Neural activity and circuitry-mediated hippocampal stress responses
神经活动和电路介导的海马应激反应
基本信息
- 批准号:10903002
- 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:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAddressAnatomyAnimal ModelAntidepressive AgentsAnxietyAreaBehaviorBehavioralBrainCellsChronicChronic stressClinicalCognitionComplexDataDevelopmentDiseaseDorsalFacultyFunctional disorderGene CombinationsGene ExpressionGenesGeneticGenetic TranscriptionGoalsGrantHippocampusImpairmentKnowledgeLifeLinkMajor Depressive DisorderMapsMediatingMemoryMentorsMolecularNeurobiologyNeuronsNew MexicoNewborn InfantPatientsPatternPersonsPharmaceutical PreparationsPhasePhenotypePositioning AttributePre-Clinical ModelProductionProductivityPropertyPublicationsRabies virusRoleSecureSignal PathwaySourceStreamStressSynapsesSynaptic plasticityTechnologyTestingTherapeuticTransgenic MiceUniversitiesWorkantidepressant effectbehavioral phenotypingbiological adaptation to stresscell typedentate gyrusdepressed patientdepression modeldepressive symptomsdisabilityeffective therapyexcitatory neuronexperiencegenetic manipulationgranule cellimprovedmolecular phenotypenetwork modelsneuralneurogenesisnew therapeutic targetnewborn neuronpresynapticpreventpromote resiliencerabies viral tracingreceptorresponseside effectsocialtherapeutic targettranscriptomics
项目摘要
Project Summary:
Since completing my K99, I have secured a faculty position at the University of New Mexico, where the work described on the R00 portion of the grant will be conducted.Major depressive disorder (MDD) is a leading cause of disability and lost productivity, but we do not know its underlying causes, nor do we have adequate treatments. The development of more effective therapies will require a better understanding of the cellular and molecular mechanisms of antidepressants (AD). Newly generated (immature) neurons within the dentate gyrus (DG) have been linked to AD action in addition to their association with hippocampus-dependent cognition, pattern separation, social memory, and stress-induced anxiety. Increased numbers of newborn DG neurons are associated with improved hippocampal function, while decreased numbers are associated with impaired hippocampal function. Moreover, my recent publication showed that suppressing the excitability of newborn neurons without altering neuronal numbers leads to MDD-related phenotypes and abolishes AD effects. Conversely, enhancing the activity of immature neurons without altering neurogenesis is sufficient to alleviate the effects of unpredictable chronic mild stress (uCMS), a well-validated, widely used model of depression. Since immature neurons form synapses more readily, are more excitable, and have greater synaptic plasticity, understanding the complex effects of neurogenesis on behavior requires knowledge of the synaptic connectivity of these neurons, the level of DG activity, the information streams within the DG, and how the experience changes these properties. Thus, I propose to establish an input-defined circuit map of mature and immature DG neurons and to identify the changes in this map, together with activitydependent changes in transcription, in the context of AD treatment and uCMS. In Aim 1, I will establish a presynaptic input map of distinctly dorsal-ventral, mature, and immature DG neurons in everyday life by combining transgenic mouse technology with monosynaptic rabies virus retrograde tracing in the intact brain. Then, I will test the impact of AD treatment and chronic chemogenetic neuronal silencing on these anatomically identified circuits. In Aim 2, I will examine the effects of uCMS, which produces MDD-related behavioral phenotypes, with and without chronic AD treatment and with acute chemogenetic neuronal activation on DG circuitry. In both Aims, I also will examine synaptic, molecular, and behavioral changes and activity-dependent single-cell transcriptomics. By combining gene expression data and DG connectivity with behavioral phenotypes in the light of changes produced by uCMS, AD treatment, and chemogenetic manipulations, I will be able to construct a biologically relevant DG network model that can be used to test functional hypotheses, including dorsal-ventral DG dichotomy. Studying chronic AD treatment and acute/chronic chemogenetic manipulations also will be valuable for identifying signaling pathways underlying AD action, especially fast-acting ADs. Development of this DG network model will help to clarify the critical role of the DG and of neurogenesis in MDDrelated phenotypes and AD action.
项目总结:
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)
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{{ truncateString('Elif Tunc-Ozcan', 18)}}的其他基金
Neural activity and circuitry-mediated hippocampal stress responses
神经活动和电路介导的海马应激反应
- 批准号:
10301288 - 财政年份:2021
- 资助金额:
$ 24.9万 - 项目类别:
Neural activity and circuitry-mediated hippocampal stress responses
神经活动和电路介导的海马应激反应
- 批准号:
10455684 - 财政年份:2021
- 资助金额:
$ 24.9万 - 项目类别:
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