Serotonergic Regulation of Behavioral Disinhibition

行为去抑制的血清素调节

基本信息

批准号：
7255727
负责人：
STEPHEN J BONASERA
金额：
$ 13.44万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7255727
关键词：
Acids Address Agitation Animals Anxiety Basic Science Behavior Behavioral Behavioral Assay Behavioral inhibition Biological Assay Brain Cells Chromosome Pairing Clinical Sciences Complex Complication Condition Data Dementia Development Diazepam Disinhibition Dopamine Dopamine Receptor Experimental Designs Faculty Family Focal Seizure Functional disorder Genetic Geriatrics Glutamate-Ammonia Ligase Glutamates Hyperactive behavior In Situ Individual Interneurons Intervention Knockout Mice Label Localized Mediating Medicine Messenger RNA Methods Microdialysis Modeling Motor Activity Mus Mutant Strains Mice Nerve Degeneration Neurology Neurons Neurosciences Neurotransmitter Receptor Nucleus Accumbens Numbers Parvalbumins Performance Phenotype Play Population Prefrontal Cortex Refractory Regulation Research Research Personnel Resistance Rodent Role Seizures Serotonin Serotonin Receptor 5-HT2C Shapes Signal Transduction Site Social Interaction Socialization Source Staging Substantia nigra structure Symptoms Synapses Syndrome System Techniques Testing Thinking Tyrosine 3-Monooxygenase Ventral Tegmental Area aged base calbindin calretinin dopaminergic neuron extracellular gamma-Aminobutyric Acid immunocytochemistry in vivo inattention mesolimbic system neurochemistry neuronal excitability neurotransmission novel pars compacta postsynaptic receptor receptor expression receptor sensitivity relating to nervous system response serotonergic regulation

项目摘要

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.

描述（由申请人提供）：被抑制的行为（例如，烦恼，煽动和社会化差）是一个重要的问题，通常伴随中后期痴呆症。这些行为可能部分是由脑血清素系统功能障碍引起的。该研究计划解决了5-羟色胺2C受体（5-HT2CR）在控制行为抑制中的作用。该研究计划还提供了一个框架，可以指导申请人从老年医学高级研究员过渡到独立研究人员，该研究人员将为行为神经科学领域做出高质量的贡献。本文提出的研究将测试主要假设，即5-HT2C受体通过增强多巴胺能神经传递和减少中溶液系统中的GABA - 凝神经传递的方法来调节行为抑制。该项目的具体目的将通过在缺乏5-HT2C受体的野生型和“基因敲除”小鼠中证明1）5-HT2CR对血清素能抑制的影响通过调节间索莫林比克多巴胺的活性以及2）5-HT2CR来对Serotongion的影响促进菌丝的影响，从而对行为抑制产生抑制作用。神经传递。具有特定神经递质受体靶向缺失的小鼠是确定对行为抑制作用的单个受体贡献的理想模型；此外，这些数据可以应用于对老年受试者的行为障碍的研究。在整个动物的行为研究中，实验设计和检验这些假设的方法（包括探索，感觉运动检测，社交相互作用，运动协调，运动活性和与焦虑相关的行为的测试）。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化学）将用于评估在野生型和5-HT2CR突变小鼠中观察到的潜在机制。申请人将利用UCSF独特的许多优势，包括在神经科学和遗传学的基本科学中备受熟悉的教师，以及医学，神经病学和老年医学的临床科学。这项研究的数据将回答有关5-羟色胺影响行为抑制的机制的关键问题，并将提供基础，以确定可能成功治疗这种难治性问题的特定药理干预措施。