The dorsal cochlear nucleus (DCN) integrates auditory nerve input with a diverse array of sensory and motor signals processed in circuitry similar to that of the cerebellum. Yet how the DCN contributes to early auditory processing has been a longstanding puzzle. Using electrophysiological recordings in mice during licking behavior, we show that DCN neurons are largely unaffected by self-generated sounds while remaining sensitive to external acoustic stimuli. Recordings in deafened mice, together with neural activity manipulations, indicate that self-generated sounds are cancelled by non-auditory signals conveyed by mossy fibers. In addition, DCN neurons exhibit gradual reductions in their responses to acoustic stimuli that are temporally correlated with licking. Together, these findings suggest that DCN may act as an adaptive filter for cancelling self-generated sounds. Adaptive filtering has been established previously for cerebellum-like sensory structures in fish, suggesting a conserved function for such structures across vertebrates.
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Cant, N.B. The cochlear nucleus: neuronal types and their synaptic organization. in The Mammalian Auditory Pathway: Neuroanatomy (eds. Webster, D.B. et al.) 66–116 (Springer, New York, 1992).
Bell, C.C. Evolution of cerebellum-like structures. Brain Behav. Evol. 59, 312–326 (2002).
Berrebi, A.S., Morgan, J.I. & Mugnaini, E. The Purkinje cell class may extend beyond the cerebellum. J. Neurocytol. 19, 643–654 (1990).
Mugnaini, E., Warr, W.B. & Osen, K.K. Distribution and light microscopic features of granule cells in the cochlear nuclei of cat, rat, and mouse. J. Comp. Neurol. 191, 581–606 (1980).
Lorente de Nó, R. Central representation of the eighth nerve. in Ear Diseases, Deafness and Dizziness (ed. Goodhill, V.) 64–86 (Harper and Row, Hagerstown, Maryland, USA, 1979).
Oertel, D. & Young, E.D. What's a cerebellar circuit doing in the auditory system? Trends Neurosci. 27, 104–110 (2004).
Fujino, K. & Oertel, D. Bidirectional synaptic plasticity in the cerebellum-like mammalian dorsal cochlear nucleus. Proc. Natl. Acad. Sci. USA 100, 265–270 (2003).
Tzounopoulos, T., Kim, Y., Oertel, D. & Trussell, L.O. Cell-specific, spike timing-dependent plasticities in the dorsal cochlear nucleus. Nat. Neurosci. 7, 719–725 (2004).
Zhao, Y. & Tzounopoulos, T. Physiological activation of cholinergic inputs controls associative synaptic plasticity via modulation of endocannabinoid signaling. J. Neurosci. 31, 3158–3168 (2011).
Young, E.D. & Davis, K.A. Circuitry and function of the dorsal cochlear nucleus. in Integrative Functions in the Mammalian Auditory Pathway (eds. Oertel, D. et al.) 160–206 (Springer, New York, 2002).
Kanold, P.O. & Young, E.D. Proprioceptive information from the pinna provides somatosensory input to cat dorsal cochlear nucleus. J. Neurosci. 21, 7848–7858 (2001).
Shore, S.E. & Zhou, J. Somatosensory influence on the cochlear nucleus and beyond. Hear. Res. 216–217, 90–99 (2006).
Wigderson, E., Nelken, I. & Yarom, Y. Early multisensory integration of self and source motion in the auditory system. Proc. Natl. Acad. Sci. USA 113, 8308–8313 (2016).
Bell, C., Bodznick, D., Montgomery, J. & Bastian, J. The generation and subtraction of sensory expectations within cerebellum-like structures. Brain Behav. Evol. 50 (Suppl. 1), 17–31 (1997).
Bell, C.C., Han, V. & Sawtell, N.B. Cerebellum-like structures and their implications for cerebellar function. Annu. Rev. Neurosci. 31, 1–24 (2008).
Luo, F., Wang, Q., Farid, N., Liu, X. & Yan, J. Three-dimensional tonotopic organization of the C57 mouse cochlear nucleus. Hear. Res. 257, 75–82 (2009).
Muniak, M.A. et al. 3D model of frequency representation in the cochlear nucleus of the CBA/J mouse. J. Comp. Neurol. 521, 1510–1532 (2013).
Ma, W.L. & Brenowitz, S.D. Single-neuron recordings from unanesthetized mouse dorsal cochlear nucleus. J. Neurophysiol. 107, 824–835 (2012).
