Of Mice, Birds and Men: The Mouse Ultrasonic Song System

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>> GOOD AFTERNOON.
AND WELCOME TO THE WEDNESDAY
AFTERNOON LECTURE SERIES.
I'M FROM THE NATIONAL INSTITUTE
ON DEAFNESS AND OTHER COMMUNICATION DISORDERS.
TODAY'S TALK IS IMPORTANT
BECAUSE UNDERSTANDING VOICE,
SPEECH AND LANGUAGE AND THEIR
ASSOCIATED DISORDERS IS CRITICAL
FOR HUMAN PATIENTS BECAUSE THE
COMMUNICATION HAS DEVASTATING
EFFECTS ON COMMUNICATION
DISORDERS INCLUDING STROKES, DIX
LEXIA AND MANY OTHERS.
SO IDENTIFYING ANIMAL MODELS FOR
A TRAIT HAS BEEN A CHALLENGE.
AND BUT SONG BIRDS HAVE PROVEN
TO BE A USEFUL MODEL FOR AFFECTS
OF VOCAL LEARNING AND
PRODUCTION.
AND TODAY'S SPEAKER, DR. ERIC
YAFFE SIS A PIONEER IN IN FIELD.
-- PUBLISHED OVER 60 ARTICLES
INCLUDING A SERIES OF SEMINOLE
STUDIES IN THE LATE 1990s WITH
DR. FERNANDO.
HE IS ALSO WELL-KNOWN FOR HIS
PERSONAL AND PROFESSIONAL
JOURNEY TOWARDS A CAREER IN
RESEARCH.
HE WAS BORN AND GREW UP IN
HARLEM, NEW YORK, WHERE HE
ATTENDED A MAJOR AT THE NEW YORK
PUBLIC HIGH SCHOOL FOR THE
PERFORMING ARTS.
HE WAS OFFERED DANCE
SCHOLARSHIPS WITH THE JAFFRAY
BALLET AND WITH THE DANCE
SCHOOL, BUT DECIDED INSTEAD TO
ATTEND HUNTER COLLEGE WHERE HE
RECEIVED A BACHELOR'S DEGREE IN
MATHEMATICS AND BIOLOGY.
HE THEN PURSUED GRADUATE AND
POST GRADUATE FELLOWSHIP
TRAINING AT ROCKEFELLER WHERE HE
EARNED HIS Ph.D. IN MOLECULAR
NEUROBIOLOGY AND BEGAN HIS LIFE
ON WORK IN VOCAL LEARNING IN
SONG BIRDS WITH.
IN 1998, HE JOINED DUKE
UNIVERSITY IN THE DEPARTMENT OF
NEUROBIOLOGY WHERE HE RISEN
THROUGH THE FACULTY RANKS TO A
TENURED POSITION AS WELL AS MANY
SECONDARY APPOINTMENTS.
HE RECEIVED DOZENS OF AWARDS AND
WIDE RECOGNITION AND IS THE
SOURCE OF CVMD FOR ME AND IN
2002, HE RECEIVED AT WELL -- THE
ALLEN WATERMAN AWARD, THE
HIGHEST AWARD FOR YOUNG
INVESTIGATORS GIVEN ANNUAL TOW
ONE SCIENTIST OR ENGINEER UNDER
THE AGE OF 35 AND MADE A
SIGNIFICANT DISCOVERY IN
SCIENCE.
AND JUST A FEW OF THE OTHER
AWARDS IN 2005, HE RECEIVED THE
NIH DIRECTOR'S PIONEER AWARD AND
IN 2008, HE BECAME A HOWARD
HUGHES MEDICAL INSTITUTE
INVESTIGATOR AND THEN 2012,
HE'LL DELIVER THE WEDNESDAY
AFTERNOON LECTURE SERIES.
SO WELCOME TO DR. JARVIS.
[ APPLAUSE ]
>> THANK YOU FOR TRA
INTRODUCTION.
SO, I HAVE BEEN TRYING TO SAY
THIS, THIS IS A BIG LECTURE HERE
SO I HOPE NOT TO DISAPPOINT.
I'M GOING GOING TO TRY TO KEEP IT
GENERAL.
AND ALSO ENCOURAGE IF THERE IS
SOMETHING WE DON'T UNDERSTAND IN
THE MIDDLE, SO, MY GUESS IS
UNDERSTANDING BRAIN MECHANISM OF
COMPLEX BEHAVIORAL TRAITS AND
THE PARTICULAR TRAITS THEY
STUDIED MOST IS BOTH LEARNING
BECAUSE IT'S CONSIDERED ONE OF
THE CRITICAL BEHAVIORAL
SUBSTRATES OF THE SPOKEN
LANGUAGE.
AND WHEN I BEGAN THIS PROJECT,
THE ASSUMPTIONS WAS THAT WE HAVE
HUMANS WHO ARE VOCAL LEARNERS
AND WE USE THAT BEHAVIOR TO
PRODUCE AND IMITATE OUR SPEECHES
AND SONG BIRDS WHO ARE TEND TO
BE MODEL SPECIES FOR THIS TRAIT
AS THAT'S THE ANIMAL MODEL THAT
FITS CLOSELY TO WHAT WE CAN SAY
IS LIKE SPEECH AND THEN MICE WHO
ARE CONSIDERED NON-VOCAL
LEARNERS.
THAT'S WHERE I'M BEGINNING.
AND I'M GOING TALK TO YOU ABOUT
ADDRESSING THAT QUESTION.
IS THAT REALLY TRUE?
AND AT WORK, AS IN MOST LABS,
IT'S NOT JUST DONE BY ONE
PERSON, BUT DONE BY MULTIPLE
PEOPLE.
IT WAS DONE BY TWO PEOPLE IN MY
LAB, ONE WHO GRADUATED AS DONE A
SHORT POSTDOC IN MY LAB, AND THE
UNDERGRADUATE STUDENT.
AND THEY REALLY DID A TOUR DE
FORCE PROJECT OVER A NUMBER OF
YEARS THAT I'M GOING TO TELL YOU
ABOUT.
WHAT IS VOCAL LEARNING AND WHO
IS VOCAL LEARNING?
VOCAL LEARNING IS THE ABILITY
FOE IMITATE SOUNDS THAT YOU
HEAR.
SOME SPECIES CAN DO IT
PROLIFICALLY LIKE HUMANS AND
SOME ARE LIMITED OTHERS CAN
IMITATE THOUSANDS OF SOUNDS.
WHEN VOCAL LEARNING IS PRESENT,
WHAT WE SEE AMONG THE MAMMALIAN
TREE, BIRD FAMILY TREE, IT'S
RELATIVELY SPARSE.
SO HERE IS ONE VIEW OF A MAMMAL
FAMILY TREE AND REGARDLESS OF
THE VIEW THAT YOU LOOK AT, YOU
WILL SEE THAT THOSE THAT ARE
VOCAL LEARNERS THAT I HIGHLIGHT
IN RED, ELEPHANTS, DOLPHINS AND
BATS, WHALES AS WELL AND AMONG
PRIMATE, ONLY HUMANS, NOT ONLY
PRIMATES, IS SPARSELY
DISTRIBUTED AMONG THE MAMMALIAN
FAMILY TREE.
THE SAME THING FOR BIRDS.
SO WE HAVE ROUGHLY 28 ORDERS OF
BIRDS HERE AND WE HAVE HUMMING
BIRDS AND PARROTS AND SONG BIRDS
THAT ARE THE VOCAL LEARNERS.
THIS IS DIFFERENT FROM AUDITORY
LEARN COMING IS THE ABILITY TO
PROCESS NOVEL SOUNDS AND LEARN
AUDITORY LEARNING DOESN'T MEAN
YOU AUTOMATICALLY HAVE VOCAL
LEARNING.
IT'S ARGUED THAT THE ABILITY OF
VOCAL LEARNING EVOLVED
INDEPENDENTLY ALSO IN BIRDS.
ONE POSSIBILITY IS THAT THERE IS
A NEW VIEW OF THE AVIAN FAMILY
TREE, SOME 16 GENETIC MARKERS
ARGUED THAT PARROTS RELATIVE TO
SONG BIRDS, THE POSSIBILITY
LEADING TO MAYBE TWO INDEPENDENT
GAINS OF VOCAL LEARNING.
ONE IN THE HUMMING BIRDS AND ONE
IN PARENTS AND SONG BIRDS.
A COMMON ANCESTOR WITH VOCAL
MUTATION IN CHAM PAN SEES LOSING
THAT ABILITY IN HUMANS
MAINTAINING IT.
SO HOW FAR THIS EVOLVED, IT'S
FASCINATING BUT IT'S ALL ALONG
ASSUMED THAT RODE ENDS HAVE OR
DO NOT HAVE THIS ABILITY.
ONCE A SPECIES HAS IT, IT SEEMS
TO COME ALONG WITH A PACKAGE OF
TRAITS.
AND THAT PACKAGE, I LISTED IN
SEVERAL BULLET POINTS HERE, IS
THAT WE DEPEND UPON AUDITORY
FEEDBACK TO ACTUALLY PRACTICE
AND DEVELOP OUR LEARNED
VOCALIZATIONS.
WE GO THROUGH CRITICAL PERIODS,
WHEN I SAY, WE, I'M TALKING
ABOUT VOCAL LEARNERS GENERALLY.
WE GO THROUGH CRITICAL PERIODS
WHERE WE LEARN HOW TO IMITATE
VOCALIZATIONS AT EARLIER STAGE
IN LIFE THAN AFTER PUBERTY.
THAT'S WHY IT'S EASY TO LEARN A
DIFFERENT LANGUAGE BEFORE
PUBERTY.
WE CULTURALLY TRANSMIT VOCAL
REPERTOIREES FROM ONE GENERATION
TO THE NEXT AND A FORM OF SYNTAX
TO VARIOUS DEGREES.
SOME PRODUCE MORE COMPLEX AND
SOME ARE MORE SIMPLE.
AND ORDERS OF VOCAL
COMMUNICATION ARE ALSO SHARED.
ONE OF THEM IS DEAF-INDUCED
VOCAL DISORDERS.
WHEN WE BECOME DEAF, AND WHEN A
SONG BIRD BECOMES DEAF, OUR
VOCALIZATIONS EVENTUALLY
DETERIORATE IF WE DON'T HAVE
SOME TYPE OF THERAPY.
THE SPEECH BECOMES MIDDLED.
THAT IS BECAUSE WE NEED TO HEAR
OURSELVES IN ORDER TO MAINTAIN
THE LEARNED VOCALIZATIONS.
WHEREAS NON-VOCAL LEARNING
SPECIES, WHETHER THEY BECOME
DEAF, THE VOCALIZATIONS REMAIN
INTACT.
WE HAVE PHASES OF SPEECH THROUGH
BRAIN DAMAGE.
WITH SONG BIRDS YOU CAN DAMAGE
THE BRAIN AND EFFECT THE LEARNED
SOUNDS AND SPEECH-SOUND
DISORDERS.
WE HAVEN'T FOUND ANYTHING LIKE
THAT IN SONG BIRDS YET BUT
PEOPLE ARE OUT THERE SEARCHING
FOR THAT INCLUDING THINGS
RELATED TO AUTISM.
SO, THAT'S THE BEHAVIOR.
WHAT ABOUT THE BRAINS?
WE KNOW MORE ABOUT THE BRAINS
FOR THESE PATHWAYS IN BIRDS THAN
IN MAMMALS.
BECAUSE WE CAN DO A LOT OF
EXPERIMENTAL WORK WITH THEM.
AND MY WORK AND OTHERS HAVE
SHOWN THAT HERE IS THE FAMILY
TREE OF BIRDS.
AND HERE IS SEMI 3D
RECONSTRUCTIONS OF THEIR BRAIN
ANATOMY FOR VOCAL COMMUNICATION
PATHWAYS.
HIGHLIGHTED IN BLUE ARE BRAIN
PATHWAYS THAT ARE INVOLVED IN
PROCESSING THE SOUNDS THAT
ANIMAL HEARS, IN THIS CASE THESE
BIRDS.
