OKAY

							>>> OKAY.
SO, IT'S MY PLEASURE TO WELCOME
DAN FELDMAN BACK TO THE NIH AND
OUR MONDAY NEUROSCIENCE SERIES.
DAN GOT HIS PH.D. FROM
NEUROBIOLOGY AT STANFORD IN
1997.
HE STUDIED AUTO TRANSMISSION IN
THE BARN OWL MIDBRAIN AND A
COUPLE OF NICE PAPERS LOOKING AT
THE SPECIFIC ROLES OF NMDA AND
RECEPTORS AND PLASTICITY IN
LEARNING.
HE THEN CONTINUED IN THE SAME
THEME BUT TO THE MAMMAL AND RATS
CORTEX AT UCSF.
THERE HE WAS LOOKING AT SYNAPTIC
PLASTICITY IN THE CORTICAL
SYNAPSES.
HE SPENT TWO YEARS HERE AS A
STAFF FELLOW AT NINDS WHERE HE
STARTED THE WORK I'M FAMILIAR
WITH SPIKE TIMING PLASTICITY AND
CARRIED THAT OVER TO HIS OWN LAB
WHICH HE STARTED AT UCLA IN 2000
LOOKING AT THE ROLE OF SPIKE
TIMING PLASTICITY AND SETTING UP
PLASTICITY IN THE RAT CORTEX.
AND RECENTLY WITHIN THE LAST FEW
MONTHS CONTINUED HIS TOUR OF
WELL KNOWN DEPARTMENTS IN
CALIFORNIA WHERE HE'S BECOME
ASSOCIATE PRESSER IN MOLECULAR
CELL BIOLOGY AT UC BURKELY AND
TODAY TALK ABOUT PLASTICITY AND
PROCESSING IN THE WHISKER MAP
AND RAT SENSOR CORTEX.
>> THANK YOU.
IT'S A REAL PLEASURE TO BE BACK
HERE.
I SEE MANY FAMILIAR FACES AND TO
SEE A LOT OF CONTINUING GROWTH
IN NEUROSCIENCE ESPECIALLY
NEUROPHYSIOLOGY SINCE I WAS
HERE.
MY LAB IS INTERESTED IN HOW THE
SENSORY CORTEX REACTS IN
RESPONSE TO THE SENSORY
EXPERIENCE AND A PROBLEM, A WELL
STUDIED AND WELL POSED PROBLEM
OF MANY YEARS.
CERTAINLY GOING BACK TO THE
WEASEL WHERE THEY NOTICED THAT
PATTERNS OF SENSORY EXPERIENCE
IN VISUAL CORTEX NOT ONLY DRIVE
ACTIVITY BUT OVER THE LONG RUN
WOULD CHANGE THE TOPOGRAPHY OF
THE REPRESENTATION OF THE WORLD.
AND SINCE THAT TIME, THAT KIND
OF PLASTICITY HAS BEEN SEEN
THROUGH DEVELOPMENT IN MANY
AREAS OF THE BRAIN WHERE USE OF
FINGERPRINT REGIONS CAN GROW THE
REGIONS AND AUDIOTORY CORTEX CAN
CHANGE THE REPRESENTATION OF
MAPS IN A-1.
THIS SORT OF PLASTICITY IS OFTEN
CALLED HEAVY MAP PLASTICITY
BECAUSE IT CAN BE EXPLAINED BY
STANDARD HEAVY LEARNING ROLES
AND TWO COMPONENTS IN CORTEX
PLASTICITY.
THE FIRST COMPONENT IS THE ONE I
LISTED SECOND, THIS HAPPENS
FIRST.
THAT ONE THE BALANCE OF IMPUT
CHANGES THAT UNDER USED INPUTS
OR INPUTS LESS REV LENT CHANGE
WITHIN THE CORTEX AND OVER USED
EXPAND WITHIN CORTEX AND TWO
DISTINCT INDEPENDENT COMPONENTS
OF THIS PLASTICITY.
NOW THIS PLASTICITY BECAUSE IT
HAPPENS IN SO MANY BRAIN AREAS
AND FULFILL BASIC PROCESSING OPT
MISSING ROLES TO ALLOCATE THE
MOST RELEVANT INPUT.
AND SEEMS LIKE A FUNDAMENTAL
ASPECT OF DEVELOPMENT OR EVEN
ONGOING PLASTICITY IN ADULTS FOR
EXAMPLE RELATED TO LEARNING, WE
AND MANY OTHERS ARE INTERESTED
IN WHAT OR THE UNDER LYING
MECHANISMS AND WORKS BOTH ON
MECHANISMS OF PLASTICITY AND
NORMAL PROCESSING AND I HOPE TO
TELL YOU TWO STORIES ABOUT EACH
OF THOSE.
WHAT I'LL TALK ABOUT FIRST IS
THIS PHENOMENON OF MAP
PLASTICITY IN THE CORTEX.
WHAT ARE THE CELLULAR MECHANISMS
THAT UNDER LIE THE CHANGES IN
MAPS.
BECAUSE THESE CAN BE EXPLAINED
IT'S BEEN LONG ASSUMED THAT THE
MAIN DRIVERS FOR RAPID PHASES OF
PLASTICITY ARE LONG-TERM
POTENTIATION OF DEPRESSION IN
THE CORTEX BECAUSE OF COURSE
THESE IMPLEMENT HEAVY LEARNING
RULES IN CORTEX.
AS WE'VE LOOKED OVER THE YEARS,
WE'VE DISCOVERED A NUMBER OF
PIECES OF IMPORTANT SUPPORTING
EVIDENCE FOR THIS HIGHWAY          HYPOTHESIS BUT
OTHER THINGS THAT CONTRIBUTE AS
WELL.
WE'VE BEEN STUDYING THIS
PHENOMENON IN THE WHISKER SYSTEM
OF RATS.
RATS HAVE FIVE ROWS OF WHISKERS
ON THE FACE LABELED A, B, C, D
AND E AND IF ONE LOOKS DOWN ON
THE BODY HERE, THERE'S A WHOLE
REGION OF THIS DEDICATED TO
PROCESSING INPUT FROM THESE TACK
TILE WHISKERS.
ONE OF THE ADVANTAGES FOR
LOOKING AT F AS MANY OF YOU KNOW
THERE'S AN ANATOMICAL MAP IN THE
CORTEX.
IF YOU STAY FOR A NUMBER OF
CLUTTERS, HERE'S A CELL CLUSTER
HERE, ANOTHER ONE HERE AND
ORGANIZIZED INTO ROADS A, B, C
AND D AND A REPRESENTATION OF
THE WHISKERS IN THE CORTEX AND
TRUE FUNCTIONALLY AS WELL.
OPTICAL IMAGING AND RECORDING
DATA TO ASK WHERE IN THE
CORTICAL MAP HERE I'M JUST
SHOWING THE REPRESENTATIONS OF
THE C, D AND E ROW OF WHISKERS.
WHERE ARE CELLS ACT VASED.
THAT ACTIVATES CELLS IN THE
COLUMNS AROUND IT.
SO YOU HAVE A NICE OVERLAPPING
BUT ORDERED FUNCTIONAL
REPRESENTATION OF THE WHISKERS.
IT TURNS OUT THIS MAP OBEYS THE
SAME PLASTICITY I SHOWED YOU
BEFORE IN THE CORTEX, OVER USE
OF WHISKERS CAUSES
REPRESENTATION TO EXPAND AND
UNDER USE CAUSES THEIR
REPRESENTATIONSING TO SHRINK.
WE'VE BEEN FOCUSING IN MY LAP ON
PLASTICITY UNDER LYING THIS AT A
PARTICULARLY SYNAPSE.
FROM LAYER FOUR UP TO LAYER
THREE AND FOCUSED ON THE LAYER
FOUR TO LAYER THREE SYNAPSE
BECAUSE MANY FORMS OF EXPERIENCE
CAUSE REGULATION HEAVY
REGULATION OF MAPS IN LAYER 23
THAT OCCUR MODESTLY OR SOMETIMES
NOT AT ALL IN LAYER 4 AND
IMPLICATES A MAIN LOCATION FOR
PLASTICITY.
NOW OVER THE LAST FIVE YEARS OR
SO WORK IN MY LAB AND OTHER LABS
HAS DEMONSTRATED THAT IN FACT
OVER USE OR UNDER USE OF CERTAIN
WHISKERS CAN CAUSE WEAKENING OR
STRENGTHENING OF THE SYNAPSES
DETECTABLE IN BRAIN SLICES MADE
FROM ANIMALS WITH THE ALTERED
WHISKERS.
WE FOCUSED ON WHAT THIS
WEAKENING AND STRENGTHENING IS
AND HOW IT MAY HAPPEN IN THE
BRAIN AND FOCUSED HERE ON THE
POSSIBILITY THAT WEAKENING IN
RESPONSE TO UNDER USE
REPRESENTED LTD AT THE SYNAPSE
WHERE AS THE STRENGTHENING
REPRESENTS LTD AT THE SYNAPSE.
I WANT TO SUMMARIZE FOR YOU HOW
WE CAN STUDY THE FORM OF
PLASTICITY AND WHY WE THINK THAT
LTD AT THE SYNAPSE MAY BE
IRRELEVANT CELLULAR MECHANISM
AND HOW THAT LTD MAY WORK.
