Brain health tips from a Nobel Prize-winning neuropsychiatrist
"Lifelong learning is extremely important," says Nobel laureate Dr. Eric Kandel, "and the more we learn about life span the more important we realize it is."
Dr. Eric Kandel is University Professor and Fred Kavli Professor and Director of the Kavli Institute for Brain Science at the Columbia University College of Physicians and Surgeons. His most recent book is The Age of Insight: The Quest to Understand the Unconscious in Art, Mind, and Brain, from Vienna 1900 to the Present.
By probing the synaptic connections between nerve cells in the humble sea slug, Eric Kandel has uncovered some of the basic molecular mechanisms underlying learning and memory in animals ranging from snails to flies to mice and even in humans. His groundbreaking studies have demonstrated the fundamental ways that nerve cells alter their response to chemical signals to produce coordinated changes in behavior. This work is central to understanding not only normal memory but also dementia and other mental illnesses that affect memory.
Kandel's research has shown that learning produces changes in behavior by modifying the strength of connections between nerve cells, rather than by altering the brain's basic circuitry. He went on to determine the biochemical changes that accompany memory formation, showing that short-term memory involves a functional modulation of the synapses while long-term memory requires the activation of genes and the synthesis of proteins to grow new synaptic connections. For this work, the Austrian-born Kandel was awarded the 2000 Nobel Prize in Physiology or Medicine.
The traumatic events of Kandel's childhood likely influenced his later interest in the biological mechanisms of memory. He was only eight when, in 1938, Nazi Germany annexed his homeland, but the humiliation and discrimination that Kandel, his family, and other Jews suffered under this oppressive regime were forever seared into his memory. In 1939, on the eve of World War II, his family fled Austria for the United States.
As a college student at Harvard, Kandel majored in history and literature, but he was drawn to psychoanalysis after befriending a native Austrian student whose parents were prominent psychoanalysts in Sigmund Freud's circle. Kandel went to medical school at New York University with the goal of studying psychiatry and becoming a psychoanalyst himself. But thinking that he should know more about how the brain works, he took a neurophysiology course that shifted his interest toward research into the biology of memory. "The cell and molecular mechanisms of learning and memory struck me as a wonderful problem to study … It was clear to me even then that learning and memory were central to behavior, and thus to psychopathology and to psychotherapy," Kandel recalled.
Initially, he focused on recording the activity of nerve cells in the hippocampus, a region of the brain vital to memory formation. The mammalian hippocampus, however, with its seemingly infinite number of neurons and synaptic connections, made it difficult to study learning and memory at the cellular level. Kandel soon realized he needed a simpler system and chose the invertebrate sea slug Aplysia, much to the dismay of his colleagues who thought that no self-respecting neurophysiologist would abandon the study of learning in mammals to work on an invertebrate.
This bold decision paid off, though, and Kandel now works to instill in his students a sense that risk-taking is important to good science. "I try to convey to students my love of science and my conviction that exploring the biology of the brain is an unmatched scientific adventure," he explained. "I also encourage them to think boldly and to work carefully; to take gambles on their ideas and to try new approaches. I also tell them never to be embarrassed in exposing their ignorance … We are all here to learn, and the learning never ends."
More recently, Kandel has expanded his studies of simple learning and memory in Aplysia to include more complex forms of memory storage in genetically modified mice. These studies have focused on explicit memory (the conscious recall of information about places and objects), revealing the importance of a balance of activation and inhibition in memory storage so that animals as well as humans do not store information in their memories that is not important to recall.
Eric Kandel: 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.
As people age, they're susceptible to two kinds of cognitive decline. One is Alzheimer's disease, and the other is Age Related Memory Loss (ARML). These operate very differently, and while Alzheimer’s is still an urgent mystery for scientists to unlock, researchers have found that ARML can be prevented, and to some degree even reversed, says neuropsychiatrist Dr. Eric Kandel.
Things that can prevent and even wind back ARML are social involvement, learning new skills, learning a foreign language, physical exercise, a good diet and good health, and in the more micro view, a hormone called osteocalcin, which acts on the brain to enhance memory storage. Dr. Kandel explains the intricacies of this hormone, how to increase it, and the intriguing experiment that led to this realization.
Eric Kandel's most recent book is Reductionism in Art and Brain Science.
A new method promises to capture an elusive dark world particle.
- Scientists working on the Large Hadron Collider (LHC) devised a method for trapping dark matter particles.
- Dark matter is estimated to take up 26.8% of all matter in the Universe.
- The researchers will be able to try their approach in 2021, when the LHC goes back online.
Researchers hope the technology will further our understanding of the brain, but lawmakers may not be ready for the ethical challenges.
- Researchers at the Yale School of Medicine successfully restored some functions to pig brains that had been dead for hours.
