经同步和振荡的电生理(EEG)测量在精神分裂症患者中是异常的，可能导致感知和认知处理的缺陷。有人假设，这些振荡缺陷可能是由于皮质和丘脑皮质回路中GABA和谷氨酸能相互作用的干扰而产生的。虽然振荡措施可以为精神分裂症的可能机制提供神经生理学探针，但这些障碍的神经基础及其与精神障碍风险因素的关系却鲜为人知。这项翻译研究将使用对精神分裂症谱系障碍患者和精神分裂症的氯胺酮啮齿动物模型的补充研究，以调查振荡障碍作为精神分裂症的潜在生物标记物的可能性。三种类型的反应将在频域中分析：a)周期性刺激(听觉稳态反应或ASSR)的振荡活动；2)音调诱导的伽马活动；3)感觉门控的频域分析。在这项人类研究中，四组人将被比较：1)精神分裂症患者，2)分裂型人格受试者，一种与精神分裂症症状相同的表型，3)精神分裂症患者的兄弟姐妹，以及4)健康对照组受试者。这些人类数据将测试这些同步缺陷是否符合疾病内表型的关键标准，或者是临床精神病的状态指标。在氯胺酮啮齿动物模型中，我们将测试这些措施对急性和长期用药氯胺酮的敏感性，氯胺酮是一种有效的NMDA拮抗剂，并确定这些措施是否可以通过非典型抗精神病药物奥氮平或甘氨酸转运蛋白1(GlyT1)抑制剂N[3-(4‘-氟苯基)-3-(4’-苯基苯氧基)丙基]肌氨酸(NFPS)逆转。因此，动物研究将产生体内证据，证明时频测量对经过充分验证的精神分裂症啮齿动物模型的敏感性，以及这些测量是否受到抗精神病药物的影响。这些结果可能有助于识别指示精神分裂症同步和振荡障碍的神经生理生物标记物，在啮齿动物模型中测试这些生物标记物的有效性，并评估这些措施评估治疗效果的潜力。 公共卫生相关性：精神分裂症患者的脑电活动(脑电波)记录显示，对刺激的反应通常表现出紊乱的同步或振荡。该项目将研究人类和精神分裂症大鼠模型的脑电振荡。这些结果有助于了解导致这种疾病的神经机制，并在遗传因素和治疗反应的研究中识别生物标志物。

DESCRIPTION (provided by applicant): Electrophysiological (EEG) measures of neural synchronization and oscillations are abnormal in schizophrenia and may contribute to deficits in perceptual and cognitive processing. It has been hypothesized that these oscillatory deficits may be produced by disturbances in GABA and glutamatergic interactions within cortical and thalamocortical circuits. While oscillatory measures could provide a neurophysiological probe into a putative mechanism for schizophrenia, the neural basis for these disturbances and their relation to risk factors for the disorder, are little understood. This translational investigation will use complementary studies of patients with schizophrenia spectrum disorders and a ketamine rodent model of schizophrenia to investigate oscillatory disturbances as a potential biomarker for schizophrenia. Three types of responses will be analyzed in the frequency domain: a) oscillatory activity entrained to periodic stimuli (auditory steady state response or ASSR); 2) gamma activity induced by tones; and 3) frequency domain analysis of sensory gating. In the human study, four groups will be compared: 1) Patients with schizophrenia, 2) subjects with schizotypal personality, a phenotype which shares symptoms with schizophrenia, 3) siblings of patients with schizophrenia, and 4) healthy control subjects. This human data will test whether these deficits in synchronization meet key criteria for an endophenotype in the disorder, or are state indicators for clinical psychosis. In the ketamine rodent model, we will test the sensitivity of these measures to acute and chronic administration of ketamine, a potent NMDA antagonist, and determine whether these are reversed by treatment with an atypical antipsychotic medication, olanzapine, or a glycine transporter 1 (GlyT1)-inhibitor N[3-(4'-flurophenyl)-3-(4'-phenylphenoxy) propyl]sarcosine (NFPS). The animal studies will therefore yield in-vivo evidence of the sensitivity of time-frequency measures to a well-validated rodent model of schizophrenia, and whether these measures are affected by anti-psychotic medications. These results may help identify neurophysiological biomarkers which index disturbances of synchronization and oscillations in schizophrenia, test the validity of these biomarkers in a rodent model, and evaluate the potential of these measures to evaluate treatment effects. PUBLIC HEALTH RELEVANCE: Recordings of EEG activity (brainwaves) in schizophrenia show that responses to stimulation often show disturbed synchronization or oscillations. This project will study EEG oscillations in humans and in a rat model of schizophrenia. These results could help in understanding the neural mechanisms responsible for the disorder, and identify biomarkers in studies of genetic factors and treatment response.