SO LTD IN THE CORTEX HAS BEEN
  PROPOSED TO UNDER LIE THE
COMPONENT IN WHICH RESPONSES TO
AN INPUT UNDER USED ARE WEAKENED
AND WE CAN STUDY THAT IN
ISOLATION USING THE WHISKER
  MANIPULATION WHERE WE TRIM OFF
THE D ROW OF WHISKERS FOR A WEEK
OF LIFE.
AS A RESULT OF THIS, THE
REPRESENTATIONS OF THE WHISKERS
TRIMMED HERE THE DELTA WHISKER
OR GAMMA WHISKER D AND D2 THEY
WEAKEN AND SHRINKEN THE CORESSEX
SO YOU LOOSE RESPONSE TO THE
DEPRIVED WHISKERS.
THIS YOU SEE IN TERMS OF OPTIMAL
IMAGING, THIS IS ONE PATCH OF
THE CORTEX FROM ONE ANIMAL AND
THE PATCH FROM ANOTHER AND IN
THE FIRST ALL THE WHISKERS IN
TACT.
THE DARK REGIONS ARE REGIONS OF
THE CORTEX ACTIVATED BY WIGGLING
HERE FOR THAT SAME PATCH HERE,
THE C1 AND YOU CAN SEE THESE
OVERLAPPING REPRESENTATIONS OF
THE THREE WHISKERS.
IN AN ANIMAL WITH THE D ROW OF
WHISKERS TRIMMED BEFORE THIS
EXPERIMENT WAS DONE AND THE
TRIMMED WHISKERS WERE ALLOWED TO
REGROW JUST A LITTLE BIT TO
SIMULATE THIS EXPERIMENT, YOU
CAN SEE TRIMMING THE WHISKER
CAUSES A WEAKENING AND SHRINKAGE
BUT NO CHANGE IN THE
REPRESENTATIONS OF SURROUND
WHISKERS.
SO THIS MANIPULATION OF TRIMMING
THE D ROW IS CONVENIENT BECAUSE
IT INDUCES THIS DEPRESSION
COMPONENT OF PLASTICITY IN
ISOLATION SO WE CAN STUDY IT.
AND IF ONE MAKES SLICES FROM
THESE ANIMALS WITH THE D ROW OF
WHISKERS TRIMMED, AS I SAID WE
CAN DETECT WEAKENING OF THE
SYNAPSES AND STEAL THE PUNCHLINE
OVER THE NEXT SLIDES, WE THINK
THAT A RELEVANT LEARNING RULE AT
DRIVING LTD BY TIMING DEPENDENT
PLASTICITY AND THINK
SURPRISINGLY THE MECHANISMS AT
THE SYNAPSE ARE NOT YOUR
CLASSICAL BUT INVOLVES SINGLING
LTD.
SO LET ME SUMMARIZE SOME OF THAT
WORK THAT WAS PUBLISHED A WHILE
AGO AND I WILL TELL YOU ABOUT
NEW WORK GOING ON.
HOW DO WE KNOW THESE THINGS?
IF YOU MAKE THE SLICE OF CORTEX
AND ALL THE TECHNIQUES TO
SIMULATE IN LAYER FOUR, YOU CAN
MEASURE THE STRENGTH OF THE
LAYER 4 TO LAYER 2 SYNAPSE IN A
NUMBER OF WAYS.
IF YOU MEASURE THE STRENGTH IN A
DEPRIVED COLUMN, THAT
DEPRIVATION WEAKENS THE
SYNAPSES, WEAKENS THEM BY
REDUCING OUTPUT OCCURS, WEAKENS
THEM IN A WAY THAT IT'S
SUGGESTIVE OF DECREASE IN
PRESYNAPTIC ABILITY.
AND THAT THIS WEAKENING SEEMS TO
RESEMBLE AND ECLUDE LTD.
IF YOU TRY TO INDUCE LTD, YOU
CAN'T INDUCE NEARLY AS MUCH
AFTER THIS EXPERIENCE SYNAPSE
WEAKENING.
THE SUGGESTION IS THE WEAKENING
OF THE SYNAPSE IN VIVO
REPRESENTS LTD AT THE SYNAPSE
AND PUBLISHED A NUMBER OF YEARS.
WHAT I WANT TO TELL YOU ABOUT IN
DETAIL TODAY NEWER WORK LOOKING
AT HOW THIS LTD AT THE LAYER 4
TO LAYER 2 SYNAPSE MAY WORK AND
THE SURPRISING RESULT IS IT MAY
RESULT IN SIGNALING OF THESE
RECEPTORS.
IT DOESN'T APPEAR TO BE THE
STANDARD FORM.
THERE'S ANOTHER MECHANISM DOING
CORELATION WEAKENING OF SYNAPSES
IN CORTEX TO THE SENSORY
EXPERIENCE.
THESE SYNAPSES, THESE LAYER 4 TO
LAYER 3 SYNAPSES REPRESENT
MULTIFORMS IN VIVO AND DEPENDENT
ON TIMING DEPENDENT PLASTICITY.
IF YOU HAVE AN INPUT AND THAT
FIRES A SPIKE AT A TIME BEFORE
THE POSTSYNAPTIC CELL FIRES ITS
SPIKE, THEN RESULTS.
IF THE ORDER IS RESULTS THEN LTD
IS INDUCED AND AN EXAMPLE OF
THIS DATA FROM THE LAYER 4 TO
LAYER 2 SYNAPSE IN A SLICE.
AN LTD EXPERIMENT PLOTTING THE
MAGNITUDE OF A BASELINE RESPONSE
WHERE WE PAIR PREAND POST
SYNAPTIC SPIKES.
PRELEADING POST PAIRING DRIVES
ROBUST LTD AND EITHER THE
PRESYNAPTIC CELL FIRES ALONE, NO
CELL INDUCED SO A CLASSICAL FORM
OF PLASTICITY.
WHEN WE MAP OUT THE LEARNING
RULE FOR THIS SYNAPSE AND THIS
IS WORK THAT I DID WHILE I WAS
HERE, THEN WE FIND THAT LTP IS
INDUCED WHEN HERE I'M PLOTTING
THE AMOUNT OF HT -- LTD AS
PRETIMING.
A NARROW WINDOW OF POST DELAYS
0-20 MILLISECONDS.
TDT OVER A BROADER WINDOW FOR
DELAYS OUT TO 60 OR 100
MILLI SECONDS AND AT THE TIME
THAT WE DISCOVERED THIS, THIS
WAS KIND OF UNUSUAL BUT WE NOW
KNOW THERE'S A WHOLE FAMILY OF
SPIKE TIME RULES THAT LOOK
EXACTLY LIKE THIS IN A NUMBER OF
SYNAPSES INCLUDING MANY UNDER
PRAMTAL CELLS.
SNOW THIS FORM OF PLASTICITY AS
AN ASIDE EXPLAINS HOW LTD COULD
OCCUR IN VIVO IN RESPONSE TO
DEPRIVATION.
IF IT'S HAPPENING AT THIS
SYNAPSE, THEN DURING NORMAL
WHISKER USE IF WHISKER USE
ACTIVATES LAYER 4 AND DRIVES
SPIKES IN LAYER 2-3 THEN THE
NATURAL ORDER OF EVENTS IS
DRIVES LATERAL 4 SPIKES AND
PRECEDE LAYER 2 SPIKES AND
MAINTAIN SYNAPTIC STRENGTH.
WOUND COULD PREDICT THAT LTP
WOULD OCCUR IF DECOR LATED THE
FIRING OF SYNAPTIC CELLS, THE
WINDOW MEANS THAT UNCORRELATED
FIRING DRIVES NET DEPRESSION IN
THE LEARNING ROLE.
OR IF SOMEHOW THE POST SYNAPTIC
CELLS FIRE, EITHER WAY YOU GET
LTD.
I WON'T SHOW YOU THE BUT WE
MEASURED THE SPIKING OF THE
CELLS IN LAYER 2-3 IN RESPONSE
IT REAL AND SIMULATED WHISKER
DEPRIVATION AND IMMEDIATELY
PRODUCES BOTH OF THESE EFFECTS
AND IN A WAY THAT'S APPROPRIATE
TO DRIVE SPIKETIME LTD.
SO THAT'S THE FORM OF LTD THAT
WE'LL STUDY.
THE CLASSICAL MODEL FROM
HIPPOCAMPUS IS A DETECTOR
DETECTING THE CORELATION BETWEEN
THE CELL FIRING TO THIS HEAVY
CELL FIRING.
STRONG COINCIDENCE BETWEEN THE
TWO GENERATES HIGH CALCIUM WHICH
ACTIVATES A SIGNALING PATHWAY IN
LTP OR LOWER CONCENTRATIONS OF
ACTIVATING ANOTHER PATHWAY WHICH
LEADS TO THE REMOVAL OR OUTWARD
MIGRATION OF RECEPTORS FROM
NAPSES WHICH IS UNDER LYING LTD.
