A zebrafish screen to identify genes affecting working memory and age-related cognitive decline.

随着饮食和保健的进步，人口的总体年龄有所增加。随着年龄的增长，与年龄有关的疾病也在增加，包括智力下降；随着动物年龄的增长，它们的记忆力和学习新事物的能力以及适应环境变化的能力都会下降。然而，这种身体和精神上的恶化是不一致的；有许多人一直健康到八九十岁，而另一些人则遭受着日益衰弱的智力衰退和疾病。影响健康老龄化的因素有很多，包括饮食和一般生活方式，但也受到一个人最初的智力和基因构成的影响。在这里，我们的目标是确定影响心智能力和年龄相关的记忆和学习退化的基因，以斑马鱼为实验系统。斑马鱼已经成为鉴定影响人类发育和疾病的基因的成熟系统，因为许多基因及其调控的细胞生物学过程在鱼类和人类之间是保守的。斑马鱼是寻找影响智力衰老的基因的理想系统，因为除了遗传结构和神经过程的保存之外，斑马鱼在2年的时间内逐渐衰老，并且能够执行类似于哺乳动物和人类用于评估智力能力和智力衰退的行为任务。最重要的是，产生携带基因突变的鱼种相对容易，而且许多可用于我们研究的丧失功能的鱼种已经存在。在这里，我们利用携带破坏单个基因功能的突变的斑马鱼系的可用性来识别影响记忆和学习以及这些过程与年龄相关的退化的基因。我们将对来自50-75个不同鱼类家族的个体进行评估，这些个体携带特定基因突变，用于评估通常用于评估工作记忆和反应时间（延迟匹配样本，5个选择序列反应时间）的行为任务的表现，这些个体在2个不同年龄：幼年（6个月）和老年（2岁）。与正常种群相比，在这些任务中表现非常好或非常差的鱼被保留下来，并从家庭中额外评估20-40个兄弟姐妹在相同任务中的表现。当一个家族中的所有突变成员表现出相同的行为时，这种突变被认为影响了控制记忆和学习某一方面的基因。6个月大的表现分析将确定影响学习、记忆和反应时间的基因，作为心理能力本身的衡量标准。通过比较2岁和6个月婴儿的反应，我们将能够识别影响记忆变化率和反应时间的基因，即心理过程的保存。这项研究的结果将是阐明影响老年心理能力和维持心理能力的基因和分子过程。深入了解与年龄相关的智力退化的遗传学是很重要的，因为它有助于理解环境因素如何与遗传学相互作用，从而影响老年人智力下降的速度。这些知识有助于我们制定策略，尽量减少老龄化对社会的影响。此外，了解与年龄相关的心智能力变化为评估病理性疾病状态（如痴呆）的影响奠定了基础。

With advances in diet and health care there has been an increase in the general age of the population. With increases in age comes an increase in age-related disease including a decline in mental ability; As animals age their memory and ability to learn new things as well as to adapt to changes in their surroundings declines. However, this physical and mental deterioration is not uniform; there are many who continue with good health well into their 80s and 90s whilst others suffer increasingly debilitating mental decline and disease. There are many factors that influence healthy ageing including diet and general life style but it is also influenced by ones initial mental ability and genetic makeup. Here we aim to identify genes that influence mental ability and age-related deterioration in memory and learning using zebrafish as the experimental system. Zebrafish have become an established system for the identification of genes affecting human development and disease as many genes and the cell biological processes the genes regulate are conserved between fish and humans. Zebrafish are an ideal system in which to search for genes affecting mental ageing as, in addition to conservation of genetic structure and neural processes, zebrafish show gradual ageing over a 2 year period and are capable of performing behavioural tasks similar to those used in mammals and humans to assess mental ability and mental decline. Above all, it is relatively easy to generate lines of fish carrying genetic mutations and many loss of function lines that can be used in our studies already exist.Here we take advantage of the availability of lines of zebrafish that carry mutations disrupting the function of individual genes to identify genes that affect memory and learning and age-related deterioration of these processes. We shall assess individuals from 50-75 different families of fish that carry mutations in specific genes for performance in behavioral tasks commonly used to assess working memory and response times (delayed matching to sample, 5 choice serial reaction time), at 2 different ages: young (6 months) and old (2 years). Fish that perform very well or very badly in these tasks when compared to a normal population are kept and an additional 20-40 siblings from the family assessed in the same tasks. When all mutant members within a family show the same behaviour, the mutation is taken as affecting a gene that controls an aspect of memory and learning. Analysis of performance at 6 months will identify genes affecting learning, memory and response times as measures of mental ability per se. By comparing responses at 2 years with those at 6 months we will be able to identify genes affecting the rate of change in memory and response times i.e the conservation of mental processes. The outcome of this study will be the elucidation of genes and molecular processes influencing mental ability and maintenance of mental ability in old age. It is important to gain insight into the genetics of age-related mental deterioration as it helps understanding of how environmental factors may interact with genetics to influence the rate of mental decline in old age. This knowledge helps us develop strategies to minimize the impact of ageing on society. Moreover, understanding age-related changes in mental ability sets a background against which it is possible to assess the effects of pathological disease states such as dementia.