Center for Eric Kandel Studies

.

2007-09-18T09:54:00.000-07:00

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

2007-09-18T09:38:00.000-07:00

(1) The History of Brain Science in a Nutshell

2007-09-18T09:37:00.000-07:00

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

2007-09-18T09:36:00.000-07:00

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

2007-09-18T09:35:00.000-07:00

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

2007-09-18T09:33:00.001-07:00

(1) Jewish-Austrian background

2007-09-18T09:20:00.000-07:00

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

2007-09-18T08:59:00.001-07:00

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

2007-09-18T08:53:00.001-07:00

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

2007-09-18T08:49:00.005-07:00

[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.

III. PERSONAL INFLUENCES

2007-09-18T08:49:00.003-07:00

A. ROLE MODELS

2007-09-18T08:49:00.001-07:00

(1) Sigmund Freud

2007-09-18T08:40:00.000-07:00

Freud and colleagues

Although Kandel never met Freud, a large part of Kandel’s life was modeled on Freud’s. Freud served almost like a mystical idol to Kandel, an invisible mentor who guided Kandel through the most difficult periods of his life, even inspiring him through his writings and neuroanatomical work to abandon Freudian psychoanalysis itself.

Toward the end of my junior year I met and fell in love with Anna Kris, a student at Radcliffe College who had also emigrated from Vienna. At the time…I was planning to take seminars with Karl Vietor [on modern German literature] in my senior year. But suddenly, at the end of my junior year, he died of cancer. Vietor’s death was a personal loss; it also created a large void in the curriculum I had planned. A few months before Vietor’s death I had met Anna’s parents, Ernst and Marianne Kris, both prominent psychoanalysts from Freud’s circle. The Krises fired my interest in psychoanalysis…

What made psychoanalysis so compelling to me while I was in college was that it was at once imaginative, comprehensive and empirically grounded—or so it appeared to my naïve mind…Ernst Kris went to great pains to…argue that part of the appeal of psychoanalysis was that, like behaviorism, it attempts to be objective, to reject conclusions drawn from introspection. My attraction to psychoanalysis was further enhanced by the facts that Freud was Viennese and Jewish and had been forced to leave Vienna….[Anna’s grandfather] was Freud’s best friend, and the physician to his children. [Anna’s mother] was a close friend of Freud’s highly accomplished daughter, Anna. Indeed, Marianne Kris named her daughter after Anna Freud…[Anna Kris] now has a highly successful practice of psychoanalysis in Cambridge…(p.42)

When psychoanalysis emerged from Vienna in the first decades of the twentieth century, it represented a revolutionary way of thinking about mind and its disorders…I shared this enthusiasm…also because it conjured up the intellectual environment of Vienna that I admired and had missed out on. Indeed, what I so enjoyed in the intellectual life that surrounded Anna Kris and her parents were the insights and perspectives it gave me on life in Vienna in the 1930s. (p.363)

To be a practicing psychoanalyst in the 1950s, it was generally considered best to go to medical school…So in the summer of 1951 I took, almost on impulse, the introductory course in chemistry…A few months later, based on that single chemistry course and my overall college record, I was accepted at NYU Medical School.

I greatly enjoyed the course on the anatomy of the brain…Each of us built out of colored clays a large-scale model that was four times the size of the human brain. While I had been taking the anatomy course, Anna and I started to drift apart. A relationship…did not work well with her in Cambridge and me in New York. In addition, our interests were starting to diverge… (p.43)

Through the Krises, I had met three psychoanalysts [interested in biology of the brain]. After some discussion with each of them, I decided in the fall of 1955 to take an elective at Columbia with the neurophysiologist Harry Grundfest. At the time…no one on the NYU faculty was teaching basic neural science. (p.47)

Grundfest listened patiently as I told him of my rather grandiose ideas [to locate the Freudian ego and id in the brain]…He explained that my hope was far beyond the grasp of contemporary brain science. Rather, he told me, to understand mind we needed to look at the brain one cell at a time. One cell at a time!...As we talked I suddenly remembered that in 1887, when Freud began his own career, he had…started out as an anatomist, studying single nerve cells…(p.55)

One evening Grundfest threw into my lap an issue of the Journal of General Physiology that contained three papers by Kuffler based on his work with single nerve cells in the crayfish. I found the idea of a contemporary neurophysiologist working on crayfish simply remarkable: one of Freud’s first scientific papers, published in 1882, when he was only twenty-six, was on the nerve cells of the crayfish!...All I knew at this point is that someday I might want to test an idea with an invertebrate animal…(p.107)

I began my resident training in psychiatry at Harvard Medical School…I asked the [director of the mental health center] if it might by possible to have some space and modest resources to set up a laboratory…He looked at me and then pointed to the pile of resumes of the twenty-two other residents and bellowed, “Who do you think you are? What makes you think that you are better than any one of these?” I was completely taken aback by the content of his remarks and even more by the tone. In all my years as an undergraduate at Harvard and a medical student at NYU, none of my professors had ever talked to me like that…He told me to go to the wards and take care of patients…Within several weeks, he approached me and said that he gathered from his colleagues that I was a good person to invest in. “What do you need?” he said.

My residency training turned out to be at once stimulating and a bit disappointing…We saw only a limited number of patients…for one-hour sessions two or even three times a week. Although we did not really improve their mental functioning, we learned a great deal about schizophrenia and depressive illnesses by simply listening to them….We learned next to nothing about the…the biological underpinnings…In response to this weakness in the program, the other residents and I organized a discussion group…Prior to our arrival, the mental health center had almost never invited outside speakers to address the residents or the faculty. This was a reflection of the vaunted self-confidence of Harvard and Boston at large…I initiated academic grand rounds, conferences that brought together all of the researchers and physicians of the hospital…

I found myself questioning my decision to become a psychoanalyst. I also missed being in the laboratory. I yearned for new data and was eager to have findings to discuss with other scientists…In those days, residents did not work very hard: from 8:30am to 5:00pm…As a result, I was able to study hypothalamic neuroendocrine cells…During my spare time I carried out a somewhat original series of experiments showing that [neuroendocrine cells in the goldfish] generative action potentials just as ordinary neurons do. (p.152)