YOU CAN FIND THIS AUDITORY
PATHWAY -- I DON'T SHOW THE
CONNECTIVITY HERE -- BUT YOU CAN
FIND IT IN ALL SPECIES OF BIRDS
AND FIND IT IN MANY OTHER
VERTEBRATES IN THE FOREBRAIN AND
THOUGHT TO BE INVOLVED IN THE
PROCESSING OF NOT ONLY OF SOUNDS
BUT ALSO IN LEARNING INFORMATION
ABOUT AUDITORY SIGNALS.
SO IT'S BEEN ARGUED THAT THIS
AUDITORY PATHWAY FOUND IN THE
VOCAL LEARNING SPECIES, THE SONG
BIRDS, PARROTS AND HUMMING BIRDS
WAS INHERIT FRIDAY A COMMON
ANCESTOR.
HOWEVER, IN THE VOCAL LEARNING
SPECIES, I HIGHLIGHTED IN RED
AND YELLOW HERE, ARE BRAIN
REGIONS THAT ARE RESPONSIBLE FOR
ACQUIRING, THAT IS LEARNING THE
VOCALIZATIONS IN THIS RED
LABELED PATHWAY, AND PRODUCING
THOSE LEARNED VOCALIZATIONS IN
THIS YELLOW-LABELED PATHWAY
HERE.
AND WHEN IT IS FOUND IN THESE
VOCAL LEARNING SPECIES, WHAT IS
INTERESTING, WE FIND SEVEN BRAIN
REEG NONCE ALL THREE OF THEM.
NOT FIVE IN ONE OR THREE IN THE
OTHER.
THEY ARE NOT IN IDENTICAL
LOCATIONS BUT HAVE SIMILAR
CONNECTIVITY.
ONCE A SPECIES EVOLVES ITS
ABILITY, IT EVOLVES IN A SIMILAR
WAY.
AND WHEN WE PUBLISHED THIS AT
THE TIME, SEVERAL RELIGIOUS
GROUPS DID CONTACT US AND SAID,
THIS HELPS TO PROVE THE
EXISTENCE OF GOD BECAUSE HOW
COULD YOU GET SUCH A SIMILAR
PATHWAY MULTIPLE TIMES IN THE
LAST 65 MILLION YEARS?
AND WE DIDN'T HAVE AN ANSWER TO
THAT.
MAYBE THERE WAS A COMMON
ANCESTOR AND THERE IS MASS
EXTINCTION OF VOCAL LEARNING OR
THERE REALLY ARE THREE
INDEPENDENT GAINS.
AND -- EXCUSE ME.
I HAVE TO DO THIS FROM HERE.
WE DIDN'T HAVE AN ANSWER TO THAT
BUT LOOKING AT THE HUMAN
NEUROBIOLOGY FOR VOCAL
COMMUNICATION, LEARNED VOCAL
COMMUNICATION, COME UP WITH A
SIMILAR SCENARIO.
I ARGUED THAT WE HAVE A AREA
THAT IS HOMOLOGOUS THESE
AUDITORY FOREBRAIN AREAS IN THE
BIRDS BECAUSE YOU CAN'T FIND A
VERTEBRATE GROUP WITHOUT THEM.
THAT INVOLVED IN PROCESSING
SPECIES SPECIFIC OR
HETEROSPECIFIC SOUNDS LIKE, COME
HERE BOY, FETCH THE NEWSPAPER,
TO YOUR DOG.
OR, AND THAT WE HAVE THE STRIP
OF CORTEX, PARTS OF THE TRIATUM,
THALAMUS AND THE FACE MOTOR
CORTEX THAT IS INVOLVED IN
LEARNING AND PRODUCING LEARNED
SPEECH.
FOR SPEECH, BASICALLY SAY SPOKEN
LANGUAGE.
AND THAT SO FAR, THESE BRAIN
PATHWAY THAT IS ARE COLOR-CODED
IN RED AND IN YELLOW HERE CANNOT
BE FOUND IN NON-VOCAL LEARNING
MAMMALIAN SPECIES.
SO A SIMILAR SCENARIO, THERE WAS
AN INDEPENDENT GAIN.
I DON'T THINK HUMANS AND SONG
BIRDS AND PARROTS SHARED A
COMMON ANCESTOR AND ALL THE
OTHER SPECIES LOST IT.
THAT IS THIS PATHWAY AND THE
TRAIT.
SO, OUR GOAL WAS TO TEST SOME
HYPOTHESES ABOUT GENES THAT
FORMED THESE CIRCUITS THAT WE
ARE LOOKING FOR, INTO PUT A
CRAZY IDEA WAS TO TRY TO
TRANSFET THOSE GENES INTO THE
MOUSE GENOME AND TRY TO INDUCE A
VOCAL LEARNING PATHWAY.
AND IN ORDER TO DO THAT, WE
NEEDED TO DECIDE OR NEEDED TO
KNOW MORE INFORMATION ABOUT THE
VOCAL SYSTEM OF MICE.
AND I AND MANY OTHERS HAD
WRITTEN IN OUR REVIEW THAT IS
MICE ARE NONVOCAL LEARNINGS.
BUT ACTUALLY WHEN YOU LOOK AT
THE LITERATURE, NO ONE EVER
TESTED THAT.
IT'S ALL BEEN ASSUMED.
AND THEN TIM HOLLY FROM
WASHINGTON UNIVERSITY PUBLISHED
THE PAPER A NUMBER OF YEARS AGO,
SOME OF YOU MAY HAVE HEARD
ABOUT, WHERE HE SHOWED THAT MICE
HAVE THESE ULTRASONIC
VOCALIZATIONS.
THAT WAS ALREADY KNOWN.
BUT THEY HAVE CHARACTERRISTIC
FEATURES LIKE SONG BIRD SONGS.
YOU WHAT SEE HERE IS A SONOGRAM
OF THE SOUND, TIME ON THE X AXIS
AND THE FREQUENCY OF THE SOUND
ON THE Y AXIS AND EACH ONE OF
THESE STRUCTURES IS BASICALLY A
SINGLE SYLLABLE MOREOVERRING
FROM ONE FORM INTO THE OTHER.
THIS IS THE ULTRASONIC RANGE.
WE DON'T REALLY HEAR THAT WELL
ABOVE 14 KILOHERTZ.
AND SO, THIS IS NOW PITCHED DOWN
TO THE HUMAN HEARING RANGE AND
THIS IS WHAT IT SOUNDS LIKE.
I'M GOING TO TURN ON THE SOUND
HERE.
[ CHIRPING ]
>> NOW WHEN I PLAY THAT, SOME
PEOPLE THINK THEY ARE HEAR
SOMETHING KIND OF SONG BIRD.
BUT IF YOU FITCH DOWN EVEN SLOW
IT DOWN, THIS IS WHAT IT SOUNDS
LIKE.
[ WHISTLING ]
SO, THIS IS NOT A SIMPLE TYPE OF
SOUND.
IT HAS SOME STRUCTURE TO IT.
IT'S A WHISTLE-LIKE SOUND AND
THEY EVEN FOUND THAT DIFFERENT
INDIVIDUALS HERE, HERE ARE THREE
DIFFERENT INDIVIDUALS WHERE THEY
CLASSIFIED THE SILL BELLS INTO
THREE BROAD CATEGORIES, ARE
PRODUCING DIFFERENT PROPORTIONS
OF THEIR SYLLABLE REPERTOIRE
AMONG THESE CATEGORIES.
SO IN OTHER WORDS, THERE ARE
INDIVIDUAL DIFFERENCES, WHICH IS
WHAT YOU EXPECT IN A VOCAL
LEARNER.
SO THIS LED TO A FLURRY OF MEDIA
AND SO FORTH, SUGGESTING THAT
MICE MIGHT BE VOCAL LEARNERS BUT
THIS DOESN'T PROVE ONE WAY OR
THE OTHER.
IT JUST SAYS THEY HAVE A VOCAL
BEHAVIOR THAT HAS SOME FEATURES
SIMILAR TO SONG BIRDS, BUT NOT,
THAT DOESN'T MEAN THEY ARE
REALLY VOCAL LEARNERS.
THERE ARE SOME SONG BIRDS
SPECIES LIKE THIS SONG BIRD,
THAT PRODUCES A SONG, BUT IT'S
IN AN IN8 SONG.
SO JUST BECAUSE IT'S SONG,
DOESN'T MEAN IT'S LEARNED.
SO WHAT DID WE DO?
WE WENT TO TEST OUT WHETHER OR
NOT MICE HAVE THIS PACKAGE OF
TRAITS THAT YOU FIND IN HUMANS
AND SONG BIRDS AND PARROTS AND
OTHER SPECIES THAT HAVE BEEN
TESTED.
WE EXAMINED THREE BRAIN TRAITS
WHETHER OR NOT THEY HAVE
FOREBRAIN AREAS INVOLVED IN
THE -- AT LEAST ACTIVE IN THE
PRODUCTION OF VOCALIZATIONS, BUT
NOT IN NONLEARNERS.
WHEN I SAY NONLEARNERS, I'M
REFERRING TO EXPERIMENTS DONE IN
NONHUMAN PRIMATES OR PIGEONS OR
CHICKENS, SOME GUINEA PIGS.
ONE THAT IS TALKED ABOUT IS THAT
THERE IS A DIRECT FOREBRAIN
PROJECTION TO THE BRAINSTEM
MOTOR NEURONS THAT CONTROL VOCAL
BEHAVIOR IN HUMANS AND PARROTS
BUT HASN'T BEEN FOUND IN
NONHUMAN PRIMATES.
REQUIRING THE CORTEX TO PRODUCE
THOSE VOCALIZATIONS.
THE BEHAVIOR ITSELF, I MENTIONED
VOCAL LIMITATION AND MORE
RECENTLY, EXPERIMENTS THAT WE
AND OTHERS HAVE BEEN CONDUCTING
TO IDENTIFY GENES THAT ARE
ASSOCIATED WITH THE EVOLUTION OF
SPEECH OR SONG AND SONG BIRDS.
SO, THESE TWO STUDENTS, MYSELF
AND A FEW OTHERS, WE ACTUALLY
MARCHED THROUGH THESE ONE BY ONE
AND WE TOOK A BOTTOM-UP APPROACH
STARTING WITH THE BRAIN AS
OPPOSED TO BEHAVIOR.
AND WE USED OUR KNOWLEDGE OF THE
SONG BIRD SYSTEM AND OF THE
HUMAN NEUROBIOLOGY FOR SPEECH TO
FORMULATE OUR EXPERIMENTS ON
MICE.
AND SO THE FIRST ONE IS SHOWN
HERE.
WORK THEY DID AS A POSTDOC SHOWN
THAT WHEN SONG BIRDS PRODUCE
THEIR LEARNED SONG, WHAT
HAPPENS, THAT BEHAVIOR IS
ASSOCIATED WITH NEUROFIRING IN
THE BRAIN, WHICH CAUSES
INCREASED mRNA EXPRESSION,
SHOWN IN WHITE, OF CERTAIN GENE
RESPONSIBLE TO ACTIVITY CALLED
EARLY GENES.
YOU'RE SEEING A THIN SLICE
THROUGH A CANARY BRAIN.
THE RED STRAINING IS JUST BASIC
STAINING OF ALL CELLS IN THE
BRAIN.
THE CEREBELLUM BACK SMEAR HERE
IS THE FOREBRAIN.
THE ANIMAL WHO SINGS, FOR 30
MINUTE PERIOD, WE FOUND THAT YOU
GET THIS WHOPPING INCREASE OF
mRNA EXPRESSION IN THESE SONG
NUCLEI IN THE FOREBRAIN THEY
SHOWED YOU IN THE PREVIOUS
DIAGRAM I LABELED RED AND
YELLOW.
WHEN ANIMAL IS HEARING PLAY
BACKS OF SONG, YOU DON'T SEE
ACTIVATION IN THE SONG
PRODUCTION AREAS.
