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:10370708
- 负责人:
- 金额:$ 10.2万
- 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 2023-01-31
- 项目状态:已结题
- 来源:
- 关键词:Academic skillsAddressAdvisory CommitteesAftercareAnimalsAntidepressive AgentsAreaBehaviorBehavioralBrainCellsClinicalClinical TrialsCodeComplexDataDevelopmentDisinhibitionDrug TargetingElectrophysiology (science)EquilibriumFunctional disorderFundingFutureGenerationsGlutamatesGoalsInterneuronsInvestigationKetamineLaboratory ResearchMajor Depressive DisorderMedialMediatingMental DepressionMentorsMentorshipMolecular BiologyMolecular GeneticsMusN-Methyl-D-Aspartate ReceptorsN-MethylaspartateNeuronsPatientsPatternPharmaceutical PreparationsPharmacologyPhasePopulationPrefrontal CortexProtein BiosynthesisProteinsPyramidal CellsResistanceRodentRoleScientific Advances and AccomplishmentsScientistScopolamineSignal TransductionStressSynapsesSynaptic plasticitySystemTechnical ExpertiseTestingTimeTrainingTranslationsWorkantidepressant effectawakebehavior testbehavioral outcomebehavioral responsecalmodulin-dependent protein kinase IIcareer developmentcell typeexperimental studygamma-Aminobutyric Acidglutamatergic signalinghippocampal pyramidal neuronin vivoknock-downnovelnovel therapeuticspreclinical studyprofessorprogramsreceptorrecruitrelating to nervous systemresponseskillssynaptogenesistranslational studytreatment response
项目摘要
PROJECT SUMMARY
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. We will test the novel hypothesis that, in addition
to glutamate-induced plasticity, increased GABA function in the medial prefrontal cortex (mPFC) 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 electrophysiological
approaches. We will address the following aims: 1) To characterize neural coding and the underlying GABAergic
mechanisms in the mPFC involved in the actions of ketamine relevant to its antidepressant efficacy, 2) To investigate electrophysiological and synaptic mechanisms involved in teh behavioral actions of α5-GABAAR NAMs and PAMs and, 3) To investigate the role of α5-GABAAR in different neuronal subpopulations in mediating
electrophysiological responses in the mPFC and associated behavioral outcomes.
In addition to significant scientific advances in understanding the pathophysiology of depression and identifying
potential novel antidepressant agents, this K99 proposal will provide training and mentorship for Dr. Fogaça that
will increase her technical and academic skills, preparing her to become an independent academic scientist with
her own research laboratory and program. Under the mentorship of Dr. Marina Picciotto, co-mentorship of Dr.
George Dragoi and the guidance of an advisory committee (Drs. Taylor and DiLeone), Dr. Fogaça will acquire
extensive training in electrophysiology in awake, behaving mice, and additional career development training,
which in combination with her array of technical skills, will equip her to transition to the independent phase as an
Assistant Professor, and to apply for R01 funding at the end of the R00 phase.
项目摘要
目前可用的抗抑郁药对治疗重度抑郁症(MDD)的严重局限性,
包括低反应率,大量的抗治疗患者以及在有时间段之前
治疗反应。值得注意的是,NMDA受体阻滞剂氯胺酮在临床上表现出了希望
由于其快速且持续的抗抑郁作用而进行的试验。尽管其行动机制仍然是
阐明的,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抑制作用,随后是谷氨酸爆发,导致突触
可塑性和快速抗抑郁反应。但是,氯胺酮的作用似乎比
谷氨酸能功能的简单增强,因为MDD受试者和压力动物表现强大
皮质大脑区域的GABA能防御,可以通过氯胺酮治疗逆转。另外,毒品
通过含α5的GABAA受体(α5-Gabaar)靶向GABA系统也已显示出来
啮齿动物的快速和持续行为影响。因此,该项目的目的是扩展我们以前的工作
并研究令人兴奋和抑制性的神经元机制如何相互作用以促进GABA介导的可塑性
最终导致氯胺酮引起的行为反应,并探索其他GABA能化合物
与MDD处理有关,包括α5-Gabaar调节剂。我们将测试新的假设,此外
对于谷氨酸诱导的可塑性,培养基前额叶皮层(MPFC)中的GABA功能提高至关重要
快速作用抗抑郁药的突触和行为效应。该假设将通过整合来研究
多个分析,包括药物,分子,遗传,行为和电生理学
方法。我们将解决以下目的:1)表征神经编码和基础GABA能
MPFC中涉及氯胺酮与其抗抑郁药相关的作用的机制,2)研究参与α5-Gabaar NAM和PAMS和PAMS的TEH行为作用的电生理和合成机制,以及3)研究α5-GABAAR在不同神经元中的作用
MPFC和相关行为结果中的电生理反应。
除了理解抑郁症的病理生理学和识别的显着科学进步外
潜在的新型抗抑郁药,该K99提案将为Fogaça博士提供培训和心态
将提高她的技术和学术技能,使她成为一名独立学术科学家
她自己的研究实验室和计划。在Marina Picciotto博士的心态下,博士的同学
乔治·德拉多(George Dragoi)和咨询委员会的指导(泰勒(Taylor and Dileone)博士),Fogaça博士将获得
在醒着,行为小鼠和其他职业发展培训中进行电生理学的广泛培训,
结合她一系列技术技能,这将使她能够过渡到独立阶段
助理教授,并在R00阶段结束时申请R01资金。
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:
10778687 - 财政年份:2022
- 资助金额:
$ 10.2万 - 项目类别:
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