I returned to Harvard Medical School in 1963 as an instructor, the lowest rung on the faculty ladder. I supervised residents in training in psychotherapy, an exercise I called the blind leading the blind…I made the…fundamental and difficult decision not to become a psychoanalyst but to devote myself full-time to biological research…and I decided to leave Harvard for NYU Medical School. There I would start a small research group…

I was also in the process of terminating a personal psychoanalysis I had undertaken in Boston. Analysis was particularly helpful to me in that difficult and stressful period; it allowed me to dismiss ancillary considerations and focus on the fundamental issues…My analyst, who was extremely supportive...readily understood that I was too single-minded at that point to carry off a dual career successfully. I am often asked whether I benefited from my analysis. To me, there is little doubt. It gave me new insights into my own actions and into the actions of others, and it made me, as a result, a somewhat better parents and a more empathetic and nuanced human being. (p.180)

A keen student of the anatomy of the brain, Freud had written repeatedly about the relevance of the biology of the brain to psychoanalaysis. For example in 1914 he wrote, “We must recollect that all of our provisional ideas in psychology will presumably one day be based on an organic substructure.” In 1920 Freud again noted, “The deficiencies in our descriptionwould probably vanish if we were already in a position to replace the psychological terms by physiological or chemical ones.” (p.46)

(2) Francis Crick

2007-09-18T08:33:00.001-07:00

Francis Crick was one of Kandel’s biggest heroes, almost on the same level as Sigmund Freud. Kandel has basically followed Crick’s example in turning toward the study of consciousness in his later career.

When Francis Crick first entered biology, after World War II, two great questions were thought to be beyond the capacities of science to answer: What distinguishes the living from the nonliving world? And what is the biological nature of consciousness? Crick turned first to the easier problem, distinguishing animate from inanimate matter, and explored the nature of the gene…In 1976, at age sicty, Crick turned to the remaining scientific mystery: the biological nature of consciousness…Despite almost thirty years of continuous effort, Crick was able to budge the problem only a modest distance…Crick’s enormous contribution to biology put him in a class with Copernicus, Newton, Darwin, and Einstein. VS Ramachandran described Crick’s last weeks:

"Three weeks prior to his death I visited him in his home in La Jolla. He was eighty-eight, had terminal cancer, was in pain, and was on chemotherapy; yet he had obviously been working away nonstop on his latest project. His very large desk—occupying half the room—was covered by articles, correspondence, envelopes, recent issues of Nature, a laptop (despite his dislike of computers), and reent books on neuroanatomy. During the whole two hours that I was there, there was no mention o fhis illness—only a flight of ideas on the neural basis of consciousness. He was especially interested in a tiny structure called the claustrum which, he felt, had been largely ignored by mainstream pundits. As I was leaving he said: “Rama, I think the secret of consciousness lies in the claustrum—don’t you? Why else woul dtheis tiny structure by connected to so many areas in the brain?”—And he gave me a sly, conspiratorial wink. It was the last time I saw him." (p.384)

B. TEACHERS

2007-09-18T08:22:00.000-07:00

(1) Mr. Campagna

At the urging of my history teacher, John Campagna, I applied to Harvard College….Mr. Campagna volunteered to cover from his own pocket the fifteen dollars required for my application. I was one of two students in our class of about 1,150 to be admitted. (p.37)

(2) Harry Grundfest

In 1953, Grundfest was [accused of Communism]and summoned by Senator Joseph McCarthy…Not a shred of evidence was ever produced by McCarthy…Nevertheless, Grundfest lost his funding…The reduction of his research capability at what proved to be the peak of his scientific career was devastating. Paradoxically, the the circumstances proved beneficial for me. Grundfest had more time available…and he devoted a substantial amount of it to teaching me…Grundfest was a leader in the biology of signaling. (p.57)

(3) Stanley Crain

In 1957, I returned to Grundfest’s lab and spent six weeks…Knowing my growing curiosity about invertebrate animals, particularly about the crayfish, Grundfest suggested that I set up an electrophysiological recording system with Stanley Crain’s help. Crain showed me how to manufacture glass microelectrodes for insertion into individual axons and how to obtain and interpret electrical recordings form them…I connected the output to a loudspeaker. Whenever I penetrated a cell, I could hear the crack of an action potential…I found the bang!bang! bang! Of action potentials intoxicating…I was becoming a true psychoanalyst: I was listening to the deep, hidden thoughts of my crayfish! (p.108)

(4) Wade Marshall

With Grundfest’s recommendation, I was accepted by Wade Marshall, chief of the Laboratory of Neurophysiology at NIMH, and was slated to arrive in July 1957. In the late 1930s Wade Marshall was probably the most promising and accomplished young scientist working on the brain in the United States…Marshall’s marvelous scientific achievements came at a price, however. The experiments were physically demanding, often lasting more than twenty-four hours at a time. Frequently deprived of sleep, he became exhausted. In addition, there was tension with [his lab partner] Bard. In 1942 Marshall collapsed with an acute psychotic paranoid episode after having actually threatened Bard physically….By the time I arrived at NIH, he had passed the peak of his brilliant career…He focused much of his energy and interest on administrative matters, which he did well. Although eccentric, moody, and somewhat suspicious in unpredictable ways, Marshall was a generous lab chief…Many young people who went on to have superb careers in science and I myself owe our start and much of our later success to the personal and professional example of Wade Marshall….Science gives one a structured opportunity to try out ideas…Marshall gave me the freedom to try to think creatively. (p.115)

(5) Stephen Kuffler

Stephen Kuffler, another scientist who left Europe to escape the Nazis, greatly influenced my thinking…Kuffler left Vienna in 1938 because, in addition to having one Jewish grandfather, he was a socialist. Kuffler was a junior tennis champion in Austria…He amazed with his surgical skills. He could dissect out individual muscle fibers to study the synaptic input from one motor axon to one muscle fiber, a real tour de force. (p.94)

Stephen Kuffler was to become one of my great neurobiological heroes. I learned from Kuffler's papers a new criterion for how good science is done - the importance of having a preparation suitable to testing the questions to be answered. Kuffler taught me to respect the power of invertebrate neurobiology. (Nobel prize essay)

Kuffler (center) and his famous lab

Kuffler had succeeded in forming the premier group of neural scientists in the country. Always a first-class experimentalist, he emerged as the most admired and effective leader of the American neuroscience community...He liked the work on Aplysia and was very supportive. Until his death in 1980, he proved a friend and counselor of immeasurable strength and generosity. He took an intense interest in people, their careers, and their families. Years after I left Harvard, he coulw call on an occasional weekend to discuss a paper of mine he had found interesting or simply to inquire about my family. (p.181)

Our group [at NYU] was very much influenced by Stephen Kuffler’s group at Harvard—not just by what it had done, but also by what it was not doing. Kuffler had developed the first unified department of neurobiology…Its focus was the single cell and the single synapse…As a result the Harvard group did not in its early days recruit anyone who specialized in the study of behavior or learning.

