Striatal Dopamine D1 Functions on Modulating Prepulse Inhibition

描述(由申请人提供)：多巴胺神经传递在人类精神障碍和药物成瘾中发挥核心作用。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，个别多巴胺受体亚型的功能仍有待阐明。敲除多巴胺D_1基因的基因消融为我们理解D_1受体的功能提供了有价值的见解。然而，由于潜在的发育并发症，这种方法是有限的。没有报道有条件的D1基因敲除小鼠处理不同大脑区域在行为调节中的作用。因此，本研究的重点是开发AAV(腺病毒相关病毒)介导的D1R shRNAs(小发夹RNA)，以沉默D1R在小鼠纹状体中的表达，从行为水平检测D1R的作用。我们假设小鼠纹状体D1R沉默将减少多巴胺激动剂引起的脉冲前抑制(PPI)缺陷。D1shRNAs的成功开发将有助于在未来的研究中研究D1R神经传递在其他脑区如前额叶皮质对PPI和其他行为活动的调节作用。为了启动对这一假说的研究，提出了以下具体目标。特异性目的1：scAAV-D1shRNA的研制特定目的2：探讨纹状体多巴胺D1R表达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：目前治疗精神分裂症的药物在治疗认知障碍方面相对无效，认知障碍给这些患者的生活质量带来了巨大负担(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质中是异常的。了解D1神经传递的区域机制将有助于确定D1对认知的影响的神经通路，并指导副作用最小的前认知药物的开发。

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.