There are two major forms of learning: implicit
or explicit or declarative and non-declarative. The simple form of learning, which I studied
in Aplysia, which holds true for all invertebrate animals, is learning of perceptual and motor
skills. More complex learning involves the hippocampus
requires conches participation and it involves learning about people, places and objects. So two different systems, implicit learning,
which does not involve conscious participation, involves a number of systems in the brain. In the simplest cases just reflects pathways
themselves, but in other cases it could involve the amygdala for emotional learning, the basal
ganglia for some motor tasks. So these are a variety of systems, but the
hippocampus is not in any fundamental way involved. In the learning of people places and objects
it involves conscious participation and it involves the hippocampus. The hippocampus is not critical throughout
the lifetime of the memory, but it's critical for the initial storing and consolidation
of the memory. So these are two very fundamental systems. Mammals have them both, invertebrate animals
only have one. Life long learning is extremely important
and the more we learn about life span the more important we realize it is. First of all it's pleasurable. Most people after a while realize when they
acquire new knowledge about something that it's really quite an enjoyable experience. But also it's like doing exercise, in fact
it's exercise of the brain. It's good for you. So as people age they're susceptible to one
of two kinds of cognitive declines. One is Alzheimer's disease, which begins in
the 70s but becomes almost an epidemic when people are in their 90s when almost have the
populations has Alzheimer's disease. And the other, which was only recently appreciated
to be quite distinct from Alzheimer's disease, is called age related memory loss. The difference between Alzheimer's disease
in the sense that it starts earlier, it starts in mid life; it involves a different part
of the brain it starts in the dentate gyrus, Alzheimer's disease starts in the entorhinal
cortex. And it is prevented. You can prevent it. And also to some degree you might be able
to reverse it. The things that prevent it, the things that
are prophylactically useful for it are social involvement, cognitive involvement, learning
new skills, learning a foreign language, physical exercise, a good diet and good health, making
sure if your blood pressure goes up that it's controlled, that if you have diabetes that
it's controlled, et cetera, et cetera, et cetera, those things act importantly to reduce
the likelihood and limit, essentially illuminate age related memory loss, or at least significantly
restrict it. And what recently emerged as a result of a
colleague of mine at Columbia Gerard Karsenty, is that there is a new approach to this. Karsenty found out that your bones are an
endocrine gland. They release a hormone called osteocalcin. And osteocalcin acts on the testes and the
ovaries, on the liver, acts on many organs of the body, but it also acts on the brain. And it acts on the brain to enhance memory
storage. It does other things as well, but it enhances
memory storage and it enhances the memory storage in young people but also enhances
memory storage in all people. And one of the reasons that exercise is important
is because exercise builds up bone mass. This is particularly important in the women
where bone mass tends to decrease more dramatically that in men, but it's important for everybody. So when you exercise you increase your bone
mass, you increase osteocalcin and you improve age related memory loss. So recently Karsenty has done a very interesting
experiment, it's been known for some time that if you take an old mouse that has age
related memory loss, et cetera, et cetera, et cetera, mice never get Alzheimer's disease
they only get age related memory loss. I found that that's one of the early clues
that made me think it might be different from Alzheimer's disease because you can have pure
age related memory loss without having Alzheimer's disease. If you take an old mouse, which has age related
memory loss, and cross perfuse it with a young mouse that doesn't, that is take the blood
out of it and give it to the blood of a young animal, you rescue age related memory loss. And Gerard Karsenty had found that one of
the critical factors in young blood is osteocalcin. So it fits in with the idea that exercise,
which builds up bone mass it releases osteocalcin, it has this rejuvenating effect on the brain. Also together with Scott Small we analyzed
some of the genetic changes that are involved in age related memory loss and we showed that
it involves a cascade that's involved in converting short-term memory into long-term memory. In earlier work I'd shown that when you convert
short-term memory to long-term memory in almost all systems it involves a particular alteration
in gene expression. A gene called CREB, cyclic AMP-responsive
element binding protein, is activated. And it acts not by itself but together with
two other components, the CREB binding protein and a protein called RbAB 48. And Scott Small and I found that RbAB 48 is
dramatically decreased in age related memory loss. And if you restore it you can to make an old
mouse young, if you knock it out you can take a young mouse and make it old. So clearly we had very good evidence that
we had identified at least part of a molecular cascade that's important for age related memory
loss and then we tested and we saw osteocalcin acts on several places in the brain, but it
also acts on this critical switch, it facilitates the working of the switch.