Occasionally, after he had had a glass or two of wine, Steve would talk freely about the higher functions of the brain, about learning and memory, but he told me that in sober moments he thought they were too complex to be tackled on the cellular level at the time…
Alden, Jimmy, and I differed with Kuffler on this point…In 1967 Alden and I announced this direction in a major review article entitled “Cellular Neurophysiological Approaches in the Study of Learning.” The impact of our review—perhaps the most influential one I have written, persists to this day. (p.184)

In 1980, he died of a heart attack…Like most of the neural science community, I was shattered when I heard the news. We were all indebted and in some ways dependent on him…I don’t think anyone on the American scene since then has been as influential or as beloved as Steve Kuffler…The death of Steve Kuffler marked the end of an era, an era in which the neural science community was still relatively small and focused on the cell as the unit of brain organization. Steve’s death coincided with the merger of molecular biology and neural science. (p.237)

Grundfest, Purpura, Crain, Marshall, and later Steve Kuffler influenced me greatly. They transformed my life. They and Mr. Campagna, who paved the way for me to go to Harvard, illustrate the importance of student-teacher relationships in one’s intellectual development….Young people must strive to have an open mind and seek out places where they will be surrounded by first-rate intellects. (p.115)

C. COLLEAGUES

2007-09-17T18:53:00.000-07:00

(1) Dominick Purpura

To my surprise, I found my first laboratory experiences to be absorbing, quite unlike the rather dry science I had been taught…More important, I found discussions with Grundfest and Purpura fascinating—they were penetrating and sometimes marvelously gossipy about other scientists’ work, their careers, their sex lives….I began to realize that what makes science so distinctive, particularly in an American laboratory, is not just the experiments themselves, but also the social context, the sense of equality between student and teacher, and the open, ongoing, and brutally frank exchange of ideas and criticism.

Had I not been exposed in Harry Grundfest’s laboratory to the excitement of actually doing research, of carrying out experiments to discover something new, I would have ended up with a very different career, and I presume, a very different life. In the first two years of medical school I took the required basic science courses, but until I had actually one research, I saw my scientific education as a a prerequisite for doing what I really cared about—practicing medicine, taking care of patients, understanding their illnesses, and preparing to become a psychoanalyst. I was astonished to discover that working in the laboratory—doing¬ science in collaboration with interesting and creative people—is dramatically different from taking courses and reading about science…

Science is done in an intense and endlessly engrossing social context. The life of a biological scientist in the United States is a life of discussion and debate—it is the Talmudic tradition writ large…The egalitarian social structure of American science encourages this camaraderie. Life at an American university bridges gaps in both age and status in ways that I have always found inspiring…In the United States, young people speak up and are listened to if they have interesting things to say.

(2) Alden Spencer

My research took an extremely fortunate turn with Alden’s arrival….Born in Portland, Alden completely changed my narrow view of life outside the East Coast. He was strongly independent, with an original turn of mind, a great interest in music and art, and an enthusiasm for life that made him exciting to be with…Alden had a considerable musical talent, having played the clarinet in the Portland Symphony Orchestra. His wife, Diane, was a fine pianist…We talked science incessantly and reinforced each other’s audacity.

Alden’s death was shattering to all of us personally and devastating to our close-knit group. We had talked almost daily for about twenty years, so for a long while afterward the whole rhythm of my working life was disrupted…Alden’s death was followed by my father’s death the same year and my brother’s death 4 years later. In each case was extensively involved in their care, and their deaths left me not only psyhoclogically despondent and depleted but also physically exhausted. I have always been grateful for the serenity I have been able to obtain by focusing hard on my work…This difficult period was made even more painful for me by my son Paul’s departure for college…I was beginning to feel like Job.

(3) Tom Carew
In 1971, we were joined by Tom Carew, a gifted, energetic, and gregarious physiological psychologist who…simply loved being in the group at NYU…Like a dry sponge, Carew soaked up the culture of the group—not only the science, but also the shared interest in art, music, and scientific gossip.

(4) Robert Hawkins
In 1980 we were joined by Robert Hawkins, an instightful young psychologist…He was already a devotee of classical music and opera. A fine athlete, Hawkins had played on the varsity soccer team and Stanford, and he proceeded to focus his athletic passion on sailing.

(5) Richard Axel
Richard Axel would prove to be the collaborator who guided me into the third stage of my biological career, one centered on the dialogue between a neuron’s genes and its synapses in the formation of long-term memory…He had developed a general method of transferring any gene into any cell…called co-transfection, widely used both by scientists in their research and by the pharmaceutical industry in generating drugs. At the end of a meeting, he walked up to me and said, “I’m getting tired of all this gene cloning. I want to do something on the nervous system. We should talk and maybe do something on the molecular biology of walking.” Richard was also an opera addict, and soon after we became friends, we went to the opera together on a number of occasions, always without tickets.

(6) Kelsey Martin
After graduating from Harvard College, Kelsey Martin and her husband joined the Peace Corps in Africa…While she was in our laboratory, they had a daughter, Maya. Kelsey proved a special presence in the laboratory, not only doing first-class science with extraordinary skill, but also lifting all of our spirits by turning our little conference-lunchroom into a joyful kindergarten for gifted children from 4:00-6:00 pm.

(7) Felix Strumwasser

Aside from Nazi sympathizers, Kandel criticizes only one other scientist in his autobiography, Felix Strumwasser (1934-2007).

Strumwasser experimenting with Kandel’s snail

Not everything was wine and roses, however. Another young scientist, Felix Strumwasser, went to work at a neighboring laboratory…I learned a great deal from him. In fact, in my conversations with Felix, I sharpened my thinking about how to tackle neurobiological studies of learning. Felix also got me to think about the hypothalamus…I was therefore taken aback—and hurt—when the day after I gave the seminar on our work, Felix stopped talking to me. I could not understand what had happened. Only with time did I realize that science is filled not simply with a passion for ideas but also with the ambition and strivings of people at different stages of their careers. Many years later, Felix renewed our friendship.