BUT YOU DO GET ACTIVATION AND
NOW WE KNOW IT'S THE AUDITORY
CORTEX EQUIVALENT OF THE SONG
BIRDBRAIN.
AND WHEN A SONG BIRD IS DEAF,
THAT AUDITORY INDUCED EXPRESSION
GOES AWAY, OR MOST GOES AWAY AND
YOU STILL SING.
SO IN OTHER WORDS A DEAF END
BIRD IS SINGING EVEN IF IT IS
SINGING A DETERIORATED SONG,
SHOWS ACTIVATION IN THE
PRODUCTION AND LEARNING OF THE
SONG.
IT'S LESS THAN YOU WHAT SEE IN
IN TACT ANIMALS.
THE AMOUNT OF GENE EXPRESSION
PRODUCED IN THIS HALF HOUR
PERIOD IS CORRELATED WITH THE
AMOUNT OF SONG PRODUCED.
AND THEN WE MADE AN ACCIDENTAL
DISCOVERY THAT ALSO WOULD BE
INFORMATIVE FOR THE MOUSE
EXPERIMENTS.
RECENTLY, THAT IS WE FIND THAT
YES, THERE ARE ACTIVATED REGIONS
DUE TO SINGING AND THERE ARE
EXACTLY SEVEN OF THEM AS I
MENTIONED, IN THE SONG BIRDS AND
PARROTS AND HUMMING BIRDS.
WE FOUND EXACTLY 7 BRAIN REGIONS
SCUR ROUNDING SONG NUCLEI ACTIVE
IN THE PRODUCTION OF MOVEMENT
BEHAVIORS N THIS CASE, ANIMAL
HOPPING IN A ROTATING WHEEL FOR
THE FIRST TIME.
AND WE FOUND THAT -- AND THAT'S
SHOWN IN WHITE.
YOU CAN SEE THE GENE ACTIVATION
IS SURROUNDING THE NUCLEI.
AND THE NEURAL CONNECTIVITY OF
THESE AREAS AROUND THE SONG
NUCLEI IS SIMILAR TO THE NEURAL
CONNECTIVITY OF THE SONG NUCLEI
THEMSELVES FORMING IN THIS CASE,
WHAT WE CALL A CORTICAL BASAL
GANGLIA THALAMIC LOOP.
I KNOW IT'S A FULL-LOADED TERM
BUT IT'S A COMMON TERM USED IN
NEUROSCIENCE, THAT IS INVOLVED
IN MOTOR LEARNING.
AND PROJECTIONS OUT OF THE
FOREBRAIN THAT CONTROL MOTOR
NEURONS.
SO THIS LED TO THE
HYPOTHESES -- SORRY.
ONE MORE SLIDE THAT IS GOING TO
LEAD TO THIS HYPOTHESES.
WE FOUND THAT IF YOU YOU WERE TO
PLAY SOUNDS TO A NON-VOCAL
LEARNING SPECIES LIKE A RING
DOVE, YOU SEE THE
HEARING-INDUCED GENE ACTIVATION
LIKE IN THE VOCAL LEARNING
BIRDS.
THEY DO HAVE THE AUDITORY
PATHWAY.
WHEN THEY PERFORM MOVEMENT
BEHAVIORS N-THIS CASE, I
COULDN'T GET THEM TO HOP.
THEY LIKE TO WALK.
SO HI TO WALK ON THE TREADMILL.
AND YOU WHAT SEE IS ONE LARGE
AREA BUT IT REALLY IS THREE
AREAS STACKED UP ON TOP OF EACH
OTHER.
TWO HERE AND ANOTHER TWO LATERAL
IN THE BRAIN.
SEVEN AREAS WHERE YOU EXPECT TO
FIND SONG NUCLEI BUT WITHOUT
HOLES OF EXPRESSION WHERE SONG
NUKELY ARE LOCATED.
SO, THIS LED TO THIS HYPOTHESES
THAT WAS THE ALTERNATIVE TO THE
INTELLIGENT DESIGN HYPOTHESES
THAT PEOPLE WERE TELLING ME
ABOUT.
THAT IS, WHAT I CALL IN THE
MOTOR THEORY OF VOCAL LEARNING
ORIGIN.
WHERE I ARGUE THAT ALL SPECIES
HAVE THIS VOCAL INNATE PATHWAY
AND WHAT HAPPENED IS THAT THEY
ALSO HAD A VOCAL -- NON-VOCAL
MOTOR PATHWAY INVOLVING
FOREBRAIN REGIONS, BASAL GANGLIA
STRUCTURES AND THAT SOMEHOW
DURING EVOLUTION, I ARGUE THAT
THIS PATHWAY DUPLICATED ITSELF
FOR NEW CONNECTIONS ON TO THIS
INNATE PATHWAY AND THAT
DUPLICATED PATHWAY THEN
BASICALLY REPLICATED THE MOTOR
LEARNING PATHWAY TO NOW FORM
EMERGING VOCAL LEARNING PATHWAY.
SO THIS IS THE BACKGROUND THAT
NOW WE ARE WORKING WITH.
THIS HYPOTHESES, WITH THE MOUSE
SONG SYSTEM.
I THOUGHT THE MOUSE INDIVIDUAL
THIS PATHWAY AND WE COULD JUST
TRY TO INFLUENCE NEW CONNECTIONS
ON TO THESE NEURONS AND THE
MOUSE BRAIN WHICH IT DOES HAVE
FOR PRODUCTION OF INNATE SOUNDS,
TO HAVE A MOTOR CONTROL PATHWAY
FROM THE FOREBRAIN CONTROL
VOCALIZATIONS.
SO, TO TRY TO GET BACK TO THE
MOUSE NOW AND ASK, WHAT BRAIN
AREAS DOES IT HAVE THAT MAYBE
LIKE OR NOT LIKE HUMANS?
WHAT WE DID IS WE TOOK WHAT WE
DID WITH THE SONG BIRDS, TOOK
MICE AND WE INTRODUCED LONG
BOUTS OF WHAT WE ARE GOING TO
CALL MOUSE SONG.
THEY LIKE TO SING TO FEMALES BUT
WE DIDN'T WANT THE FEMALES TO
ACT AS A STIMULUS.
SO WE PUT FEMALE URINE IN THEIR
CAGE AND IT'S BEEN SHOWN THAT
FEMALE URINE HAS A POTENT FAIR
MOAN THAT INDUCES SINGING
BEHAVIOR.
AND I SHOWED YOU BEFORE THIS ONE
LITTLE SNIPPET OF SONG.
BUT THAT ONE SNIPPET COMES FROM
LONG SEQUENCES OF THIS
ULTRASONIC SONG THAT THE BIRDS
SING.
SO THE SOUND IS JUST CONDENSED
SO I CAN FIT THIS 45-SECOND OF
SOUND IN HERE.
I'M NOT GOING TO PLAY IT FOR YOU
BUT BASICALLY IT SOUNDS SIMILAR
TO WHAT I PLAYED BEFORE.
AND THEN HAVE THEM PRODUCE THIS
ULTRASONIC SINGING FOR ABOUT 30
MINUTES, AS WE DID WITH SONG
BIRDS, DISSECT THE BRAIN, DO THE
IN SITU HYBRIDIZATION TO MEASURE
THE mRNA OF THESE GENES AND
SCAN THE BRAIN FOR VOCALIZING
DRIVEN GENE EXPRESSION IF IT
EXISTS AT ALL, AND THEN COMPARE
TO CONTROL GROUPS LIKE YOUR
SILENT, DEAF SINGING AND
HEARING-ONLY CONTROLS.
AND THIS IS THE RESULT THAT WE
ATTAINED.
WE SCANNED THROUGHOUT THE ENTIRE
FOREBRAIN AND COMPARED TO ANIMAL
WHOSE HEARING PLAY BACKS EVER
SOUNDS, WE FOUND ONE REGION IN
THE CORTEX, ONE SPECIFIC REGION
HERE, INCLUDING CINGULATE CORTEX
SECONDARY AND PRIMARY MOTOR
CORTEX ABOVE THE LEVEL OF THE
INTERIOR COMMISSIONER, THAT
SHOWED HIGHER GENE EXPRESSION
COMPARED TO HEARING-ONLY ANIMAL.
OR ANIMAL WHO IS IN SILENT
CONTROL CONDITIONS.
AND THE HEARING-ONLY ANIMAL
DIDN'T SHOW A DIFFERENCE.
WHAT WAS DIFFERENT WITH SONG
BIRDS IS EVEN AT BASELINE
CONDITIONS, YOU DO SEE SOME GENE
ACTIVATION OR EXPRESSION IN THIS
AREA AS IF THERE IS SOMETHING
ELSE THAT MIGHT BE HAPPENING.
AND THIS IS IN THE MOTOR CORTEX.
QUANTITATIVELY, IT WAS CLEAR
THAT THERE WAS INDUCTION HERE
SHOWN IN THIS GRAPH, IF YOU JUST
FOCUS ON THIS PART OF THE GRAPH
HERE, HERE IS THE SINGING ANIMAL
WHO IS HEARING, RELATIVE
EXPRESSION TO THE SILENT
CONTROL, AND THEN THE ANIMAL WHO
IS HEARING, THIS THIS ANIMAL
SING, AND THEN THE DEAF ANIMAL
WHO IS SINGING BUT CAN'T HEAR.
AND IT EVEN SHOWS HIGHER
EXPRESSION IN THIS CASE.
AND IN THE DEAF ANIMALS, OR
LET'S SAY IN THE HEARING IN TACT
ANIMALS, WHEN THEY HEAR THE PLAY
BACKS OF VOCALIZATIONS IN THE
BRAIN, YOU DO GET ACTIVATION IN
THE PRIMARY AUDITORY CORTEX THAT
IS SHOWN HERE AS OPPOSED TO THE
M1 REGION AND WHEN THEY ARE
DEAF, THAT ACTIVATION GOES DOWN.
OR BASICALLY SUPPORTING THE FACT
THAT WE ACTUALLY REALLY DID DEAF
EN THESE ANIMALS.
SO, BASED UPON THIS RESULT, AND
THERE IS MORE TO IT BUT I DON'T
HAVE TIME TO GET INTO THE
DETAILS, BECAUSE I WANT TO MOVE
ON, THE ANSWER IS YES, WE DID
FIND CORTICAL -- I JUST SKIPPED
THAT, AND STRIATAL REGIONS RIGHT
BELOW THE CORTEX REGION, THAT
ARE ACTIVE IN THE PRODUCTION OF
MOUSE ULTRASONIC SONGS IN THE
ABSENCE OF AUDITORY FEEDBACK.
AND SO, WE KNOW IT'S NOT FAIR
MOAN STIMULATION BECAUSE SOME
MICE WHO SMELL THE URINE DON'T
SING AND DON'T SHOW THIS
ACTIVATION OR OL FACTORY
STIMULATION.
IF YOU GIVE THEM ETHANOL YOU
DON'T SEE IT EITHER.
WHAT ABOUT CONNECTIVITY?
WELL, FOR CONNECTIVITY, HERE I'M
SHOWING YOU NOW SECTIONS THROUGH
THE SONG BIRDBRAIN AND THE HUMAN
BRAIN OF THIS PATHWAY IN THE
FOREBRAIN THAT IS INVOLVED IN
SONG LEARNING AND THIS THE
PATHWAY INVOLVED IN THE
PRODUCTION OF THE SONG AND THE
BIG DEAL HAS NOT ONLY BEEN MADE
OUT OF THE PRESENCE OF FOREBRAIN
AREAS THAT CONTROL VOCALIZATIONS
AND VOCAL LEARNINGS COMPARED TO
A CHICKEN WHICH DOESN'T HAVE ANY
OF THEM OR A MACAQUE WHICH HAS
AN AREA THAT WHEN STIMULATED,
CAUSES -- THE BIG DEAL HAS BEEN
MADE OUT OF THIS PROJECTION HERE
FROM THE FOREBRAIN SINNANS AND
DIRECTLY ON TO THE MOTOR NEURONS
THAT THEN CONTROL THE MUSCLES.
THIS DIRECT PROJECTION HAS TO
DATE, ONLY BEEN FOUND IN VOCAL
LEARNING SPECIES.
SONG BIRDS, PARROTS, HUMMING
BIRDS AND HUMANS.
IT'S BEEN LOOKED FOR IN THE LAST
50 YEARS BY MANY LABORATORIES
AND NON-HUMAN PRIMATES AND NEVER
FOUND.
IT'S BEEN LOOKED FOR IN GUINEA
PIGS.
HAVEN'T FOUND IN CHICKENS OR
PIGEONS AND OTHER BIRD SPECIES.
SO A NUMBER OF SCIENTISTS HAVE
HYPOTHESIZED THIS PROJECTION IS
PERHAPS ONE OF THE MOST CRITICAL
TO THE EVOLUTION OF VOCAL
LEARNING AND SPOKEN LANGUAGE.
AND FISHER AND HAMMERSCHMIDT WAS
CONNECTED HERE AT NIH RECENTLY
SAID THE MOST IMPORTANT DERIVED
FEATURE IN THE HUMAN LINEAGE
APPEARS TO BE THE EVOLUTION OF
THE DIRECT PATHWAY FROM THE
MOTOR CORTEX, ENABLING SO
ENGLISH MOTOR CONTROL OVER THE
VOCAL FOLDS.
AND THERE IS A REASON WHY I
BROUGHT THIS QUOTE OUT.
YOU'LL SEE IN A MINUTE.
I WANT TO SHOW YOU SOME OF THE
EVIDENCE IN BIRDS AND HUMANS.
IF YOU PLACE NEURAL TRACER INTO
THE RA THAT MOTOR OUTPUT NUCLEUS
OF SONG BIRDS AND GO DOWN TO THE
VOCAL MOTOR NEURONS IN THE
BRAINSTEM, THE WHITE SIGNAL HERE
BASICALLY IS AXONS COMING FROM
THE CORTEX.
AND YOU CAN SEE THERE IS A HEAVY
INNOVATION OF MOTOR NEURONS AND
RESPIRATORY PRE-MOTOR NEURONS
HERE IN THE SONG BIRD THAT HAS
NOT BEEN FOUND IN NON-SONG
BIRDS.
HUMAN LITERATURE IS NOT AS
ROBUST BECAUSE YOU CAN'T DO
SIMILAR KINDS OF EXPERIMENTS IN
HUMANS BUT IF YOU LOOK AT POST
MORTEM STROKE VICTIMS OR TRAUMA
WHERE THERE IS DAMAGE TO THE
FACE MOTOR CORTEX AND LOOK AT
NUCLEUS AMBIGUOUS MOTOR NEURONS
HERE IN THE HUMAN BRAIN, YOU CAN
STAIN FOR DEGENERATING AXONS
THAT ARE PROJECTED THIS AND YOU
CAN SEE STRIPES HERE, MANY AXONS
THAT ARE AT LEAST INSIDE OF
NUCLEUS AMBIGUOUS NEXT TO MOTOR
NEURONS.
IN NON-HUMAN PRIMATES, SO FAR IN
THE LITERATURE, THE DRAWINGS
HAVE BEEN SHOWN BECAUSE I DON'T
HAVE ANY DATA TO SHOW YOU.
BUT HERE IS NUCLEUS AMBUGGUOUS
WITH TRACER INJECTED INTO THE
MOTOR CORTEX OR PREMOTOR CORTEX
OF NONHUMAN PRIMATES AND THEY
HAVE BASICALLY SAY NO
CONNECTIONS HAVE BEEN FOUND.
SO, WHAT ABOUT MICE?
WHY JUST ASSUME MICE DIDN'T HAVE
IT?
PEOPLE WROTE IN THEIR REVIEWS,
MICE DON'T HAVE THIS PROJECTION
BUT NO ONE HAS ACTUALLY TESTED
IT.
SO WE TESTED IT.
AND THE WAY WE DID THAT IS TO
INJECT TRANSSYNAPTIC TRACING
INTO MUSCLES AND THESE TRACERS,
THEY HAVE THE PROPERTY THEY WILL
JUMP SYNAPSES AND GET TAKEN UP
BY THE AXON AND INFECT THE CELL
BODY HERE AND AFTER 12 OR SO
HOURS, THEN JUMP ANOTHER SYNAPSE
AND GO BACK AND IF YOU GOT
FOREBRAIN CONNECTIVITY, THEY
WILL JUMP ANOTHER.
AND DEPENDING ON THE TIMING OF
THE TRACER, YOU SEE IN THE
CONNECTED REGION, WILL DEPEND ON
WHETHER IF IT'S A FIRST ORDER,
SECOND ORDER, THIRD ORDER
CONNECTED NEURON.
SO, WE DID THAT AND WE FOUND THE
WHITE SIGNAL HERE IS A TRACER.
WE FOUND YES, AFTER A DAY, WE
CAN FIND TRACER IN NUCLEUS
AMBIGUOUS IN THE MOUSE BRAINSTEM
AS EXPECTED.
WE CAN FIND IT IN THE SOLITARY
NUCLEUS WHICH WE KNOW FROM OTHER
WORK IT PROJECTS TO NUCLEUS
AMBIGUOUS AND CONTROLS
VOCALIZATION FOR RESPIRATORY
LINKING AND VOCALIZATIONS.
SO THAT MADE SENSE.
SECOND ORDER CONNECTIONS, WE
FOUND LATER ON.
THE NEXT DAY.
BAY INTO THE CENTRAL GRAY, WHICH
IS KNOWN FOR MANY YEARS IN
MAMMALS TO CONTROL THE
PRODUCTION OF INNATE
VOCALIZATIONS.
SO THAT MAKES SENSE.
THIS IS THE MID BRAIN HERE.
AND THEN WE WANT TO THE
FOREBRAIN AND SCANNED THROUGHOUT
THE ENTIRE FOREBRAIN AND DIDN'T
SEE ANYTHING EXCEPT FOR ONE
REGION.
THAT IS SHOWN RIGHT HERE ABOVE
THE LEVEL OF THE ANTERIOR
COMMISSIONER IN THE EXACT
LOCATION WHERE WE FOUND THE
SINGING-DRIVEN GENE EXPRESSION
IN THE MOUSE FOREBRAIN.
AND NOT ALL OF THE REGION SHOWED
BACKFILL OF THE TRACER, JUST THE
M1, THE PRIMARY MOTOR CORTEX
REGION,S YOU EXPECT.
THE NEURONAL MORPHOLOGY OF THIS
REGION HERE, AND ITS
POSITIONINGS IN THE CORTEX
BASICALLY INDICATED IT WAS LAYER
5 PARAMEATAL NEURONS WITH LONG
DENDRITES GOING UP INTO THE
CORTEX, WHICH IS YOU WHAT EXPECT
IF YOU'RE IN THE NEUROSCIENCE
FIELD.
YOU KNOW THESE ARE THE NEURONS
THAT SEND LONG PROJECTIONS TO
THE SPINAL CORD AND THE
BRAINSTEM.
SO THIS WAS A SURPRISE FOR US TO
FIND THIS AND THEN WE THOUGHT,
MAYBE THE CONNECTION IS THERE
AND PEOPLE MISS TODAY BEFORE.
IT'S JUST INDIRECT.
SOMEHOW OUR TRANSSYNAPTIC TRACER
JUMPED SYNAPSES PRETTY QUICKLY.
WE ONLY SAW THIS WHENEVER WE GOT
THE PERRY -- GRAY BACKFILL T
SUGGESTED A DIRECT PROJECTION
BUT DOESN'T PROVE IT.
TO TEST THAT, WHAT WE DID IS TRY
TO VERIFY THE PROJECTION BY
INJECTING ANOTHER TRACER CALLED
BIOTEX TRIN AMINE INTO THE M1
MOTOR CORTEX AND THIS TRACER
DOESN'T JUMP SYNAPSES.
AND WE ARE GOING TO SEE WHERE
DOES THIS M1 REGION PROJECT TO.
AND WE WANT TO SEE IF IT
PROJECTS TO THE MOTOR NEURONS
HERE TO MAKE SURE THAT WE
IDENTIFY THOSE MOTOR NEURONS
ACCURATELY, WE ALSO INJECTED A
DIFFERENT TRACER LABELED IN
BROWN, THAT WILL THEN FILL UP
THE MOTOR NEURONS HERE AND WON'T
JUMP A SYNAPSE.
WE ARE ASKING, DO THESE TWO
MEET?
HERE IS SOME OF THE DATA.
WE INJECTED A LOT OF TRACER
THAT'S WHY YOU SEE DAMAGE BUT WE
INJECTED A LOT OF TRACE TORE
FILL AS MUCH OF THE MOTOR CORTEX
AS POSSIBLE, AT LEAST THE
SINGING PART, AND WE FOUND THAT
THIS REGION PROJECTS TO -- THESE
ARE AXONS HERE, TO THE PART OF
THE TRIATUM THAT SHOWED THE
SINGING-DRIVEN ACTIVATION.
SO THAT MADE SENSE.
AND THEN GOING DOWN TO THE
BRAINSTEM, HERE IS YOUR CHOLERA
TOXIN BACKFILL FROM THE MOTOR
NEURONS THAT PROJECT TO THE
MUSCLE AND HERE ARE YOUR AXONS
COMING FROM THE CORTEX.
AND WE LOOK TO SEE IF THEY MET
THERE AND THE ANSWER IS, YES.
THIS SHOWN HIGH POWER NOW AND WE
FOUND MANY EXAMPLES OF THIS.
THIS IS A MOTOR NEURON THAT
SYNAPSES ON TO THE MUSCLES AND
THESE BLACK LINES ARE AXONS THAT
CAME DOWN FROM THE PRIMARY MOTOR
CORTEX.
AND SOME OF THEM MAKE MULTIPLE
CONTACTS.
AND YOU ROUGHLY FIND 1-2 AXONS
PER MOTOR NEURON OR 2-3
CONTACTS.
AND SO, THIS DEMONSTRATED THAT
THE DIRECTION IS PROJECTED -- I
MEAN THE PROJECTION IS DIRECT.
BUT, THERE IS A DIFFERENCE OF
WHAT WE HAD SEEN IN SONG BIRDS
AND EVEN WITH LIMITED MATERIAL
IN HUMANS.
THE PROJECTION IS PRETTY SPARSE.
IT'S ONLY ONE OR TWO AXONS PER
MOTOR NEURON.
WHEREAS WE CAN FIND 10S IF NOT
HUNDREDS COMING DOWN FROM THE
CORTEX IN BIRDS TO THE VOCAL
MOTOR NEURONS.
IT MADE ME WONDER, DID FOLKS WHO
HAD STUDIED NONHUMAN PRIMATES
MISS THIS PROJECTION?
OR ARE MICE MORE SIMILAR TO
HUMANS THAN PRIMATES ARE?
FOR THIS CONNECTIVITY?
AND THERE ARE A LOT OF PEOPLE
WHO ARE DOUBTING THAT MICE WOULD
BE MORE SIMILAR TO HUMANS THAN
NONHUMAN PRIMATES AND I'M SURE
MOST OF YOU WOULD DOUBT THAT.
SO I MENTIONED BEFORE THAT THOSE
WHO DID THE WORK IN NONHUMAN
PRIMATES FOR THE LAST 20 YEARS,
PRESENTED A DRAWING BUT NOT THE
ACTUAL PRIMARY DATA.
SO THE LAST PERSON WHO PUBLISHED
ON THIS WAS CHRISTINA SIMONE WHO
ACTUALLY WORKED HERE AT NIDCB
AND FOR HER Ph.D. THESIS
BEFORE SHE CAME HERE, SHE
ACTUALLY TRIED TO VERIFY THE
ABSENCE OF THIS PROJECTION IN
NON-HUMAN PRIMATES AND I VISITED
HER LAB.
