Information Processing and Age-Related Declines in General Cognitive Abilities

描述(申请人提供)：关于年龄相关认知缺陷的动物研究通常集中在衰老对特定学习任务或领域的影响。虽然这种方法提供了关于特定任务(甚至特定领域)学习障碍的大脑基础的信息，但这种方法几乎没有提供关于衰老对一般认知/学习能力的影响的洞察力。对孤立任务或领域的普遍关注限制了我们对“认知老化”的理解，因为据估计，35%-60%的与年龄相关的认知表现下降可归因于个人总体认知能力的下降，即超越任何单一任务或领域的特定要求的认知表现能力的下降。我们已经开发了独特的测试和分析方案，这些方案对一般学习因素敏感，该因素可以解释年轻成年实验室小鼠一般认知表现的32%的差异。我们已经开始将这种方法应用于对整个生命周期的动物的研究，并在20个月大的BALB-C小鼠中分离出了一个一般认知因素，它可以解释这些动物一般认知能力差异的40%以上。虽然在结构上与幼年动物的结构相似，但在老年动物中，这一“一般认知因素”始终占老年动物认知表现总差异的更大比例，这表明一般认知能力在动物的整个生命周期中变得越来越重要。此外，我们已经证实，在老年动物中，一般认知能力越来越依赖于工作记忆的各个方面，特别是工作记忆广度(抵抗衰退)和工作记忆容量(抵抗干扰)。此外，在整个生命周期中，认知能力的普遍下降并不是均匀的，因此，一些老年动物保留了他们的认知能力，而在另一些动物中，这些能力迅速下降，这种影响与体重增加和一般活动减少有关。我们现在假设，老年动物的普遍认知能力下降是工作记忆系统效能受到干扰的结果，工作记忆系统包括工作记忆广度、容量和选择性注意。我们将在目标1和目标2中测试这些可能性，在这样做的过程中，我们将获得关键的洞察力，了解与年龄相关的认知下降的基础过程。然后，在目标3中，可以测试特定的行为策略(包括对体重、活动和工作记忆效能的控制)，以使动物免受这些下降的影响，并可能减缓先前例示的与年龄相关的下降的进展。这项工作将为随后阐明与年龄相关的认知障碍的大脑底物(如我们的辅助目标中所述)提供概念和经验上的坚实基础，并最终开发克服这些障碍的策略。公共卫生相关性：迫切需要制定治疗与衰老相关的正常但普遍存在的认知障碍的策略。要做到这一点，我们必须量化与衰老相关的认知缺陷，了解认知衰老出现的变异性(即个体差异)，并阐明认知衰老背后的心理过程。这项研究计划的目标是量化整个生命周期中认知能力的下降，并制定行为干预策略，促进认知能力在老年时的成功维持。

DESCRIPTION (provided by applicant): Animal research on age-related cognitive deficits has typically focused on the impact of aging on specific learning tasks or domains. While informative regarding the brain substrates for task- specific (or even domain-specific) learning impairments, this approach provides little insight into the impact of aging on general cognitive/learning abilities. The prevailing focus on isolated tasks or domains has limited our understanding of "cognitive aging", as it has been estimated that 35-60% of age-related declines in cognitive performance are attributable to a diminishment of individuals' general cognitive ability, i.e., the capacity for cognitive performance that transcends the specific demands of any single task or domain. We have developed unique testing and analysis regimens that are sensitive to a general learning factor that accounts for >32% of the variance in the general cognitive performance of young adult laboratory mice. We have begun to apply this approach to studies of animals across the life span, and have isolated a general cognitive factor in 20 month old BALB-C mice that accounts for greater than 40% of the variance in the general cognitive abilities of these animals. While comparable in structure to that of young animals, in old animals this "general cognitive factor" consistently accounts for a greater proportion of the total variance in the cognitive performance of aged animals, suggesting that general cognitive abilities become increasingly dominant across the animal's life span. Moreover, we have established that in aged animals, general cognitive abilities become increasingly reliant on aspects of working memory, particularly, working memory span (resistance to decay) and working memory capacity (resistance to interference). Furthermore, general cognitive declines do not accrue homogeneously across the life span, such that some percentage of aged animals retain their cognitive abilities, while in others, these abilities decline rapidly, an effect associated with increasing body mass and decreases in general activity. We now hypothesize that the general cognitive decline in aged animals is the consequence of perturbations in the efficacy of the working memory system, including working memory span, capacity, and selective attention. We will test these possibilities in Aims 1 and 2, and in so doing, will gain critical insight into the processes that underlie age-related cognitive declines. It will then be possible in Aim 3 to test specific behavioral strategies (including manipulations of body weights, activity, and working memory efficacy) to innoculate animals against these declines, and possibly, to mitigate the progression of age-related declines that were previously instantiated. This work will provide a conceptually and empirically strong foundation for subsequent elucidation of the brain substrates for age-related cognitive impairments (as described in our Ancillary Aim), and ultimately, the development of strategies to overcome these impairments. PUBLIC HEALTH RELEVANCE: A critical need has emerged to develop strategies with which to treat the normal but pervasive cognitive impairments that are associated with aging. To do so, we must quantify the cognitive deficits associated with aging, understand the variability (i.e., individual differences) in the emergence of cognitive aging, and elucidate the psychological processes that underlie cognitive aging. The goal of this research program is to quantify cognitive declines across the life span, and to generate behavioral intervention strategies that facilitate the successful maintenance of cognitive abilities into old age.