WE ASSUME THIS IS GOING TO BE
THE MECHANISM OF CORTEX WHEN WE
STUDY SPIKE TIMING LTP AND LTD
IN THE CORTEX, WE FOUND THAT IN
FACT THESE FORMS OF PLASTICITY
ARE DEPENDENT ON POST SYNAPTIC
CALCIUM.
BLOCKS LTP AND LTD.
THINGS LOOK GOOD FROM THE
HIPPOCAMPAL MODEL.
HERE WE GOT A SURPRISE.
IF YOU WATCH LTP AND BLOCK POST
SYNAPTIC OCCURRENCE, THAT'S ALL
THAT'S SHOWING HERE.
IF YOU APPLY SO 95% OF
OCCURRENCES ARE BLOCKED, THIS
DOESN'T BLOCK LTD AT ALL.
I WON'T SHOW YOU A SECOND
EXPERIENCE SHOWING IF WE
HYPERPOLERRIZE THE CELLS TO
BLOCK 90% OF NMDA, THAT DOESN'T
BLOCK LTD.
HERE IS A HORPERSUASIVE
EXPERIMENT.
WE WANTED TO COME UP WITH A
SITUATION THAT BLOCKED NMDA
RECEPTORS.
A CHANNEL AN TAGGIST OF THE
RECEPTOR THAT BONDS IN LAYER 4.
WHEN APPLIED FROM THE INSIDE HAS
ACCESS TO THE POOR BINDING SITE.
AND IT TURNS OUT THAT LOADING A
CELL POWERFULFULLY BLOCKS THE
OCCURRENCE.
IT SHOWS THAT AT THE LAYER 4 TO
LAYER 2 SYNAPSE IF ONE HOLDS THE
SHOW YOU SEE A STRONG
OCCURRENCE.
TO POLARIZE THE CELL YOU SEE A
VERY POWERFUL SLOW NMDA
OCCURRENCE.
IF YOU RECORD FROM A CELL THEN
THERE'S NO TRACE OF AN NMDA
OCCURRENCE.
ACROSS CELLS, BLOCKED 99% OF THE
SYNAPTICALLY EVOKED CONDUCTANCE
IN THE CELLS.
AND ACTS INSIDE THE POST
SYNAPTIC CELL AND NOT BY
SPILLING OUT TO NEIGHBORS.
ANOTHER PATCH AND PATCH THE CELL
NEXT TO THE ONE, THAT
NEIGHBORING CELL HAS NORMAL
RATIO.
SO DESPITE THE FACT WE CAN BLOCK
ALL OF POST SYNAPTIC RECEPTORS,
STILL UNBLOCKED AND IF ANYONE
BIGGER.
ALL THESE MANIPULATIONS,
HYPERPOLARIZATION THEY BLOCK LTP
INDICATING INVOLVES NMDA
RECEPTORS.
WHAT COULD UNDER LIE THIS LTD?
WE'VE GONE THROUGH A LOT OF
TESTS AND LET ME SUMMARIZE THE
PLAYERS IMPLICATED HERE.
SO NMDA RECEPTORS ARE NOT THE
SOURCE OF POST SYNAPTIC CALCIUM
BUT CALCIUM CHANNELS CONTRIBUTE
BECAUSE IF YOU BROCK THESE WITH
BLOCKERS YOU CAN BLOCK LTD.
CALCIUM RELEASED FROM STORES
SEEMS TO BE IMPORTANT BECAUSE IF
YOU EMPTY THE STORES OR BLOCK
STORE RELEASE OR IF YOU BLOCK
RECEPTOR RELEASED STORES OF
HEPARIN YOU BLOCK LTD.
RECEPTORS WHICH ARE THE CLASS TO
PRODUCE IPC NECESSARY, ALSO
BLOCKS LTD.
THREE SIGNALING MOTIFS POST
SYNAPTICALLY ARE IMPLICATED.
CALCIUM CHANNELS, RELEASE OF IP3
CALCIUM STORES AND ACTIVATION OF
GROUP ONE AND THROUGH FORMCOLOGY
COULD IMPLICATE THE DOMINANT
GROUND ONE CELLS.
SOMEHOW THESE ARE PRODUCING LTD.
AND IS NOT SURPRISING.
MANY FORMS OF LTD AS WELL.
BUT AT THE TIME WE DID THE
STUDY, THE FIRST INKLINGS IN THE
CORTEX LTD MIGHT BE INVOLVING
RETROGRADES SIGNALING BACK AND
SO WE WERE ABLE TO SHOW AT THIS
SYNAPSE AS WELL BLOCKED BY THE
SPECIFIC BLOCKER OF RECEPTORS.
IT'S BLOCKED BY INHIBITOR OF THE
SYNTHESIS THIS THE DIRECTLY AND
BLOCKED BY A DRUG THAT BLOCKS A
TRANSPORT MECHANISM TO ALLOW TO
LEAVE THE POST SYNAPTIC CELL.
THAT IS IN ORDER TO GET LTD TO
THE SYNAPSE, THE CELL NEEDS TO
GENERATE, IT NEEDS TO RELEASE
THEM AND NEED TO BIND TO
RECEPTORS AT PRESYNAPTIC
TERMINALS.
IF THIS IS TRUE, THAT
CANNABINOID SIGNALING DRIVES IS
HEPRESSION TO DRIVE LTD, ONE
THIS BE ABLE TO BYPASS THE
MACHINERY AND ADD IN THE AGONIST
AGONIST.
>> IF WE RECORD TRANSMISSION AT
THE SYNAPTAND WASH IN ONE OF THE
NATURAL AGONISTS, THEN CAUSES A
DECREASE IN TRANSMISSION LONG
LASTING IN THAT WHEN YOU WASH IT
AND WITH GOOD EFFECT CHASE IT
WITH A BLOCKER AND PRODUCES LONG
DEPRESSION OF THAT SYNAPSE.
SO WECLUDE THIS LTD IS NOT
DEPENDENT ON NMDA RECEPTORS AND
AS I'M SURE MAYBE OR YOU ARE
AWARE, MANY OF THESE
CB DEPENDENT ARE COMMON THROUGH
THE BRAIN.
THEY ARE HARDER TO SEE AND MAY
NOT OCCUR FOR EXCITETORY LTD.
IN OTHER REGIONS OF THE BRAIN
AND PROBABLY A DOZEN SITES NOW,
  CEREBELLUM SIGNALING IS
REQUIRED.
WE DON'T HAVE MUCH DATA ON THIS
BUT WE DO HAVE THE OBSERVATION
IF ONE LOOKS AT ARABIAS
RESPONSES TO TRAINS OF STIMULI
HERE'S A RESPONSE BEFORE AND
AFTER LTD INDUCTION.
THE FIRST RESPONSE IS WEAKENED.
YOU CAN SEE THE SECOND IS
LARGER, AN AVERAGE OVER MANY
CONNECTIONS.
INCREASED SIGNIFICANTLY AND IN A
MANNER CORRELATED WITH
EXPRESSION FOR LTD AT THE
SYNAPSE.
ALL THIS PHARMACOLOGY IMPLICATES
A MECHANISM FOR LTD AND NMDA NOT
ACTING AT ALL AT THE SYNAPSE BUT
INSTEAD SOME GROUP OF PLAYERS
REACTING.
A LOT OF ARROWS HERE AND KIND OF
CONFUSING WHY I DRAW THESER
ARROWS IN.
A LOT OF STUDIES OF RELEASE IN
MANY CELLS NOW AND COMMON
FINDINGS THAT HAVE EMERGED IS
THAT AT THE CAN BE SYNTHESIZED
BY GROUP ONE PATHWAYS, BY
CALCIUM DEPEND PATHWAYS AND BY
SYNERGISM AND JUST IN THE
PLAYERS HERE, TWO KNOWN SITES OF
SYNERGISM OF THE SITES ARE BOTH
MOLECULAR DETECTORS THAT REQUIRE
ACTIVATION AND A SEED AMOUNT OF
CALCIUM TO FULLY BE EFFECTIVE
AND ACTIVATE SYNTHESIS.
WE ARE WORKING OBHOW THESE MIGHT
WORK TO DRIVE LTD.
THE SUGGESTION I WANT TO MAKE IS
THAT THIS IS NOT JUST THE
PATHWAY FOR LTD BUT A NOVEL
  DETECTION MECHANISM AND WHY DO I
SAY THIS IT?
SPIKE TIMING PLASTICITY IS
DRIVEN BY A POST SYNAPTIC SPIKE
HAPPENING AND ONLY WITH THE TIME
INTERVALUES AND THAT MEANS THAT
THIS MECHANISM IS ENGAGED WHEN A
POST SYNAPTIC SPIKE OCCURS FIRST
AND ACTIVE INVITES CHANNELS AND
YOU CAN MEASURE CALCIUM COMING
INTO SPINES IN RESPONSE TO THAT.
AND THEN SOME VARIABLE TIME
LATER THE TERMINAL RELEASES FROM
THE SPIKE AND HYPOTHESIZE THIS
SIGNALING PATHWAY AND THE
SYNERGISM BETWEEN THEM ONLY
BETWEEN THESE TIME INTERVALUE
GENERATES LTD.
SO HOW DO WE KNOW THIS IS A
MECHANISM FOR DETECTING
COINCIDENCE OR CORELATION FOR
THIS?
