WHO İS ERİC KANDEL?

AqxB...ce4w

19 Mar 2024

For humans, learning, along with memory, is a process that begins before birth and continues throughout life. As individuals gain new experiences, they learn new information, behaviors, skills or update existing ones and store them in their memories. Curiosity about how learning and memory occurs is not new. For example, the ancient philosopher Plato thought that memory was provided by a substance that could change shape, and that it was preserved as if leaving a mark on a wax tablet. French philosopher and mathematician René Descartes, who lived much later than Plato, suggested that memory occurs through traces formed by activity in the brain. Undoubtedly, one of the most striking discoveries regarding learning was Ivan Pavlov, who demonstrated conditioning behavior in dogs. Pavlov's research has led scientists around the world to study behavior using experimental animals. In particular, John Watson and Karl Lashley's experimental approach to psychology and behavioral neuroscience increased experimental studies on learning and memory. This deficiency of memory and learning, which was beginning to be understood behaviorally but whose cellular and molecular basis remained obscure, was completed by an Austrian who escaped from Nazi Germany and settled in America; Eric Kandel.

From History to Neurons

Eric Kandel, one of three people who won the Nobel Prize in Physiology or Medicine in 2000 for his discoveries on the molecular mechanisms of memory and learning (the other two scientists are Arvid Carlsson and Paul Greengard), is a very familiar name for those interested in neuroscience. It is important to briefly touch on the journey of Eric Kandel, who is the chief editor of the book called "Principles of Neural Sciences", which is defined as the reference book of neuroscience, leading to Nobel Prize, in order to understand his contribution to science.

Born in Vienna on November 7, 1929, Eric Kandel overcame the difficulties of being a child of a Jewish family by escaping from his country to America with his family against the increasing Nazi oppression of the time when he was 9 years old. Kandel received religious education until 1944, then graduated from high school and went to Harvard University to study history, which interested him very much. Here, his curiosity about learning and memory increases, but the psychological approach is inadequate for him. Meanwhile, Kandel, who became interested in psychoanalysis, enrolled in New York University School of Medicine to study medicine. During medical education, his interest shifts to the biological foundations of the mind, neurophysiology and neuropsychology. He will specialize in psychiatry.

Following in the footsteps of Karl Lashley, Kandel, together with Alden Spencer, demonstrated electrophysiologically that the anatomical center of memory in the brain is the hippocampus. From now on, for Kandel, it is a process of focusing on memory and memory. Inspired by the studies of scientists such as Konrad Lorenz and Karl von Frisch with simple animals, Kandel thought that he would find the cellular and molecular basis of learning and memory by working with a simple animal and started a long study process.

A “Soft” Approach to the Human Brain

Kandel thought that the way to reveal learning and memory in humans was to simplify the complex structure called the brain. That's why he decided to work with a species of mollusc, crossing small mammals and even other vertebrates. This was a very courageous decision; Researchers of the time did not think that Kandel could reach a positive conclusion because they believed that simple animals did not have the complexity that could explain human behavior. Kandel was sure that no matter how simple it was, the underlying cell, that is, the neuron, had the same functional and chemical properties in all animals and therefore would show commonality with the neuron in humans.

For this study, Kandel chose the giant sea snail Aplysia californica . This animal had three important features that would be advantageous for the study. First, compared to the billions of neurons in the human brain, Aplysia had only 20,000 neurons. The neurons were divided into 10 individual ganglia, and these ganglia controlled various behaviors, so examining a learning function could be achieved through approximately 100 neurons. Second, these neurons were the largest neurons in the animal kingdom, with a diameter of approximately 1000 μm and visible even to the naked eye. There were also pigment differences, making it very easy to work with. Finally, antibodies, labeled molecules, and genetic factors could be easily applied to these neurons.

Together with Irving Kupfermann, Kandel tried the simplest behavior they could study on Aplysia and decided that Aplysia's gill and siphon (a tube-like organ used for various exchanges in mollusks) inhalation reflex in response to touch stimulation was useful for their study. Kandel and his team realized that the learning process in this mollusk through this simple reflex is very similar to that in humans and occurs in two stages: a temporary memory that lasts minutes and a more stable memory that lasts days. Thus, they were able to simplify the transition from short-term memory to long-term memory.

Having identified the neural circuits of rapid learning mechanisms, the next goal of Kandel and his team was to learn how neural circuits enable learning and memory formation at the cellular level. It has been suggested that there are DNA and RNA changes in neurons along with learning behavior, but this has not yet been proven. Observing that synaptic connections between neurons strengthen as they are exposed to a certain experience, as the famous neuroscientist histologist Ramón y Cajal thought, Kandel and his team turned their attention to the chemical changes that strengthen synaptic connections.

Famous Secondary Messenger; Cyclic Adenosine Monophosphate

First, they turned to protein synthesis and examined what synaptic changes occurred when they inhibited protein synthesis. Interestingly, the synapses were not affected by this inhibition and continued to show changes. Thereupon, they turned to cyclic adenosine monophosphate (cAMP), which is a secondary messenger and is increased inside the cell by some neurotransmitters. There was an increase in cAMP in the abdominal ganglion, which they thought was associated with learning and memory. When they administered various neurotransmitters and looked at which ones caused an increase in cAMP, they came across two candidate neurotransmitters: dopamine and serotonin. Among these two neurotransmitters, serotonin came to the fore, and Kandel and his team showed that the interneurons that provide the modulation are serotonergic. Serotonin was an important neurotransmitter in short-term memory and synaptic strengthening.

In addition, in their study with Paul Greengard, another Nobel Prize winner, they showed that cAMP causes synaptic strengthening through cAMP-dependent protein kinase (PKA). PKA became active, phosphorylated potassium channels, and more calcium entered the neuron, releasing more neurotransmitters. Additionally, when they inhibited PKA, serotonin also lost its effect. These findings showed that PKA is highly important for direct short-term synaptic regulation.

So what provided long-term memory? Kandel was sure that this required protein synthesis within the cell. For this, they worked on a cell culture consisting of a sensory neuron, a serotonergic interneuron and a motor neuron. When they applied serotonin to the medium, as the amount of PKA in the cell increased, the amount of mitogen-activated protein kinase (MAPK) also increased, and both of them entered the nucleus, that is, the starting point of gene expression. The starting point of gene expression was cAMP responsive binding protein 1 (CREB-1), a transcription factor that binds to the promoter regions of genes. Thus, proteins that would provide new synaptic connections were synthesized.

These studies, carried out by Kandel and his team of many famous names, have provided many basic information, such as the cellular and genetic mechanisms in synaptic connections, the importance of cAMP and PKA in neuronal signal transmission, and the explanation of how learning and memory occur through these findings. Considering that today's neuroscience studies are built on this basic knowledge, the value of Eric Kandel's pioneering in this field, along with Arvid Carlsson and Paul Greengard, is understood.