Lateral Superior Olive: Organization, Development, and Plasticity
Abstract and Keywords
Auditory neurons in the mammalian brainstem are involved in several basic computation processes essential for survival; for example, sound localization. Differences in sound intensity between the two ears, so-called interaural level differences (ILDs), provide important spatial cues for localizing sound in the horizontal plane, particularly for animals with high-frequency hearing. The earliest center of ILD detection is the lateral superior olive (LSO), a prominent component of the superior olivary complex (SOC) in the medulla oblongata. LSO neurons receive input from both ears of excitatory and inhibitory nature and perform a subtraction-like process. The LSO has become a model system for studies addressing inhibitory synapses, map formation, and neural plasticity. This review aims to provide an overview of several facets of the LSO, focusing on its functional and anatomical organization, including development and plasticity. Understanding this important ILD detector is fundamental in multiple ways—among others, to analyze central auditory processing disorders and central presbyacusis.
Keywords: activity-dependent processes, auditory brainstem, excitatory neurotransmission, inhibitory neurotransmission, interaural level differences, map formation, sound localization, synaptic fidelity, synaptic plasticity, synaptic refinement
Organization of the Lateral Superior Olive
The lateral superior olive (LSO) is a conspicuous structure in the medullary brainstem of mammals and a principal component of the superior olivary complex (SOC), the first major site of input convergence from both ears. The SOC consists of three principal nuclei, namely the LSO, the medial superior olive (MSO), and the medial nucleus of the trapezoid body (MNTB). LSO neurons play a distinct role in binaural hearing (Boudreau & Tsuchitani, 1968). They are involved in sound source localization (Tollin, 2003; Tollin & Yin, 2002), which, according to the classic Duplex theory (Rayleigh, 1907), employs time differences in incoming sound of low frequency and intensity differences of high-frequency sound (Casseday & Neff, 1973; Middlebrooks, 2015). LSO neurons compute intensity differences occurring at the two tympanic membranes (eardrums; Figure 1A; Irvine, 1992; Masterton, Jane, & Diamond, 1967; Tsuchitani & Johnson, 1991). For interaural level difference (ILD) coding beyond the LSO, see Yin & Kuwada (2010). Neurons in the anatomically adjacent MSO are thought to exploit interaural time differences (ITD; see chapter by Grothe et al., this volume).
An animal’s ability to determine the position of a sound source is a crucial step in auditory scene analysis and toward appropriate behavior. The sound shadow cast by an animal’s head leads to a situation in which the sound at the shadowed ear is less intense than the sound arriving at the tympanic membrane of the other ear (Figure 1B). ILDs are detected by the auditory hindbrain via binaural processing mechanisms. This greatly facilitates localization of the direction of sound sources. When a sound source is positioned at an angle of ~90° from the midline, the ILD in humans amounts to 3 dB and 35 dB for frequencies of 200 Hz and 10 kHz, respectively (Middlebrooks, Makous, & Green, 1989; Shaw & Vaillancourt, 1985). The threshold of human listeners for ILD detection in high-frequency tones is ~1 dB (Middlebrooks & Green, 1991). In general, the ILD is larger when the sound is of higher than lower frequency. High-frequency sound signals have short waves, and obstacles, such as the head, reflect these waves rather than diffracting them.
The human head size relates to an interaural distance (distance between the two ears) of ~20 cm. In small mammals, such as rats, mice, or bats, the interaural distance can be < 2 cm. Acoustic shadowing becomes effective if the wavelength (λ) of a sound signal is shorter than the head size. For an interaural distance of 2 cm, the sound frequency (f) must therefore be above 17 kHz to generate analyzable ILDs (; v = 340 m/s). The aforementioned small animals encounter ILDs as large as 40 dB for sound stimuli in the 10–90 kHz range (Figure 1C; Greene, Anbuhl, Williams, & Tollin, 2014; Grothe & Pecka, 2014; Harnischfeger, Neuweiler, & Schlegel, 1985; Koka, Read, & Tollin, 2008; Maki & Furukawa, 2005). Noticeably, such ultrasound frequencies are physiological stimuli for small animals, because evolutionary pressure has favored small head size with high-frequency hearing (Heffner, Koay, & Heffner, 2001). Studies of the spatial cues employed by mice for sound localization are rare and have not focused on ILD (Chen, Cain, & Jen, 1995). This is somewhat surprising because, with the multitude of available (deaf) mutants, mice have become a key species in hearing research over the past two decades or so (Malmierca & Ryugo, 2012).
