Project 2

项目2

基本信息

批准号：
10678938
负责人：
Lu Chen
金额：
$ 43.2万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-25 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10678938
关键词：
Acute Adult Animal Model Animals Autopsy Behavior Behavioral Biological Models Brain Cells Cerebrum Clinical Trials Cognitive Cognitive deficits Collaborations Computer Models Cre driver Development Disease Electrodes Electrophysiology (science)Enterobacteria phage P1 Cre recombinase Exhibits FMR1 FMRP Fragile X Syndrome Functional disorder Gene Expression Profiling Genetic Goals Hippocampus Human Impairment Investigation Joints Knockout Mice Learning Lentivirus Vector Link Long-Term Depression Long-Term Potentiation Mediating Memory Modeling Molecular Mus Mutation Nature Neurodevelopmental Disorder Neurologic Neurologic Dysfunctions Neurons Organoids Outcome Patients Phenotype Process Regulation Research Research Project Grants Runaway Running Signal Pathway Signal Transduction Slice Synapses Synaptic plasticity System Testing Therapeutic Therapeutic Intervention Tissues Tretinoin Work behavioral phenotyping cell type cognitive function cognitive testing drug discovery embryonic stem cell environmental enrichment for laboratory animals experience experimental study fear memory flexibility functional disability human model immunocytochemistry in vivo induced pluripotent stem cell insight knowledge base memory recall model organism mouse model neural circuit neuromechanism neuron development novel prevent small molecule synaptic function synergism tool development virtual

项目摘要

Project Summary Our research focuses on uncovering the molecular mechanisms and investigating the functional impact of a form of non-Hebbian synaptic plasticity, namely homeostatic synaptic plasticity. In contrast to the self-reinforcing nature of Hebbian plasticity, homeostatic plasticity operates under different rules as a “corrective” mechanism to prevent run-away Hebbian plasticity. Compared to Hebbian plasticity, the contribution of defective homeostatic synaptic plasticity to neuronal and behavioral phenotypes in neurodevelopmental disorders is virtually unexplored. Work from our labs in the past years show that retinoic acid (RA) signaling, a major signaling pathway mediating homeostatic synaptic plasticity, is severely impaired in the absence of FMRP expression, resulting in a lack of homeostatic plasticity in both mouse and human FXS neurons. Moreover, we demonstrate that under a more natural, enriched environment, compromised homeostatic synaptic plasticity in adult mice induces run-away Hebbian plasticity as manifested by greatly enhanced long-term potentiation (LTP) and diminished long-term depression (LTD). As a behavioral consequence, animals with defective homeostatic plasticity exhibit enhanced learning but reduced behavioral flexibility when raised in an enriched environment. Together, our work establishes a link between synaptic RA signaling, homeostatic plasticity and cognitive function, and suggests that impaired homeostatic plasticity may contribute to cognitive deficits in FXS. The goal of the proposed research project is to build upon this knowledge base, and establish a disease research platform from which translationally relevant FXS phenotypes at cellular and synaptic levels can be identified and their functional implication in cognitive function at behavioral level can be further explored in model organisms. To achieve this, we will use both a mouse FXS model and human cerebral organoids generated from human FXS patient cells, run parallel experiments at molecular and cellular levels, and identify shared phenotypes between the two model systems. We will then explore the impact of these shared phenotypes on learning and memory formation in behaving FXS mice, thus gaining further insight into how altered homeostatic synaptic plasticity may compromise cognitive function in human patients. Establishing such a platform for disease research will facilitate animal model-based drug discovery by focusing on treatment of phenotypes that are pertinent to human patients.

项目摘要我们的研究重点是发现分子机制并研究形式的功能影响非希比亚合成可塑性，即体内稳态可塑性。与自我强化相反 Hebbian可塑性的性质，稳态可塑性在不同的规则下作为“纠正”机制运行防止Hebbian可塑性。与Hebbian可塑性相比，稳态有缺陷的贡献神经发育障碍中神经元和行为表型的突触可塑性实际上是意外。过去几年我们实验室的工作表明视黄酸（RA）信号传导，这是一个主要信号传导介导稳态突触可塑性的途径在没有FMRP表达的情况下严重受损导致小鼠和人FXS神经元缺乏稳态可塑性。而且，我们证明了在更自然，丰富的环境下，成年小鼠的稳态可塑性受损诱导HEBBIAN可塑性，这表现为大大增强的长期增强（LTP）和长期抑郁症减少（LTD）。作为行为后果，稳态有缺陷的动物在丰富的环境中提出时，可塑性暴露了增强的学习，但行为灵活性降低了。一起，我们的工作建立了合成RA信号，稳态可塑性和认知之间的联系功能，并表明稳态可塑性受损可能有助于FXS的认知定义。目标拟议的研究项目的建立在这个知识基础上，并建立一个疾病研究平台可以从中鉴定出在细胞和突触水平上的翻译相关的FXS表型，它们在模型生物体中，可以进一步探索在行为水平上认知功能的功能含义。到实现这一目标，我们将同时使用人类FXS产生的小鼠FXS模型和人类大脑器官患者细胞，在分子和细胞水平上进行并行实验，并确定共享表型两个模型系统。然后，我们将探索这些共享表型对学习和记忆的影响表现FXS小鼠的形成，从而进一步了解了改变的稳态合成可塑性可能如何人类患者的认知功能妥协。建立这样的疾病研究平台将有助于基于动物模型的药物发现通过专注于与人类患者有关的表型的治疗。