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

通过斑马鱼筛选来识别影响工作记忆和与年龄相关的认知能力下降的基因。

基本信息

批准号：
BB/M007863/1
负责人：
Caroline Brennan
金额：
$ 53.47万
依托单位：
Queen Mary University of London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2015
资助国家：
英国
起止时间：
2015 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FM007863%2F1
关键词：
zebrafish screen identify genes affecting

项目摘要

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.

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会增加，包括心智能力的下降;随着动物年龄的增长，他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，这种身体和精神的恶化并不一致;许多人在80多岁和90多岁时仍然保持良好的健康状况，而另一些人则遭受着日益衰弱的精神衰退和疾病。影响健康老龄化的因素有很多，包括饮食和一般生活方式，但它也受到一个人最初的心理能力和基因构成的影响。在这里，我们的目标是确定基因的影响心理能力和年龄相关的退化记忆和学习使用斑马鱼作为实验系统。斑马鱼已经成为鉴定影响人类发育和疾病的基因的既定系统，因为许多基因和基因调节的细胞生物学过程在鱼类和人类之间是保守的。斑马鱼是寻找影响心理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护外，斑马鱼在2年内逐渐衰老，并且能够执行与哺乳动物和人类相似的行为任务，以评估心理能力和心理衰退。最重要的是，产生携带基因突变的鱼类品系相对容易，并且已经存在许多可以用于我们研究的功能丧失品系。在这里，我们利用携带破坏单个基因功能的突变的斑马鱼品系的可用性来鉴定影响记忆和学习以及这些过程与年龄相关的退化的基因。我们将评估来自50-75个不同鱼类家族的个体，这些鱼类携带特定基因突变，用于评估工作记忆和反应时间（延迟匹配样本，5选择系列反应时间）的行为任务，在2个不同年龄：年轻（6个月）和老年人（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，并在相同的任务中评估来自家庭的另外20-40个兄弟姐妹。当一个家族中的所有突变成员都表现出相同的行为时，突变被认为影响了控制记忆和学习的基因。对6个月时的表现进行分析，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个月时的反应，我们将能够识别影响记忆和反应时间变化率的基因，即心理过程的保守性。这项研究的结果将是阐明基因和分子过程影响心理能力和维持心理能力在老年。重要的是要深入了解与年龄相关的智力衰退的遗传学，因为它有助于了解环境因素如何与遗传学相互作用，以影响老年智力衰退的速度。这些知识有助于我们制定战略，尽量减少老龄化对社会的影响。此外，了解与年龄有关的心理能力变化为评估痴呆等病理疾病状态的影响提供了背景。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Developmental role of acetylcholinesterase in impulse control in zebrafish.

DOI：
10.3389/fnbeh.2015.00271
发表时间：
2015
期刊：
Frontiers in behavioral neuroscience
影响因子：
3
作者：
Parker MO;Brock AJ;Sudwarts A;Teh MT;Combe FJ;Brennan CH
通讯作者：
Brennan CH

Identification of Slit3 as a locus affecting nicotine preference in zebrafish and human smoking behaviour

鉴定 Slit3 作为影响斑马鱼尼古丁偏好和人类吸烟行为的基因座

DOI：
10.1101/453928
发表时间：
2018
期刊：
影响因子：
0
作者：
García-González J
通讯作者：
García-González J

Molecular psychiatry of zebrafish.

DOI：
10.1038/mp.2014.128
发表时间：
2015-02
期刊：
MOLECULAR PSYCHIATRY
影响因子：
11
作者：
Stewart, A. M.;Ullmann, J. F. P.;Norton, W. H. J.;Parker, M. O.;Brennan, C. H.;Gerlai, R.;Kalueff, A. V.
通讯作者：
Kalueff, A. V.

Stress reactivity elicits a tissue-specific reduction in telomere length in aging zebrafish (Danio rerio).