Plasticity of the entorhinal-hippocampal circuit as a vulnerability in AD
内嗅海马回路的可塑性是 AD 的一个弱点
基本信息
- 批准号:10078733
- 负责人:
- 金额:$ 21.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-15 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAcuteAdultAffectAgingAlzheimer&aposs DiseaseAnimal ModelAnimalsAreaAxonBehaviorBehavioralBrainCaspaseCell DeathCellsCerebellumChloride ChannelsCodeDataDevelopmentDisadvantagedDiseaseElderlyEngineeringFinancial compensationFunctional disorderGeneticHippocampus (Brain)HourImpairmentIon ChannelIvermectinLearningLifeLigandsLinkMapsMemoryModelingModificationMorphologyMotor NeuronsMusNerve DegenerationNeurobehavioral ManifestationsNeurodegenerative DisordersNeurofibrillary TanglesNeuronsNeurophysiology - biologic functionPathologyPatternPerforant PathwayPerformancePharmaceutical PreparationsPhysiologicalPopulationPredispositionProcessPropertyReactionRecoverySpinal CordStructureSubstantia nigra structureSymptomsSynapsesSynaptic TransmissionSynaptic plasticitySystemTemporal LobeTestingTransgenic MiceTransgenic OrganismsWorkagedbasebehavior testcell cortexcell injurycognitive functioncognitive recoverycritical perioddentate gyrusdopaminergic neuronentorhinal cortexexperimental studyhippocampal pyramidal neuronmemory consolidationmolecular pathologyneocorticalneuron lossneuronal survivalnoveloverexpressionpreventrelating to nervous systemrepairedresilienceresponsetau Proteinstransmission processyoung adult
项目摘要
SUMMARY
Our study will test the hypothesis that the specific functional properties of entorhinal-hippocampal neurons may
contribute to their heightened vulnerability in AD. Our proposal is based on our preliminary data showing that neurons in
the entorhinal cortex (EC) are unusually sensitive to inactivity. Unlike neural populations affected in other
neurodegenerative diseases (including dopaminergic neurons in the substantial nigra, Purkinje neurons in the cerebellum,
and motor neurons in the spinal cord), EC neurons underwent cell death following even acute bouts of experimentally-
induced electrical arrest. Using a novel chemogenetic ion channel to prevent the firing of action potentials in EC layer 2
neurons, we found that entorhinal axons retracted from the dentate gyrus, followed by caspase activation at the cell body,
microglial activation in both areas, and finally, cell loss. This patterned degeneration in the adult brain mimics the
activity-dependent processes used in the developing brain to sculpt the perforant path (Yasuda et al., 2011). While it was
long believed that the critical period for wholesale structural remodeling closed during maturation, mounting evidence
indicates that some cortical areas maintain the potential for substantial modification throughout life. Based on our
findings, we hypothesize the ongoing plasticity required to support learning and memory throughout life also renders
neurons in the entorhinal-hippocampal circuit vulnerable to ongoing activity-dependent competition for survival in the
adult. We will test this hypothesis through three specific aims. Aim 1 will determine whether cell death arises from
competition between active and inactive cells or instead from inactivity itself. Restated, is cell death in EC neurons
initiated by a cell-autonomous or non-autonomous mechanism? This aim will also test whether other subfields of the tri-
synaptic loop with similar plasticity requirements are also dependent on continued electrical activity for survival in the
adult. Heightened plasticity in this circuit predicts that any initial impairments caused by EC cell loss will be quickly
offset by homeostatic compensation. Consistent with this idea, we find that young mice quickly regain normal learning
and memory performance after transient EC silencing despite ongoing cell death. Aim 2 will map the structural and
physiological reactions to loss of layer 2 neurons to identify changes in excitability or morphology that support circuit
repair. While the young adult brain can readily engage homeostatic mechanisms to compensate for circuit perturbation,
AD is a disease of aging when plasticity is more limited and the damage caused by insult more extensive. Aim 3 will test
whether a greater fraction of inactive neurons die in geriatric animals than in healthy young adults, and if the recovery of
perforant path transmission and hippocampal-dependent behaviors are slower and ultimately less successful. Collectively,
these aims test a bold new hypothesis for the selective vulnerability of entorhinal-hippocampal neurons in early AD. If
successful, these experiments will advance a profound idea that neural function itself may contribute to selective demise
in AD.
