Sex differences in fast-spiking interneurons promote AUD-related PFC dysfunction: remediation by modulating mGlu1 and mGlu5
快速峰值中间神经元的性别差异促进 AUD 相关的 PFC 功能障碍:通过调节 mGlu1 和 mGlu5 进行修复
基本信息
- 批准号:10177823
- 负责人:
- 金额:$ 13.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-06-02 至 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAlcohol consumptionAlcoholsAreaBehaviorBehavioralBrain regionCellsCommunitiesDataDevelopmentDiseaseDisease OutcomeElectrophysiology (science)EthanolEtiologyExhibitsFacultyFemaleFiberFunctional disorderGRM1 geneGRM5 geneGlutamatesImageInterneuron functionInterneuronsInterventionLabelLifestyle-related conditionLimbic SystemMeasuresMediatingMembraneMetabotropic Glutamate ReceptorsMinorModelingMusNeurobiologyNeuronsOutputParvalbuminsPathway interactionsPharmaceutical PreparationsPharmacologyPhasePhotometryPhysiologicalPhysiologyPopulationPositioning AttributePrefrontal CortexPreparationProcessPropertyPyramidal CellsReporterReportingScheduleSex DifferencesShapesSliceStructureSynapsesSynaptic plasticityTechniquesTestingTimeTrainingTransgenic MiceTransgenic OrganismsViralWomanalcohol availabilityalcohol exposurealcohol researchalcohol seeking behavioralcohol use disorderbasebehavioral pharmacologycareer developmentcell typecognitive functioncravingdesigndrinkingdrinking behaviorexperienceglutamatergic signalingin vivoinnovationinterestmalemenmonoaminemotivated behaviorneuroregulationnoveloptogeneticsreceptorremediationsexsexual dimorphismside effecttranslational approachtransmission process
项目摘要
Project Summary
Sex differences in fast-spiking interneurons promote AUD-related PFC dysfunction: remediation by
modulating mGlu1 and mGlu5. Alcohol use disorder (AUD) affects both men and women, however women are
disproportionately harmed by several disease outcomes. A key brain region dysregulated by alcohol is the
prefrontal cortex (PFC), which exhibits significant sexual dimorphism and is essential for managing appropriate
drinking. PFC output is mediated by pyramidal cells, glutamatergic neurons that course onto the limbic system,
each one typically projecting to a single subcortical structure. Pyramidal cell activity is dynamically regulated by
fast-spiking parvalbumin-expressing interneurons (PV-INs). Increasing evidence suggests that excitatory
transmission onto PV-INs regulates sex differences in drinking behaviors, therefore pharmacological
modulation of PV-INs provides a promising means to ameliorate AUD-related symptomology. PFC PV-INs
express several druggable receptors, notably including metabotropic glutamate (mGlu) receptor subtypes 1
and 5. Our preliminary data indicate that mGlu1 and mGlu5 modulate PV-INs in a sex-specific manner, and
further, that intermittent voluntary drinking induces sex-specific alterations to several mGlu1- and mGlu5-related
PV-IN physiology. Our central hypothesis is that sex differences in PFC PV-IN function underlie AUD-
related pathophysiology, and that modulating mGlu1 and mGlu5 can ameliorate maladaptive changes
induced by binge-like alcohol consumption. This hypothesis will be tested through two specific aims.
Aim 1 (K99): To test the hypothesis that mGlu1 and mGlu5 modulation can ameliorate sex-specific alcohol-
induced pathophysiology through actions on PFC PV-INs. PV-IN synaptic physiology and plasticity will be
interrogated in an ex vivo slice preparation. In addition, PV-IN function will be examined in vivo with fiber
photometry while female and male mice seek alcohol and perform other PFC-dependent behaviors.
Aim 2 (R00): To test the hypothesis that sex-specific alcohol-induced dysregulation of distinct PFC outputs can
be remediated through mGlu1 and mGlu5 modulation of inhibitory transmission. A viral approach will be used to
label PFC pyramidal cells based on projection target in female and male transgenic optogenetic mice (PV-
ChR2). We will assess how PV-INs control specific PFC output pathways following intermittent alcohol
exposure, and how these phenomena are regulated by sex and mGlu1/mGlu5.
Training: I will gain extensive experience with drinking models and in vivo cell type-specific Ca2+ imaging.
Training in alcohol models and fiber photometry will allow me to apply my interest in mGlu synaptic
plasticity and PFC circuitry to unanswered questions about how sex differences are manifested in
AUD. I will also receive essential career development training to facilitate a transition to an independent junior
faculty position within the alcohol research community.
项目总结
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Sex differences and hormonal regulation of metabotropic glutamate receptor synaptic plasticity.
代谢型谷氨酸受体突触可塑性的性别差异和激素调节。
- DOI:10.1016/bs.irn.2022.10.002
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Fabian,CarlyB;Seney,MarianneL;Joffe,MaxE
- 通讯作者:Joffe,MaxE
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{{ truncateString('Max E Joffe', 18)}}的其他基金
Sex differences in fast-spiking interneurons promote AUD-related PFC dysfunction: remediation by modulating mGlu1 and mGlu5
快速峰值中间神经元的性别差异促进 AUD 相关的 PFC 功能障碍:通过调节 mGlu1 和 mGlu5 进行修复
- 批准号:
10686993 - 财政年份:2021
- 资助金额:
$ 13.82万 - 项目类别:
Sex differences in fast-spiking interneurons promote AUD-related PFC dysfunction: remediation by modulating mGlu1 and mGlu5 - Supplement Rev
快速峰值中间神经元的性别差异促进 AUD 相关的 PFC 功能障碍:通过调节 mGlu1 和 mGlu5 进行修复 - 补充修订版
- 批准号:
10757096 - 财政年份:2021
- 资助金额:
$ 13.82万 - 项目类别:
Sex differences in fast-spiking interneurons promote AUD-related PFC dysfunction: remediation by modulating mGlu1 and mGlu5
快速峰值中间神经元的性别差异促进 AUD 相关的 PFC 功能障碍:通过调节 mGlu1 和 mGlu5 进行修复
- 批准号:
10455279 - 财政年份:2021
- 资助金额:
$ 13.82万 - 项目类别:
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