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

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.
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.
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

JOANNA L JANKOWSKY其他文献

JOANNA L JANKOWSKY的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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:

相似海外基金

Un/kindness, shame & resistance: the care of inpatients in NHS adult acute mental health units and how it might be improved
Un/善良,羞耻
  • 批准号:
    2885806
  • 财政年份:
    2023
  • 资助金额:
    $ 21.41万
  • 项目类别:
    Studentship
Post-Acute Care Transitions for Older Adult Medicare Beneficiaries with Serious Mental Illness
患有严重精神疾病的老年医疗保险受益人的急性后护理过渡
  • 批准号:
    10772386
  • 财政年份:
    2023
  • 资助金额:
    $ 21.41万
  • 项目类别:
Paving The Way to a Canadian Standard of Care with CAR-T Cellular Therapy: Phase II Trial of CD19 CAR-T for Relapsed/Refractory Adult Acute Lymphoblastic Leukemia (CLIC-01A)
通过 CAR-T 细胞疗法为加拿大护理标准铺平道路:CD19 CAR-T 治疗复发/难治性成人急性淋巴细胞白血病的 II 期试验 (CLIC-01A)
  • 批准号:
    474619
  • 财政年份:
    2022
  • 资助金额:
    $ 21.41万
  • 项目类别:
    Operating Grants
Investigating the impact acute inhalation of cannabis with a high content of delta-9-tetrahydrocannabinol has on myelination and microglia in adult and aged mice
研究急性吸入高含量 delta-9-四氢大麻酚的大麻对成年和老年小鼠髓鞘形成和小胶质细胞的影响
  • 批准号:
    485965
  • 财政年份:
    2022
  • 资助金额:
    $ 21.41万
  • 项目类别:
    Studentship Programs
Paving The Way to a Canadian Standard of Care with CAR-T Cellular Therapy: Phase II Trial of CD19 CAR-T for Relapsed/Refractory Adult Acute Lymphoblastic Leukemia (CLIC-01A)
通过 CAR-T 细胞疗法为加拿大护理标准铺平道路:CD19 CAR-T 治疗复发/难治性成人急性淋巴细胞白血病的 II 期试验 (CLIC-01A)
  • 批准号:
    466358
  • 财政年份:
    2022
  • 资助金额:
    $ 21.41万
  • 项目类别:
    Operating Grants
Metabolomics for prediction of cisplatin mediated acute kidney injury: a Canadian multi-centre adult and pediatric study
预测顺铂介导的急性肾损伤的代谢组学:加拿大多中心成人和儿童研究
  • 批准号:
    402040
  • 财政年份:
    2019
  • 资助金额:
    $ 21.41万
  • 项目类别:
    Operating Grants
Study of pathogenic mechanism of age-dependent chromosome translocation in adult acute lymphoblastic leukemia
成人急性淋巴细胞白血病年龄依赖性染色体易位发病机制研究
  • 批准号:
    18K16103
  • 财政年份:
    2018
  • 资助金额:
    $ 21.41万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Causal effect of time-varying driving pressures on mortality in mechanically ventilated, adult patients with acute respiratory distress syndrome
时变驱动压力对机械通气成年急性呼吸窘迫综合征患者死亡率的因果影响
  • 批准号:
    377313
  • 财政年份:
    2017
  • 资助金额:
    $ 21.41万
  • 项目类别:
    Studentship Programs
Role of SETBP1 in adult Ph+ acute lymphoblastic leukemia
SETBP1 在成人 Ph 急性淋巴细胞白血病中的作用
  • 批准号:
    9315111
  • 财政年份:
    2016
  • 资助金额:
    $ 21.41万
  • 项目类别:
Acute Inhibition of Adult-born Granule Cells and its Effect on Antidepressant Act
成体颗粒细胞的急性抑制及其抗抑郁作用
  • 批准号:
    8734273
  • 财政年份:
    2013
  • 资助金额:
    $ 21.41万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了