.

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

In Search of Memory:

The Emergence of a New Science of Mind (2007)

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

I. OVERVIEW

(1) The History of Brain Science in a Nutshell

1	brain	whoa...the mind is THERE!
2	brain regions	megascopic
3	brain cells (neurons)	microscopic
4	neurotransmitters	between neurons
5	receptors	in neural membrane
6	second messengers	inside neuron
7	gene regulators	inside nucleus

Equipment:

1	bodies	human & animal
2	paper	for anatomical drawings
3	microscopes	...
4	heavy chemicals	stains to trace nerves
5	drugs	random discovery-->bioengineered
6	electrical gear	voltage clamps, EEG
8	X-rays/nuclear magnetism	CAT, MRI,3D molecular imaging [X-ray crystallography/protein NMR]
9	bioinformatic computer systems	automated 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 brain	gray=technology
light blue=microanatomy of neuron	orange=observation of behavior
pink=drugs, transmitters	purple=study of consciousness
green=DNA, genes	yellow=holism, emergence

-1700	Imhotep (Egypt)	first use of word “brain,” with description of distal symptoms of brain damage from 30 clinical cases
-500	Alcmaeon of Crotona	locates vision and senses in localized brain regions
-370	Hippocrates	locates epilepsy, sensation, all mental processes in brain
-360	Plato	locates mental processes in brain
-350	Aristotle	describes memory formation as the association of simple ideas (mistakenly thinks thought occurs in heart)
-300	Herophilus of Alexandria	father of anatomy, locates human intelligence in brain, distinguished sensory and motor nerves, first anatomical drawings
-280	Erasistratus of Chios	describes origin of nerves in brain, divisions of the brain
-150	Poseidonus of Byzantium	reported effects of localized brain damage (though incorrect)
177	Galen	localized mental processes in solid brain matter (not ventricles), traced sensory nerve system
1021	Ibn al-Haytham (Iraq)	discovers that vision occurs in brain, not eyes
1504	Leonardo da Vinci	modern anatomical drawing, wax injection of ventricles
1543	Andreas Vesalius	father of modern anatomy, realistic drawings
1550	Bartolomeo Eustachio	locates origin of optic nerves in brain
1590	Zacharias Janssen	invents the compound microscope
1611	Lazarus Riverius	describes impaired states of consciousness
1621	Robert Burton	describes depression
1637	Descartes	proposes that mind+body interact in brain
1665	Robert Hooke	develops microscopes
1673	Joseph DuVerney	performs experimental ablation in pigeons
1684	Raymond Vieussens	uses boiling oil to harden the brain
1690	Locke	proposes that mind is a blank slate that develops through sense data--eliminates a lot of nonscientific psychological BS, but ignores DNA
1695	Humphrey Ridley	anatomy text -- first describes peduncles, mamillary bodies, etc
1709	George Berkeley	describes how concepts like distance are constructs of the brain, based on past experience
1717	Antony van Leeuwenhoek	describes nerve fiber in cross section
1740	Emanuel Swedenborg	theorizes motor cortex map, neurons, neuroendocrine system, etc -- ideas ignored b/c not a professor
1749	David Hartley	the first English work using the word "psychology"
1755	J.B. Le Roy	uses electroconvulsive therapy for mental illness
1760	Charles Lorry	demonstrates that damage to the cerebellum affects motor coordination
1772	John Walsh	conducts experiments on torpedo (electric) fish
1781	Kant	argues we are born with built-in templates of a priori knowledge (more neuroscientifically sound than Locke)
1791	Luigi Galvani	discovers nervous system = electrical
1800	Franz Joseph Gall	proposes that brain has special regions for all mental functions, even emotion
1800	Humphrey Davy	synthesizes nitrous oxide
1801	Adam Friedrich Wilhelm Serturner	crystalizes opium and obtains morphine
1809	Johann Christian Reil	uses alcohol to harden the brain
1809	Luigi Rolando	uses galvanic current to stimulate cortex
1811	Julien Jean Legallois	discovers respiratory center in medulla
1812	Benjamin Rush	father of american psychiatry, promotes asylums, treatment for alcoholism
