Neurological disorders: mechanisms and therapies

Neurological disorders that affect the central nervous system can be highly debilitating. However, it is difficult to access the relevant affected tissue because it is not possible to safely biopsy the brain in living patients.

Post-mortem brain tissue is limited in availability and is often affected by variation in quality and medication taken by patients when they were alive. Many neurological disorders, including common disorders like autism and Parkinson’s disease, have a genetic basis. Because the vast majority of human genes have a mouse counterpart, it is possible to introduce a human disease-causing mutation into the same gene in mice. Moreover, the brains of both species have the same elemental structure, so mouse models provide a powerful alternative way to study neurological disorders.

This project will study mice with disease-causing mutations to better understand the causes, progression and treatment of neurological disorders, which may provide clues to better treatments for human patients. Neurological disorders lead to altered behaviour, eg forgetfulness, as a core symptom, so it is necessary to study behaviour in living animals in order to obtain the most appropriate data.

The project will study mouse models of neurological disorders that begin in infancy (eg alternating hemiplegia of childhood) and those that begin in late adulthood (eg Alzheimer’s disease). By examining mice at different ages, the project will determine how the diseases progress with age, and whether this progression can be halted by experimental interventions. We will subject mice to behavioural tests that assess various brain functions, such as attention, cognition and motor coordination. Some of the behavioural tests include aversive stimuli such as a mild electric foot shock, but these will be kept to a minimal level. Electrodes will be implanted in some mice, so that we can record whether they exhibit hyperexcitability in the brain, a physiological anomaly found in many neurological disorders. We will give mice substances such as medicines and dietary supplements to see whether they have therapeutic effects. Interventions that are therapeutic in mice can be subsequently tested in human clinical trials.

The project will use the minimum number of mice required for statistically robust findings. We do not expect for mice to suffer more than mild adverse effects because of our interventions. A robust method of monitoring is followed to implement humane end points and for early termination of experiment if animals are likely to suffer.

Non-technical summary 

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