NEUROSTEROIDS & PROXIMAL INHIBITION IN THE HIPPOCAMPUS
神经类固醇
基本信息
- 批准号:9589698
- 负责人:
- 金额:$ 23.35万
- 依托单位:
- 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:
- 关键词:AddressAnti-Anxiety AgentsAnticonvulsantsAntidepressive AgentsBehaviorBiologicalBrainCell physiologyCellsChemosensitizationChloride ChannelsCholesterolClinicalDendritesDisciplineDistalDrug ExposureDrug KineticsEffectivenessFunctional ImagingGABA-A ReceptorGolgi ApparatusHippocampus (Brain)KineticsLaboratoriesLightMediatingMediator of activation proteinMembraneNatureNeuronsPharmacodynamicsPhotoaffinity LabelsPhysiologicalPlayPositioning AttributeRattusRoleSeriesSliceSourceSteroidsSynapsesSynaptic TransmissionTestingTherapeuticTherapeutic AgentsTimeanalogantidepressant effectaqueousbasecell typecellular imagingdrug developmentenantiomerexcitatory neurongamma-Aminobutyric Acidhippocampal pyramidal neuronimaging modalityinnovationneuronal cell bodyneuropsychiatryneurosteroidsnovelpositive allosteric modulatorreceptorreceptor functionsedativesteroid analogsynaptic functiontargeted treatmenttooltransmission processtreatment 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.
项目摘要
某些神经类固醇是G-氨基丁酸A受体(GABAARS)的有效调节剂,在低浓度下增强了GABA的作用,并直接以较高浓度激活Gabaar氯化物通道。目前的证据表明,Gabaar增强是抗焦虑,抗抑郁药,镇静和抗惊厥作用的关键机制。我们开发了新的工具,这些工具帮助我们探究了神经活性类固醇的作用,包括一系列类固醇映体和荧光类固醇。这些药物表明,膜和细胞积累参与神经固醇对GABAARS的动力学和效力,并调节涉及神经元细胞附近近端抑制性输入的特定抑制作用形式。我们还开发了用于探测内源性神经类固醇作用的工具。尽管取得了这些进步,但在生物学基础和各种类固醇池的生理作用方面仍然存在关键问题。在本提案中,我们将解决以下目的:确定神经类固醇在GABAAR调节中的膜和细胞内池的作用,重点是刺激GABA能输入到海马锥体神经元的体细胞区域引起的抑制作用。这些研究将结合生理和细胞成像方法的组合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,并基于我们对新型映体荧光类固醇类似物和可用于细胞生理学和成像的新型映体荧光类固醇类似物和光疗法的初步观察,涉及机械研究。这些研究将提供有关中枢神经系统中神经固醇作用的新信息,并更好地了解类固醇介导的GABAAR调节和神经精神效应。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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CHARLES F ZORUMSKI其他文献
CHARLES F ZORUMSKI的其他文献
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{{ truncateString('CHARLES F ZORUMSKI', 18)}}的其他基金
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