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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