WE CAN TELL THAT FROM THE STUDY.
THE SPIKETIME LEARNING RULE
AGAIN FOR THESE SYNAPSES AND
THIS PLOT I SHOWED YOU BEFORE
AND NEWER DATA, THE AMOUNT OF
LTD OR LTP AND I APOLOGIZE, THIS
IS INCREASING DELAY OF THE POST
SPIKE TIMING AND POST LEADING
PRESPIKE TIMING.
PRELEADING DRIVES LTD AND POST
LEADING PREDRIVES LTP.
WE CAN REPEAT THIS EXPERIMENT
NOW THAT WE KNOW IT REQUIRES
RECEPTORS.
WE CAN A APPLY THE ANTAGONIST 51
TO BLOCK THE SIGNALING AND
REMEASURE SPIKE TIMING
PLASTICITY AND THAT'S WHAT'S
SHOWN IN THE OPEN CIRCLES AND
UNDER THAT CONDITION PRESUMABLY
THE POST SYNAPTIC RECEPTOR
THAT'S FUNCTIONING.
AS WE VARY SPIKE TIMING, THE
ONLY RESULT IS LTD.
AND THAT MEANS THAT THE NMDA
RECEPTORS INVOLVED IN A
MECHANISM DETECTING RAPID
COINCIDENCE ON THE ORDER OF 10,
20, 30 MILLISECONDS AND
GENERATING LTP.
WE CAN BLOCK THAT MECHANISM BY
PUTTING 1 INSIDE THE CELL AND
THIS LEAVES THE CD1 MECHANISM IN
TACT AND MEASURE THE RESULT OF
THAT IN ISOLATION AND NOW AS WE
VARY SPIKE TIME RESULTS IN A
BROAD WINDOW THAT'S INDUCED IN
RESPONSE IT ANY TIMED INTERVALUE
PRELEADING POST AND THAT IS THIS
CB MECHANISM ON THE 150
MILLISECOND TIME SCALE PRODUCING
LTD AND WHAT THIS SEEMS TO BE IS
THOSE TWO RULES WORKING
TOGETHER.
TWO CONSEQUENCES WORKING.
SO THAT'S A GOOD QUESTION.
IF YOU SUM THIS PLUS THIS, A
GOOD APPROXIMATATION OF THIS
CURVE EXCEPT FOR THIS ONE POINT
HERE WHERE IT'S LINEAR --
NONLINEAR WITH LTP WINNING.
A NAIVE MOLDS IS THAT CALCIUM
FROM THE TWO SOURCES MAY BE
SUMMING IN SOME SENSE AND THAT
IF THERE'S HIGH CALCIUM FROM ONE
SOURCE, IT MAY WIN.
OKAY.
SO IF IT'S TRUE THAT LTD AT THIS
SYNAPSE REQUIRES CB1 RECEPTORS,
THEN WHISKER DEPRIVATION WEAKENS
THE SYNAPSE IN VIVO.
THAT SHOULD BE A CB DEPENDENT
PHENOMENON SO WE'VE BEGUN TO
TEST THE ROLE OF CB1 RECEPTORS
IN THESE SYNAPSES AND I WANT TO
SHOW YOU ONE SLIDE.
IT OCCURS TO ME AS I DID THIS TO
SHORTEN THE POCKETS I TOOK OUT A
SLIDE EARLIER.
LET ME SHOW YOU WHAT YOU MISSED.
WE CAN TRIM WHISKERS OFF THE
ANIMALS, FIND THE COLUMNS IN THE
CORTEX THAT CORRESPOND AND
ASSESS THE STRENGTHS OF THE
LAYER 4 TO LAYER 3 SYNAPSE IN
THE COLUMN.
WE CAN ASSESS THEM IN MANY WAYS.
ALL OF THEM SHOW PRESYNAPTIC
WEAKENING.
ONE WAY EASY TO DO IS MEASURE
PERIPULSE RATIO.
THE SYNAPSES ARE SLIGHTLY
DEPRESSING.
SHOW MODEST DEPRESSION THAT'S
WHAT'S SHOWN HERE.
IF YOU TAKE S1 SLICE FROM AN
ANIMAL WITH ALL WHISKERS IN TACT
AND A B ROW COLUMN OR D ROW
COLUMN THERE'S A PERIPULSE
DEPRESSION PLOTTED HERE.
IF YOU TAKE A WHISKER AND TRIM
IT FOR A FEW DAYS BEFORE YOU
TAKE THE MEASUREMENT AND HERE
WE'VE TRIMMED THE D ROW JUST IN
COLUMNS REPRESENTING THE
WHISKERS YOU SEE A SHIFT AND THE
SLIDE I TOOK OUT AND DIDN'T SHOW
YOU IS IF WE SHOW YOU THIS, A
LARGE INCREASE IN FACILITATION
WHICH IS ONE OF THE WAYS WE KNOW
THE SYNAPSE IS WEAKENING.
EVEN WITH A SHORT PERIOD OF A
FEW DAYS OF WHISKER DEPRIVATION,
YOU CAN SEE THE SHIFT FROM
PERIPULSE DEPRESSION TO
FACILITATION WHICH WE THINK
REPRESENTS PRESYNAPTIC.
IF YOU DO THE SAME EXPERIMENT
BUT NOW DURING THE PROCESS OF
WHISKER DEPRIVATION IF EVERY DAY
OF WHISKER DEPRIVATION WE INJECT
AN ANTAGONIST, NOW WE ARE
INJECTING IT SYSTEMICALLY.
IT'S KNOWN TO CROSS THE
BLOOD-BRAIN BARRIER AND BIND AND
EACH INJECTION WILL BLOCK
RECEPTORS FOR A PORTION OF THE
DAY AND COME IN THE NEXT DAY AND
MAKE ANOTHER INJECTION.
THOSE INJECTIONS DAILY DURING
DEPRIVATION PREVENT SYNAPSE
WEAKENING BY THIS ONE MEASURE.
IN CONTRAST, IF WE GIVE VEHICLE
INJECTIONS THERE'S NO EFFECTIVE
AND WEAKENS OF THE SYNAPSES.
THE FIRST STEP OF AN ONGOING
PROJECT.
INDICATING ALSO THAT CB1
RECEPTORS ARE REQUIRED TO GET
WEAKENS OF THE SYNAPSES
CONSISTENT WITH A CB1 DEPENDENT
MECHANISM IN VIVO.
IF THAT'S TRUE, I ENCOURAGE YOU
TO THINK WHEN YOU THINK ABOUT
PARTICLE PLASTICITY AND SYNAPSES
RESPONDING BY CHANGING THEIR
STRENGTH, DON'T JUST THINK ABOUT
NMDA RECEPTORS, ANOTHER
DETECTOR, THE CB1 RECEPTOR
MECHANISM.
CLEARLY INFLUENCING IN THE
CORTEX IN RESPONSE TO
EXPERIENCE.
SO I WANT TO TELL YOU SOMETHING
NUNOW ABOUT NMDA RECEPTORS, ARE
THEY RELEVANT?
WHAT ARE THEY DOING THERE.
THEY ARE POST SYNAPTICALLY
PRESENT.
HERE I WANTED TO TOUCH ON THE
ISSUE WHETHER THEY COULD BE
FUNCTIONING PRESYNAPTICALLY.
IT'S OF COURSE KNOWN FOR A
DECADE THAT RECEPTORS ARE HIGHLY
EXPRESSED AND ACTIVATION HAS
STRONG EFFECT ON TRANSMISSION
AND TENDS TO DECREASE.
AND MORE RECENTLY SUGGESTED THAT
RECEPTORS MAY BE PRESENT AND
THESE MAY HAVE EFFECTS AND THE
EFFECT HAS BEEN PROPOSED IS THAT
THEY DO THE OPPOSITE TO ENHANCE
TRANSMISSION.
THIS HAS BEEN SHOWN NICELY IN A
COUPLE OF PAPERS PRESYNAPTICALLY
AND A LARGE LITERATURE OUT THERE
SUGGESTING THAT NMDA RECEPTORS
PRESYNAPTIC AS WELL AND PERFORM
A SIMILAR FUNCTION BUT IT'S BEEN
DIFFICULT TO GET HIGH QUALITY
PHYSIOLOGY THAT YOU NEED TO KNOW
HOW THAT WORKS AND WHETHER
THAT'S WORKING AND HOW PREVALENT
IT MAY BE.
NMDA RECEPTORS ARE EXPRESSED BUT
FUNCTION HAS BEEN HARDER TO NAIL
DOWN.
SO WE WANTED TO LOOK AT THIS
UNTIL WE GET EVIDENCE.
SO THE EXPERIMENT THAT FOLLOWS
SIMULATE PRAMMAL CELLS LOOKING
AT EXCITETORY TRANSMISSION.
WE ARE HOLDING THE CELLS
HYPERPOLARIZED.
AND TO MAKE SURE NO POST
SYNAPTIC RECEPTORS CONTRIBUTING
TO THE EFFECTS.
ALWAYS INCLUDE IN THE CELL TO
BLOCK THEM.
WE WANT TO STUDY EXCITATION IN
ISOLATION AND THESE EXPERIMENTS
IN THE NEXT SLIDES DONE AT ROOM
TEMPERATURE AND IN A MODEST
AMOUNT OF TBOA.
