BDNF and Spine-Related Disorders of Memory and Cognition

BDNF 和脊柱相关的记忆和认知障碍

基本信息

批准号：
8914677
负责人：
Christine M Gall
金额：
$ 116.11万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-30 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8914677
关键词：
Accounting Actins Address Adult Adverse effects Affect Aging Angelman Syndrome Animal Model Animals Award Beds Behavior Behavioral Biological Assay Brain-Derived Neurotrophic Factor Calpain Chronic Clinical Clinical Trials Cognition Cognition Disorders Cognitive Collaborations Complex Computer software Corticotropin-Releasing Hormone Cytoskeletal Modeling Cytoskeleton Data Defect Dendritic Spines Detection Development Disease Disease model Electrophysiology (science)Estrogens Event Evolution F-Actin Failure Fragile X Syndrome Functional disorder Funding Funding Agency Goals Hippocampus (Brain)Hormone Receptor Human Huntington Disease Impaired cognition In Vitro Infusion procedures Interneurons Laboratories Learning Ligands Long-Term Potentiation Maps Measures Mediating Membrane Memory Memory Disorders Memory impairment Mental disorders Methods Microfilaments Microscopy Modeling Modification Morphology Movement Mus Neurobiology Neurotrophic Tyrosine Kinase Receptor Type 2 Pathology Pathway interactions Pattern Peptide Hydrolases Pharmaceutical Preparations Phase Physiological Physiology Population Process Protein Biosynthesis Proteins Protocols documentation Rattus Reagent Research Research Design Rodent Rodent Model Route Signal Pathway Signal Transduction Slice Space Explorations Speed Staging Stress Synapses Synaptic plasticity Technology Testing Therapeutic Time Translating Translations Up-Regulation Vertebral column Work base behavioral study calcium dependent protease inhibitor clinically relevant cognitive function cognitive performance design dosage effective therapy experience extracellular human FRAP1 protein improved in vivo memory consolidation memory encoding middle age model building mouse model neurochemistry neurotrophic factor novel polymerization programs protein phosphatase inhibitor-2 public health relevance receptor rho GTP-Binding Proteins success therapeutic evaluation therapeutic target translational study virtual reality

项目摘要

DESCRIPTION (provided by applicant): Memory and cognitive disorders are associated with abnormal dendritic spines and/or disturbances to signaling regulating the spine actin cytoskeleton. Complementary results show that long-term potentiation (LTP), a form of synaptic plasticity thought to underlie memory encoding, requires spine actin remodeling. These observations suggest the hypothesis that defects in the cytoskeletal mechanisms of LTP consolidation represent a shared neurobiological basis for memory disturbances, and a therapeutic target for improving cognitive performance, in a variety of conditions. The present proposal for renewal of #P01NS045260 funding, addresses this hypothesis. Program studies have shown that LTP stabilization is impaired in rodent models of six different types of memory disorder: middle-aging, early-stage Huntington's Disease (HD), Fragile-X Syndrome (FXS), Angelman Syndrome, short-term stress, and low estrogen levels. In each instance thus far tested, LTP-related reorganization of the spine cytoskeleton was defective and infusions and/or upregulating Brain-Derived Neurotrophic Factor (BDNF) rescued LTP and cytoskeletal changes. Moreover, activity-driven actin remodeling was shown to involve distinct cascades mediating spine F-actin assembly and stabilization, that are differentially impaired across the animal models, but both facilitated by BDNF. The proposed studies build on these findings to: i) identify defects in activity-driven signaling to actin, associated with LTP, in seven distinctly different rodent models of memory impairment; ii) determine if behaviorally induced actin signaling and learning is impaired in the rodent models; iii) test if chronic up-regulation of BDNF protein content increases signaling through BDNF's TrkB receptor and actin regulatory cascades as assessed in vitro and in vivo; and iv) test the prediction that the latter effects are accompanied by a reduction in behavioral abnormalities in each of the rodent models. There will be four Projects, directed by different PIs: each with its own rodent models and with different aspects of cytoskeletal signaling as a focus. Core A will provide analytical facilities for microscopy, electrophysiology, behavioral studies, and select neurochemical assays employed by all projects, and will support Administrative and Animal/Reagent functions. In all, the proposed studies are expected to test for the presence of a final, common defect in memory disorders and to thoroughly evaluate a clinically relevant strategy for normalizing synaptic plasticity and behavior.

