Behavioral/Systems/CognitiveA Model for Interaural Time Difference Sensitivity in theMedial Superior Olive: Interaction of Excitatory andInhibitory Synaptic Inputs, Channel Dynamics, andCellular MorphologyYi Zhou,1Laurel H. Carney,2and H. Steven Colburn11Department of Biomedical Engineering, Center for Hearing Research, Boston University, Boston, Massachusetts 02215, and2Department ofBioengineering and Neuroscience, Institute for Sensory Research, Syracuse University, Syracuse, New York 13244-5290This study reports simulations of recent physiological results from the gerbil medial superior olive (MSO) that reveal that blockingglycinergic inhibition can shift the tuning for the interaural time difference (ITD) of the cell (Brand et al., 2002). Our simulations indicatethat the model proposed in the study by Brand et al. (2002) requires precisely timed, short-duration inhibition with temporal accuracyexceeding that described in the auditory system. An alternative model is proposed that incorporates two anatomic observations in theMSO: (1) the axon arises from the dendrite that receives ipsilateral inputs; and (2) inhibitory synapses are located primarily on the somain adult animals. When the inhibitory currents are activated or blocked, the model cell successfully simulates experimentally observedshifts in the best ITD. The asymmetrical cell structure allows an imbalance between the ipsilateral and contralateral excitatory inputs andshifts the ITD curve such that the best ITD is not at zero. Fine adjustment of the best ITD is achieved by the interplay of somatic sodiumcurrents and synaptic inhibitory currents. The shift of the best ITD in the model is limited to ⬃0.2 ms, which is behaviorally significantwith respect to ITDs encountered in perceptual tasks. The model suggests a mechanism for dynamically “fine-tuning” the ITD sensitivityof MSO cells by the opponency between depolarizing sodium currents and hyperpolarizing inhibitory currents.Key words: interaural time differences; medial superior olive; inhibition; asymmetrical cell morphology; binaural hearing; neuralmodelingIntroductionInteraural time difference (ITD) is the primary cue for localizinglow-frequency sounds in the horizontal plane (Wightman andKistler, 1992). Jeffress (1948) hypothesized that ITD informationis carried by an array of coincidence detectors, each of whichdischarges maximally when the external ITD is equal to the inter-nal delay difference of the cell.Neural mechanisms of coincidence detection have been stud-ied and confirmed in avian nucleus laminaris (NL) neurons (Jo-seph and Hyson, 1993; Reyes et al., 1996) and mammalian medialsuperior olive (MSO) neurons (Goldberg and Brown, 1969; Yinand Chan, 1990; Spitzer and Semple, 1995; Brand et al., 2002).However, anatomical evidence of the delay-line structure is lessclearly demonstrated in the mammalian system (Smith et al.,1993; Beckius et al., 1999) than in the avian system (Young andRubel, 1983; Carr and Konishi, 1990; Overholt et al., 1992).McAlpine and Grothe (2003) hypothesized that inhibitorysynaptic inputs can systematically shift the best ITD (i.e., the ITDat which an MSO cell discharges maximally) and thus that thebest ITD can be manipulated independently of the physical delay-line structure. Their hypothesis is based on the experimental ob-servation in vivo that blocking glycinergic inhibition shifts therate-ITD curve in MSO cells of gerbils (Brand et al., 2002). Tointerpret the experimental results, Brand et al. (2002) proposed amodel that includes a precisely timed inhibition with a shortduration (leading excitation by 0.2 ms;␶⫽ 0.1 ms for the synapticconductance). However, the observed time constant of the gly-cinergic inhibitory synapses in the MSO is much longer than 0.1ms [e.g., 2 ms (Smith et al., 2000)]. Furthermore, no experimen-tal studies have investigated the precision of the relative timing ofexcitatory and inhibitory inputs to the MSO in response to acous-tic stimuli.Here, we present an alternative explanation for the data ofBrand et al. (2002). This model incorporates a morphologicalfeature of MSO: the axons of some principal MSO neurons arisefrom the dendrites instead of the soma [cat (LaVilla, 1898; Kissand Majorossy, 1983), gerbil (N. Golding, personal communica-tion), guinea pig (Smith, 1995), mouse (Ramo´ n y Cajal, 1909)](see Fig. 1). Figure 1 illustrates this asymmetry in sample MSOcells from guinea pig and gerbil. Brew (1998) first suggested thatReceived July 27, 2004; revised Jan. 26, 2005; accepted Jan. 26, 2005.This work was supported by National Institutes of Health Grants DC00100 and DC01641. We thank Dr. NaceGolding for providing us with reconstructions of MSO cells from gerbil and Dr. Philip H. Smith for providing histo-logical material from the MSO of guinea pig.CorrespondenceshouldbeaddressedtoDr.H.StevenColburn,DepartmentofBiomedicalEngineering,CenterforHearing Research, Boston University, Boston, MA 02215. E-mail: [email protected]:10.1523/JNEUROSCI.3064-04.2005Copyright © 2005 Society for Neuroscience 0270-6474/05/253046-12$15.00/03046 • The Journal of Neuroscience, March 23, 2005 • 25(12):3046 –3058the asymmetry may cause different delays between two interden-dritic excitatory inputs en route to the axon; however, no studieshave explored whether the asymmetry could affect the interac-tion between excitation and inhibition. We postulated that theobserved shift of the ITD curves attributable to blocking inhibi-tion might be associated with the effective asymmetry of excita-tory and inhibitory inputs because of the relative locations of theaxon and of the inhibitory synapses. To examine our hypothesis,we used a multicompartment model to study the interaction ofexcitation, inhibition, and ionic currents on this asymmetricalstructure. This model simulated the shift of the ITD function byinhibition with a time constant comparable to available data. Themodel results suggest a potential mechanism for dynamic “fine-tuning” of ITD sensitivity at the single neuron level, which hasimplications for our understanding of auditory spatial attention.Materials and MethodsSimulations presented here were generated by two types of neural mod-els: a point-cell model that was insensitive to spatial distribution of syn-apses and a bipolar-cell model that incorporated asymmetric morphol-ogy (Fig. 1), dendritic glutaminergic excitation, somatic glycinergicinhibition, and somatic sodium channels. We simulated both