Serotonergic Regulation of Behavioral Disinhibition

描述(由申请者提供)：失控行为(如注意力不集中、情绪激动和社交能力差)是一个严重的问题，经常伴随着中晚期痴呆症。这些行为可能部分是由大脑5-羟色胺系统功能障碍引起的。本研究计划探讨5-羟色胺2C受体(5-HT2CRs)在控制行为抑制中的作用。该研究计划还提供了一个框架，指导申请人从老年医学高级研究员转变为将为行为神经科学领域做出高质量贡献的独立研究员。本文提出的研究将验证5-HT2C受体通过增强多巴胺能神经传递和抑制中脑边缘系统的GABA能神经传递来调节行为抑制的基本假设。该项目的具体目的将通过在野生型和缺乏5-HT2C受体的“敲除”小鼠中验证这一假说：1)5-HT2CRs通过调节中脑边缘多巴胺活性而对行为抑制产生5-羟色胺能影响，以及2)5-HT2CRs通过调节GABA能神经传递对行为抑制产生5-羟色胺能影响。靶向缺失特定神经递质受体的小鼠是确定个体受体对行为抑制的贡献的理想模型；此外，该数据可用于研究老年人的行为障碍。检验这些假说的实验设计和方法建立在整个动物行为研究的基础上(包括探索、感觉运动门控、社会互动、运动协调、运动活动和焦虑相关行为的测试)。将利用神经化学(微透析)和神经解剖学研究(包括原位mRNA杂交和受体免疫细胞化学)来评估在野生型和5-HT2CR突变小鼠中观察到的潜在行为机制。申请者将利用加州大学旧金山分校的许多独特优势，包括在神经科学和遗传学的基础科学以及医学、神经病学和老年病学的临床科学方面高度知名的教员。这项研究的数据将回答有关5-羟色胺影响行为抑制控制的机制的关键问题，并将为确定可能成功治疗这一顽固问题的特定药物干预提供基础。

DESCRIPTION (provided by applicant): Disinhibited behaviors (such as inattention, agitation, and poor socialization) are a significant problem that often accompanies mid- to late-stage dementia. These behaviors are likely caused in part by dysfunction of brain serotonin systems. This research plan addresses the role of serotonin 2C receptors (5-HT2CRs) in the control of behavioral inhibition. The research plan also provides a framework to guide the applicant's transition from senior fellow in geriatric medicine to an independent investigator who will make high quality contributions to the field of behavioral neuroscience. The studies proposed herein will test the primary hypothesis that 5-HT2C receptors regulate behavioral inhibition both by enhancing dopaminergic neurotransmission and diminishing GABA-ergic neurotransmission in the mesolimbic system. The specific aims of this project will test this hypothesis by demonstrating in wildtype and "knockout" mice lacking the 5-HT2C receptor that 1) 5-HT2CRs contribute to serotonergic influence on behavioral inhibition through regulation of mesolimbic dopamine activity, and 2) 5-HT2CRs contribute to serotonergic influence on behavioral inhibition through the regulation of GABA-ergic neurotransmission. Mice with targeted deletion of specific neurotransmitter receptors are ideal models to determine individual receptor contributions toward behavioral inhibition; furthermore, this data can be applied to the study of behavioral disturbances in aged subjects. Experimental design and methods to test these hypotheses are grounded in whole animal studies of behavior (including tests of exploration, sensorimotor gating, social interaction, locomotor coordination, locomotor activity, and anxiety-related behaviors). Neurochemical (microdialysis) and neuroanatomical studies (including in situ mRNA hybridization, and receptor immunocytochemistry) will be utilized to evaluate potential mechanisms underlying behaviors observed in wildtype and 5-HT2CR mutant mice. The applicant will take advantage of the many strengths unique to UCSF, including a highly reknowned faculty in both the basic sciences of Neuroscience and Genetics, and the clinical sciences of Medicine, Neurology, and Geriatrics. Data from this study will answer key questions regarding the mechanism of serotonin influences on control of behavioral inhibition, and will provide the groundwork to identify specific pharmacological interventions that may be successful in treating this refractory problem.