(8) Other Colleagues

2007-09-17T17:49:00.000-07:00

Kandel’s autobiography is full of name-dropping. He describes all his colleagues in superlative terms. His account of the history of neuroscience likewise sounds like a hagiography or religious adoration of past scientists.

In thinking about the students and postdoctoral fellows with whom I have collaborated in my laboratory, I am reminded of the painting workshop of the Renaissance artist Andrea del Verrocchio…filled with a succession of gifted artists, including Leonardo da Vinci…When I give talks, I tell my audience, “This new culture system was developed by Kelsey Martin, this CREB activator and repressor were found by Dusan Bartsch, and these wonderful prion-like molecules at the synapse were discovered by Kausik Si!” (p.418)

Table: Collaborators mentioned in In Search of Memory, with Kandel’s comments.

Walter Gilbert	an extraordinary person, one of the most intelligent, gifted, and versatile biologists of the second half of the twentieth century
Dominick Purpura	extremely bright, technically strong, and highly entertaining
Angelique Arvantiaki-Chalazonitis	a senior, highly accomplished scientist
Irving Kupfermann	a gifted an idiosyncratic behaviorist
Vincent Castellucci	a delightful and highly cultivated Canadian scientist…who regularly trounced me in tennis
Robert Hawkins	an insightful young psychologist
Craig Baily	a talented and creative young cell biologist
Paul Greengard	a gifted biologist
Steven Siegelbaum	a technically gifted young biophysicist
Richard Axel	remarkably interesting, intelligent, and generous
Richard Scheller	creative and bold, extraordinary
Tom Jessell	the leading scientist working on the development of the vertebrate nervous system
Kelsey Martin	an extremely gifted cell biologist
Kausik Si	a remarkably original and effective scientist
Seth Grant, Mark Mayford	talented postdoctoral fellows
Amit Etkin	a bold and creative Ph.D. student

IV. INSTITUTIONAL SUPPORT

2007-09-17T15:51:00.001-07:00

(1) National Institutes of Health

2007-09-17T15:47:00.001-07:00

Besides being a good place to do research, NIH was also a good place to learn about new developments in biology. During the course of any given year, most good scientists working on the brain visit the NIH campus. As a result, I was able to speak with many people and to attend seminars in which I learned about the experimental advantages of various invertebrate animals, such as crayfish, lobsters, honeybes, flies, land snails, and the nematode work Ascaris…

After about six months of careful consideration, I settle on the giant marine snail Aplysia as a suitable animal for my studies. I had been greatly impressed with lectures I had heard about the snail…The American species of Aplysia that lives off the California coast, and which I have spent most of my career studying, measures more tha one foot in length and weights several pounds…It is a large, proud, attractive, and obviously highly intelligent beast…Aplysia has a small number of cells…In addition, some of Aplysias cells are the largest in the animal kingdom, making it relatively easy to insert microelectrodes into them…It had been found that few nerve cells are uniquely identifiable—that is, the same cells can easily be recognized by sight under the microscope in every single snail. In time I realized that the same thing is true of most other cells in its nervous system, heightening the prospect of mapping the entire neural circuitry controlling a behavior….No one in the United States was working on Aplysia. The only two people in the world who were studying it in 1959 were in France…

As I left NIH in June 1960, I felt a deep sadness, somewhat similar to that which I experienced when I graduated from Erasmus Hall High School. I had come as a novice, and I left as a limited but nonetheless working scientist. (p.145)

(2) Howard Hughes

2007-09-17T15:44:00.001-07:00

The final event that promoted my goal of learning molecular biology and using it to study memory occurred in 1983, when the Howard Hughes Medical Institute asked me to join the nucleus of a group devoted to this new science of mind…By 2004 the institute’s endowment had risen to over $11 billion, and it supported 350 investigators…The motto of the Howard Hughes Medical Institute is “People, not projects.” It believes that science flourishes when outstanding researchers are provided both the resources and the intellectual flexibility to carry out bold, cutting-edge work…With the support of the Howard Hughes Medical Institute in hand, we could now address questions about genes and memory. (p.252)

(3) The Biotech Industry

2007-09-17T15:42:00.002-07:00

Kandel and Axel, 2000

In 1985, Richard Axel asked me to talk about Alzheimer’s disease at a meeting in NYC of the board of directors of Biotechnology General, a company for which Axel consulted…After that meeting, the chairman proposed that we start a new biotechnology company focused exclusively on the brain. At first I was reluctant…I shared the view held earlier by a large part of the academic community that biotechnology and pharmaceutical companies did humdrum science…

In 1987, we formed Synaptic Pharmaceuticals…I asked Walter Gilbert to join the board. Wally is an extraordinary person, one of the most intelligent, gifted, and versatile biologists of the second half of the twentieth century…Denise and I developed a habit that continues to this day—dining with Wally, usually at a wonderful restaurant, the night before scientific advisory board meetings…We formed effective partnerships with Eli Lilly and Merck. The company went public in 1992 and disbanded its extraordinary scientific advisory board….

In 1995, as Denise and I were having one of our dinners with Walter Gilbert, Denise suggested that we start a company to develop a “little red pill” for age-related memory loss. In 1996 the four of us formed a new company, Memory Pharmaceuticals….Both Columbia and Howard Hughes have experienced lawyers who helped me work out consulting agreements….In 2004, the company went public. It has developed four new families of drugs…Some of the compounds improve a rat’s memory of a new task for months! (p.324)

V. DISCOVERIES

2007-09-17T15:42:00.001-07:00

(1) Learning = Synaptic Growth

2007-09-17T15:40:00.000-07:00

Genetic and developmental processes specify the connections among neurons—that is, which neurons form synaptic connections with which other neurons and when. But they do not specify the strength of those connections…Learning selects among a large repertoire of preexisting connections and alters the strength of a subset of those connections…The anatomy of the neural circuit is a simple example of Kantian a priori knowledge, while changes in the strength of particular connections in the neural circuit reflect the influence of experience.

