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1Center for Neural Science and 2Department of Biology, New York University, New York, New York
Submitted 10 June 2005; accepted in final form 22 August 2005
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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; Goldberg and Brown 1969; Spitzer and Semple 1995; Yin and Chan 1990). Furthermore, lesions of the SOC impair sound localization capabilities, suggesting that binaural computations in this area are necessary for spatial perceptual tasks (Kavanagh and Kelly 1992; Masterton et al. 1967). According to the simplest models of ILD and ITD processing, monaurally activated afferents converge at the lateral or medial superior olivary nuclei (LSO or MSO), where they are integrated by postsynaptic neurons. However, the monaural projections to SOC include an assortment of excitatory and inhibitory afferents (Grothe and Sanes 1993; Kil et al. 1995; Kuwabara and Zook 1992; Wu and Kelly 1994). Furthermore, there is growing recognition that many ventral cochlear nucleus neurons themselves receive a binaural input (Cant and Gaston 1982; Needham and Paolini 2003; Schofield and Cant 1996a,b; Shore et al. 1992, 2003).
The elaborate connectivity of SOC binaural circuits is of particular interest during postnatal development when axonal and dendritic arbors are remodeled (Henkel and Brunso-Bechtold 1991; Kapfer et al. 2002; Kil et al. 1995; Kim and Kandler 2003; Rietzel and Friauf 1998; Russell and Moore 1995; Sanes and Siverls 1991; Sanes et al. 1992). These connections also display alterations in neurotransmitter-receptor phenotype synaptic transmission, and intrinsic membrane properties (Joshi and Wang 2002; Kandler and Friauf 1995a,b; Kim and Kandler 2003; Korada and Schwartz 1999; Kotak et al. 1998; Sanes 1993; Svirskis et al. 2004). Together, these structural and functional changes may lead to qualitative differences in auditory coding properties. For example, juvenile LSO neurons display broader frequency tuning and encode a smaller range of ILDs as compared with those in adult animals (Sanes and Rubel 1988).
Coding properties are also influenced heavily by the pinnae and head size. In the juvenile ferret, auditory cortex neurons can display adult-like spatial coding properties when activated with dichotic stimuli that reflect the filtering characteristic of adult external ears (Mrsic-Flogel et al. 2003). Despite these peripheral and central constraints on auditory processing, developing animals can localize sounds using binaural cues (Kelly and Potash 1986). This raises the possibility that the developing nervous system makes use of age-specific specializations that improve perceptual discrimination given the physical limitations of the organism. Age-specific specializations are common in species that undergo metamorphosis, but they have not been explored in mammals.
The maturation of auditory coding properties was examined in the medial nucleus of the trapezoid body (MNTB), neurons that are activated by a single excitatory synapse from the contralateral cochlear nucleus called the calyx of Held (Friauf and Ostwald 1988; Galambos et al. 1959; Goldberg and Brown 1968; Guinan and Li 1990; Guinan et al. 1972; Held 1893; Kuwabara et al. 1991; Morest 1968; Smith et al. 1998; Sommer et al. 1993). MNTB neurons are also inhibited by contralateral tones outside of the conventional frequency response area (Kopp-Scheinpflug et al. 2003). In the present study, we found that 50% of MNTB neurons were binaurally influenced, and this effect was much stronger in juvenile animals, suggesting a developmental mechanism that could facilitate ILD coding.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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All protocols were reviewed and approved by the New York University Institutional Animal Care and Use Committee. Gerbils (Meriones unguicalatus) at postnatal day (P) 15–19 and adults were anesthetized with chloral hydrate (350 mg/kg) and ketamine (15 mg/kg). Surgical anesthesia was maintained with chloral hydrate (at least P19) or chloral hydrate and ketamine (adults) as described previously (Sanes and Rubel 1988). Supplements were given as indicated by a withdrawal response to toe pinch. Atropine (0.08 mg/kg) was given with initial anesthesia to minimize pulmonary secretions, and tracheotomies were performed on all animals. Core body temperature was monitored with a rectal probe and maintained at 37°C with a homeothermic blanket (Harvard Apparatus, Kent, UK). For stable recordings, the skull was glued to a head post, and the head and torso were raised so that the torso would not move against a surface during breathing. The pinnae were removed, and the tympanic annuli were exposed. The nervous system was accessed by making a dorsal midline incision, removing the external neck muscles, and transecting the dura mater underneath the foramen magnum.
