Scott Waddell, University of Oxford
Kat - Also at the Genetics Society autumn meeting we heard from Scott Waddell from the University of Oxford, one of the scientific organisers of the conference. He’s studying tiny fruit flies in order to figure out how they decide what to do when faced with conflicting choices. I asked him to explain what he’s up to.
Scott - The general idea is to try and understand what the neural mechanisms are in the brain that allow an animal to do the right thing at the right time. We, more often than not, focus on hunger on thirst-directed behaviour. So, how does an animal approach food when it’s hungry and not approach food when it’s satiated. How does it look for a drink of water when it’s thirsty rather than look for a piece of food. So, how does it select and prioritise one behaviour over another?
Kat - So, I guess when it boils down to it, we kind of eat, drink, sleep, reproduce. How do we decide what to do?
Scott - Exactly. So obviously, if all of these possibilities provide the animal with a conflict, they have to decide which of these potential things should I bother engaging at any given time. Of course, if they're more sleepy than hungry, then the thing they should do to promote their survival is to sleep rather feed and vice versa.
Kat - So, how are you trying to understand what's going on here? What organisms are you looking at?
Scott - So, we specifically use the fruit fly and the reason for that is that the genetics and the small nervous system allow us to bring these mechanisms down to a cellular resolution. The genetics in turn allows us to manipulate molecules within these cells.
Kat - So, what are you actually looking at? How do you test what's going on when a fly is making a decision what to do?
Scott - So typically, we train flies with an odour accompanied with a food reward or an odour accompanied with a water reward. And then the thing that we actually measure is when given a choice between two odours, we ask which one do they prefer. Obviously, in an experiment where we’ve rewarded one of the odours with food, we would expect them to approach that food associated odour in the later test. The same kind of thing is true for water associated odours.
Kat - It seems incredible to me that something as small as a fruit fly and as simple I guess as an insect like that, you can train it to do something.
Scott - You can train them very well and the memory that you form is incredibly robust, lasting a few days.
Kat - So, how do you then try to go in at a molecular level and work out what's going on when they’ve learned to distinguish and to go to the smell that they like?
Scott - So, the molecular level was first approached firstly with a classical mutagenesis approach like everything else in flies, people just mutagenize them. But instead of looking for morphological defects on the exterior – a damaged wing, slightly strangely shaped eye or so forth - people screen for flies that couldn’t remember. People don’t so often use that kind of approach now. Instead, we use genetic based approaches that allows to manipulate specific neurons. These tools allow us to switch neurons on and off.
Kat - What does a fly’s brain actually look like? How do you study it and look inside what's going on?
Scott - So, we can just pop out the head capsule, kind of like shelling a pea and look at it under the microscope or in principle, we can also image neural activity in the brain of a live fly just by peeling off a little piece of the head capsule and looking at the brain with a microscope in the live animal.
Kat - So, you kind of pin it down, for want of a better word, prise open its skull and open what the nerves are doing.
Scott - Pretty much, yeah.
Kat - That seems quite fiddly to me.
Scott - It requires some skill. It’s true.
Kat - So, when you do this, when you're actually looking at the brain and seeing what’s lighting up, what's it telling you about how flies are making these kinds of decisions in their life?
Scott - That’s a difficult question. It depends which neurons you're looking at. So, up until now, we’ve mostly looked at neurons that represent values. So, good or bad event in a fly’s life and then we can see that certain neurons are activated by food rewards for example. In other experiments, we’ve looked at neurons that required for the flies to do the appropriate thing with its memory. Their assumption is the activation of that neuron is part of the process where the brain is making the appropriate decision to either run away from something or run towards something.
Kat - In terms of actually starting to understand more general neural mechanisms, how organisms learn, do you think some of the things that you found out will apply in higher organisms like humans, mammals?
Scott - I'm quite sure. I mean, the conservation of genes tells us that many of the processes at least use conserved molecular mechanisms and certainly, some of the work we’ve done has uncovered conserved molecules - so the fly equivalent of neuropeptide Y which is involved in energy homeostasis in mammals is clearly involved in food-seeking related behaviours in the fruit fly dopamine which is the known reward signal in mammalian brain that is clearly the reward signal in the fly brain and so on. So, I think it’s going to be generally informative.
Kat - We’ve heard at the meeting, a lot of people talking about the idea of the engram, like where in the brain is this knowledge encoded. How close do you think we’ve got so far in uncovering it and how long do you think it will be before we really understand how it works?
Scott - I think I can be pretty optimistic here. So, I think we have at least located a synaptic junction, a junction between two sets of neurons where the memory is probably represented. So, I think that is essentially the engram or part of the engram in the fly brain. But I think we’ve already gotten that. The question is, at what resolution can we actually get to, can we say it’s a specific synaptic connection. So yeah, I think it’s only a matter of time.
Kat - Kind of philosophically, it’s a bit strange to think that all the memories we have, everyone we’ve ever known is just somehow written into the junctions between our nerve cells.
Scott - I find that quite reassuring that you can explain it rather than not. But yes, some people…
Kat - It’s kind of a spooky thing.
Scott - No, but some people are very uncomfortable. We’ve been able to explain their life in some sort of physical process in the brain, but it doesn’t affect me that way at all.
Kat - What are you now trying to figure out?
Scott - We would like to know what the mechanisms are that are involved in changing the efficiency of these synapses. The same synaptic connection may be bidirectionally changed by either a pleasant learning event or an unpleasant learning event. And so, we’d like to know how that difference is generated. As I said, we’re ultimately involved in trying to understand how the fly chooses whether to approach a food relevant cue rather than a water relevant cue. So, that kind of higher interpretetive kind of mechanism and we’re very interested in potential individual differences between animals and how that’s represented in the neural circuit properties.
Kat - Scott Waddell from Oxford University.