ESTROGEN-INDUCIBLE PNNS ENHANCE EXCITATORY SYNAPTIC STRENGTH ONTO GABA NEURONS IN THE MEPD TO PREVENT OBESITY AND METABOLIC DYSREGULATION
雌激素诱导的 PNNS 增强 MEPD 中 GABA 神经元的兴奋性突触强度,以预防肥胖和代谢失调
基本信息
- 批准号:10712725
- 负责人:
- 金额:$ 44.76万
- 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:2023-08-24 至 2028-04-30
- 项目状态:未结题
- 来源:
- 关键词:AdultAgeAlzheimer&aposs DiseaseAmericanAmygdaloid structureAppetite StimulantsBiologyBipolar DisorderBlood GlucoseBody WeightBrainBrain regionBuffersCellsCellular StructuresCenters for Disease Control and Prevention (U.S.)Chemical ModelsChildChronicDigestionDiseaseDorsalElectronsEquilibriumEstradiolEstrogen Receptor alphaEstrogensEtiologyExtracellular MatrixFatty acid glycerol estersFemaleGeneticGenetic ModelsGlucoseGlucose IntoleranceGlycosaminoglycansHealthHigh Fat DietHomeostasisHyaluronanHyperglycemiaHyperinsulinismHyperphagiaHypothalamic structureIn SituIonsMedialMediatingMetabolicMetabolic syndromeMetabolismModelingMolecularMolecular ConformationMusNeurobiologyNeurogliaNeuronsNeurosecretory SystemsNutritional statusObesityOverweightPatternPlayPopulationPrevalenceRegulationReportingRoleSchizophreniaSignal TransductionStructureStructure of nucleus infundibularis hypothalamiSynapsesSynaptic plasticityTestingTherapeutic InterventionTomogramVisualizationWeightWeight Gainaddictionadult obesitybehavioral responseblood glucose regulationcombatcomorbidityeffective therapyfeedingfollow-upgain of functiongamma-Aminobutyric Acidgenetic approachglobal healthhormonal signalsimprovedinsulin sensitivityloss of functionmalemouse modelneuralneural circuitobesity preventionpandemic diseaseparacrinepreventsextargeted treatment
项目摘要
PROJECT SUMMARY
Perineuronal nets (PNNs) are condensed extracellular matrix around a subset of neurons. PNNs can provide
physical protection and ion buffering for neurons and regulate their synaptic plasticity and intracellular signaling.
Recent evidence indicates that PNNs enmesh GABA neurons in the arcuate nucleus of the hypothalamus (ARH)
to regulate energy and glucose homeostasis. However, little is known about the potential metabolic function of
PNNs in other brain regions that are also implicated in metabolic health.
We observed abundant PNNs in the posterodorsal medial amygdala (MePD) and found that PNN-enmeshed
neurons in the MePD are mostly GABA neurons. Digestion of PNNs drastically reduces excitability and synaptic
activity of these GABAMePD neurons. Importantly, we showed that chronic disruption of MePD PNNs leads to
hyperphagia and modest weight/fat gain in chow-fed mice. On the other hand, chronic increases in MePD PNNs
result in lower body weight/fat in chow-fed mice. These results suggest that MePD PNNs and PNNs-enmeshed
GABAMePD neurons are required to prevent overeating and obesity. We will follow up these findings to establish
the function of MePD PNNs (Aim 1) and GABAMePD (Aim 2) neurons in energy and glucose homeostasis.
Meanwhile, we will delineate the mechanisms by which PNNs regulate excitability and synaptic activity of
GABAMePD neurons.
17β-estradiol (E2) can act on estrogen receptor-α (ERα) to regulate energy and glucose balance in both
females and males. Previous reports showed that ERα in many brain regions mediates the metabolic effects of
E2 only in female mice, but not male mice. Our pilot observations indicate that E2 can increase PNNs in MePD
in both male and female mice. Importantly, loss of ERα in the medial amygdala (containing the MePD) causes
obesity not only in female mice, but also in male mice, suggesting the potential metabolic role of MePD in male
metabolic health. In Aim 3, we will follow up these findings to test whether E2 induces PNNs to facilitate GABA
neurons in the MePD to prevent obesity and metabolic dysregulation in both male and female mice.
Together, we will reveal a new metabolic regulation mechanism: E2-ERα-PNNs-GABAMePD-energy/glucose
homeostasis. Our studies will advance our understanding about the estrogen biology in both female and male
metabolism and the metabolic role of PNNs in a new brain region MePD. Finally, we will identify a unique
anorexigenic GABA population, which is different from previous reported orexigenic GABA neural populations in
many other brain regions.
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)
专利数量(0)
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Chunmei Wang其他文献
Chunmei Wang的其他文献
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- 批准号:
10436077 - 财政年份:2019
- 资助金额:
$ 44.76万 - 项目类别:
A TAP63 TRANSCRIPTIONAL AXIS CONTRIBUTES TO THE SEXUAL DIMORPHISM IN POMC NEURON FUNCTIONS AND ENERGY HOMEOSTASIS
TAP63 转录轴有助于 POMC 神经元功能和能量稳态中的性二态性
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10197116 - 财政年份:2019
- 资助金额:
$ 44.76万 - 项目类别:
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