Neurobiology of Anxiety in 5-HT1A Receptor Knockout Mice

描述（由申请人提供）：5-羟色胺（5-HT）功能障碍， γ-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-1 a 或调节GABA神经传递的苯二氮受体。具体 涉及的脑区以及5-HT和GABA之间的特殊相互作用 神经递质系统在焦虑和治疗过程中， 很好理解。本提案的长期目标是了解 焦虑的细胞和分子基质以及特定的神经 电路可能会受到影响，在这种疾病，以确定新的 抗焦虑治疗的目标。本申请的目的是 检查由改变引起的特定恐惧和焦虑状态， 不同脑区的5-HT和GABA系统， 电生理学和分子技术在焦虑的动物模型中的应用： 5-HT-1a基因敲除（1AKO）小鼠。在AIM 1中，我将比较 1aKO和野生型对照（WT）至中缝背核（DRN） 系统依赖性与中缝核（MRN）系统依赖性恐惧模型 和焦虑这些研究将表明特定的恐惧/焦虑状态 1aKO小鼠以及特定的电路被破坏， 基因缺失然后我会用电生理学和分子技术 在AIMS 2和3中检测5-HT和GABA的特异性改变 1aKO中不同神经回路的神经传递。在AIM 2中，我将 测量膜特性、5-HT-1a和GABAA受体介导的反应 在1aKO和WT的DRN和MRN中使用脑切片电生理 记录技术。在AIM 3中，我将测量5-HT-1a和GABAA 1aKO的杏仁核或海马切片中受体介导的反应， WTs我将比较测量到的细胞电生理反应， 其GABAA受体亚单位表达。我的假设是， 5-HT-1a受体破坏特定细胞体中的5-HT神经传递， 它们的投射，改变GABA神经传递，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 这种焦虑的动物模型所表达的焦虑状态。这些实验 将导致更好地理解5-HT和 GABA系统在慢性焦虑症的表达过程中可能起作用 焦虑症的新型药物治疗的潜在靶点。

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.