WE DISCOVERED THAT AT ROOM
TEMPERATURE ONE NEEDS EXTRA TO
GET THIS EFFECT.
IN VIVO THIS IS NOT NEEDED.
SO WE ARE RECORDED A SYNAPTIC
RESPONSE.
HERE'S THE EXPERIMENT.
WE RECORD THAT RESPONSE FOR AN
HOUR OR SO EVERY TEN SECONDS
MEASURING THE SIZE OF THE EPSC
AND THE SIMPLE EXPERIMENT OF
WASHING ON.
NO TRANSMISSION BUT DESPITE THAT
REDUCES THE SIZE OF THE RECEPTOR
RESPONSE AND HERE I THINK THIS
IS FOR SOMETHING LIKE 6 SHOWING
THAT EFFECT.
A 30% BLOCK.
NOW THIS SUGGESTS THAT BECAUSE
THE NMDA RECEPTORS HAVE BEEN
BLOCKED, SOME OTHER RECEPTOR AND
HYPOTHESIZE IT'S PRESYNAPTIC AND
NORMALLY SUPPORTING TRANSMISSION
BUT THIS BECOMES BLOCKED AND
TRANSMISSION GOES DOWN AND
THAT'S GOING TO BE THE
HYPOTHESIS.
IF THIS IS TRUE, WE SHOULD BE
ABLE TO INCREASE THE
CONCENTRATION THE ACTIVATION OF
THE PRESYNAPTIC RECEPTORS AND
DRIVE INCREASED TRANSMISSIONS SO
THIS IS DONE WITH NO TBOA SO NO
GLUTAMATE TRANSMISSION AND
MEASURE THE POST SYNAPTIC CELL
SO MINIATURES AND MEASURE THEM
IN BASELINE AND ADD NMDA AND
FREQUENCY GOES UP.
AN EFFECT OF 10%.
HERE THIS IS A ACCUMULATIVE
FREQUENCY WHERE FREQUENCY GOES
UP.
THERE'S NO CHANGE WHATSOEVER IN
THE POST SYNAPTIC RESPONSE.
ACTIVATING RECEPTORS CAN
INCREASE MINI FREQUENCY.
NOW HERE WE ARE MEASURING THIS
BUT REALLY STIMULATING LAYER 4.
THERE ARE OTHER SYNAPTIC
RECEPTIONS AS WELL.
IS THIS REALLY AN EFFECT AND SO
A STUDENT IN MY LAB DID A BRAVE
EXPERIMENT OF LOOKING FOR LAYER
4 TO LAYER 2 CELL PAIRS.
WHEN HE FOUND THEM HE WOULD
APPLY ATP.
A PAIR OF ETSPs AND APPLY ATP,
THE SAME EFFECT.
A LITTLE BIT MESSY BECAUSE THE
CELL NUMBERS ARE LOW HERE.
THE SAME MAGNITUDE AS BEFORE.
THE SYNAPSE EXHIBITS THIS
REGULATION BY NMDA RECEPTORS.
I'M NOT GOING TO SHOW YOU THE
DATA BUT USING AN ANTAGONIST WE
WERE ABLE TO SHOW TWO THINGS.
IF THESE RECEPTORS ARE TWO A
CONTAINING RECEPTORS BUT THESE
ARE SENSITIVE.
EXACTLY WHAT ATP DOES.
WHERE ARE THESE EXPRESSED IN THE
CORTEXT?
THINK OF THESE AS UNIVERSAL
EXPRESSED IN THESE CORTICAL
SLICES OR IS IT SELECTIVE.
WE STARTED OFF IN AN EXPERIMENT
WHERE WE COMPARE INPUTS ON THE
PATHWAY TO A RECORDED CELL WITH
INPUTS ON A LAYER 2-3 HORIZONTAL
PATHWAY THAT CONVERGED ON THE
SAME CELL AND BY RECORDING THE
RESPONSES, OBSERVED IS THAT ATP
ON 2-4 INPUT SO A SELECTIVE
FUNCTION OF NMDA RECEPTORS.
TWO DIFFERENT INPUTS, ONLY ONE
OF THEM IS SUBJECT TO THE
REGULATION BY RECEPTORS.
HOW ABOUT TARGET SPECIFICITY.
THIS REFERS TO THE PHENOMENON
WHEN YOU HAVE A BRANCH THE SAME
AXON TERMINALS HAVE THE SAME
PROPERTIES SO.
WE TOOK ADVANTAGE OF THE FACT
THAT LAYER 4 CELLS SYNAPSE ON
LAYER 2 TARGETS BUT MAKE MANY
SYNAPSES ON NEIGHBORING CELLS.
SO RECORDED LAYER 4 PAIRS TO
ASSAY THE OTHER BRANCH OF THAT
AXON AND FOUND THAT ATV NO
TARGET WHATSOEVER.
SNOW THESE MUST BE TRAFFICKING
NMDA RECEPTORS TO EFFECT 4-2
SYNAPSES BUT NOT 4-4.
THIS IS A BUSY SLIDE.
I APOLOGIZE.
THE POINT IS THIS WHOLE THING
I'VE BEEN TELLING YOU THE ART
FACT BEING AT ROOM TEMPERATURE
COULD IT BE CONSTIPATION OR
SOMETHING ELSE.
WE REPEATED MANY OF THE SAME
EXPERIMENTS AT 32 DEGREES
WITHOUT TBOA SO NORMAL AMIANT
CONCENTRATIONS IN THE SLICE.
BASICALLY NOW WE DISCOVERED THAT
WE DON'T NEED TO INCREASE
GLUTAMATE CONSECRATIONS TO MAKE
THIS HAPPEN.
NOW RECORDING AT 4-2, 3 SYNAPSES
YOU GET THE SUPPRESSION HERE.
THIS INCREASES PERIPULSE RASCH.
I NESTED TO MENTION THIS BEFORE,
ALL THE DEPRESSIONS, CONSISTENT
WITH PRESYNAPTIC EXPRESSION.
GLUTAMATE IS ABLE TO ACTIVATE
RECEPTORS NORMALLY.
NOT FULLY SATURATED.
WHEN WE APPLY ANOTHER AGONIST WE
GET AN INCREASE AS WELL AND
TARGET SELECTED BECAUSE IN LAYER
4 STILL NO EFFECT.
AND SO THE BOTTOM LINE FROM ALL
THIS IS THAT AT THESE LAYER 4 TO
LAYER 2 SYNAPSES, PRESYNAPTIC
EXIT.
THEY ARE ACTIVATED BY
CONCENTRATIONS AT TEMPERATURES
AT LEAST IN SLICES AND ACT TO
REGULATE FUNCTION IN A HIGHLY
SYNAPSE MANNER AND MY GUESS
WOULD BE IF THE LAYER 4 CELL
BOTHERS ENOUGH TO EXPRESS THESE
RECEPTORS IN A TARGET SELECTIVE
WAY IT MAY BE DOING SOMETHING
IMPORTANT FOR FUNCTION OF THESE
SYNAPSES IN VIVO BUT THAT
REMAINS TO BE DETERMINED WHAT
THAT MAY BE.
WHAT I WANT TO DO IN THE LAST
TEN MINUTE IS TELL YOU ABOUT
SOMETHING DIFFERENT IN MY LAB
AND THIS IS SOMETHING THAT HALF
OF MY LAB IS WORKING NOW.
IT HAS NOTHING TO DO WITH
CORTICAL PLASTICITY BUT HAS TO
DO WITH WATCHING RATS MOVE THEIR
WHISKERS FOR SO MANY YEARS I
BECAME FASCINATED WITH THE
TACTILE SYSTEM.
THIS IS OFTEN A SYSTEM THAT GOES
UNDER APPRECIATED.
YOU CAN DETECT AN AMAZING NUMBER
OF FEATURES OF OBJECTS.
DETECT LOCATION, THE WEIGHT OF
AN OCJECT, SHAPE, TEXTURE,
PROPERTIES NOT ONLY BYPASSIVELY
LISTENING TO WHAT THE SIGNALS
ARE FROM YOUR SKIN BUT BY MOVING
THOSE RECEPTORS OUT SO ANY
PROCESSING TASK THAT'S DONE IN
THE TACTILE SYSTEM HAS TO
INVOLVE SENSORY AND MOTOR
ASPECTS.
A REAL SENSORIMOTOR EXPLORATION
PROBLEM.
WE'RE GOOD AT MANY THINGS.
THE ONE I WANT TO FOCUS ON IS
HOW TACTSILE DETECTORS ARE USED
FOR FORM AND TEXTTURE, THINGS
LIKE SAND PAPERS.
AND FORM HAS BEEN STUDIED IN
HUMANS BUT TEXTURE IS HARDER TO
GET AT.
IF YOU MOVE YOUR FINGER ACROSS A
TEXTURE, HARD TO SEE HOW THAT
TEXTURE IS ACTIVATING YOUR
FINGERPRINT RECEPTORS AND HARD
TO STUDY HOW THE SYSTEM WORKS TO
FIGURE OUT WHAT TEXTURES ARE
THERE.
