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（由申请人提供）：皮质谷氨酸传入和传出投射功能的改变被认为有助于精神分裂症的病理生理学。特别是，人们的注意力集中在前额皮质 (PFC) 中谷氨酸 N-甲基-D-天冬氨酸 (NMDA) 受体可能发生的变化。各个 NMDA 受体由共同的 NR1 亚基（功能性 NMDA 受体所必需）和 NR2A-D 亚基的组合组成。最近的尸检研究发现，精神分裂症患者前额皮质中 NR1 转录物减少。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会导致与疾病相关的认知和神经化学缺陷。本研究将在小鼠模型中进行，其中 loxP 位点位于 NR1 亚基功能必需的外显子（fNR1 小鼠）的侧翼。基因删除将通过腺相关病毒 Cre 重组酶的局部施用来进行。我们之前的研究表明，fNR1 小鼠内侧 PFC 和 CA3 海马 NR1 亚基功能受损，分别会不同程度地破坏持续注意力和工作记忆。本提案的目标 1 是进一步探讨 PFC 和 CA3 海马中 NR1 亚基的局部破坏对成年 fNR1 小鼠认知功能的影响。将使用延迟空间赢移、非延迟随机觅食和视觉持续注意力任务来检查认知功能。目标 2 将评估 PFC 中的 NR1 功能障碍是否会导致中前额叶多巴胺 (DA) 神经元的神经化学活性继发性破坏。长期以来，中前额叶 DA 神经元的功能障碍一直被认为是导致精神分裂症认知缺陷的原因。此外，大量实验证据支持 PFC 中谷氨酸-DA 相互作用的存在，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。将使用体内微透析检查局部 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 小鼠中进行微透析的可行性。拟议研究的总体目标是检查前额皮质（PFC）中谷氨酸N-甲基-D-天冬氨酸（NMDA）受体功能障碍的行为和神经化学影响，以进一步了解与精神分裂症相关的认知缺陷的神经生物学基础。与 AREA 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都已经并将继续让本科生参与我们在西华盛顿大学新设立的行为神经科学专业。 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。与该疾病相关的认知缺陷最具破坏性，不幸的是，对目前可用的治疗方法反应最差。拟议的研究致力于进一步了解这些缺陷的神经生物学基础，希望最终有助于开发认知障碍的新疗法。