Cell Assemblies, Brain Adaptation and Cognitive Aging

 近年来，在如何在神经网络中表示、存储和检索信息的理论以及研究神经元组之间相互作用的方法学方面取得了巨大进展。啮齿类动物衰老的动物模型表明，海马内连接和可塑性机制的改变有助于改变与空间认知变化相关的网络功能。除了老化过程中颞叶回路和情景记忆的变化外，在整个生命周期中检测到的记忆中的一些最早的变化发生在额叶依赖性任务中，包括工作记忆和注意力。当然，这些认知功能中的每一个都是与我们的环境进行有效互动的必要条件。只有人类才会自发地患上阿尔茨海默病。因此，其他动物提供了一个很好的标准年龄变化的模型。即使是在人类中，美国71岁以上的人中，因各种原因而患痴呆症的比例也是14%。这表明，了解正常的认知老化过程本身是至关重要的，因为这反映了86%的老年人。该提案的两个目的是更好地了解认知老化的两个标志-行为减缓和多任务缺陷的根本原因。这两种认知操作都对前额叶皮层功能和工作记忆的不同方面敏感。每个目标中提出的系统研究利用最适合深入了解人类认知老化这两种现象起源的动物模型来解决这些问题。目的1研究青年和老年大鼠在W-轨迹连续交替任务下的工作记忆及年龄对网络动力学速度的影响。在这个目标中解决的问题包括老化的大脑如何适应海马和PFC固有的动态变化，以及这些结构如何在老化过程中相互作用或竞争，以找到解决这个空间工作记忆问题的方法。虽然啮齿动物模型具有使用不受限制的行为条件和更复杂的记录配置的优势，但在某些情况下，使用非人类灵长类动物具有显着的进化优势，特别是在前额叶皮层和不需要自由运动的任务方面。因此，目的2在干扰任务中检查年轻和老年帽子猕猴的工作记忆，该干扰任务评估清醒时的多任务处理能力，同时监测PFC中记录的神经元群体的活动。在该目的中，首次在衰老灵长类动物模型中检查多任务处理的细胞相关性，来评估衰老是如何削弱工作记忆回路在面对干扰时的恢复力的。对于这些不同的问题，每个模型都有独特的优势，并将使我们能够开始弥合从研究动物模型中学到的原理与人类认知老化的神经基础之间的差距。

 DESCRIPTION (provided by applicant): Dramatic advances have been made in recent years in the theory of how information may be represented, stored and retrieved in neural networks and in the methodology for studying interactions among groups of neurons. Animal models of aging in rodents suggest that altered connectivity and plasticity mechanisms within the hippocampus contribute to altered network function associated with changes in spatial cognition. In addition to changes in temporal lobe circuits and episodic memory during aging, some of the earliest alterations detected in memory across the lifespan occur in frontal lobe-dependent tasks, including working memory and attention. Each of these cognitive functions, of course, is essential for effective interaction with our environment. Only humans spontaneously develop Alzheimer's disease. Thus other animals provide a good model of normative age changes. Even in humans, the proportion of people across the USA over 71 who are demented, from all causes, is 14%. This suggests that it is critical to understand normal cognitive aging processes in their own right, as this reflects 86% of aged individuals. The two Aims of this proposal are to better understand the underlying causes of two hallmarks of cognitive aging - behavioral slowing and multi-tasking deficits. Both of these cognitive operations are sensitive to prefrontal cortical function and different aspects of working memory. The systematic studies proposed in each Aim address each of these questions utilizing the animal model best suited to gaining insight into the origins of these two phenomena of cognitive aging in humans. Aim 1 examines working memory and the effect of age on speed of network dynamics in young and aged rats while performing the W-track continuous alternation task and recording simultaneously from the prefrontal cortex (PFC) and the hippocampus. The questions addressed in this Aim include how the aging brain adapts to the changed dynamics intrinsic to both hippocampus and PFC, and how these structures interact or compete during aging to find solutions to this spatial working memory problem. While rodent models have the advantage of the use of unrestrained behavior conditions and more complex recording configurations, there are cases in which there is significant evolutionary advantage to using nonhuman primates, particularly with respect to the prefrontal cortex and tasks that do not require free movement. Aim 2, therefore, examines working memory in young and aged bonnet macaques in an interference task that evaluates multi-tasking ability in the awake, behaving state while monitoring activity across populations of neurons recorded in PFC. In this Aim, the cellular correlates of multi-tasking are examined for the first time in an aging primate model, to assess how aging weakens the resilience of working memory circuits in the face of interference. For these different questions, each model has unique strengths and will allow us to begin to bridge the gap between principles learned from studying animal models, to those that underlie the neural basis of human cognitive aging.