Molecular and physiological determinants of age-related working memory decline

与年龄相关的工作记忆衰退的分子和生理决定因素

• 批准号: 9135918
• 负责人: Joseph Aloysius McQuail
• 金额: $ 5.8万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-14 至 2018-08-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9135918
• 关键词: Adaptive Behaviors; Age; Age-associated memory impairment; Aging; Aging-Related Process; American; Attenuated; Automobile Driving; Behavioral; Biochemical; Biological Neural Networks; Chronic; Clinical; Cognition; Cognitive; Data; Disease; Elderly; Electrophysiology (science); Foundations; Functional disorder; Future; GABA-B Receptor; Glucocorticoids; Goals; Health; Hippocampus (Brain); Impaired cognition; Impairment; Individual; Interneurons; Intervention; Laboratories; Lead; Life; Link; Longevity; Maintenance; Mediating; Memory; Memory Loss; Memory impairment; Methods; Mind; Modeling; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Neurophysiology - biologic function; Neurotransmitter Receptor; Oxidative Stress; Peripheral; Personal Satisfaction; Physiological; Play; Population; Positioning Attribute; Prefrontal Cortex; Publishing; Quality of life; Rattus; Receptor Signaling; Recurrence; Research; Research Project Grants; Role; Short-Term Memory; Signal Transduction; Specificity; Stress; Synapses; System; Techniques; Testing; Therapeutic; Training; Work; age related; aged; aging brain; base; brain health; career; cell type; cognitive capacity; cognitive change; cognitive function; developmental disease; experience; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; hypothalamic-pituitary-adrenal axis; improved; insight; interdisciplinary approach; mental representation; middle age; neural circuit; neural model; neuropsychiatric disorder; novel; patch clamp; prevent; public health relevance; receptor; relating to nervous system; research study; social; success

 DESCRIPTION (provided by applicant): Successes in improving somatic and peripheral health outpace our ability to protect brain health later in life. With advanced age, memory complaints become more frequent and severe and the manifestation of cognitive dysfunction poses a threat to the personal independence and well-being of our growing senior citizen population. Working memory, the ability to hold and manipulate information "in mind", is widely known to decline with age although the neural changes within the prefrontal cortex that underlie this decline remain poorly defined. Most neural models of working memory support that persistent excitation of pyramidal neurons is required for the maintenance of information in working memory stores. Co-distributed GABAergic interneurons also play an important role in sculpting pyramidal network activity and providing specificity for the to-be-remembered information. As such, it is not surprising that shifts in excitatory and inhibitory signaling dynamcs that occur in a number of diseases have profound consequences for working memory abilities. Preliminary data from our laboratory indicates that aging is accompanied by cell-type specific alterations in both prefrontal cortical GABA(B) receptor and NMDA receptor signaling. Our long-term goal is to understand both the causative factors and cognitive consequences of these signaling alterations within PFC and to use this information to identify novel intervention strategies that can optimize cognitive function across the full lifespan. Our rationale is that thee receptors are particularly vulnerable to cellular insults that accompany the aging process (e.g., oxidative stress or excessive glucocorticoid exposure) and that compromised signaling at GABA(B) and NMDA receptors in the aged PFC could markedly alter excitatory-inhibitory dynamics required for normal cognition. This project will, therefore, use a rat model of impaired working memory to test the hypotheses that 1) altered signaling at NMDA and GABA(B) receptors contributes to age-related decline of working memory abilities and 2) that chronic variable stress that mimics age-related hypothalamic-pituitary- adrenal axis dysfunction is sufficient to produce both working memory impairment and alterations in GABA(B) and NMDA receptors. Using a multidisciplinary approach that integrates rigorous behavioral/cognitive analysis with biochemical, electrophysiological and pharmacological techniques we will test our hypotheses by 1) determining if NMDAR dysfunction contributes to impaired working memory in aged rats; 2) determining how changes in GABA(B) and NMDA receptor signaling on prefrontal cortical pyramidal neurons and interneurons contribute to age-related working memory impairment; and 3) determining the contribution of stress and glucocorticoid signaling to age-related changes in GABA(B) and NMDA receptors and working memory abilities. Findings from this proposal will be significant because they will provide a critical foundation for developing ne therapeutic approaches to both prevent and reverse age-related cognitive decline. Furthermore, the proposed research will afford the applicant significant technical, conceptual and professional training in support of his stated career goals and objectives.

 描述（由申请人提供）：改善躯体和周围健康的成功超过了我们在以后的生活中保护大脑健康的能力。随着年龄的增长，记忆问题变得更加频繁和严重，认知功能障碍的表现对我们不断增长的老年人口的个人独立和福祉构成威胁。众所周知，工作记忆，即“记住”和操纵信息的能力，会随着年龄的增长而下降，尽管导致这种下降的前额皮质内的神经变化仍不清楚。大多数工作记忆的神经模型都支持锥体神经元的持续兴奋是维持工作记忆存储中的信息所必需的。共同分布的 GABA 能中间神经元在塑造金字塔网络活动和为要记住的信息提供特异性方面也发挥着重要作用。因此，许多疾病中发生的兴奋性和抑制性信号动力学的变化对工作记忆能力产生深远的影响也就不足为奇了。我们实验室的初步数据表明，衰老伴随着前额皮质 GABA(B) 受体和 NMDA 受体信号传导的细胞类型特异性改变。我们的长期目标是了解 PFC 内这些信号改变的致病因素和认知后果，并利用这些信息来确定可以优化整个生命周期认知功能的新干预策略。我们的理由是，这些受体特别容易受到伴随衰老过程的细胞损伤（例如，氧化应激或过量的糖皮质激素暴露），并且老年PFC中GABA（B）和NMDA受体信号传导的受损可能会显着改变正常认知所需的兴奋-抑制动力学。因此，该项目将使用工作记忆受损的大鼠模型来测试以下假设：1) NMDA 和 GABA(B) 受体信号传导的改变导致与年龄相关的工作记忆能力下降；2) 模拟与年龄相关的下丘脑-垂体-肾上腺轴功能障碍的慢性可变应激足以产生工作记忆损伤和 GABA(B) 和 GABA(B) 的改变。 NMDA 受体。使用将严格的行为/认知分析与生化、电生理学和药理学技术相结合的多学科方法，我们将通过以下方式测试我们的假设：1）确定 NMDAR 功能障碍是否会导致老年大鼠工作记忆受损； 2) 确定前额皮质锥体神经元和中间神经元上的 GABA(B) 和 NMDA 受体信号传导的变化如何导致与年龄相关的工作记忆损伤； 3) 确定压力和糖皮质激素信号传导对 GABA(B) 和 NMDA 受体以及工作记忆能力的年龄相关变化的影响。该提案的结果将具有重要意义，因为它们将为开发新的治疗方法来预防和逆转与年龄相关的认知衰退提供重要的基础。此外，拟议的研究将为申请人提供重要的技术、概念和专业培训，以支持其既定的职业目标和目标。