Behavioral and Neurochemical Effects of Cortical NMDA Receptor Dysfunction: Impli

皮质 NMDA 受体功能障碍的行为和神经化学影响：隐含

• 批准号: 7983292
• 负责人: JANET M FINLAY
• 金额: $ 37.27万
• 依托单位: WESTERN WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-21 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7983292
• 关键词: Activities of Daily Living; Adult; Affect; Affective; Antipsychotic Agents; Attention; Autopsy; Behavioral; Chronic; Cognitive; Cognitive deficits; Data; Dependovirus; Disease; Dopamine; Exons; Functional disorder; Future; Gene Deletion; Glutamates; Goals; Grant; Hippocampus (Brain); Impaired cognition; Individual; Knock-in Mouse; Laboratories; Medial; Microdialysis; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 gene; Neurobiology; Neurons; Neurosciences; Play; Population; Prefrontal Cortex; Regulation; Research; Rewards; Role; Schizophrenia; Short-Term Memory; Site; Students; Symptoms; System; Testing; Transcript; Universities; Visual; Washington; adeno-associated viral vector; base; cognitive function; dopaminergic neuron; extracellular; in vivo; mouse model; neurochemistry; novel; public health relevance; recombinase; research study; theories; virus Cre recombinase

DESCRIPTION (provided by applicant): Altered function of cortical glutamate afferent and efferent projections is thought to contribute to the pathophysiology of schizophrenia. In particular, attention has focused on possible alterations in glutamate N-methyl-D-aspartate (NMDA) receptors in the prefrontal cortex (PFC). Individual NMDA receptors are comprised of a common NR1 subunit (necessary for functional NMDA receptors) together with a combination of NR2A-D subunits. Recent postmortem studies have found evidence of decreased NR1 transcript in the PFC of schizophrenic subjects. A goal of our research is to examine whether regionally restricted loss of NR1 function in the PFC contributes to cognitive and neurochemical deficits associated with the illness. The present studies will be performed in a mouse model in which loxP sites flank a functionally requisite exon of the NR1 subunit (fNR1 mice). Gene deletions will be performed by local administration of adeno-associated-virus Cre recombinase. Our previous studies indicate that impaired function of the NR1 subunit in the medial PFC and CA3 hippocampus of fNR1 mice differentially disrupts sustained attention and working memory, respectively. Aim 1 of the present proposal is to further explore the effects of localized disruptions of the NR1 subunit in the PFC and CA3 hippocampus on cognitive function in adult fNR1 mice. Cognitive function will be examined using delayed spatial win-shift, non-delayed random foraging, and visual sustained attention tasks. Aim 2 will assess whether NR1 dysfunction in the PFC results in secondary disruptions in the neurochemical activity of mesoprefrontal dopamine (DA) neurons. Dysfunction of mesoprefrontal DA neurons has long been thought to contribute to cognitive deficits in schizophrenia. Furthermore, considerable experimental evidence supports the existence of a glutamate-DA interaction in the PFC and, in turn, our hypothesis that chronic NR1 dysfunction will impair the functional capacity of mesocortical DA neurons. The effects of localized PFC NR1 dysfunction on regulation of local extracellular DA will be examined using in vivo microdialysis. Preliminary data from our lab supports the feasibility of performing microdialysis in fNR1 mice. The overall goal of the proposed research is to examine the behavioral and neurochemical effects of dysfunction of glutamate N-methyl-D-aspartate (NMDA) receptors in the prefrontal cortex (PFC) in an effort to further understand the neurobiological basis of cognitive deficits associated with schizophrenia. Consistent with the objective of the AREA grant mechanism, all preliminary and future experiments described in this proposal have involved and will continue to involve undergraduate students in our newly established behavioral neuroscience major at Western Washington University. PUBLIC HEALTH RELEVANCE: Schizophrenia is a debilitating disease affecting ~1% of the population. Cognitive deficits associated with the disease are the most disruptive and unfortunately, the least responsive to currently available treatments. The proposed research endeavors to further our understanding of the neurobiological basis of these deficits in the hopes of ultimately, contributing to ongoing efforts to develop novel treatments for the cognitive impairment.

描述(申请人提供)：皮质谷氨酸传入和传出投射功能改变被认为与精神分裂症的病理生理学有关。特别是，人们的注意力集中在前额叶皮质(PFC)谷氨酸N-甲基-D-天冬氨酸(NMDA)受体的可能变化上。单个NMDA受体由一个共同的NR1亚基(功能NMDA受体所必需的)和一组NR2A-D亚基组成。最近的尸检研究发现，精神分裂症受试者的PFC中NR1转录减少的证据。我们研究的一个目标是检查PFC中NR1功能的区域性限制性丧失是否导致与疾病相关的认知和神经化学缺陷。目前的研究将在一种小鼠模型中进行，在该模型中，loxP位点位于NR1亚单位功能必需的外显子的两侧(fNR1小鼠)。基因删除将通过腺相关病毒Cre重组酶的局部给药进行。我们以前的研究表明，fNR1小鼠内侧PFC和CA3海马区NR1亚单位的功能受损分别对持续注意力和工作记忆造成了不同程度的干扰。本研究的目的1是进一步探讨成年fNR1小鼠PFC和CA3海马区NR1亚单位的局部破坏对认知功能的影响。认知功能将通过延迟的空间取胜转移、非延迟的随机觅食和视觉持续注意任务来测试。目的2将评估PFC中的NR1功能障碍是否导致中脑前叶多巴胺(DA)神经元的神经化学活动继发性中断。长期以来，中脑前额叶DA神经元的功能障碍一直被认为是精神分裂症认知障碍的原因之一。此外，大量的实验证据支持PFC中存在谷氨酸-DA相互作用，进而支持我们的假设，即慢性NR1功能障碍将损害中皮质DA神经元的功能能力。我们将使用体内微透析法研究局部PFC NR1功能障碍对局部细胞外DA调节的影响。我们实验室的初步数据支持在fNR1小鼠身上进行微透析的可行性。这项拟议研究的总体目标是研究前额叶皮质(PFC)谷氨酸N-甲基-D-天冬氨酸(NMDA)受体功能障碍对行为和神经化学的影响，以进一步了解与精神分裂症相关的认知障碍的神经生物学基础。与区域资助机制的目标一致，本提案中描述的所有初步和未来实验已经并将继续涉及我们在西华盛顿大学新设立的行为神经科学专业的本科生。 公共卫生相关性：精神分裂症是一种使人衰弱的疾病，影响约1%的人口。与这种疾病相关的认知缺陷是最具破坏性的，不幸的是，对目前可用的治疗最不敏感。拟议的研究努力加深我们对这些缺陷的神经生物学基础的理解，希望最终为开发认知障碍的新治疗方法做出贡献。