Besides the acoustic shadowing effect of the head, the dimension, shape, and position of the pinnae contribute substantially to ILD (Chen et al., 1995). Interestingly, and in contrast to humans, many mammalian species feature vigorous pinnae movements. By changing pinna directionality, they can actively modulate ILDs, thereby optimizing listening conditions (Friauf & Herbert, 1985; Populin & Yin, 1998; Ruhland, Jones, & Yin, 2015; Walker, Peremans, & Hallam, 1998; Young, Rice, & Tong, 1996). Mice can resolve differences of ~15° at 15 kHz, which corresponds to an ILD of < 1 dB (Chen et al., 1995; Ehret & Dreyer, 1984; Walker et al., 1998). Thus, their ILD hearing capability is very well established.
Anatomical Organization of the LSO
Virtually every mammal possesses an LSO (well, in fact, two LSOs), but the size and the shape vary considerably across species (Figure 2). Across 53 species analyzed (Glendenning & Masterton, 1998), the volume of the LSO, in relation to the whole brain size, ranges from 0.8% in mice (0.32 mm3/0.4 g) to 0.00026% in humans (3.22 mm3/1,240 g). Neuron numbers differ more than 7-fold across species, from less than 1,000 in hamsters and squirrels to more than 7,000 in the orangutan (Hilbig, Beil, Hilbig, Call, & Bidmon, 2009; Irving & Harrison, 1967). The LSO of cats, rats, and mice comprises about 3,400, 1,400, and 1,200–1,600 neurons, respectively (Casey, 1990; Hirtz et al., 2011; Irving & Harrison, 1967; Satheesh et al., 2012). The human LSO is composed of ~2,000 neurons (Hilbig et al., 2009).
In transverse brainstem sections, the LSO of lower eutherian mammals is easily recognizable by its distinctive convoluted, convexo-concaved S-shape (cat, chinchilla, dog, mouse, rat; Table 1). In cats and dogs, the lateral limb extends dorsally, whereas the medial limb extends ventrally. The opposite holds for rats. In some species, authors have attributed a U-shape to the LSO (gerbil, guinea pig, mouse: Bazwinsky-Wutschke, Härtig, Kretzschmar, & Rübsamen, 2016; Hirtz et al., 2012; Nothwang, 2016; Rosengauer et al., 2012; Sanes, Merickel, & Rubel, 1989; Sterenborg et al., 2010), an N-shape (hamster: Reuss et al., 2009), a W-shape (ferret: Moore, Russell, & Cathcart, 1995), or a drop-shape (opossum: Bazwinsky-Wutschke et al., 2016; Willard & Martin, 1983). In the galago, a lemuriform monkey and extant example of the lowest level of primate organization, the LSO is small and not S-shaped. Instead, it is ovoid with indistinct convolutions (Moore, 2000). In the common marmoset, a more advanced simian monkey, the LSO is an irregularly oval nucleus with some indication of convolutions (Illing, Kraus, & Michler, 2000; Moore, 2000). The LSO of the rhesus macaque, another simian monkey, is not clearly S-shaped (Harrison & Irving, 1966; Hilbig et al., 2009); however, it is described to be more convoluted than that of non-primates (Bazwinsky, Bidmon, Zilles, & Hilbig, 2005). In the gibbon, an ape, the LSO is small and indistinct (Moore, 2000), and similar findings were made in bonobos, chimpanzees, and orangutans (Hilbig et al., 2009). With its reduced size, the LSO of these apes is very similar to the human LSO, which is also small and roughly oval or h-shaped in some cases (Kulesza, 2007; Moore, 2000).
Table 1. Comparison of LSO size, contour, and highest audible frequency across a variety of species
LSO Contour in Transverse Sections
HAF @ 60 dB SPL∗ [kHz]
136 (in H2O)
roughly oval, h-shaped
Grothe & Park, 2000; Harrison & Irving, 1966; Gillespie, Kim, & Kandler, 2005; Harrison & Warr, 1962; Kraus & Illing, 2004; Löhrke, Srinivasan, Oberhofer, Doncheva, & Friauf, 2005; Saldana & Berrebi, 2000; Vitten, Reusch, Friauf, & Löhrke, 2004
Cytology of the LSO
The LSO of placental mammals is composed of a variety of neuronal classes. Overall, up to seven cell types have been described (Rietzel & Friauf, 1998). By far the most dominant class are principal neurons, which comprise ~75% of the population (Helfert & Schwartz, 1987). These neurons have fusiform somata and eccentric nuclei (Figure 3). Primary dendrites emerge from the two somatic poles and, in the coronal plane, tend to be oriented at right angles to the tonotopic axis (Cant, 1984; Helfert & Schwartz, 1987; Ollo & Schwartz, 1979; Rietzel & Friauf, 1998; Schofield & Cant, 1991). These dendrites branch extensively and extend over a substantial rostro-caudal distance, resulting in disc-shaped dendritic trees in parasagittal or horizontal sections (Helfert & Schwartz, 1986; Pickles, 1982; Scheibel & Scheibel, 1974).
