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Dan H. SanesDevelopment and Plasticity of the Auditory SystemSanes LabAlthough most synaptic connections within the brain have formed accurately by the time animals begin to hear, their precise number and strength remain malleable. It is this phase of development - the time during which auditory networks are susceptible to the sound environment - that engages our research program. In fact, despite enormous advances in our understanding of the growth and formation of the nervous system, we know little about the function of developing networks or the computations they perform. Our lab studies the development and function of brain circuits that encode auditory cues, and the emergence of adult perceptual skills. At the cellular level, we explore how early auditory experience influences the development of inhibitory synapses in the central auditory neuraxis and, more recently, in areas downstream from auditory cortex. At the systems level, we ask how auditory experience influences the maturation of auditory perception, and the cortical properties that support these skills. Ultimately, we seek to understand how the development and plasticity of synaptic and membrane properties permit networks to properly encode auditory cues, thereby supporting adult perceptual skills.
Inhibitory Synaptic Plasticity During Development We initially studied inhibitory projections in the auditory brainstem, and found that they become more precise during development, similar to excitatory projections. This process is influenced by the activity of inhibitory connections, and we have described candidate mechanisms, inhibitory long-term depression or potentiation, that may support the refinement of these contacts in response to the auditory experience (Kotak and Sanes, 2000; Chang et al., 2003; Kotak and Sanes, 2014).
Early Hearing Loss Disrupts Inhibitory Synapse Function In the short-term, we find that early hearing loss leads to a dramatic decrease of inhibitory synaptic strength and an increase in excitatory strength. This is true for both the auditory midbrain and the auditory cortex. For example, within 24 hours of hearing loss, inhibitory synapses within the auditory midbrain have become extremely weak, and this is due to a significant depolarization of the inhibitory synaptic reversal potential (Vale and Sanes, 2000; Vale et al., 2003). In cortex, the amplitude of fast spiking interneuron-evoked inhibitory postsynaptic currents declines by 60%, and the short-term plasticity of low threshold spiking interneuron-evoked responses fails to mature (Takesian et al., 2010).
Many of these synaptic and biophysical changes can be observed following a period of relatively mild hearing loss, and persist long after normal hearing is restored. When bilateral earplugs are inserted during the first week after the ear canals open, inhibitory synaptic and discharge properties remain depressed long after the plugs are removed and normal hearing is restored (Mowery et al., 2015). These findings suggest that even a transient period of hearing loss during childhood can lead to a long-lasting changes to central auditory nervous system function. Furthermore, they draw attention to the importance of considering both peripheral and central factors when trying to explain the perceptual deficits associated with early hearing loss. Until a few years ago, we would have concluded that the changes in synaptic gain or firing properties which attend early hearing loss can largely explain many of the known behavioral deficits. However, we have also discovered that that the synaptic mechanisms commonly thought to support learning (i.e., long-term potentiation) do not mature properly in the auditory cortex following early hearing loss. This is true for both excitatory and inhibitory synapses (Kotal et al., 2007; Xu et al., 2010). Furthermore, we have recently discovered that hearing loss induces cellular deficits in regions downstream from auditory cortex (Mowery, unpublished; Kotak, unpublished). The general implication is that both sensory and non-sensory deficits may contribute to behavioral problems associated with early hearing loss.
Maturation of Auditory Processing and Perception
To address these issues, we have characterized the development of auditory perception and established that even a brief period of auditory deprivation can lead to perceptual deficits (Sarro and Sanes, 2010, 2011; Rosen et al., 2012; Buran et al., 2014b; Caras and Sanes, 2015). Furthermore, findings suggest that auditory cortex processing is similarly impaired in animals reared with hearing loss (Rosen et al., 2012; Caras, unpublished). In addition, we now measure auditory cortex neuron processing with telemetry in freely moving animals that are performing psychometric tasks (Buran et al., 2014a). Finally, we have begun to study the development of auditory learning (Sarro and Sanes, 2011), and the impact of transient hearing loss on this cognitive skill (Caras and Sanes, 2015). In fact, we can combine auditory training with a brain slice analysis to assess synaptic plasticity mechanisms that are associated with auditory learning (Sarro et al., 2015)
Through each of these approaches, we seek to understand the cellular mechanisms that permit synaptic activity to influence the developing nervous system, and how they contribute to the construction of auditory computational circuits.
