Elucidating the role of Locus Coeruleus projections to the Cognitive Cerebellum in mouse models of Alzheimer's Disease (Administrative Supplement)

阐明蓝斑投射对阿尔茨海默氏病小鼠模型中认知小脑的作用(行政补充)

基本信息

项目摘要

This supplemental grant proposal is for the currently funded RO1, “Genetic Dissection of Catecholaminergic Innervation of the Cognitive Cerebellum.” Work derived from this grant so far has implicated an noradrenergic projection circuit from the Locus Ceruleus (LC) to the dentate or lateral nucleus of the cerebellum (LCN) in mice as a locus modulating several cognitive behaviors affected by dementias such as Alzheimer's Disease, including working memory, response inhibition, associative learning of fear, and behavioral flexibility. We propose to interrogate the role of this circuit in order to understand tauopathies such as Alzheimer's Disease. Tauopathies are a group of progressive neurodegenerative disorders with no known disease modifying treatments. Tauopathies include a range of illnesses, including Alzheimer's disease (AD), Chronic Traumatic Encephalopathy (CTE) from traumatic brain injury, some frontotemporal dementias (FTD), and progressive supranuclear palsy (PSP). These illnesses are associated with cognitive dysfunction, neuropsychiatric symptoms, and collectively affect millions of Americans, causing significant morbidity and mortality. The cerebellum has different pathological patterns in these illnesses: in Alzheimer's disease, cerebellar tau deposition and cell death is seen in early onset and familial cases, whereas tau deposition and cell death in cerebellum is commonly seen in CTE, PSP and FTD. While a global effort to cure tauopathies is underway, it is estimated that merely suppressing or delaying the clinical expression of the particular tauopathy, AD, by half could lower the prevalence of dementia by ~80% because of its exponential relationship to age. The deposition of tau is a pathophysiological process that drives both synaptic and neuronal cell loss, leading to cognitive dysfunction. The essential neuropathologic changes of AD are the accumulation of β- amyloid (Aβ) peptides and hyperphosphorylated paired-helical filament (PHF)-τ containing neurofibrillary tangles. The distribution of Aβ and PHF-τ accumulation follows distinct stereotypic patterns across brain regions as AD advances and this pattern seems core to AD pathogenesis. It is also now clear that there is progressive degeneration and neuropathologic changes in subcortical regions of the AD brain. Aβ and PHF-τ deposition in the cerebellum is involved in AD cases with earlier disease onset and greater clinical penetrance. While LC degeneration has long been implicated in the pathogenesis of AD and LC is one of the first brain regions to develop PHF-τ containing neurofibrillary tangles, very little is known about the influence of PHF-τ in the LC on cognitive cerebellar function in AD or PSP. We hypothesize that tau pathology has direct and indirect effects on the cerebellum that contribute to cognitive impairment. We will interrogate the pathological and behavioral consequences with manipulations: first, we will characterize involvement of a LC->LCN circuit in a known mouse model of tauopathy, the P301L mouse line, and second, we will characterize the pathological and behavioral consequences of expressing hyperphosphorylated paired-helical filament (PHF)-τ in two regions: LC and LCN.
这项补充拨款建议是针对目前资助的RO1项目,“基因解剖”。 认知小脑的儿茶酚胺能神经支配.到目前为止,从这笔拨款中得出的研究结果表明 从蓝斑(LC)到齿状核或外侧核的去甲肾上腺素能投射回路 小鼠小脑(LCN)作为调节痴呆影响的认知行为的基因座,如 阿尔茨海默病,包括工作记忆、反应抑制、恐惧的联想学习,以及 行为灵活性。我们建议询问这个回路的作用,以便理解这样的变态现象 是阿尔茨海默氏症。肌萎缩侧索硬化症是一组进行性神经退行性疾病,没有已知的 疾病修正疗法。焦虑症包括一系列疾病,包括阿尔茨海默病(AD), 由创伤性脑损伤引起的慢性创伤性脑病(CTE),一些额颞痴呆(FTD), 和进行性核上性麻痹(PSP)。这些疾病与认知功能障碍有关, 神经精神症状,并共同影响数百万美国人,导致显著的发病率和 死亡率。在这些疾病中,小脑有不同的病理模式:在阿尔茨海默病中, 小脑tau沉积和细胞死亡见于早期和家族性病例,而tau沉积和细胞死亡 小脑细胞死亡多见于CTE、PSP和FTD。虽然全球治疗肥胖症的努力是 正在进行中,估计仅仅是抑制或延迟特定的临床表达 由于AD的指数关系,将AD减半可以将痴呆症的患病率降低约80% 为了变老。Tau的沉积是一个导致突触和神经细胞丢失的病理生理过程, 导致认知功能障碍。阿尔茨海默病的基本神经病理改变是β-1的蓄积。 含有神经原纤维的淀粉样多肽(Aβ)和过度磷酸化的双螺旋微丝(PHF-τ) 唐格斯。β和PHF-τ积聚在大脑中的分布遵循不同的刻板印象模式 随着AD的进展,这一模式似乎是AD发病的核心。现在也很清楚,有 阿尔茨海默病患者大脑皮质下区域的进行性变性和神经病理改变。Aβ和PHF-τ 阿尔茨海默病患者发病较早,临床外显性较强,可累及小脑沉积。 而LC变性长期以来一直与AD的发病机制有关,LC是最早的大脑之一 含有神经原纤维缠结的PHF-τ的发生区域,对PHF-τ对血管内皮细胞生长的影响知之甚少 LC对AD和PSP患者认知小脑功能的影响我们假设tau病理有直接和 对小脑造成认知障碍的间接影响。我们将审问病态的 和操作的行为后果:首先,我们将描述涉及LC->LCN电路的特征 在一个已知的尾部病变小鼠模型中,P301L小鼠品系,第二,我们将描述 表达过磷酸化的双螺旋微丝-τ的病理和行为后果 在两个地区:LC和LCN。