Axon terminals on LSO principal neurons are in the form of conventional boutons whose size is quite large. Electron microscopy studies have shown that, on average, 74% of the somatic surface are apposed to such bouton-type synaptic endings (Helfert & Schwartz, 1986) and that these perisomatic terminals contain flattened synaptic vesicles and form symmetric synaptic contacts, indicative of an inhibitory transmitter phenotype (Brunso-Bechtold, Linville, & Henkel, 1994; Cant, 1984). Indeed, immunocytochemistry employing antibodies against glycine has demonstrated punctate labeling on LSO neurons, suggestive of immunopositive presynaptic terminals (Helfert, Bonneau, Wenthold, & Altschuler, 1989; Wenthold, Huie, Altschuler, & Reeks, 1987), and immunogold labeling has confirmed a glycinergic phenotype in terminals containing flattened vesicles (Helfert et al., 1992). In contrast, terminals with round synaptic vesicles contact relatively thin and distal dendrites via asymmetric synaptic junctions and are associated with glutamate. A glycinergic phenotype has also been demonstrated in quantitative autoradiography studies that revealed very heavy 3H-strychnine binding in the LSO (Glendenning & Baker, 1988), with ~4-fold higher labeling in the high-frequency than in the low-frequency region (Sanes, Geary, Wooten, & Rubel, 1987). Immunohistochemistry has demonstrated the presence of glycine receptors (GlyRs), which densely encrust the somata and proximal dendrites of adult LSO principal cells (Friauf, Hammerschmidt, & Kirsch, 1997; Sato, Shiraishi, Nakagawa, Kuriyama, & Altschuler, 2000).
Another protein characteristic at glycinergic synapses, the glycine transporter 2 (GlyT2), is also abundant in the LSO (Friauf, Aragon, Löhrke, Westenfelder, & Zafra, 1999). Regarding the excitatory input to the LSO, high transcript levels of the glutamate receptor subunits GluA3 and GluA4flop have been described (Caicedo & Eybalin, 1999; Schmid, Guthmann, Ruppersberg, & Herbert, 2001). These subunits provide very rapid kinetics as well as high Ca2+ permeability to glutamate receptors of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) type (Raman, Zhang, & Trussell, 1994). Various subunits of N-methyl-D-aspartate receptors (NMDARs) are abundant in the LSO, namely GluN1 (Nakagawa, Sato, Shiraishi, Kuriyama, & Altschuler, 2000) and GluN2A-2D (Munemoto et al., 1998; Sato, Nakagawa, Kuriyama, & Altschuler, 1999). NMDARs assemble as heteromers endowed with distinct properties, are developmentally regulated, and play crucial roles in synaptic plasticity (Alexander et al., 2017; Paoletti, Bellone, & Zhou, 2013). Together, LSO principal cells are equipped with fast gating receptors that render them suited to preserving timing information (Rothman & Manis, 2003). Moreover, the diversity in NMDAR subunits predicts considerable pharmacological differences.
The glycinergic and glutamatergic inputs to LSO principal cells are also demonstrated by immunofluorescence studies employing a variety of presynaptic (e.g., vesicular glutamate transporters VGluT1 and VGluT3, GlyT2) and postsynaptic marker proteins (e.g., GlyRα1). The intensity of the immunosignals, together with the perisomatic location of the glycinergic axon terminals, is indicative of powerful synaptic strength. Serial block face scanning electron microscopy has shown that MNTB axon terminals contacting the soma of a single LSO neuron, presumably a principal cell, have several large boutons (diameter 3.7 µm), most of which contain several (up to 11) active zones (Gjoni, Aguet, Sahlender, Knott, & Schneggenburger, 2018). These large and multi-active-zone boutons probably provide the ultrastructural basis for strong inhibition caused by the MNTB-LSO synapses. Concerning the transmitter phenotype of LSO principal cells, the neurons are equipped with glutamate and glycine (Altschuler & Shore, 2010). Glutamatergic LSO neurons tend to project into the contralateral inferior colliculus (IC), whereas glycinergic neurons project into the ipsilateral IC (details in the section “Efferent Projections from the LSO”).
