Mapping a route through age-related cognitive decline

Even in the absence of neurodegenerative diseases, our brains age, disrupting memory and affecting our decision-making processes. Stephen Brickley and Paul Chadderton of Imperial College London are using a number of new techniques to investigate how changes in the connections between neurons may hold the key to understanding the brain’s ageing process.
Some people maintain excellent cognitive function well into old age, while others’ abilities markedly decline even though there is no sign of neurodegeneration. To date, investigations have focused on using techniques such as functional magnetic resonance imaging (fMRI, a non-invasive method of examining the brain whilst completing set tasks) to evaluate which changes take place as the individual ages. These data have helped identify reduced brain volume and connectivity as possible causes of the reduced cognitive function that plagues our elderly population. Nonetheless, much higher resolution data from animal models is now needed to further refine our understanding of the neuronal changes that are taking place during the ageing process.
Cartographers extraordinaire
The highly regarded Brickley and Chadderton labs are looking at both structural and functional changes in ageing brains. Dr Brickley in the Life Sciences Department at Imperial College London is using his extensive experience of manipulating neurons in isolated slices of brain tissue to perform experiments on defined neuronal populations. Aided by Dr Chadderton, who is based in the Bioengineering Department, they are linking the observed cellular and anatomical changes with changes in functional activity as the mice perform specific cognitive tasks. The team are developing their novel anatomical and functional mapping techniques in the Centre for Neurotechnology at Imperial College London.

Studies on the human brain have shown that age-related changes do not happen uniformly across the entire brain structure

Studies on the human brain have shown that age-related changes do not happen uniformly across the entire brain structure. Instead, certain regions are more heavily affected than others. Their work is focused on the prefrontal cortex (PFC, commonly known as the frontal lobe), an area of the brain thought to be important in shaping our personality and controlling ‘executive’ functions such as decision-making. This area has been shown to be disproportionately affected, and it is this loss of executive function which is most damaging to individuals with age-related cognitive impairment. However, human studies (such as brain imaging techniques) have been unable to shed any light on the mechanism which results in this decline.
Animal companions
Animal studies which probe the brain during this period of functional decline are therefore vital to fully understand the role the individual elements play in the observed effects. Dr Chadderton’s lab are able to label individual nerve fibres which arrive at the prefrontal cortex from other areas of the brain, particularly the hippocampus which is crucial in memory storage. Using circuit mapping techniques (which attempt to establish the links between brain cells), they assay the cognitive performance and network dynamics of individual mice, helping them identify the hallmarks of successful, as opposed to degradative, ageing.
Studies like this will be able to establish whether connectivity, rather than a reduction in neuronal number through cell loss, is responsible for age-related cognitive decline. The work is particularly focused on the junctions between neurons (synapses) and the electrical properties of cortical neurons (such as excitability), with the aim of establishing a relationship between the changes in connectivity and cognitive performance. One of the more challenging aspects of this work will be the development of methods that enable the researchers to document the trajectory of individual animals to complement the longitudinal studies that are now beginning to provide vital information on the risk factors associated with human ageing.
Three routes to success
In order to achieve these goals, the groups will investigate three distinct, but related, aims in parallel. Using electrophysiological recording, anatomical mapping and behavioural measurements the team will fill the gaps in our knowledge of the physiological properties of synapses in the ageing brain. The short life expectancy of mice (around three years) means that they display neurological ageing as young as 18 months, so by injecting a range of mice with purpose-designed tracers, to highlight the cells of interest, the teams can directly observe this process.

This exciting work bridges the gap between the
observed human conditions and neuronal connectivity, network
dynamics and cognitive performance