AND WE WENT THROUGH OUR MOUSE
AND PRIMATE BRAIN SECTIONS
TOGETHER SIDE-BY-SIDE TO SEE IF
IN MACAQUES THEY DON'T HAVE THIS
PROJECTION FROM HER CORTICAL
INJECTIONS.
AND WHAT YOU SEE HERE IS THIS
STAINED SECTION IN NUCLEUS
AMBIGUOUS IN THE VERTICULAR
FORMATION AROUND IT.
AND YOU CAN SEE MANY AXONS IN
THE VERTICULAR FORMATION NEXT TO
NUCLEUS AMBIGUOUS FROM HOAR
CORTICAL INJECTIONS BUT COULDN'T
FIND ANY AXONS IN THE PRIMARY
DATA.
NOT EVEN A SINGLE ONE.
SO THAT IS SUGGESTING THERE IS A
DIFFERENCE.
BUT LI COME TO THE END THAT
THERE MIGHT BE OTHER
EXPLANATIONS FOR THESE
DIFFERENCES BEYOND SPECIES
DIFFERENCES.
BUT I WANT YOU TO HOLD ON TO
THAT THOUGHT.
ANOTHER THING WE LEARNED ABOUT
IS AUDITORY CONNECTIVITY.
THERE IS ANOTHER HYPOTHESES
DIFFERENT FROM THE DIRECT
PROJECTION FROM THE CORTEX
HYPOTHESES.
THAT HYPOTHESES GOES THAT IN
HUMANS, WE HAVE THE AUDITORY
CORTEX SENDS A DIRECT PROJECTION
TO PREMOTOR AND MAYBE MOTOR
VOCAL AREAS THAT NONHUMAN
PRIMATES DO NOT HAVE, THAT
NONHUMAN PRIMATES MAY HAVE A
VOICE AREA OR SPEECH AREA BUT
THEY DON'T HAVE PROPER
CONNECTIVITY TO THESE REGIONS.
AND THIS REGION, THIS CONNECTION
OF FAMOUS NEUROSCIENCE IS CALLED
THE -- [ INDISCERNIBLE ] SO WHEN
WE WERE LOOKING AT THE
CONNECTIVITY OF MICE WITH THE
INJECTIONS IN THE MOTOR CORTEX,
IT SURPRISED US TO FIND THAT THE
DISTINCTLY LABELED AREA COMPARED
TO ALL OF THE OTHER AREAS IN THE
SECONDARY AUDITORY CORTEX LAYER
THREE NEURONS OF THE SECONDARY
AUDITORY CORTEX WHICH ARE KNOWN
TO BE THE TYPE OF NEURONS THAT
CONNECT ONE CORTICAL REGION TO
THE OTHER.
AND SO, WE ACTUALLY FOUND SUCH A
PROJECTION AND WE ALSO FOUND
THAT THIS CORTICAL REGION
PROJECTS TO A PART OF THE
THALAMUS, AND THAT IS WHAT THESE
BLACK LINES ARE IN THE BLACK
DOTS OR CELLS THAT PROJECT UP TO
THIS MOTOR CORTEX REGION.
SO IT LOOKS LIKE IT'S FORMING
INTEGRATED CIRCUIT WITH THE
STRATUM, THALAMUS AND WITH THE
AUDITORY CORTEX.
NOT VISUAL CORTEX.
FOR THIS PART OF THE STRATUM.
JUST TO THROW YOU, HERE IS A
PRIMARY AUDITORY CORTEX,
SECONDARY IS NEXT TO IT SENDING
PROJECTION HERE.
AND WE STILL NEED TO VERIFY WITH
A TRACER INJECTED HERE IN THE
AUDITORY CORTEX TO SHOW AXONS
GOING UP TO THE M1.
SO, TO SUMMARIZE, THIS PART OF
THE EXPERIMENT, WHAT WE HAVE
SHOWN HERE IS THE MOUSE AND SONG
BIRD IN THE HUMAN AND THE
CHICKEN AND THE MACAQUE BRAIN
AGAIN, AND THE MOUSE BRAIN
CONNECTIVITY IS LOOKING MORE AND
MORE LIKE A SONG BIRD IN THE
HUMAN THAN IT IS IN THE MACAQUE
OR CHICKEN, WITH SOME
DIFFERENCES N THIS CASE, A WEAK
OR A SPARSE PROJECTION FROM THE
PRIMARY MOTOR CORTEX AS OPPOSED
TO A HEAVY ONE IN SONG BIRD AND
HUMAN.
IT'S NOT IDENTICAL BUT IT LOOKS
LIKE SOMETHING MORE DEGREE
RATHER THAN ABSOLUTE DIFFERENCE.
SO, THE NEXT QUESTION WE ASKED
IS WHETHER MICE REQUIRE THE
MOTOR CORTEX TO PRODUCE THESE
VOCALIZATIONS.
WE DON'T FINISH THEY ARE LEARNED
BUT DO THEY REQUIRE IT?
IN SONG BIRDS, WHENEVER YOU
KNOCK OUT OR BASICALLY LESION
THESE MOTOR PATHWAY SONG NUCLEI,
YOU ELIMINATE THE ABILITY TO
PRODUCE SONGS, NOT EVEN A PHASIA
SONG.
JUST ELIMINATE THE ABILITY TO
PRODUCE IT.
INNATE CALLS ARE IN TACT.
I'M GOING TO SHOW YOU AN EXAMPLE
FROM MY FORMER Ph.D.'S WORK.
HERE IS A CANARY SONG.
I'LL PLAY THE SOUND.
[ BIRDS SINGING ]
THIS IS A CANARY SONG THAT IS
LEARNED.
IT SOUNDS DIFFERENT THAN MICE.
AND HERE IS A CANARR THEY HAS
HBC OR -- A LESION AND HE IS
TRYING TO PRODUCE SONG OPENING
UP THE BEAK GETTING OUT FAINT
SOUNDS.
BUT ACTUALLY NO LEARNED SONG.
SO THEY DOCK
THEIR -- [ CHIRPING ]
-- THEY CAN DO INNATE ALARM
CALLS AND YOU THEY CAN SCREAM
WHEN YOU PICK THEM UP BUT THEY
DON'T PRODUCE LEARNED
VOCALIZATIONS.
IN HUMANS, IF YOU -- IF THE
MOTOR CORTEX, SO BASICALLY THE
GENERAL ORAL FACIAL CORTEX
REGION IS DAMAGED, THE REGION
THAT MAKES THAT DIRECT
PROJECTION, WE ALSO LOSE THE
ABILITY TO PRODUCE SPEECH.
WE CAN STILL CRY, WE CAN STILL
LAUGH, WE CAN STILL MAKE WHAT IS
SUPPOSED LIE INNATE SOUNDS BUT
WE CAN'T PRODUCE LEARNED SPEECH.
AT LEAST THAT'S WHAT I READ IN
LITERATURE AND THAT'S WHAT HAS
BEEN TOLD.
IN MICE, WHAT DO WE KNOW?
WE DIDN'T KNOW ANYTHING.
SO WE PLACED LESIONS IN THE M1
MOTOR CORTEX AS WELL AS IN THE
VISUAL CORTEX FOR CONTROL GROUP
AND PERFORM SURGERIES FOR
ANOTHER CONTROL AND TO DO THIS
EXPERIMENT, WHEY TO FIND A WAY
TO CATEGORIZE MOUSE
VOCALIZATIONS.
THEY WERE QUITE VARIABLE.
WE CATEGORIZED THEM BY THEIR
FREQUENCY PROFILE THAT IS NO
PITCHED JUMPS IN THIS ONESHIRE
PITCHED JUMP THAT GOES DOWN.
THAT'S THE RED DOT.
A PITCHED JUMP GOES UP.
AND WE WERE ABLE TO GET ROUGHLY
8-12 DIFFERENT CATEGORIES OF
VOCALIZATIONS.
AND THEN WE IN THESE ANIMALS
THAT WE PERFORMED LESIONS, WE
RECORDED THOSE VOCALIZATIONS AND
THEN AFTERWARDS, WE INJECTED THE
RABIES VIRUS IN THE LA RINKAL
MUSCLES AND THEN SHAM SURGERY
MUSCLES, WE VERIFIED THE NEURONS
ARE STILL THERE.
IN THE OTHER ANIMALS, WE CAN SEE
VERY FEW NEURONS LEFT.
THIS IS JUST TO SHOW YOU A
PERCENTAGE OF THE LAYER 5
NEURONS THAT ARE GONE.
AND THESE ANIMALS AND WE LOOKED
AT THEIR SONGS OR THEIR BEFORE
AND AFTER LESIONS.
AND WHAT WE FOUND, SHAM
SURGERY-TREATED ANIMALS ARE
FINE.
THEY ARE SINGING SONGS BEFORE
AND AFTER BUT MOTOR CORTEX
LESION ANIMALS UNLIKE SONG BIRDS
AND UNLIKE HUMANS, WERE ALSO
SINGING WHAT LOOKED LIKE A SONG
AFTERWARDS.
NOT LITTLE FAINT PEEPS OR SORT
OF INNATE TYPE OF OR SIMPLE
SOUNDS.
BUT WE ALSO NOTICED SOMETHING
DIFFERENT.
IF YOU NOTICE WHAT I'M POINTING
TO THESE SILL BELLS, IT'S
SHOWING A LOT MORE FREQUENCY
MODULATION THAN WHAT THE MICE
PRODUCED BEFORE THE CORTICAL
LESION.
AND THAT IS SHOWN QUANTITATIVELY
HERE.
THE RED BAR IS THE MOTOR CORTEX
LESION ANIMALS AND THIS
REPRESENTS THE BASICALLY THE
STANDARD DEVIATION OF THE PITCH
AND THE FREQUENCY MODULATION.
BOTH OF THEM ARE MUCH HIGHER
ACTIVE LESION THAN BEFORE
COMPARED TO THE SHAM SURGERY OF
THE VISUAL CORTEX LESIONS.
AND TO SHOW YOU THAT IN MORE
DIAGRAMMATIC -- OR IN A
DISTRIBUTION, SHOWING THE
FREQUENCY OF THE PITCH, AND THE
PERCENT OF THE SYLLABLE
REPERTOIRE WITHIN THAT FREQUENCY
RANGE, YOU CAN SEE BEFORE THE
LESION THERE IS A MORE TIGHTER
DISTRIBUTION OF THE PITCH, WHERE
AFTER THE LESION, THIS ANIMAL IS
PRODUCING PITCH THAT IS MUCH
MORE DISTRIBUTED.
INDICATING LESS CONTROL OR LESS
MODULATION OR LESS CONTROL OF
THE MODULATION OF THE
VOCALIZATION.
AT THE TIME, WE DISCOVERED THIS,
A PAPER CAME OUT LAST YEAR FROM
THE COLLEAGUE OF MINE SHOWING
THAT WHEN MALE MICE AND THIS IS
MALES IN THIS CASE, GO FROM PUP
EARLY VOCALIZATIONS TO
ADULTHOOD, THEY HAVE A WIDER
DISTRIBUTION IN THEIR PITCH THAT
THEN BECOMES MORE NARROWLY
FOCUSED AS ADULTS.
SO WHAT WE THINK MIGHT BE
HAPPENING HERE IS THAT THE MOTOR
CORTEX MAY BE HAVING SOME
CONTROL OVER THE PITCH OR THE
FREQUENCY MODDIZATION OF THE
VOCALIZATIONS WHEREAS THE
BRAINSTEM MAY BE CONTROLLING THE
ACTUAL PRODUCTION OF THE SOUNDS.
WHICH IS SIMILAR TO SNAG IS
FOUND IN SONG BIRDS, NOT FROM
LEARNED SONG BUT FROM LEARNED
CALLS.
A SONG BIRD, MALE SONG BIRD HAS
INNATE CALLS AND IT WILL LEARN
TO MODIFY THOSE INNATE
VOCALIZATIONS WITH CORTICAL
INPUT FOR WHATEVER REASONS, AND
IF YOU LESION THAT CORTICAL
INPUT AFTERWARDS, THE BIRD CAN'T
SING THE LEARNED SONG BUT CAN
STILL PRODUCE THE CALLS IN THEIR
INNATE FORM.
