Professor of Neurobiology, Wellcome Principal Research Fellowscott.firstname.lastname@example.org
Scott Waddell studied biochemistry as an undergraduate at the University of Dundee, and researched cancer for his Ph.D. at the University of London. He switched fields and continents as a postdoc in the Department of Brain and Cognitive Sciences at Massachusetts Institute of Technology. After 10 years leading a research group in the Department of Neurobiology at the University of Massachusetts Medical School, he moved to Oxford as a Wellcome Senior Research Fellow in November 2011. He is a member of EMBO and was awarded the 2014 Liliane Bettencourt Prize for the Life Sciences. Scott became a Wellcome Principal Research Fellow in 2016.
Scott’s group has studied neural circuit mechanisms of memory-directed behaviour in the fly since 2001.
Your PhD was in cancer biology. What got you interested in neuroscience?
Cancer research is interesting and very important work but I felt that there was too much fighting over details. I knew I had to find a different field. Throughout my Ph.D. my advisor John Jenkins encouraged me to read different areas of science. John left a photocopy of a paper from Tim Tully on my bench, so I searched the literature to find other labs using genetics to study fly learning and memory. This lead me to Chip Quinn’s pioneering studies. Seeing that single genes impacted this level of behaviour amazed me. Once I read these papers, and others from Martin Heisenberg, Yadin Dudai and Ron Davis, I knew that I had found the field I wanted to be in.
And not just the field; it sounds like you knew where you wanted to be too?
Chip Quinn first taught fruit flies in the early 1970s as a post-doc in Seymour Benzer’s lab at Caltech. After meeting Chip and other researchers at MIT, I realised MIT was where I wanted to work. It was also clear that I would be supported but very independent with Chip, and that is exactly what I wanted. The first time we walked into his lab he remarked, with a high voice, “This could be all yours, including the curtains!”. And so in 1996 I moved out of cancer research and joined the MIT Center for Learning and Memory as a post-doc with Chip. It was a radical shift for sure, and for a couple of years I wondered if the change was too great. But it was something I was genuinely interested in, and I eventually made some exciting progress.
What was your first breakthrough?
I found two neurons in the fly brain that are required for memory. The discovery came from the analysis of amnesiac—one of Chip Quinn’s original memory defective single gene mutant flies. Chip had shown in 1979 that amnesiac flies learn, but forget quickly. Looking for the sites of amnesiac production led me to two large neurons in the brain. I showed, using a genetic switch of synaptic transmission, that if I crippled the function of these neurons the flies forgot, like amnesiac mutants. It seemed likely that the amnesiac gene mutation had in some way impaired the function of these neurons and that memory stability was controlled by these neurons in normal flies. The output of these two neurons can be traced to a brain structure called the mushroom body. The mushroom body had previously been implicated in olfactory memory in the fly, but it still has about 5,000 neurons. So the resolution of memory processing was radically improved and at the same time a philosophical change was taking place in the field. We were starting to alter acutely the function of small groups of neurons as a way of learning how the relevant neural circuits operate.
And this led to other breakthroughs?
In my own lab we have used similar genetic strategies to show that the mushroom body neuron population is functionally divisible into a group whose activity is required after training for memory consolidation, and a group required for later memory retrieval. This is reminiscent of how memory is consolidated by the hippocampus and cortex in mammals. It seems likely that this ensemble process relies on the two ‘amnesiac’ neurons we previously identified.
We also located small groups of neurons representing a motivational control system for behaviour. Only hungry flies will pursue an odour that they have previously learned signifies the presence of food. My students found that a subset of six dopamine neurons inhibit behaviour in well-fed flies. These dopamine neurons are in turn switched off, releasing memory-guided food-seeking behaviour in hungry flies, by neurons that release the fly analogue of mammalian neuropeptide Y.
More recently my group identified rewarding dopaminergic neurons in the fly. Again, the work uncovers a striking mechanistic similarity between flies and mammals – reward and motivation signalling even uses the same neurotransmitter molecule. However, our work also revealed a few surprises. We found that both the sweet taste and nutrient value properties of sugars are rewarding, but that nutrition is essential to trigger dopaminergic neurons that form persistent long-term memories. We also showed that water and sugar rewards use separate subsets of dopaminergic neurons, suggesting these memories are stored in different places in the fly brain. This seems fairly logical because we know that hunger and thirst can specifically direct food or water-seeking behaviours.
What drives your work today?
I am generally fascinated by how the brain orchestrates intelligent behaviour and we are tackling this at several levels. How are stimuli represented and associated, and how is experience encoded? How are memories consolidated? How are memories appropriately accessed and retrieved to guide behaviour? How are memories updated? How are behaviours instructed? We now know that some of these complex processes can be controlled by manipulating small groups or even single pairs of neurons.
