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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.

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。