1820	Johann Shweigger	invents galvanometer (precursor to voltage clamps, EEGs to study neurons)
1822	Pierre Flourens	locates movement in cerebellum, shows brain has regions for mental functions but NOT memory: finds that memory is distributed; also describes ablation for studying behavior
1825	Jean Baptiste Bouillaud	presents cases of loss of speech after frontal lesions
1825	Robert B. Todd	discusses the role of the cerebral cortex in mentation, corpus striatum in movement and midbrain in emotion
1826	Johannes Muller	proposes theory of "specific nerve energies" (early notion of electrical transmission by nerves)
1827	E. Merck & Company	markets morphine
1832	Justus von Liebig	discovers chloral hydrate
1832	Jean Pierre Robiquet	isolates codeine
1832	Sir Charles Wheatstone	invents the stereoscope
1833	Philipp L. Geiger	isolates atropine
1836	Marc Dax	descrives effects on speech from left hemisphere damage
1836	Gabriel Gustav Valentin	identifies neuron nucleus and nucleolus
1838	Eduard Zeis	studies dreams in people who are blind
1838	Robert Remak	suggests that nerve fiber and nerve cell are joined
1838	Jean Esquirol	promotes asylums
1839	Theodor Schwann, Mattias Jakob Schleiden	discovers CELLS, which make up all living things
1840	Adolph Hannover	uses chromic acid to harden nervous tissue
1842	Crawford W. Long	uses ether on man
1847	James Young Simpson	uses chloroform anesthesia
1848	John Harlow	patient Phineas Gage loses moral judgment with damage to ventromedial cortex
1849	Hermann von Helmholtz	measures speed of frog nerve impulses= 90 feet per second, slowly actively propagated
1850	Emil Du Bois Reymond	invents nerve galvanometer
1853	William Benjamin Carpenter	proposes "sensory ganglion" (thalamus) as seat of consciousness
1855	Bartolomeo Panizza	shows the occipital lobe is essential for vision
1855	Richard Heschl	describes the transverse gyri in the temporal lobe (Heschl's gyri)
1856	Albrecht von Graefe	describes homonymous hemianopia
1859	Darwin	describes how humans evolved from animals
1860	Gustav Theodor Fechner	develops "Fechner's law"--intensity of perception is logarithm of sense stimuli (i.e. progressively less sensitive)
1860	Albert Niemann	purifies cocaine
1864	Pierre Paul Broca	describes how expressive (speech) aphasia is caused by frontal lobe damage
1865	Gregor Mendel	descrobes jpw hereditary information is passed in units (genes)
1867	Theodore Meynert	performs histologic analysis of cerebral cortex
1873	Gustav Fritsch, Eduard Hitzig	shows that a dog moves when motor cortex stimulated
1873	Camillo Golgi	discovers silver nitrate staining of nerves, used by Cajal (below)
1874	Roberts Bartholow	electrically stimulates human cortical tissue
1875	Richard Caton	records electrical activity from the brain
1878	Paul Broca	publishes work on the "great limbic lobe"
1878	Harmon Northrop Morse	synthesized acetaminophen
1878	Claude Bernard	describes nerve/muscle blocking action of curare
1879	Carl Wernicke	sensory aphasia caused by temporal lobe damage
1879	Wilhelm Wundt	sets up lab devoted to study human behavior
1879	Mathias Duval	introduces an improved method of embedding tissue using collodion
1879	William Crookes	invents the cathode ray tube
1881	Hermann Munk	reports on visual abnormalities after occipital lobe ablation in dogs
1883	Emil Kraepelin	coins the terms neuroses and psychoses, discovers schizophrenia
1885	Paul Ehrlich	notes that intravenous dye does not stain brain tissue : blood-brain barrier
1885	Hermann Ebbinghaus	determines that people can memorize 7 nonsense words one session, forget most in 1 hour (short-term), rest in 1 month (long-term)
1885	Carl Weigert	introduces hematoxylin to stain myelin
1889	Santiago Ramon y Cajal	describes how brain = network of unique neurons which fire in one direction
1890	John Hughlings Jackson	describes how temporal seizures elicit dreamy states
1890	William James	describes how memory can be short-term, long-term, habitual, or autonomic (unconscious)
1895	William His	first uses the term hypothalamus, dendrite
1895	Wilhelm Konrad Roentgen	invents the X ray
1895	Heinrick Quincke	performs lumbar puncture to study cerebrospinal fluid
1897	Felix Hoffmann	synthesizes aspirin
