Thalamic Reticular Nucleus Dysfunction in Alzheimer's Disease
阿尔茨海默病中的丘脑网状核功能障碍
基本信息
- 批准号:10612400
- 负责人:
- 金额:$ 66.3万
- 依托单位:
- 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:2020-08-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:Abeta clearanceAbeta synthesisAcuteAddressAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease patientAlzheimer&aposs disease riskAmyloid beta-ProteinAnimal ModelAttentionBehaviorBrainBrain regionCell NucleusCellsChronicCognitionCognitiveCognitive deficitsComplexDepositionDiseaseDisease ProgressionDisinhibitionElectrophysiology (science)ExhibitsFunctional disorderGoalsHippocampusHuman Amyloid Precursor ProteinImpairmentIntercellular FluidLeadMaintenanceMediatingMemoryMemory impairmentMicrodialysisMusNeuronsPathologyPeptidesPharmacologyPhasePropertyProteinsSeizuresSleepSleep ArchitectureSleep DeprivationSleep FragmentationsSleep Wake CycleSleep disturbancesSliceSlow-Wave SleepSynapsesTestingThalamic structureTherapeuticTransgenic MiceViralWakefulnessabeta accumulationabeta depositiondaily functioningdesigndesigner receptors exclusively activated by designer drugsimprovedimprovement on sleepin vivoinsightinterstitialmemory consolidationmouse modelmutantneuron lossneurotoxicnovelnovel therapeutic interventionpoor sleeppublic health relevancerestorationrisk predictiontargeted treatmenttau Proteins
项目摘要
PROJECT SUMMARY
Sleep disturbances predict risk of Alzheimer’s disease (AD). Sleep-wake cycles critically regulate brain
interstitial fluid (ISF) levels of Aβ and tau, two critical proteins that accumulate in AD. Both Aβ and tau are
released by neuronal activity, which is higher during wakefulness than in sleep. Moreover, sleep is a critical
phase during which factors in the ISF are cleared from the brain. Therefore, sleep disturbances affect daily
function and also contribute to disease progression. However, little is known about which brain regions are
affected in AD to give rise to sleep disturbances, making it difficult to identify the circuit level mechanisms that
drive dysfunction, or to design targeted therapeutic strategies. This project tests the hypothesis that the
thalamic reticular nucleus (TRN) is a critical brain region in AD, and that impairments in its activity drive sleep
disturbances and exacerbate disease progression. The TRN is a major component of the thalamocortical-
corticothalamic network that regulates sleep, attention, and memory, which are all affected in AD. However,
little is known about the state of TRN in AD patients or in animal models. We found that in transgenic mice
expressing mutant human amyloid precursor protein (APP mice), TRN activity is strikingly reduced, in the
absence of cell loss. Such reductions in TRN activity led to sleep fragmentation and reductions in slow wave
sleep (SWS), and predicted the magnitude of Aβ deposition in both hippocampus and cortex, which may relate
to the fact that SWS is the phase of sleep during which activity-dependent production of Aβ is reduced, and Aβ
is cleared from the brain. Moreover, deficits in SWS and sleep maintenance manifest early in disease in APP
mice, prior to hippocampal deficits, suggesting that TRN impairment may both predict and contribute to
disease progression. The goals of this proposal are to identify cellular mechanisms that impair TRN activity,
and test if selectively manipulating neuronal activity in the TRN can normalize sleep, reduce Aβ accumulation,
and improve memory. To achieve these goals, in Aim 1 we will use electrophysiology and pharmacology in
thalamic slices to identify the intrinsic, synaptic, and network properties of TRN that result in its hypoactivity in
APP mice. In Aim 2, we will use DREADDs to acutely activate TRN cells in APP mice to test if TRN activation
affects dynamics of interstitial Aβ, and/or memory consolidation. In Aim 3, we will use DREADD-mediated
activation of TRN in APP mice to test if chronic activation of TRN can normalize sleep parameters, reduce Aβ
accumulation, and improve memory. Results from this project will have major impact because they: 1) highlight
a vulnerable network early in disease that may predict and contribute to disease progression, and 2) identify a
novel therapeutic strategy with potential to normalize sleep, improve memory, and delay disease progression
in Alzheimer’s disease. Insights gained will also be used to derive general principles about the dynamics of
AD-related proteins like Aβ and tau in the brain, which will impact our ability to treat this complex disease.