SO THAT IS THE HYPOTHESES WE ARE
WORKING ON ON THAT.
SO I'M GOING PUT THIS AS A
PARTIAL, YES.
THAT THEY DO REQUIRE PARTIAL
INPUT OR PARTIAL REQUIREMENT FOR
THE VOCAL MOTOR CORTEX TO
PRODUCE THE VOCALIZATIONS.
IN THIS CASE TO PRODUCE A MORE
SHARPER TUNING OF THOSE
VOCALIZATIONS.
SO WHAT ABOUT THE AUDITORY
FEEDBACK?
IN SONG BIRDS, AND IN HUMANS, AS
I MENTIONED EARLIER, WHEN WE
BECOME DEAF, OUR VOCALIZATIONS
DETERIORATE.
HERE IS A EXAMPLE FROM A
COLLEAGUE OF MINE ON THE CEREBRA
FINCH T SOUNDS DIFFERENT THAN A
CANARY.
I'M GOING PLAY THIS.
CAN WE HAVE THAT VOLUME TURNED
BACK UP.
[ CHIRPING ]
THAT'S AN ECHO BUT YOU GET THE
POINT.
HERE IS ROUGHLY A YOUNG ANIMAL
AFTER BEING DEAF.
[ CHIRPING ]
YOU CAN TELL IT SOUNDS MORE
VARIED.
IT SOUNDS LESS STEREOTYPED.
WHEREAS, I DON'T HAVE THE
RECORDINGS OF THIS BUT IN A SUB
SONG BIRD LIKE THE CHIMP OF THE
SONG BIRD WORLD, BEFORE AND
AFTER DEAFENING, THEY DIDN'T SEE
ANY DIFFERENCES IN THE SYLLABLE
STRUCTURE IN THESE SIMPLE SONGS.
IT'S THE EASTERN FEE BEE.
SO WHAT ABOUT MICE?
SO, IF WE DEAF END MICE, IT TOOK
US HOW TO FIGURE OUT HOW TO DEAF
EN THEM, BUT WE REMOVED THE
COAKLEYIA AND I'M GOING PLAY YOU
THE SONG NOW PITCHED DOWN TO THE
HUMAN HEARING RANGE BUT SLOW IT
DOWN.
>> WHIT ELFING ]
>> THIS IS BEFORE DEAFENING.
>> ]
WHISTLING ]
YOU GET THE POINT.
IT ALMOST SOUNDS LIKE A WHALE
WHEN YOU SLOW IT DOWN.
YOU CAN SEE WITHOUT ME PLAYING
IT YET THAT ROUGHLY 8 MONTHS
AFTER DEAFENING, IT TOOK TIME
BUT IT DID SHOW UP.
YOU HAD TO WAIT.
IT LOOKED LIKE THERE WAS SOME
DEGRADATION AND PART OF THE TIME
THAT THE BIRD WAS SINGLING
SYLLABLES HERE, PARTICULARLY FOR
THE MORE COMPLEX SYLLABLE TYPE.
THIS IS WHAT IT SOUNDS LIKE.
[ WHISTLING ]
SO YOU CAN HEAR THEIR RASPINESS
IN THAT SOUND.
SO IT'S NOT A -- IT'S
DEGRADATION.
IT'S NOT AS ROBUST AS THE TYPE
OF DEGRADATION YOU SEE IN SONGS
BIRDS BUT IT'S THERE AS OPPOSED
TO NOT BEING THERE AT ALL.
THAT'S SHOWN IN THE TIME COURSE.
WE SAW IT ROUGHLY 3-8 MONTHS YOU
START TO SEE THESE ROBUST
DIFFERENCES DIFFERENCES THE
FREQUENCY OF THE SOUND GOES UP
AND THE STANDARD DEVIATION OF
THE PITCH.
IN OTHER WORDS, THE SOUNDS
BECOME MORE NOISIER.
THE RED LINE IS THE DEAF END
ANIMALS AND IN HUMANS AND SONG
BIRDS, WHEN WE ARE DEAF, EARLY
IN LIFE, OUR SPEECH IS EVEN
WORSE THAN LATER ON.
SO, WE HAD A HARD TIME GETTING
VIABLE DEAF END MICE EARLY ON AS
PUPS BECAUSE THE EAR CANAL IS
CLOSED, IT'S HARD TO DO THE
SURGERY.
SO WHAT WE DID IS FOR GENETIC
TOOL, WE CASPASE 3 KNOCKOUT,
IT'S A GENE INVOLVED IN CELL
DEATH, THOSE ANIMALS SHOWED
NORMAL MOTOR BEHAVIOR BUT THEY
LOSE HEARING WITHIN THE FIRST
FEW WEEKS AFTER BEING BORN.
AND LISTENING TO THEIR SONGS
BASICALLY BEFORE DEAFENING IT'S
SIMILAR.
I'M GOING PLAY AFTERWARDS.
I CALL IT THE MOUSE GODZILLA.
SO THIS IS ALSO MORE
DETRIMENTAL.
NOW THERE COULD BE SECONDARY
EFFECTS HERE THAT WE DON'T KNOW
ABOUT.
WE HAVE TO TEST THIS IN OTHER
ANIMALS WHO ARE ALSO DEAF WITH
OTHER GENETIC DISORDERS TO BE
CERTAIN ABOUT IT.
BUT IN TERMS OF GENETIC
MUTATIONS, IT'S THE MOST ABARENT
SONG I HAVE HEARD OF IN ANY
MOUSE THAT SOMEONE HAS KNOCKED
OUT A PARTICULAR GENE IN.
AND THIS IS JUST TO SHOW YOU
QUANTITATIVELY THAT THE PITCH
GOES DOWN.
THERE IS MORE NOISE IN THE
SPECTRUM PURITY OF THESE
VOCALIZATIONS.
FIND IT QUANTITATIVELY AND THE
SIMPLE TYPE BOTTLES ARE MORE OF
THEM AND THAT'S THE ORANGE
LABELED AREA HERE.
AND JUST TO SHOW YOU, WE CAN
FIND AS SHOWN IN THE ORIGINAL
PAPERS IN THESE CASPASE KNOCKOUT
ANIMALS, THE EAR HAIR CELLS ARE
MISSING IN THESE ANIMALS
COMPARED TO THE WILDTYPE C
PETCHES.
SO, I'M GOING TO SAY -- C57s,
A PARTIAL REQUIREMENT ON
AUDITORY FEEDBACK TO MAINTAIN
AND DEVELOP THE VOCALIZATIONS,
THE CASPASE THREE KNOCK OUT AN
SMALL DRAMATIC.
THE ADULT DEAF UNDERSTAND
ANIMALS ARE NOT AS DRAMATIC --
DEAF END.
IT'S THERE AS OPPOSED TO
COMPLETELY ABSENCE.
SO WHAT ABOUT VOCAL LIMITATION?
WE HAD A HARD TIME TESTING THIS
BECAUSE IT'S HARD TO QUANTIFY
THESE MOUSE VOCALIZATIONS.
NOT ONLY THAT, WE WERE SEEING
MICE SHOW CHANGES IN THEIR
VOCALIZATIONS BUT WE COULDN'T
FIGURE OUT WHAT WAS CAUSING IT.
AND WE NOTICED THAT THESE TWO
DIFFERENT STRAINS THAT WE
MEASURED, THE CASPASE 3 ANIMALS,
THEIR WILDTYPE PRECURSORS AND
ANOTHER SET OF MICE CALLED
BXDs, WERE PRODUCING THEIR
SONGS AT DIFFERENT PITCHES.
IF YOU KEPT THEM IN SAME COLONY
CONDITIONS.
AND WE MIXED THEM TOGETHER AND
SAW THE PITCHES START TO CHANGE
BUT COULDN'T GET A RELIABLE
CHANGE.
THEN WE DISCOVERED THAT IF WE
TOOK A C57 MALE, PAIR IT WITH A
BXD MALE, AND A BXD FEMALE, WHAT
HAPPENED IS THAT THOSE C57 MALES
CHANGED OVER THE COURSE OF TWO-8
WEEKS REALLY BY 8 WEEKS, THE
PITCH OF THEIR SONGS CHANGE COME
DOWN TO THE LEVEL OF THE BXD
MALE THAT THEY WERE HOUSED WITH.
AND WE THOUGHT IT WAS THE FEMALE
THAT WAS MAYBE COULD HAVE BEEN
DRIVING THAT CHANGE.
SO WE DID THE COMPLEMENTARY
EXPERIMENT IN C57 MALE A BXD
MALE AND A C57 FEE NILE MATCH
THAT MALE THERE AND AGAIN, THE
C57 MALES WENT DOWN.
THE BXD MALES WENT UP A LITTLE
BIT THIS TIME.
THESE ARE BOX PLOTS.
SO THEY ARE REPRESENTING THE
FULL RANGE OF THE PITCH.
SO YOU CAN SEE THERE IS NO
OVERLAP IN ANY OF THE ANIMALS
BEFORE CROSS HOUSING AND NOW
HAVE YOU MUCH MORE OVERLAP BY
THE END OF THE EIGHT WEEK
PERIOD.
SO IS THIS PITCH IMITATION?
DIFFERENT ANIMALS, YOU CAN SEE
THE RANGE HERE, THERE SAY RANGE
ROUGHLY A 20 KALE HERTZ RANGE IN
THE PITCH DISTRIBUTION EVEN OF
THE BXDs BEFORE YOU HOUSE THEM
AND LIKEWISE A RANGE HERE.
SO WE LOOKED AT THE DIFFERENCE
OF THE PITCH OF INDIVIDUAL CAGE
MATES AND GRAPHED THAT
DIFFERENCE AND FOUND THAT THOSE
INDIVIDUAL CAGED MATES, EVEN
THOUGH THEIR RANGES WERE
DIFFERENT, THEY WERE CONVERGING
ON TO THIS SAME PITCH RANGE TO
EACH OTHER OVER THIS EIGHT-WEEK
PERIOD.
TO SHOW YOU THIS IN A MORE
DRAMATIC FORM BEFORE AND AFTER,
HERE IS THE PITCH DIFFERENCE
BEFORE THE CROSS HOUSING
CONDITION.
HERE IS THE PITCH DIFFERENCE
AFTERWARDS.
SOME ANIMALS WENT TO A ZERO
PITCH DIFFERENCE IN THEIR SONGS.
AND THERE WAS ONE PAIR, MALE
PAIR WHERE AT SIX WEEKS THEY
WERE AT ZERO PITCH DIFFERENCE
AND THEN THE FOLLOWING WEEK ONE
OF THE ANIMALS SHOT WAY UP TO GO
WAY OUT OF THEIR RANGE.
MY INTERPRETATION IF I CAN PUT A
HUMAN BEND TO THIS IS STOP
SINGING
SINGING IN MY PITCH RANGE
OTHERWISE I'M GOING TO CHANGE OR
YOU CHANGE.
SO THIS IS EVIDENCE OF PITCH
MATCHING.
I DON'T WANT TO CALL IT PITCH
IMITATION YET, BUT IT IS AS
CLOSE AS WE GET TO SOME FORM OF
IMITATION.
WE DIDN'T SEE CHANGE IN THE
REPERTOIRE COMPOSITION BUT THE
REP TIRE COMPOSITION DIDN'T
DIFFER TO BEGIN WITH.
WHILE WE WERE WORKING ON THE
STUDY, A COLLEAGUE OF MINE WERE
ALSO TRYING SIMILAR EXPERIMENT
IN ANOTHER GROUP OF MICE WHERE
THEY CROSS FOSTERED PUPS OF TWO
DIFFERENT STRAINS AT A YOUNG AGE
AND CLAIMED TO NOT SEE THE
FOSTERED ANIMALS SHIFT UP IN
PITCH WITH THEIR FOSTER PARENTS.
CLAIMING THAT THE VOCALIZATIONS
ARE INNATE.