Multipolar and marginal cells represent the other two major cell types in the LSO (Majorossy & Kiss, 1990). Multipolar neurons (~11% of the population) have round somata and 3–6 primary dendrites that can originate from all parts of the soma and branch repetitively, giving rise to 3-dimensional stellate dendritic trees (Figure 3). Marginal cells are the largest type, composing ~4% of the population (Helfert & Schwartz, 1986), and are primarily located along the border of the LSO (Figure 3). Synaptic terminals around their somata are similar in number and type to those found at principal neurons. Despite the peripheral location of their somata, their dendrites appear to stay within the nuclear area (Ollo & Schwartz, 1979; Rietzel & Friauf, 1998). Both γ-amino butyric acid (GABA) and glycine have been identified in somata of marginal cells (Korada & Schwartz, 1999), implying that many, if not all, of them are inhibitory neurons. Whereas physiological studies have concentrated on LSO principal cells, we know relatively little about the functional properties of the other types.
The LSO also contains neurons that send descending projections into the cochlea via the olivo-cochlear bundle (Warr & Boche, 2003). Because of their lateral location in the SOC, they belong to the lateral olivo-cochlear complex (LOC), which shows some interspecies differences (Aschoff & Ostwald, 1987; Warr, Beck Boche, Ye, & Kim, 2002). In rodents, the somata of LOC neurons are scattered in and around the LSO. Those located within the LSO are spherical, and their dendrites are oriented perpendicular to the curvature of the nucleus, similar to LSO principal cells (Vetter & Mugnaini, 1992). In “Functional Properties of LSO Neurons in Vitro” we will show that the LSO principal cells and LOC neurons are also physiologically distinct.
Effects of aging on the cytoarchitecture of the LSO have been analyzed in Fischer 344 rats, which, like most humans, slowly lose their hearing with age. In these animals, the LSO maintains a stable neuron number between 3 and 30 months of age, although there is a significant reduction of the neuron number in the MNTB (Casey, 1990). In Sprague-Dawley rats, loss of MNTB principal cells is even more severe than in Fisher 344 rats (34% vs. 8%; Casey & Feldman, 1982). As the LSO has remained unaddressed in this strain, whether massive cell loss in an input nucleus would affect the aging LSO remains an open question.
Afferent Projections to the LSO
The right half of Figure 4A depicts a general summary of the axonal projections into the LSO. From the cochlear nuclear complex (CNC), LSO principal neurons receive excitatory (glutamatergic) input from spherical bushy cells (SBCs) located in the ipsilateral anteroventral cochlear nucleus (AVCN). LSO principal neurons also receive inhibitory (glycinergic) input from principal cells of the ipsilateral MNTB (Bledsoe et al., 1990; Moore & Caspary, 1983; Sommer, Lingenhöhl, & Friauf, 1993; Spangler, Warr, & Henkel, 1985), which receive excitatory input from globular bushy cells (GBCs) of the contralateral AVCN (Figure 4B). Thus, inputs from the ipsilateral and the contralateral ear converge on single LSO neurons. In all mammals investigated, these inputs show a systematic medial-to-lateral, high-to-low best frequency arrangement termed cochleotopy or tonotopy (Figure 4B). The area devoted to high frequencies is disproportionately large in the LSO. The AVCN and MNTB afferents to the LSO display no polarity; rather, they terminate on both sides of the spindle-shaped somata (Glendenning, Hutson, Nudo, & Masterton, 1985). This is in contrast to the MSO, where the binaural inputs show a sharp polarity by terminating on homolateral dendrites (afferents from the right AVCN form synapses with laterally oriented dendrites in the ipsilateral MSO and with medially oriented dendrites in the contralateral MSO).
Aside from the elegant yet simplistic ipsilateral-excitatory (EI)/contralateral-inhibitory input scheme underlying ILD sensitivity (Figure 4B), LSO neurons receive inputs from cells other than SBCs and MNTB principal neurons. These inputs are provided by GBCs (Friauf & Ostwald, 1988; Kuwabara & Zook, 1991; Smith, Joris, Carney, & Yin, 1991) and by planar multipolar neurons (Darrow, Benson, & Brown, 2012; Doucet & Ryugo, 2003, 2006), residing in the ipsilateral ventral cochlear nucleus (VCN; Figure 4A). Projections from the ipsilateral posteroventral cochlear nucleus (PVCN) are tonotopically organized (Thompson & Thompson, 1987). LOC neurons receive excitatory and inhibitory inputs, but with longer latencies and slower kinetics than LSO principal cells (Adam, Finlayson, & Schwarz, 2001; Adam, Schwarz, & Finlayson, 1999; Fujino, Koyano, & Ohmori, 1997; Sterenborg et al., 2010). It is assumed that the excitatory input is preferentially provided by planar multipolar neurons in the cochlear nucleus (CN), which have relatively thin axons (Gomez-Alvarez & Saldana, 2016; Oertel, Wright, Cao, Ferragamo, & Bal, 2011; see also chapter by Oertel et al., this volume). There is no evidence for intrinsic connections within the LSO (G. Kim & Kandler, 2003).
