Striatal Dopamine D1 Functions on Modulating Prepulse Inhibition

描述（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的受体介导。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澄清。通过敲除多巴胺D1基因的遗传消融为我们理解D1受体功能提供了有价值的见解。然而，这种方法是有限的，由于潜在的发展并发症。没有条件性D1基因敲除小鼠的报告，以解决不同的大脑区域在行为的调制中的作用。因此，该建议的中心焦点是开发AAV（腺病毒相关病毒）介导的D1 R shRNA（小发夹RNA）来沉默小鼠纹状体中的D1 R表达，以在行为水平上检查D1 R效应。我们假设，D1 R沉默小鼠纹状体将减少由多巴胺激动剂引起的前脉冲抑制（PPI）的赤字。D1 shRNA的成功开发将有助于在未来的研究中研究D1 R神经传递在其他大脑区域（如前额叶皮层）中对PPI和其他行为活动的调节作用。为了启动对这一假设的调查，提出了以下具体目标。具体目的1：scAAV-D1 shRNA的构建。具体目标2：研究纹状体多巴胺D1 R表达神经元在小鼠前脉冲抑制（PPI）和自发活动调节中的作用。公共卫生相关性：目前的精神分裂症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于正常的认知功能是至关重要的，并且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对认知影响的神经通路，并指导开发副作用最小的促认知药物。

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.