Neurodevelopmental model of sensorimotor deficits

感觉运动缺陷的神经发育模型

• 批准号: 7831577
• 负责人: Michael W Vogel
• 金额: $ 2.53万
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7831577
• 关键词: Acoustics; Adolescent; Adult; Affect; Age; Animal Model; Antimitotic Agents; Behavior; Behavioral; Bromodeoxyuridine; Cytarabine; Development; Embryo; 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; Pathway interactions; Perinatal; Pharmaceutical Preparations; Physiologic pulse; Rattus; Research; Schizophrenia; Series; Specificity; Synaptic plasticity; Techniques; Testing; Time; Ursidae Family; age group; base; cohort; morris water maze; neural circuit; neurogenesis; neurophysiology; novel; postnatal; pregnant; 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）：该项目的长期目标是开发一种精神分裂症神经病理学和行为缺陷的大鼠模型，可用于分析精神分裂症样行为缺陷的神经生物学基础，并确定开发新疗法的新靶标。所提出的动物模型基于抗有丝分裂药物阿糖胞苷（AraC）对神经发生的破坏。该模型的基本原理是基于这样的想法：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重大影响。在初步实验中，我们确定成年大鼠在产前注射 AraC 后感觉运动门控发生选择性改变；仅在胚胎第 19 天和第 20 天注射 AraC 后，才发现基线 PPI 一致且显着的缺陷。初步解剖学研究表明，E19/20 AraC 治疗年龄组的海马体受到破坏。 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。该应用程序的目标是提供一套新的工具来探索该模型作为精神分裂症研究工具的价值。我们将重点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。该研究假设，特定时间注射 AraC 会在海马皮质回路中产生微妙的变化，从而导致依赖于该回路的行为和神经生理学破坏。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。在本应用的第一个和第二个具体目标中，开放场探索将用于表征一般异常，而感觉运动门控、空间导航和皮质长期增强将用于评估海马皮质回路。在第三个具体目标中，神经解剖学技术，包括用 BrdU 标记的神经元出生日期，将用于表征围产期神经发生抑制对海马皮质回路发育的影响，并选择调节该回路的其他区域。该项目的长期目标是开发一种精神分裂症神经病理学和行为缺陷的大鼠模型，其基础是用抗有丝分裂药物阿糖胞苷破坏围产期神经发生。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，并确定开发针对这种毁灭性精神疾病的新疗法的新目标。

项目成果

Desire, disease, and the origins of the dopaminergic system.

欲望、疾病和多巴胺能系统的起源。

• DOI: 10.1093/schbul/sbm170
• 发表时间: 2008
• 期刊: Schizophrenia bulletin
• 影响因子: 6.6
• 作者: Sillitoe,RoyV;Vogel,MichaelW
• 通讯作者: Vogel,MichaelW

Altered spatial learning, cortical plasticity and hippocampal anatomy in a neurodevelopmental model of schizophrenia-related endophenotypes.

• DOI: 10.1111/j.1460-9568.2012.08204.x
• 发表时间: 2012-09
• 期刊: The European journal of neuroscience
• 作者: Brown PL;Shepard PD;Elmer GI;Stockman S;McFarland R;Mayo CL;Cadet JL;Krasnova IN;Greenwald M;Schoonover C;Vogel MW
• 通讯作者: Vogel MW