Electrophysiology and sound delivery
All stimuli were delivered under closed-field calibrated conditions in a double-walled sound attenuated chamber (Industrial Acoustics) as described previously (Sanes et al. 1998). Speculae for sound delivery were placed close to the tympanic membrane and agar was applied to create a reliable seal. Glass electrodes containing 5–10% tetramethylrhodamine or fluorescein dextrans (3,000 MW, Molecular Probes, OR) in 2 M NaCl, or 2 M NaCl without dye, were lowered into the brain stem. Neural signals were amplified, filtered, and monitored on an oscilloscope and loudspeaker. A MALab system (Kaiser instruments, Irvine, CA) was used for stimulus generation, discrimination of unit activity, and data acquisition. During simultaneous acquisitions of pre- and postsynaptic action potentials, an oscilloscope (Yokogawa DL1540C) was used to trigger the MALab system off the postsynaptic action potentials, and MALab was used directly to discriminate the prepotentials. Stimulus delivery was calibrated for SPL relative to 20 µPa before each experiment with a condenser microphone (Brüel and Kjaer).
Response characterization
After isolation, each single unit was characterized for frequency tuning and for the presence of ipsilateral inhibition (50-ms tone pips, 2-s intertrial intervals, 5 trials for frequency tuning, 10 trials for rate-intensity functions). The 2-s intertrial interval was used to avoid response adaptation (Sanes and Constantine-Paton 1985). Sound-evoked responses were taken as spike counts obtained during the stimulus presentations. The best frequency (BF) is that which evokes the greatest discharge rate at a single intensity. Excitatory rate-intensity functions were obtained by presenting contralateral tones at increasing intensity levels. Excitatory thresholds were derived from visual inspection of these data. To confirm that these visual judgments were accurate, 10 rate-intensity functions were selected at random and processed with a MATLAB algorithm that searched for the first intensity at which the mean of the distribution of firing rates was significantly greater (P < 0.05, 1-tailed Student's t-test) than that of the distribution obtained over all lower intensities. An additional requirement was that the two subsequent data points also met the same criterion. In 9 of 10 instances, the algorithm agreed with our visual judgments; this success rate was considered sufficient to support the visual procedure.
To obtain inhibitory rate-level functions, a suprathreshold contralateral tone was delivered to evoke a baseline discharge rate, and ipsilateral tones were delivered concurrently at increasing intensities. The presence of inhibition was inferred visually by a decrease in spike rates associated with increasing ipsilateral intensities; the inhibitory threshold was the intensity level at which the decrease was first observed. To increase confidence in our assessments of inhibitory threshold, we again evaluated 10 functions at random using a MATLAB algorithm. In 9 of 10 cases tested, algorithmic and visual judgments were in agreement; as before, this result was considered adequate validation of the visual method.
One measure of the robustness of inhibition was the threshold difference between the two ears. A second method of quantifying inhibition involved presenting stimuli of increasing average binaural level at zero ILD, a physiologic ILD corresponding to a midline stimulus location. This procedure was used only when the presence of inhibition was established with an inhibitory rate-intensity function. To assess the influence of ipsilateral inhibition, the contralateral stimuli were repeated in the absence of ipsilateral sound. The strength of inhibition was computed by dividing the area between the binaural curve at 0 ILD and the corresponding monaural curve by the total area under the monaural curve (see Fig. 7A). To test whether the inhibition was significantly greater than random changes in discharge rate, monaural and binaural data were randomly reshuffled and the distribution of inhibition strengths expected by chance was derived from repeated reshuffling (MATLAB). For each of 110 observed inhibitory strengths, the probability of having obtained the result by chance was calculated by comparing the result with a distribution of inhibitory strengths derived from 2,000 pairs of simulated monaural and binaural curves. Cases in which P was calculated to be >0.05 were considered not to have inhibition at the physiologic ILDs and were assigned an inhibitory strength of 0.