Habituation weakens the synapse, whereas sensitization or classical conditioning strengthens it…The strength can be modified in two ways, depending on which of two neural circuits is activated by learning—a mediating circuit or a modulatory circuit…
The [modulatory circuit] activated by a shock to Aplysia’s tail release a neurotransmitter called serotonin…In fact, we could simulate the enhancement of synaptic strength, and the strengthening of [behavioral reflexes] simply by applying serotonin to the connections between the sensory and motor neurons.

The stage was set for a biochemical analysis of memory storage…But even a single Aplysia neuron contains thousands of different proteins and other molecules. Which of these molecules are responsible for short-term memory?...The sequence of biochemical reactions that I sought would have to…translate the brief action of serotonin into molecules whose signals would last for minutes within the sensory neuron. Second, those molecules would have to broadcast signals from the cell membrane, where serotonin acts…to the specialized regions of the axon terminal involved in the release of glutamate. We speculated on the possibility that a specific molecule known as cyclic AMP might be involved….

(2) cAMP

2007-09-17T15:39:00.001-07:00

cAMP binding to an enzyme

Of all the known second-messengers, the cAMP system is probably the most primitive. It is the most important, and in some cases the only second-messenger system found in single-celled organisms such as the bacterium E.CColi, in which it signals hunger. Thus the biochemical actions underlying memory did not arise specifically to support memory…Science has found surprisingly few proteins that are truly unique to the human brain and no signaling systems that are unique to it.

I discovered that cAMP second-messenger signaling is also turned on by serotonin during sensitization….In 1976, we injected cAMP directly into a sensory cell of Aplysia and found that it dramatically increased the amount of glutamate release and, therefore, the strength of the synapse…We injected protein kinase A directly into a sensory neuron and found that it does exactly what cAMP does—it strengthens the connection…In 1980 [lab partner Steven Siegelbaum] discovered one of the targets of cAMP and protein kinase A: a potassium ion channel in sensory neurons that responds to serotonin. Steven found that he could cause it to close either by applying serotonin to the outside of the cell membrane or by applying cAMP or protein kinase A to the inside…When it is closed, potassium ions move out of the cell [after the cell fires] less rapidly, slightly increasing the duration of the impulse…which allows more time for calcium to flow in…which increases the release of glutamate. In addition, cAMP and protein kinase A directly [promote glutamate] synaptic vesicles.

(3) CREB

2007-09-17T15:28:00.000-07:00

Longterm memory is not simply an extension of short-term memory: not only do the changes in synaptic strength last longer but, more amazingly, the actual number of synapses in the circuit changes…We could see for the first time that the number of synapses in the brain is not fixed—it changes with learning!

I had a hunch that long-term memory, which involves enduring changes in synaptic strength, could be tracked to changes in the genetic machinery of sensory neurons.

[Richard Scheller, a lab partner] succeeded in isolating the gene that controls egg laying [in Aplysia] and showed that it encodes a peptide hormone…He synthesized the peptide hormone, injected it into Aplysia, and watched as it set off the animal’s whole egg-layign ritual.

In short-term memory, synapses use cAMP and protein kinase A inside the cell to call for the release of more neurotransmitter. I hypothesized that in long-term memory this kinase moves from the synapse to the nucleus, where it somehow activates proteins that regulate gene expression…We now collaborated with Roger Tsien at UCSD and used a method developed by him that allowed us to visualize the location of the cAMP and protein kinase A in the neuron. We found that whereas a single pulse of serotonin increases cAMP and protein kinase A primarily at the synapse, repeated pulses of serotonin produce even higher concentrations of cAMP, causing protein kinase A to move into the nucleus, where it activates genes…We knew from recently published studies of non-neuronal cells that protein kinase A can activate a regulatory protein called CREB, which binds to a promoter…In 1990, we found that CREB is present in the sensory neurons of Aplysia and is indeed essential tot eh long-term strengthening of synaptic connections…In 1995 [a lab partner] found that there are in fact two forms of the CREB protein: one that activates gene expression (CREB-1) and one that suppresses gene expression (CREB-2). Repeated stimulation causes protein kinase A and MAP kinase to move to the nucleus, where protein kinase A activates CREB-1 and MAP kinase inactivates CREB-2…CREB’s opposing regulatory actions provide a threshold for memory storage, presumably to ensure that only important, life-serving experiences are learned…In 1993 Tim Tully discovered that CREB proteins are essential for long-term memory in Drosophila. As in Aplysia, CREB activators and repressors played critical roles. The CREB repressor blocked the conversion of short-term memory to long-term memory. Even more fascinating, mutant flies bred to produce more copies of the CREB activator had the equivalent of flashbulb memories.

In principle, a highly emotional state could bypass the normal restraints on long-term memory…This might account for socalled 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.

When we inhibited local protein synthesis at a synapse, new terminals grew, making use of the proteins sent to the synapse from the cell body. That new growth could not be sustained, however, and after one day it regressed…Two independent mechanisms are at work. One process initiates long-term synaptic facilitation by sending protein kinase A to the nucleus to activate CREB, thereby turning on the effector genes that encode the proteins needed for the growth of new synaptic connections. The other process perpetuates memory storage by maintaining the newly grown synaptic terminals, a mechanism that requires local protein synthesis.

(4) prions

2007-09-17T15:27:00.000-07:00

In 1999 [lab partner] Kausik Si found that a novel form of CPEB in Aplysia was present only in the nervous system, at all the synapses of a neuron, activated by serotonin, and required at the activated synapses to maintina…new terminals…As Kausik looked carefully at the amino acid sequence of the novel CPEB, he noticed something very peculiar. One end of the protein had all the characteristics of a prion. Prions are probably the weirdest proteins known to modern biology…The genes that encode prions give rise to the recessive form, but the recessive form can be converted to the dominant form…The dominant form is self-perpetuating; it causes the recessive conformation to change its shape as well…I remember it was a beautiful New York afternoon in the spring of 2001…when Kausik walked into my office and asked, “what would you say if I told you that the CPEB has prion-like properties?” Clearly, a self-perpetuating molecule could remain at a synapse indefinitely, regulating the local protein synthesis needed to maintain newly grown synaptic terminals. In my late-night thoughts about long-term memory, I had once briefly entertained the idea that prions might somehow be involved in long-term memory storage.