Firstly, they will use state of the art electrophysiological techniques to assess age-related changes to the network connectivity of both local and distant neuronal synapses. By taking thin slices of dissected brains, the team can probe pairs of cells to establish their connectivity and compare this across age groups. Knowing which cell pairs are being studied, local or distant, is vital to understanding which connections are diminished in the changes observed in the human PFC.
This effect can also be studied by using genetically encoded fluorescent labels of the different cell types to see whether the total number of projections into the PFC is reduced in older subjects. Painstakingly developed labelling proteins, provided by the collaborating laboratory of Prof Wisden, coupled with advanced imaging equipment recently installed in the Department of Bioengineering, allows for accurate analysis of the density of connections in the separate experimental groups.
Individual pathways
The in vivo work will consist of carefully constructed tasks which mice perform whilst brain activity is being recorded. The performance of individual mice will be repeatedly compared as they age. By measuring the electrical activity of neurons whilst the animal is performing the task, it will be possible to assess whether cognitive performance is impaired due to aberrant activity, either through reduced activity or excess neuronal ‘noise’.
In the final element of the study, the team will use the variability between individual animals to assess whether there is any correlation between the observed cellular and network dysfunction, and impaired cognitive behaviour. This unique approach of relating in vitro assays and imaging analyses to the specific behaviours displayed during the in vivo testing phase enables the team to directly relate changes in the cognitive performance of individual mice with alterations in the functional and anatomical properties of local and long-range PFC synapses.
A roadmap for healthy ageing
This exciting work bridges the gap between the observed human conditions, which suggest changes in PFC connectivity, and the data required to relate this to neuronal connectivity, network dynamics and cognitive performance. By applying advanced electrophysiological and behavioural techniques, this team of researchers are on the cusp of identifying the important features of cognitive impairment due to normal ageing.
Taking this forward, the team aim to improve understanding of the ageing process, enabling early identification of the tendency to cognitive decline and, from this, provide the information required to develop strategies that can address individual disparities in ageing outcomes.

Dr Brickley, how does your previous work on ion channels in adult neurons feed into this complex study of the ageing process?
My work on how ion channels contribute to synaptic communication between neurons has involved looking at the changes in ion channels during development as well as studying how ion channels work in the adult brain. Like many neuroscientists, I have been closely following the observations made in human studies and it seemed important to apply the skills I have learnt over the years to explore how synaptic transmission between neurons changes in the ageing brain. This could be the key to interpreting the changes described in human studies.
Dr Chadderton, what specific skills and experience do you bring to the team?
My research is focused on understanding how brain circuits encode signals about the outside world. We use a variety of techniques to measure electrical activity from single nerve cells in intact brains, and plan to apply this technology to understand how signalling changes during the ageing process.
Why is it so important to use an animal model of ageing for this study?
The first thing to appreciate is that we cannot measure parameters like synaptic transmission in humans. Also, the lifespan of small animals gives us the ability to examine changes in the brain over a short period of time. Importantly, as cognitive decline is a feature of all animals studied in both the laboratory and in the wild, the lessons we learn in animal models will quickly impact on our understanding of human ageing. This is clearly important given that the number of elderly people is set to expand considerably and we desperately need healthspan to catch up with lifespan.
How has the Centre for Neurotechnology aided your work?
The Centre for Neurotechnology has brought our team together and provides much of the infrastructure necessary for this exciting work. Along with our colleagues Professor Bill Wisden and Dr Simon Schultz in the Department of Bioengineering, we have been a part of this important initiative from the very start in 2013. The Centre provides a vibrant mix of biologists, engineers, physicists and mathematicians all interested in applying new technology to brain science.
What are the potential benefits of increased understanding of the mechanisms underlying age-related cognitive decline?
Without wishing to scare anyone, it is important to remember that ageing is the single biggest risk factor for cardiac disease, cancer and dementia. But, senescence is probably the most poorly understood of all these conditions and the one inevitable consequence of ageing that, at present, looks totally untreatable with modern medicine. This is largely because we do not understand what is happening in the brain as we age and why this leads to cognitive decline. Therefore, the work we are doing, funded by the BBSRC, will hopefully go some way to changing this.

Research Objectives
The team’s research focuses on the science of ageing, investigating the mechanisms behind cognitive impairment. Their current work explores the link between changes in synaptic function and cognitive decline during the normal ageing process.
Funding
Biotechnology and Biological Sciences Research Council (BBSRC)
Collaborators
Professor William Wisden of Imperial College London provides cutting-edge molecular biology techniques needed to study defined neuronal populations.
Bio
Dr Brickley works in the Department of Life Sciences at Imperial College London. His work has helped demonstrate the remarkable adaptive plasticity of the mature brain and has identified key targets for neuroactive steroids and sedative drugs in the brain.
Dr Chadderton is based in the Department of Bioengineering at Imperial College London. He has pioneered the study of synaptic and population activity in the mammalian brain helping to explain how sensory experiences are encoded in the electrical activity of our brains.
 
Contact
Stephen G Brickley PhD, FRSB
Department of Life Sciences
Centre for Neurotechnology
South Kensington Campus
Imperial College London
London, SW7 2AZ
UK
E: [email protected]
T: +44 207 594 7699
W: www.imperial.ac.uk/people/s.brickley