Eric Kandel – The Man who Explained Memory

How do we remember events that happened twenty years ago or this morning? How do we learn new techniques, poems, places, languages? Which brain changes are behind these mechanisms? Eric Richard Kandel is an Austrian-American neurobiologist who dedicated his life to understanding the mechanisms of memory and learning. His work yielded him the Nobel Prize in Physiology or Medicine in 2000, which he shared with Arvid Carlsson and Paul Greengard ‘for their discoveries concerning signal transduction in the nervous system’.

The beginnings
Eric Kandel was born in Vienna in 1929, where he suffered through the Anschluss in 1938 and the hostile anti-Semitic climate. The persecution and humiliation under Nazi rule prompted the Kandel family to migrate to the United States, where they joined one of his uncles who had settled in New York. The tragic events of Kandel’s youth profoundly shaped  his personality and fostered his interest in memory and behavior. “The experiences of my last year in Vienna helped to determine my later interests in the mind, in how people behave, the unpredictability of motivation, and the persistence of memory”.

After high school, Kandel went to Harvard where he got acquainted with Ernst Kris, a psychoanalyst from Freud’s circle who had also moved from Vienna. The interactions with him sparked a fascination for the understanding of the mind and the processes involved in consciousness. After starting his medical studies at the New York University (NYU) Medical School in 1952, Kandel got interested in the biology of the mind and realized the importance of the brain’s activity in psychoanalysis. He then took an elective period to work in the lab of Harry Grundfest at Columbia University. During this time Kandel met sociology student Denise Bystryn, a French Jew who emigrated to the US in 1949. They married in 1956 and had two children.  

In 1957, Eric Kandel moved to NIH to work in Wade Marshall’s Laboratory of Neurophysiology. In the same year, Brenda Milner and William Scovill published their famous work on the patient H.M. who could not form new memories after hippocampal ablation, a surgery performed to treat his epilepsy. This study encouraged Kandel to perform intracellular recordings of neurons in the hippocampus of mammals to investigate neuronal properties of learning and memory, albeit with no results. Mammals are complex animals and Kandel in fact identified the need for a simpler model in which a sensory stimulation reaching the hippocampus leads to a change in the animal’s behavior. At that time,  Kandel’s peers were criticizing other reductionist approaches, such as the study on the squid giant axon by Hodgkin and Huxley or Katz’s nerve-muscle synapse of the frog. Nevertheless, inspired by Stephen Kuffler’s work on neuronal excitation and inhibition in marine invertebrates, and by Grundfest’s work on the excitability of nerve fibers in vertebrates, Kandel developed his idea of intracellular recording in invertebrate animals to decipher processes involved in the memory of vertebrate brains.

Aplysia: an original model to study memory
While working as a postdoc in the lab of Ladislav Tauc in Paris in 1962, Kandel learnt how to work on an unusual animal model: Aplysia californica, a marine mollusc with only 20,000 neurons, some of which are giant (1 mm of diameter) and easy to identify even without a microscope. Moreover, the aplysia is able to show a defensive behavioral reflex of gill withdrawal after siphon stimulation. Kandel thereby selected the aplysia as an experimental model to pursue his work on the neurobiology of behavior in his own group, which he opened in 1965 in the Departments of Physiology and Psychiatry at the NYU Medical School.

With this model, Kandel could explain that there are different forms of learning recruiting different molecular pathways, each specific to the given stimulus and correlating to a neuronal electrophysiological response. The defensive behavioural reflex presented by aplysia could in fact be modified by three forms of learning: habituation, sensitization and conditioning.

• Habituation: when a stimulus is repeated or presented for a prolonged period of time, there is a decline in the response to the stimulus
• Sensitization: when a stimulus is repeatedly applied, the response to the stimulus is enhanced
• Conditioning: a conditioned stimulus (that is usually neutral) is paired with an unconditioned stimulus. After pairing is repeated, the response to the conditioned stimulus is maintained, even if the stimulus is presented alone.

Habituation and sensitization are short-term memories, while conditioning is a form of associative learning (long-term memory).  After moving his lab to Columbia University in 1974 and becoming director of the Center for Neurobiology and Behavior, Kandel worked on the identification of proteins required for long-term memory. He successfully showed that long-term memory, contrary to short-term memory, requires the synthesis of new proteins and the formation of new synapses. This means that gene expression is essential for the maintenance of long-term memory.

The legacy
In 1990, having reached the age of 60, Kandel eventually started working on a more complex experimental model - the mouse - to confirm his findings. At the same time, he continued his work in aplysia studying analogs of memory which are unconscious and do not require the activation of hippocampal circuits (the hippocampus is in fact involved in explicit memory that requires conscious participation). Kandel’s subsequent work shed light on the role of genes in memory formation in mice, on how hippocampal neurons encode a spatial map, and on some molecular mechanisms of the long-term memory of extra-personal space (a positioning system discovered in 1971 by John O’Keefe, for which he was awarded with a Nobel Prize in 2014).  

With his work and his discoveries, Kandel built the basis of modern neuroscience. For him, it was essential to know how we create memories to understand what makes us. He also tried to bridge molecular neuroscience and psychiatry. He thinks in fact, that studying the biology of the mind could help to better understand complex human behaviors and perhaps to find better treatment for psychiatric disorders.

Eric Kandel has been a member of the National Academy of Sciences USA since 1974. Later he also became a member of the National Science Academies of Germany and France, the American Academy of Arts and Sciences, the American Philosophical Society, the National Institute of Medicine, and Germany’s Orden Pour Le Mérite für Wissenschaften und Künste. He also received many awards, such as the Harvey Prize in 1993 or the Wolf Prize in Medicine in 1999, until the greatest of all recognitions: the 2000 Nobel Prize in Physiology or Medicine. All these awards to Kandel and his work highlight how significant his scientific contribution has been. While he was teaching neural science at Columbia University, he had the idea to write a textbook: Principles of Neural Science, which was first published in 1981. Kandel’s work and discoveries have become staples of the education of neuroscientists and his book, which is widely known amongst academics as “the Kandel”, is a reference for all neuroscientists around the world - hailed by some as the “Bible of neuroscience”.

“Memory is everything. Without it we are nothing.” – E. Kandel    

Written by Isabelle Arnoux; Edited by Chiara Galante & Radhika Menon. Featured Image: NGC/Design.

Sources:
The Nobel Prize website:
https://www.nobelprize.org/prizes/medicine/2000/kandel/biographical/