greetings it's bill Mobley and this is on our mind and I'm pleased to be here today with Roberto Milano a professor at UCSD in the department's of neurosciences and neurobiology Roberto studies learning and memory and has made some very important contributions to understanding about how the brain learns Roberto welcome thanks for being with me and let's hear a little bit about you and about the exciting work that's going on in learning and memory in your lab thanks Bill thanks for the invitation well I've studied synapses my whole life my whole career and synapses as you know are the sites of communication between nerve cells and that's basically how nerve cells communicate and how all our actions and our thoughts are mediated by the communication between nerve cells now synapses in particular are relevant to this series because they're one of the first sites affected in Alzheimer's disease but my work has tended to be more in the basic side asking questions like what happens when you learn something and it turns out that we think and there's fairly good evidence now that when you learn something when I tell you something and it sticks in your brain for 90 years it's because synapses have been modified the communication between nerve cells of some specific cells for specific memories have been modified and they stay modified for a long period of time so that's been the hypothesis for many many years and it's been difficult to nail down and but there's been a lot of people working on it and there have been a lot of very exciting findings relevant to synapses and their relation to memory and also diseases so these synapses exist but what's going on and learning and memory is there changing in some way how does that what's the change look like and how do you measure that well synapses are very complex little structures there's a lot going on in them and they're very very tiny which makes it difficult to study in some ways they're basically like one one thousandth the size of the width of a hair so it's very very tiny little structures and of course sir many many of them they're 300 billion or so of them in in their brain so what is the synapses in apps is has a side which from one nerve cell to the other nerve cell so and when one nerve cell is communicating to the other nerve cell through the synapse there's a presynaptic side which is on the sending side of the nerve cell and that's where neurotransmitter is contained and when a Selectric 'el signal comes down to this and nor Lietz their release of neurotransmitter which then flows across the distance between these two nerve cells which is very very small but then the neurotransmitter binds on to what are called receptors which sense this neurotransmitter and when receptors are hit by this neurotransmitter they open and allow electrical signals to the receiving cell so that's how an electrical signal from the sending cell is transmitted through a synapse through this complex process of going through a chemical and then a receptor leading to a signal in the receiving cell now all of those the the magnitude of communication through a synapse can be affected by all of those processes like for instance how much neurotransmitter is released when an electrical signal comes down how many receptors are there for the neurotransmitter and how sensitive are the receptors so there are many many things that can be modified at between at the communication between these nerve cells at these synapses so you asked what happens when you learn something well any one of those could in theory be changed and so we've had to go back a little bit and look at models of how synapses change when increased or decreased levels of signaling occurs levels of activity occurs and nineteen early 1970s there was a very important finding made where this group working in Scandinavia found that if you activate nerve cells briefly for one second at one hundred times it's a burn that leads to the strengthening of the synapse and that strengthening is maintained for as long as they could record it and that's called long-term potentiation so that's a it's a cellular model then of learning I guess yes it's a cellular model and initially and they said well this might be one of the building blocks of memory in other words how when you learn something there's some rapid stimulus that leads to a rapid and persistent change in the communication of some specific nerve cells and they found an example of that where they could produce it in the laboratory and so people have studied this phenomenon long term potentiation and I've studied it for twenty years or so and we've understood a lot about it about what changes at the synapse during LTP and there's another process called Ltd long term depression which essentially reverses the process of LTP where you can stimulate at once a second for 15 minutes and that weakens the synapse so these two processes as you mentioned cellular models of learning are ones one where if you stimulate very hard it increases the synaptic communication and if you stimulate at this low frequency it reduces the level of communication and so it's been hypothesized that these could combine to make memory and both the the the potentiation and the depression are rationally seen as regulating circuit function regulating the ability of cells to to speak to other cells absolutely and there's a whole biology behind that that's exciting you've had a recent paper that where you've really actually helped elucidate in a very clear way models models of learning could you tell us a little bit about this recent fine I'm sure we were testing a very specific hypothesis that LTP was underlying memory formation and so we used a very simple math memory in rats where rats are placed in a cage and initially they