Of mice, birds, and men: the ultrasonic song system of mice has features in common with vocal learners

Of mice, birds, and humans: The mouse ultrasonic song system has features similar to humans and song-learning birdsErich D. JarvisDuke University Medical CenterHoward Hughes Medical InstituteDepartment of NeurobiologyOctober 9th, 2012Researchers mouse song projectGustavo Arriaga, PhD(Graduate student) Graduated May 20111-st authorEric Zhou, BAGraduated May 2010Now in Medical School2nd-author

Erich Jarvis, PhDProject leaderProfessor Duke UnivSenior-author

Vocal learners

Convergent behavior: vocal learning substrate for speechDepends on auditory feedback, vocal critical periods,cultural transmission, syntax,Deaf-induced vocal disorders, aphasias, speech sound disorder, autism,AVIAN FAMILY TREEHackett et al 2008 tree****onlyhumans3

Holy and Guo showed mice have songs with acoustic features like song learning birds?Holy and Guo 2005 PLoS BiolIndividual differencesGoal was to test hypothesis using vocal non-learning species: chicken for birds and mice for mammalsAre mice vocal learners or not? Never tested!Mouse song in real timeMouse song slowedHypothesis about evolution of vocal learning trait: birds and mammalsProject 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 recordingsCould not find any study that tested vocal learning and the mouse song systemSo we set out discover the system and test whether or not these vocalizations have traits of vocal learners.41. Mouse singing-driven gene expression

M1A1brainatlas.mbi.ufl.eduArriaga, Zhou, Jarvis 2012 From Figure 2Activated brain regions: ambiguus, central grey, motor cortex, striatum, auditory cortexComparison with learners and non-learnersIn-situs of ambiguus, laryngeal motor cortex, underlying dorsal striatum, and auditory cortex (olfactory bulb, ventralateral thalamus)Quantifications arc, egr1

5

Exclusively in Layer V neurons of singing-induced M1 cortex regionIIIIIIIV

V

VI

CgM2M1Arriaga, Zhou, Jarvis 2012 From Figure 3Is 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 darkfield6

Singing activated M1 projects directly to vocal motor neurons (Amb)But projection is sparse: 1-2 axons per motor neuronArriaga, Zhou, Jarvis 2012 From Figure 32. Mouse song system connectivity more similar to songbird and human

Arriaga, Zhou, Jarvis 2012 From Figure 1

3. Posterior vocal motor pathway produces learned vocalizations

XXXXEliminate song productionInnate calls intactEliminate song/speech productionCrying/laughing intactEXPERIMENT 3:Motor cortex lesion (n=5)Visual cortex lesion (n=5)Sham surgery (n=6)

Nottebohm et al 1976 J Comp Neurol9Lesions: in vocal learners

down jumpsup jumps

Record song, ibotenic acid lesion, record song again, backfill with PRV and verify lesion.Experiment 3. M1 laryngeal cortex lesionsLead to greater singing variation: aphasia of song?

Arriaga, Zhou, Jarvis 2012 From Figure 4

Deafened mice show some song deteriorationCaspase-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

5. Song pitch convergence caused by competitive social experienceCo-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 6TraitsVocal learners*Vocal non-learners**MiceBRAINCortical & striatal brain regions active in vocal productionYESNOYESDirect forebrain projection to brainstem vocal motor neuronsYESNOYES, sparseRequire vocal motor cortex to produce learned vocalizationsYESNOYES, partialBEHAVIORRequire auditory feedback to develop and maintain vocalizations: deafened-induced vocal deteriorationYESNOYES, partialVocal imitationYESNOYES, pitchTraits unique to vocal learners*Vocal learners: e.g. humans, songbirds, parrots, hummingbirds. **Vocal non-learners: e.g. non-human primates, cat, chicken, pigeonReviewed 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.What is vocal learning?Traits unique to vocal learners:

In brain: Use of the cortical/pallial regions active in producing vocalizationsDirect projection from motor cortex to vocal motor neurons.Requirement of the cortex to produce and learn vocalizations

Behavior:Requirement of auditory feedback to maintain vocalizationImitation of sounds of heard

13SummaryWe 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.humansongbirdmicemacaquechickenVocal learning and brain pathway continuum(not solely based on species related)Funding for projects presentedNIH Directors Pioneer AwardHoward Hughes Medical InstituteNIDCD R01-DC007218

15Big questionsEITHERMice are more similar to humans and song learning birds for vocal communication traits than are non-human primates are to humansORMuch of the last 50 years of research on differences between vocal learners and non-learners needs to be re-evaluated