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

衰老是一个不可避免的生理过程，从受孕开始，随着时间的推移导致所有器官功能的逐渐丧失。衰老过程还会导致认知功能的普遍下降，比如学习或记忆障碍。如阿尔茨海默氏病中所见，与年龄有关的认知能力下降更为严重，导致受影响个人的生活质量大幅下降，并产生重大的社会经济影响。为了使认知能力日益老化的人口更加健康，我们需要确定导致这种衰退的机制。越来越清楚的是，其中一个主要因素是压力。当个体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，他们就会承受压力。在压力下，被称为下丘脑-垂体-肾上腺轴的激素系统中一系列复杂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，这些激素有利于个体，因为它们促进了能够应对压力的活动。然而，如果压力持续下去，这些激素会产生有害的长期影响，包括大脑中与学习和记忆有关的区域细胞的死亡增加，以及个体对后续压力的反应。重要的是，如果母亲感到压力，她会将更多的压力激素传递给正在发育的后代，这可能会对这些后代成年后的行为产生长期影响。这些行为上的变化与在紧张情况下释放压力激素的时间改变有关，这是由于调节系统的破坏。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，因此确定每个特定的发育阶段（产前和产后）是否以及如何影响后来的认知能力是很重要的。因此，我们提出的问题是，早期生活经历如何与成年压力相互作用，从而影响认知表现。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，我们不能忽视这样一种可能性，即发育和成年压力会对认知和神经元细胞死亡产生累积影响，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能力下降，然而，目前还不可能使用哺乳动物来区分压力对认知能力的原因和影响。因此，我们将日本鹌鹑作为我们的实验模型动物，这是一种成熟的鸟类生理系统，我们可以进行适当的实验操作。在我们的实验中，我们将创建4个实验组，这些实验组将在产前和产后发育期间经历不同程度的压力：1)没有实验压力；2)产前和产后发育期间的压力；3)和4)仅在一个发育阶段的压力。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学的相对贡献。我们使用的压力源是精心设计的，以模仿这个物种在野外经历的对自然压力源的先天反应。一旦这些鸟都成年了，我们将进一步把它们分成两组，形成两个成年压力组，一个没有压力，另一个在几次短时间内经历不可预测的食物供应。我们将测量个体从性成熟（8周龄）到衰老（2岁）对压力的生理反应、认知表现以及大脑中HPA轴的细胞死亡和功能障碍水平。

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).