1897	Karl Ferdinand Braun	invents the oscilloscope
1897	Ferdinand Blum	uses formaldehyde as brain fixative
1899	Francis Gotch	describes a "refractory phase" between nerve impulses
1900	Georg Muller, Alfons Pilzecker	longterm memory blocked by disruption within 1 hour
1900	Sigmund Freud	describes mental illnesses as unconscious neurobiological processes, observed through dreams, free association, slips
1902	Julius Bernstein	calculates nerve impulse = 70 millivolt ionic shift across membrane of neuron
1903	Ivan Pavlov	shows in dogs hows training creates direct connections between sense and motor nerves
1905	John Newport Langley	introduces the concept of receptor molecules , describes "parasympathetic nervous system" –
1906	Charles Sherrington	cat reflexes = senses integrated by excitatory/inhibitory interneurons to single motor output
1907	Ross Granville Harrison	describes tissue culture methods
1908	Richard Goldschmidt	neurons in animals are always in the same place
1908	Victor Alexander Haden Horsley,Robert Henry Clarke	design stereotaxic instrument
1908	Willem Einthoven	makes string galvanometer recordings from the vagus nerve
1909	Harvey Cushing	first to electrically stimulate human sensory cortex
1911	George Barger,Henry Dale	discover norepinephrine
1913	Edwin Ellen Goldmann	finds blood brain barrier, impermeable to large molecules
1913	Santiago Ramon y Cajal	develops gold chloride mercury stain to show astrocytes
1913	Walter Samuel Hunter	devises delayed response test
1914	Henry H. Dale	isolates acetylcholine
1915	J.G. Dusser De Barenne	describes activity of brain after strychnine application
1915	Thomas Hunt Morgan	each gene in fruit fly is located in certain place on chromosomes
1919	Gordon Morgan Holmes	localizes vision to striate area
1919	Walter E. Dandy	introduces air encephalography
1920	Stephen Walter Ranson	demonstrates connections between the hypothalamus and pituitary
1920	Otto Loewi, Henry Dale	fluid from frog vagus nerve directly slows heart of another frog
1921	Hermann Rorschach	develops the inkblot test
1921	John Augustus Larsen, Leonard Keeler	develop the polygraph
1927	Chester William Darrow	studies galvanic skin reflex
1928	Philip Bard	suggests the neural mechanism of rage is in the diencephalon
1928	Walter Rudolph Hess	reports "affective responses" to hypothalamic stimulation
1928	Lord Edgar Douglas Adrian	nerve impulses are all identical, with 1 millisecond upstroke + downstroke
1928	John Fulton	observes sounds of blood flowing over the human visual cortex
1929	Walter B. Cannon	coins the term homeostasis
1929	Hans Berger	first human electroencephalogram
1929	Karl Lashley	removing parts of rat brains does not eliminate memory
1930	Carlyle Jacobsen	frontal lobe in monkeys controls short-term memory
1931	Ulf Svante von Euler,J.H. Gaddum	discover substance P
1932	Smith, Kline	first amphetamine, Benzedrine
1932	Max Knoll, Ernst Ruska	invent the electron microscope
1932	Jan Friedrich Tonnies	develops multichannel ink writing EEG machine, differential amplifier
1933	Ralph Waldo Gerard	describes first experimental evoked potentials
1934	S. Howard Bartley	performs studies on cortical visual evoked potentials in rabbits
1935	Frederic Bremer	uses cerveau isole preparation to study sleep
1936	Egas Moniz	publishes work on the first human frontal lobotomy
1936	Walter Freeman	performs first lobotomy in the United States
1936	Wade Marshall, Wilder Penfield	sensory nerves connect to neurons arranged in shape of body
1937	James Papez	describes limbic circuit, visceral theory of emotion
1937	Heinrich Kluver, Paul Bucy	describe bilateral temporal lobectomies
1938	Albert Hofmann	synthesizes LSD
1938	Ugo Cerletti, Lucino Bini	treat human patients with electroshock
1939	Alan Hodgkin, Andrew Huxley	nerve impulse of squid = 110 millivolts
1942	Stephen Kuffler	develops the single nerve muscle fiber preparation
1943	John Raymond Brobeck	describes hypothalamic hyperphasia
1948	Wilder Penfield	elicits memories/auras from 8% patients with temporal lobe stimuli
1948	Jerzy Kornorski	neuron voltage drops after excitation (refractory period)