they run around and but if you give expose them to a tone they keep on running around they don't really care but if you give them the tone and briefly shock likely their their paws on their ground that association makes them associate the tone with this foot shock such that subsequently if you just give them the tone the animal freezes because it's anticipating the shock and so it remembers that the tone means that's going to get a shock and so that's a form of associative memory which it's a very simple kind of memory but many of our memories are basically associating things so we studied that form of memory and what we could do is show that instead of we replaced a tone with this new kind of technology called optogenetics where you use a protein from an algae that has been engineered so that you can put it inside a nerve cell now this protein is sensitive to light in algae and when you put it inside a nerve cell it makes it so that if you briefly shine light on that nerve cell that nerve cell becomes excited and very much like it would be excited by normal stimuli and so what we did in our experiment is instead of giving a tone we delivered this protein to a number of nerve cells in the part of the brain that mediates audition and we excited those nerve cells initially because no effect on the animals movement but if we activated those nerve cells at the same time as giving the animal a foot shock subsequently when we activated those nerve cells with flight they animal froze and so essentially we formed a memory by associating the activation of these very specific nerve cells with shock very powerful study well so that was the beginning of it we could form a memory so now is that memory form by LTP well if LTP long-term potentiation between those nerve cells that we stimulated with light and some downstream nerve cells if LTP at those synapses was responsible for formation of this memory by the way these nerve cells are making projections into part of the brain that is called the fear center and so we hypothesize that these nerve cells were making stronger connections after they were associated with this foot shock onto this fear Center now if LTP is responsible for that then if we induce Ltd onto those nerve cells another word to weaken those synapses in the fear center in the fear center then the memory should be removed and so that's what we did we first formed the memory by associating the activation of these nerve cells with a shock and subsequently we delivered a stimulus to those nerve cells that produced Ltd long term depression and weakened those synapses the subsequent to that we had the rat moving around and now we activated those nerve cells that before had made them freeze after we induced Ltd if we stimulate those nerve cells the animals no longer froze they just kept on going as if nothing had happened so essentially we had inactivated that memory so the next part of the experiment was to say well if we inactivated that memory by weakening those synapses can we bring the memory back by activating by stimulating and strengthening those synapses with LTP and so that's what we did after we tested this animal that were stimulating the nerve cells it kept on running around now we induced LTP by simulating those specific nerve cells in a way that caused potentiation on to the fear center and subsequent to that if we now activate these nerve cells while the animal is running around it froze so basically the memory was reinstated and basically we could just go back and forth removing the memory with Ltd bringing it back with LTP back and forth at will fantastic experiment and so so in a way very important for showing that this business of strengthening or weakening synapses has a direct behavioural effect and that essentially it is a piece of memory that you're either erasing or making they're exciting very this is a series on Allosaurus disease tell us about the state of the field with under it with respect to understanding synaptic function and Alzheimer's and your own work in this field if you will sure so as I mentioned one of the first places that is affected in the brain by during Alzheimer's disease are synapses and that was actually established in studies here at UCSD a number of years ago with anatomical studies our work has and trying to understand what beta-amyloid which you know is a small peptide that accumulates during Alzheimer's disease and it's thought to be causative in Alzheimer's disease we want to know what beta amyloid does to synapses and very simply what we've found is that beta amyloid weakens synapses and in fact it weakens synapses much in the same way that is using all the kinds of cellular signaling that occurred during long term depression so beta amyloid weakens synapses much as much in the same way as long-term depression and if you remember the studies I just mentioned to you with Ltd we could remove a memory and so we believed and we're testing this currently that in this kind of model where we can form a memory and remove a memory we want to know that if we form a memory can that memory be removed with beta amyloid and so those are some of the studies that that we're doing very exciting and the work certainly has the possibility of informing the development of new therapies so that one can see this basic neuroscience is actually informing what we know about disease and helping us to figure out what we can do for our patients to prevent memory loss or perhaps to restore memory and these folks that are afflicted with Alzheimer's disease or who are about to be Roberto thanks for being with me keep up the wonderful work and thanks so much ok thank you this was on our mind and we hope you'll join us again soon for another segment in this series on else Armas disease thank you you