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

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).

We intend to address two important questions relevant to a range of biomedical and behavioural disciplines: how do developmental and adult environments interact to impact on cognitive decline during ageing and what are the mechanisms that drive these age-related changes? We will gather longitudinal data on cognitive, physiology and neural responses of 128 Japanese quail that have experienced differential exposure to stress during pre- and post-natal development, using yolk injection of physiologically relevant doses of corticosterone and unpredictable food availability, respectively.

We will create 4 distinct developmentally programmed phenotypes: pre-and post-natally stressed; post-natal stress only; pre-natal stress only and pre-and post-natal controls. Birds from each treatment will experience differential exposure to stress during adulthood to allow us to tease apart interactions both within and between life history stages on cognitive performance. We will quantify the physiological stress response (repeated sampling over 30 minutes of corticosterone release following an acute stressor) over the course of the individual's lifetime using validated radioimmunoassay techniques available in the principal applicant's laboratory in association with tests of cognitive performance and measures of HPA axis dysfunction (qPCR techniques analysing expression of GR and MR intracellular receptors in the hippocampus). We will also use fundamental measures of apoptosis in brain regions key for learning and memory (e.g. hippocampus), including quantification of Capsase-3, which initiates the process of DNA cleavage by proteolyzing endonucleases that facilitate neuronal cell death. Conversely, measurement of brain derived neurotrophic factor secretion (BDNF), a neurotrophin growth factor, using validated qPCR techniques, will allow us to determine levels of positive support for neuronal survival and cell growth as well as programmed cell death.

The proposed work will have implications for several research areas, as has already been described in the Academic Beneficiaries section. However, there is significant scope for the results of this study to have a wider societal impact, due to the fundamental nature of our research questions. Every individual faces the prospect of ageing and there is worldwide interest in finding ways to ameliorate the potential negative effects of this degenerative process, particularly with respect to cognitive decline. In order to do this we have to understand not only how different phenotypes may respond to ageing, but also the mechanisms that underlie such age-related changes. The results of this study could therefore feed into social policy making, clinical research and provide a novel animal model for drug interventions and further basic biomedical studies downstream of this application.

This work also has significant welfare implications, as understanding how environmental conditions experienced during early life and during adulthood affect cognitive abilities and responses to stress throughout life is vital in maintaining good practice in animal wellbeing. Members of the research team have already been involved in translating research such as this into practical guidelines for welfare organisations. The proposed project is likely to provide valuable baseline data on which to base suggestions for further changes to current housing and experimental protocols for a range of taxa.
We will maximise the impact of this work by working with relevant stakeholders in industry, where appropriate, and disseminating our results to the general public at science festivals and via museum exhibitions, both at the local and national level. We will also strive to publish our data in high impact journals and maximise media attention in order to enhance our outreach.