I think an important thing to say is that we are exploring many things at the CNCB that I am confident we can answer.
Is there a single area of research that stands out?
Understanding neural processes of memory is centre stage. Memory is a difficult thing to study, because it is measured by observing a behavioural outcome. However, this immediately introduces a problem that is of particular interest from the point of appetitive memory: has the fly actually forgotten, or is it just choosing not to respond? The dogma is that memory is represented as a specific set of changes in synaptic strength—perhaps within a single circuit. I think we are very close to being able to observe these changes and understand how their use is controlled in an appropriate way. We already know some relevant neural pathways and synaptic connections and we have detailed ideas of how they are regulated.
The main thing we’re doing in Oxford that we weren’t doing in the US is to make physiological recordings of neural events. We are watching and measuring reward signals and trying to understand how they are generated and what they represent. We are also trying to visualise how rewards and motivational states change neural circuit activity.
Such fine experimenting on something as small as a fly’s brain must require sophisticated techniques and sophisticated equipment?
My colleagues at the CNCB are pioneers of optical imaging and we have all the required hardware. That hardware includes machinery like the two-photon microscope—a fluorescence-imaging technique that allows us to see several hundred micrometres into living tissue, which in this work is a very great depth; importantly, more than the thickness of the entire fly brain. Advanced optics becomes even more important as we start to look at molecular processes.
Optogenetic control was pioneered by your colleague Gero Miesenböck and others. What is special about optogenetics?
The beauty of optogenetics—and a related discipline called thermogenetics, in which neurons are activated by heat—is that you can jump into the middle of a circuit. You don’t need to know where the signal has come from, or where it is going. We can identify the neurons that are involved in the expression of some behaviour without knowing how they themselves are controlled; but ultimately, of course, we would like to know what the prior and next step is in the process. And this is where high resolution analysis becomes important and where we hope to make advances.
Is this work unique to the CNCB?
It is clear that, although the most important questions in science are of interest to many, others will not necessarily investigate them in the same way, from the same vantage point, or to the same level of detail. We like to first design a relevant behavioural task for the flies and then identify the neurons and mechanisms that allow the fly to perform it. Surprisingly, some others seem to approach it the other way round – find a few neurons and then try to work out what they do.
Do you have a number of research projects running at the same time?
Yes, many. I like to balance the work going on in the lab, having some relatively simple and apparently straightforward things and some more difficult going on at the same time. The relatively simple projects often don’t work!
What’s the atmosphere like in the lab?
The lab is very interactive, collaborative and social. I encourage people to work on something that is a shared interest so that they are personally invested and motivated enough to get on with it. This work is not a 9 to 5 job for me at all. It’s something I can’t put to one side. I think about experiments in the middle of the night and I think about them in the middle of conversations with people when I should be listening.
Do you think about the potential benefits of your work?
I’m curiosity driven. I genuinely believe that what we’re doing will have some benefit for human health down the road, but it’s not necessarily what drives me on a daily basis. I think history has told us that some of the most spectacular advances in our biological understanding have been happened upon by open-minded, curiosity-driven researchers getting a result they don’t understand and re-interpreting it.
What are your goals for next few years at the CNCB?
Our hope is that we can identify and understand the operation of small neural circuits that support memory and direct educated behaviours. If we can do this, we will not just be understanding the fly’s mind, but intelligence in all animals. Given the remarkable conservation of genes, I am willing to bet that several fundamental principles of neural circuit operation will be similarly conserved. In the fly I think we can realistically investigate some of these processes down to the level of handfuls of, and in some cases single, neurons. This cellular resolution allows us to understand what the signals are, how they are generated by molecules and where they are conveyed to, and how these signals affect the function of the circuit. Having that level of understanding of the neural mechanisms of behavioural control would be quite profound.
It is sometimes said that the problem of consciousness is the big problem for the 21st century. Would you agree?
I think every field – including learning and memory—has terms that people have trouble with and argue about. It’s fascinating to think about how you could define consciousness with an experiment, but with an animal that can’t communicate anything to you except through its actions, it is difficult. That said, I don’t think consciousness is limited to humans. Even fruit flies appear to attend selectively to sensory stimuli and can form memories of prior experience. Focusing on certain things at the expense of others and remembering are parts of consciousness; if you didn’t have these functions, you wouldn’t be aware of who you are, where you are and in control of what you are doing; assuming we are in control! So I’m working on processes that are relevant to consciousness, but it’s not something I feel I need to define in the brain of the fruit fly. Honestly, I’d get frustrated by the lack of progress.