In 1992, we found that by knocking out a particular gene encoding a protein that is important for LTP, we could compromise synaptic strengthening in the Schaffer collateral pathway. Morever, the genetic defect was correlated with a defect in the mouse’s spatial memory.
I examined slices of the hippocampus taken from genetically modified mice and found that in each of the three major pathways of the hippocampus, LTP has two phases similar to those of LTP in Aplysia. A single train of electrical stimuli produces a transient, early phase of LTP that lasts only one to three hours and does not require the synthesis of new protein. NMDA receptors in the postsynaptic cel are activated, leading to the flow of calcium ions inot the postsynaptic cell. Here calcium acts as asecond messenger; it triggers LTP by enhancing the existing AMPA receptors’ response to glutamate and by stimulating the insertion of new AMPA receptors into the membrane of the postsynaptic cell…Repeated trains of electrical stimuli produce a late phase of long-term potentiation that lasts for more than a day…by modulatory interneurons. In mice those neurons release dopamine…Like serotonin in Aplysia, dopamine prompts a receptor in the hippocampus to activate an enzyme that increases the amount of cyclic AMP…which recruits protein kinase A and other protein kinases, which leads to the activation of CREB and the turning on of effector genes…I discovered that the mammalian brain requires several gene regulators in addition to CREB.

We found that although neither protein kinase A nor protein synthesis is needed for the initial formation of a spatial map, they both are essential for the map to become “fixed” over the long term, so that the mouse recalls the same map every time it enters the same space…When we blocked protein kinase A or inhibited protein synthesis, we interfered not only with the long-term stability of the spatial map but also with the ability to retain long-term spatial memories…We found that blocking the action of dopamine in the hippocampus blocked the stabilization of the spatial map in an animal that was paying attention. Conversely, activating dopamine receptors in the hippocampus stabilized the spatial map of an animal that was not paying attention…In implicit memory storage, the attentional signal is recruited involuntarily (reflexively), from the bottom up: the sensory neurons of the tail, activated by a shock, act directly on the cells that release serotonin. In spatial memory, dopamine appears to be recruited voluntarily, from the top down: the cerebral cortex activates the cells that release dopamine, and dopamine modulates activity in the hippocampus…The hippocampus of the mouse contains at least one prion-like protein…Dopamine modulates the amount of the prion-like CPEB protein (CPEB-3) in the mouse hippocampus. This discovery raised the intriguing possibility—so far only that—that spatial maps may become fixed when an animal’s attention triggers the release of dopamine in the hippocampus and that dopamine initiates a self-perpetuating state also mediated by CPEB.

We explored the Schaffer collateral pathway in the hippocampus of older mice with age-related memory deficits and found that the late phase of long-term potentiation, which we and others had found to be strongly correlated with long-term explicit memory, was defective…We had found earlier that the late phase of long-term potentiaion is mediated by cyclic AMP and protein kinase A and that this signaling pathway is activated by dopamine…We found that drugs which activate these dopamine receptors, and thereby overcome the deficit in the late phase of long-term potentiaion. They also reverse the hippocampus-dependent memory deficit…The drug Rolipram inbhits the enxyme that breaks down cyclic AMP,increasing signaling. In old mice, I found, Rolipram significantly improves learning that involves the hippocampus…Rolipram even increased long-term potentiaion and hippocampus-dependent memory in young animals…Exposing the mouse hippocampus to the most toxic component of B-amyloid plaques, known as the AB peptide…impairs LTP before any neurons die or plaques form. The peptide decrease the activity of cyclic AMP and protein kinase A.

(5) fear signaling

2007-09-17T15:24:00.001-07:00

Every animal with a well-developed central nervous system—from snails to mice to monkeys to people—can become afraid, or anxious…Anxiety—fear itself—is a universal, instinctive response to a threat to one’s body or social status and is therefore critical for survival…William James proposed that the cognitive experience of emotion is secondary to the physiological expression of emotion….”We feel sorry because we cry, angry because we strike, afraid because we tremble”…Objectively distinguishable emotions are correlated with specific patterns of autonomic, endocrine, and voluntary responses. Furthermore, people whose spinal cord has been accidentally severed, cutting off feedback from the autonomic nervous system in regions of the body below the injury, appear to experience less intense emotions….

Yet feelings can be sustained long after a threat has subsided. Conversely, some feelings arise much more rapidly than changes in the body…Antonio Damasio argues that the experience of emotion is essentially a higher order representation of the bodily reactions and that this representation can be stable and persistent…A consensus is emerging on how emotions are generated. The first step is thought to be the unconscious, implicit evaluation of a stimulus, followed by physiological responses, and finally by conscious experience that may or may not persist…

The unconscious component of emotion involves the operation of the ANS and the hypothalamus, which regulates it. The conscious component of emotion involves the evaluative functions of the cerebral cortex, which are carried out by the cingulated cortex. Central to both components is the amygdala, thought to coordinate the conscious experience of feeling and the bodily expression of emotion, particularly fear…Damage to the amygdala, disrupts the ability of an emotionally charged stimulus to elicit an emotional response. In contrast, damage to the hippocampus interferes with the ability to remember the context in which the stimulus occurred…Joseph LeDoux and Michael Davis delineated how information from conditioned and unconditioned stimuli reaches the amygdala and how the amygdala initiates a fear response…The sensory neurons send their axons to a cluster of neurons in the thalamus…that form two pathways: a direct pathway that goes straight to the lateral nucleus of the amygdale without ever contacting the cortex, and an indirect pathway that goes first to the auditory cortex and then to the lateral nucleus.

I studied slices of the mouse amygdala. Earlier studies had shown that both the direct and indirect pathways are strengthened through a variant of long-term potentiation…We found that it has a molecular signaling pathway that includes cAMP, protein kinase A, and the regulatory gene CREB…WE found that the pyramidal cells express a gene that encodes a peptide neurotransmitter called gastrin-releasing peptide. We next found that the target cells are a special population of inhibitory interneurons that contain receptors for gastrin-releasing peptide. The target cells then connect back to the pyramidal cells. The circuit we traced is called a negative feedback circuit…We tested a genetically modified mouse whose receptors for gastrin-releasing peptide had been deleted, thus interrupting the inhibitory feedback circuit…We found dramatically enhanced long-term potentiation in the lateral nucleus and a significantly enhanced and persistent memory of fear. The effect proved to be remarkably specific to learned fear: the same mutant mice showed normal innate fear on a variety of other tests.

