1. Of mice, birds, and humans: The mouse ultrasonic song system has features similar to humans and song-learning birds
Erich D. Jarvis
Duke University Medical Center
Howard Hughes Medical Institute
Department of Neurobiology
October 9th, 2012

2. Researchers – mouse song project
Erich Jarvis, PhD
Project leader
Professor Duke Univ
Senior-author
Gustavo Arriaga, PhD
(Graduate student)
Graduated May 2011
1-st author
Eric Zhou, BA
Graduated May 2010
Now in Medical School
2nd-author

3. Convergent behavior: vocal learning – substrate for speech
AVIAN FAMILY TREE
only
humans * *
Hackett et al 2008 tree * *
Depends on auditory feedback, vocal critical periods,
cultural transmission, syntax,…
Deaf-induced vocal disorders, aphasias,
speech sound disorder, autism,…
Vocal learners

4. Are mice vocal learners or not? Never tested!
Goal was to test hypothesis using vocal non-learning species: chicken for birds and mice for mammals
Holy and Guo showed mice have songs with acoustic features like song learning birds?
Mouse song in real time
Hypothesis about evolution of vocal learning trait: birds and mammals
Project to identify axon guidance molecule mutations unique to vocal learners, and then manipulate them. Needed to use mice as controls.
But mouse songs like songbird songs – Guo and Holly 2005 sonograms and recordings
Could not find any study that tested vocal learning and the mouse song system
So we set out discover the system and test whether or not these vocalizations have traits of vocal learners.
Mouse song slowed
Individual differences
Are mice vocal learners or not? Never tested!
Holy and Guo 2005 PLoS Biol

5. 1. Mouse singing-driven gene expressionA1
brainatlas.mbi.ufl.edu
Activated brain regions: ambiguus, central grey, motor cortex, striatum, auditory cortex
Comparison with learners and non-learners
In-situs of ambiguus, laryngeal motor cortex, underlying dorsal striatum, and auditory cortex (olfactory bulb, ventralateral thalamus)
Quantifications arc, egr1
Arriaga, Zhou, Jarvis 2012 From Figure 2

6. Exclusively in Layer V neurons of singing-induced M1 cortex regionII
III IV V VI Cg
Is the connection direct or indirect.
Inject BDA tracer into motor cortex region and simultaneously inject Cholera Toxin B into laryngeal muscles to backfill ambiguus motor neurons.
8 animals on target, bilaterally.
Found projection to lateral dorsal striatum, same location as singing regulated gene expression: brightfield to darkfield
Arriaga, Zhou, Jarvis 2012 From Figure 3

7. Singing activated M1 projects directly to vocal motor neurons (Amb)
But projection is sparse: 1-2 axons per motor neuron
Arriaga, Zhou, Jarvis 2012 From Figure 3

8. 2. Mouse song system connectivity more similar to songbird and human
Arriaga, Zhou, Jarvis 2012 From Figure 1

9. 3. Posterior vocal motor pathway produces learned vocalizationsX X X X
EXPERIMENT 3:
Motor cortex lesion (n=5)
Visual cortex lesion (n=5)
Sham surgery (n=6)
Eliminate song production
Innate calls intact
Eliminate song/speech production
Crying/laughing intact
Lesions: in vocal learners
Nottebohm et al 1976
J Comp Neurol

10. Experiment 3. M1 laryngeal cortex lesions
Record song, ibotenic acid lesion, record song again, backfill with PRV and verify lesion.
down jumps
up jumps
Lead to greater singing variation: aphasia of song?
Arriaga, Zhou, Jarvis 2012 From Figure 4

11. Deafened mice show some song deterioration
Caspase-3 a cystein proteases that play essential roles in programmed cell death. CASP3 KO causes loss of ear hair cells by 1 month (Takahasi et al 2001 Brain Res)
Arriaga, Zhou, Jarvis 2012 From Figure 5

12. 5. Song pitch convergence caused by competitive social experience
Co-house adult C57 males + BxD males that sing at different pitches
in the presence of either a C57 female or BxD female
Arriaga, Zhou, Jarvis 2012 From Figure 6

13. Traits unique to vocal learners
Vocal non-learners**
Mice
BRAIN
Cortical & striatal brain regions active in vocal production
YES NO
Direct forebrain projection to brainstem vocal motor neurons
YES, sparse
Require vocal motor cortex to produce learned vocalizations
YES, partial
BEHAVIOR
Require auditory feedback to develop and maintain vocalizations: deafened-induced vocal deterioration
Vocal imitation
YES, pitch
What is vocal learning?
Traits unique to vocal learners:
In brain:
Use of the cortical/pallial regions active in producing vocalizations
Direct projection from motor cortex to vocal motor neurons.
Requirement of the cortex to produce and learn vocalizations
Behavior:
Requirement of auditory feedback to maintain vocalization
Imitation of sounds of heard
*Vocal learners: e.g. humans, songbirds, parrots, hummingbirds.
**Vocal non-learners: e.g. non-human primates, cat, chicken, pigeon
Reviewed in: Doupe & Kuhl 1999 Ann Rev Neurosci; Hauser et al 2002 Science; Jarvis 2004 Ann NY Acad Sci; Jurgens & Ehrenreich 2007 Brain Res; Fischer & Hammerschmidt 2010 Genes, Brain & Behav.

14. Summary
We propose that vocal learning is not dichotomous, but a continuous trait. Mice are limited vocal learners, in the middle.
Mice might serve as genetic models for some properties thought unique to humans for speech-language disorders.
Given the convergent behavior, neural networks, and genetics for vocal learning, it is theoretically possible to genetically enhance the circuit.
chicken
macaque
mice
songbird
human
Vocal learning and brain pathway continuum
(not solely based on species related)

15. NIH Director’s Pioneer Award Howard Hughes Medical Institute
Funding for projects presented
NIH Director’s Pioneer Award
Howard Hughes Medical Institute
NIDCD R01-DC007218

16. Big questions
EITHER
Mice are more similar to humans and song learning birds for vocal communication traits than are non-human primates are to humans OR
Much of the last 50 years of research on differences between vocal learners and non-learners needs to be re-evaluated