LN: Hello, I'm Laura Nelson from the Medical Research Council. Welcome to this podcast PG: There's clear evidence now from our studies that at the molecular level there is a sex difference. LN: Professor Peter Geise from King's College, London showed that male mice learned to avoid a dangerous situation better than females. PG: In these tasks one can observe and we observe that normal male mice can learn better than normal female mice, however this is just one performance measure. We have not really checked for example for the quality of the memories, the quality of the memory may be better in the females than the males so more studies really need to be done to address this.
LN: In the test the team placed mice in a chamber and attempted to train them to avoid a potentially dangerous situation. They exposed the mice to an audio signal while subjecting them to a mild electric shock to their feet. Subsequently, more males than females learned to physically freeze when they entered the chamber associating the new environment and the sound signal with danger. The males' superior ability to learn this task was absent in genetically engineered mice that lacked a particular brain protein known to be involved in the memory forming process. So are males better than females at remembering things?
PG: Our science would basically suggest that males and females can simply use different processes and it's not fair to say that the male is better than the female; one cannot just look at one particular behaviour or criterion and say ok male is superior than the female. I think that would be too simplistic in my view.
LN: So we can't conclude that males learn better than females but what we can infer is that male and female mice use different molecular pathways in the brain to store memories. Memory research funded by the Medical Research Council started decades ago. I spoke to Dr Tim Bliss at the National Institute for Medical Research who was one of the pioneers in research in this area.
TB: Round about 1900 it became clear to scientists, largely as a result of a Spanish neuro anatomist, Ramon Cajal that there was a junction between neurons that when one nerve cell made contact with a target cell there was a gap and that gap was called a synapse.
LN: But that didn't quite establish that signalling between nerve cells was chemical rather than electrical. TB: It wasn't really finally resolved that transmission of these synapses was chemical rather than electrical until sometime near the middle of the 20th century. LN: If information is to be stored at synapses then synapses have to change in some way. The only way that this change can be brought about is by the activity of nerve cells.
TB: The brain is an unbelievably complex structure, the most complex structure that we know about in fact but it does consist of billions of neurons and those neurons are widely interconnected so there are many, many more connections than there are neurons, orders of magnitude more and so that the patterns of activity within the brain which are set up by exterior events so my talking to you here is so far as the brain is concerned, is a pattern of neuro activity which begins with the sense organs – touch, hear, smell and so on. And when I come to recreate a conversation here this afternoon, when I come to recreate it in my memory at some later date, it's presumably I'm setting up a similar pattern of activity in my brain as to what was actually set up during our real time conversation. It's like some sort of imprint but the imprint has to be brought about by neural activity. LN: The neural patterns that Dr Tim Bliss is talking about are associated with changes in nerve cells at the level of individual molecules, a process known as long term potentiation or LTP. Researchers have established LTP as a molecular model of learning; the basis of the change that occurs in the brain when a memory is stored.
TB: For instance if you put your hand on a hot plate you'll never do it again. That's a permanent memory and yet it only took a second to learn because as soon as you put it on the hot plate you took it off again. PG: We think that we have maybe here a window into understanding the molecular basis of sex differences and memory formulation.
LN: What does this actually mean though for sex differences in memories; how does this translate to reality and how males and females differ in their ability to remember things?
PG: I think there are two points to consider. First is why is there a sex difference and secondly what does it mean. And if I may start first with why is there a sex difference; there is two potential reasons why there could be sex differences in memory formulation. One is that there are hormonal differences in the brain and it's known for example that oestrogen can modulate the activity between neurons, it can change the connection between neurons and potentially testosterone can do it as well. So there may be hormonal differences but in addition of course men and women have different genes because men have the y chromosome, so they have some genes women don't have and women have some genes expressed at higher levels than men because they have two x chromosomes whereas men have only one x chromosome. So there are also genetic differences and we want to study in the future basically whether the genetic differences or the hormonal differences are responsible for these sex differences we have observed. Potentially it means that not all mechanisms may be different for learning memory but we have some kind of differences in how males and females learn and that may be reflected by for example using alternative strategies which has been shown for some behavioural tasks, for example with spatial search tasks males and females use different strategies to find a hidden location. There are differences which may have been important for evolution.
LN: Whatever the reasons for them the differences between males and females are not only important in understanding how normal brains work but also what happens when things go wrong.
PG: This has of course also implications for diseases and the observations from the clinic has been that there are sex differences for many cognitive disorders. For example for Alzheimer's disease women are more frequently affected than men and it's not understood why this is the case and if it is so that indeed males and females can use different mechanisms to learn then maybe in some disease conditions the male mechanism is affected whereas in other disease conditions the female mechanism is more affected, which could explain sex differences observed in the clinic. And this has been observed not only for Alzheimer's disease but also for Schizophrenia, it has also been observed for learning disabilities, for a wide range of learning, memory disorders I would say. LN: And indeed scientists have found that in some learning disorders the molecular mechanisms thought to underlie learning and memory are disrupted. Long term potentiation or LTP no longer works as it should.
TB: Well there's been a great deal of interest, particularly in Alzheimer's disease where of course one of the symptoms is loss of memory and if LTP is the basis of memory one might predict, I'm not sure one's forced to predict but one might predict in animal models of Alzheimer's disease of which there are several quite good ones there should be an impairment of long term potentiation. And in many cases there is, not in every case but one of the things that happens in the more advanced stages of Alzheimer's disease is that you actually get a loss of cells and if you have a loss of cells in the hippocampus then even though long term potentiation is not badly affected, you've got an overall loss if you like, of computing power. But in most models of Alzheimer's disease, most mouse models, there certainly is an impairment in LTP and that's also true of other neuro degenerative and other sorts of disease in which memories are affected including Down syndrome as we've recently shown. LN: Scientists at the National Institute for Medical Research have created a model of Down syndrome by engineering a mouse which contains an extra chromosome, the cause of the syndrome in humans. The team discovered that these mice have deficits in their LTP and their memory. The memory molecule that Peter Geise found is a protein called Cam KK, it functions abnormally in some brain diseases.
PG: Most models suggest that in some diseases this protein is affected; these are diseases like the Angelman syndrome, Down syndrome, it's also in the model of Down syndrome, a change in this molecule. There's also evidence within the early stages of Alzheimer's disease when learning deficits are observed before neurons degenerate. At these early stages also this enzyme seems to be affected, so in a variety of learning deficiencies in humans this enzyme seems to be affected. So we are seeking to find out first what is the normal function of this molecule and then we want to go to these disease either models or studies with post mortem tissue to see basically what is happening to the enzyme, how we can potentially rectify the function of the enzyme.
LN: How would you do that? With drugs?
PG: That would be the ultimate goal, but it depends what this molecule regulates. We need to do more mechanistic studies before we can really establish how we can mimic the effect of this molecule.
LN: Laura Nelson PG: Professor Peter Geise TB: Dr Tim Bliss
