Information Processing and Age-Related Declines in General Cognitive Abilities

描述（由申请人提供）：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上。虽然关于任务特异性（或甚至领域特异性）学习障碍的大脑基质的信息，但这种方法对衰老对一般认知/学习能力的影响提供了很少的见解。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体一般认知能力的降低，即，超越任何单一任务或领域的特定需求的认知能力。我们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，该因素占年轻成年实验室小鼠一般认知表现方差的>32%。我们已经开始将这种方法应用于整个生命周期的动物研究，并在20个月大的BALB-C小鼠中分离出一种一般认知因素，该因素占这些动物一般认知能力方差的40%以上。虽然在结构上与年轻动物相当，但在老年动物中，这种“一般认知因素”始终占老年动物认知表现总方差的更大比例，这表明一般认知能力在动物的寿命中变得越来越占主导地位。此外，我们已经确定，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（抗衰退）和工作记忆容量（抗干扰）。此外，一般认知能力的下降在整个生命周期中并不均匀，因此一些老年动物保留了他们的认知能力，而在其他动物中，这些能力迅速下降，这与体重增加和一般活动减少有关。我们现在假设，老年动物的一般认知能力下降是工作记忆系统（包括工作记忆广度、容量和选择性注意力）功效紊乱的结果。我们将在目标1和2中测试这些可能性，并在这样做的过程中，将获得关键的洞察力，以了解与年龄相关的认知能力下降的过程。然后，在目标3中可以测试特定的行为策略（包括体重、活动和工作记忆功效的操作），以接种动物对抗这些下降，并可能减轻先前实例化的年龄相关下降的进展。这项工作将提供一个概念和经验上的强大基础，为随后的阐明与年龄相关的认知障碍的大脑基板（如我们的辅助目标中所述），并最终制定策略，以克服这些障碍。公共卫生相关性：一个关键的需求已经出现，以制定战略，以治疗正常的，但普遍的认知障碍，与老化。要做到这一点，我们必须量化与衰老相关的认知缺陷，了解变异性（即，个体差异）在认知老化的出现，并阐明认知老化的心理过程。这项研究计划的目标是量化整个生命周期中的认知下降，并制定行为干预策略，以促进认知能力的成功维持到老年。

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.