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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：
JOANNA L JANKOWSKY
金额：
$ 21.41万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
https://reporter.nih.gov/project-details/10078733
关键词：
Action Potentials Acute Adult Affect Aging Alzheimer&apos s Disease Animal Model Animals Area Axon Behavior Behavioral Brain Caspase Cell Death Cells Cerebellum Chloride Channels Code Data Development Disadvantaged Disease Elderly Engineering Financial compensation Functional disorder Genetic Hippocampus (Brain)Hour Impairment Ion Channel Ivermectin Learning Life Ligands Link Maps Memory Modeling Modification Morphology Motor Neurons Mus Nerve Degeneration Neurobehavioral Manifestations Neurodegenerative Disorders Neurofibrillary Tangles Neurons Neurophysiology - biologic function Pathology Pattern Perforant Pathway Performance Pharmaceutical Preparations Physiological Population Predisposition Process Property Reaction Recovery Spinal Cord Structure Substantia nigra structure Symptoms Synapses Synaptic Transmission Synaptic plasticity System Temporal Lobe Testing Transgenic Mice Transgenic Organisms Work aged base behavior test cell cortex cell injury cognitive function cognitive recovery critical period dentate gyrus dopaminergic neuron entorhinal cortex experimental study hippocampal pyramidal neuron memory consolidation molecular pathology neocortical neuron loss neuronal survival novel overexpression prevent relating to nervous system repaired resilience response tau Proteins transmission process young 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.

总结我们的研究将验证这一假设，即内鼻-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。与其他神经系统中受影响的神经群不同，神经变性疾病（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神经元在甚至急性发作的实验性- 诱导电击。使用新型化学发生离子通道防止EC层2中的动作电位放电神经元，我们发现内嗅轴突从齿状回缩，随后在细胞体激活半胱天冬酶，两个区域的小胶质细胞活化，最后是细胞损失。成年人大脑中的这种模式化退化模仿了在发育中的大脑中用于塑造贯穿路径的活动依赖性过程（Yasuda等人，2011年）。虽然长期以来认为，大规模结构重塑的关键时期在成熟期结束，越来越多的证据表明，表明某些皮层区域在整个生命过程中保持着实质性改变的潜力。基于我们研究结果，我们假设持续的可塑性需要支持整个生命的学习和记忆，也使内鼻-海马回路中的神经元容易受到持续的活动依赖性生存竞争的影响，成年人了我们将通过三个具体目标来检验这一假设。目的1将确定细胞死亡是否源于活性和非活性细胞之间的竞争，或者相反来自非活性本身。重申一下，EC神经元的细胞死亡是由细胞自主机制还是非自主机制发起的这一目标也将测试是否其他子领域的三- 具有类似可塑性要求的突触环也依赖于持续的电活动，成年人了该回路的可塑性增强，预示着EC细胞丢失引起的任何初始损伤将很快被修复。通过自我平衡补偿来抵消。与这一想法相一致的是，我们发现年轻的老鼠很快就恢复了正常的学习能力和记忆性能后的短暂EC沉默，尽管正在进行的细胞死亡。目标2将绘制结构和对第2层神经元损失的生理反应，以识别支持回路的兴奋性或形态学变化修复.虽然年轻的成年人的大脑可以很容易地利用自我平衡机制来补偿电路干扰， AD是一种衰老性疾病，当可塑性更有限时，损伤引起的损害更广泛。目标3将测试老年动物中不活跃神经元的死亡比例是否高于健康的年轻人，以及穿孔路径传输和依赖于休眠的行为是较慢的，并且最终不太成功。总的来说，这些目标测试了一个大胆的新假设，在早期AD的内鼻-海马神经元的选择性脆弱性。如果如果实验成功，这些实验将提出一个深刻的想法，即神经功能本身可能有助于选择性死亡在AD中。