Small multipolar neurons in the contralateral ventral nucleus of the trapezoid body (VNTB; Gomez-Alvarez & Saldana, 2016; Gomez-Nieto, Rubio, & Lopez, 2008; Warr & Beck, 1996) and posteroventral aspects of the ipsilateral lateral nucleus of the trapezoid body (LNTB) also project into the LSO (Glendenning, Masterton, Baker, & Wenthold, 1991). In the LNTB-LSO projection, axons terminate perisomatically (Kuwabara & Zook, 1992), and the projection is most likely glycinergic (Spirou & Berrebi, 1997). It is unclear whether an LNTB-LSO projection exists in rodents (Franken, Smith, & Joris, 2016). Finally, there are descending projections into the LSO that originate directly in the primary auditory cortex (AC) of both hemispheres (Coomes & Schofield, 2004; Feliciano, Saldaña, & Mugnaini, 1995). The cortico-olivary axons are thin, and some terminate on somata of LSO neurons that project into the IC (Coomes Peterson & Schofield, 2007). In summary, the basic connectivity of the LSO appears solved, but future research is needed to address interspecies differences. Moreover, several open questions concern the fine structure of connectivity. For example, the type of target neuron in the LSO and the transmitter phenotype are still unclear for several afferents (Gomez-Alvarez & Saldana, 2016). Likewise, the projection pattern of LSO neurons has not been clearly associated with biophysical response patterns and the transmitter repertoire that is present in the input-output microcircuits.
Efferent Projections from the LSO
The left half of Figure 4A depicts a general summary of the axonal projections emerging from the LSO. Principal neurons are a major source of ascending projections to the auditory midbrain (pioneer papers are summarized in Cant, 1984). They give rise to ipsilateral projections terminating in the intermediate nucleus of the lateral lemniscus (INLL), dorsal nucleus of the lateral lemniscus (DNLL), and IC, as well as to contralateral projections terminating in the DNLL and IC (Kelly, Liscum, van Adel, & Ito, 1998; Kelly, van Adel, & Ito, 2009; Malmierca & Hackett, 2010; Shneiderman, Stanforth, Henkel, & Saint Marie, 1999). Both types of projection appear to contribute relatively equally. Only a small portion (< 5%, cats) of LSO neurons project bilaterally via axon collaterals (Glendenning & Masterton, 1983). Ipsilateral projections are mainly inhibitory and glycinergic, whereas contralateral projections are excitatory and glutamatergic (Altschuler & Shore, 2010; Glendenning, Baker, Hutson, & Masterton, 1992; Ito & Oliver, 2010; Saint Marie & Baker, 1990; Saint Marie, Ostapoff, Morest, & Wenthold, 1989; Schofield, 2010). The olivo-collicular projections are tonotopically organized and terminate in laminae in the IC (Oliver, 2000). Among the glutamatergic neurons projecting contralaterally, ~6% are reportedly also glycinergic in rats, and among the glycinergic neurons projecting ipsilaterally, ~60% are also glutamatergic (Fredrich, Reisch, & Illing, 2009). Thus, at least four types of LSO neurons appear to exist concerning outputs to the (rat) IC. The functional implications of the two-transmitter scenario are unknown. At least in rats, all LSO neurons projecting into the IC are positive for the Ca2+-binding protein parvalbumin (Fredrich et al., 2009). Since parvalbumin-expressing cells play a role in action potential (AP)–dependent homeostasis (Xue & Liu, 2014), these neurons may mediate the relationship between synaptic excitation and inhibition in an activity-dependent manner and participate in the formation of EI balance.