1949	Giuseppi Moruzzi, Horace Winchell Magoun	discover reticular activating system: cutting a cat's sense nerves does not affect wakefulness, but cuttin RAS does
1949	John Cade	discovers that lithium is an effective treatment for bipolar depression
1949	Kenneth Cole	develops the voltage clamp
1949	D.O. Hebb	reverbatory circuits are responsible for short-term memory
1949	CP Duncan	longterm memory blocked by seizures within 1 hour
1950	Steven Kuffler	retinal cells signal contrast, not brightness
1950	Vernon Mountcastle	place cells = cortical neurons that respond to stimuli from certain directions
1950	B.F. Skinner, Jerome Bruner	pigeon training creates direct connections between sense and motor nerves
1950	Eugene Roberts, J. Awapara	independently identify GABA in the brain
1950	Henri Laborit	antihistamine chlorpromazine tranquilizes patients, also antipsychotic, with Parkinsonism side-effect
1951	John Eccles	neurotransmitters can modulate neuron potential (excite to -55mV or inhibit to +75mV)
1952	Alan Lloyd Hodgkin, Andrew Fielding Huxley	describes action potential in mathematical terms, by using voltage clamp on squid neurons
1953	Eugene Aserinski , Nathaniel Kleitman	describe rapid eye movements (REM) during sleep
1953	H. Kluver, E. Barrera	introduce Luxol fast blue MBS stain
1953	James Watson, Francis Crick	discover double helix of DNA, with 4 nucleotides=copying mechanism
1954	James Olds	describes rewarding effects of hypothalamic stimulation
1954	John Lilly	invents the "isolation tank"
1955	Kandel, Purpura	LSD increases (not stops) serotonin inhibition of visual cortex exposed to flashes of light
1956	DW Woolley, EN Shaw	LSD stops serotonin contractions of rat uterus
1956	Rita Levi Montalcini, Stanley Cohen	isolate and purify nerve growth factor
1956	L. Leksell	uses ultrasound to examine the brain
1957	Brenda Milner, William Scoville	H.M. hippocampectomy, loss of long-term memory encoding
1958	Harry Harlow	monkeys isolated from mother devastated behaviorally, partially reversed by cloth-covered wooden dummy and a few hours with normal infant monkey
1958	Arvid Carlsson	discovers dopamine in brain, lack causes Parkinsonism, L-Dopa causes schizoid
1958		Haloperidol introduced as a neuroleptic
1959	David Hubel, Torsten Wiesel	visual thalamus responds to contrast, visual cortex responds to contours with specific orientation
1959	P. Karlson,M. Lusher	describe pheromones
1960	Louis Flexner	protein inhibitors block consolidation during and shortly after learning, but not short-term memeory
1960	Geoffrey Watkins	GA is main transmitter, with 2 hippocampal receptors, rapid AMPA depolarizes cell 20mV-->opens NMDA-->Ca+-->kinase-->additional AMPA receptors
1960	Aaron Beck	cognitive behavioral therapy (CBT) = short-term psychological treatment
1961	Robert Doty	classical conditioning by stimulus to dog visual cortex and motor cortex
1961	Earl Sutherland	describes 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
1961	Brenner and Crick	triplets of 4 nucleotides yield 20 amino acids
1962	Eldon Foltz	performs the first cingulotomy to treat chronic pain
1962	Francois Jacob, Jacques Monod	discover how genes are switched on/off: regulatory gene-->regulatory protein-->(in absence of lactose) binds to promoter-->frees effector gene-->protein/enzymes
1965	Ronald Melzack,Patrick D. Wall	gate control theory of pain
1966	Ed Evarts, Robert Wurtz, Michael Goldberg	single cell recordings from behaving and attentive monkeys
1968	Ed Krebs	cAMP-->binds regulatory units on protein kinase A, freeing catalytic units to phosphorylate proteins
1969	D.V. Reynolds	describes the analgesic effect of electrical stimulation of the periaqueductal gray
1969	Bernard Katz	nerve impulse opens voltage-gated ion channel at synapse, releasing neurotransmitters
1970	Paul Greengard	dopamine receptor in brain-->cAMP, activates protein kinase
1970	Walter Gilbert, Frederick Sanger	rapid DNA sequencing, recombinant DNA (snip out gene, clone it, stitch to bacterial DNA)
1971	John O’Keefe	place cells in hippocampus respond to any sense from certain direction
1972	Godfrey N. Hounsfield	develops x ray computed tomography
1973	Terje Lomo, Tim Bliss	hippocampal cells strengthened for days after rapid stimuli
