Karla Kaun - Hungover flies
Kat - I'm sure this has never happened to you, but I bet you know someone who's been for a big night out on the booze, woken up feeling awful and swearing they'll never drink again, only to be back on the sauce a few days later. It turns out that forgetting the horrible effects of drinking is something we share with tiny fruit flies. Karla Kaun, from Brown University in the USA, is training flies to associate a particular smell with an alcoholic tipple and figuring out how they switch between so-called aversive memory - when they recall how bad they feel - to appetitive memory, when they can't wait to get back to the fly pub.
Karla - So, what I study is memories for the intoxication experience. What I found is that even in flies, the initial effects of alcohol are always aversive, something like a hangover effect. But what's intriguing is, like going to the bar on a Friday and Saturday morning not feeling well, but wanting to go out again Saturday night, the long lasting effects of alcohol are appetitive. And what I'm interested in figuring out is, how are neural circuits mediating this effect and what the molecular mechanisms acting in these circuits to affect them.
Kat - Obviously, fruit flies don't go out to the pub, what's fruit flies' relationship with alcohol normally like? Are they big drinkers?
Karla - So, flies, like humans have a long natural history with alcohol. So, humans have been consuming alcohol for centuries and flies actually spend a good portion of their life and little concentrations of alcohol. They lay their eggs in fermenting fruit and in fermenting fruit of course are patches of moderate concentrations of alcohol. So, as larvae, they eat this alcohol and it's evolutionary advantageous to them. For example, a larvae that has a 6 per cent alcohol concentration in its body is less likely to be parasitised by wasps. So, what's very interesting also is that flies' effects to higher concentrations of alcohol are remarkably behaviourally similar to those in humans. They go through the same stages. At first, you get disinhibition and then you get a loss of locomotor coordination and then the flies will just pass out in the bottom of the vial. The time it takes for him to recover is almost the same as the time it would take us to recover.
Kat - How long does it take a fly to kind of go from, "I'm never doing that again" to "Yeah, let's have another drink.?
Karla - Well, with the parameters I tested, it's somewhere between 12 and 15 hours.
Kat - That's pretty good going. So, the next time that flies encounter alcohol, they think, "Yeah, this is great! Let's party!"
Karla - Pretty much, yeah. They find the reward long lasting, so it lasts up to seven days which is a long time for a memory for a fly. They'll also walk over a 120 volt electric shock to get to the odour that was previously paired with alcohol. So, this suggests that it's an extremely appetitive and intense memory.
Kat - So, I'm sure some of us would deeply sympathise with that. But tell me then, you're trying to understand what's going on at a molecular level. What have you found out so far about how they form these different types of memories, the kind of, "Oh my God, no" and then the, "Yeah, let's do it again"?
Karla - So, what I think is happening is you're getting parallel circuits that encode both the aversive memory and the appetitive memory, and then you get feedback between these circuits. The appetitive memory can turn off the aversive memory circuit for example or potentially vice versa if something goes wrong. I'm interested in figuring out what inside of these neurons is affecting it and one of the molecules that I looked at is a regulator in the Notch signalling pathway. Notch is really important for maintaining long term memory. So, we're trying to figure out how alcohol affects this to potentially result in aberrant memory formation.
Kat - So, Notch is one of these kind of signals that tells cells what to do, what kind of cell to be, what to get up to.
Karla - Pretty much. It's a cell-cell signalling molecule. so, it's like an early signal that affects a lot of downstream effectors.
Kat - So now, you're kind of starting to understand some of the molecules that are involved in these different types of memory and how the, "Yes, let's do it" overwrites the, "Oh God! Never again" kind of thing. How are you going forward with this and do you think that there may be similar mechanisms at work in human brains?
Karla - So, I absolutely do think there are similar mechanisms affecting human brains. Notch signalling is actually one of the most well-conserved signalling pathways. It's been studied for over 100 years in flies now. And biochemically, things work extremely similarly. I'm interested in figuring out how to target different types of Notch signalling changes to different kinds of brain regions. I think this will be extremely informative for developing pharmacological treatments. There are currently treatments for cancer being developed for drugs in the Notch signalling pathway and I'm hoping that I'll be able to perhaps use some of these drugs to treat addiction-related disorders.
Kat - Could you make an anti-hangover pill?
Karla - I'll tell you what, I'll work on it. More realistically, what we'll probably try to do is decrease the really strong appetitive memories by enhancing the aversive memories, so that people don't crave alcohol quite as strongly.
Kat - That was Karla Kaun, from Brown University in the States.