BUT WHAT THEY DID IN THEIR
EXPERIMENTS, THEY ONLY CROSS
FOSTERED THEM FOR A 3-WEEK
PERIOD.
WHEN WE CROSS HOUSED FOR 3
WEEKS, WE ALSO DON'T SEE THE
CHANGE.
IT HAS TO BE ANYWHERE FROM LIKE
4-8 WEEKS.
AND YOU REALLY NEED WAIT THAT
FULL 8 WEEKS TO SEE THAT CHANGE.
STOW THEY ARE REPEATING THEIR
EXPERIMENT BASED UPON OUR
FINDING TO SEE IF WE CAN EXPLAIN
THIS DIFFERENCE BETWEEN STUDIES.
SO WE GET YES HERE AGAIN.
I DON'T KNOW HOW FAR VOCAL
LIMITATION GOES BUT WE DO HAVE
PITCH MATCHING.
SO NOW I'M GOING TO END OFF WITH
GENES AND THEN SUMMARIZE.
SO, THERE ARE MOLECULAR
SIMILARITIES BETWEEN SONG BIRDS
AND HUMANS THAT WE CAN ASK FOR
THE PRESENCE OR ABSENCE IN MICE?
AND WE DIDN'T KNOW AN ANSWER TO
THAT UNTIL THE LAST FEW YEARS
AND EVEN MORE SO RECENTLY BUT
THE HYPOTHESES IS THE HBZ
SIMILAR TO THE HUMANS IN THE
STRATUM WOULD BE SIMILAR TO PART
OF THE STRATUM IN HUMANS THAT
WOULD DAMAGE THESE TO A PHASEIO
DEFICIT AND THAT RA, WHICH MAKES
THAT DIRECT PROJECTION, IS GOING
TO BE FUNCTIONALLY ANALOGOUS TO
THE MOTOR CORTEX WHICH MAKES THE
DIRECT PROJECTION.
AND TO THEFT HYPOTHESES, WE DID
LASER DISECTION OF THE SONG
NUCLEI IN SONG BIRDS AND THE
SURROUNDING AREAS HERE, POPPED
THEM UP TO A -- AND THEN
ISOLATED RNA, HYBRIDIZED THEM TO
MICROARRAYS AND THE SAME THING
WAS DONE BY THE ALLEN BRAIN
INSTITUTE WITH THE HUMAN BRAIN.
IT'S LARGER BRAIN, OF COURSE.
THEY DISSECTED 900 BRAIN REGIONS
FROM ROUGHLY TWO DIFFERENT
PEOPLE, A MAN AND A WOMAN, POST
MORTEM, OF COURSE, AND ISOLATED
RNA AND HYBRIDIZED THEM TO
MICROARRAYS.
AND FORTUNATELY, THEY MAKE THIS
DATA PUBLICLY AVAILABLE, WHICH
THEY DID THIS PAST YEAR.
AND WE COMPARED OUR DATA WITH
THE HUMAN DATA AND TO DO THIS,
TO COMPARE 900 BRAIN REGIONS
WITH THESE SONG NUCLEI IN SONG
BIRDS, WE ASKED, IS THERE ANY
GENE EXPRESSION DIFFERENCE IN
THE SONG NUCLEI OF SONG BIRDS?
WE ALSO DID PARROTS AND HUMMING
BIRDS.
COMPARED TO THE SURROUNDING
BRAIN AREAS THAT SAY THIS IS A
SPECIALIZED GENE EXPRESSION
PATTERN THAT YOU FIND IN THE
SONG BIRD VOCAL REGION.
CAN YOU FIND A SIMILAR
SPECIALIZED PATTERN OUT OF THESE
900 DISSECTED LOCATIONS IN THE
HUMAN BRAIN?
AND THE ANSWER, WE WHITE NOT
FIND ANYTHING.
THE ANSWER WAS, YES.
WE DEMONSTRATE THAT IN TREE FORM
HERE.
SO THIS IS PART OF THE FRONTAL
CORTEX AND THESE ARE DIFFERENT
REGIONS OF THE FRONTAL CORTEX
AND FOR THE RA SONG NUCLEUS IN
SONG BIRDS, THERE WAS ONE REGION
HIGHLIGHTING GREEN HERE, THAT
HAD A STRONGLY SIGNIFICANT GENE
EXPRESSION CORRELATION WITH THE
PRESENT RECALL GYRUS OF THE
CENTRAL SULK AS PART OF THAT AT
THE VENTRAL BANK OF THE CORTEX,
WHERE YOU FIND PHASE MOTOR
CORTEX.
THAT WAS QUITE EXCITING AND IT
WAS HIGHLY SIGNIFICANT AS I
SAID.
AND A NUMBER OF THESE GENES THAT
SHOWED THIS SPECIALIZED
EXPRESSION SHOWED EVIDENCE OF IF
ANYBODY HEARD ABOUT THIS,
POSITIVE SELECTION, ON CUTTING
SEQUENCE AS WELL, IN CEREBRA
FITCH RELATIVE TO CHICKEN --
ZEBRA FITCH.
LOOKING AT THESE PATTERNS, WHAT
WE FIND IS THAT THE RA GENE
EXPRESSION PROFILE IS MOSTLY IN
THE MOTOR CORTEX IN HUMANS.
HBC, WE DON'T FIND ANY PARALLEL,
NOT YET, AND IT IS THE HEAD OF
THE -- IN HUMANS COMPARED TO ALL
OTHER STRAY 8AL REGIONS.
TO SHOW YOU EXAMPLE OF THESE
GENES, IT'S THE HEAT MAP.
THREE DIFFERENT INDIVIDUAL ZEBRA
FITCHES AND THREE PARROTS, AND
BLUE MEANS DOWN REGULATED
RELATIVE TO SURROUNDING CORTICAL
AREAS.
RED MEANS UP REGULATED AND WE
FIND A NUMBER OF AXON GUIDANCE
GENES IN THIS LIST.
THE TOP ONE BEING SLIT ONE WHICH
HAPPENS TO BE A TARGET OF FOX P2
FOR THOSE WHO HEARD ABOUT THAT
GENE.
AND THE HUMAN FOX P2 GENE
MUTATED WHICH CAUSES SPEECH
DEFICITS, REGULATES SLEEP 1 MORE
ROBUSTLY THAN THE CHIMPANZEE
VERSION OF FOX P2 AND WE SEE IT
DOWN EGULATED IN THIS MOTOR
CORTEX REGION.
SO WE STUDIED THAT FORWARD ARE
FURTHER VERIFIED THAT THE FOX P2
GENE, THIS IS NOW WHAT IS CALLED
THE ARCO PAIL YON, IT'S THE
NEURON THAT PROJECT OUT OF THE
FOREBRAIN, THE SONG NUCLEUS PART
OF THE -- HAS DOWNREGULATION OF
THAT GENE AND THE SONG BIRD AND
THE HUMMINGBIRD AND THE PARROT.
BUT NOT IN THE RING DOVE OR THE
QUAIL.
WHICH ARE NONVOCAL LEARNING
SPECIES.
SO, WE ASKED, WHAT ABOUT MICE?
AND SO, WE LOOKED AT THE MOTOR
CORTEX REEG WRONG WE FOUND THE
SINGING-DRINK GENE EXPRESSION IN
MICE.
HERE IS THE MOTOR CORTEX REGION.
HERE IS THE SINGING-DRIVEN GENE
EXPRESSION IN SONG BIRDS AND
MICE.
AND WE FOUND SOME GENES WHICH WE
JUST PUBLISHED, NOT ONLY THE
AXON GUIDANCE MODEL, THE CALCIUM
BINDING PROTEINS OVEREXPRESSED
IN THE SONG BIRDS AND WE DID NOT
FIND OVEREXPRESSION IN THE MOTOR
CORTEX REGION RELATIVE TO OTHER
CORTICAL REGIONS IN MICE.
SO IT WASN'T LIKE A VOCAL
AR -- VOCAL LEARNING.
THE SAME THING WITH THE FOX P2
TARGETS.
HERE IS THE DOWNREGULATION AGAIN
COMPARED TO THE OTHER NEURONS
THAT PROJECT OUT OF THE
FOREBRAIN WHEREAS IN MICE, IT'S
NOT OVERALL IN LAYER 5, IT'S NOT
LOWER THAN THE OTHER ADJACENT
CORTICAL REGIONS.
ROBO 1, THE RECEPTOR FOR SLIT 1
HAS ALSO A DIFFERENTIAL PATTERN
ISOLATED CELLS THAT EXPRESSION
OF RA.
WE DON'T SEE SUCH A DIFFERENTIAL
PATTERN IN THE MOTOR CORTEX.
IT'S A LITTLE HIGHER.
IN THIS CASE, IT IS CLOSER TO
THE SONG BIRD SITUATION.
THEN, A PAPER WAS PUBLISHED THIS
YEAR AND WE STARTED TO THINK THE
MICE ARE NOT LIKE SONG BIRDS IN
THE GENE EXPRESSION PROFILES.
BUT A PAPER PUBLISHED IN
NEUROSCIENCE, HAD SHOWN THAT IN
THE MOUSE FOREBRAIN, THERE ARE
ISOLATED LAYER 5 NEURONS
SPARSELY DISTRIBUTED THAT
EXPRESS FOX P2, THE RED SIGNAL
HERE, AND C TIP 2, A MOLECULE
THAT TAGS CELLS THAT MAKE
PROJECTIONS OUT OF THE
FOREBRAIN.
SO, LIKE IN SONG BIRDS, JUST NOT
AS MANY, WE HAVE THESE LAYER 5
NEURONS EXPRESSING SOME OF THESE
GENES BUT JUST NOT AS HIGH
LEVELS.
AND WE ARE GOING TO ASK THE SAME
QUESTION OF SLIT 1 EXPRESSING
THESE NEURONS MORE SPARSELY
DISTRIBUTED?
I'M GOING TO END AUTOPSY WITH A
FOX PERCEIVE 2 STORY TO TELL YOU
WHAT WE KNOW ABOUT IT IN SONG
BIRDS AND A LITTLE BIT IN MICE.
I'M GOING PLAY TO YOU A SOUND
FILE OF CHILDREN AT DIFFERENT
DEVELOPMENTAL STAGES THAT HAVE
FOX P2 MUTATION, AND SHOW YOU
HOW IT EFFECTS PEACH PRODUCTION.
-- SPEECH PRODUCTION.
COULD YOU TURN THE SOUND UP?
[ CLICKS ]
[ CHILD MAKING SOUNDS ]
THIS IS A 2-YEAR-OLD CHILD.
YOU CAN'T TELL WHAT SHE'S
SAYING.
[ CHILD MAKING SOUNDS ]
IS SO THIS IS SOMEONE WHO IS
OLDER.
[ CHILD MAKING SOUNDS ]
HE IS 6 YEARS OLD [ CHILD MAKING
SOUNDS-SPEAKING ]
I'M GOING TO STOP HERE.
THAT IS SOMEONE WHO IS 11.
BASICALLY BY THE TIME THEY GET
BETTER AND SO FORTH BUT THEY ARE
NOT GOOD AT SPEECH PRODUCTION IN
THE WAY THAT A NORMAL CHILD IS.
THEY ARE BETTER AT COMPREHENSION
BUT EVEN COMPREHENSION IS
EFFECTED BUT NOT AS MUCH AS
SPEECH PRODUCTION.
IN SONG BIRDS, I'M GOING TO GO
QUICKLY SO WE CAN FINISH UP.
IN SONG BIRDS, WE FIND FOX P2 IS
EXPRESSED IN THE BASAL GANGLIA
AS IT IS IN HUMANS AND OTHER
VERTEBRATES.
IT'S UPREGULATED IN A JUVENILE
BIRD DURING THE CRITICAL PERIOD
FOR VOCAL LEARNING.
IT THERE IS A CORRELATION.
