.

A Celebration
of the
Scientific Achievement
of the Great
Jewish American Austrian Molecular Neuroscientist

Eric R. Kandel, M.D.

featuring a
Summary & Analysis
of his great work



------Sign the Guestbook------

I. OVERVIEW

(1) The History of Brain Science in a Nutshell

1 brainwhoa...the mind is THERE!
2brain regionsmegascopic
3brain cells (neurons)microscopic
4neurotransmittersbetween neurons
5receptorsin neural membrane
6second messengers inside neuron
7gene regulators inside nucleus


Equipment:

1bodieshuman & animal
2paperfor anatomical drawings
3microscopes...
4heavy chemicals stains to trace nerves
5drugsrandom discovery-->bioengineered
6electrical gearvoltage clamps, EEG
8X-rays/nuclear magnetismCAT, MRI,3D molecular imaging [X-ray crystallography/protein NMR]
9bioinformatic computer systemsautomated gene/protein sequencing

(note: brain technology has long been restricted to highly trained researchers. However, we are approaching the age of inexpensive noninvasive imaging and PC-based neural nets and brain models. EEG and ANS monitoring equipment is already available to hobbyists, and $1 MRIs, gene chips, and MBIs (mind-brain interfaces) are on the horizon.)

Timeline:

dark blue=anatomy of braingray=technology
light blue=microanatomy of neuronorange=observation of behavior
pink=drugs, transmitterspurple=study of consciousness
green=DNA, genesyellow=holism, emergence

