Sensitive and Treatable Periods of Brain-Redox Imbalance in Schizophrenia

精神分裂症脑氧化还原失衡的敏感期和可治疗期

• 批准号: 7980131
• 负责人: M MARGARITA BEHRENS
• 金额: $ 45.39万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-19 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7980131
• 关键词: Abbreviations; Acetylcysteine; Adolescence; Adult; Affect; Affective; American; Analysis of Variance; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Appearance; Arthritis; Attenuated; Autopsy; Behavior; Behavioral; Biological Markers; Blocking Antibodies; Brain; Clinical; Cognitive; Cognitive Therapy; Cognitive deficits; Conditioned Stimulus; Data; Development; Discrimination; Disease; Early treatment; Environmental Risk Factor; Equilibrium; Exposure to; Functional disorder; Genetic; Glutamate Decarboxylase; Glutathione; Immunohistochemistry; Inflammation Mediators; Inflammatory; Interleukin-6; Interneurons; Intervention; Ketamine; Knowledge; Lead; Life; Light; Link; Measures; Memory; Mental disorders; Messenger RNA; Modeling; Mus; N-Methylaspartate; NADP; NADPH Oxidase; NMDA receptor antagonist; Neurons; Oxidation-Reduction; Oxidative Stress; Parvalbumins; Pathway interactions; Patients; Perinatal; Perinatal Exposure; Peripheral; Pharmacological Treatment; Phencyclidine; Plasma; Prefrontal Cortex; Prevention; Preventive; Process; Prosencephalon; Psychotic Disorders; Public Health; Reactive Oxygen Species; Research Support; Risk; Role; Schizophrenia; Social isolation; Staging; Stimulus; Superoxide Dismutase; Superoxides; Symptoms; System; Testing; Time; Weaning; acetovanillone; attenuation; brain behavior; cognitive function; conditioned fear; critical period; emerging adult; executive function; gamma-Aminobutyric Acid; inhibitor/antagonist; inhibitory neuron; intraperitoneal; loss of function; mature animal; mouse model; neural circuit; neurochemistry; neurodevelopment; novel; postnatal; prepulse inhibition; prevent; public health relevance; resilience; treatment strategy

DESCRIPTION (provided by applicant): A significant body of research supports the idea that deficits in cortical fast-spiking inhibitory systems may underlie the psychotic features and cognitive deficits associated with schizophrenia-related disorders. Recent data from neurodevelopmental animal models indicate that the loss of function of the parvalbumin-(PV) positive fast-spiking inhibitory neurons may occur early during postnatal development, specifically during the critical period of their maturation. These results strongly suggest that the period of active maturation of this fundamental inhibitory system may constitute a sensitive period during which the confluence of genetic and environmental factors may set the stage for the development of schizophrenia-like symptoms in late adolescence/early adulthood. Thus, studies directed to determine factors that affect the maturational process of this inhibitory system may shed light into the origins of schizophrenia. This project will test two primary hypotheses: (1) that the period of maturation of PV-interneuronal circuits constitutes a sensitive period in which increased oxidative stress in brain, due to the activation of the IL-6/Nox2 pathway, leads to schizophrenia-like behavior in early adulthood; and (2) that this sensitive period also constitutes a "window of intervention" for pharmacological treatment strategies aimed at prevention of psychosis. These hypotheses will be tested in mice subjected to two developmental manipulations known to lead to disruptions in the PV- interneuronal circuitry and schizophrenia-related behaviors in early adulthood: i.e. perinatal exposure to the NMDA receptor antagonist ketamine (pNM model), and social isolation rearing (SI model). Three specific aims will be developed: Aim 1 will test the hypothesis that there is a sensitive period of brain redox dysregulation in the pNM and SI models that leads to schizophrenia-like neurochemical and behavioral disruptions in late adolescence/early adulthood. Aim 2 will determine whether increased brain and circulating IL-6 correlate with active oxidative stress in brain in the two developmental models, assess whether circulating IL-6 constitutes a peripheral biomarker predictive of brain dysfunction, and test whether the neurochemical and behavioral effects of SI and pNM are absent in IL-6 KO mice. And finally, Aim 3 will assess whether early or late interventions leading to attenuation of brain oxidative stress, by use of a Nox2 inhibitor (apocynin), an IL-6 blocker, or by increasing antioxidant defenses with N-acetyl cysteine, protects the PV-interneuronal system and prevents development of schizophrenia-like behaviors in late adolescence/early adulthood. Public Health Impact: This project studies a specific set of inhibitory neurons which are critical for normal cognitive function, and known to be dysfunctional in schizophrenia. The proposed studies may suggest novel anti-inflammatory and/or anti-oxidant treatments during early life to protect this fundamental GABAergic system and thus prevent the development of schizophrenia and other psychotic conditions. PUBLIC HEALTH RELEVANCE: Schizophrenia affects millions of Americans when they reach early adulthood, but to date, there is scarce knowledge of the underlying disease processes occurring before symptoms appear. Using two neurodevelopmental mouse models of schizophrenia, this project will determine whether the period of maturation of inhibitory circuits, during early postnatal development, constitutes a sensitive period when the brain is most vulnerable to oxidative stress processes that lead to the dysfunction of specific inhibitory circuits and the appearance of schizophrenia-like symptoms in early adulthood. These studies will delineate the mechanisms inducing the increased oxidative stress in two models and the periods when they occur, and assess whether strategies that prevent oxidative stress ameliorate the neurochemical and behavioral disruptions.

