MICA: Sensory plasticity and adaptation in neurodegeneration

Plasticity of nerve cell activity is important for normal brain function. In brain areas that are involved in sensation, including vision, this plasticity includes a process called sensory adaptation. The purpose of the proposed research is to understand how sensory adaptation is affected by neurodegenerative diseases, like Alzheimer's Disease, that are known to affect plasticity in other brain areas that are involved in learning and memory.

In humans and animals adaptation normally changes how the world looks - for example, looking out of a moving train's window for a long time causes the world to appear to 'move backwards' when the train stops. This change in how the world looks is due to the effects of adaptation on activity in visual areas of the cerebral cortex, which occur automatically during prolonged exposure to visual scenes. In exciting preliminary experiments we have recently discovered that similar forms of adaptation are impaired in the visual cortex of rodents in the early stages of neurodegeneration.

In this project we will use these simple visual tests to understand how degeneration affects the signals of nerve cells in the visual cortex of a rodent model of dementia. We will test the hypothesis that neurodegeneration has a specific impact on the normal processes of adaptation. We will establish 1) how the signals provided by the visual cortex are modified by neurodegeneration, 2) how degeneration affects the plasticity of those signals, and 3) if sensory adaptation may therefore provide a sensitive and early indicator of neurodegeneration. The final outcome will shed light on how degeneration affects nerve cell circuits in the cerebral cortex, in a system likely common to all animals.

The project is important, because sensory adaptation can be measured non-invasively in humans as well as other animals, and the mechanisms that provide adaptation are conserved across species and are well understood. As well as providing fundamental knowledge about how neurodegeneration affects sensory adaptation the proposed study therefore also offers the possibility of a novel and sensitive framework for understanding the impact of degeneration on nerve cell circuits in the brain, that may provide new ways to detect and track the impact of degeneration.

The aim of this project is to understand the impact of neurodegeneration on sensory adaptation in the cerebral cortex. Neurodegenerative disorders have widespread impact on the cerebral cortex but the main target of research has been its impact on memory and cognition, processes that are poorly understood even in healthy humans and disease model organisms. Adaptation is an automatic form of sensory plasticity that relies on intrinsic cellular and synaptic mechanisms also thought important for learning and memory in other brain areas. Measurements of adaptation's effects therefore offer simple, direct measurements of plasticity in brain circuits, and a potential target for understanding, detecting and tracking neurodegeneration.

Our hypothesis is that neurodegeneration has an early impact on sensory adaptation. We will test our hypothesis by measuring adaptation in the visual cortex of the rTg4510 mouse model of tauopathy, a group of neurodegenerative diseases including Alzheimer's disease. In preliminary experiments we find that adaptation is robustly affected in these mice even in early stages of degeneration. The proposed experiments will characterise the impact of degeneration on adaptation in visual and auditory cortex in this mouse model, and the temporal relationship between pathological and functional changes. We will gain knowledge of whether changes in adaptation are widespread, and whether these changes arise early in the degenerative process. The experiments will therefore tell us whether adaptation is a translational target for understanding, detecting and perhaps treating degeneration.

These experiments will open up new directions for research, since the impact of degeneration on sensory plasticity has previously been largely ignored in both discovery research and clinical testing. Our experiments in mouse models of tauopathy will therefore push neuroscience research - and potentially, clinical practice - in new directions.

Academic impact:
Our approach brings together sensory and neurodegeneration disciplines that have previously had little connection, and therefore offers to be of substantial interest to a large proportion of the neuroscience community. We expect that our work is therefore likely to be the subject of invited talks at leading international institutions, for the PDRA as well as the primary and co-investigators. To ensure that the proposed work has the widest possible academic impact, we have requested funds to present it at the leading international conferences. In addition, we have proposed collaboration with leading clinical researchers at UCL, and our aim is to utilize this collaboration to help disseminate our research findings to the broader neurodegeneration community.

Societal impact:
Understanding how degeneration affects sensory processing is of clear potential importance to the design of transport, care homes and other public spaces. Because adaptation processes are ubiquitous in sensory systems, and therefore shapes how animals and we interact with the world, the proposed research offers potential insight into how the brain's sensory systems are affected by neurodegeneration, in humans as well as animals. Academic studies of human neurodegeneration in humans are already used to inform the design of public spaces, but there has been little assimilation with sensory neuroscience. To encourage a multi-disciplinary approach with real potential impact, our Pathways to Impact includes collaboration with affected human populations and potentially with relevant regulatory bodies. This collaborative work is straightforward, and may offer a natural entry point for undergraduate students interested in neurodegeneration. By helping us engage with future students, this proposal would facilitate understanding of neurodegeneration among our large undergraduate programme.

Economic and technological impact:
The proposed research offers a clear avenue to economic and technological impact. Evaluating the efficacy of potential therapies for neurodegenerative diseases requires new quantitative, sensitive frameworks. Knowledge of how visual cortical processes are affected by neurodegeneration, and how these effects are reflected in non-invasive measurements, may be incorporated into new testing regimes in academic and industrial research. Pathways to developing commercial applications of this knowledge require interest from potential industrial partners. We will start by working with UK-based Eli Lilly, to refine the methodologies for use in high-throughput, industrial settings, and thereby providing new frameworks for progress into the understanding and treatment of neurodegenerative diseases.