-1700Imhotep (Egypt)first use of word “brain,” with description of distal symptoms of brain damage from 30 clinical cases
-500Alcmaeon of Crotona locates vision and senses in localized brain regions
-370Hippocrates locates epilepsy, sensation, all mental processes in brain
-360Plato locates mental processes in brain
-350Aristotledescribes memory formation as the association of simple ideas (mistakenly thinks thought occurs in heart)
-300Herophilus of Alexandria father of anatomy, locates human intelligence in brain, distinguished sensory and motor nerves, first anatomical drawings
-280Erasistratus of Chios describes origin of nerves in brain, divisions of the brain
-150Poseidonus of Byzantiumreported effects of localized brain damage (though incorrect)
177Galenlocalized mental processes in solid brain matter (not ventricles), traced sensory nerve system
1021Ibn al-Haytham (Iraq)discovers that vision occurs in brain, not eyes
1504Leonardo da Vinci modern anatomical drawing, wax injection of ventricles
1543Andreas Vesalius father of modern anatomy, realistic drawings
1550Bartolomeo Eustachio locates origin of optic nerves in brain
1590Zacharias Janssen invents the compound microscope
1611Lazarus Riverius describes impaired states of consciousness
1621Robert Burton describes depression
1637Descartesproposes that mind+body interact in brain
1665Robert Hooke develops microscopes
1673Joseph DuVerneyperforms experimental ablation in pigeons
1684Raymond Vieussens uses boiling oil to harden the brain
1690Lockeproposes that mind is a blank slate that develops through sense data--eliminates a lot of nonscientific psychological BS, but ignores DNA
1695Humphrey Ridley anatomy text -- first describes peduncles, mamillary bodies, etc
1709George Berkeley describes how concepts like distance are constructs of the brain, based on past experience
1717Antony van Leeuwenhoekdescribes nerve fiber in cross section
1740Emanuel Swedenborgtheorizes motor cortex map, neurons, neuroendocrine system, etc -- ideas ignored b/c not a professor
1749David Hartley the first English work using the word "psychology"
1755J.B. Le Roy uses electroconvulsive therapy for mental illness
1760Charles Lorry demonstrates that damage to the cerebellum affects motor coordination
1772John Walsh conducts experiments on torpedo (electric) fish
1781Kantargues we are born with built-in templates of a priori knowledge (more neuroscientifically sound than Locke)
1791Luigi Galvanidiscovers nervous system = electrical
1800Franz Joseph Gallproposes that brain has special regions for all mental functions, even emotion
1800Humphrey Davy synthesizes nitrous oxide
1801Adam Friedrich Wilhelm Serturner crystalizes opium and obtains morphine
1809Johann Christian Reil uses alcohol to harden the brain
1809Luigi Rolando uses galvanic current to stimulate cortex
1811Julien Jean Legallois discovers respiratory center in medulla
1812Benjamin Rush father of american psychiatry, promotes asylums, treatment for alcoholism
1820Johann Shweiggerinvents galvanometer (precursor to voltage clamps, EEGs to study neurons)
1822Pierre Flourenslocates movement in cerebellum, shows brain has regions for mental functions but NOT memory: finds that memory is distributed; also describes ablation for studying behavior
1825Jean Baptiste Bouillaudpresents cases of loss of speech after frontal lesions
1825Robert B. Todd discusses the role of the cerebral cortex in mentation, corpus striatum in movement and midbrain in emotion
1826Johannes Muller proposes theory of "specific nerve energies" (early notion of electrical transmission by nerves)
1827E. Merck & Company markets morphine
1832Justus von Liebig discovers chloral hydrate
1832Jean Pierre Robiquet isolates codeine
1832Sir Charles Wheatstone invents the stereoscope
1833Philipp L. Geiger isolates atropine
1836Marc Dax descrives effects on speech from left hemisphere damage
1836Gabriel Gustav Valentin identifies neuron nucleus and nucleolus
1838Eduard Zeis studies dreams in people who are blind
1838Robert Remak suggests that nerve fiber and nerve cell are joined
1838Jean Esquirol promotes asylums
1839Theodor Schwann, Mattias Jakob Schleidendiscovers CELLS, which make up all living things
1840Adolph Hannover uses chromic acid to harden nervous tissue
1842Crawford W. Long uses ether on man
1847James Young Simpson uses chloroform anesthesia
1848John Harlowpatient Phineas Gage loses moral judgment with damage to ventromedial cortex
1849Hermann von Helmholtzmeasures speed of frog nerve impulses= 90 feet per second, slowly actively propagated
1850Emil Du Bois Reymond invents nerve galvanometer
1853William Benjamin Carpenter proposes "sensory ganglion" (thalamus) as seat of consciousness
1855Bartolomeo Panizza shows the occipital lobe is essential for vision
1855Richard Heschl describes the transverse gyri in the temporal lobe (Heschl's gyri)
1856Albrecht von Graefe describes homonymous hemianopia
1859Darwindescribes how humans evolved from animals
1860Gustav Theodor Fechner develops "Fechner's law"--intensity of perception is logarithm of sense stimuli (i.e. progressively less sensitive)
1860Albert Niemann purifies cocaine
1864Pierre Paul Brocadescribes how expressive (speech) aphasia is caused by frontal lobe damage
1865Gregor Mendeldescrobes jpw hereditary information is passed in units (genes)
1867Theodore Meynert performs histologic analysis of cerebral cortex
1873Gustav Fritsch, Eduard Hitzigshows that a dog moves when motor cortex stimulated
1873Camillo Golgi discovers silver nitrate staining of nerves, used by Cajal (below)
1874Roberts Bartholow electrically stimulates human cortical tissue
1875Richard Caton records electrical activity from the brain
1878Paul Broca publishes work on the "great limbic lobe"
1878Harmon Northrop Morse synthesized acetaminophen
1878Claude Bernard describes nerve/muscle blocking action of curare
1879Carl Wernickesensory aphasia caused by temporal lobe damage
1879Wilhelm Wundt sets up lab devoted to study human behavior
1879Mathias Duval introduces an improved method of embedding tissue using collodion
1879William Crookes invents the cathode ray tube
1881Hermann Munk reports on visual abnormalities after occipital lobe ablation in dogs
1883Emil Kraepelin coins the terms neuroses and psychoses, discovers schizophrenia
1885Paul Ehrlich notes that intravenous dye does not stain brain tissue : blood-brain barrier
1885Hermann Ebbinghausdetermines that people can memorize 7 nonsense words one session, forget most in 1 hour (short-term), rest in 1 month (long-term)
1885Carl Weigert introduces hematoxylin to stain myelin
1889Santiago Ramon y Cajaldescribes how brain = network of unique neurons which fire in one direction
1890John Hughlings Jacksondescribes how temporal seizures elicit dreamy states
1890William Jamesdescribes how memory can be short-term, long-term, habitual, or autonomic (unconscious)
1895William His first uses the term hypothalamus, dendrite
1895Wilhelm Konrad Roentgen invents the X ray
1895Heinrick Quincke performs lumbar puncture to study cerebrospinal fluid
1897Felix Hoffmann synthesizes aspirin
1897Karl Ferdinand Braun invents the oscilloscope
1897Ferdinand Blum uses formaldehyde as brain fixative
1899Francis Gotch describes a "refractory phase" between nerve impulses
1900Georg Muller, Alfons Pilzeckerlongterm memory blocked by disruption within 1 hour
1900Sigmund Freud describes mental illnesses as unconscious neurobiological processes, observed through dreams, free association, slips
1902Julius Bernsteincalculates nerve impulse = 70 millivolt ionic shift across membrane of neuron
1903Ivan Pavlovshows in dogs hows training creates direct connections between sense and motor nerves
1905John Newport Langley introduces the concept of receptor molecules , describes "parasympathetic nervous system" –
1906Charles Sherringtoncat reflexes = senses integrated by excitatory/inhibitory interneurons to single motor output
1907Ross Granville Harrison describes tissue culture methods
1908Richard Goldschmidtneurons in animals are always in the same place
1908Victor Alexander Haden Horsley,Robert Henry Clarke design stereotaxic instrument
1908Willem Einthoven makes string galvanometer recordings from the vagus nerve
1909Harvey Cushing first to electrically stimulate human sensory cortex
1911George Barger,Henry Dale discover norepinephrine
1913Edwin Ellen Goldmann finds blood brain barrier, impermeable to large molecules
1913Santiago Ramon y Cajal develops gold chloride mercury stain to show astrocytes
1913Walter Samuel Hunter devises delayed response test
1914Henry H. Dale isolates acetylcholine
1915J.G. Dusser De Barenne describes activity of brain after strychnine application
1915Thomas Hunt Morganeach gene in fruit fly is located in certain place on chromosomes
1919Gordon Morgan Holmes localizes vision to striate area
1919Walter E. Dandy introduces air encephalography
1920Stephen Walter Ranson demonstrates connections between the hypothalamus and pituitary
1920Otto Loewi, Henry Dalefluid from frog vagus nerve directly slows heart of another frog
1921Hermann Rorschach develops the inkblot test
1921John Augustus Larsen, Leonard Keeler develop the polygraph
1927Chester William Darrow studies galvanic skin reflex
1928Philip Bard suggests the neural mechanism of rage is in the diencephalon