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). In the cases presented here, the largest component of the postsynaptic waveform and the prepotential had opposite polarities and could thus be segregated by simple adjustment of separate trigger thresholds. The recordings consisted of 25 trials; 500-ms contralateral and 100-ms ipsilateral tones were used. Recording site verification
Most recordings were localized to the MNTB by a reliable electrophysiological criterion, the presence of a prepotential (Guinan and Li 1990). On occasion, fluorescent dye (see preceding text) was iontophoresed by passing anodal current (10 µA) for 
30 min to mark the recording site. After experiments, animals injected with dye were perfused with 4% paraformaldehyde, and the brains were post fixed for 
24 h. Fixed brains were cut at 80 µm on a freezing microtome. Sections were viewed with a fluorescence microscope equipped with fluorescein and rhodamine-exciting filters. In all cases in which cells had a prepotential and were marked (n = 8), the dye was found within the MNTB. Recording sites that were within 20 µm of the marked site, or that were recorded between other cells localized to the MNTB, were also considered to be within the nucleus (n = 3 adult neurons, n = 2 juvenile neurons). All recordings presented here are from neurons confirmed to be in the MNTB by the above physiological and/or histological criteria. Examples of prepotentials and of an injection site are shown in Fig. 1.
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LSO responses at BF were modeled by adding the responses of simulated monaural inputs. These inputs included the ipsilateral anteroventral cochlear nucleus (AVCN), the ipsilateral MNTB, and the crossed AVCN pathway (a possible locus of inhibition of the MNTB). To evaluate the effect of inhibition of the MNTB, LSO responses were generated with and without ipsilateral inhibition to the MNTB. Michaelis-Menten equations were used to model inputs; the form of the equations was, R = (I*Rmax)/(Km + I) where R is the response at the input nucleus, I is the intensity level re threshold, Rmax is the maximum firing rate, and Km is a constant re threshold that sets the intensity level at which the response is half the maximal value. This equation was chosen for its monotonicity and for having parameters that relate to saturation and dynamic range. Values were chosen to approximate the conditions obtaining for juvenile animals. In particular, the thresholds, maximum firing rates and dynamic ranges (i.e., the Km value) of the ipsilateral AVCN and the ipsilateral MNTB were set equal in accord with earlier observations in the LSO (Sanes and Rubel 1988). The crossed AVCN threshold was set to 15 dB higher than the thresholds for the other inputs because 15 dB was the median threshold difference between excitatory and inhibitory thresholds in the MNTB. The Km value of the crossed AVCN pathway was set such that the dynamic range would be 93% of that of the other inputs; this was the average value obtained when the dynamic ranges of ipsilateral inhibition and contralateral excitation in the MNTB were compared (data not shown). Rmax for the crossed pathway was set to half of that for the other nuclei, resulting in an inhibition strength near the median value for juvenile animals (inhibition strength = 0.24; median inhibition strength = 0.26). The spontaneous discharge rate of the LSO was set to 5 spikes/s (Sanes and Rubel 1988) by adding 5 spikes/s to all values in the response curve of the ipsilateral AVCN. All parameter settings are summarized in Table 1. The ranges of physiologic ILDs were derived from unpublished data (Green, Semple, and Sanes). In the case of the theoretical LSO response surfaces in Fig. 8, the chosen range was 5 dB, corresponding to the appropriate range at 3–5 kHz.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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2 analysis). The latency of excitation and inhibition were similar to one another, as shown in Fig. 4A. In four neurons examined, the inhibitory latency was 0, 2, 2, and 4 ms longer than the excitatory latency. An example of a cell that was responsive to ipsilateral sound, and a cell that was not responsive, are shown in Fig. 4B. To assess whether inhibition was observed only in some animals, perhaps due to the anesthetic state, we computed the proportions of cells inhibited within each animal for cases in which there were two or more recorded cells studied (Fig. 4C). A lack of clustering at the highest and lowest values indicated that inhibition did not appear to be restricted to a particular group of animals; within animals, cells were often heterogeneous with respect to ipsilateral inhibition. In some cases, it was possible to demonstrate that stronger excitatory drive could obscure the ipsilaterally evoked inhibition that was observed with lower contralateral sound levels, as shown in Fig. 4D.
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). Using this approach, the effect of inhibition on both components was obtained in four adult cells. As shown in Fig. 5, prepotential and postsynaptic action potential activity were nearly identical before, during, and after the inhibition evoked by ipsilateral sound stimulation. This result was interpreted to mean that inhibition operates outside of the MNTB, perhaps at its cochlear nucleus afferent neurons via a crossed projection.
