Neurobiology of Anxiety in 5-HT1A Receptor Knockout Mice

描述(申请人提供)：5-羟色胺(5-羟色胺)功能障碍和 伽马-氨基丁酸(GABA)系统与焦虑有关。 大多数临床有用的抗焦虑化合物通过刺激5-羟色胺-1a起作用 或者是调节GABA神经传递的苯二氮卓类受体。具体的 5-羟色胺和γ-氨基丁酸的特殊相互作用及相关脑区 焦虑时的神经递质系统及其治疗不是 很好理解。这项建议的长期目标是理解 焦虑的细胞和分子底物以及特定的神经 在这种疾病中可能受到影响的电路，以便识别新的 治疗焦虑症的靶点。此应用程序的目标是 检查由变化引起的特定恐惧和焦虑状态 不同脑区的5-羟色胺和GABA系统使用行为， 焦虑动物模型中的电生理和分子技术： 5-HT-1a基因敲除(1AKO)小鼠。在目标1中，我将比较 1aKO与中缝背核(DRN)野生型对照(WTS) 系统依赖与中缝中核(MRN)系统依赖恐惧模型的比较 和焦虑。这些研究将指出特定的恐惧/焦虑状态 由1aKO小鼠演示，以及由 基因缺失。然后我将使用电生理学和分子技术 在目标2和目标3中测试5-羟色胺和GABA的特异性变化 1aKO患者不同神经回路的神经传递。在AIM 2中，我将 测定膜特性、5-羟色胺-1a和GABAA受体介导的反应 脑片电生理在1AKO和WTS的DRN和MRN中的应用 录音技术。在AIM 3中，我将测量5-HT-1a和GABAA 1aKO和1AKO大鼠杏仁核或海马片受体介导的反应 WTS。我会将测量到的细胞的电生理反应与 其GABAA受体亚单位的表达。我的假设是删除 5-羟色胺-1a受体干扰特定细胞体的5-羟色胺神经传递 它们的投射，改变GABA的神经传递，最终产生 焦虑的表型。这项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殊的 焦虑的动物模型所表达的焦虑状态。这些实验 将有助于更好地理解5-羟色胺和 GABA系统在慢性焦虑中的表达及可能识别 焦虑症的新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.