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

• 批准号: 7470989
• 负责人: XIANJIN ZHOU
• 金额: $ 20.37万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470989
• 关键词: Ablation; Address; Adenoviruses; Adverse effects; Agonist; Antibodies; Antipsychotic Agents; Area; Behavior; Behavioral; Behavioral Paradigm; Biochemistry; Brain region; Cholinergic Agents; Cognition; Cognitive; Corpus striatum structure; Development; Disruption; 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; Numbers; Output; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Physiological; Play; Prefrontal Cortex; Public Health; Quality of life; RNA Interference; Rate; 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; receptor; receptor function; response; size; small hairpin RNA; success; tool

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起着核心作用。多巴胺的生理功能是由五种已知受体介导的。由于所有已知多巴胺受体配体的特异性有限，个体多巴胺受体亚型的功能仍有待阐明。通过敲除多巴胺D1基因的基因消融为我们理解D1受体功能提供了有价值的见解。然而，由于潜在的发育并发症，这种方法受到限制。没有条件D1基因敲除小鼠的报道来解决不同脑区在行为调节中的作用。因此，本研究的中心重点是开发AAV（腺病毒相关病毒）介导的D1R shRNAs（小发夹RNA）来沉默小鼠纹状体中D1R的表达，以研究D1R在行为水平上的作用。我们假设，小鼠纹状体中D1R的沉默将减少多巴胺激动剂引起的脉冲前抑制（PPI）缺陷。D1 shrna的成功开发将有助于在未来的研究中研究D1R神经传递在其他大脑区域（如前额皮质）中对PPI和其他行为活动的调节作用。为了启动这一假设的调查，提出了以下具体目标。特异性目标1:scAAV-D1shRNA的发展。特异性目的2：研究纹状体表达多巴胺d1r的神经元在小鼠脉冲前抑制（PPI）和运动活动调节中的作用。公共卫生相关性：目前用于精神分裂症的药物在治疗认知障碍方面相对无效，这对这些患者的生活质量造成了重大负担（例如低就业率）。由D1受体介导的多巴胺神经传递对正常认知功能至关重要，在精神分裂症患者的前额叶皮层中是异常的。了解D1神经传递的区域机制将有助于确定D1影响认知的神经通路，并指导开发副作用最小的促认知药物。