1928Walter Rudolph Hess reports "affective responses" to hypothalamic stimulation
1928Lord Edgar Douglas Adriannerve impulses are all identical, with 1 millisecond upstroke + downstroke
1928John Fulton observes sounds of blood flowing over the human visual cortex
1929Walter B. Cannon coins the term homeostasis
1929Hans Berger first human electroencephalogram
1929Karl Lashleyremoving parts of rat brains does not eliminate memory
1930Carlyle Jacobsenfrontal lobe in monkeys controls short-term memory
1931Ulf Svante von Euler,J.H. Gaddum discover substance P
1932Smith, Kline first amphetamine, Benzedrine
1932Max Knoll, Ernst Ruska invent the electron microscope
1932Jan Friedrich Tonnies develops multichannel ink writing EEG machine, differential amplifier
1933Ralph Waldo Gerard describes first experimental evoked potentials
1934S. Howard Bartley performs studies on cortical visual evoked potentials in rabbits
1935Frederic Bremer uses cerveau isole preparation to study sleep
1936Egas Moniz publishes work on the first human frontal lobotomy
1936Walter Freeman performs first lobotomy in the United States
1936Wade Marshall, Wilder Penfieldsensory nerves connect to neurons arranged in shape of body
1937James Papez describes limbic circuit, visceral theory of emotion
1937Heinrich Kluver, Paul Bucy describe bilateral temporal lobectomies
1938Albert Hofmann synthesizes LSD
1938Ugo Cerletti, Lucino Bini treat human patients with electroshock
1939Alan Hodgkin, Andrew Huxleynerve impulse of squid = 110 millivolts
1942Stephen Kuffler develops the single nerve muscle fiber preparation
1943John Raymond Brobeck describes hypothalamic hyperphasia
1948Wilder Penfieldelicits memories/auras from 8% patients with temporal lobe stimuli
1948Jerzy Kornorskineuron voltage drops after excitation (refractory period)
1949Giuseppi Moruzzi, Horace Winchell Magoun discover reticular activating system: cutting a cat's sense nerves does not affect wakefulness, but cuttin RAS does
1949John Cade discovers that lithium is an effective treatment for bipolar depression
1949Kenneth Cole develops the voltage clamp
1949D.O. Hebbreverbatory circuits are responsible for short-term memory
1949CP Duncanlongterm memory blocked by seizures within 1 hour
1950Steven Kufflerretinal cells signal contrast, not brightness
1950Vernon Mountcastleplace cells = cortical neurons that respond to stimuli from certain directions
1950B.F. Skinner, Jerome Brunerpigeon training creates direct connections between sense and motor nerves
1950Eugene Roberts, J. Awapara independently identify GABA in the brain
1950Henri Laboritantihistamine chlorpromazine tranquilizes patients, also antipsychotic, with Parkinsonism side-effect
1951John Ecclesneurotransmitters can modulate neuron potential (excite to -55mV or inhibit to +75mV)
1952Alan Lloyd Hodgkin, Andrew Fielding Huxley describes action potential in mathematical terms, by using voltage clamp on squid neurons
1953Eugene Aserinski , Nathaniel Kleitman describe rapid eye movements (REM) during sleep
1953H. Kluver, E. Barrera introduce Luxol fast blue MBS stain
1953James Watson, Francis Crick discover double helix of DNA, with 4 nucleotides=copying mechanism
1954James Olds describes rewarding effects of hypothalamic stimulation
1954John Lilly invents the "isolation tank"
1955Kandel, PurpuraLSD increases (not stops) serotonin inhibition of visual cortex exposed to flashes of light
1956DW Woolley, EN ShawLSD stops serotonin contractions of rat uterus
1956Rita Levi Montalcini, Stanley Cohen isolate and purify nerve growth factor
1956L. Leksell uses ultrasound to examine the brain
1957Brenda Milner, William ScovilleH.M. hippocampectomy, loss of long-term memory encoding
1958Harry Harlowmonkeys isolated from mother devastated behaviorally, partially reversed by cloth-covered wooden dummy and a few hours with normal infant monkey
1958Arvid Carlssondiscovers dopamine in brain, lack causes Parkinsonism, L-Dopa causes schizoid
1958Haloperidol introduced as a neuroleptic
1959David Hubel, Torsten Wieselvisual thalamus responds to contrast, visual cortex responds to contours with specific orientation
1959P. Karlson,M. Lusher describe pheromones
1960Louis Flexnerprotein inhibitors block consolidation during and shortly after learning, but not short-term memeory
1960Geoffrey WatkinsGA is main transmitter, with 2 hippocampal receptors, rapid AMPA depolarizes cell 20mV-->opens NMDA-->Ca+-->kinase-->additional AMPA receptors
1960Aaron Beckcognitive behavioral therapy (CBT) = short-term psychological treatment
1961Robert Dotyclassical conditioning by stimulus to dog visual cortex and motor cortex
1961Earl Sutherlanddescribes how cells may learn from environment: epinephrine at metabotropic receptors on fat/muscle membrane-->binds adenylyl cyclase which makes 1000 molecules of cAMP for minutes second-messenger changes cell
1961Brenner and Cricktriplets of 4 nucleotides yield 20 amino acids
1962Eldon Foltz performs the first cingulotomy to treat chronic pain
1962Francois Jacob, Jacques Monoddiscover how genes are switched on/off: regulatory gene-->regulatory protein-->(in absence of lactose) binds to promoter-->frees effector gene-->protein/enzymes
1965Ronald Melzack,Patrick D. Wall gate control theory of pain
1966Ed Evarts, Robert Wurtz, Michael Goldbergsingle cell recordings from behaving and attentive monkeys
1968Ed KrebscAMP-->binds regulatory units on protein kinase A, freeing catalytic units to phosphorylate proteins
1969D.V. Reynolds describes the analgesic effect of electrical stimulation of the periaqueductal gray
1969Bernard Katznerve impulse opens voltage-gated ion channel at synapse, releasing neurotransmitters
1970Paul Greengarddopamine receptor in brain-->cAMP, activates protein kinase
1970Walter Gilbert, Frederick Sangerrapid DNA sequencing, recombinant DNA (snip out gene, clone it, stitch to bacterial DNA)
1971John O’Keefeplace cells in hippocampus respond to any sense from certain direction
1972Godfrey N. Hounsfield develops x ray computed tomography
1973Terje Lomo, Tim Blisshippocampal cells strengthened for days after rapid stimuli
1973Candace Pert,Solomon Snyder discover opioid receptors in brain
1973Paul Bergfirst recombinant DNA molecule
1973Herbert Boyer, Stanley Coheninvents gene cloning
1973Konrad Z. Lorenz, Nikolaas Tinbergen, Karl von Frisch discover imprinting in animals (=postnatal gene regulation)
1974Alan Baddeleyworking memory = moment-to-moment memory for executing complex behavior
1974Thomas Nagel, John Searlebinding/NCC, subjectivity—what are the elements of subjective consciousness
1974John Hughes,Hans Kosterlitz discover enkephalin
1974M.E.Phelps, E.J.Hoffman,M.M.Ter Pogossian develop first PET scanner
1974First NMR image (a mouse) is taken
1974Seymour Benzermutatogenic chemicals on drosophila, flies with defective gene for disposing of cAMP have no short-term memory
1976Choh Hao Li,David Chung describe beta endorphins
1976Erwin Neher ,Bert Sakmann invents the patch clamp, which can record from individual membrane channels
1980Richard Morrisblocking NMDA blocks longterm potentiation--shows how a short-term transmitter can affect longterm neural activity (memory)
1980Gerald Klerman, Myran Weissmandevelops interpersonal psychotherapy = CBT for mistaken beliefs about others
1981Roger Wolcott Sperry shows how sense data is filled out by brain, by observing patients with split hemispheres
1982Bengt Ingemar Bergstrom, John Robert Vane, Sune K. Bergstrom discovers of prostaglandins
1983Benjamin Libetdiscovers readiness potential in EEG 1 second before movement, 200 ms before “willing”
1987Larry Squire, Daniel Schacterdescribes how implicit/procedural (conditioning motor skills) versus explicit/declarative memory are recorded by different modules of the brain
1987Gerald Edelmanproposes that consciousness is widely distributed throughout the cortex and thalamus
1987Eli Lillyprozac introduced as treatment for depression
1989Colin McGinnproposes that consciousness cannot be studied by limited mind
1990Thomas Ebertdiscovers that musicans' cortical finger maps expand 5-fold
1990Crick and Kochproposes neural correlates of consciousness, perhaps claustrum
1990Michael Merzenichdiscovers that cortical maps vary among monkeys and expands with use
1990Eric Lumerdescribes binocular rivalry-- the prefrontal and posterior pariental regions of the cortex seem to relay the decision regarding which image is to be enhanced to the visual system, which then brings the image into consciousness
1992Craig Baileydiscovers long-term memory in aplysia based on new axon terminals
1992Daniel Dennettproposes that consciousness is function of neural computation, nothing else
1994Alfred G. Gilman,Martin Rodbell discovers G protein coupled receptors, key part of nerve signalling and memory
1996Lewis Baxter, Jeffrey Schwartzproves CBT for OCD=SSRI=inhibit caudate; psychotherapy for depression=SSRI=shift in activity from dorsal to ventral PFC
1996Anthony Movshon, William Newsomeperforms single cell recordings from behaving and attentive monkeys -- reveals consciousness on a cellular level
1999Patricia Goldman-Rakicfinds that removing monkey PFC destroys working (not all short-term) memory
2004Rene Henmouse dentate gyrus lesion abolishes effect of antidepressants