When we looked in the lateral nucleus of mice that had undergone safety training, we found the opposite of long-term potentiation: namely, a long-term depression in the neural response to the tone…We found that the response ni the striatum is dramatically enhanced, consisten with the positive sensation of feeling safe.

We engineered mice with a gene that expresses a superabundance of D2 receptors in the striatum, as is found in schizophrenics. We found that such mice do indeed have deficits in working memory…Once a mouse reached adulthood, we turned off the transgene responsible for the production of excessive dopamine receptors and found that the defect in working memory was unabated. In other words, correcting the molecular defect in adult brains did not correct the cognitive defect. This result suggest that an overabundance of D2 receptors during development causes changes in the mouse brain that persist into adulthood…We have now tracked down at least one change that occurs in the PFC as a result of the overproduction of D2 receptors: a decrease in the activation of another dopamine receptor: the D1 receptor…Decreasing D1 receptor activation also decreases cAMP, causing a deficiency in working memory.

Monoamine oxidase inhibitor (MAOI) was initially developed to fight a very different disorder, tuberculosis…Physicians soon notice dthat patients receiving these MAOIs were amazingly upbeat…The most effective antidepressant drugs are known as selective serotonin reuptake inhibitors…Antidepressant drugs also increase the ability of a small region of the hippocampus, the dentate gyrus, to generate new nerve cells…Hen used radiation to destroy the dentate gyrus in a mouse model of depression caused by stress. He found that anti-depressants could no longer reverse depression like behavior in mice.

We showed volunteers pictures of faces with fearful expressions, we found prominent activity in the amygdala. Unconscious perception of fearful faces activated the basolateral nucleus…in direct proportion to a person’s background anxiety…Conscious perception of fearful faces, in contrast, activated the dorsal region of the amygdala, which contains the central nucleus, and it did so regardless of a person’s background anxiety. (p.339-351)

VI. SHINING MOMENTS

2007-09-17T15:22:00.000-07:00

(1) Eureka - 1961

2007-09-17T15:21:00.000-07:00

By applying the powerful methodologies of cell biology to the hippocampus, Alden and I easily picked some low-hanging intellectual fruit. Soon after we started we had our first successful experiment. I shall never forget it. I work all morning and part of the afternoon to complete the surgery…I connected the recording electrode to a loudspeaker…We were trying to record from neurons in the hippocampus…Suddenly we heart the loud bang! Bang! Bang! Of action potentials, a sound I recognized immediately from my experiments on crayfish. Alden had penetrated a cell! Every stimulus I applied elicited a beautiful, large action potential…Alden and I were euphoric—we had obtained the first intracellular signals ever recorded from the region of the brain that stores our fondest memories! We almost danced around the lab…

This experiment and the ones that followed were physically exhausting, sometimes lasting twenty-four hours. It was a good thing we had both just finished a medical internship, where working twenty-four hours at a stretch was not uncommon…

As we became more familiar with the hippocampus, we realized that finding out how its neural networks process learned information…was an extraordinarily difficult task that would take a very long time. I was initially drawn to the hippocampus because of my interest in psychoanalysis…But it became clear to me…that to make any reasonable progress, it would be desirable, at least initially, to study the simplest instance of memory storage and to study it in an animal with the simplest possible nervous system…But what animal? Here Alden and I parted intellectual company. He was committed to mammalian neurophysiology…

Even though it meant swimming against the tide of current thinking, I yearned for a more radical, reductionist approach…In the 1950s and 1960s, most biologists shared Alden’s reluctance to apply a strictly reductionist strategy to the study of behavior…Not surprisingly, I was discouraged from pursuing this research strategy by a number of senior scientists in neurobiology…Although some scientists were studying behavior in invertebrates, that work was not considered important—indeed, it was largely ignored—by most people working on the mammalian brain. Of even greater concern to me was the skepticism of knowledgeable psychologists and psychoanalysts that anything interesting…could be found by focusing on individual nerve cells.

Alden Spencer and I had found few differences in the basic properties of neurons that participate in memory storage and those that do not. Those findings supported the idea that memory relies not on the properties of the nerve cell per se but on the nature of the connections…This led me to think that memory may result from changes in synaptic strength brought about by certain patterns of sensory stimulation…

John Eccles had been very enthusiastic about the possibility that synapses change in response to excessive use, but when he tested the idea, he found that they changed for only a brief period of time..It now dawned on me that perhaps Pavlov was so successful in producing learning because the simple patterns of sensory stimulation he used elicited certain natural patterns of activation that were particularly suited for producing longer changes…With further reflection I decided to try to stimulate in the nerve cells of Aplysia the patterns of sensory stimulation that Pavlov had used in his learning experiments…I would remove the nervous system and work on a single ganglion, a single cluster of about two thousand nerve cells. Second, I would select a single nerve cell—a target cell—in that ganglion to serve as a model of any changes that might occur as a result of learning…I would then apply different patterns of electrical pulses modeled on the different forms of learning to a particular bundle of axons extending from sensory neurons on Aplysia’s body surface to the target cell.

To simulate habituation, I would apply repeated, weak electrical pulses to this neural pathway. To simulate sensitization, I would apply repeated, weak electrical pulses to this neural pathway. To simulate sensitization, I would stimulate a second neural pathway very strongly, one or more times, and see how it affected the target cell’s response to weak stimulation of the first pathway. Finally, to simulate classical conditioning, I would pair the strong stimulus to the second pathway with the weak stimulus to the first pathway in such a way that the strong stimulus would always follow and be associated with the weak stimulus.

I dissected out the abdominal ganglion [of an Aplysia snail], with its two thousand nerve cells, and mounted it in a small chamber bathed with aerated seawater. I placed microelectrodes inside one cell and then recorded that cell’s responses to various sequences of stimuli applied to the neural pathways that converged on it. I used three patterns of stimulation, based on Pavlov’s work in dogs..The experiments proved even more effective than I had anticipated…

I applied a weak electrical stimulus…and then repeated that stimulus ten tens. I found that the cell’s response to the stimulus decreased progressively. By the tenth stimulus, the response was only about one-twentieth as strong as it had been initiatlly, just as an animal’s behavioral response abates when aneutral stimulus is presented repeatedly…Then I a applied a series of five stronger stimuli to a different pathway leading to the same cell. The cells’ response to stimulation of the first pathway was greatly enhanced..up to thirty minutesThen I repeatedly paired a weak stimulis to one neural pathway with a strong stimulus to another pathway. The weak stimulus came first and acted as awarning of the strong stimulus. The pairing of the two stimuli greatly enhanced the cell’s response to the weak stimulus.

