Case study: Professor David Gaffan

Research: Determining the processes in the brain that result in loss of memory and memory disorder, a very distressing symptom common to many types of dementia and human neurological disease.

Animals used: Primates

Professor Gaffan: ‘Problems with memory are often a symptom in early Alzheimer’s disease. They are also a symptom in the early stages of other kinds of dementia. In fact, memory disorder is a frequent part of human neurological disease.

‘There are currently 700,000 people with dementia in the UK, and there are expected to be over a million people with dementia by 2025.‘These diseases are extremely distressing for the patient, but we should also never underestimate how much stress it puts on the family. As memories are lost, people lose the ability to maintain social connections. It’s impossible to have discussions about when a daughter visited yesterday, for example, when there is no memory of that visit.

‘Spouses and family members will describe it as being “like having a non-person in the family”, or “It’s like having a corpse in the room.” It’s because it’s impossible to have social contact with them.

‘It is this traumatic nature of memory disorder that provides the justification for research.

‘We’re interested in deciphering the disease process in the brain, so that we can connect changes in the brain with the symptoms of memory disorder.

‘We need powerful methods to achieve this because, as you’d imagine, diseases are a messy business. In vascular dementia, there can be more or less random damage in the brain. Out of all the changes that occur, which of them cause the memory loss? It’s an open question, but by looking at each component of the disease we can begin to see which of the changes are involved in impairing cognitive abilities and memory.

'There are a number of ways to advance our understanding. We can look at the neuropathology of human patients (studying tissue samples from the brain after death). Rodents are also widely used and their brains are well understood in many ways. You can get a lot of information about rodent memory and see what happens when changes are made.

'But there is a small niche – small in terms of the number of researchers working in the area and small in terms of the number of animals used – involving questions that you can only ask and answer in macaque monkeys, questions that you either can’t ask or can’t answer in humans or mice.

‘It’s down to the fact that monkey brains are much more similar to human brains than rodent brains. One example is the prefrontal cortex area. The prefrontal cortex is very much bigger in primates than in non-primates. The spectacular intellectual powers of humans are in the main down to our large prefrontal cortex, and a monkey has a lot more prefrontal cortex than a rodent.

‘Another example involves a neurotransmitter called acetylcholine. There are a relatively small number of neurons in the brain that produce this neurotransmitter, and they degenerate early on in Alzheimer’s and are strongly correlated with memory disorder. There is a very different arrangement and organisation of these neurons and their connections in humans and other primates from rodents. That severely limits the amount you can learn from rodents.

‘We’ve recently been able to gain new insight into amnesia. There are two types of amnesia: loss of the ability to form new memories (anterograde amnesia) and loss of the ability to recall memories (retrograde amnesia). Both are normally seen together in humans. In order to improve our knowledge of human response to brain injury and disease we’d like to understand the mechanisms behind amnesia much better.

‘It’s clearly easier to measure anterograde amnesia in humans. Retrograde amnesia is a different matter, as you can’t know who is going to develop amnesia in advance and measure their memories before it occurs! But you can do this in animals.

‘We can train a small number of animals over a period of anything between six months and two years to do clever things on a touch screen. We can test their visual memory – ask whether they remember photos of objects, recognise photos of real objects they’re familiar with, pick out remembered objects from complex scenes, etc. All of this is done for food rewards.

‘The best way to show this is done in an entirely humane manner is to point out that these tests are not regulated by the Home Office. The Animals (Scientific Procedures) Act covers everything that has the potential to produce pain, harm or distress. The memory tests we use do not produce these effects and so are not regulated by this act.

‘After this period of training, we introduce some change to brain function. This is done in a surgical operation under general anaesthetic with pain relief and care of the highest possible standard. A small set of neurons is removed by its location, or by a specific nerve chemistry type.

‘On return to the social group, the monkeys then resume the original memory tests on the touch screen. We can then measure how much memory they retain from before, and how fast they acquire and store new information. At the completion of the research, the primates are humanely euthanised and some brain tissue samples analysed to see what has changed.

‘We’ve shown anterograde and retrograde amnesia are quite sharply differentiated and located in different parts of the brain. This is an important result for learning about memory disorder.

‘The new Biomedical Sciences Building is working very well. The monkeys have much more room to play and climb. More space enables the social groups to be more stable. That’s really important because social groups are key for the happiness and welfare of the monkeys. In addition, this provides better stability for behavioural tests of cognitive ability.

‘There are other benefits too. The sound proofing of the rooms in which the monkeys do the memory tests means the sessions are less disrupted by external noises and therefore the results are more reliable. We are also able to use vastly more sophisticated equipment, including an MRI scanner. This machine helps in detecting changes in brain activity in a non-invasive way. It’s one example of refining the experiments we carry out to improve the welfare of the animals.’