Note:This timeline is based on Kandel's summary, plus this timeline and other web sources. Obviously the two last entries do not begin to suggest the huge explosion of research in the last 10 years. The timeline as a whole leans toward Kandel's interest in memory.

The timeline is almost all white males from a few Western nations, comprising an exclusive old-boy network. Kandel describes this vividly in his book. His career, in fact, probably coincides with the peak of the old-boy system.

This system is phasing out for several reasons--the PC/Internet Revolution, China, the changing nature of science itself. Most discoveries of the past were made by men puttering around with tangible equipment such as microscopes. Future research will be done by software; what human involvement remains will be spread among a global network of researchers from private enterprise as well as university labs--as well as late-night hackers. The age of the lone researcher who stumbles almost randomly into a celebrated place in scientific history is over.

Thankfully, the age of unethical and crude experimentation on animals and the mentally ill is also phasing out. Kandel describes how one of the seminal anatomical texts was based on dissections of Holocaust victims. The entirety of brain research history, though including some of the most fascinating and profound revelations about the nature of human experience, is a ghastly and chaotic tale of dissections and intoxications and horrifying injuries. The future may not provide such a riveting story, but it will be fundamentally better in almost every respect.

As Kandel told an interviewer in 2004, looking back on his career, "We've had a wonderful run on cellular molecular biology. The time has now come to use more synthetic approaches."

Theory:

date"ism"VIPstructuresmethods
-500-1853humoralismGalen4 humors: black bile - yellow bile -phlegm - bloodwild speculation
1858-1900sstructuralismWundt (father of psychology)3 elements: sensation -affection-perceptionsemi-controlled introspection
1903-1950sbehaviorismPavlovstimulus-->responsecontrolled animal studies
1900-1960sFreudianismFreud3 divisions: ego - id - superegosemi-controlled talk therapy
1950-1980shumanismMaslow5 needs: physiological-->safety-->love-->esteem-->self-actualization" " (more sensitive, respectful; less dogmatic)
1960-2000scognitivismBeck3 modalities: cognition-->emotion-->behaviorcontrolled human studies
1980-2000scomputationalismMinsky3 quantities: input-->nodes-->outputhighly controlled simulations, AI

Treatments:

datetreatmentmethods
1247institutionalized psychiatry (Bedlam=first asylum, London)confinement, restraint, lobotomy, electroshock, insulin shock
1900psychoanalysistalk therapy
1950psychopharmacologydrugs
1960sspecific therapiescognitive behavioral therapy (CBT), interpersonal therapy, music therapy, etc.