E-mail: sanes@cns.nyu.edu To see the software we use, please click here. Representative PublicationsSanes, D. H. (1990). An in vitro analysis of sound localization mechanisms in the gerbil lateral superior olive. J Neurosci 10, 3494-3506. [Reprint pdf file] Sanes, D. H., Markowitz, S., Bernstein, J., and Wardlow, J. (1992). The influence of inhibitory afferents on the development of postsynaptic dendritic arbors. J Comp Neurol 321, 637-644. [Reprint pdf file] - Large File Sanes, D. H. (1993). The development of synaptic function and integration in the central auditory system. J Neurosci 13, 2627-2637. [Reprint pdf file] - Large File Sanes DH, Takacs C (1993) Activity-dependent refinement of inhibitory connections. European J Neurosci 5, 570-574. [Reprint pdf file] Grothe, B., and Sanes, D. H. (1994). Synaptic inhibition influences the temporal response properties of gerbil medial superior olivary neurons: An in vitro study. J Neurosci 14, 1701-1709. Hafidi, A., Sanes, D. H., and Hillman, D. E. (1995). Regeneration of central auditory connections in an organotypic culture system. European J Neurosci 15, 1298-1307. Kotak VC, Sanes DH (1996) Developmental influence of glycinergic inhibition: Regulation of NMDA- mediated EPSPs. J Neurosci 16, 1836-1843. [Reprint pdf file]- Large File Sanes DH, Hafidi A (1996) Glycinergic transmission regulates dendrite size in organotypic culture. J Neurobiol 31, 503-511. [Reprint pdf file]- Large File Kotak VC, Sanes DH (1997) Deafferentation of glutamatergic afferents weakens synaptic strength in the developing auditory system. Eur J Neurosci 9, 2340-2347. Lo Y-J, Rao SC, Sanes DH (1998) Modulation of calcium by inhibitory systems in the developing auditory system. Neurosci 83, 1075-1084. [Reprint pdf file]- Large File Sanes DH, Malone BL, Semple MN (1998) Modulation of binaural level stimuli in gerbil inferior colliculus: role of synaptic inhibition. J Neurosci 18, 794-803. [Reprint pdf file]- Large File Kotak VC, Korada S, Schwartz IR, Sanes DH (1998) A developmental shift from GABAergic to glycinergic transmission in the central auditory system. J Neurosci 18, 4646-4655. [Reprint pdf file]- Large File Moore DR, Kotak VC, Sanes DH (1998) Commissural and lemniscal synaptic input to the gerbil inferior colliculus. J Neurophysiol 80, 2229-2236. [Reprint pdf file] Sanes DH, McGee J, Walsh EJ (1998) Metabotropic glutamate receptor activation modulates auditory processing in the cochlear nucleus. J Neurophysiol 80, 209-217. [Reprint pdf file] Thornton S, Semple MN, Sanes DH (1999) Development of auditory motion processing in the gerbil inferior colliculus. Eur J Neurosci 11, 1414-1420. [Reprint pdf file]- Large File Fitzgerald KK, Sanes DH (1999) Serotonergic modulation of synapses in the developing gerbil lateral superior olive. J Neurophysiol 81, 2743-2752. [Reprint pdf file] Hafidi A, Guo L, Sanes DH (1999) Transected commissural axons survive and grow, but do not cross a lesion site in organotypic culture. J Neurobiol 40, 267-280. [Reprint pdf file]- Large File Vale C, Sanes DH (2000) Afferent regulation of inhibitory synaptic transmission in the developing auditory midbrain. J Neurosci 20, 1912-1921. [Reprint pdf file]- Large File Kotak VK, Sanes DH (2000) Long-Lasting Inhibitory Synaptic Depression is Age- and Calcium Dependent. J Neurosci 20, 5820-5826. [Reprint pdf file] Sanes DH, Friauf E (2000) Review: Development and influence of inhibition in the lateral superior olivary nucleus. Hear Res 147, 6-58. [Reprint pdf file]- Large File Kotak VC, DiMattina C, Sanes DH (2001) GABAB and Trk receptor signaling mediates long lasting inhibitory synaptic depression. J Neurophysiol 86, 536-540. [Reprint pdf file] Kotak VC, Sanes DH (2002) Postsynaptic kinase signaling underlies inhibitory synaptic plasticity. J Neurobiol 53, 36-43. [Reprint pdf file] Vale C, Sanes DH (2002) The effect of bilateral deafness on excitatory synaptic strength in the auditory midbrain. Eur J Neurosci 16: 