Jason Rihel, University College London,
How can we probe what’s going on in the brain of someone who have a sleep disorder? Chris Smith and Priya Crosby spoke to Jason Rihel, from University College London, about how he uses zebrafish to learn more about sleep.
Chris - How on Earth do you understand sleep from watching fish?
Jason - So, the first thing we can do is very simply watch a fish with a video camera. In fact, we can watch thousands of fish at once. And then what we can do is we can manipulate them genetically or we can add drugs into the water and ask, how does their sleep patterns change? And then from there, we can try to understand what's happening.
Chris - Are fish a good representation of the patterns of sleep and the systems in the brain that control sleep in even more complicated animals including us?
Jason - Yes. So, this concept of non-mammalian sleep is a relatively new one. It’s only been about the last 12 or 15 years when scientists have reached a consensus that most organisms including fruit flies and fish have a sleep-like state. And in the fish in particular, not only do drugs that regulate or manipulate sleep in humans, also give the same effect in the fish. But also, many of the neurons including those neurons that are lost during narcolepsy also are present in the fish and seem to have many of the same kinds of neuronal connections that are present in mammalian brains. And also, some of the same functional consequences that we see in mammalian brains as well.
Chris - So, you can do many, many parallel experiments watching these fish and you can put chemicals into the environment the fish are in to see if they change their sleep behaviour. Have you discovered anything that can manipulate sleep?
Jason - So, in fact, one of the things that we did was we can do a screen because we can do so many at once, we can do a screen of thousands of small molecules. In fact, we did a screen for several thousand small molecules and we identified hundreds of different compounds that regulate sleep, either upregulating or downregulating various parts of their behavioural experience. The other thing I should say is that the larval zebra fish are also optically transparent. So, another thing that we can do is, we can use calcium indicators which will respond to when neurons are active. We can actually watch the fish brain while they're sleeping or while they're awake, and ask what neurons are doing during different behaviours.
Chris - How old are these fish because we know that if you study a human, a baby spends the majority of its life asleep whereas an elderly person spends half the night awake because they can't drop off - So, are your fish therefore a good model for a human in that regard?
Jason - One thing to realise is that when we talk about larval zebra fish, the comparison to mammalian models is a little bit overly simplistic. So, one problem for example is that the larval fish – so, they go from one cell to a fully patterned animal in about 24 hours. And then at 4 or 5 days post fertilisation, they can actually do complex behaviours including, they can learn, they can hunt. So, in some ways, they're more on their own very early on. So, they're not necessarily like a human baby per se, they're more like an adolescent maybe.
Chris - We heard just before you from Julie Flygare and she’s been describing her experiences of the condition narcolepsy. What can your fish reveal about why she’s having those symptoms?
Jason - Narcolepsy is a syndrome that is accompanied by loss of these very specific neurons deep in the hypothalamus of our brains that produce a peptide called hypocretin or orexin. That peptide gets secreted and through mechanisms that were very complex and somewhat not well understood yet seems to promote arousal. One of the things that we’ve done in the zebra fish is be able to manipulate the orexin hypocretin system. We can make mutations that eliminate that function or we can kill those neurons just like in the human patients and then this is one of the things that we’re doing right now actively is, we can then test say, some of the drugs that we identified from our previous screen and ask, now these fish, they have no hypocretin signalling. How do they respond to these drugs?
Chris - Have you got any leads? Do you think you're going to be able to come up with some compounds that will help people with narcolepsy better than the present agents which all have many side effects that they're currently forced to take?
Jason - Well, it’s very early days. So, I'm reluctant to say too much, but I think we’re hopeful that we could screen a large enough compound set that maybe we’ll be able to find something.
Priya - Jason, you were talking about sleep in baby animals and larval zebra fish earlier. I've got a question in from one of our listeners, David Stovel and he’s asking about sleep in the foetus in the womb and he says, “When a foetus is developing in the womb, does it wake up for the first time, or does it go to sleep for the first time?” I think what he’s asking here is, when do we start to see sleep and wake cycles in a baby human?
Jason - So, I know from studies in rodents that you can in fact, by measuring brain activity, identify what appears to be a sleep-like state during late foetal development. I don’t know exactly when in humans that kicks on, but certainly in other species, you can identify a sleep-like state during development.