Catecholaminergic Signaling in Normal Cognition, Aging and Models of Alzheimer's Disease

正常认知、衰老和阿尔茨海默病模型中的儿茶酚胺能信号传导

• 批准号: 10121456
• 负责人: STEVEN A THOMAS
• 金额: $ 250.61万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10121456
• 关键词: Adrenergic Agents; Adrenergic Receptor; Affect; Aging; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Animal Model; Behavioral Paradigm; Brain; Brain Stem; Cell Nucleus; Cognition; Cognitive; Complement; Data; Dementia; Disease; Dopamine; Dorsal; Episodic memory; Exhibits; Functional disorder; Genetic; Goals; Hippocampus (Brain); Impaired cognition; Impairment; Incidence; Lead; Learning; Levodopa; Memory; Memory impairment; Microtubule-Associated Proteins; Modern Medicine; Molecular; Mus; Mutant Strains Mice; Neocortex; Neurodegenerative Disorders; Neuromodulator; Neurons; Norepinephrine; Pathology; Pharmaceutical Preparations; Pharmacology; Phase; Play; Population; Process; Retrieval; Risk Factors; Rodent; Role; Serotonin; Short-Term Memory; Signal Transduction; Source; Symptoms; System; Testing; Time; Training; Ventral Tegmental Area; Wild Type Mouse; aged; cell type; cognitive benefits; dopaminergic neuron; genetic approach; genetic manipulation; hippocampal pyramidal neuron; hyperphosphorylated tau; improved; locus ceruleus structure; memory encoding; memory process; memory recall; memory retrieval; mouse model; neuropathology; neuroregulation; normal aging; novel; novel strategies; novel therapeutics; receptor; restoration; tau Proteins

SUMMARY Alzheimer’s disease (AD) and other dementias are a substantial and rapidly growing societal burden due to the aging of our population. This aging has occurred in part because modern medicine has identified risk factors and treatments for many other diseases, but not for AD. Thus there is a great and unmet need to do so. A hallmark symptom of AD and aging without dementia is impaired memory, including retrieval. Further, some of the earliest neuropathology found in AD is within the systems that provide the neuromodulators dopamine (DA) and norepinephrine (NE) to the brain (including the hippocampus, a center for declarative/episodic memory). The largest brainstem adrenergic nucleus is the locus coeruleus (LC), which supplies all of the NE and a substantial portion of the DA found in the dorsal hippocampus. The LC can also be affected in normal aging. As such, the goal of this proposal is to better understand the roles and mechanisms by which LC-derived DA and NE modulate the encoding and retrieval of declarative/episodic memory. Toward this goal, pharmacologic and genetic manipulations will be performed in rodents, for which there are excellent behavioral paradigms that rely on hippocampus-dependent memory. Our preliminary studies indicate that all three -adrenergic receptors that are activated by NE play a critical role in the hippocampus to promote memory retrieval. They also suggest that adrenergic DA is required for hippocampus-dependent memory. Thus the first aim will examine the molecular and cellular mechanisms by which -adrenergic receptors promote hippocampus-dependent memory using combined pharmacologic and genetic approaches. Subcellular localization of  receptors in the hippocampus will also be determined. The second aim will examine the modulation of hippocampus-dependent memory by “adrenergic” DA using combined pharmacologic and genetic approaches. The third aim will examine the ability of drugs that enhance DA and NE signaling to promote memory in models of AD and aging. The completion of these aims will provide a better understanding of how memory encoding and retrieval is facilitated within the hippocampus, and ultimately may suggest potential targets for enhancing memory in AD and aging.

概括 阿尔茨海默病 (AD) 和其他痴呆症是一个巨大且快速增长的社会负担，原因是 我们的人口老龄化。这种衰老的发生部分是因为现代医学已经确定了危险因素 以及许多其他疾病的治疗方法，但不适用于 AD。因此，这样做的需求巨大且尚未得到满足。一个 AD 和不伴有痴呆的衰老的标志性症状是记忆力受损，包括检索。此外，一些 AD 中最早发现的神经病理学是在提供神经调节剂多巴胺 (DA) 的系统中 去甲肾上腺素 (NE) 进入大脑（包括海马体，陈述性/情景记忆的中心）。 最大的脑干肾上腺素能核是蓝斑 (LC)，它提供所有的 NE 和 大部分 DA 存在于背侧海马体中。正常老化过程中，LC 也会受到影响。 因此，本提案的目标是更好地理解 LC 衍生 DA 的作用和机制 NE 调节陈述性/情景记忆的编码和检索。为实现这一目标，药理学 基因操作将在啮齿类动物中进行，对于啮齿类动物来说，有很好的行为范式 依赖于海马体的记忆。我们的初步研究表明所有三种 -肾上腺素能受体 被 NE 激活的神经元在海马体中对于促进记忆提取起着至关重要的作用。他们还建议 海马依赖性记忆需要肾上腺素能 DA。因此第一个目标将检查 -肾上腺素能受体促进海马依赖性记忆的分子和细胞机制 使用药理学和遗传学相结合的方法。  受体的亚细胞定位 海马体也将被确定。第二个目标将检查海马依赖性的调节 使用药理学和遗传学相结合的方法，通过“肾上腺素能”DA 进行记忆。第三个目标将审查 增强 DA 和 NE 信号传导的药物在 AD 和衰老模型中促进记忆的能力。这 完成这些目标将有助于更好地理解如何促进记忆编码和检索 在海马体内，最终可能会提出增强 AD 和衰老记忆的潜在目标。