1973	Candace Pert,Solomon Snyder	discover opioid receptors in brain
1973	Paul Berg	first recombinant DNA molecule
1973	Herbert Boyer, Stanley Cohen	invents gene cloning
1973	Konrad Z. Lorenz, Nikolaas Tinbergen, Karl von Frisch	discover imprinting in animals (=postnatal gene regulation)
1974	Alan Baddeley	working memory = moment-to-moment memory for executing complex behavior
1974	Thomas Nagel, John Searle	binding/NCC, subjectivity—what are the elements of subjective consciousness
1974	John Hughes,Hans Kosterlitz	discover enkephalin
1974	M.E.Phelps, E.J.Hoffman,M.M.Ter Pogossian	develop first PET scanner
1974		First NMR image (a mouse) is taken
1974	Seymour Benzer	mutatogenic chemicals on drosophila, flies with defective gene for disposing of cAMP have no short-term memory
1976	Choh Hao Li,David Chung	describe beta endorphins
1976	Erwin Neher ,Bert Sakmann	invents the patch clamp, which can record from individual membrane channels
1980	Richard Morris	blocking NMDA blocks longterm potentiation--shows how a short-term transmitter can affect longterm neural activity (memory)
1980	Gerald Klerman, Myran Weissman	develops interpersonal psychotherapy = CBT for mistaken beliefs about others
1981	Roger Wolcott Sperry	shows how sense data is filled out by brain, by observing patients with split hemispheres
1982	Bengt Ingemar Bergstrom, John Robert Vane, Sune K. Bergstrom	discovers of prostaglandins
1983	Benjamin Libet	discovers readiness potential in EEG 1 second before movement, 200 ms before “willing”
1987	Larry Squire, Daniel Schacter	describes how implicit/procedural (conditioning motor skills) versus explicit/declarative memory are recorded by different modules of the brain
1987	Gerald Edelman	proposes that consciousness is widely distributed throughout the cortex and thalamus
1987	Eli Lilly	prozac introduced as treatment for depression
1989	Colin McGinn	proposes that consciousness cannot be studied by limited mind
1990	Thomas Ebert	discovers that musicans' cortical finger maps expand 5-fold
1990	Crick and Koch	proposes neural correlates of consciousness, perhaps claustrum
1990	Michael Merzenich	discovers that cortical maps vary among monkeys and expands with use
1990	Eric Lumer	describes 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
1992	Craig Bailey	discovers long-term memory in aplysia based on new axon terminals
1992	Daniel Dennett	proposes that consciousness is function of neural computation, nothing else
1994	Alfred G. Gilman,Martin Rodbell	discovers G protein coupled receptors, key part of nerve signalling and memory
1996	Lewis Baxter, Jeffrey Schwartz	proves CBT for OCD=SSRI=inhibit caudate; psychotherapy for depression=SSRI=shift in activity from dorsal to ventral PFC
1996	Anthony Movshon, William Newsome	performs single cell recordings from behaving and attentive monkeys -- reveals consciousness on a cellular level
1999	Patricia Goldman-Rakic	finds that removing monkey PFC destroys working (not all short-term) memory
2004	Rene Hen	mouse 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"	VIP	structures	methods
-500-1853	humoralism	Galen	4 humors: black bile - yellow bile -phlegm - blood	wild speculation
1858-1900s	structuralism	Wundt (father of psychology)	3 elements: sensation -affection-perception	semi-controlled introspection
1903-1950s	behaviorism	Pavlov	stimulus-->response	controlled animal studies
1900-1960s	Freudianism	Freud	3 divisions: ego - id - superego	semi-controlled talk therapy
1950-1980s	humanism	Maslow	5 needs: physiological-->safety-->love-->esteem-->self-actualization	" " (more sensitive, respectful; less dogmatic)
1960-2000s	cognitivism	Beck	3 modalities: cognition-->emotion-->behavior	controlled human studies
1980-2000s	computationalism	Minsky	3 quantities: input-->nodes-->output	highly controlled simulations, AI

Treatments:

date	treatment	methods
1247	institutionalized psychiatry (Bedlam=first asylum, London)	confinement, restraint, lobotomy, electroshock, insulin shock
1900	psychoanalysis	talk therapy
1950	psychopharmacology	drugs
1960s	specific therapies	cognitive 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)