Neurobiology of Anxiety in 5-HT1A Receptor Knockout Mice

5-HT1A 受体敲除小鼠焦虑的神经生物学

基本信息

批准号：
6437934
负责人：
LYNN G KIRBY
金额：
$ 13.69万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-01-01 至 2006-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Dysfunction of the serotonin (5-HT) and gamma-aminobutyric acid (GABA) systems have been implicated in anxiety since most clinically useful anxiolytic compounds act by stimulating either 5-HT-1a or benzodiazepine receptors that modulate GABA neurotransmission. The specific brain regions involved and the particular interactions between 5-HT and GABA neurotransmitter systems during anxiety and its therapeutic treatment are not well understood. The long-term goal of this proposal is to understand the cellular and molecular substrates of anxiety as well as the specific neural circuits that may be affected in this disorder in order to identify novel targets for anxiolytic treatment. The objective of this application is to examine the particular fear and anxiety states resulting from alterations in the 5-HT and GABA systems in different brain regions using behavioral, electrophysiological and molecular techniques in an animal model of anxiety: the 5-HT-1a knockout (1AKO) mouse. In AIM 1 I will compare the behavior of 1aKOs and wild-type controls (WTs) to dorsal raphe nucleus (DRN) system-dependent vs. median raphe nucleus (MRN) system-dependent models of fear and anxiety. These studies will indicate the particular fear/anxiety states demonstrated by 1aKO mice as well as the particular circuits disrupted by the genetic deletion. I will then use electrophysiological and molecular techniques in AIMS 2 and 3 to test the specific alterations of 5-HT and GABA neurotransmission in different neural circuits in 1aKOs. In AIM 2 I will measure membrane characteristics, 5-HT-1a and GABAA receptor-mediated responses in DRN and MRN of 1aKOs and WTs using brain slice electrophysiological recording techniques. In AIM 3 I will measure 5-HT-1a and GABAA receptor-mediated responses in amygdala or hippocampal slices from 1aKOs and WTs. I will compare the measured electrophysiological response of the cell with its GABAA receptor subunit expression. My hypothesis is that deletion of the 5-HT-1a receptor disrupts 5-HT neurotransmission in specific cell bodies and their projections, altering GABA neurotransmission and ultimately producing the anxious phenotype. The experiments described in this proposal will elucidate neural circuits and altered neurotransmission that may underlie the particular anxiety states expressed by this animal model of anxiety. These experiments will lead to a better understanding of the interactions between the 5-HT and GABA systems during the expression of chronic anxiety and may identify potential targets for novel pharmacological treatments of anxiety disorders.

描述（由申请人提供）：5-羟色胺（5-HT）和伽马氨基丁酸（GABA）系统与焦虑有关大多数临床上有用的抗焦虑化合物通过刺激5-HT-1A 或调节GABA神经传递的苯二氮卓受体。具体涉及的大脑区域以及5-HT和GABA之间的特定相互作用焦虑及其治疗治疗过程中的神经递质系统不是理解。该提议的长期目标是了解焦虑的细胞和分子底物以及特定的神经可能在这种疾病中受到影响以识别新颖的电路抗焦虑治疗的靶标。该应用的目的是检查因改变的特殊恐惧和焦虑状态使用行为的不同大脑区域中的5-HT和GABA系统，动物焦虑模型中的电生理和分子技术： 5-HT-1A敲除（1ako）鼠标。在AIM 1中，我将比较 1akos和野生型对照（WTS）至背raphe核（DRN）系统依赖性与中值raphe核（MRN）系统依赖的恐惧模型和焦虑。这些研究将表明特殊的恐惧/焦虑状态由1ako小鼠以及被扰动的特定电路证明遗传缺失。然后，我将使用电生理和分子技术在目标2和3中测试5-HT和GABA的特定变化 1akos的不同神经回路中的神经传递。在目标2我会测量膜特性，5-HT-1A和GABAA受体介导的反应在使用脑切片电生理的1akos和WT的DRN和MRN中记录技术。在AIM 3中，我将测量5-HT-1A和GABAA 来自1akos的杏仁核或海马切片中的受体介导的反应， WTS。我将比较细胞的测量电生理反应它的GABAA受体亚基表达。我的假设是删除 5-HT-1A受体在特定细胞体中破坏5-HT神经传递他们的预测，改变了GABA神经传递，并最终产生焦虑表型。本提案中描述的实验将阐明神经回路和改变的神经传递可能是特定的基础这种焦虑模型表达的焦虑状态。这些实验将会更好地理解5-HT和5-HT之间的相互作用慢性焦虑表达期间的GABA系统，可能会识别新型焦虑症药理治疗的潜在靶标。