Hypocretin/orexin modulation of cognitive correlates of brain aging

下丘脑分泌素/食欲素对大脑衰老认知相关性的调节

基本信息

批准号：
10445459
负责人：
JIM R FADEL
金额：
$ 110.09万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10445459
关键词：
Acetylcholine Acute Age Age-associated memory impairment Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Animals Attention Behavioral Cells Chronic Cognition Cognitive Dementia Disease Eating Exposure to Functional disorder Gene Transfer Hippocampus (Brain)Hypothalamic structure Impaired cognition Impairment Inflammatory Intervention Intranasal Administration Lead Learning Lewy Body Dementia Lewy Body Disease Link Lipopolysaccharides Long-Term Effects Longevity Maintenance Mediating Memory Microglia Morphology Narcolepsy Nerve Degeneration Neurobehavioral Manifestations Neurons Neuropeptides Neurotransmitters Pathology Peptides Performance Peripheral Pharmacology Physiological Play Process Rattus Regulation Rodent Model Role Signal Transduction Sleep Wake Cycle Source Stimulus System Testing Therapeutic Vascular Dementia Virus Work age related aged aging brain analog basal forebrain basal forebrain cholinergic neurons cholinergic cholinergic neuron cognitive function cognitive performance cytokine executive function experimental study gene therapy hypocretin knock-down middle age nerve supply neurochemistry neurocognitive disorder neuroinflammation neurotransmission novel preservation prevent response restoration sustained attention targeted treatment transmission process

项目摘要

The primary neurotransmitter hallmark of Alzheimer’s Disease (AD) is a loss of acetylcholine, produced by neurons of the basal forebrain cholinergic system (BFCS). Cholinergic cell loss or dysfunction is also a prominent component of Lewy Body Dementia and vascular dementia, respectively. Thus the BFCS contributes to several aspects of cognitive function that are negatively impacted in AD and related dementias, including attention, learning and memory. Regulation of the BFCS by afferent inputs, including those from the hypothalamus, is important for integration of homeostatic and cognitive functions. Because homeostatic and physiological disturbances, such as altered food intake or sleep-wake cycles, often precede and predict cognitive decline in AD, understanding these interactions may lead to novel points of intervention to treat or delay cognitive decline in conditions such as AD. An important source of this afferent regulation is the hypothalamic orexin/hypocretin neuropeptide system, which activates cholinergic neurons in response to stimuli that signal physiological valence. We have previously shown that aging, the strongest risk factor for AD, is associated with reduced orexin expression. Recently, orexin transmission has been shown to play a role in limiting neuroinflammation, suggesting that a diminished orexin system in aging may promote neuroinflammatory processes that further negatively impact cholinergic-dependent signaling and cognition. In this renewal application, we will dissect the mechanisms underlying the association between loss of orexin signaling, neuroinflammation and subsequent cholinergic dysfunction and neurodegeneration in an aged rodent model using virus-mediated gene transfer, neurochemical, pharmacological and cognitive behavioral approaches. We will further test the hypothesis that chronic restoration and maintenance of orexin function beginning in early aging will preserve the integrity of the BFCS by modulating local microglial dynamics. The proposed studies will begin to delineate the mechanisms by which age-related loss of orexin signaling drives cholinergic dysfunction and cognitive decline and suggest the potential for orexin-targeted therapies in preventing or ameliorating AD or related dementias, all of which are characterized by neuroinflammation and cholinergic dysfunction.

阿尔茨海默氏病 (AD) 的主要神经递质标志是由基底前脑胆碱能系统 (BFCS) 神经元产生的乙酰胆碱丧失，胆碱能细胞丧失或功能障碍也分别是路易体痴呆和血管性痴呆的重要组成部分。 BFCS 有助于认知功能的多个方面，这些方面在 AD 和相关痴呆症中受到负面影响，包括传入神经对 BFCS 的调节。包括来自下丘脑的输入对于稳态和认知功能的整合非常重要，因为稳态和生理紊乱（例如食物摄入或睡眠-觉醒周期）通常先于并预测 AD 的认知衰退，了解这些相互作用可能会带来新的结果。治疗或延缓 AD 等认知能力下降的干预点这种传入调节的一个重要来源是下丘脑食欲素/下丘脑分泌素神经肽系统，它会激活胆碱能神经元以响应刺激。我们之前已经证明，衰老是 AD 的最强危险因素，与食欲素表达减少有关。最近，食欲素传递已被证明在限制神经炎症方面发挥作用，这表明衰老过程中食欲素系统的减少可能会促进食欲素的表达。进一步负面影响胆碱能依赖性信号传导和认知的神经炎症过程在这个更新应用中，我们将剖析食欲素信号传导丧失、神经炎症和随后的胆碱能功能障碍之间的关联机制。我们将使用病毒介导的基因转移、神经化学、药理学和认知行为方法，在老年啮齿动物模型中进一步检验这样的假设：从衰老早期开始慢性恢复和维持食欲素功能将通过调节局部小胶质细胞来保持 BFCS 的完整性。拟议的研究将开始描述与年龄相关的食欲素信号丧失导致胆碱能功能障碍和认知能力下降的机制，并表明食欲素靶向疗法在预防或改善 AD 或相关疾病方面的潜力。痴呆症，所有这些疾病的特征都是神经炎症和胆碱能功能障碍。