Davis, K.A., Ding, J., Benson, T.E. & Voigt, H.F. Response properties of units in the dorsal cochlear nucleus of unanesthetized decerebrate gerbil. J. Neurophysiol. 75, 1411–1431 (1996).
Hancock, K.E. & Voigt, H.F. Intracellularly labeled fusiform cells in dorsal cochlear nucleus of the gerbil. I. Physiological response properties. J. Neurophysiol. 87, 2505–2519 (2002).
Rhode, W.S. Vertical cell responses to sound in cat dorsal cochlear nucleus. J. Neurophysiol. 82, 1019–1032 (1999).
Young, E.D. & Brownell, W.E. Responses to tones and noise of single cells in dorsal cochlear nucleus of unanesthetized cats. J. Neurophysiol. 39, 282–300 (1976).
Young, E.D. Identification of response properties of ascending axons from dorsal cochlear nucleus. Brain Res. 200, 23–37 (1980).
Manis, P.B., Spirou, G.A., Wright, D.D., Paydar, S. & Ryugo, D.K. Physiology and morphology of complex spiking neurons in the guinea pig dorsal cochlear nucleus. J. Comp. Neurol. 348, 261–276 (1994).
Zhang, S. & Oertel, D. Cartwheel and superficial stellate cells of the dorsal cochlear nucleus of mice: intracellular recordings in slices. J. Neurophysiol. 69, 1384–1397 (1993).
Eliades, S.J. & Wang, X. Sensory-motor interaction in the primate auditory cortex during self-initiated vocalizations. J. Neurophysiol. 89, 2194–2207 (2003).
Poulet, J.F. & Hedwig, B. A corollary discharge maintains auditory sensitivity during sound production. Nature 418, 872–876 (2002).
Rummell, B.P., Klee, J.L. & Sigurdsson, T. Attenuation of responses to self-generated sounds in auditory cortical neurons. J. Neurosci. 36, 12010–12026 (2016).
Schneider, D.M., Nelson, A. & Mooney, R. A synaptic and circuit basis for corollary discharge in the auditory cortex. Nature 513, 189–194 (2014).
Portfors, C.V. & Roberts, P.D. Temporal and frequency characteristics of cartwheel cells in the dorsal cochlear nucleus of the awake mouse. J. Neurophysiol. 98, 744–756 (2007).
Haenggeli, C.A., Pongstaporn, T., Doucet, J.R. & Ryugo, D.K. Projections from the spinal trigeminal nucleus to the cochlear nucleus in the rat. J. Comp. Neurol. 484, 191–205 (2005).
Zhou, J. & Shore, S. Projections from the trigeminal nuclear complex to the cochlear nuclei: a retrograde and anterograde tracing study in the guinea pig. J. Neurosci. Res. 78, 901–907 (2004).
Cullen, K.E. Sensory signals during active versus passive movement. Curr. Opin. Neurobiol. 14, 698–706 (2004).
May, B.J. Role of the dorsal cochlear nucleus in the sound localization behavior of cats. Hear. Res. 148, 74–87 (2000).
Sutherland, D.P., Glendenning, K.K. & Masterton, R.B. Role of acoustic striae in hearing: discrimination of sound-source elevation. Hear. Res. 120, 86–108 (1998).
Malmierca, M.S., Merchán, M.A., Henkel, C.K. & Oliver, D.L. Direct projections from cochlear nuclear complex to auditory thalamus in the rat. J. Neurosci. 22, 10891–10897 (2002).
Anderson, L.A., Izquierdo, M.A., Antunes, F.M. & Malmierca, M.S. A monosynaptic pathway from dorsal cochlear nucleus to auditory cortex in rat. Neuroreport 20, 462–466 (2009).
Lingenhöhl, K. & Friauf, E. Giant neurons in the rat reticular formation: a sensorimotor interface in the elementary acoustic startle circuit? J. Neurosci. 14, 1176–1194 (1994).
Ohlrogge, M., Doucet, J.R. & Ryugo, D.K. Projections of the pontine nuclei to the cochlear nucleus in rats. J. Comp. Neurol. 436, 290–303 (2001).
Tzounopoulos, T., Rubio, M.E., Keen, J.E. & Trussell, L.O. Coactivation of pre- and postsynaptic signaling mechanisms determines cell-specific spike-timing-dependent plasticity. Neuron 54, 291–301 (2007).
Dean, P., Porrill, J., Ekerot, C.F. & Jörntell, H. The cerebellar microcircuit as an adaptive filter: experimental and computational evidence. Nat. Rev. Neurosci. 11, 30–43 (2010).