2394-2404. [Reprint pdf file] Svirskis G, Kotak VC, Sanes DH, Rinzel J (2002) Enhancement of signal-to-noise ratio and phase locking by a low threshold outward current in auditory neurons. J Neurosci 22: 11019-11025. [Reprint pdf file] Vale C, Schoorlemmer J, Sanes DH (2003) Deafness disrupts chloride transport and inhibitory synaptic transmission. J Neurosci 23: 7516-7524. [Reprint pdf file] Chang EH, Kotak VC, Sanes DH (2003) Long-term depression of synaptic inhibition is expressed postsynaptically in the developing auditory system. J Neurophysiol 90: 1479Ð1488. [Reprint pdf file] Green J, Kotak, VC, Sanes DH (2003) GABA and glycine evoked pH transients in developing auditory brain stem neurons. Brain Res 989: 122-127. [Reprint pdf file] Kotak VC, Sanes DH (2003) Gain adjustment of inhibitory synapses in the auditory system. Biol Cybernetics 89: 363-370. [Reprint pdf file] Hafidi A, Dastugue B, Grumet M, Sanes DH (2004) Factors preventing regeneration of inferior colliculus commissural axons in organotypic culture. J Comp Neurol 470: 80-92. [Reprint pdf file] Svirskis G, Kotak VC, Sanes DH, Rinzel J (2004) Sodium along with low threshold potassium currents enhance coincidence detection of subthreshold noisy signals in MSO neurons. J Neurophysiol 91: 2465-2473. [Reprint pdf file] Vale C, Juiz J, Moore, D, Sanes DH (2004) Unilateral hearing loss produces greater loss of inhibition in the contralateral inferior colliculus. Eur J Neurosci 20: 2133-2140. [Reprint pdf file] Kotak VC, Fujisawa S, Lee FA, Karthikeyan O, Aoki C, Sanes DH (2005) Hearing loss raises excitability in the auditory cortex. J Neurosci 25: 3908-3918. [Reprint pdf file] Yu X, Wadghiri YZ, Sanes DH, Turnbull DH (2005) In vivo auditory brain mapping in mice with Mn-enhanced MRI. Nat Neurosci 8: 961-968. [Reprint pdf file] Green JS, Sanes DH (2005) Early appearance of inhibitory input to the MNTB supports binaural processing during development. J Neurophysiol 94: 3826-3825. [Reprint pdf file] Sanes DH, Harris WA, Reh TA (2006) Development of the Nervous System, Academic Press: San Diego. [Publishers URL] Kotak VC, Breithaupt AD, Sanes DH (2007) Developmental hearing loss eliminates LTP in the auditory cortex. Proc Natl Acad Sci USA 104: 3550-3555. [Reprint pdf file] Xu H, Kotak VC, Sanes DH (2007) Conductive hearing loss disrupts synaptic and spike adaptation in developing auditory cortex. J Neurosci 27: 9417-9426. [Reprint pdf file] Yu X, Sanes DH, Aristizabal O, Wadghiri YZ, Turnbull DH (2007) Large-scale reorganization of the tonotopic map in mouse auditory midbrain revealed by MRI. Proc Natl Acad Sci USA 104: 12193-12198. [Reprint pdf file] Ter-Mikaelian M, Sanes DH, Semple MN (2007) Transformation of temporal properties between auditory midbrain and cortex in the awake Mongolian gerbil. J Neurosci 27: 6091-6102. [Reprint pdf file] Yu X, Zou J, Babb JS, Johnson G, Sanes DH, Turnbull DH (2008) Statistical mapping of sound-evoked activity in the mouse auditory midbrain using Mn-enhanced MRI. Neuroimage 39: 223-230. [Reprint pdf file] Kotak VC, Takesian AE, Sanes DH (2008) Hearing Loss Prevents the Maturation of GABAergic Transmission in the Auditory Cortex. Cereb Cortex 18: 2098-2108. [Reprint pdf file] Sarro EC, Kotak VC, Sanes DH, Aoki C (2008) Hearing Loss Alters the Subcellular Distribution of Presynaptic GAD and Postsynaptic GABAA Receptors in the Auditory Cortex. Cereb Cortex 18: 2855-2867. [Reprint pdf file] Miko IJ, Sanes DH (2009) Transient gain adjustment in the inferior colliculus is serotonin- and calcium-dependent. Hear Res 251: 39-50. [Reprint pdf file] Sanes DH, Bao S (2009) Tuning up the developing auditory CNS. Curr Opin Neurobiol 19: 188-199. [Reprint pdf file] Takesian AE, Kotak VC, Sanes DH (2009) Developmental hearing loss disrupts synaptic inhibition: implications for auditory processing. Future Neurol 4: 331-349. [Reprint pdf file] Xu H, Kotak VC, Sanes DH (2010) Normal hearing is required for the emergence of long-lasting