THEY INJECTED AN RNAI HOOKED UP
TO A GFP MOLECULE HERE IN THE
AREA X NUCLEUS AND SHOWN IT
DOWNREGULATES THE FOX P2 HERE
WHEREAS IT IS EXPRESSED AND
SHOWN HERE THE PROTEIN IS DOWN
REGULATED BUT NOT OTHER GENES
LIKE ACTIN, AND THEN GIVE THESE
FOX P2 KNOCKDOWN ANIMALS A TUTOR
AND HAVE A CONTROL GROUP THAT
HAS CONTROL HERE THAT HAS ALSO
HAS A TUTOR.
I'M GOING PLAY YOU THE TUTOR
SONG.
[ JOKING ]
>> HERE IS THE CONTROL
KNOCKDOWN.
[ SQUEAKING ]
HERE IS ANOTHER TUTOR AND HERE
IS THE FOX P2 KNOCKDOWN 2T
[ SQUEAKING ]
SO YOU CAN HEAR THE DIFFERENCE.
LIKE HUMANS, THE BIRDS CAN STILL
SING THEY CAN STILL LEARN
SOMETHING ABOUT THE SONG.
THERE IS SOME RESEMBLANCE IN THE
SYLLABLES BUT THEY DON'T
ACCURATELY LEARN THE SILL BELLS
OR THE STRUCTURE AND THEY GET
THE SEQUENCING INCORRECTLY.
SO THIS IS A PARALLEL.
WHAT ABOUT MICE?
THERE HAS BEEN A NUMBER OF
STUDIES DONE ON NICE A LOT OF
THE BEHAVIORAL WORK I WOULD SAY
IS NOT BEEN UP TO THE KIND OF
PARTHAT WE HAVE APPLIED TO SONG
BIRDS IN HUMANS.
SO WE STARTED COLLABORATING WITH
SONG AND -- SIMON FISHER
WELL-KNOWN FOR HIS STUDIES.
THEY GENERATE A KNOCKIN MICE
WITH THE KE FAMILY MUTATION AND
SOME PEOPLE STUDIED THOSE MICE
AND FOUND THAT THEY VOCALIZE
LESS BUT THAT IS ALL THEY LOOKED
AT.
THEY HAVEN'T CHARACTERIZED MUCH
FURTHER.
WE BEGAN CHARACTERIZING THOSE
MICE AND WE FOUND THAT
COMPARED -- YOU HAVE TO DO A
HETEROZYGOUS.
IF YOU DO A HOMOZYGOUS ON BOTH
CHROMOSOMES, THE ANIMALS DIE.
ONLY HETEROZYGOUS HUMANS
SURVIVE.
THIS SAY MOUSE WITH THE KE
FAMILY MUTATION AND YOU CAN SEE
THAT BY LOOKING AT THESE TWO
SONO GRAMS, I HOPE YOU NOTICE
THAT AT LEAST THIS EXAMPLE,
SOUNDS LOOK MORE SIMPLE.
IF YOU DO A PLOT OF THE
REPERTOIRE HERE, YOU SEE THERE
IS MORE SIMPLE SOUNDS IN THERE
REPERTOIRE.
AND YOU CAN SEE THAT HERE ALSO
THAT THE FREQUENCY VARIANCE, THE
FREQUENCY MODULATION IS MUCH
LESS IN THE FOX P2 KNOCKIN MICE,
WHEREAS THE PITCH AT WHICH THEY
SING IS NO DIFFERENT.
SO IT'S NOT EFFECTING ALL THINGS
ABOUT THE VOCALIZATIONS BUT A
LOT OF THE MODULATION.
AND SO, THIS IS SIMILAR OR MAYBE
EVEN OPPOSITE WHAT YOU HAVE
MIGHT FIND IN CHILDREN DEPENDING
ON YOUR INTERPRETATION.
BUT IS EFFECTING THE
VOCALIZATIONS HERE.
SO I'M GOING SAY THAT WE DON'T
FIND GENE EXPRESSION
SPECIALIZATIONS IN MICE, BLAINE
WE FIND IN HUMANS AND SONG
BIRDS, BUT WE DO FIND A PARTIAL
REQUIREMENT ON GENES LIKE FOX P2
AS WE FIND IN SONG BIRDS AND
HUMANS.
I'M GOING SAY NONE YET FOR THE
GENE EXPRESSION SPECIALIZATIONS.
SO WHAT IS GOING TO HERE?
I THINK THAT VOCAL LEARNING MAY
NOT BE A DICHOTOMOUS TRAIT.
SPEECH WHO HAS IT AND WHO
DOESN'T HAVE IT?
THAT ABILITY MY NOT BE
DICHOTOMOUS.
THAT MICE ARE LIMITED VOCAL
LEARNINGS AND SOME ARE
INTERIMMEDIATE IT CONTINUUM THAT
I PROPOSED THAT MAY EXIST.
AND THAT MICE, IF THAT IS THE
CASE, IF BELIEVE ME, MICE SERVE
AS GOOD GENETIC MODELS FOR SOME
PROPERTIES THOUGHT TO BE UNIQUE
TO HUMANS FOR SPEECH-LANGUAGE
DISORDERS.
AND GIVEN THAT IT COULD BE
CONVERGENT, I WOULD SAY -- OR IF
CONTINUE Y WE MIGHT BE ABLE TO
USE MICE TO TRY TO GENETICALLY
ENHANCE THE CIRCUIT.
THIS IS A HYPOTHESES I'M GOING
TO BE TESTING NEXT OR TRYING TO
TEST IN MY LAB.
NOW WE HAVE THESE MOLECULES THAT
WE KNOW ARE VO LUSTILY EXPRESSED
IN THE HUMAN BRAIN CIRCUIT FOR
SPEECH.
AND IN THE SONG BIRD IN THE
PARROT BRAIN CIRCUIT FOR VOCAL
LIMITATION.
AND THAT YOU DON'T SEE IN THE
MICE.
AND WHAT WE ARE GOING TO TRY TO
DO IS TO OVEREXPRESS SOME OF
THESE GENES OR UNDEREXPRESS THEM
DEPENDING ON THE PATTERN IN
HUMANS AND SONG BIRDS, IN THE
MOUSE AND ONE REGION -- M1
REGION TO SEE IF WE CAN ENHANCE
THIS PROJECTION THAT ALREADY
EXISTS.
SO THIS STORY HAS MADE THIS GOAL
OF MINE EASIER BECAUSE THE MICE
ALREADY HAS THE CONNECTION.
1-2 AXONS PER MOTOR NEURON.
CAN I MAKE IT 10?
AND ALLOW THE MOUSE TO POTENTIAL
VE GREATER VOLITIONAL CONTROL
OVER HIS VOCALIZATIONS?
AND I WILL GIVE CREDIT TO THE
FUNDERS FOR THIS PROJECT, NIH
DIRECTOR'S PIONEER AWARD WHO
WOULD, ALLOWED ME TO GO IN THIS
RISKY DIRECTION.
HOWARD HUGHES MEDICAL INSTITUTE
AND NIDCD.
AND I HAVE TO GIVE CREDIT, THIS
IS MY TEAM HERE, ALTHOUGH I
MENTIONED THIS IS THE WORK OF
TWO PEOPLE IN THE LAB, BUT
COLLABORATIVE WORK FROM OTHERS
AND I'LL END THERE.
THANK YOU.
[ APPLAUSE ]
>> WE HAVE TIME FOR A FEW
QUESTIONS FROM DR. JARVIS.
I'D LIKE TO REMIND EVERYONE
THERE IS A RECEPTION IN THE
LIBRARY IMMEDIATELY AFTERAWARDS
WITH REFRESHMENTS PROVIDED AND
SPONSORED BY FAES.
>> ALL RIGHT.
YES?
>> HI.
SO THAT IS A LOT OF VERY LOVELY
DATA.
SO, AS I THINK YOU KNOW, ANOTHER
GROUP HAS DEAF END NEWBORN MICE
ON DAY ONE USING A DIFFERENT
MECHANISM AND THE MOMENT I THINK
THEY ARE CLAIMING THEY DON'T OR
SEEM NORMAL DEVELOPMENT OF MOUSE
SONG.
SO, WHAT DO YOU MAKE OF THAT?
>> I WISH I COULD SHARE THAT
DATA.
THEY DID MENTION IT AT A
MEETING.
ANOTHER GROUP HAS -- SO THERE
ARE SEVERAL GROUPS LOOKING THAT
THE.
THEY HAVE A DIFFERENT
STRAIN -- THERE IS A WAY OF
FEEDING THESE MICE A DRUG THAT
CAUSES THEIR EAR HAIR CELLS TO
DIE-OFF AT A EARLY AGE AND THEY
START LOSING THE EAR HAIR CELLS
ABOUT TWO DAYS OLD AND THEY ARE
GONE AT ABOUT 10 DAYS.
AND MICE DON'T REALLY START
HEARING UNTIL ABOUT 12 DAYS.
THEY CLAIM TO SEE NO EFFECT ON
THE VOCALIZATIONS.
ON THE MICE AND THEY LOOKED AT
MANY DIFFERENT PARAMETERS.
AND I DON'T KNOW THE ANSWERS TO
WHY THE DIFFERENCE IS THERE
EXCEPT TO SAY THAT I KNOW THAT
THEY DIDN'T LOOK AT THE
FREQUENCY MODULATION.
WHICH IS WHAT WE LOOKED AT.
AND THE PITCH DISTRIBUTION.
THE PITCH OF THE FREQUENCY RANGE
OF THE PITCH.
AND WITH THAT GROUP, WE DECIDED
WE ARE GOING TO SWITCH DATASETS
AND ANALYZE THE DATA WITH EACH
OTHER'S APPROACHES TO SEE IF WE
CAN RECONCILE WHAT THE
DIFFERENCES ARE.
YES IS THIS.
>> HI.
I WONDERED IF ANYBODY HAD
RECORDED THE VOCALIZATIONS OF
WILD FIELD MICE IN DIFFERENT
NEIGHBORHOODS?
AND IF IT WERE DISTRIBUTEDLY
DIFFERENT IN DIFFERENT
NEIGHBORHOODS IF THAT WOULD BE
INFORMATIVE?
>> THAT IS AN INTERESTING
QUESTION BECAUSE BEFORE I EVEN
STARTED DOWN THIS MOUSE PATH, IT
WAS ALREADY KNOWN THAT COUNTER
INTUITIVELY, VOCAL LEARNING BIRD
SPECIES IN CAPTIVITY SING MORE
COMPLEX SONGS THAN THEIR
WILDTYPE COUNTERPARTS.
THAT IS NOT BECAUSE WE ARE
SELECTING.
IT LOOKS LIKE THE FEMALES ARE
SELECTING FOR THIS.
THE MORE VARIED THE SOUNDS, THE
MORE THE FEMALE LIKES IT.
AND SO WHAT IS SELECTING AGAINST
IS THE IDEA OF PREDATION OR AT
LEAST MY HYPOTHESES IS THAT YOU
DON'T HA BIT 8 TO VARIED SOUNDS
THAT EASILY, EVEN PREDATORS.
SO I WAS THINKING MAYBE WHAT IS
HAPPENED IS THAT JACKSON
LABORATORIES UNINTENTIONALLY
EVOLVING VOCAL LEARNING WITH
WITH THE LABORATORY WITH THESE
RESULT SONIC COURTSHIP SONGS AND
MAYBE LABORATORY MICE ARE MORE
DOWN THIS PATH THAN WILDTYPE.
AND IF THEY WERE TRUE, THEN THE
WILDTYPE MICE SHOULD SING MORE
STEREOTYPED SONGS AND SOMEONE
PUBLISHED A PAPER LAST YEAR
SAYING THAT WILDTYPE MICE DO
SING MORE STEREOTYPED SONGS.
SO, WHAT WE WOULD LIKE TO DO IS
GET WILD MICE AND ACTUALLY DOT
TRACER INJECTIONS AND SEE IF
THEY HAVE THIS PROJECTION OR
NOT.
>> I GUESS THAT'S IT.
THANK YOU FOR YOUR ATTENDANCE.
[ APPLAUSE ]
>> THANK YOU.