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2 analysis). Theoretical implications for LSO coding
To consider how ipsilateral inhibition of MNTB neurons could influence the response of their postsynaptic target neurons in the LSO, we implemented a simple linear model of the LSO (see METHODS). The data suggested that strong inhibition occurred more frequently in juvenile MNTB neurons, and the model focuses on this age group. Figure 8 (top) shows the LSO response when it is activated by two monaural inputs, the AVCN and an uninhibited MNTB. The LSO neuron response over the stimulus space of intensity levels at the two ears is equal to the AVCN activity minus the MNTB activity. The unshaded portion of the LSO response surface represents physiological ILDs in the 3- to 5-kHz range (J. S. Green, M. N. Semple, and D. H. Sanes, unpublished observations), one of the most commonly tested ranges in juvenile animals in this study. In this region, LSO responses are relatively small. In contrast, adding inhibition of the MNTB to the model (bottom) results in greater LSO responsiveness within the region of physiological ILDs. Thus inhibition of the MNTB may enable juvenile LSO neurons to modulate their discharge rate to the relatively small physiological ILDs present at that age.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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). This may reflect the fact that only half of adult MNTB neurons are inhibited, and many of these display weak inhibition that is obscured at high contralaterally evoked discharge rates. Thus the rarity of strong inhibition in adults, coupled with the fact that inhibition is most likely to be revealed by careful testing at near-threshold contralateral intensity levels, may account for differences between the present report and published findings. Alternatively, there may be differences between species. Source of inhibition to the MNTB
We found that pre- and postsynaptic action potentials within the MNTB were inhibited equally by ipsilateral sound. Therefore inhibition must be presynaptic to the principal cells. Because electron microscopic studies have not revealed synapses on the calyces of Held (Smith et al. 1998), we conclude that ipsilateral inhibition is not acting within the MNTB. Alternative sources of inhibition include any inhibitory input to the cochlea or to the cochlear nucleus that provides excitatory afferent input to the MNTB.
One possible locus of inhibition is the cochlea because olivocochlear inputs can suppress cochlear activity in response to contralateral sound. However, this effect increases with age in gerbils, and no evidence of suppression was found at 22 days, the youngest age tested (Huang et al. 1994). Moreover, olivocochlear suppression requires 100–200 ms to emerge (Warren and Liberman 1989), a much longer time scale than observed in the present study.
A second potential locus for inhibition is the globular bushy cells within the VCN. Each cochlear nucleus sends glycinergic projections to the opposite VCN, and both in vitro and in vivo recordings confirm that short-latency inhibition in the CN is elicited by contralateral stimulation (Babalian et al. 2002; Needham and Paolini 2003; Schofield and Cant 1996a,b; Shore et al. 2003; Wenthold 1987). In the rat cochlear nucleus, 30% of neurons are inhibited by contralateral stimuli, and the latency is only 2 ms longer than ipsilateral excitation (Shore et al. 2003). Therefore this crossed inhibitory pathway provides the simplest explanation for the present results.
Several SOC and periolivary nuclei project to the VCN (Ostapoff et al. 1997; Schofield 1994; Shore et al. 1991), and these may provide alternative sources of inhibition. The ipsilateral MNTB, itself, projects to the VCN, and labeled presynaptic boutons appear to contact globular bushy cells (Schofield 1994). Therefore a projection from the MNTB to its ipsilateral cochlear nucleus could mediate inhibition by contralateral sound. Similarly, VNTB neurons can be excited by contralateral sound, and VNTB axons send a putative inhibitory projection to VCN (Goldberg and Brown 1968; Guinan et al. 1972; Ostapoff et al. 1997). Finally, descending inputs to the cochlear nucleus from the IC could also contribute to the present phenomenon, although these inputs are not thought to be inhibitory, do not contact the part of the nucleus that contains bushy cells (reviewed by Ostapoff et al. 1997) and would have produced longer inhibitory latencies than were observed in our recordings (Fig. 4A).
Implications for postsynaptic brain stem nuclei
Our findings suggest that, during juvenile development, the MNTB may exhibit distinct coding properties. As illustrated in Fig. 8, inhibition to the MNTB could permit LSO neurons to respond to an acoustically relevant range of ILDs. In fact, inhibitory thresholds are relatively low in juvenile LSO neurons, particularly for those with lower characteristic frequencies, and discharge rate varies for level differences favoring the ipsilateral ear (Sanes and Rubel 1988). Thus without the ipsilateral inhibition to MNTB, the LSO neuron would respond poorly, or not at all, to most binaural stimuli. One qualification to the model-based conclusions is that, in the case of very proximal sound, ILDs may be much larger than normal (Brungart et al. 1999). Therefore the major effect of the inhibition on LSO could be to shift responsiveness into the frontal azimuthal field rather than to rescue the LSO from nonresponsiveness.
