Building a mouse model with relevance to schizophrenia

描述（由申请人提供）：职业发展和研究 本提案中描述的程序支持申请辅导 Kenneth N博士获得研究科学家发展奖。鱼，并打算 为候选人提供背景知识，研究经验， 并研究管理技能，这将使他为独立的 精神分裂症的研究生涯培训将在哈罗德L。 Dorris神经药理学系神经学研究中心（Dr. 弗洛伊德E.布卢姆，主席）的斯克里普斯研究所，根据直接 塔马斯·巴特菲医生的监督Bartfai博士非常有资格担任 候选人的导师，因为他在方法论方面的经验 他在抑郁症和精神分裂症方面的积极研究计划， 他致力于培养年轻的研究科学家。部 神经药理学强调多学科的方法来解决问题， 精神障碍因此，这是候选人的理想环境， 实现了他的目标，发展多学科的研究方法， 精神分裂症的神经生物学。研究计划的总体目标是 对卷取器和扰频器鼠标进行全面分析，以确定测试 这些参数将用于研究新的小鼠模型，并确定其 作为精神分裂症研究模型的适用性。测试将包括 新皮层、小脑和海马的形态学分析， NeuroZoom三维重建，免疫细胞化学分析， DA、GLU和GABA表达，定量行为测量[前脉冲 抑制（PPI）的惊吓反应]，以及他们的反应， 临床有效的抗精神病药（氟哌啶醇、利培酮和氯氮平）。 此外，为了进一步表征reeler表型，我们将生成一个 转基因小鼠，其中reelin的表达受到时间调节， 生成具有条件性卷轴功能块的小鼠模型， 诱导改变前脉冲所需的脑形态的特定变化 抑制和/或诱导共济失调。这些研究将促进我们的理解 神经发育异常如何与行为变化和意志 协助开发新的抗精神病药物， 精神分裂症

DESCRIPTION (provided by applicant): The career development and research program described in this proposal supports the application for a Mentored Research Scientist Development Award for Dr. Kenneth N. Fish, and is intended to provide the candidate with the background knowledge, research experience, and research management skills that will prepare him for an independent research career in schizophrenia. Training will take place at the Harold L. Dorris Neurological Research Center in the Department of Neuropharmacology (Dr. Floyd E. Bloom, Chair) of the Scripps Research Institute, under the direct supervision of Dr. Tamas Bartfai. Dr. Bartfai is highly qualified to serve as Preceptor for the Candidate, because of his experience with the methodologies to be used, his active research program in depression and schizophrenia, and his commitment to the development of junior research scientists. The Department of Neuropharmacology emphasizes a multi-disciplinary approach to problems of mental disorders. Thus, this is an ideal environment for the Candidate to materialize his goal of developing a multidisciplinary research approach to the neurobiology of schizophrenia. The overall objective of the research plan is to perform a thorough analysis of the reeler and scrambler mice to define test parameters that will be used to study new mouse models and to determine their applicability as models to study schizophrenia. Tests will include a morphological analysis of the neocortex, cerebellum, and hippocampus using three-dimensional reconstruction with NeuroZoom, immunocytochemical analysis of DA, GLU, and GABA expression, quantitative behavioral measurements [prepulse inhibition (PPI) of the startle response], and their responsiveness to clinically effective antipsychotics (haloperidol, risperidone, and clozapine). In addition, to further characterize the reeler phenotype we will generate a transgenic mouse in which reelin expression is temporally regulated and generate a mouse model that has a conditional block of reelin function to induce specific changes in brain morphology that are required to alter prepulse inhibition and/or induce ataxia. These studies will advance our understanding of how neurodevelopmental abnormalities relate to behavioral changes and will assist in the development of new antipsychotic drugs with relevance to schizophrenia.