In addition to ascending projections, the LSO provides descending projections to the cochlea (Schofield, 2010; Warr, 1992) and, to a much smaller extent, to all three subdivisions of the ipsilateral CNC, predominantly the dorsal cochlear nucleus (DCN; Covey, Jones, & Casseday, 1984; Winter, Robertson, & Cole, 1989). LSO neurons projecting into the ipsilateral VCN are small, having a mean soma diameter of ~5 µm (Fredrich et al., 2009). The projections into the cochlea are part of the LOC system (Warr & Boche, 2003). LOC cells are chemically distinct and provide cholinergic, GABAergic, dopaminergic, and peptidergic feedback to the cochlea (Vetter, Adams, & Mugnaini, 1991). Robust glutamate decarboxylase (GAD67) messenger ribonucleic acid (mRNA) levels characterize the GABAergic portion of the adult LOC system (Jenkins & Simmons, 2006). Functionally, LOC cells may provide a binaural adjustment required for accurate sound localization (Darrow, Maison, & Liberman, 2006). We will discuss further functional differences between LSO principal neurons and LOC neurons in the section, “Functional Properties of LSO Neurons in Vitro.”
Functional Properties of LSO Neurons in Vivo
As stated previously, LSO neurons extract and encode ILDs. Accordingly, most LSO neurons are EI units, that is, their response type is ipsilateral excitatory and contralateral inhibitory (classification scheme after Goldberg & Brown, 1969). Notice that the inverse sequence, namely IE = contralateral-inhibitory; ipsilateral-excitatory, is also used by some authors; for example, Tollin & Yin, 2002. The existence of EI units is in perfect harmony with the converging contralateral glycinergic and ipsilateral glutamatergic inputs (cf. the section, “Afferent Projections to the LSO”). As mentioned already, there are species-specific peculiarities in the anatomical organization of the LSO (Figure 2). Despite these peculiarities, electrophysiological studies have revealed many general similarities of LSO neurons across species. For example, one major similarity is the tonotopic organization (bat: Covey, Vater, & Casseday, 1991; Harnischfeger et al., 1985; cat: Caird & Klinke, 1983; Guinan, Norris, & Guinan, 1972; chinchilla: Caspary & Faingold, 1989; Caspary & Finlayson, 1991; Finlayson & Caspary, 1989; Moore & Caspary, 1983; dog: Tsuchitani, 1988a, 1988b; Tsuchitani & Boudreau, 1966, 1967; gerbil: Sanes & Rubel, 1988).
Basically, LSO neurons perform a subtraction-like process. Upon ipsilateral stimulation with tone bursts, typical peri-stimulus time histograms (PSTHs), which provide information about the spiking pattern before, during, and after a stimulus, are sustained (Figure 5B), chopper-like, or primary-like (like in [primary] auditory nerve (AN) fibers). Such PSTHs demonstrate a robust on response with low variability in timing, which is followed by a tonic plateau discharge (Caird & Klinke, 1983; Joris, 1996; Tsuchitani, 1977, 1988a). Higher sound pressure levels (SPLs) decrease the first spike latency and increase the firing rate. Frequency tuning of LSO neurons is sharp as indicated by narrow V-shaped tuning curves (Figure 5A left). For a given neuron, tuning curves obtained upon contralateral stimulation are similarly sharp and display the highest sensitivity at the same tone frequency as those after ipsilateral stimulation, except that spontaneous activity is efficiently blocked throughout the stimulus duration (Figure 5A right). In other words, characteristic frequencies (CF) for ipsi- and contralateral inputs match very well, and the response area for the contralateral inhibition is a horizontal mirror image of the ipsilateral excitatory response area. Therefore, ipsilaterally evoked excitation is matched by contralateral inhibition in both tonotopicity and efficacy. When stimulated binaurally, LSO EI cells generate APs when the sound at the ipsilateral ear is louder than the sound present at the contralateral ear (Figure 5C; Park, Monsivais, & Pollak, 1997). With increasing levels of the contralateral stimulus, the spike rate becomes more and more depressed, and the majority of EI cells are completely inhibited when the contralateral stimulus is 10 dB louder than the ipsilateral. Therefore, LSO neurons have spatial receptive fields in the ipsilateral sound field and sigmoid spike rate−ILD functions. Via the aforementioned projection pattern into the midbrain, namely excitatory output to the contralateral IC and inhibitory input to the ipsilateral IC (cf. section “Efferent Projections from the LSO”), LSO neurons set up the representation of space in the contralateral cerebral neocortex, which is characteristic for all sensory systems. In in vivo patch-clamp recordings, the first of this kind in the LSO, morphologically identified principal neurons did not respond with a phasic-tonic spike pattern to ipsilaterally presented 25-ms tones, but rather with an onset spike (Franken, Joris, & Smith, 2018). In contrast, non-principal LSO neurons fired throughout the stimulus. The authors proposed a revision of the prevailing notion of the LSO as a high-frequency nucleus integrating auditory information over time to send ILD cues to higher brain centers. Rather, they suggested that LSO principal cells are temporal differentiators and more akin to MSO cells in that they are also involved in temporal processing. The suggestion goes along with an earlier report stating that time and intensity are processed together in both the LSO and the MSO (Grothe & Park, 1995).