Note: Although cognitive and computational neuroscience have gradually become more rigorous and falsifiable, and psychiatry has moved towards short-term, empirically based specific therapies, all psychological theories and treatments are essentially reductionistic and their purported "elements" and "structures" are all vulnerable to criticism on the basis of the distributed, emergent, and holistic nature of the brain and mind. In general psychiatry is a grand reification "signifying nothing" and is widely assumed to be gradually yielding to more empirical neurology, perhaps as a subspecialty, "neuropsychiatry."

(2) Kandel’s Big Discovery


Eric Kandel (1929-) (lab site) won the Nobel prize in 2000 for cracking the memory code. Memory was a “black box” when Kandel began his research in the 1950s. Behaviorists such as B.F. Skinner, following Pavlov’s experiments with dogs, studied memory indirectly, by observing animal behavior. But no one before Kandel ventured inside the brain and figured out what was happening on a cellular and chemical level. From about 1965 to 1985, through dozens of scientific papers, Kandel effectively cracked the code.

Kandel’s big eureka moment occurred in the early 1960s when he decided to repeat Pavlov’s dog experiments on sea snails. Aplysia snails happen to have extra-large neurons which can be manipulated easily. Instead of teaching the snails with Pavlov’s bells and other sensory cues, Kandel stimulated the snails’ sensory neurons directly with electrodes. By a process of elimination, neuron by neuron, he mapped out the entire neural circuit of a simple behavior in the snails (the gill-withdrawal reflex) that changes and learns in response to its environment. Then, by removing parts of the circuit to a petri dish and subjecting the neurons to electric shocks and different chemicals, he determined many of the chemical pathways that mediate memory formation.



Pavlov's dog


Kandel's Aplysia

It should be noted that prior to Kandel’s discovery, scientists knew that some kind of chemical change must occur between neurons when we learn. Neurons themselves can’t change much—they are insulated fibers which are basically fixed in place according to our DNA. However, the connections between neurons are very flexible. There are small gaps between neurons called synapses across which neurons communicate by pumping out chemical messengers called neurotransmitters. Kandel found that neurons constantly adjust these neurotransmitters and, as Kandel dramatically discovered, sprout entirely new synaptic terminals, according to the rate of impulses passing through the neuron. Kandel wrote:

The growth and maintenance of new synaptic terminals makes memory persist. Thus, if you remember anything of this book, it will be because your brain is slightly different after you have finished reading it.Kandel discovered the chemical sequences for both short-term and long-term memory. In short-term memory, the neuron does not grow new synaptic terminals but adjusts the amount of neurotransmitters:

neurotransmitter -->cAMP-->kinases-->potassium-->calcium-->neurotransmitter

In long-term memory, new synaptic terminals appear—this only happens when neurotransmitters are pumped in high concentrations repeatedly, so that their chemical byproducts reach the nucleus of the cell and activate DNA, which encodes proteins needed to build new synaptic terminals:

neurotransmitter-->cAMP-->kinases-->CREB-->DNA-->mRNA+CPEB-->proteins

Kandel went on to perform experiments in the hippocampus of mouse brains, where he found an similar chemical sequence as found in snails. In the mouse, he found that the sequence correlated with a much more complex form of memory than he had found in snails—memory of the spatial layout of a room—which closely resembled human memory. Kandel also found that both age-related and Alzheimer’s memory loss in mice (as in humans) involve breakdowns in the sequence which could be offset by drugs. He also found that deficiencies in the sequence in other parts of the mouse brain (amygdala, striatum) are major contributors to other mental disorders such as anxiety disorders and schizophrenia.
Kandel found an interesting variation of the chemical sequence for memory formation in the mouse hippocampus:

neurotransmitter-->NMDA-->calcium-->AMPA-->glutamate

This sequence is affected by firing of different neurons converging on a third neuron—this creates a logical circuit called a “coincidence detector.” In humans, there are several other variations of the basic sequence discovered by Kandel which allow for different functions of neural computation. The general rule is that “cells that fire together, wire together.” This is the essence of associative learning.

(3) Aplysia Californicus

Aplysia was extremely enjoyable to work with…Because placing a tiny electrode into such a gigantic cell causes essentially no damage, one can record for five to ten hours. I could go to lunch and come back to find the cell still in perfect health.The system for supplying the snails was not very reliable, so it was difficult to obtain them in Paris. We therefore spent close to the entire autumn of 1962 in Arcachon, a beautiful little resort not far from Bordeaux. (p.174)

We were fascinated by its sexual behavior. These snails are hermaphrodites; they can be both male and female, with different partners at different times or even simultaneously. By recognizing one another appropriately they can form impressive copulating chains in which each member serves as both male for the animal in front of it and female for the animal behind it in the chain. (p.188)




After a season studying Aplysia…I felt that I was developing a style of doing science…Without quite knowing it, I had found my voice, much as a writer must feel after having written an number of satisfactory stories. With that finding cam self-assurance, a sense that I could make a go of it in science…Maturation as a scientist involves many components…One needs to learn what problems are important. I sensed myself developing taste, distinguishing what was interesting from what was not—and among the things that were interesting, I also learned what was doable. (p.172)