- They hope the technology will advance our understanding of the brain, potentially developing new treatments for debilitating diseases and disorders.
- The research raises many ethical questions and puts to the test our current understanding of death.
The image of an undead brain coming back to live again is the stuff of science fiction. Not just any science fiction, specifically B-grade sci fi. What instantly springs to mind is the black-and-white horrors of films like Fiend Without a Face. Bad acting. Plastic monstrosities. Visible strings. And a spinal cord that, for some reason, is also a tentacle?
But like any good science fiction, it's only a matter of time before some manner of it seeps into our reality. This week's Nature published the findings of researchers who managed to restore function to pigs' brains that were clinically dead. At least, what we once thought of as dead.
What's dead may never die, it seems
The researchers did not hail from House Greyjoy — "What is dead may never die" — but came largely from the Yale School of Medicine. They connected 32 pig brains to a system called BrainEx. BrainEx is an artificial perfusion system — that is, a system that takes over the functions normally regulated by the organ. The pigs had been killed four hours earlier at a U.S. Department of Agriculture slaughterhouse; their brains completely removed from the skulls.
BrainEx pumped an experiment solution into the brain that essentially mimic blood flow. It brought oxygen and nutrients to the tissues, giving brain cells the resources to begin many normal functions. The cells began consuming and metabolizing sugars. The brains' immune systems kicked in. Neuron samples could carry an electrical signal. Some brain cells even responded to drugs.
The researchers have managed to keep some brains alive for up to 36 hours, and currently do not know if BrainEx can have sustained the brains longer. "It is conceivable we are just preventing the inevitable, and the brain won't be able to recover," said Nenad Sestan, Yale neuroscientist and the lead researcher.
As a control, other brains received either a fake solution or no solution at all. None revived brain activity and deteriorated as normal.
The researchers hope the technology can enhance our ability to study the brain and its cellular functions. One of the main avenues of such studies would be brain disorders and diseases. This could point the way to developing new of treatments for the likes of brain injuries, Alzheimer's, Huntington's, and neurodegenerative conditions.
"This is an extraordinary and very promising breakthrough for neuroscience. It immediately offers a much better model for studying the human brain, which is extraordinarily important, given the vast amount of human suffering from diseases of the mind [and] brain," Nita Farahany, the bioethicists at the Duke University School of Law who wrote the study's commentary, told National Geographic.
An ethical gray matter
Before anyone gets an Island of Dr. Moreau vibe, it's worth noting that the brains did not approach neural activity anywhere near consciousness.
The BrainEx solution contained chemicals that prevented neurons from firing. To be extra cautious, the researchers also monitored the brains for any such activity and were prepared to administer an anesthetic should they have seen signs of consciousness.
Even so, the research signals a massive debate to come regarding medical ethics and our definition of death.
Most countries define death, clinically speaking, as the irreversible loss of brain or circulatory function. This definition was already at odds with some folk- and value-centric understandings, but where do we go if it becomes possible to reverse clinical death with artificial perfusion?
"This is wild," Jonathan Moreno, a bioethicist at the University of Pennsylvania, told the New York Times. "If ever there was an issue that merited big public deliberation on the ethics of science and medicine, this is one."
One possible consequence involves organ donations. Some European countries require emergency responders to use a process that preserves organs when they cannot resuscitate a person. They continue to pump blood throughout the body, but use a "thoracic aortic occlusion balloon" to prevent that blood from reaching the brain.
The system is already controversial because it raises concerns about what caused the patient's death. But what happens when brain death becomes readily reversible? Stuart Younger, a bioethicist at Case Western Reserve University, told Nature that if BrainEx were to become widely available, it could shrink the pool of eligible donors.
"There's a potential conflict here between the interests of potential donors — who might not even be donors — and people who are waiting for organs," he said.
It will be a while before such experiments go anywhere near human subjects. A more immediate ethical question relates to how such experiments harm animal subjects.
Ethical review boards evaluate research protocols and can reject any that causes undue pain, suffering, or distress. Since dead animals feel no pain, suffer no trauma, they are typically approved as subjects. But how do such boards make a judgement regarding the suffering of a "cellularly active" brain? The distress of a partially alive brain?
The dilemma is unprecedented.
Setting new boundaries
Another science fiction story that comes to mind when discussing this story is, of course, Frankenstein. As Farahany told National Geographic: "It is definitely has [sic] a good science-fiction element to it, and it is restoring cellular function where we previously thought impossible. But to have Frankenstein, you need some degree of consciousness, some 'there' there. [The researchers] did not recover any form of consciousness in this study, and it is still unclear if we ever could. But we are one step closer to that possibility."
She's right. The researchers undertook their research for the betterment of humanity, and we may one day reap some unimaginable medical benefits from it. The ethical questions, however, remain as unsettling as the stories they remind us of.
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