Iontophoretic application of glycine onto LSO neurons during ipsilateral acoustic stimulation mimics the inhibition obtained with contralateral stimulation (Moore & Caspary, 1983). Both contralaterally evoked inhibitory responses and the effects of iontophoretically applied glycine are abolished by strychnine, a GlyR antagonist. The results are corroborated by the presence of adult-type, strychnine-sensitive GlyRs containing ligand-binding α1 subunits. These subunits provide GlyRs with both short open and short decay times, thereby ensuring brief inhibitory postsynaptic potentials (IPSPs; Takahashi, Momiyama, Hirai, Hishinuma, & Akagi, 1992).
In intracellular in vivo recordings from EI LSO neurons of chinchillas (Finlayson & Caspary, 1989), stimulation with 3-ms tone pips evokes robust IPSPs and excitatory postsynaptic potentials (EPSPs) from the contralateral and ipsilateral ear, respectively, which have similar onset latencies (Figure 6B). AP bursts sit on top of the EPSPs. When the tone stimuli are presented simultaneously, the IPSP appears to be the dominant response, demonstrating its robustness.
The ipsilateral and contralateral pathways to the LSO vary in terms of axon length and number of synaptic relays (Figure 6A). Nevertheless, latency differences between ipsilateral inputs and contralateral inputs, which are also called characteristic delay (Yin & Kuwada, 1983), are remarkably small (Joris, 1996), indicating faster conduction velocity contralaterally than ipsilaterally. In cat LSO neurons, the latency differences average < 200 µs (Joris & Yin, 1998; Tollin & Yin, 2005). Several elements of the ILD pathway to the LSO are morphologically special. This holds for the endbulbs of Held on GBCs (Ryugo & Fekete, 1982) and the thick (5 µm) and heavily myelinated axons of GBCs (Malmierca & Ryugo, 2012; Moritz, Eckstein, Tenzer, & Friauf, 2015) that give rise to a calyx of Held on MNTB principal cells (Borst & Soria van Hoeve, 2012; Schneggenburger & Forsythe, 2006; von Gersdorff & Borst, 2002). Even in the neuropil of the LSO, myelinated axons are abundant and non-myelinated fibers are almost absent (Cant, 1984). In addition, MNTB-LSO synapses release synaptic vesicles reliably and with high temporal precision, even at high frequency (Krächan, Fischer, Franke, & Friauf, 2017). All these features suggest that LSO inputs are also designed to process timing information (Figure 6C). Indeed, LSO neurons, especially low-frequency ones with a CF < 3 kHz, are sensitive to interaural phase differences, implying ITD sensitivity to the fine structure of sound (Finlayson & Caspary, 1991). Moreover, LSO neurons can be sensitive to ILDs in the envelopes of amplitude-modulated high-frequency tones (Batra, Kuwada, & Fitzpatrick, 1997a, 1997b; Joris & Yin, 1995). Inhibition is maximal when one presents stimuli to the ears in-phase (Tollin & Yin, 2005). When an ipsilateral stimulus lags the contralateral stimulus by the characteristic delay, excitatory and inhibitory postsynaptic inputs arrive coincidentally at the LSO neuron, resulting in maximal inhibition. The temporal integration of excitatory and inhibitory inputs does not only lead to spike suppression, but it can also promote spike generation. Microsecond-precise arrival differences of inhibition, relative to excitation, facilitate spiking in LSO neurons, thus increasing the separability of ILDs for faint sounds (Beiderbeck et al., 2018).
Rats with unilateral kainic acid lesions restricted to the LSO are impaired in localizing a noise burst (van Adel & Kelly, 1998). Such neurotoxic lesions destroy somata while sparing fibers of passage, and axon terminals. The destruction of the rat LSO by itself is sufficient to produce sound localization deficits similar in severity to those caused by complete unilateral destruction of the whole SOC. These results reflect the importance of the LSO circuitry for processing binaural cues, particularly ILDs. Surprisingly, and in some contrast, conditional genetic ablation of MNTB neurons in Egr2;En1cko mice affects the ability of binaural sound localization only subtly (Jalabi et al., 2013). Furthermore, functional glycinergic innervation of the LSO remains substantial in such mice. One possible explanation for these unexpected results is the existence of a parallel glycinergic input to the LSO that is obscured in normal mice because glycinergic MNTB inputs dominate.
