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:10058690
- 负责人:
- 金额:$ 75.8万
- 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-ProteinAmyloid beta-Protein PrecursorAnimal ModelAttentionBehaviorBrainBrain regionCell NucleusCellsChronicCognitionCognitiveCognitive deficitsComplexDepositionDiseaseDisease ProgressionDisinhibitionElectrophysiology (science)ExhibitsFunctional disorderGoalsHippocampus (Brain)Human Amyloid Precursor ProteinImpairmentIntercellular FluidLeadMaintenanceMediatingMemoryMemory impairmentMicrodialysisMusNeuronsPathologyPeptidesPharmacologyPhasePropertyProteinsSleepSleep ArchitectureSleep DeprivationSleep FragmentationsSleep Wake CycleSleep disturbancesSliceSlow-Wave SleepSynapsesTestingThalamic structureTherapeuticTransgenic MiceViralWakefulnessabeta accumulationabeta depositionbasedaily functioningdesigndesigner receptors exclusively activated by designer drugsimprovedin vivoinsightinterstitialmemory consolidationmouse modelmutantneuron lossneurotoxicnovelnovel therapeuticspublic health relevancerestorationtargeted 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.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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:
$ 75.8万 - 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:
$ 75.8万 - 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:
10612400 - 财政年份:2020
- 资助金额:
$ 75.8万 - 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:
$ 75.8万 - 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:
$ 75.8万 - 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:
$ 75.8万 - 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:
$ 75.8万 - 项目类别: