Cognitive decline during ageing: understanding the roles of developmental and adult stress.

衰老过程中的认知衰退：了解发育压力和成人压力的作用。

• 批准号: BB/L002264/1
• 负责人: Karen Spencer
• 金额: $ 62.68万
• 依托单位: University of St Andrews
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL002264%2F1
• 关键词: Cognitive; decline; during; ageing; understanding

Ageing is an unavoidable physiological process that begins at conception and results in the progressive loss of function in all organs over time. The ageing process also leads to a general decline in cognitive function, such as learning or memory impairment. More dramatic age-related cognitive decline, as seen in Alzheimer's Disease, causes major reductions in the quality of the affected individual's life as well as significant socio-economic effects. In order to work towards a more healthy cognitively ageing population, we need to determine which mechanisms underlie that decline. It is becoming clear that one of the major factors is stress. When an individual's environment changes unpredictably, for example during periods of food shortage or social conflict, they suffer stress. During stress a series of complex interactions within a hormonal system called the hypothalamic-pituitary-adrenal axis lead to the release of specific chemical messengers (stress hormones) into the bloodstream. In the short-term these hormones benefit the individual as they promote activities that enable coping with that stress. If the stress continues, however, these hormones can have harmful long-term effects, including increased death of cells in brain regions involved in learning and memory and how the individual responds to subsequent stress. Importantly, if a mother is stressed she passes on more stress hormones to her developing offspring, which can have long-term effects on how those offspring behave when they are adults. These changes in behaviour are linked to modifications in the timing of release of stress hormones in a stressful situation, due to a disruption in regulatory systems. Importantly, early life stress results in reduced cognitive performance in adulthood but as stress can occur throughout life, it is important to determine whether, and how, each specific developmental stage (pre- and post-natal) affects later cognitive performance. Therefore the question we propose to address is how early-life experience interacts with adult stress to impact on cognitive performance. Stress is a fact of life and most individuals experience activation of the hypothalamic-pituitary-adrenal axis during both development and adulthood. Therefore we cannot ignore the possibility that developmental and adult stress will have cumulative effects on cognition and neuronal cell death, hastening cognitive decline and potentially increasing the risk of cognitive disorders. Experiments usually use mammalian models of human cognitive disorders to look at cognitive decline, however, discriminating amongst the causes and effects of stress on cognition using mammals is not currently possible. Therefore, we will use Japanese quail as our experimental model animal, a well-developed bird physiological system so that we can conduct the appropriate experimental manipulations required. For our experiments, we would create 4 treatment groups that will experience differing levels of stress during pre- and post-natal development: 1) no experimental stress; 2) stress during both pre- and post-natal development and, 3) and 4) stress during only one developmental phase. This will allow us to determine the relative contribution of each developmental stage to cognitive function and brain physiology in later life. The stressors we use are carefully designed to mimic innate responses to natural stressors that this species experiences in the wild. Once these birds have all reached adulthood, we will further subdivide the groups in 2 to create two adult stress groups, one receiving no stress and the other experiencing unpredictable food availability for short periods on several occasions. We will measure the physiological response to stress, cognitive performance and the levels of cell death and dysfunction of the HPA axis in the brain of individuals from sexual maturity (8 weeks old) through to senescence (2 years old).

衰老是一个不可避免的生理过程，从受孕开始，随着时间的推移，所有器官的功能逐渐丧失。衰老过程还导致认知功能普遍下降，如学习或记忆障碍。更戏剧性的与年龄相关的认知能力下降，如在阿尔茨海默病中所见，导致受影响个体的生活质量大幅下降以及显著的社会经济影响。为了努力实现更健康的认知老龄化人口，我们需要确定这种下降的机制。越来越明显的是，其中一个主要因素是压力。当一个人的环境发生不可预测的变化时，例如在食物短缺或社会冲突期间，他们会受到压力。在压力期间，一系列复杂的激素系统（称为下丘脑-垂体-肾上腺轴）之间的相互作用导致特定化学信使（压力激素）释放到血液中。在短期内，这些激素有利于个人，因为它们促进了能够应对这种压力的活动。然而，如果压力持续下去，这些激素可能会产生有害的长期影响，包括参与学习和记忆的大脑区域的细胞死亡增加，以及个体如何应对随后的压力。重要的是，如果母亲有压力，她会将更多的压力激素传递给她正在发育的后代，这会对这些后代成年后的行为产生长期影响。这些行为的变化与在紧张的情况下，由于调节系统的中断，应激激素释放时间的改变有关。重要的是，早期生活压力会导致成年后认知能力下降，但由于压力可能贯穿一生，因此确定每个特定发育阶段（产前和产后）是否以及如何影响后期认知能力非常重要。因此，我们提出要解决的问题是，早期生活经验如何与成人压力相互作用，影响认知表现。压力是生活中的一个事实，大多数人在发育和成年期间都会经历下丘脑-垂体-肾上腺轴的激活。因此，我们不能忽视发育和成人压力对认知和神经元细胞死亡产生累积影响的可能性，加速认知能力下降并可能增加认知障碍的风险。实验通常使用人类认知障碍的哺乳动物模型来观察认知下降，然而，目前还不可能使用哺乳动物区分压力对认知的原因和影响。因此，我们将使用日本鹌鹑作为我们的实验模型动物，这是一种发育良好的鸟类生理系统，以便我们可以进行所需的适当实验操作。对于我们的实验，我们将创建4个处理组，其将在产前和产后发育期间经历不同水平的压力：1）无实验压力; 2）产前和产后发育期间的压力;以及3）和4）仅在一个发育阶段期间的压力。这将使我们能够确定每个发育阶段对以后生活中认知功能和大脑生理的相对贡献。我们使用的压力源是经过精心设计的，以模仿这个物种在野外经历的自然压力源的先天反应。一旦这些鸟都达到成年，我们将进一步细分为2组，创建两个成年压力组，一个没有压力，另一个在几个场合经历短期不可预测的食物供应。我们将测量从性成熟（8周龄）到衰老（2岁）的个体对压力的生理反应，认知能力以及大脑中HPA轴的细胞死亡和功能障碍水平。

项目成果

Long-term effects of adolescent stress on neophobic behaviors in zebra finches are modulated by social context when in adulthood.

• DOI: 10.1016/j.yhbeh.2017.02.004
• 发表时间: 2017-04
• 期刊: Hormones and behavior
• 影响因子: 3.5
• 作者: Emmerson MG;Spencer KA
• 通讯作者: Spencer KA

Glucocorticoid programming of neuroimmune function.

• DOI: 10.1016/j.ygcen.2017.07.016
• 发表时间: 2018-01
• 期刊: General and comparative endocrinology
• 影响因子: 2.7
• 作者: David J. Walker;K. Spencer

Early-life adversity programs long-term cytokine and microglia expression within the HPA axis in female Japanese quail.

早年的逆境会影响雌性日本鹌鹑 HPA 轴内细胞因子和小胶质细胞的长期表达。

• DOI: 10.1242/jeb.187039
• 发表时间: 2019
• 期刊: The Journal of experimental biology
• 作者: Walker DJ

Wild jackdaws' reproductive success and their offspring's stress hormones are connected to provisioning rate and brood size, not to parental neophobia.

• DOI: 10.1016/j.ygcen.2016.11.006
• 发表时间: 2017-03-01
• 期刊: General and comparative endocrinology
• 影响因子: 2.7
• 作者: Greggor AL;Spencer KA;Clayton NS;Thornton A
• 通讯作者: Thornton A

Transgenerational transmission of a stress-coping phenotype programmed by early-life stress in the Japanese quail.

• DOI: 10.1038/srep46125
• 发表时间: 2017-04-07
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Zimmer C;Larriva M;Boogert NJ;Spencer KA
• 通讯作者: Spencer KA