II. FAMILY / CULTURAL INFLUENCES

(1) Jewish-Austrian background



I have written this book as an introduction to the new science of mind for the general reader who has no background in science. A further impetus for writing this book came in the fall of 2000… In the course of writing my Nobel essay, I saw more clearly than before how my interest in the nature of memory was rooted in my childhood experiences in Vienna. (p.xiv)


Kandel’s parents’ store (down the street from their apartment)


My parents shared the values of most other Viennese parents: they wanted their children to achieve something professionally—ideally, something intellectual. Their aspirations reflected typical Jewish values. Ever since the destruction of the Second Temple in Jerusalem in 70 A.D…Jews have been a people of the book…It meant a great deal, even to a poor Jewish family in Vienna, that at least one son succeed in becoming a musician, a lawyer, a doctor, or, better still, a university professor. Vienna was one of the few cities in Europe where the cultural aspirations of the Jewish community coincided fully with the aspirations of most non-Jewish citizens…As their political and military power waned, they replaced their desire for territorial preeminence with a desire for cultural preeminence. (p.22)



Location of Kandel’s childhood home in Vienna

While I was in Vienna in 2003, I learned that the Viennese Kultusgemeinde, the Jewish social service agency was going bankrupt trying to protect synagogues against continuing vandalism…I met Michael Haupl, the mayor of the city of Vienna…He succeeded in persuading the governors of the Austrian states to help out financially…In these negotiations, I felt that the Kultusgemeinde needed our support in principle—on moral grounds. As far as I knew, I had no personal involvement with the agency…In July 2004 I received through the Holocaust Museum in Washington, D.C. my father’s file from the Kultusgemeinde. In it were requests from my father for funds to pay first for my transportation and that of my brother to the United States and then to pay for the transportation of my parents. Simply stated: I owe my existence in the United States to the generosity of the Viennese Kultusgemeinde. (p.411)



Kultusgemeinde, Vienna

My fondest early memories are typically Viennese: one, a modest but sustained bourgeois contentment…and the other, a moment of erotic happiness that came naturally from our seductive housekeeper Mitzi….One of the criteria bourgeois families in Austria-Hungary used in selecting girls for housework was that they be suitable to relieve the family’s adolescent boys of their virginity, in part to entice them away from any possible attraction to homosexuality….My encounter with Mitzi, an attractive, sensual young woman of about twenty-five, began one afternoon as I was recovering from a cold at age eight. She sat down at the edge of my bed and touched my face. When I responded with pleasure, she opened her blouse, exposing her ample bosom, and asked me whether I would like to touch her. I barely grasped what she was talking about, but her attempt at seduction had its effect on me, and I suddenly felt different than I ever had before…Several weeks after our brief rendezvous in my bed, she took up with a gas repairman who came gby to fix our stove. A month or two later, she ran off with him to Czechslovakia. For many years thereafter, I thought that running off to Czechoslovakia was the equivalent of devoting ones’ life to the happy pursuit of sensuality. (p.23)

We can even recall past emotional states…To this day I remember some of the emotional context of my romantic encounter with our housekeeper Mitzi. (p.280)

In principle, a highly emotional state could bypass the normal restraints on long-term memory…This might account for so-called flashbulb memories, memories of emotionally charged events that are recalled in vivid detail—like my experience with Mitzi—as if a complete picture had been instantly and powerfully etched on the brain. (p.265)

What, in principle, has sustained my memory of Mitzi for a lifetime? (p.272)



Parents

I owe an enormous personal debt to my parents and my brother Lewis. My parents were able in mid-life to relocate to a foreign country - my father spoke not a word of English when he first arrived in New York - and to create a new life for themselves and their sons. My parents not only succeeded in establishing themselves in their small store in Brooklyn, but were sufficiently successful to support me through college and medical school. (Nobel prize essay)

My parents were so preoccupied with the store—the key to financial stability for them and their children—that they did not share in the cultural life which Lewis and I were beginning to enjoy. Despite their constant labors, however, they were always optimistic and supportive of us, and they never tried to dictate decisions about our work or play. My father was an obsessively honest person…But other than a general expectation of reasonable and correct behavior, I never felt any pressure from him to follow one academic track or another. (p.35)



Brother


Kandel (left) and Lewis

My older brother Lewis was exceptionally gifted. Throughout my childhood in Vienna I felt that he had an intellectual virtuosity I would never match. By the time I began reading and writing, he was starting to master Greek, to become proficient at piano, and to construct radio sets…He was an academic star throughout his school years …Despite his academic ambitions, he sensed that his major efforts should be to help support our family, since my father’s income was small and the Depression had not yet ended. So rather than enrolling in an academic curriculum, he…learned to be a printer…He was drafted into the US Army…and was wounded by shrapnel in the Battle of the Bulge…All service personnel were eligible for the GI Bill, which enabled them to go to the college of their choice tuition free..

In 1952 Lewis began work on his Ph.D. dissertation in linguistics and Middle High German at Brown University…One night while he was dining out, someone broke into his car and stole his belongings, including his research notes and the early drafts of his dissertation. He tried at first to reconstruct his work, but he never succeeded in overcoming this setback to his academic career…He decided to remain in France and became a connoisseur of fine wines and cheeses…His wife Elise converted [from Judaism to Christianity]. Elise also converted their five children, to my mother’s deep dismay and my astonishment…Elise moved from being a Baptist to being a Methodist…a Presbyterian and finally, as I once humorously predicted to her, a Roman Catholic…In 1969 Lewis developed cancer of the kidney…and died at age fifty-seven…My brother is an enormous influence on me to this day. My interest in…classical music, and my joy in learning new things were shaped to a great extent by him. (p.13,176-9)

Wife

Kandel’s ability to devote himself to memory experiments for 40 years was largely due to his wife, who not only valued his scientific work over domestic concerns, as a fellow scientist, but also subordinated her own scientific career to his. She did play a large part in deciding where Kandel lived and studied, and she did insist that he spend some time with his family, but ultimately these demands seem to have benefited his work. Kandel makes clear that she satisfied all his needs as a wife and created an comforting home in New York for him to settle down and focus on several decades of nonstop experimentation. As a fellow Holocaust survivor and Columbia medical professor, she was an ideal companion, and she even shared his taste in 1930s-era European art with which they gradually filled their house.

