Molecular and physiological determinants of age-related working memory decline

 描述（由申请人提供）：在改善身体和外周健康方面的成功超过了我们在以后生活中保护大脑健康的能力。随着年龄的增长，记忆投诉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，即在头脑中保存和处理信息的能力，会随着年龄的增长而下降，尽管这种下降背后的前额叶皮层的神经变化仍然不清楚。大多数工作记忆的神经模型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。共分布的GABA能中间神经元在塑造锥体网络活动和提供待记忆信息的特异性方面也起着重要作用。因此，在许多疾病中发生的兴奋性和抑制性信号动力的变化对工作记忆能力有深远的影响，这并不奇怪。我们实验室的初步数据表明，衰老伴随着细胞类型特异性改变，在前额叶皮层GABA（B）受体和NMDA受体信号。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新的干预策略，可以优化整个生命周期的认知功能。我们的基本原理是这些受体特别容易受到伴随衰老过程的细胞损伤（例如，氧化应激或过量糖皮质激素暴露）以及老年PFC中GABA（B）和NMDA受体的受损信号传导可显著改变正常认知所需的兴奋-抑制动力学。因此，本项目将使用工作记忆受损的大鼠模型来检验以下假设：1）NMDA和GABA（B）受体的信号改变有助于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受损和GABA（B）和NMDA受体的改变。本研究采用多学科的方法，将严格的行为/认知分析与生物化学、电生理学和药理学技术相结合，通过1）确定NMDAR功能障碍是否导致老年大鼠工作记忆受损; 2）确定前额叶皮质锥体神经元和中间神经元上GABA（B）和NMDA受体信号的变化如何导致与年龄相关的工作记忆受损;和3）确定应激和糖皮质激素信号传导对GABA（B）和NMDA受体和工作记忆能力的年龄相关变化的贡献。这项提议的发现将是重要的，因为它们将为开发新的治疗方法提供重要的基础，以预防和逆转与年龄相关的认知能力下降。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。

 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.