RATS CAN DO THIS WELL.
HERE ARE THE RATS ROWS OF
WHISKERS.
THE WHISKERS ARE MOVABLE.
THEY PIVOT BACK AND FORTH.
I WOULD SHOW YOU HERE A VIDEO OF
RATS MOVING BUT IT'S BROKEN BUT
RATS ARE GOING LIKE THIS AT 10
HERTZ BACK AND FORTH.
TRUST ME.
HOW CAN THEY DISTINGUISH
TEXTURE?
RATS ARE AS GOOD AS HUMAN
FINGERTIPS ARE IN THE DARK USING
WHISKERS.
TWO MODELS OVER THE YEARS.
AS A WHISKER SKIDS ALONG ACROSS
THE SAND PAPER, THE TIP OF THE
WHISKER MOVES ACROSS EACH OF THE
MICROFEATURES OF THE SAND PAPER.
EVERY TIME IT SLIDES THERE'S
CONTACT EVENT AND SENDS SPIKES
UP.
AS IT GOES POP, POP OVER
ELEMENTS OF TEXTURE SPIKES COME
UP.
SO IT TURNS OUT WHILE THE
AFFERENTS CAN ENJED WELL
TEXTURES ARE SO FINE AND
WHISKERS MOVE SO FIND YOU HAVE
TO PREDICT RATES IN THE
KILLOHERTZ RANGE.
THIS FEATURE BY FEATURE
ENCOATING CANNOT WORK.
CHRIS WORD AT M.I.T. AND
CAL-TECH AT THE SAME TIME CAME
UP WITH AN ALTERNATIVE
HYPOTHESIS.
THEY NOTICED IF YOU LOOKED AT
RATS' WHISKERS, THEY ARE VARYING
LENGTH.
SHORTER IN THE FRONT AND LONGER
IN THE BACK AND RESIDENT OBJECTS
LIKE ALL BEINGS, THE LONGER ONES
LIKE TO VIBRATE AT LOWER
FREQUENCIES AND THE SHORT AT
HIGH FREQUENCIES.
THEY MEASURED THE FREQUENCY ON
THE FACE AND A BEAUTIFUL MAP
FROM LOW RESIDENTS FREQUENCY THE
TO THE LONG WHISKERS AND HIGH TO
THE SHORT WHISKERS.
IF THE ANIMAL CAN MOVE ALL
WIN WHISKERS ACROSS THE PARALLEL
OF THE SURFACE, ONLY THOSE
WHISKERS FOR WHOM THE TIP
VIBRATION FREQUENCY MATCHES,
ONLY THOSE WILL TRANSMIT
VIBRATIONS BACK TO THE FOLICAL
AND GED ENCODED AND THIS RESULTS
IN A PLACE CODE FOR TEXTURES ON
THE FACE.
THIS IS A COCHLEA USED TO DETECT
TEXTURE.
I SAID MY GOD, THIS MUST BE
TRUE.
NO ONE HAD DONE EXPERIMENTS TO
TEST THIS IN ANIMALS, A FEW IN
AANESTHETIZED ANIMALS BUT WHEN
ANIMALS ARE OUT THERE MOVING THE
WHISKERS, DO AT THE MOVE THEM IN
A WAY TO EXTRACT INFORMATION AND
ENCODED IN THE CNS.
THAT'S WHAT WE SET OUT TO TEST.
THESE EXPERIMENTS WERE DONE BY A
STUDENT IN MY LAB WHO GOT HIS
PH.D. A FEW MONTHS AGO.
JASON TRAINED RATS TO COME INTO
A REGION OF BEHAVIORAL CHAMBER,
STICK THEIR NOSE IN A LOCATION
AND WHISK BACK OPINION FORTH.
AND THESE ARE DIFFERENT SAND
PAPERS.
SOME ARE TRAINED TO
DISCRIMINATE, OTHERS ARE BLINDLY
SCANNING.
JASON CAST A LASER BEAM OVER THE
WHISKERS TO CAST A SHADOW ON TO
A FAST LINEAR ARRAY, AN IMAGING
ARRAY WHICH LETS US RECORD THE
WHISKERS TO KNOW WHAT FREQUENCY
THEY ARE RESONATING AT A.
WE TRIMMED THE ANIMALS DOWN TO
FOUR WHISKERS IN A ROW.
THE RAT IS MOVING ALL BACK AND
FORTH AND YOU SEE THE TRACKING
OF EACH OF THOSE WHISKERS
TOGETHER AT 0 HERTZ WHISKING
FREQUENCY.
AN EXAMPLE.
COMES IN FROM THE TOP, THE NOSE
POKE HERE.
THE WHISKERS ARE OVER THAT SLOT
IN THE FLOOR, THAT'S A TEXTURE.
DURING THAT WHISKER WE GATHER
THE DATA RIGHT THERE AND GOES TO
DRINK.
THESE ARE RIDGES, NOT SAND
PAPERS.
WHAT KIND OF DATA?
FIRST WE WANTED TO ASK IS IT
TRUE THE WHISKERS FORM A MAP IN
THE WAKE BEHAVING FREQUENCY?
WE TOOK ADVANTAGE OF THE FACT
WHEN ANIMALS MOVE THEIR WHISKERS
OR TRY TO HOLD THEM STILL,
THERE'S HIGH FREQUENCY ACTIVITY
GOING ON, THEY ARE NEVER
PERFECTLY STILL, ALWAYS JIGGLING
BACK AND FORTH AND EASY TO
MEASURE BY MEASURING THE SLOW
COMPONENTS.
HERE ARE THE JIGGLES OF THE
WHISKERS.
AND JUST BY ANYLIZING THE
VIBRATION SPECTRUM WE CAN
MEASURE.
HERE'S A D3 WHISKER AND DOESN'T
FOLLOW OFF BUT NUMBER HUMPS.
A HUMP THERE AND THESE TURN OUT
TO CORRESPOND TO THE FREQUENCIES
OF THE WHISKERS.
WE CAN MEASURE THE RESIDENCE
FREQUENCIES BY GIVING AN IMPULSE
LIKE A TWANG ON A TUNING FORK
AND HOW THEY RELAX BACK DOWN AND
HOW WE KNOW THAT THIS HUMP IS
THE REPRESENT FREQUENCY OF THAT
WHISKER, THIS IS THE HARE MONIC
AND A DIFFERENT RISKER.
A SHORTER WHISKER -- LONGER AT
LOWER FREQUENCIES AND ACROSS
MANY WHISKERS, A BEAUTIFUL
CORRESPONDENCE BETWEEN THE
PEAKS.
THIS IS WHISKING IN AIR NOW AND
THE RESIDENT FREQUENCY AND THIS
MEANS WHEN THE RATS ARE JUST
SITTING THERE AND THE WHISKERS
ARE MOVING A LITTLE BIT, THEY
HAVE A TENDENCY TO RESONATE AND
WE CAN COMPARE THIS NOW AND IT
TURNS OUT TO BE TRUE.
THE LONGEST WHISKERS HAVE THE
LOWEST RESIDENT FREQUENCIES AND
THE SHORTEST HAVE THE HIGHEST
FREQUENCIES.
IN THE WAKE ANIMALS, THEY MAP
THE FACE.
NOW DOES THAT ENCODE TEXTURE?
A WHISKER TRACE MOVING BACK AND
FORWARD ACROSS THE SAND PAPER
AND YOU CAN SEE THE WHISKER
DOESN'T MOVE SMOOTHLY BUT JERKS
AND STOPS AND JERKS AND STOPS AS
THE ANIMAL TRAYS TO FORCE ACROSS
THE SURFACE.
AND DURING THESE EPICS OF MOTION
YOU SEE WHAT LOOKS LIKE RINGING
IN THE WHISKERS.
WE CAN DETECT THAT BY MAKING
ACCELERATION TRACES AND THESE
OSCILLATIONS AND ACCELERATIONS
TURN OUT TO CORRESPOND TO
RESIDENTS POWER AT CERTAIN
FREQUENCIES WHICH ARE THE
FREQUENCIES OF THE WHISKERS.
EVEN AS THE ANIMAL PAL PATES ON
A SAND PAPER, WHISKER RESNANCE.
THE LONG WHISKERS SHOW EXTRA
POWER AND THE SHORTER WHISKERS
SHOW POWER AT HIGHER
FREQUENCIES.
HOWEVER, IN ORDER FOR THE
RESIDENTS MODEL TO BE TRUE,
THINK ABOUT THE COCHLEA, IF ALL
WERE TO SAMPLE A SURFACE, IT
SHOULD BE ONLY THOSE WHISKERS
WHOSE FREQUENCY MATCHES BY
GETTING MAXIMUMLY ACTIVATED.
WHEN YOU BROADCAST A SOUND IT'S
ONLY THE COCHLEA REGION THAT
CORRESPONDS TO THE FREQUENCY
ACTIVATED.
THAT TURNS OUT NOT TO HAPPEN
HERE AT ALL WE WERE SURPRISED TO
FIND.
IF WE MEASURE THE POWER AT THE
REPS FREQUENCY FOR A NUMBER OF
REGIONS FROM ROUGHEST SAND
PAPERS TO SMOOTH, THERE IS NO
DIFFERENCE IN THE POWER AT THE
RESIDENT FREQUENCY ACROSS
DIFFERENT SAND PAPERS.
