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.
摘要 我们的研究将检验这一假设,即内嗅觉-海马神经元的特定功能特性可能 导致他们在AD中的脆弱性增加。我们的建议是基于我们的初步数据显示,神经元在 内嗅皮层(EC)对不活动异常敏感。与其他受影响的神经种群不同 神经退行性疾病(包括黑质中的多巴胺能神经元,小脑中的浦肯野神经元, 和脊髓中的运动神经元),EC神经元即使在实验上急性发作后也会经历细胞死亡- 诱导的电击停。利用一种新的化学发生离子通道阻止EC第二层动作电位的激发 神经元,我们发现内嗅轴突从齿状回回缩回,然后在细胞体激活caspase, 这两个区域的小胶质细胞都被激活了,最后是细胞丢失。成人大脑中的这种有模式的退化模仿 在发育中的大脑中用于塑造穿通径的活动依赖的过程(Yasuda等人,2011年)。虽然它是 Long认为,大规模结构重塑的关键期在成熟期结束,越来越多的证据表明 表明某些皮质区域在整个生命过程中保持着实质性修改的潜力。基于我们的 发现,我们假设支持一生学习和记忆所需的持续可塑性也呈现出 内嗅觉-海马环路中的神经元容易受到持续的活动依赖性竞争的影响 成年人。我们将通过三个具体目标来检验这一假设。目标1将确定细胞死亡是否源于 活跃和非活跃细胞之间的竞争,或者来自不活跃本身。重申,EC神经元中的细胞死亡 是由细胞自主还是非自主机制发起的?这一目标还将测试三个子领域是否- 具有相似可塑性要求的突触环也依赖于持续的电活动来生存 成年人。这个电路的高度可塑性预测,任何由EC细胞丢失引起的初始损伤都将很快 通过动态平衡补偿来抵消。与这一观点一致,我们发现幼鼠很快就恢复了正常的学习能力 以及尽管细胞正在死亡,但短暂的EC沉默后的记忆表现。目标2将绘制出结构和 对第二层神经元丢失的生理反应,以确定支持回路的兴奋性或形态的变化 修理。虽然年轻的成年大脑可以很容易地利用体内平衡机制来补偿电路扰动, AD是一种衰老的疾病,当可塑性更有限,侮辱造成的损害更广泛。AIM 3将测试 老年动物的非活动神经元是否比健康的年轻人死亡的比例更大,以及 穿透通路传递和海马体依赖行为速度较慢,最终不太成功。总而言之, 这些目标测试了一个大胆的新假设,即在AD早期,内嗅觉-海马神经元的选择性脆弱性。如果 这些实验的成功将推动一个深刻的观点,即神经功能本身可能导致选择性死亡 在公元后。

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.
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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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