项目成果

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Erik Sean Carlson其他文献

Erik Sean Carlson的其他文献

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{{ truncateString('Erik Sean Carlson', 18)}}的其他基金

Recruitment of Cerebellar Circuits with Balance Training for Cognitive Rehabilitation in a Mouse Model of Mild Traumatic Brain Injury
在轻度创伤性脑损伤小鼠模型中通过平衡训练募集小脑回路进行认知康复
  • 批准号:
    10753349
  • 财政年份:
    2023
  • 资助金额:
    $ 33.47万
  • 项目类别:
Recruitment of Cerebellar Circuits to Modulate Cognition, Reward and Avoidance of Threat
招募小脑回路来调节认知、奖励和避免威胁
  • 批准号:
    10589435
  • 财政年份:
    2023
  • 资助金额:
    $ 33.47万
  • 项目类别:
Genetic Dissection of Catecholaminergic Innervation of the Cognitive Cerebellum
认知小脑儿茶酚胺能神经支配的基因解剖
  • 批准号:
    10223107
  • 财政年份:
    2019
  • 资助金额:
    $ 33.47万
  • 项目类别:
Genetic Dissection of Catecholaminergic Innervation of the Cognitive Cerebellum
认知小脑儿茶酚胺能神经支配的基因解剖
  • 批准号:
    10424496
  • 财政年份:
    2019
  • 资助金额:
    $ 33.47万
  • 项目类别:
Genetic Dissection of Cerebellar Circuitry in Cognitive and Affective Behavior
小脑回路在认知和情感行为中的基因解剖
  • 批准号:
    9294163
  • 财政年份:
    2014
  • 资助金额:
    $ 33.47万
  • 项目类别:
Genetic Dissection of Cerebellar Circuitry in Cognitive and Affective Behavior
小脑回路在认知和情感行为中的基因解剖
  • 批准号:
    8871796
  • 财政年份:
    2014
  • 资助金额:
    $ 33.47万
  • 项目类别:
Genetic Dissection of Cerebellar Circuitry in Cognitive and Affective Behavior
小脑回路在认知和情感行为中的基因解剖
  • 批准号:
    8749902
  • 财政年份:
    2014
  • 资助金额:
    $ 33.47万
  • 项目类别:
Genetic Dissection of Cerebellar Circuitry in Cognitive and Affective Behavior
小脑回路在认知和情感行为中的基因解剖
  • 批准号:
    9099953
  • 财政年份:
    2014
  • 资助金额:
    $ 33.47万
  • 项目类别:
A Genetic Model of Perinatal Iron Deficiency
围产期缺铁的遗传模型
  • 批准号:
    6998625
  • 财政年份:
    2005
  • 资助金额:
    $ 33.47万
  • 项目类别:
A Genetic Model of Perinatal Iron Deficiency
围产期缺铁的遗传模型
  • 批准号:
    7101906
  • 财政年份:
    2005
  • 资助金额:
    $ 33.47万
  • 项目类别:

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激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
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