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)
Doxycycline for transgene control disrupts gut microbiome diversity without compromising acute neuroinflammatory response.
- DOI:10.1186/s12974-023-03004-4
- 发表时间:2024-01-04
- 期刊:
- 影响因子:9.3
- 作者:
- 通讯作者:
Practical considerations for choosing a mouse model of Alzheimer's disease.
- DOI:10.1186/s13024-017-0231-7
- 发表时间:2017-12-22
- 期刊:
- 影响因子:15.1
- 作者:Jankowsky JL;Zheng H
- 通讯作者:Zheng H
The TMEM106B T186S coding variant increases neurite arborization and synaptic density in primary hippocampal neurons.
- DOI:10.3389/fnins.2023.1275959
- 发表时间:2023
- 期刊:
- 影响因子:4.3
- 作者:Nguyen, Quynh;Wood, Caleb A.;Kim, Peter J.;Jankowsky, Joanna L.
- 通讯作者:Jankowsky, Joanna L.
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JOANNA L JANKOWSKY其他文献
JOANNA L JANKOWSKY的其他文献
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{{ truncateString('JOANNA L JANKOWSKY', 18)}}的其他基金
TMEM106b as a lysosomal adaptor to influence brain aging and tau pathogenesis
TMEM106b 作为溶酶体适配器影响大脑衰老和 tau 发病机制
- 批准号:
10583546 - 财政年份:2021
- 资助金额:
$ 21.41万 - 项目类别:
TMEM106b as a lysosomal adaptor to influence brain aging and tau pathogenesis
TMEM106b 作为溶酶体适配器影响大脑衰老和 tau 发病机制
- 批准号:
10413976 - 财政年份:2021
- 资助金额:
$ 21.41万 - 项目类别:
Gene therapy for Alzheimer's disease using virally delivered Aβ variants
使用病毒传递的 Aβ 变体进行阿尔茨海默氏病的基因治疗
- 批准号:
10316624 - 财政年份:2021
- 资助金额:
$ 21.41万 - 项目类别:
Gene therapy for Alzheimer's disease using virally delivered Aβ variants
使用病毒传递的 Aβ 变体进行阿尔茨海默氏病的基因治疗
- 批准号:
10609343 - 财政年份:2021
- 资助金额:
$ 21.41万 - 项目类别:
TMEM106b as a lysosomal adaptor to influence brain aging and tau pathogenesis
TMEM106b 作为溶酶体适配器影响大脑衰老和 tau 发病机制
- 批准号:
10172237 - 财政年份:2021
- 资助金额:
$ 21.41万 - 项目类别:
Plasticity of the entorhinal-hippocampal circuit as a vulnerability in AD
内嗅海马回路的可塑性是 AD 的一个弱点
- 批准号:
9438665 - 财政年份:2017
- 资助金额:
$ 21.41万 - 项目类别:
Deconstructing the pathogenic effect of APP in memory circuits
解构APP对记忆回路的致病作用
- 批准号:
8938903 - 财政年份:2015
- 资助金额:
$ 21.41万 - 项目类别:
Deconstructing the pathogenic effect of APP in memory circuits
解构APP对记忆回路的致病作用
- 批准号:
9104241 - 财政年份:2015
- 资助金额:
$ 21.41万 - 项目类别:
Selective neuronal silencing to study hippocampal neurogenesis in depression
选择性神经元沉默研究抑郁症中海马神经发生
- 批准号:
8687749 - 财政年份:2013
- 资助金额:
$ 21.41万 - 项目类别:
Selective neuronal silencing to study hippocampal neurogenesis in depression
选择性神经元沉默研究抑郁症中海马神经发生
- 批准号:
8564283 - 财政年份:2013
- 资助金额:
$ 21.41万 - 项目类别:
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