I was strongly supported in my decision [to study with Grundfest] by Denise Bystryn, an extremely attractive and intellectually stimulating Frenchwoman I had recently started to date.

A graduate student in sociology at Columbia, she was a fine cook, had excellent taste in clothing—some of which she made herself—and like to surround herself with vases, lamps, and art…Much as Anna influenced my thinking about psychoanalysis, Denise influenced my thinking about both empirical science and the quality of life…Denise’s father had trained as a rabbi in Poland…He left Poland when he was twenty-one years old and went to France, where he studied mathematics and engineering…became an agnostic and stopped going to synagogue…During the war, Denis was separated from her parents, hidden in a Catholic convent…Over the years, our memories of our individual experiences in a Europe dominated by Hitler…brought us closer together…

Denise sensed, perhaps more than I did, that my research ideas were original and bold, and she urged me to explore it. I was concerned however. Neither of us had any financial resources, and I thought it essential to have a private practice in order to support us. Denise simply gave the issue of money short shrift. It was of no importance, she insisted. Her father, who had died a year before I met her, had advised his daughter to marry a poor intellectual because such a man would value scholarship above all and would strive to pursue exciting academic goals. (p.50)

I learned something in marrying Denise. I had been reluctant and fearful of marriage, even to Denise, whom I loved much more than any other woman I had ever thought of marrying. But Denise was confident that our marriage would work, so I took a leap of faith and went ahead. I learned from that experience that there are many situation in which one cannot decide on the basis of cold facts alone—because facts are often insufficient. One ultimately has to trust one’s unconscious, one’s instincts, one’s creative urge. I did this again in choosing Aplysia. (p.149)

Shortly after our son, Paul, was born, in March 1961, Denis and I had a serious crisis, by far the most serious of our life together….One Sunday afternoon she showed up as I was working in the lab and simply exploded on me. Carrying Paul in her arms, she screamed, “You can’t go on like this! You are only thinking of yourself and your work! You are just ignoring the two of us!”…I sulked, pouted, and took days to recover…I decided to spend more time at home with her and Paul…It has required conscious effort on my part and help from Denise and from my psychoanalysis to be more realistic and to structure my time so as to make room for the responsibilities and pleasures of my life with [my children] and with their children.

Richard Strauss commented that he often wrote his best music after an argument with his wife. This has not generally proven to be the case for me. But the argument with Denise…did cause me to pause and think. As a consequence I learned from this argument that the obvious lesson that hard thinking, especially if it leads to even one useful idea, is much more valuable than simply running more experiments.

Spending more time at home with Denise and our son also gave me more time to think about how to approach the study of learning in Aplysia…(p.156)

[In deciding where to do postdoctoral study, Denise decides…] Denise, ever the Paris chauvinist, thought Paris the better choice. (p.148)

I moved in 1974 to Columbia University’s College of Physicians and Surgeons to replace my mentor Harry Grundfest, who was retiring...The decisive factor was that Denise was on the faculty. (p.247)

(2) Nazi Austria


Extermination camp, Austria

Kandel returns again and again to the topic of the Holocaust—in particular, the complicity of Viennese intellectuals at the time and their forgetfulness afterward. Throughout his life, Kandel embodies the Jewish motto, “Never again!” In college he majored it modern German history, and then he plunged himself into psychoanalysis, by which he sought to come to grips with his past. His subsequent scientific career was propelled by a desire to confront his demons directly by penetrating the secret of memory itself. He was also inspired by a sort of Jewish solidarity and academic patriotism, seeking to redeem the memory of Jewish scientists expelled and discredited by the corrupt academic system of Austria.


“Invasion” of Austria



Jews scrubbing streets, Vienna

The day after Hitler marched into Vienna, I was shunned by all of my classmates…I was taunted, humiliated, and roughed up….On the day of Kristallnacht, as my father was rounded up, his store was taken away from him and turned over to a non-Jew…(p.28)
My last year in Vienna was a defining one. Certainly, it fostered a profound, lasting gratitude for the life I found in the United States…How is one to understand the sudden, vicious brutality of so many people? How could a highly educated society so quickly embrace policies…rooted in contempt for an entire people? (p.29)



Eduard Pernkopf, dean of University of Vienna (and anatomist, see below)


My undergraduate honors thesis at Harvard was on the attitude toward National Socialism of three German writers…I came to the depressing conclusion that many German artists and intellectuals had succumbed all too eagerly…Had intellectuals mobilized, Hitler’s aspirations might well have been prevented…(p.38)
Certainly one important reason for the actions of the Viennese in 1938 was sheer opportunism…Viennese were eager to advance themselves by replacing Jews in the professions….Another reason was the move from a cultural to a racial form of anti-Semitism….This idea derives from the Doctrine of Deicide…the popular belief that the Jews killed Christ. The Jewish perpetrators of deicide were a race so innately lacking in humanity that they must be genetically different, subhuman….Although racial anti-Semitism had not been a dominant force in Vienna before 1938, it became official public policy after March of that year…The only solution to the Jewish question was expulsion or elimination of the Jews. (p.31)

