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

Lead Research Organisation: University of St Andrews
Department Name: Psychology

Abstract

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).

Technical Summary

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.

Planned Impact

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.

Publications

10 25 50
 
Description We have now found that pre-natal stress can have positive impacts on the ability of a bird to learn about a food resource in later life. We have also found that pre-natal stress can have a positive impact on the stress response in later life that lasts throughout ageing. Also we have discovered that early life exposure to stressful stimuli can influence the way in which birds use information from their conspecifics. We are continuing to analyse a large data set on the neural mechanisms that underlie these effects and are still analysing several other behavioural measures that were taken for the birds over a 2 year period.
Exploitation Route Our findings will be of interest to people working in animal welfare as well as neuroscience and behavioural ecology.
Sectors Agriculture, Food and Drink,Environment,Healthcare

 
Description EASTBIO Studentship 2014
Amount £88,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2014 
End 09/2018
 
Description East Bio DTP studentship
Amount £88,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2017 
End 09/2021
 
Description East Bio DTP studentship - Developmental programming of biological rhythms
Amount £88,000 (GBP)
Organisation University of St Andrews 
Sector Academic/University
Country United Kingdom
Start 09/2017 
End 09/2021
 
Description ISSF Wellcome Trust initiative
Amount £19,000 (GBP)
Organisation University of St Andrews 
Sector Academic/University
Country United Kingdom
Start 02/2017 
End 01/2018
 
Description ISSF Wellcome Trust initiative - Eggcellent Roadshow
Amount £13,000 (GBP)
Organisation University of St Andrews 
Sector Academic/University
Country United Kingdom
Start 04/2018 
End 08/2018
 
Description Impact Fund/KE - PokeHormoneGo roadshow funding.
Amount £5,000 (GBP)
Organisation University of St Andrews 
Sector Academic/University
Country United Kingdom
Start 05/2017 
End 01/2018
 
Description RSE sabbatical award
Amount £64,000 (GBP)
Organisation University of St Andrews 
Sector Academic/University
Country United Kingdom
Start 01/2020 
End 12/2020
 
Description Research Grant
Amount £4,992 (GBP)
Organisation British Society for Neuroendocrinology 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2017 
End 03/2018
 
Title Data And Script For: A Marker Of Biological Age Explains Individual Variation In The Strength Of The Adult Stress Response 
Description Data and script for: A marker of biological age explains individual variation in the strength of the adult stress response. Comprises 2 CSV data files and one R script. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
 
Title Early-life adversity programs long-term cytokine and microglia expression within the HPA axis in female Japanese quail 
Description Q-PCR data from published manuscript: Walker, D. J., Zimmer, C., Larriva, M., Healy, S.D. & Spencer, K. A. (2019). Early-life adversity programs long-term cytokine and microglia expression within the HPA axis in female Japanese quail. Journal of Experimental Biology (in press). 
Type Of Material Database/Collection of data 
Year Produced 2019 
Provided To Others? Yes  
 
Title Transgenerational transmission of a stress-coping phenotype programmed by early-life stress in the Japanese quail (dataset) 
Description  
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
 
Description European collaboration on Avian Endocrinology 
Organisation Max Planck Society
Department Max Planck Institute for Ornithology
Country Germany 
Sector Academic/University 
PI Contribution Organisation of symposium at ECBB 2018, Current preparation of Marie Curie International Training Network grant Jan 2019, participation on two international meetings to cement collaboration
Collaborator Contribution As above - also leading the ITN application.
Impact Symposium organised for August 2018
Start Year 2017
 
Description European collaboration on Avian Endocrinology 
Organisation University of Groningen
Country Netherlands 
Sector Academic/University 
PI Contribution Organisation of symposium at ECBB 2018, Current preparation of Marie Curie International Training Network grant Jan 2019, participation on two international meetings to cement collaboration
Collaborator Contribution As above - also leading the ITN application.
Impact Symposium organised for August 2018
Start Year 2017
 
