Cortical GABAergic mechanisms underlying rapid and sustained antidepressant responses
皮质 GABA 能机制是快速和持续抗抑郁反应的基础
基本信息
- 批准号:10778687
- 负责人:
- 金额:$ 24.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-01 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:AddressAftercareAnimalsAntidepressive AgentsAreaBehavioralBrainCalciumClinicalClinical TrialsComplexDataDevelopmentDisinhibitionDrug TargetingEquilibriumFunctional disorderFutureGenerationsGeneticGlutamatesGoalsInterneuronsInvestigationKetamineLiteratureMajor Depressive DisorderMedialMediatingMental DepressionMolecularN-Methyl-D-Aspartate ReceptorsNeuronsPatientsPharmaceutical PreparationsPharmacologyPhasePhysiologyPrefrontal CortexProtein BiochemistryProtein BiosynthesisResistanceRodentRoleScientific Advances and AccomplishmentsSignal TransductionStressSynapsesSynaptic plasticitySystemTestingTimeTranslationsUniversitiesVertebral columnWorkabuse liabilityantidepressant effectbehavioral outcomebehavioral responsecalmodulin-dependent protein kinase IIcell typedensityexcitatory neurongamma-Aminobutyric Acidgenetic approachglutamatergic signalinghippocampal pyramidal neuronin vivoinhibitory neuronknock-downneural circuitnovelnovel therapeuticspharmacologicpreclinical studyreceptorreceptor functionresponseside effectsynaptogenesistranslational studytreatment response
项目摘要
This project describes the aims that will be addressed during the R00 phase in the Department of Pharmacology and Physiology at the University of Rochester. Currently available antidepressants have serious limitations for treating major depressive disorder (MDD), including low response rates, a significant number of treatment resistant patients, and a time-lag before there is a therapeutic response. Notably, ketamine, an NMDA receptor blocker, has demonstrated promise in clinical trials because of its rapid and sustained antidepressant effects. Although its mechanisms of action are still to be elucidated, our previous studies suggest that ketamine first inhibits cortical GABA interneurons, leading to disinhibition of excitatory pyramidal neurons, and subsequently, a glutamate burst, which results in synaptic plasticity and fast antidepressant responses. However, the effects of ketamine seem to be more complex than a simple enhancement of glutamatergic function, since MDD subjects and stressed animals show robust GABAergic deficits in cortical brain areas, which can be reversed by ketamine treatment. In addition, drugs that target the GABA system via α5-containing GABAA receptors (α5-GABAAR) have also been shown to produce fast and sustained behavioral effects in rodents. Therefore, the goal of this project is to extend our previous work and investigate how excitatory and inhibitory neuronal mechanisms interact to promote GABA-mediated plasticity that culminates in ketamine-induced behavioral responses, and explore additional GABAergic compounds relevant to MDD treatment, including α5-GABAAR modulators. The candidate will test the novel hypothesis that, in addition to glutamate-induced plasticity, increased GABA function in the medial prefrontal cortex (mPFC), specifically through α5-GABAAR, is critical for the synaptic and behavioral effects of fast-acting antidepressants. This hypothesis will be investigated by integrating multiple levels of analysis, including pharmacological, molecular, genetic, behavioral and circuit-level approaches. The lab will address the following aims: 1) To investigate cellular and synaptic mechanisms involved in the behavioral actions of α5-GABAAR NAMs and PAMs and, 2) To investigate the role of α5GABAAR in mediating cell type-specific neuronal activity in the mPFC and associated behavioral outcomes. In addition to significant scientific advances in understanding the pathophysiology of depression, this project will guide efforts to develop a new generation of agents to treat MDD.
该项目描述了罗切斯特大学药理学和生理学系在R 00阶段将解决的目标。目前可用的抗抑郁药在治疗重性抑郁障碍(MDD)方面存在严重的局限性,包括反应率低,大量患者对治疗耐药,以及在出现治疗反应之前存在时滞。值得注意的是,氯胺酮是一种NMDA受体阻滞剂,由于其快速和持续的抗抑郁作用,已在临床试验中证明了其前景。虽然其作用机制仍有待阐明,但我们以前的研究表明,氯胺酮首先抑制皮质GABA中间神经元,导致兴奋性锥体神经元的去抑制,随后是谷氨酸爆发,导致突触可塑性和快速抗抑郁反应。然而,氯胺酮的作用似乎比简单的谷氨酸能功能增强更复杂,因为MDD受试者和应激动物在皮质脑区显示出强烈的GABA能缺陷,这可以通过氯胺酮治疗逆转。此外,通过含α5-GABAA受体(α5-GABAAR)靶向GABA系统的药物也已被证明在啮齿动物中产生快速和持续的行为效应。因此,本项目的目标是扩展我们以前的工作,并研究兴奋性和抑制性神经元机制如何相互作用,以促进GABA介导的可塑性,最终导致氯胺酮诱导的行为反应,并探索与MDD治疗相关的其他GABA能化合物,包括α5-GABAAR调节剂。候选人将测试新的假设,即除了谷氨酸诱导的可塑性,内侧前额叶皮层(mPFC)中GABA功能的增加,特别是通过α5-GABAAR,对快速作用的抗抑郁药的突触和行为效应至关重要。这一假设将通过整合多个层次的分析,包括药理学,分子,遗传学,行为和电路水平的方法进行研究。该实验室将致力于以下目标:1)研究α5-GABAAR NAM和PAM行为作用中涉及的细胞和突触机制,2)研究α 5-GABAAR在介导mPFC中细胞类型特异性神经元活动和相关行为结果中的作用。除了在了解抑郁症的病理生理学方面取得重大科学进展外,该项目还将指导开发新一代治疗MDD的药物。
项目成果
期刊论文数量(0)
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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Manoela Fogaca其他文献
Manoela Fogaca的其他文献
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{{ truncateString('Manoela Fogaca', 18)}}的其他基金
Cortical GABAergic mechanisms underlying rapid and sustained antidepressant responses
皮质 GABA 能机制是快速和持续抗抑郁反应的基础
- 批准号:
10370708 - 财政年份:2022
- 资助金额:
$ 24.9万 - 项目类别:
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