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Striatal Dopamine D1 Functions on Modulating Prepulse Inhibition

纹状体多巴胺 D1 调节前脉冲抑制的功能

基本信息

批准号：
7586584
负责人：
XIANJIN ZHOU
金额：
$ 17.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7586584
关键词：
Ablation Address Adenoviruses Adverse effects Agonist Antibodies Antipsychotic Agents Area Behavior Behavioral Behavioral Paradigm Biochemistry Brain region Cognition Cognitive Corpus striatum structure Development Dopamine Dopamine Agonists Dopamine D1 Receptor Dopamine Receptor Drug Addiction Employment Future Gene Expression Genes Genetic Human Individual Infection Interneurons Investigation Knock-out Knockout Mice Ligands Mediating Mental disorders Motor Activity Mus Neural Pathways Neurons Output Patients Pattern Pharmaceutical Preparations Phenotype Physiological Play Prefrontal Cortex Quality of life RNA Interference Rattus Recombinants Relative (related person)Reporting Research Role Satellite Viruses Schizophrenia Specificity Staining method Stains Substantia nigra structure Technology Yang cholinergic cognitive function design dopamine D4 receptor endophenotype functional genomics gene function human DRD4 protein insight neurotransmission prepulse inhibition public health relevance receptor receptor function response small hairpin RNA success tool

项目摘要

DESCRIPTION (provided by applicant): Dopamine neurotransmission plays a central role in both human psychiatric disorders and drug addiction. The physiological functions of dopamine are mediated by five known receptors. Due to limited specificity of all known dopamine receptor ligands, the functions of individual dopamine receptor subtypes remain to be clarified. Genetic ablation by knocking out dopamine D1 gene provides valuable insight in our understanding of the D1 receptor function. However, this approach is limited due to the potential of developmental complications. No conditional D1 knockout mice have been reported to address the roles of different brain regions in the modulation of behavior. Therefore, the central focus of this proposal is to develop AAV (adenovirus-associated virus) mediated D1R shRNAs (small hairpin RNA) to silence D1R expression in mouse striatum to examine D1R effects at the behavioral level. We hypothesize that D1R silencing in mouse striatum will reduce the deficit of prepulse inhibition (PPI) caused by dopamine agonists. The successful development of the D1 shRNAs will help examine the role of D1R neurotransmission in other brain regions such as prefrontal cortex in the modulation of PPI and other behavioral activities in future studies. To initiate the investigation of this hypothesis, the following specific aims are proposed. SPECIFIC AIM 1: The development of scAAV-D1shRNA. SPECIFIC AIM 2: To examine the contribution of the striatal dopamine D1R-expressing neurons in the modulation of mouse prepulse inhibition (PPI) and locomotor activity. PUBLIC HEALTH RELEVANCE: Current medications for schizophrenia are relatively ineffective in treating cognitive disruptions, which incur a substantial burden on the quality of life of these patients (e.g. low employment rates). Dopamine neurotransmission mediated by the D1 receptor is critical for normal cognitive functions and is aberrant in the prefrontal cortex of schizophrenia patients. Understanding of the regional mechanisms of D1 neurotransmission will help identify the neural pathways for D1 effects on cognition, as well as guide the development of pro-cognitive drugs with minimal side effects.

描述（由申请人提供）：多巴胺神经传递在人类精神疾病和药物成瘾中发挥着核心作用。多巴胺的生理功能由五种已知受体介导。由于所有已知的多巴胺受体配体的特异性有限，各个多巴胺受体亚型的功能仍有待阐明。通过敲除多巴胺 D1 基因进行基因消除，为我们了解 D1 受体功能提供了宝贵的见解。然而，由于潜在的发育并发症，这种方法受到限制。目前还没有条件性 D1 敲除小鼠能够解决不同大脑区域在行为调节中的作用的报道。因此，该提案的中心重点是开发AAV（腺病毒相关病毒）介导的D1R shRNA（小发夹RNA）来沉默小鼠纹状体中的D1R表达，以检查D1R在行为水平上的作用。我们假设小鼠纹状体中的 D1R 沉默将减少多巴胺激动剂引起的前脉冲抑制 (PPI) 缺陷。 D1 shRNA 的成功开发将有助于在未来的研究中检查 D1R 神经传递在其他大脑区域（例如前额皮质）在 PPI 和其他行为活动调节中的作用。为了开始对该假设的研究，提出了以下具体目标。具体目标 1：scAAV-D1shRNA 的开发。具体目标 2：检查表达纹状体多巴胺 D1R 的神经元在调节小鼠前脉冲抑制 (PPI) 和运动活动中的作用。公共卫生相关性：目前治疗精神分裂症的药物在治疗认知障碍方面相对无效，这给这些患者的生活质量带来了沉重负担（例如就业率低）。 D1 受体介导的多巴胺神经传递对于正常认知功能至关重要，并且在精神分裂症患者的前额皮质中存在异常。了解 D1 神经传递的区域机制将有助于确定 D1 对认知产生影响的神经通路，并指导开发副作用最小的促认知药物。