Following annexation, Austrians made up about 8 percent of the population of the greater German reich, yet they accounted for more than 30 percent of the officials working to eliminate the Jews. Austrians commanded four Polish death camps and held other leadership positions in the Reich in addition to Hitler…It is estimated that of the 6 million Jews who perished during the Holocaust, approximately half were killed by Austrian functionaries led by Eichmann. Yet despite their active participation in the Holocaust, the Austrians claimed to be victims of Hitler’s aggression…Austria never underwent the soul-searching and cleansing that Germany did after the war…In the end, few people were tried, and most of those were acquitted…

Many professors who remained in Vienna during the war were Nazis, yet they retained their academic appointments afterward…Eduard Pernkopf , dean of the faculty of medicine was a Nazi even before Hitler entered Austria…After the war, he was allowed to finish his book Atlas of Anatomy, a work thought to be based on dissection of the bodies of people who had been killed in Austrian concentration camps. (p.405-7)



Eduard Pernkopf






In 1980 Steve Kuffler and I were both invited to Vienna to be inducted as honorary members of the Austrian Physiological Society. Steve had fled Vienna in 1938. We were introduced by…a pretentious academic who had accomplished little scientifically and who acted as if nothing out of the ordinary had caused these two sons of Vienna to flee the country…His silence regarding our actual experiences in Vienna spoke volumes. Neither Steve nor I responded to his comments. (p.236)

By 1989 I had reached the limit of my silence…In a symposium for the Institute of Molecular Pathology [in Vienna]…I began my lecture with some comments about…the anger, disappointment, and pain caused by the humiliation I suffered there. I added how fortunate I was to have been able to go to the United States. After I finished my comments there was no applause, no recognition. No one said a word. (p.409)


Extermination camp, Austria

In 2004 I observed Yom Kippur in the main synagogue of Vienna…At one point in the service, the rabbi wanted to honor me and asked me to come up on the stage and open the curtains of the Ark that contains the Torah scrolls. My eyes filled with tears; I froze and could not bring myself to do it…

I heard the vigorous and well-known eighty-year-old urban geographer Elizabeth Lichtenberger present a lecture on the future of Europe…Lichtenberger leaned over to me and said, Let me explain what happene din 1938 and 1939. There was massive unemployment in Vienna until 1938. The Jews controlled everything—the banks, the newspapers. Most physicians were Jewish, and they were simply squeezing every penny out of these impoverished people. It was terrible. That’s why it all happened.” At first I thought she was joking, but as I realized she was not, I turned to her and literally screamed, “Ich glabue nicht was Si emir sagen!” “I can’t believe you are talking to me this way! You, an academic, are blindly mouthing anti-Semitic Nazi propaganda!”…

I met the newly elected president of Austria, Heinz Fischer…He is even more involved with Jewish life in Vienna than the former one. In addition, I found it uplifting to think that sizty-five years after being forced to leave Vienna, I would be invited by the president of Austria to join with him in a private and frank conversaion about Jewish life in Vienna over wine, dinner, and Sacher torte at the Hotel Sacher. I stopped at Severingasse 8 on the way to the airport…I felt amazingly at peace: so glad to have survived, and to have emerged from that building and from the Holocaust relatively unscathed. (p.413-15)

Denise later told me that were it not for my deep and continuing fascination with Vienna, whe sould have found the city boring compared with Paris. Her comment reminded me of when her imposing Aunt Sonia, a large, intellectually powerful, and slightly arrogant woman who worked for the United Nations…asked in her strong French accent, “Where do you come from?” “Vienna,” I replied. Without changing her overall condescending expression, she forced a small smile and said, “That’s nice. We used to call that little Paris”….It’s clear to me that she did not really understand Vienna—it’s lost grandeur, its enduring beauty, or its present-day complacency and latent anti-Semitism. (p.151)

(3) America




I traveled on the S.S.Gerolstein of the Holland-American Line for the ten-day journey—directly past the welcoming Statue of Liberty…My father found a job in a toothbrush factory…He loved America. Like many other immigrants, he often referred to it as the goldene Medina, the land of gold that promised Jews safety and democracy. In Vienna he had read the novels of Karl May, which mythologized the conquest of the American West and the bravery of American Indians…




I attended a Hebrew parochial school. By the time I graduated in 1944, I spoke Hebrew almost as well as English…I went to Erasmus Hall High School, a local public school…There, I became interested in history, in writing, and in girls. I worked on the school newspaper, The Dutchman, and became sports editor. I also played soccer and was one of the captains of the track team…[No science???] I was apprehensive about leaving Erasmus Hall, convinced that I would never again feel the sheer joy of social acceptance and academic and athletic achievement….At Harvard, I majored in modern European history and literature. (p.34-38)




For many Viennese émigrés of my generation, the solid education we obtained in Vienna, combined with the sense of liberation we experience on arriving in America, released boundless energy and inspired us to think in new ways. (p.33)




I am reminded of a story about Sigmund Freud when he arrived in England…On seeing the tranquility and civility that his forced emigration had brought him to, he was moved to whisper with typical Viennese irony, “Heil Hitler!” (p.42)

(4) France

[In France], I felt at times intensely isolated and alone. French society and French science are hierarchical, and I was a relatively unknown scientist at the bottom of the latter…Neither Tauc nor any of the other senior people at the institute invited us or any of their other postdoctoral fellows to their homes or interacted with us socially. Moreover, I experienced a subtle degree of anti-Semitism—particularly from the technical people in the laboratory, the technicians and secretaries—that I had not experienced since escaping Vienna…Tauc’s technician quizzed me on whether I participated in the international Jewish conspiracy to control the world…This experience led me to wonder whether Elise, during her many years away from the United States, had encountered similar anti-Semitism and whether this demon might have contributed to her conversion.