Fujita, M. Adaptive filter model of the cerebellum. Biol. Cybern. 45, 195–206 (1982).
Chabrol, F.P., Arenz, A., Wiechert, M.T., Margrie, T.W. & DiGregorio, D.A. Synaptic diversity enables temporal coding of coincident multisensory inputs in single neurons. Nat. Neurosci. 18, 718–727 (2015).
Huang, C.C. et al. Convergence of pontine and proprioceptive streams onto multimodal cerebellar granule cells. Elife 2, e00400 (2013).
Ishikawa, T., Shimuta, M. & Häusser, M. Multimodal sensory integration in single cerebellar granule cells in vivo. Elife 4, e12916 (2015).
Kennedy, A. et al. A temporal basis for predicting the sensory consequences of motor commands in an electric fish. Nat. Neurosci. 17, 416–422 (2014).
Sawtell, N.B. Multimodal integration in granule cells as a basis for associative plasticity and sensory prediction in a cerebellum-like circuit. Neuron 66, 573–584 (2010).
Brooks, J.X., Carriot, J. & Cullen, K.E. Learning to expect the unexpected: rapid updating in primate cerebellum during voluntary self-motion. Nat. Neurosci. 18, 1310–1317 (2015).
Roy, J.E. & Cullen, K.E. Selective processing of vestibular reafference during self-generated head motion. J. Neurosci. 21, 2131–2142 (2001).
We thank L. Abbott, C. Bell and T. Jessell for comments on the manuscript. This work was supported by grants from the NIH (DC015449), the Alfred P. Sloan Foundation, the McKnight Endowment Fund for Neuroscience and the Irma T. Hirschl Trust to N.B.S. and an NIH grant (F30DC014174) to S.S.
The authors declare no competing financial interests.
Integrated supplementary information
Fusiform cells integrate direct auditory nerve fiber input (orange) with a diverse array of auditory and non-auditory inputs conveyed by a mossy fiber-granule cell-parallel fiber system (blue) similar to that found in the cerebellum and cerebellum-like structures associated with electrosensory processing in fish. Cartwheel cells (green) also receive parallel fiber input but lack direct input from the auditory nerve. Cartwheel cells inhibit fusiform cells. Our hypothesis regarding DCN function is that mossy fibers convey information related to the animal’s own movements and behavior, which serves to cancel out responses to self-generated acoustic stimuli. Such cancellation could be achieved by anti-Hebbian plasticity at parallel fiber synapses onto fusiform and/or cartwheel cells, as has been shown for cerebellum-like sensory structures in fish. For clarity, some DCN cell types and inputs have been omitted.
(a) Video stills from a representative mouse. Top, still of the mouse at rest. Bottom, zoomed in stills of the dash white box at different points during the lick cycle: i. jaw opening, ii. tongue protrusion and lick spout contact, iii-iv. tongue retraction, v. jaw closure. (b) The average spectrogram of licking sounds across mice (n = 20) triggered on tongue contact with the lick spout. White circles show the time-frequency peaks of the spectrograms of each individual mouse. Red crosses show time-frequency peaks of the average spectrogram. Dotted white line indicates time of tongue contact with the spout. Solid white line indicates the average RMS across mice. Roman numerals indicate the timing of the video stills shown in a. (c) Four examples of lick-triggered spectrograms from individual mice. White crosses show time-frequency peaks. Dotted line shows time of tongue contact with spout. (d) Histogram of the timing of the largest RMS peak of the licking sound with respect to onset of tongue contact with the lick spout. (e) Histogram of the timing of the largest RMS peak of the licking sound with respect to offset of tongue contact with the lick spout. (f) Histogram of the frequencies at which peaks in the lick-triggered spectrogram occur, showing that the lick-triggered sound consists of three distinct spectral peaks (dotted lines).
(a) Rectified extracellular multiunit activity (each row is the average of 15 presentations) recorded on an electrode penetration through the auditory brainstem in response to 100 ms tones ranging in frequency from 5-50 kHz (gray rectangles). As the electrode passes through DCN the frequency evoking the largest multiunit response smoothly decreases. DCN units were isolated in DCN at depths between 100 μm and 300 μm. A sudden increase in frequency (occurring between depths of 400 μm and 600 μm) indicated entrance into VCN. VCN units were isolated at depths between 800 μm and 1000 μm. (b) Histological verification of recording sites in the same animal as the multiunit recordings shown in a. Dextran-conjugated Alexa 594 (green) was iontophoretically injected at depths of 100 μm and 800 μm. Scale bar = 200 μm. (c) Iontophoretic injections of dextran-conjugated Alexa 594 at recording sites (arrows) in DCN (top) and VCN (bottom) in 3 additional animals. Scale bars = 200 μm.
