Progression of Entorhinal-hippocampal Spatial and Emotional Processing Deficits in a Mouse Model of Temporal Lobe Epilepsy
颞叶癫痫小鼠模型内嗅海马空间和情绪处理缺陷的进展
基本信息
- 批准号:10829101
- 负责人:
- 金额:$ 4.71万
- 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:2023-09-15 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffinity ChromatographyAnhedoniaAnimalsAnxietyAutomobile DrivingAwardBehaviorBehavioralBiological AssayBrainCalciumChronicCodeCognitive deficitsDataData AnalysesDevelopmentDiseaseDorsalEmotionalEmotionsEpilepsyFunctional disorderFutureGene ExpressionGeneticGoalsHippocampusImageImpairmentInterventionLearningLinear ModelsLinkLocationMedialMediatingMemoryMemory impairmentModelingMolecularMolecular ProfilingMusNeuronsPatientsPharmacological TreatmentPhasePilocarpinePopulationPostdoctoral FellowQuality of lifeRecurrenceResearchResearch PersonnelResistanceRibosomesRunningScientistSeizuresSignal TransductionSiteStressTechnical ExpertiseTechniquesTemporal LobeTemporal Lobe EpilepsyTestingTimeTrainingTranslatingViralWorkanxiety-like behaviorcareercell typeclinical phenotypecombinatorialcomorbiditydentate gyrusemotion regulationemotional behaviorentorhinal cortexexperimental studyhippocampal pyramidal neuronin vivo calcium imagingin vivo imaginginsightlarge scale datamolecular markermouse modelneuralneural circuitnovelprogramspsychiatric symptomskillsspatial memorystellate celltargeted treatmenttimelinetooltranscriptome sequencingtranscriptomics
项目摘要
PROJECT SUMMARY
Temporal lobe epilepsy (TLE) is a debilitating disorder characterized by spontaneous and recurring seizures as
well as pervasive memory and psychiatric impairments. These TLE-induced comorbidities do not respond to
pharmacological treatment, and little is known about how specific brain circuits are altered by disease to drive
these clinical phenotypes. Recent evidence suggests that these comorbidities are driven by deficits along the
dorsoventral axis of the entorhinal-hippocampal circuit and that they are dissociable from seizures themselves.
As such, it is imperative to study how epilepsy may detrimentally alter temporal lobe circuitry that is a key node
in memory and emotion processing. In previous work, our lab and others have established CA1 of dorsal
hippocampus (dCA1) as a site of poor spatial processing in epileptic mice. However, it remains unclear if
upstream inputs to dCA1 are impaired which may be driving downstream changes in hippocampus. In the F99
phase, I will test the hypothesis that medial entorhinal cortex (MEC) has disrupted spatial coding in epileptic
mice and will specifically test how distinct hippocampal inputs from layer 3 (MECIII) pyramidal neurons and
layer 2 (MECII) stellate cells are altered. I will perform in vivo calcium imaging in these isolated subpopulations
as epileptic and control mice perform spatial foraging and memory tasks, both before and after the onset of
progressive memory impairments. This will allow me to determine the relationship between these spatial
coding metrics and progressive memory deficits found in epileptic mice. During this phase I will receive
technical training on in vivo calcium imaging and large-scale data analysis, as well as conceptual training on
epilepsy models, learning and memory circuits, spatial coding, and integrating neural recordings with behavior.
In the K00 phase, I plan to combine my previous expertise in stress-induced changes in entorhinal-
hippocampal signaling with my current work in epilepsy circuits to determine how the ventral extent of this
circuit contributes to altered emotional regulation in epilepsy. I will combine state-of-the-art mouse behavior,
molecular assays, gene expression studies, calcium imaging, and virally mediated manipulation techniques to
characterize ventral entorhinal-hippocampal circuit changes that drive psychiatric symptoms in epilepsy.
Results from these studies will provide new insights into the neural and circuit mechanisms of epilepsy induced
emotion deficits. Together, this training across F99 and K00 phases will support my successful transition to
postdoctoral researcher and ultimately a career as an independent research scientist focusing on molecular,
cellular, behavioral, and circuit-level signatures of behavioral dysfunction associated with epilepsy and stress.
项目总结
项目成果
期刊论文数量(0)
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