描述（由申请人提供）：一大批研究支持了这样的观念，即皮质快速刺激性抑制系统的缺陷可能是与精神分裂症相关疾病相关的精神病特征和认知缺陷的基础。来自神经发育动物模型的最新数据表明，白细胞蛋白（PV）阳性快速抑制性神经元的功能丧失可能在产后发​​育期间发生，特别是在其成熟的关键时期。这些结果强烈表明，这种基本抑制系统的积极成熟时期可能构成一个敏感的时期，在此期间，遗传和环境因素的汇合可能为在青春期晚期/成年早期形成类似精神分裂症样症状的发展奠定了基础。因此，针对确定影响这种抑制系统成熟过程的因素的研究可能会揭示精神分裂症的起源。该项目将检验两个主要的假设：（1）PV intrenerronal回路的成熟时期构成了一个敏感的时期，在该时期中，由于IL-6/NOX2途径的激活，大脑中氧化应激的增加，导致了早期的成年早期的精神分裂症样行为。 （2）这个敏感时期还构成了旨在预防精神病的药理治疗策略的“干预窗口”。这些假设将在接受两种发育操作的小鼠中进行测试，该操作已知导致PV-Neuronal电路中的破坏和成年初期的精神分裂症相关行为：即围产期暴露于NMDA受体酮酮（PNM模型）和社交隔离模型（SI I SI型）。将开发三个具体目标：AIM 1将检验以下假设：PNM和SI模型中脑氧化还原失调的敏感时期导致青少年/成年早期的精神分裂症样神经化学和行为破坏。 AIM 2将确定在两个发育模型中的大脑和循环IL-6与大脑中的主动氧化应激相关，评估循环IL-6是否构成了脑功能障碍的外周生物标志物，并且测试IL-6 KO小鼠中SI和PNM的神经化学和行为效应是否不存在。最后，AIM 3将评估通过使用NOX2抑制剂（Apocynin），IL-6阻滞剂或通过N-乙酰基半胱氨酸增加抗氧化剂防御措施来评估导致脑氧化应激的衰减，导致pV-Interneronal andneronal系统的抗氧化剂防御量，以保护pV-Interneronal系统，并预测pV-Interneronal systemia-Adfertinia-Ad Adullection ind deffertimiaia sike ind deff ind deff in in Ad deprull sike in in/devillibe ind deff in in/def/def。公共卫生影响：该项目研究一组特定的抑制性神经元，对于正常的认知功能至关重要，在精神分裂症中已知功能失调。拟议的研究可能建议在早期生命中进行新颖的抗炎和/或抗氧化剂治疗，以保护这种基本的GABA能体系，从而防止精神分裂症和其他精神病性疾病的发展。 公共卫生相关性：精神分裂症会影响成年初的数百万美国人，但迄今为止，人们对出现症状之前发生的潜在疾病过程的了解很少。使用两个精神分裂症的神经发育小鼠模型，该项目将确定抑制回路的成熟期（在产后早期发育中）是否构成了一个敏感时期，当大脑最容易受到氧化应激过程的影响，从而导致特定抑制作用的功能障碍，并早期与精神分裂症症状症状的出现。这些研究将描述在两个模型和发生时期诱导氧化应激增加的机制，并评估预防氧化应激的策略是否可以改善神经化学和行为破坏。