(a) Histogram of spontaneous firing rates of all units recorded in DCN (n = 73), excluding complex-spiking units. The average spontaneous rate was 48.3 ± 28.2 Hz (mean and s.d.). No DCN units met previously established criteria for type II or type I/III responses, i.e. a spontaneous rate less than 2.5 Hz (arrow). Type II and I/III responses are associated with a major class of DCN interneuron known as vertical cells. (b) Histogram of responses to sound stimuli in DCN units (n = 60), excluding units with complex spikes. Stimuli included the mimic of the licking sound (12 dB SPL), 5-15 kHz bandpassed noise (15 dB SPL), and broadband noise used in pairing experiments recorded with a silicon probe. Average maximum noise response was 50.6 ± 26.3 Hz (mean and s.d.). No units showed inhibitory sound responses, a criterion for type III-i response cell types.
Representative 16-channel silicon probe recordings from the mouse dorsal cochlear nucleus. Electrode sites were arranged in a vertical linear array with individual sites separated by 25 μm. Tracks were made until a well-isolated unit emerged on a single electrode site. (a) A single unit with clear responses to 25 kHz and broadband noise (bottom trace). (b) A recording from the dorsal cochlear nucleus in another mouse showing multiunit responses to 35 kHz, 40 kHz, and broadband noise across multiple sites. A well-isolated single unit appears on the fourth most ventral site and has clear responses to 30 kHz (bottom trace), 35 kHz, and broadband noise.
Supplementary Figure 6 Pairing-induced reductions in DCN responses to correlated sounds are not related to variability in behavior or neural responses.
(a) Changes in licking behavior cannot explain pairing induced reductions in DCN responses. Lick rates at the start (first 150 licks) and end (last 150 licks) of the pairing experiments shown in Fig. 6. There was no difference in early versus late lick rates in DCN correlated (n = 20, P = 0.9, Wilcoxon Signed Rank Test), uncorrelated (n = 11, P = 0.9, Wilcoxon Signed Rank Test), or VCN correlated conditions (n = 7, P = 0.56, Wilcoxon Signed Rank Test). There also was no difference in lick rates between the three groups (P = 0.08, Kruskal Wallis test). (b-h) To examine possible sources of the variance in cancellation amongst DCN units in which acoustic stimuli were paired with licking, we also performed a multilinear regression with the variables shown in the figure as regressors. (b) The slope of the change during the pairing period (if any) in the lick rate did not correlate with decay rate during pairing (n = 20, P = 0.81). (c) The variability of licking, defined as the standard deviation of the interlick intervals between the twenty most recent licks, did not correlate with the decay rate during pairing (n = 20, P = 0.29). (d) The mean lick rate did not correlate with the decay rate during pairing (n = 20, P = 0.86). (e) Initial magnitude of DCN unit responses to the correlated sound did not correlate with the decay rate during pairing (n = 20, P = 0.19). (f) Mean baseline firing rate calculated for the entire recording did not correlate with decay rate during pairing (n = 20, P = 0.17). (g) The slope of the change (if any) in a unit’s baseline firing rate, defined as the mean firing rate in periods at least 20 ms before the next lick and 150 ms after the previous lick, did not correlate with decay during pairing (n = 20, P = 0.98). (h) Magnitude of a unit’s response to licking alone before pairing did not correlate with the decay rate during pairing (n = 10, P = 0.73).
Supplementary Figures 1–6 (PDF 1127 kb)
Left, Video of a head-fixed mouse licking a metal spout for water. The lick spout is the small metal tube with a spherical end in the bottom left of the frame. Video was recorded at 300 fps and played back at 30 fps and thus is slowed by a factor of ten. Right, r.m.s. amplitude of microphone recording; dashed line represents the time of the current frame. The microphone is the black object with metallic tip located just above the lick spout. By pausing the video, it is possible to see the relationship between RMS amplitude of the microphone recording and different phases of the licking behavior. (MP4 6538 kb)
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Singla, S., Dempsey, C., Warren, R. et al. A cerebellum-like circuit in the auditory system cancels responses to self-generated sounds. Nat Neurosci 20, 943–950 (2017). https://doi.org/10.1038/nn.4567
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