MNTB inhibitory projections also play an important role in ITD processing by the MSO (Brand et al. 2002). The inhibition shifts the discharge rate to vary with ITD values near the midline. Thus ipsilateral inhibition of the MNTB could adjust the degree to which tuning shifts of this sort occur. Because ITD sensitivity is also found in the LSO (Batra et al. 1997; Finlayson and Caspary 1991; Joris 1996; Joris and Yin 1995), similar implications may apply.
Additional MNTB projections include those to the superior paraolivary nucleus (SPN) and ventral nucleus of the lateral lemniscus (VNLL). Evidence suggests that the MNTB inhibits some SPN neurons in response to contralateral sound (Kulesza et al. 2003a). The inhibition of the MNTB may permit more discharge in SPN neurons during sound stimulation and weaken offset responses. If SPN neurons are involved in duration tuning by being offset responders (Kulesza et al. 2003b), then the developmental decrease in the strength of inhibition of the MNTB may be necessary for the expression of mature SPN responses. An important qualification to these possibilities is that the globular bushy cells that drive the MNTB also project to SPN neurons (Cant and Benson 2003). Therefore inhibition of the globular bushy cells may produce opposing effects in the SPN by reducing direct excitation and releasing inhibition from the MNTB.
A minority of VNLL neurons are inhibited by contralateral stimulation and others have offset responses that may be due to release from inhibition (Batra and Fitzpatrick 1999). If inhibition from the MNTB is responsible for these effects, then ipsilateral inhibition of the MNTB would decrease the strength of the inhibition and offset responses in the VNLL. As with SPN, the supposition must be qualified by the observation that the VNLL receives a contralateral projection from globular bushy cells (Cant and Benson 2003) and opposing effects may therefore result from inhibition of the globular bushy cells.
Functional specializations during maturation
Functional specializations are found in the immature stages for species that undergo metamorphosis, often correlated with a dramatic change of habitat. For example, auditory midbrain neurons of the tadpole phase lock to AM frequencies 
250 Hz, but the frequency range becomes quite restricted beginning at metamorphic climax (Boatright-Horowitz et al. 1997, 1999). In holometabolous insects, many neurons exhibit stage-specific properties (Tissot and Stocker 2000). For example, in the moth (Manduca sexta), a larval skeletal muscle motoneuron undergoes dramatic changes in dendritic arborization and electrical properties that accompany its de novo innervation of the adult cardiac chamber (Dulcis and Levine 2004).
The functional properties of developing neurons have often been shown to be inferior to those of adults. In the case of binaural processing, neurons from juvenile animals display limited dynamic ranges and irregular ILD functions as compared with adults (Moore and Irvine 1981; Sanes and Rubel 1988; Thornton et al. 1999). Limitations of auditory coding properties may be attributable, in part, to immature peripheral structures, such as the external ears. In the developing ferret, single auditory cortex neurons are not very directional but can respond in mature fashion when stimulated with sound cues that are only available to the adult due to the external ear filtering properties (Mrsic-Flogel et al. 2003). Gerbils clearly have the ability to localize species-specific vocalizations from a very early age, and the use of binaural cues is required (Kelly and Potash 1986). Therefore it is possible that their nervous system includes age-specific specializations that permit some minimum degree of performance given the constraints of small head and pinna size. In summary, the present results demonstrate that the MNTB, a major inhibitory projection nucleus in the auditory brain stem, is inhibited by stimuli to the ipsilateral ear. This result is observed in approximately half of the recorded neurons, and the strength of inhibition is far greater in neurons recorded from juvenile animals. MNTB target nuclei, such a LSO, which encode azimuthal sound location may, therefore perform these computations with the support of an additional brain stem circuit during juvenile development. The age-specific functional properties of MNTB neurons would permit responsiveness to small level differences that would otherwise go undetected.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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Address for reprint requests and other correspondence: Correspondence: Dan H. Sanes, Center for Neural Science, 4 Washington Place, New York University, New York, NY 10003, Office 212-998-3924, FAX 212-995-4348, Email sanes{at}cns.nyu.edu
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in rate-intensity function plotted in 
, 1st-spike latency. B: distribution of 1st-spike latencies for both age groups shows that latency significantly shorter for adult neurons than those in juvenile animals.
). The effects of inhibition on pre- and post potentials were virtually identical. Inset: the waveform of the 2nd cell (bottom). All simultaneous pre- and postpotential recordings were made in adult animals.