Epigenetic mechanisms of stress and age-related cognitive decline

压力和年龄相关认知能力下降的表观遗传机制

• 批准号: 10374129
• 负责人: Joseph Aloysius McQuail
• 金额: $ 11.93万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374129
• 关键词: Adrenal Glands; Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; American; Award; Behavioral; Bioinformatics; Brain; Brain region; Censuses; Chronic stress; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Cognitive; Collaborations; Competence; DNA Methylation; DNA Structure; Data; Dependence; Elderly; Epigenetic Process; Equilibrium; Exposure to; Female; Foundations; Functional disorder; Funding; Gene Expression; Genes; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Glutamates; Goals; Hippocampus (Brain); Hypothalamic dysfunction; Hypothalamic structure; Impaired cognition; Impairment; Individual; Interneurons; Intervention; Knowledge; Laboratories; Lead; Life; Link; Longevity; Medial; Mediating; Mediator of activation protein; Memory; Memory Loss; Memory impairment; Mentored Research Scientist Development Award; Mentorship; Mineralocorticoid Receptor; Modeling; Modification; Molecular; Morphology; N-Methyl-D-Aspartate Receptors; Neurobiology; Neurons; Neurophysiology - biologic function; Neurosecretory Systems; Physiological; Pituitary Gland; Predisposition; Prefrontal Cortex; Proteins; Publishing; Rattus; Research; Research Project Grants; Severities; Sex Differences; Short-Term Memory; Signal Transduction; Site; Stress; Stressful Event; Synapses; Techniques; Technology; Temporal Lobe; Testing; Training; Translating; United States National Institutes of Health; Viral Vector; Work; age related; age related neurodegeneration; aging brain; base; career; design; experience; experimental study; frontal lobe; hippocampal pyramidal neuron; human old age (65+); hypothalamic-pituitary-adrenal axis; improved; mRNA Expression; male; neural circuit; neurotransmission; novel; novel therapeutic intervention; prevent; programs; receptor; relating to nervous system; response; skills; social; synaptic function; therapeutic development; young adult

Project Summary/Abstract. Dysfunction of the hypothalamic-pituitary-adrenal axis, the major neuroendocrine system regulating physiological responses to stress, is a common feature of older individuals with memory loss, including those with Alzheimer’s disease. Indeed, accumulating effects of stress and glucocorticoid exposure across the lifespan are presumed to contribute to age-related memory loss and enhance susceptibility to Alzheimer’s disease via deleterious signaling alterations in glucocorticoid receptor-expressing neurons residing in the medial temporal and frontal lobes that support normal memory. Neural activity in the hippocampus, which supports declarative memory, or the prefrontal cortex, a region that is indispensable for working memory, requires a fine balance between persistent excitation of glutamatergic, pyramidal neurons and competitive inhibition provided by GABAergic interneurons. Recently published and preliminary findings from our laboratory indicate that memory loss observed in aging or following chronic stress is mechanistically linked to altered signaling via ionotropic NMDA receptors and metabotropic GABAB receptors in these brain regions. These similarities suggest a common mechanism contributes to memory loss in chronic stress and aging and, by extension, stress may interact with aging to increase severity of memory loss and susceptibility to age-related neurodegenerative disease. Our long-term goal is to understand the molecular mechanisms that translate stressful experiences into lasting changes in neural function that contribute to memory loss across the full lifespan and, in so doing, identify new targets that will lead to the development of therapeutics that protect or restore memory in older individuals. This project will use a rat model of age-related memory loss to test the hypotheses that 1) stress increases vulnerability to memory loss across the lifespan via DNA methylation that durably modifies transcriptional activity of genes that encode for synaptic proteins and 2) that stress-dependent molecular changes in the aged brain require signaling transduced by glucocorticoid and mineralocorticoid receptors. Such findings would be significant because they will identify specific molecular bases that transform experiential and physiological factors into impaired synaptic function and memory loss in later life and also establish a critical foundation for developing new therapeutic approaches to both prevent and reverse age- related memory loss. This proposal builds on the applicant’s long-standing scientific commitment to investigate the neural basis for cognitive decline in aging and Alzheimer’s disease. Productive collaborations initiated in a prior F32 award will be advanced and combined with new mentorship, affording significant technical and conceptual training in cutting-edge molecular approaches and bioinformatics. The scientific knowledge, technical competence, professional skills and original data cultivated under this K01 award will directly support the applicant’s transition to an independent scientific career as a PI leading his own NIH-funded research program.

项目摘要/摘要。下丘脑 - 垂体 - 肾上腺轴的功能障碍，主要神经内分泌 系统调节对压力的身体反应，是老年人有记忆力丧失的人的共同特征， 包括患有阿尔茨海默氏病的人。确实，累积压力和糖皮质激素暴露的影响 在整个寿命中，都会提出与年龄相关的记忆丧失，并增强对年龄的敏感性 阿尔茨海默氏病通过删除的表达糖皮质激素受体神经元的信号变化 在内侧和额叶中，支持正常内存。海马中的神经活动，该活动 支持声明性记忆或前额叶皮层，该区域对于工作记忆必不可少的区域， 需要在谷氨酸能，金字塔神经元的持续兴奋与竞争性之间保持良好的平衡 GABA能中间神经元提供的抑制作用。最近发表和初步发现的实验室发现 表明在衰老或慢性压力之后观察到的记忆丧失与改变 通过离子NMDA受体和这些大脑区域中代谢性GABAB受体的信号传导。这些 相似性表明一种共同的机制有助于慢性压力和衰老中的记忆力丧失，以及 伸展，压力可能与衰老相互作用，以增加记忆丧失的严重程度和对年龄相关的敏感性 神经退行性疾病。我们的长期目标是了解翻译的分子机制 压力很大的经历，导致神经功能的持久变化，这会导致整个记忆丧失 生命周期以及这样做，确定将导致保护或的理论发展的新目标 恢复老年人的记忆。该项目将使用与年龄相关的记忆损失的大鼠模型来测试 假设1）压力通过DNA甲基化增加了整个生命周期的脆弱性，即 持久地修改了编码突触蛋白的基因的转录活性，2）应激依赖性 老年大脑的分子变化需要糖皮质激素和矿物皮质激素翻译的信号传导 接收者。这样的发现将是重要的，因为它们将确定特定的分子碱基的转化 经验和物理因素，使以后的生命中的突触功能受损和记忆力丧失以及 为开发新的治疗方法建立关键基础，以预防和逆转年龄 相关的记忆损失。该提案以申请人长期的科学承诺为基础 衰老和阿尔茨海默氏病认知能力下降的神经基础。在 先前的F32奖项将得到提出并结合新的Mentalship，提供大量技术和 尖端分子方法和生物信息学的概念培训。科学知识，技术 根据本K01奖培养的能力，专业技能和原始数据将直接支持 申请人过渡到独立的科学生涯，因为PI领导了自己由NIH资助的研究计划。