项目摘要
睡眠障碍可预测阿尔茨海默病(AD)的风险。睡眠-觉醒周期对大脑的调节至关重要
Aβ和tau的间质液(ISF)水平,这两种关键蛋白在AD中积累。
神经元活动释放的,这是在清醒时高于睡眠。此外,睡眠是一个关键的
ISF中的因素从大脑中清除的阶段。因此,睡眠障碍影响日常生活
功能,也有助于疾病的进展。然而,很少有人知道哪些大脑区域是
在AD中受影响引起睡眠障碍,使得难以确定电路水平机制,
驱动功能障碍,或设计有针对性的治疗策略。该项目测试的假设,
丘脑网状核(TRN)是AD的关键脑区,其活动的损伤驱动睡眠
TRN是丘脑皮层神经元的主要组成部分,
皮质丘脑网络调节睡眠、注意力和记忆,这些都在AD中受到影响。然而,
我们对AD患者或动物模型中TRN的状态知之甚少。我们发现,在转基因小鼠中,
表达突变型人淀粉样前体蛋白(APP小鼠),TRN活性显著降低,
这种TRN活性的减少导致睡眠片段化和慢波的减少。
睡眠(SWS),并预测海马和皮质中Aβ沉积的幅度,这可能与
SWS是睡眠的一个阶段,在这个阶段,Aβ的活动依赖性产生减少,
此外,SWS和睡眠维持的缺陷在APP疾病的早期就表现出来,
小鼠,海马缺陷之前,这表明TRN损伤既可以预测,并有助于
该提议的目标是鉴定损害TRN活性的细胞机制,
并测试选择性地操纵TRN中的神经元活动是否可以使睡眠正常化,减少Aβ积累,
为了实现这些目标,在目标1中,我们将使用电生理学和药理学,
丘脑切片,以确定TRN的内在,突触和网络特性,这些特性导致TRN的活动减退,
在Aim 2中,我们将使用DREADD来急性激活APP小鼠中的TRN细胞,以测试TRN激活是否
影响间质Aβ的动力学和/或记忆巩固。在目标3中,我们将使用DREADD-β介导的
在APP小鼠中激活TRN,以测试TRN的慢性激活是否可以使睡眠参数正常化,减少Aβ
积累,并提高记忆力。从这个项目的结果将有重大影响,因为他们:1)突出
疾病早期的脆弱网络,可以预测和促进疾病进展,以及2)识别
一种新的治疗策略,有可能使睡眠正常化,改善记忆,延缓疾病进展
获得的见解也将用于推导关于阿尔茨海默病的动力学的一般原则。
大脑中与AD相关的蛋白质如Aβ和tau蛋白,这将影响我们治疗这种复杂疾病的能力。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Hippocampal ΔFosB expression is associated with cognitive impairment in a subgroup of patients with childhood epilepsies.
- DOI:10.3389/fneur.2023.1331194
- 发表时间:2023
- 期刊:
- 影响因子:3.4
- 作者:
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Michael Beierlein其他文献
Michael Beierlein的其他文献
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{{ truncateString('Michael Beierlein', 18)}}的其他基金
Corticothalamic circuits mediating behavioral adaptations to unexpected reward omission
皮质丘脑回路介导对意外奖励遗漏的行为适应
- 批准号:
10734683 - 财政年份:2023
- 资助金额:
$ 66.3万 - 项目类别:
Thalamic Reticular Nucleus Dysfunction in Alzheimer's Disease
阿尔茨海默病中的丘脑网状核功能障碍
- 批准号:
10058690 - 财政年份:2020
- 资助金额:
$ 66.3万 - 项目类别:
Thalamic Reticular Nucleus Dysfunction in Alzheimer's Disease
阿尔茨海默病中的丘脑网状核功能障碍
- 批准号:
10396654 - 财政年份:2020
- 资助金额:
$ 66.3万 - 项目类别:
Thalamic Reticular Nucleus Dysfunction in Alzheimer's Disease
阿尔茨海默病中的丘脑网状核功能障碍
- 批准号:
10221592 - 财政年份:2020
- 资助金额:
$ 66.3万 - 项目类别:
Synaptic Integration in Neurons of the Thalamic Reticular Nucleus
丘脑网状核神经元的突触整合
- 批准号:
8273239 - 财政年份:2012
- 资助金额:
$ 66.3万 - 项目类别:
Synaptic Integration in Neurons of the Thalamic Reticular Nucleus
丘脑网状核神经元的突触整合
- 批准号:
8787517 - 财政年份:2012
- 资助金额:
$ 66.3万 - 项目类别:
Synaptic Integration in Neurons of the Thalamic Reticular Nucleus
丘脑网状核神经元的突触整合
- 批准号:
8413847 - 财政年份:2012
- 资助金额:
$ 66.3万 - 项目类别: