Jenny Morton from Cambridge University, Russell Schnell, Auckland University, Dr. Ailsa McGregor from Auckland University
Hannah - I wanted to find out more about this sheep and how they behave, so I met up with Jenny, a professor back in my hometown of Cambridge, UK.
Jenny - Sheep in a flock have a poor reputation. They follow each other, they do daft things if one sheep get stuck in a fence, another sheep will get stuck in a fence, and they also look a bit silly. But I always liken them to teenagers. Teenagers in a group don't always behave perfectly, but you get a teenager by themselves, and they're usually really quite civilised. It’s the same with sheep. Sheep in a flock can be very silly. You get a sheep by itself working under controlled conditions. They perform very well. They're very intelligent, a little bit moody, but they understand things. They learn very quickly.
Hannah - So, the kind of experimental tests that you do...
Jenny - We’re trying to design experiments that will test cognitive function in decision making in particular. Sheep can do tasks where the rule changes and they can figure out that there is a new rule and what the new rule is and perform accordingly.
Hannah - So for example, if I go down a corridor, I know at the left hand side, there's going to be a little treat for me, a little chocolate bar. And so, I keep going down the left hand side and then suddenly, you might switch that treat to the right hand side corridor and then I’ll learn to get on to the right instead of the left. That's the kind of thing you do with your sheep?
Jenny - Yeah, that's almost exactly what we do, except we use coloured buckets. So, we’ll say, “If you go to the yellow bucket, there will be a reward. If you go to the blue bucket, there won’t be a reward.” So, the sheep learn very quickly to go to the yellow and then you can switch colours so you can suddenly present them with a new pair of colours and they have to make a new decision. First, they have to go, “Oh, that's just the colour bucket test. I’ll choose one of them and then I can learn what the new rule of these new colours is.” What we now do though is we actually use computer screens. So, we don't need to have buckets and they don't have to walk in. We actually just use computer screens and choose symbols off a computer screen.
Hannah - And this type of decision making, it’s important isn’t it in everyday human life and as we’re hearing, it can be affected in Huntington's disease.
Jenny - It’s absolutely critical. In fact, that's why I started with two choice discrimination tasks because Huntington's patients can learn to do these sort of tasks that they have trouble with the sort of reversals that you were talking about. So, they learn something, but then when the rule changes, they perseverate on the old rule. So, they'll stick to the same thing they knew and they have great difficulty with flexible thinking. That's why I chose to develop that task for the sheep.
Hannah - I've heard that you've even managed to get some of your sheep playing games of football with proper goal posts and are the sheep counting the goals as well? Are they able to know who’s the victorious team?
Jenny - The sheep don't play football with each other but I did teach sheep how to kick a ball into a goal because again, I'm looking for tasks of skill and motor coordination. I also wanted something that sheep didn’t normally do. Now, sheep don't normally kick a football. If they see a football on the field, they would be afraid of it because it was weird. But I taught the sheep how to kick a football because I know that it’s a good test of balance, coordination, and skill that might be useful for testing balance coordination and skill in the HD sheep.
Hannah - Thanks to Jenny Morton from Cambridge University. And Russell and colleagues developed a Huntington's disease flock of transgenic sheep that he’s called the Kiwis. They've been genetically tweaked to contain a short number of CAG genetic repeats. Looking at their brains, they show the same pathology as very early stage Huntington's. Russell is using the kiwi model to help find out how to safely stop full Huntington's progressing by preventing the bad Huntington's protein from accumulating in the brain as he explains...
Russell - So, the central dogma of molecular biology is that a gene in the genome is read and it is read and copied into the stuff called RNA or messenger RNA and then that's get read and copied into protein. If we could remove the messenger RNA, then the message won’t go forward and be translated into a protein. Actually, that is the language we use. If you make small molecules of RNA that could stick to the copy carrying the mutation, then the cell has this wonderful mechanism of recognising when two RNA molecules are stuck together and comes along with an enzyme called dicer. It nibbles it and chops it up and then removes it. So, if we can get those small RNA molecules into the brain and they're going to do that by injecting a virus, and, if that virus gets taken up by the vulnerable cells, expressing or producing these small molecules which will stick very specifically to the aberrant or mutant RNA and just chop it up.
Hannah - Thanks to Russell Snell. Exciting studies and the results are expected in the summer of 2014.
As well as sheep, genetically tweaked mice are also being used to study Huntington's. This time though, to accelerate the disease and discover drugs that could help patients in later stages of Huntington's. To find out more, I spoke with Dr. Ailsa McGregor from Auckland University.
Ailsa - So, our mice have also an increased CAG repeat length, but it’s 120 repeats. So, it’s much, much more than you would see in a human patient because we need an accelerated pathology in the animals to fit with the lifespan of a mouse.
Hannah - So, what are you seeing this mega long CAG repeats of this Huntington gene?
Ailsa - So, we see there's really classical motor impairments that human patients see. We also see very early cognitive problems. So, these mice are not able to learn how to do the motor test that we usually use to assess coordination in these animals. They also really have a lot of problems with what we call delayed dependent memory. So, can you remember this one piece of information in 5 minutes time or in a day’s time? They also are very poor in recognition memory. So, recognizing that there is a new object in their environment. We also see psychiatric impairments in these animals which are much more difficult to measure, but we have ways that we can assess that type of behaviour in animal models and our transgenic mice also show a depressive-like behaviour from about 6 months of age. There is a very specific way that we look at depression in mice because they obviously can't tell you how they feel about things. We typically use swim test and the mice will either swim or they're immobile. In this environment, it’s quite small environment and they can't generally get out. So, we can correlate time spent immobile or floating with depression and that actually uses a screen by a lot of pharmaceutical companies to look at anti-depressant activity of new drugs. It has a real correlate with human behaviour I guess. So, if you imagine the time spent immobile, like despair or helplessness, we see a lot less of that following our drug treatment that we’ve been working on so the animals are swimming much more and they're much more active. Another interesting correlation with human patients because other tests that we used to look at shifting strategies or cognitive tests where you have to change the way that you do something. Normally, we survey that strategy shifting type behaviour. It’s how they find food. They alternate between different ways of doing things. Our Huntington's disease mice are very bad at that and they persevere with the same strategy over and over again even when it’s not successful. The types of compounds that we are interested in are involved in cholinergic transmission which is involved in attention and memory. These compounds, even in normal mice are what we call cognitive enhancers. So, they improve performance in memory tasks and attention to do these tasks. We’re also seeing really significant improvements in motor function in very, very elderly Huntington's disease mice. So, we had really expected that by then we would be beyond the point where we could see any benefits, but we’re actually restoring motor function in these aged Huntington's disease mice back to a normal aged mouse’s performance which is great.