The Science of Brain Health and Cognitive Decline | Eric Kandel | Big Think

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; it requires conscious 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, it just reflects pathways themselves, but in other cases, it could involve the amygdala for emotional learning and the basal ganglia for some motor tasks. 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 is critical for the initial storing and consolidation of the memory. So, these are two very fundamental systems. Mammals have them both, while invertebrate animals only have one. Lifelong learning is extremely important, and the more we learn about the lifespan, 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 for the brain. It's good for you. So, as people age, they are 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 half the population has Alzheimer's disease.

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 and age-related memory loss is that it starts earlier; it starts in mid-life. It involves a different part of the brain; it starts in the dentate gyrus, while Alzheimer's disease starts in the entorhinal cortex. And it is preventable. You can prevent it.

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, and 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.

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. 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. It acts on the brain to enhance memory storage.

It does other things as well, but it enhances memory storage in young people and also enhances memory storage in older people. One of the reasons that exercise is important is that exercise builds up bone mass. This is particularly important in women, where bone mass tends to decrease more dramatically than 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. 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.

Gerard Karsenty 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, releases osteocalcin and 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 had 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. It acts not by itself but together with two other components: the CREB binding protein and a protein called RbAB 48.

Scott Small and I found that RbAB 48 is dramatically decreased in age-related memory loss. If you restore it, you can 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.

Then, we tested and saw that osteocalcin acts on several places in the brain, but it also acts on this critical switch; it facilitates the working of the switch.