By 1985, after more than fifteen years of hard work, we had shown that a simple behavior in Aplysia could be modified by various forms of learning…Next we needed to map the neural circuitry…To my surprise, I found that I could readily map the synaptic connections between cells. By inserting a microelectrode into a target cell and stimulating action potentials in other cells of the ganglion, one cell at a time…it proved possible for the first time in any animal to map the working synaptic connections between individual cells.

(2) Nobel Prize

2007-09-17T15:19:00.002-07:00

On the day of Yom Kippur, October 9, 2000, I was awakened by the ringing of the telephone at 5:15 in the morning…The conversation felt unreal. In my state of disbelief, I didn’t know what to say except to acknowledge my gratitude…Denise said, “Look, it’s so early. Why don’t you go back to sleep?” “Are you kidding?” I replied. “How can I possibly sleep?”…
The ceremony at the Stockholm Concert Hall was the most remarkable and memorable event of all…When I sat down, the Stockholm Philharmonic played the third movement of Mozart’s unsurpassed clarinet concerto. On this occasion the melodic solos, written for a Viennese temperament like mine, sounded even lovelier than usual…Denise and I had taken lessons to brush up on our limited and rarely practiced waltzing skills, but sadly, and to Denise’s unending disappointment, we didn’t get much of a chance to dance. As soon as dinner was over, we were approached by our friends, and I so enjoyed chatting with them that I found it hard to break away.

VII. PRACTICAL LESSONS

2007-09-17T15:19:00.001-07:00

(1) How to Win A Nobel Prize

2007-09-17T15:14:00.000-07:00

“[In Search of Memory is] a wonderful self-help book for those who seek a Nobel prize.” —Lewis Rowland, editor in chief, Neurology Today

There are two basic ingredients for success in any field: natural ability and training. (On the neuronal level, as Kandel shows, neurons are more-or-less hard-wired from DNA, but synaptic connections are changed through training.) In terms of Kandel’s career (on the behavioral level), scientific experimentation is a variation on the form of previous experiments, replicated and tinkered with over many iterations—as the scientist himself is an iteration of an evolving strand of DNA.

Kandel reveals a third element, in addition to nature and nurture, which is necessary for Nobel-caliber science. Scientists must be self-trained and self-motivated in order to produce original work. They cannot be controlled or preprogrammed. They require a special kind of freedom—you could call it “hyperfreedom”—freedom within a accelerating and enriching sociocultural environment.

Kandel asserts that “science is done in an intense and endlessly engrossing social context.” In regard to his own work, he largely attributes his success to his own social context as a Holocaust refugee living in New York within a close-knit group of friends, family, and colleagues. He describes how he was not even a science- or math-oriented student, and how throughout his life he pursued a wide variety of nonscientific interests. These extracurricular activities, he claims, were far more important to his work than his school training.

Kandel’s most influential work was done approximately 1965-1985, when he was in his late thirties to late fifties. The climax of his career occurred at the beginning of this period, when several elements of his background came together at the moment when he was choosing the basic direction of his scientific life. It was at that point that he made the revolutionary choice to study mental function in a snail—as he described it, an act of “radical reductionism.” While Kandel had a scientific rationale for this approach, it was largely inspired by a remarkable confluence of people in Kandel’s life and the sacrifices which they made for him—his wife and family, four selfless teachers, the Jewish community in Vienna, the fraternal structure of American science, and the figure of Sigmund Freud.

(2) How to Enhance Your Memory

2007-09-17T15:10:00.000-07:00

Would it be desirable for young people who could afford them to buy memory-enhancing drugs before taking the college entrance exams? There is a range of opinions on this issue, but mine is that healthy young people are capable of studying and learning on their own and in school without the aid of chemical memory enhancers. Studying well is, without a doubt, the best cognitive enhancer for those capable of learning. (p.333)

VIII. APPENDIX

2007-09-17T15:04:00.001-07:00

(1) Map: Kandel's Life

2007-09-17T15:03:00.000-07:00

(2) Map: Kandel’s Life in New York

2007-09-17T15:01:00.001-07:00

(3) Timeline

2007-09-17T14:59:00.000-07:00

1929 Vienna

1939 New York

1944: Erasmus Hall High School

1948: Harvard

1950-3: dates Anna Kris

1952: NYU Medical School

1955 meets Denise; Columbia (6-month elective)

1956 marries Denise; Montefiore Hospital (intern)

1957 Columbia (6-week elective); NIMH (war service)

1960 Harvard Medical School (resident)

1962 Paris (postdoctoral fellow)

1963 Harvard Medical School (teacher)

1963 NYU(teacher)

1974 Columbia (teacher)

1983-2007 Columbia (tenured professor)

(4) chemical pathways

2007-09-17T14:57:00.001-07:00

short term memory:
neurotransmitter -->cAMP-->kinases-->potassium-->calcium-->glutamate

longterm memory:
neurotransmitter-->cAMP-->kinases-->CREB-->DNA-->mRNA+CPEB-->synaptic proteins

short term spatial memory/coincidence detector:
neurotransmitter-->NMDA-->calcium-->AMPA-->glutamate-->short-term map

longterm spatial memory/memory loss:
DA(age-related)-->cAMP(Rolipram)-->kinases (xAB peptide)-->CREBs+CPEB-->fixed map

emotional memory:
Amygdala: transmitter-->cAMP-->kinase-->CREB-->gastrin-releasing peptide: negative feedback

sensory-->hippocampus

depression:
no new nerve cells in dentate gyrus from transmitters

schizophrenic memory loss:
Excess D2 in striatum-->decrease in D1-->cAMP

emotional circuit (ledoux)
Sensory-->amygdala / sensory cortex-->hypothalamus / cingulate cortex

conscious circuit:
unconscious background fear-->amygdala

IX. GUESTBOOK

2007-09-17T14:00:00.000-07:00

Welcome!

Feel free to sign your name or leave comments...