The circuit basis of sundowning-related circadian dysfunction in Alzheimer's disease and Alzheimer's disease-related dementias
阿尔茨海默病和阿尔茨海默病相关痴呆中日落相关昼夜节律功能障碍的回路基础
基本信息
- 批准号:10807621
- 负责人:
- 金额:$ 35.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-21 至 2028-08-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAcuteAddressAggressive behaviorAgingAgitationAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease related dementiaAmyloid beta-ProteinAnimal ModelAreaBehavioralBody TemperatureBrain StemCaregiversCholecystokininCircadian DysregulationCircadian RhythmsClinicalDarknessDynorphinsEnterobacteria phage P1 Cre recombinaseFemaleFunctional disorderGoalsHypothalamic structureInstitutionalizationLateralLeadLightModelingMotor ActivityMusMutationNerve DegenerationNeural PathwaysNeuroanatomyNeurobehavioral ManifestationsNeurobiologyNeuronsPathologyPathway interactionsPatientsPhasePhase TransitionPhysiologicalPopulationQuality of lifeResearch Project GrantsResting PhaseRoleSiteSymptomsSyndromeSystemTestingTimeTransgenic MiceWild Type Mouseagedcircadiancircadian pacemakercomorbiditygenetic manipulationhyperphosphorylated tauimprovedmalemouse modelnovelparabrachial nucleuspostsynapticpre-clinicalsuprachiasmatic nucleustetra-4-amidinophenoxypropanetherapeutic targetvector
项目摘要
The long-term goal of this project is to gain an understanding of the circuit mechanisms underlying circadian
dysfunction and associated behavioral disturbances in Alzheimer’s disease (AD) and Alzheimer’s disease
related dementias (ADRD). AD/ADRD are associated with progressive disruption of circadian rhythms,
including body temperature, locomotor activity, and other rhythms, compared to healthy aged-matched
controls. This suggests that AD-related pathology alters the ability of the master circadian pacemaker (the
suprachiasmatic nucleus of the hypothalamus, SCN), to synchronize such rhythms to the daily light-dark cycle.
A particular form of circadian dysfunction in around 20% of AD/ADRD patients is “sundowning”, characterized
by agitation, aggression, and wandering during the late afternoon and early evening. The neurobiology of
sundowning remains unknown, but our lab has developed a working model for how disruption of circadian
pathways in mice may lead to temporal disturbances relevant to sundowning. The SCN is known to regulate
body temperature and locomotor activity rhythms by a pathway through its major postsynaptic target, the
subparaventricular zone (SPZ). We recently showed that aggression propensity in mice also follows a daily
rhythm regulated by the SCN and SPZ through a separate downstream pathway. Importantly, disrupting this
pathway increases aggression around the active-to-rest phase transition, which is temporally analogous to
when sundowning patients show agitation and aggression. AD-associated disruptions to the SCN, SPZ, or their
input pathways, may thus lead to disturbances in body temperature, locomotor activity (in the form of
wandering), and also sundowning-related aggression. To address potential mechanistic connections between
AD-related pathology and circadian function, we conducted behavioral and neuroanatomical analyses in the
TAPP mouse model of AD. We identified the lateral parabrachial nucleus (LPB) in the brainstem as a major
site of pTau, found that the LPB projects to both the SCN and SPZ, and reveal strong evidence of a role for
LPB pTau in AD-related circadian dysfunction and aggression. Here, we will test our hypotheses that the
LPBàSCN/SPZ pathway is required for normal circadian function and that pTau in this pathway underlies AD-
related circadian dysfunction and sundowning-related behavioral disturbances. We will use retrograde delivery
of Cre recombinase from the SCN and SPZ, and Cre-dependent vectors in the LPB to specifically manipulate
LPBàSCN/SPZ neurons. We will determine if chemogenetic manipulations of LPBàSCN/SPZ neurons acutely
ameliorate or exacerbate circadian dysfunction and increased aggression in TAPP mice. We will also express
the P301L mutation (and subsequently pTau) in only LPBàSCN/SPZ neurons in wild-type mice and in mice with
high levels of a-beta to examine interactions between pTau and a-beta in this pathway. Finally, we will use
Cre-mouse lines to target specific LPB subpopulations that differentially project to the circadian system to
determine their respective roles in normal circadian function and pTau-related circadian dysfunction.
该项目的长期目标是了解昼夜节律背后的电路机制
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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William David Todd其他文献
Night and day: distinct retinohypothalamic innervation patterns predict the development of nocturnality and diurnality in two murid rodent species
夜晚和白天:不同的视网膜下丘脑神经支配模式预测两种鼠科啮齿动物的夜间和白天的发展
- DOI:
10.17077/etd.6mzpucsa - 发表时间:
2012 - 期刊:
- 影响因子:2.7
- 作者:
William David Todd - 通讯作者:
William David Todd
William David Todd的其他文献
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{{ truncateString('William David Todd', 18)}}的其他基金
Parsing the pathways of circadian dysfunction and sundowning-related behavioral aggression in dementia and Alzheimer's disease
解析痴呆症和阿尔茨海默病中昼夜节律功能障碍和日落相关行为攻击的途径
- 批准号:
10076507 - 财政年份:2019
- 资助金额:
$ 35.18万 - 项目类别:
Circadian behavior circuits, Alzheimer’s pathology, chemogenetic output and input
昼夜节律行为回路、阿尔茨海默病病理学、化学遗传学输出和输入
- 批准号:
10216281 - 财政年份:2017
- 资助金额:
$ 35.18万 - 项目类别:
Subparaventricular zone pathways to circadian synchrony
室旁区昼夜节律同步途径
- 批准号:
8716117 - 财政年份:2014
- 资助金额:
$ 35.18万 - 项目类别:
Circadian behavior circuits, Alzheimer’s pathology, chemogenetic output and input
昼夜节律行为回路、阿尔茨海默病病理学、化学遗传学输出和输入
- 批准号:
10214051 - 财政年份:
- 资助金额:
$ 35.18万 - 项目类别:
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