Epigenetic mechanisms of stress and age-related cognitive decline

项目概要/摘要。下丘脑-垂体-肾上腺轴功能障碍， 调节对压力的生理反应的系统，是老年人记忆丧失的共同特征， 包括老年痴呆症患者事实上，压力和糖皮质激素暴露的累积效应 在整个生命周期中，被认为有助于与年龄相关的记忆丧失，并增强对 阿尔茨海默病通过糖皮质激素受体表达神经元的有害信号改变 在内侧颞叶和额叶中支持正常记忆。海马体的神经活动， 支持陈述性记忆，或前额叶皮层，一个对工作记忆不可或缺的区域， 需要在海马体、锥体神经元和竞争性神经元的持续兴奋之间保持良好的平衡。 抑制由GABA能中间神经元提供。最近发表的和我们实验室的初步研究结果 这表明在衰老或慢性压力下观察到的记忆丧失与改变的 通过这些脑区域中的离子型NMDA受体和代谢型GABAB受体进行信号传导。这些 相似之处表明，在慢性压力和衰老中，一种共同的机制导致记忆丧失， 延伸，压力可能与衰老相互作用，增加记忆丧失的严重程度和对年龄相关疾病的易感性。 神经退行性疾病我们的长期目标是了解转译的分子机制 压力经历转化为神经功能的持久变化，导致整个过程中的记忆丧失。 寿命，并在这样做，确定新的目标，这将导致治疗的发展，保护或 恢复老年人的记忆。这个项目将使用与年龄相关的记忆丧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记忆丧失的脆弱性， 持久地改变编码突触蛋白的基因的转录活性，和2）应激依赖性 老年大脑中的分子变化需要糖皮质激素和盐皮质激素转导的信号 受体。这些发现将是重要的，因为它们将确定特定的分子碱基， 经验和生理因素导致突触功能受损和晚年记忆丧失， 为开发预防和逆转衰老的新治疗方法奠定了重要基础- 相关的记忆丧失。该提案建立在申请人长期致力于研究 衰老和阿尔茨海默病认知能力下降的神经基础在一个 先前的F32奖励将被提前并与新的导师制相结合，提供重要的技术和 尖端分子方法和生物信息学的概念培训。科学知识，技术 在K 01奖项下培养的能力、专业技能和原始数据将直接支持 申请人过渡到一个独立的科学生涯作为PI领导自己的NIH资助的研究计划。

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.