Description European collaboration on Avian Endocrinology 
Organisation University of Lisbon
Country Portugal 
Sector Academic/University 
PI Contribution Organisation of symposium at ECBB 2018, Current preparation of Marie Curie International Training Network grant Jan 2019, participation on two international meetings to cement collaboration
Collaborator Contribution As above - also leading the ITN application.
Impact Symposium organised for August 2018
Start Year 2017
 
Description European collaboration on Avian Endocrinology 
Organisation University of Veterinary Medicine Vienna
Country Austria 
Sector Academic/University 
PI Contribution Organisation of symposium at ECBB 2018, Current preparation of Marie Curie International Training Network grant Jan 2019, participation on two international meetings to cement collaboration
Collaborator Contribution As above - also leading the ITN application.
Impact Symposium organised for August 2018
Start Year 2017
 
Description Development of PE pages in group website 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact We have developed a new website showcasing our research and alongside this we have created PE activity pages, with a dedicated form for PE involvement by several sectors, including schools. We have not assessed hot rates yet and whilst the pages were developed in 2018, the site was only launched in Feb 2019. WE will endeavour to monitor the impacts via correspondence we receive to engage with schools etc. Already 5 schools have contacted us about our Schools roadshow.
Year(s) Of Engagement Activity 2018
URL https://www.moblabgroup.com/public-engagement-outreach
 
Description Development of interactive app - several national science festivals attended 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact 4 major festivals attended - development of interactive app for explanation of research
Year(s) Of Engagement Activity 2017,2018
 
Description Interaction with industry 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Industry/Business
Results and Impact Invited participation to act on an advisory team consisting of representatives at Stonegate Ltd, Clarence Court Eggs Ltd, Crediton Milling (feed supplier), Premier Nutrition and a range of small scale egg producers who work with the company. My work with this group has already resulted in changes to housing conditions and we are now undertaking joint research projects in order to maximise welfare and egg production in socially housed birds.
Year(s) Of Engagement Activity 2019
 
Description Organisation of Science Fair St Andrews 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Science fair organisation - annual event organised by myself.
Year(s) Of Engagement Activity 2016,2017
 
Description Organisation of Science fair 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Annual science fair organised
Year(s) Of Engagement Activity 2018
 
Description Outreach at primary schools 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact PI is currently running an Easter themed activity with local Primary schools. Information given is based on the research being undertaken. Children are incubating and hatching out their own chick sin tie for Easter. Levels involved include P1-P7. media coverage expected in mid March 2016 and further projects like this planned for next year on a larger scale
Year(s) Of Engagement Activity 2016
 
Description Participation in Science fair (UK wide) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Attendance at National science fair with Hypothalamus Hunt app, related to research undertaken on grant. Over 500 members of the general public attended and feedback was highly favourable. App has continued to gather downloads from IOS and Android platforms.
Year(s) Of Engagement Activity 2018
URL https://pocketsizedhands.com/our-work/HypothalamusHunt/
 
Description Participation in explorathon 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Exploration night at Byre Theatre. Stall involving several aspects of group research.
Year(s) Of Engagement Activity 2016
URL http://www.explorathon.co.uk/
 
Description Schools roadshow 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Roadshow based on the App we developed.
Year(s) Of Engagement Activity 2017,2018
 
Description Schools roadshow - developmental biology 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Schools roadshow developed to increase understanding of general developmental biology principles. Interactive sessions (3-4 per class over 4 weeks) at Primary and Pre-school institutions all over Fife and Angus, including special needs units in Dundee. In total 17 institutions were visited reaching multiple classes within these schools. Our work engaged 854 pupils, with 50% of these at pre-school levels. In each of these nurseries we reached the entire cohort. Primary school sessions ranged from P1-6. We have had requests for a more widespread program this year (2019), however funding will be required. In 2019 we have scaled this to 6 institutions due to funding issues.
Year(s) Of Engagement Activity 2018
URL https://www.moblabgroup.com/public-engagement-outreach
 
Description Science Fair organisation 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The PI organised a science fair within the town of St Andrews. Several stalls relevant to her School and her research were designed and run by undergraduate students. Over 150 people attended and left evaluation questionnaires. The plan is also to run this every year.
Year(s) Of Engagement Activity 2015