Neurobiology of anxiety in mice lacking 5HT 1A receptor

缺乏 5HT 1A 受体的小鼠焦虑的神经生物学

基本信息

批准号：
7216961
负责人：
Miklos Toth
金额：
$ 34.66万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-23 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7216961
关键词：
Adult Agreement Animal Model Anxiety Anxiety Disorders Apoptosis Behavior Behavioral Benzodiazepines Blood Pressure Brain region Cell Cycle Cell Proliferation Cells Characteristics Cyclin D1 Cyclin Gene Cyclin-Dependent Kinases Cyclins Defect Development FOS gene Face Fright Funding Gene Cluster Gene Expression Gene Expression Regulation Gene Targeting Generalized Anxiety Disorder Genes Genetic Glutamates Goals Heart Rate Hippocampus (Brain)Human Individual Knock-out Knockout Mice Life Link Medial Mediating Mental disorders Modeling Molecular Mouse Strains Mus Neurobiology Neurons Numbers Panic Panic Disorder Pathway interactions Phenotype Population Post-Traumatic Stress Disorders Prefrontal Cortex Prevalence Process Progress Reports Proteins Research Research Personnel Resistance Serotonin Serotonin Receptor 5-HT1A Signal Pathway Signal Transduction Specific qualifier value Symptoms System Testing To specify Transcriptional Regulation Traumatic Stress Disorders Variant Work base bcl-1 Genes c-myc Genes dentate gyrus granule cell member neuronal excitability neuronal survival neurotransmission postnatal programs receptor synaptic function transcription factor transmission process vigilance

项目摘要

DESCRIPTION (provided by applicant): Anxiety disorders, including panic, generalized anxiety and posttraumatic stress disorders, are common. Some symptoms of anxiety such as avoidance, increased vigilance, increased heart rate and blood pressure can be reproduced in animal models, in particular in genetically modified mice. One of these models, the 5-HT1A receptor (R) deficient mouse strain has construct validity because low 5-HT1AR level has been repeatedly found in psychiatric disorders. Although 5-HT1 AR deficient mice have been extensively characterized at the behavioral level, little is known about the molecular and cellular basis of their anxiety-like phenotype. The major goal of our funded research was to elucidate some of the neurobiological processes and mechanisms which are associated with the anxiety-like behavior of the 5- HT1 AR knockout (KO) mice. This work identified a number of gene-expression changes in the fearf'anxiety" circuit; in particular in the prefrontal cortex (PFC) and the hippocampus. The PFC-specific abnormalities involve defects in GABAergic and glutamatergic neurotransmission and associated with loss of inhibition/increased excitability. The hippocampus shows changes in cell cycle related genes (cyclin D1/2 and some cyclin dependent kinases (cdks)), which are associated with reduced proliferation and probably increased survival of postmitotic neurons during early postnatal life. The main goal of the current application is to specify the neurobiological abnormalities in the hippocampus of 5-HT1AR deficient mice including 1) the mechanism of 5-HT1AR-mediated regulation of gene expression, 2) effect of the 5-HT1AR on neuronal precursor proliferation and 3) programmed cell death during early postnatal development. Similar mechanisms may also be involved in the pathomechanism of some anxiety disorders.

描述（由申请人提供）：焦虑症很常见，包括恐慌、广泛性焦虑和创伤后应激障碍。一些焦虑症状，如回避、警惕性提高、心率和血压升高等，可以在动物模型中重现，特别是在转基因小鼠中。其中一种模型，5-HT1A 受体 (R) 缺陷型小鼠品系具有构建有效性，因为在精神疾病中反复发现低 5-HT1AR 水平。尽管 5-HT1 AR 缺陷小鼠在行为水平上已得到广泛表征，但对其焦虑样表型的分子和细胞基础知之甚少。我们资助的研究的主要目标是阐明与 5-HT1 AR 敲除 (KO) 小鼠的焦虑样行为相关的一些神经生物学过程和机制。这项工作确定了“恐惧焦虑”回路中的许多基因表达变化；特别是在前额叶皮层 (PFC) 和海马体中。PFC 特异性异常涉及 GABA 能和谷氨酸能神经传递缺陷，并与抑制/丧失相关。海马体显示细胞周期相关基因（细胞周期蛋白 D1/2 和一些细胞周期蛋白依赖性激酶 (cdks)）的变化，这些变化与细胞周期相关。在出生后早期，有丝分裂后神经元的增殖减少，并可能增加其存活率。当前应用的主要目标是明确 5-HT1AR 缺陷小鼠海马的神经生物学异常，包括 1) 5-HT1AR 介导的基因调节机制。表达，2) 5-HT1AR 对神经元前体增殖的影响和 3) 出生后早期发育过程中的程序性细胞死亡。类似的机制也可能涉及一些焦虑症的病理机制。