THE WHISKERS ARE NOT TEXTURE
TUNED OR SELECTIVE AT ALL.
HOW CAN THIS BE RESONATING ON
THE SURFACES AND THE ANSWER
TURNS OUT TO BE BECAUSE THEY ARE
RESONATING THEY ARE RESONATING
FOR A DIFFERENT REGION.
AS THEY MOVE ACROSS THE SURFACE,
THESE LITTLE JUMPS THAT I SHOWED
YOU BEFORE.
A JUMP AND STOPS AND RINGS,
STICKS AND RINGS AND A SLIP AND
A STICK AND A RING AND A SLIP
FOLLOWED BY A STICK AND RING
EVENT.
HERE'S ANOTHER EXAMPLE OF A
CLEAR SLIP AND THEN A RING
EVENT.
AND WHEN YOU LOOK AT THE
FREQUENCY CONTENT OF THE RINGS,
THE RINGS PRODUCE THE MOTION OF
THE WHISKERS.
A LINE, A POSITION TRACE OF THE
WHISKER ON A SLIP EVENT DOWN THE
MIDDLE.
THE ACCELERATION VERSION SO THE
WHISKERS MOVING ALONG, SLIPS
SUDDENLY AND CAUSED THAT
DECAYING OSCILLATION.
A MEASURE OF THE SAME TIME, IT
SLIPS SUDDENLY AND IF YOU LOOK
AT THE POWER SPECTRUM USE THESE
ARE WHAT RING AT THE RESIDENT
FREQUENCIES OF THE WHISKERS.
WE CAN ACCOUNT FOR00% OF THE
RINGING POWER OF THESE WHISKERS
BY WHAT THEY DO AFTER A SLIP.
FOUR SLIPS NOT RINGING LIKE
THIS.
THIS MEANS THAT THE WHISKERS ARE
MOVING LIKE TUNING FORKS ACROSS
THE SURFACE.
TRYING TO MOVE ACROSS THE
SURFACE.
MICROFEATURES THERE, POP, POP.
AS THE ANIMAL TRIES TO MOVE
FORWARD, INTERACTION BETWEEN THE
SURFACE AND THE ANIMAL CAN APPLY
ENOUGH FORCE IT MAKE THE
WHISKERS SLIPPED AND WHEN IT
SLIPS IT RINGS AT ITS OWN
FREQUENCY.
IF YOU TAKE A TUNING FORK ACROSS
THESE SAND PAPERS THEY WILL RING
AT THE SAME FREQUENCY OF THE
TUNING FORK NOT THE SAND PAPER.
SO SEEMED LIKE A GREAT IDEA BUT
WHEN YOU MEASURE HOW THEY
EXPOSURE SURFACES, IT DOESN'T
HOLUP.
WHAT ELSE COULD BE HAPPENING?
WE THOUGHT MAYBE THESE STICKS
AND SLIPS COULD DETECT.
WHISKER POSITION CASES IN THREE
CASES FOR ONE WHISKER AND ONE
WHISKING IN AIR AND ON A SMOOTH
SAND PAPER IN SEQUENCE.
AND HERE'S THE ACCELERATION
TRACE FOR THE SAME PLOTS.
I'VE BOXED, TRYING TO BOX THE
SLIPS OF THE WHISKERS.
YOU CAN SEE IN AIR NO FAST
EVENTS BECAUSE NOTHING TO SLIP
AGAINST.
ON SMOOTH SAND PAPERS ONLY
OCCASIONAL LARGE SLIPS AND ON
ROUGH SAND PAPERS, A BUNCH OF
LARGE SLIPS AND A BUNCH OF HIGH
ACCELERATION EVENTS.
AND IF YOU LOOK QUANTITATIVELY
NOW ACROSS SURFACES AND PLOT
WHAT IS THE LIKELIHOOD OF
OBSERVING SLIPS OF DIFFERENT
SIZES FROM SMALL TO VERY LARGE
ON DIFFERENT SAND PAPERS, WHAT
YOU FIND IS THAT RELATIVELY
LARGE SLIPS OCCUR MUCH MORE
OFTEN ON LARGE SAND PAPERS.
A FACTOR OF 0 OR 100 ON SMOOTH.
AND, IN FACT WE COULD SHOW THAT
ONE OF THE BEST MEASURES WE
COULD COME UP WITH TO
DISTINGUISH TEXTURES BY
LISTENING TO THE SLIPS ON THE
SAND PAPER IS THE RATIO OF LARGE
SLIPS TO LARGE SLIPS.
FAST TO SLOW SLIPS.
AND THAT THIS RATIO TRACKS THE
ROUGHNESS OF THE TEXTURE VERY
WELL.
ANIMALS ARE PAYING ATTENTION TO
THE SLIPS AND STICKS ALONG THE
SURFACE.
AND THAT'S WHAT'S GIVING THEM
TEXTURE INFORMATION.
WE STARTED TO TEXT THIS BY
RECORDING SPIKES IN NEURONS TO
ASK IF ALTHOUGH ENCODE THE
EVENTS AND TURNS OUT THEY DO.
ANIMALS DOING THE SAME TASK BUT
IMPLANTED.
WE CAN GET UNIT ISOLATION.
I CAN GO THROUGH THIS WITH
  ANYBODY AFTERWARDS.
A PLOT FROM AN EXAMPLE NEURON
SHOWING SPIKING ON 80 DIFFERENT
TRIALS OF MOVEMENT OVER SAND
PAPER AND ALL ALIGNED ON THE
FIRST SLIP OF THE WHISKER ON A
SURFACE.
THE WHISKER WILL COME, IT WILL
SLIP ON IT ONCE, SLIP A SECOND
OR THIRD TIME AND THE ANIMAL
WILL GO TO DRINK ITS WATER.
WHAT YOU CAN SEE IS THAT ALIGNED
TO THE FIRST SLIP EVENT ARE
SPIKES AND INCREDIBLY SPARSE.
ONLY A SPIKE EVERY THIRD,
FOURTH, FIFTH TRIAL AND
PRECISELY ALIGNED IN TIME.
OVER A NUMBER OF UNITS, WE KNOW
THAT THE PRECISION OF EVOKING
THESE SPIKES BY SLIPS IS ON THE
PRECISION OF 3-4 MILLI SECONDS
OF STANDARD DEVIATION OF TIMES.
VERY SMALL INCREASE IN FIRING
LIGHT BUT PRECISE ALIGNMENT OF
SPIKES.
IF YOU LOOK AT THE TRIALS YOU
CAN SEE THE RESPONSE OF NOT JUST
THE FIRST BUT THE SECOND SLIP
AND THIRD AND SOMETIMES EVEN A
FOURTH SLIP.
SO IN ORDER TO KNOW WHAT THE
TEXTTURE IS, THE ANIMAL NEEDS TO
KNOW WHEN SLIPS OCCUR.
IS THAT ENCODED IN THE CORTEX?
HERE'S ONE NEURONAL IN RESPONSE
TO LARGER SLIP EVENTS, LARGER
AND LARGER AND THE LARGEST AND
YOU CAN SEE AT THE PEAK THIS
NEURON IS DRIVEN BETTER BY THE
LARGEST OR FASTEST SLIP EVENT
AND HERE EXAMPLE NEURONS THIS IS
TRUE FOR EVERY CELL WE LOOKED
AT, NEURONS ENCODE WITH
DIFFERENT THRESHHOLDS AND
AMPLITUDES OF SPIKES.
SO THIS SUGGESTS, THIS
DEMONSTRATES AND NOT GOING TO
SHOW YOU THE POPULATION DATA.
I WILL TELL YOU WE'VE ANALYZED
40 UNITS SO FAR AND HALF SHOW
EFFECTS LIKE THIS.
KEEPING TRACK OF WHEN THE
WHISKERS ARE SLIPPING ALONG
SURFACES AND KEEPING TRACK OF
THE SIZE OF THE SLIP EVENTS AND
THAT SUGGESTS AS THE WHISKERS
MOVE ALONG SURFACES AND INTERACT
WITH THEM THAT IT'S BY KEEPING
TRACK OF THESE THAT THE ANIMAL
MAY BE INFERRING TEXTURE
INFORMATION FROM THE SAND
PAPERS.
I WOULD PROPOSE THAT THE STICK
EVENTS MAY BE AN ELEMENTARY
FEATURE OF TACT I'LL INFORMATION
EVEN WHEN YOUR FINGERPRINT MOVES
ACROSS.
INCIDENTALLY, THE WAY THAT
SENSORY CORTEXT ENCODES THE
EVENTS HAS IMPORTANT
IMPLICATIONS FOR THINKING ABOUT
SPIKE TRAINS OF NEURONS GOING
BACK TO THE FIRST A HALF OF THE
TALK.
SPIKING IN S IS SPARSE.
THESE CELLS WILL FIRE IN
RESPONSE TO THE OPTIMAL STIMULUS
ON AVERAGE OF HALF A SPIKE AND
IN VIVO WHEN ONE MEASURES AN
UNBIASED WAY TO INCLUDE NEURONS
THAT ARE NOT FIRING, THE
ESTIMATES OR SPIKE RATES ARE
DRAMATICALLY LOWER THAN THAT.