描述（由申请人提供）：记忆和认知障碍与树突异常和/或对调节脊椎肌动蛋白细胞骨架的信号传导有关。补充结果表明，长期增强（LTP）是一种突触可塑性，认为是记忆编码的基础，需要脊柱肌动蛋白重塑。这些观察结果表明，LTP巩固的细胞骨架机制缺陷代表了记忆障碍的共同神经生物学基础，以及在各种条件下改善认知性能的治疗靶点。＃P01NS045260资金续签的当前建议介绍了这一假设。计划研究表明，LTP稳定在六种不同类型的记忆障碍的啮齿动物模型中受到了损害：中期，早期亨廷顿氏病（HD），脆弱-X综合征（FXS），Angelman综合征，短期应激和低雌激素水平。在迄今已测试的每种情况下，LTP脊柱细胞骨架的与LTP相关的重组都是有缺陷的，输注和/或上调脑衍生的神经营养因子（BDNF）救出了LTP和细胞骨架变化。此外，活动驱动的肌动蛋白重塑涉及介导脊柱F-肌动蛋白组装和稳定化的不同级联反应，这些脊柱构成在动物模型中差异障碍，但两者都促进了BDNF的促进。拟议的研究基于以下发现的基础：i）在与LTP相关的肌动蛋白中，在七个截然不同的记忆障碍模型中确定与LTP相关的肌动蛋白的缺陷； ii）确定在啮齿动物模型中，行为诱导的肌动蛋白信号传导和学习是否受损； iii）测试BDNF蛋白含量的慢性上调是否通过BDNF的TRKB受体和肌动蛋白调节级联反应增加信号传导，并在体外和体内评估； iv）测试以下预测，即后一种效应伴随着每个啮齿动物模型中行为异常的降低。将有四个由不同的PI指导的项目：每个项目都有自己的啮齿动物模型，并以细胞骨架信号的不同方面为重点。核心A将提供显微镜，电生理学，行为研究和所有项目采用的神经化学测定的分析设施，并支持行政和动物/试剂功能。总之，拟议的研究有望测试记忆障碍中最终的常见缺陷，并彻底评估临床相关的策略，以使突触可塑性和行为正常化。

项目成果

期刊论文数量（54）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Calpain-2-mediated PTEN degradation contributes to BDNF-induced stimulation of dendritic protein synthesis.

DOI：
10.1523/jneurosci.4907-12.2013
发表时间：
2013-03-06
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Briz V;Hsu YT;Li Y;Lee E;Bi X;Baudry M
通讯作者：
Baudry M

Brain-derived neurotrophic factor and epidermal growth factor activate neuronal m-calpain via mitogen-activated protein kinase-dependent phosphorylation.

DOI：
10.1523/jneurosci.5120-09.2010
发表时间：
2010-01-20
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Zadran S;Jourdi H;Rostamiani K;Qin Q;Bi X;Baudry M
通讯作者：
Baudry M

Cofilin Activation Is Temporally Associated with the Cessation of Growth in the Developing Hippocampus.

Cofilin 激活与发育中的海马体生长停止暂时相关。

DOI：
10.1093/cercor/bhw088
发表时间：
2017
期刊：
Cerebral cortex (New York, N.Y. : 1991)
影响因子：
0
作者：
Lauterborn,JulieC;Kramár,EniköA;Rice,JeffreyD;Babayan,AlexH;Cox,ConorD;Karsten,CarleyA;Gall,ChristineM;Lynch,Gary
通讯作者：
Lynch,Gary

Targeting calpain in synaptic plasticity.