Developmental Models of Gating Deficits in Schizophrenia

精神分裂症门控缺陷的发育模型

基本信息

批准号：
7231347
负责人：
MARK A GEYER
金额：
$ 27万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-04-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7231347
关键词：
3-hydroxykynurenine Abbreviations Acetylcysteine Acids Acoustics Acute Adolescence Adult Animals Antipsychotic Agents Anxiety Attenuated Autopsy Behavior Behavioral Biological Birth Brain Brain region Chronic Chronic stress Cognitive Corticotropin-Releasing Hormone Corticotropin-Releasing Hormone Receptors D Aspartate Development Disease Disruption Elevation Endotoxins Epigenetic Process Etiology Excitatory Amino Acid Antagonists Exposure to Female Functional disorder Funding Globus Pallidus Grant Hippocampus (Brain)Housing Immune Infection Inflammatory Interleukin-10 Interleukins Knock-out Kynurenic Acid Kynurenine Lead Lesion Link Lipopolysaccharides Measures Mediating Mental disorders Metabolism Modeling Monitor Motor Mus Mutant Strains Mice N-Methylaspartate N-acetylaspartate NMDA receptor antagonist Neurobiology Neuropeptides Neurosecretory Systems Nucleus Accumbens Oxidopamine Pathway interactions Patients Pattern Phenotype Physiology Play Principal Investigator Prostaglandin-Endoperoxide Synthase Quinolinic Acid Quinolinic Acids Rattus Recovery Reflex action Reporting Role Schizophrenia Sensory Social isolation Stimulus Stress System Testing Theoretical model Time Trauma Tryptophan Metabolism Pathway Ventral Tegmental Area Virus Weaning acid stress antisauvagine 30 atypical antipsychotic base biological adaptation to stress bipiperidyl mustard cyclooxygenase 1 cyclooxygenase 2 day hypothalamic-pituitary-adrenal axis insight intraperitoneal male neural circuit neurobehavioral neuropsychiatry neurotoxic postnatal prenatal prenatal exposure prepulse inhibition prevent receptor relating to nervous system research study response therapy design

项目摘要

DESCRIPTION (provided by applicant): Prepulse inhibition (PPI) of the acoustic startle reflex refers to the ability of a weak stimulus preceeding a startling stimulus to inhibit the response to that stimulus. PPI is an operational measure of sensorimotor gating that is amenable to cross-species comparisons. Deficits in PPI have been reported repeatedly in patients with schizophrenia and other psychiatric disorders characterized by abnormalities in sensory, cognitive, or motor gating. Because some forms of schizophrenia appear to be attributable to early developmental insults such as prenatal infection or birth complications, many animal studies have examined the influences of specific developmental manipulations on behaviors and neural circuitry relevant to schizophrenia. Isolation rearing of rats and mice from weaning is a non-pharmacological manipulation that leads to deficits in prepulse inhibition of startle. Similar deficits in PPI are produced in rats'exposed to a prenatal immune challenge. The current proposal will extend and integrate studies of isolation rearing into the broader framework of neurodevelopmental insults, based on the conceptual and empirical connections between social isolation, chronic stress, and immune/inflammatory activation. To clarify the biological underpinnings of this integrated model, the aims of this grant are to examine the mechanistic role of alterations in the endogenous NMDA receptor antagonist, kynurenic acid (KYNA), and the stress-related neuropeptide, corticotropin releasing factor (CRF) in isolation- and immune-mediated developmental models of sensorimotor gating deficits. Recently the endogenous NMDA receptor antagonist kynurenic acid has been shown to disrupt PPI in rats. Hence, Aim 1 studies will assess the contribution of KYNA and its metabolites 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) to isolation rearing-induced PPI deficits in rats. Based on the observation that schizophrenia may be associated with a prenatal immune insult (e.g. exposure to a virus), Aim 2 studies will further characterize the effects of prenatal immune challenge on PPI and examine the contribution of KYNA to these immune-related effects on PPI. The anxiety-like phenotype and exaggerated stress responses in isolation-reared rats are consistent with alterations in the brain's CRF system. Hence, Aim 3 studies will test the hypothesized differential roles of specific CRF receptors in mediating isolation rearing-induced deficits in PPI in mice, using CRF-R1 and CRF-R2 null mutant mice.

描述（由申请人提供）：声学惊吓反射的预脉冲抑制（PPI）是指弱刺激的能力，该刺激的能力是在惊人的刺激中抑制对刺激的反应的能力。 PPI是对跨物种比较的感觉运动门控的操作度量。在精神分裂症患者和其他精神病患者中，PPI缺陷反复报道，以感觉，认知或运动门控为异常。由于某些形式的精神分裂症似乎归因于早期发育侮辱，例如产前感染或出生并发症，因此许多动物研究研究了特定发育操作对与精神分裂症相关的行为和神经回路的影响。从断奶中隔离大鼠和小鼠是一种非药物操纵，会导致在抑制惊吓方面缺陷。在暴露于产前免疫挑战的大鼠中会产生类似的PPI缺陷。当前的建议将基于社会隔离，慢性压力和免疫/炎症激活之间的概念和经验联系，将隔离饲养的研究扩展和整合到神经发育侮辱的更广泛框架中。 To clarify the biological underpinnings of this integrated model, the aims of this grant are to examine the mechanistic role of alterations in the endogenous NMDA receptor antagonist, kynurenic acid (KYNA), and the stress-related neuropeptide, corticotropin releasing factor (CRF) in isolation- and immune-mediated developmental models of sensorimotor gating deficits.最近，内源性NMDA受体拮抗剂kynurenic酸已证明会破坏大鼠的PPI。因此，AIM 1研究将评估Kyna及其代谢产物3-羟基苯胺（3-HK）和喹啉酸（Quin）对大鼠分离饲养诱导的PPI缺陷的贡献。基于观察到精神分裂症可能与产前免疫损伤有关（例如接触病毒），AIM 2研究将进一步表征产前免疫挑战对PPI的影响，并研究Kyna对这些免疫相关作用对PPI的贡献。隔离大鼠中焦虑状的表型和夸张的压力反应与大脑CRF系统的改变一致。因此，AIM 3研究将使用CRF-R1和CRF-R2 NULL突变小鼠在介导的小鼠中介导孤立饲养引起的PPI缺陷中测试特定CRF受体的假设差异作用。