ONE SPIKE FOR EVERY TEN APPLIED.
SO INSTEAD OF PRODUCING RATES,
THEY ARE PRODUCING SINGLE SPIKES
OR FRACTIONS OF SPIKE RESPONSES
ALIGNED IN TIME SYNCHRONIZED
LIKE I SHOWED YOU FOR THE
NEURONS.
AND IF THAT'S THE CASE, THAT
SUGGESTS THAT MECHANISMS FOR
INFORMATION PROCESSING AND
PLASTICITY MAY BE TOO STRAINED
TO WORK ON FIRING PROBABILITIES
AND SPIKE TIMING ESSENTIALLY AND
NOT BY FIRING RATES AND MAY BE
WHY WE FIND FORMS OF PLASTICITY
POWERFUL ENOUGH IN S1 AND WHY WE
ATTRIBUTE CHANGES IN THE
STRENGTHS OF SYNAPSES AT LEAST
LAYER 4 TO LAYER 3 TO INDUCE
CHANGING IN SPIKE TIMING OF THE
SPIKES AND NOT FIRING RATE OF
SPIKES.
SO LET ME THANK A NUMBER OF
PEOPLE IN THE LABS.
THE FIRST STUDENT TO RECEIVE HER
PH.D. IN MY LAB WAS KARA ALLEN
HERE AT NIH.
KEVIN BENDER, JASON WOLF, THE
SPIKE RECORDINGS I SHOWED YOU AT
THE END.
THANK YOU VERY MUCH.




[ QUESTION NOT HEARD ]
>> I'M SO GLAD YOU ASKED THAT.
CAN I SHOW YOU A MOVIE?
IT DOES PREDICT THAT IN THE
RESIDENT HYPOTHESIS IT'S A PLACE
CODE ACROSS WHISKERS.
IN THE STICK AND SLIP A SINGLE
WHISKER WILL DO IT FOR YOU?
DOES THE ANIMAL NEED TO COMPARE
CROSS WHISKERS?
AN ANIMAL COMPARING.
A SMOOTH TEXTTURE AND A ROUGH
TEXTURE.
THE ANIMAL COMES THROUGH THE
LAUNCH PLATFORM, HAS TO DECIDE
WHICH IS ROUGH AND JUMP TOWARD
THE ROUGH TEXTTURE AND GET A
REWARD.
IF YOU WATCH AN ANIMAL CLOSELY.
THIS IS AN ANIMAL WE TRIMMED
DOWN TO ONE WHISKER.
THIS IS THE ROUGH AND THIS IS
THE SMOOTH TEXTTURE.
NOW IT'S GOING TO ROTATE.
THIS IS THE ROUGH NOW.
NO THAT WAS THE ROUGH.
THESE ANIMALS CAN PERFORM AT 90%
CORRECT USING A SINGLE WHISKER
AND TELLS US IT CANNOT BE A
PLACE CODE.
IT MUST BE A SINGLE WHISKER
CODE.
[ QUESTION UNHEARD ]
>> SMALL IN CORTEXT.
>> CAN YOU INDUCE.
>> SO THE STRONGEST PROTOCOL
THAT HAS WORKED RELIABLY FOR US
IS A PLANT PAIRING PROTOCOL.
IN THAT CASE FOR LTD, 50% LTD
WITH THAT MEASURE WHERE IT'S 30%
WITH THE SPIKE TIMING EVENT.
IT IS A BIT MORE.
I DON'T KNOW OF ANYBODY WORKING
AT THESE FAIRLY MATURE AGES IN
DEVELOPMENT AT LEAST 38 EARLIER
THAT CAN GET 200% PLASTICITY
ROUTINELY.
IT IS POSSIBLE IN HIPPOCAMPUS.
I THOUGHT OF THIS AS A CORTEX
VERSUS HIPPOCAMPUS.
[ QUESTION UNHEARD ]
>> WE DON'T HAVE ANY DATA ON
THAT.
WE DO KNOW -- WE TYPICALLY USE
60 OR 100 PAIRINGS.
IF YOU GO SHORTEDDER THAN THAT,
YOU GET LESS PLASTICITY.
WE DIDN'T SEE ANY ADVANTAGE
GOING 200.
PART HAS TO DO WITH TIME.
IF THERE'S A RAPID MECHANISM
THAT WORKS OVER A PERIOD OF TIME
AND THIS IS ALL WE CAN SEE IN
THE SPLICE USING THE TECHNIQUE,
THAT WILL TELL YOU HOW MANY CAN
BE ENGAGED IN THAT TIME PERIOD.
THE SAME MECHANISM OPERATING IN
VIVO, AFTER 30 MINUTES
CONSOLATION WHERE ANOTHER IS
POSSIBLE AND YOU MAY OVERTIME
PROVE PLASTICITY BUT WE CAN'T
TELL THAT YOU IN A SPLICE,
OBVIOUSLY.
[ QUESTION UNHEARD ]
>> WHEN WE MEASURE THE SPIKING
OF THE CELLS, THE RESPONSES ARE
TIME LOCKED.
OH, YOU MEAN MOVEMENT.
AN INTERESTING QUESTION.
ACTUALLY THERE'S MULTIPLE
DIFFERENT STREAMS COMING INTO
THE CORTEXT.
NOT ONLY WHEN A WHISKER WAS
CONTACTED BUT ANOTHER STREAM OF
INFORMATION THAT CARRIES
INFORMATION ABOUT WHERE IN
PHASE OF THE WHISKING CYCLE.
NICE DATA IN THE DATA SHOWING
THE SPIKES DO TRACK THAT
QUANTITIY.
IN OUR CASE A MODEST
CONTRIBUTION THAN THE CONTACT IS
BUT CLEARLY THERE AS A WELL.
SO THE SUPPOSITION IS THAT THE
ANIMALS CAN DECODE WHERE AN
OBJECT IS BY WHY IN PHASE THE
WHISKER IS WHEN THE CONTACT
OCCURS.
[ QUESTION UNHEARD ]
>> I WOULD LOVE TO KNOW THE
ANSWER TO HAVE THAT QUESTION.
UPTAKE IS FASTER BUT PROBABILITY
OF RELEASE IS HIGHER.
MAYBE ENOUGH EXTRA GLUTAMATE
AROUND THAT IT HAS AN EFFECT BUT
I WOULD LOVE TO KNOW THE ANSWER
TO THAT.
[ QUESTION UNHEARD ]
>> YOU KNOW, NO ONE HAS DONE
THAT EXPERIMENT.
SO IT'S NOT KNOWN.
WE HAVE LOOKED HIGHER UP IN THE
SYSTEM WONDERING WHETHER IN THE
CORTICAL COLUMNS THAT REPRESENT
SHORTER WHISKERS IF THEY ARE
RECEIVING HIGHER FREQUENCY INPUT
ON AVERAGE THAN THE COLUMNS
REPRESENTING LONGER WHISKERS,
ARE THEY SPECIALIZED FOR FASTER
FREQUENCY BUT WE HAVEN'T FOUND
ANY POSITIVE EVIDENCE FOR THAT.
[ QUESTION UNHEARD ]
>> YOU MEAN WHICH WHISKER IS
ACTIVATED?
[ QUESTION UNHEARD ]
>> I THINK TAQUESTION IS REALLY
INTERESTING ON MANY LEVELS.
ONE LEVEL IS THE WHOLE QUESTION
OF NETWORK AND SNAP DYNAMICS.
IF YOU APPLY A TRAIN OF STIMULI
YOU'LL GET A BIG RESPONSE TO THE
ELEMENT OF THE TRAIN
PARTICULARLY IN CORTEX THAT
SHOWS A LOT OF SYNAPTIC
DEPRESSION.
AND IN VIVO IT'S ARGUED THAT IN
AWAKE BEHAVING ANIMALS RATES ARE
ENOUGH TO DEPRESS SYNAPSES SO
YOU CAN FOLLOW THE TRAINS OF
EVENTS.
HASN'T BEEN A MEASURE TO SEE
WHETHER THAT'S TRUE AND
SOMETHING WE ARE TRYING TO DO.
THE LEARNING QUESTION IS A
REALLY INTERESTING ONE AS WELL.
WHAT EXTENT OF THE RECEPTOR
FEELS OR ASPECTS LEARNED VERSUS
STABLE IN THESE NETWORKS AND MY
PRESUMPTION IS BECAUSE WE CAN
CHANGE THE WHISKER TREMENDOUSLY
BY HAVING IT IN PLACE OR
TRIMMING IT OFF FOR A FEW DAYS,
TRAINING WILL CHANGE THE
CHARACTERISTICS OF THESE CELLS
AND, AGAIN THAT'S SOMETHING WE
WANT TO TEST.
THAT WAS THE MOTIVATION FOR THE
EXPERIMENT.
IF WE WANT TO EXTEND THE BASIS
FOR LEARNING, HOW ENCODES A
PARAMETER LEARNED AND HOW
LEARNING CHANGES THAT LEARNING
AND THAT IS THE LONG-TERM GOAL
OF THE EXPERIMENTS.
[ APPLAUSE ]