Neurodevelopmental model of sensorimotor deficits

感觉运动缺陷的神经发育模型

• 批准号: 7305829
• 负责人: Michael W Vogel
• 金额: $ 20.25万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-04 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7305829
• 关键词: Acoustics; Adolescent; Adult; Affect; Age; Animal Model; Antimitotic Agents; Behavior; Behavioral; Bromodeoxyuridine; Cytarabine; Development; Disruption; Embryo; End Point; Exploratory Behavior; Goals; Hippocampus (Brain); Injection of therapeutic agent; Investigation; Label; Lesion; Long-Term Potentiation; Measures; Mental disorders; Mitotic; Modeling; Nervous system structure; Neurobiology; Neurons; Numbers; Pathway interactions; Patient currently pregnant; Perinatal; Pharmaceutical Preparations; Physiologic pulse; Pulse taking; Purpose; Range; Rattus; Research; Schizophrenia; Series; Specificity; Synaptic plasticity; Techniques; Testing; Time; Ursidae Family; age group; base; cohort; day; morris water maze; neural circuit; neurogenesis; neurophysiology; novel; postnatal; prenatal; prepulse inhibition; pup; research study; response; tool; way finding

DESCRIPTION (provided by applicant): The long-term goal of this project is to develop a rat model for the neuropathological and behavioral deficits of schizophrenia that can be used to analyze the neurobiological basis of schizophrenia-like behavioral deficits and to identify novel targets for the development of new treatments. The proposed animal model is based on disruption of neurogenesis with the anti- mitotic drug, cytosine arabinoside (AraC). The rationale for the proposed model is based on the idea that subtle lesions in the developing nervous system will have significant effects on the subsequent development and plasticity of the neural circuits that regulate adult behaviors. In preliminary experiments, we determined that sensorimotor gating is selectively altered in adult rats following prenatal AraC injections; consistent and significant deficits in baseline PPI were found only following AraC injections at embryonic days 19 and 20. Preliminary anatomical studies suggest that the hippocampus is disrupted in the E19/20 AraC treated age group. The purpose of this R21 proposal is to initiate a new series of investigations based upon these initial findings. The goal of this application is to bring to bear a new set of tools to probe the value of the model as a research tool in schizophrenia. We will focus on analyzing the hippocampal- cortical circuitry and how the timing of disruptions in neurogenesis affect a range of behavioral, functional, and neuroanatomical end points. The study hypothesis is that specifically-timed injections of AraC will produce subtle alterations in hippocampal-cortical circuitry resulting in behavioral and neurophysiological disruptions dependent upon this circuitry. A cohort of rats will be exposed to AraC on embryonic days 17 and 18 or 19 and 20 or on postnatal days 0 and 1. In the first and second specific aims of this application, open-field exploration will be used to characterize general abnormalities while sensorimotor gating, spatial navigation, and cortical long-term potentiation will be used to assess hippocampal-cortical circuitry. In the third specific aim, neuroanatomical techniques, including neuronal birthdate labeling with BrdU, will be used to characterize the effects of perinatal inhibition of neurogenesis on the development of the hippocampal-cortical circuit and select other regions that modulate this circuit. The long-term goal of this project is to develop a rat model of neuropathological and behavioral deficits in schizophrenia based on perinatal disruption of neurogenesis with an antimitotic drug, cytosine arabinoside. The model will be used to analyze the neurobiological basis of schizophrenia-like behavioral deficits and to identify novel targets for the development of new treatments for this devastating mental illness.

描述（由申请人提供）：本项目的长期目标是开发精神分裂症神经病理和行为缺陷的大鼠模型，该模型可用于分析精神分裂症样行为缺陷的神经生物学基础，并确定开发新治疗方法的新靶点。所提出的动物模型是基于用抗有丝分裂药物阿糖胞苷（AraC）破坏神经发生。该模型的基本原理是基于这样的想法，即发育中的神经系统中的细微病变将对调节成人行为的神经回路的后续发育和可塑性产生显着影响。在初步的实验中，我们确定，感觉运动门控选择性地改变成年大鼠产前AraC注射后，一致的和显着的赤字，在基线PPI发现只有在胚胎第19和20天AraC注射。初步解剖学研究表明，海马在E19/20 AraC治疗的年龄组中被破坏。本R21提案的目的是根据这些初步调查结果启动一系列新的调查。这个应用程序的目标是带来承担一套新的工具，以探讨精神分裂症的研究工具的模型的价值。我们将集中分析海马-皮质回路，以及神经发生中断的时间如何影响一系列行为、功能和神经解剖学终点。研究假设是，特定时间注射AraC将在大脑皮层回路中产生微妙的变化，导致依赖于该回路的行为和神经生理学中断。一组大鼠将在胚胎第17天和第18天或第19天和第20天或出生后第0天和第1天暴露于AraC。在本申请的第一个和第二个特定目标中，将使用旷场探查来表征一般异常，而将使用感觉运动门控、空间导航和皮层长时程增强来评估大脑皮层-皮层回路。在第三个具体的目标，神经解剖技术，包括神经元的出生日期标记BrdU，将被用来表征围产期抑制神经发生的影响的发育的大脑皮层电路和选择其他地区，调制这个电路。该项目的长期目标是建立一个精神分裂症神经病理和行为缺陷的大鼠模型，该模型基于用抗有丝分裂药物阿糖胞苷对围产期神经发生的破坏。该模型将用于分析精神分裂症样行为缺陷的神经生物学基础，并确定开发这种毁灭性精神疾病新疗法的新目标。