NEUROSTEROIDS & PROXIMAL INHIBITION IN THE HIPPOCAMPUS

神经类固醇

基本信息

批准号：
9589698
负责人：
CHARLES F ZORUMSKI
金额：
$ 23.35万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9589698
关键词：
Address Anti-Anxiety Agents Anticonvulsants Antidepressive Agents Behavior Biological Brain Cell physiology Cells Chemosensitization Chloride Channels Cholesterol Clinical Dendrites Discipline Distal Drug Exposure Drug Kinetics Effectiveness Functional Imaging GABA-A Receptor Golgi Apparatus Hippocampus (Brain)Kinetics Laboratories Light Mediating Mediator of activation protein Membrane Nature Neurons Pharmacodynamics Photoaffinity Labels Physiological Play Positioning Attribute Rattus Role Series Slice Source Steroids Synapses Synaptic Transmission Testing Therapeutic Therapeutic Agents Time analog antidepressant effect aqueous base cell type cellular imaging drug development enantiomer excitatory neuron gamma-Aminobutyric Acid hippocampal pyramidal neuron imaging modality innovation neuronal cell body neuropsychiatry neurosteroids novel positive allosteric modulator receptor receptor function sedative steroid analog synaptic function targeted treatment tool transmission process treatment response

项目摘要

PROJECT SUMMARY Certain neurosteroids are effective modulators of g-aminobutyric acid-A receptors (GABAARs), augmenting the actions of GABA at low concentrations and directly activating GABAAR chloride channels at higher concentrations. Present evidence indicates that GABAAR potentiation is a key mechanism in the antianxiety, antidepressant, sedative and anticonvulsant actions of neurosteroids. We have developed novel tools that have helped us to probe the effects of neuroactive steroids, including a series of steroid enantiomers and fluorescent steroids. These agents demonstrate that membrane and cellular accumulation participate in the kinetics and potency of neurosteroids on GABAARs and modulate a specific form of inhibition involving proximal inhibitory inputs near neuronal cell bodies. We have also developed tools for probing the roles of endogenous neurosteroids. Despite these advances, key questions remain with regard to the biological basis and the physiological roles of various steroid pools. In the present proposal, we will address the following aim: To determine the roles of membrane and intracellular pools of neurosteroids on GABAAR modulation, focusing on a form of inhibition resulting from stimulation of GABAergic inputs to the somatic regions of hippocampal pyramidal neurons. These studies will use a combination of physiological and cellular imaging methods to examine steroid effects in cultured rat hippocampal neurons and hippocampal slices, and will involve mechanistic studies based upon our initial observations with novel enantiomeric fluorescent steroid analogues and photoaffinity labels that can be used for cellular physiology and imaging. These studies will provide new information about neurosteroid effects in the CNS and a better understanding of steroid-mediated GABAAR modulation and neuropsychiatric effects.

项目概要某些神经类固醇是 g-氨基丁酸-A 受体 (GABAAR) 的有效调节剂，在低浓度时增强 GABA 的作用，在高浓度时直接激活 GABAAR 氯离子通道。目前的证据表明，GABAAR 增强作用是神经类固醇抗焦虑、抗抑郁、镇静和抗惊厥作用的关键机制。我们开发了新的工具来帮助我们探索神经活性类固醇的作用，包括一系列类固醇对映体和荧光类固醇。这些药物证明膜和细胞积聚参与 GABAAR 上神经类固醇的动力学和效力，并调节涉及神经元细胞体附近的近端抑制输入的特定形式的抑制。我们还开发了用于探索内源性神经类固醇作用的工具。尽管取得了这些进展，但各种类固醇库的生物学基础和生理作用仍然存在关键问题。在本提案中，我们将实现以下目标：确定膜和细胞内神经类固醇库对 GABAAR 调节的作用，重点关注刺激海马锥体神经元体细胞区域的 GABA 能输入所产生的抑制形式。这些研究将结合生理学和细胞成像方法来检查培养的大鼠海马神经元和海马切片中的类固醇效应，并将涉及基于我们对新型对映体荧光类固醇类似物和可用于细胞的光亲和标记的初步观察的机制研究。生理学和影像学。这些研究将提供有关中枢神经系统中神经类固醇作用的新信息，并更好地了解类固醇介导的 GABAAR 调节和神经精神作用。