inhibitory potentiation in cortex. J Neurosci 30: 331-341. [Reprint pdf file] Takesian AE, Kotak VC, Sanes DH (2010) Presynaptic GABA(B) receptors regulate experience-dependent development of inhibitory short-term plasticity. J Neurosci 30: 2716-2727. [Reprint pdf file] Sarro EC, Sanes DH (2010) Prolonged maturation of auditory perception and learning in gerbils. Dev Neurobiol 70: 636-648. [Reprint pdf file] Jercog PE, Svirskis G, Kotak VC, Sanes DH, Rinzel J (2010) Asymmetric excitatory synaptic dynamics underlie interaural time difference processing in the auditory system. PLoS Biol 8(6): e1000406. [Reprint pdf file] Rosen MJ, Semple MN, Sanes DH (2010) Exploiting development to evaluate auditory encoding of amplitude modulation. J Neurosci 30: 15509-15520. [Reprint pdf file] Sarro EC, Sanes DH (2011) The cost and benefit of juvenile training on adult perceptual skill. J Neurosci 31: 5383Ð5391. Sanes DH, Woolley SMN (2011) A behavioral framework to guide research on central auditory development and plasticity. Neuron 72: 912-929. Sanes DH, Harris WA, Reh TA (2012) Development of the Nervous System, Third Edition, Academic Press: San Diego. Takesian AE, Kotak VC, Sanes DH (2012) Age-dependent effect of hearing loss on cortical inhibitory synapse function. J Neurophysiol 107: 937-947. Overath T, Zhang Y, Sanes DH, Poeppel D (2012) Sensitivity to temporal modulation rate and spectral bandwidth in the human auditory system: fMRI evidence. J Neurophysiol 107: 2042-2056. Rosen MJ, Sarro EC, Kelly JB, Sanes DH (2012) Diminished behavioral and neural sensitivity to sound modulation is associated with moderate developmental hearing loss. PLoS One 7(7):e41514. Sanes DH (2013) Synaptic and Cellular Consequences of Hearing Loss. In: Deafness (Kral A, Fay RR, Popper AN, Eds) Springer-Verlag: New York. Kotak VC, Takesian AE, MacKenzie PC, Sanes DH (2013) Rescue of inhibitory synapse function following developmental hearing loss. PLoS One 8(1): e53438. Takesian AE, Kotak VC, Sharma N, Sanes DH (2013) Hearing loss differentially disrupts thalamic drive to two cortical interneurons. J Neurophysiol 110: 999-1008. Ter-Mikaelian M, Semple MN, Sanes DH (2013) Effects of spectral and temporal disruption on cortical encoding of gerbil vocalizations. J Neurophysiol 110: 1190-1204. Buran BN, von Trapp G, Sanes DH (2014a) Behaviorally-gated reduction of spontaneous discharge can improve detection thresholds in auditory cortex. J Neurosci 34:4076-4081. Buran BN, Sarro EC, Manno F, Kang R, Caras, ML, Sanes DH (2014b) A sensitive period for the impact of hearing loss on auditory perception. J Neurosci 34:2276-2284. Sarro EC, Sanes DH (2014) Few juvenile auditory perceptual skills correlate with adult performance. Behav Neurosci 128:29-41. Mowery TM, Kotak VK, Sanes DH (2015) Transient deprivation within a critical period causes persistent cellular deficits in cortex. Cerebral Cortex 25:2083-2094. [Epub ahead of print 2014] Kang R, Sarro EC, Sanes DH (2014) Auditory training during development mitigates a hearing loss-induced perceptual deficit. Front Syst Neurosci 8:49. Gai Y, Kotak VC, Sanes DH, Rinzel J (2014) On the Localization of Complex Sounds: Temporal Encoding Based on Input-Slope Coincidence Detection of Envelopes. J Neurophysiol 112:802-813. Kotak VC, Sanes DH (2014) Developmental expression of inhibitory synaptic long-term potentiation in the lateral superior olive. Front. Neural Circuits 8:67. Sarro EC, von Trapp G, Kotak VC, Mowery TM, Sanes DH (2015) Auditory task learning is associated with diminished cortical inhibition. J Neurosci 35:6318-6325. Caras ML, Sanes DH (2015) Sustained perceptual deficits from transient developmental deprivation. J Neurosci 35:10831-10842. Kotak VC, Mowery TM, Sanes DH (2015) Characterization of auditory synaptic inputs to gerbil perirhinal cortex. Frontiers in Neural Circuits 9:40. Additional publications can be obtained through PubMed |
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