Relatively few aging studies have been performed in the SOC, and even fewer in the LSO (Frisina, 2010). Significant age-related functional deficits have been reported for LSO neurons in 20–23-month-old Fischer 344 rats, in which thresholds of both inhibitory and excitatory responses are elevated by 15–20 dB, particularly in LSO neurons with CFs > 8 kHz (Finlayson & Caspary, 1993). However, rate-level functions, maximal discharge rates, threshold-adjusted conduction latencies, and maximal inhibition are all unchanged between young and aged rats. Therefore, it is likely that the threshold shifts occur peripherally to the LSO. The resistibility of LSO neurons to age-related deterioration is surprising in light of the fact that MNTB neurons are selectively lost in Fischer 344 rats after 2 to 3 months (Casey & Feldman, 1985). It is possible that homeostatic plasticity, that is, compensatory changes in response to deafferentation, render LSO neurons able to perform efficiently in the relatively narrow operating range of excitation and inhibition (Caspary, Ling, Turner, & Hughes, 2008). The mechanisms for such compensations are completely unknown. In Sprague-Dawley rats, where massive age-related decreases occur in the number of MNTB neurons, this cell loss is not reflected in a change in LSO function (Finlayson, 1995). The lack of age-related changes in inhibitory responses of LSO neurons in Sprague-Dawley rats is unexpected, and increased innervation from other MNTB neurons may compensate for the lost inhibitory inputs. Alternatively, but less likely, the excitatory innervation may become decreased.
Studies in other species (mice, gerbils) have also found relatively modest, if any, age-related changes in the SOC (Gleich, Weiss, & Strutz, 2004; O'Neill, Zettel, Whittemore, & Frisina, 1997). For example, calbindin immunoreactivity does not change in any obvious way with age in the LSO in C57 and CBA mouse strains, whereas it declines in the MNTB of C57 mice (Caspary et al., 2008). Similar to Fischer 344 rats, C57 mice are a well-established model for studying progressive hearing loss, because they share the same pattern of hearing loss as humans suffering from presbyacusis (Willott, 1997).
Functional Properties of LSO Neurons in Vitro
The ILD pathways converging on the LSO provide a favorable system to analyze neurotransmission of both excitatory and inhibitory nature and are characterized by high-frequency signaling, temporal precision, and robustness. Because MNTB projection neurons are much more accessible for experimental manipulations than local interneurons from which inhibitory inputs often arise, the MNTB-LSO projection in particular is suitable for studying inhibitory synapses. Moreover, the fact that the projection is maintained in transverse brainstem slices renders it amenable to in vitro experiments, which reveal mechanisms of synaptic performance, for example, during sustained synaptic activity, that cannot be revealed through in vivo experiments.
Earliest electrophysiological experiments employing LSO slices go back to the 1990s (Kandler & Friauf, 1995b; Sanes, 1990; Wu & Kelly, 1991). They confirmed the EI characteristics of LSO neurons by demonstrating graded EPSPs and IPSPs upon electrical activation of afferent fibers from the ipsilateral AVCN and the MNTB, respectively (Figure 7A). The latency of these EPSPs and IPSPs is similarly short (~1.1 ms vs. 1.3 ms), thus implying fast synaptic transmission, and their AMPA/glutamatergic and glycinergic nature was demonstrated in pharmacological blocking experiments (Kandler & Friauf, 1995b; Kotak, Korada, Schwartz, & Sanes, 1998; Wu & Kelly, 1991, 1992b, 1995). EPSPs last 1.5 ms, IPSPs last 3.2 ms (Sanes, 1990), and decay kinetics of both evoked excitatory (EPSCs) and inhibitory postsynaptic currents (IPSCs) are fast, displaying time constants of less than 1 ms (Figure 11B; Pilati et al., 2016). Whereas unitary EPSCs are relatively weak, unitary IPSCs are strong (mean conductances 0.7 nS vs. 9 nS), and there is a ~10-fold variability across separate inhibitory inputs onto a given LSO neuron (Gjoni, Zenke, Bouhours, & Schneggenburger, 2018). In terms of EI integration, these features are possibly key determinants of the spontaneous firing properties of LSO neurons, and the weak excitatory inputs, which converge from SBCs, appear to filter out the relatively high spontaneous AP activity of these cells (Gjoni, Zenke, et al., 2018). Indeed, whereas spontaneous firing of bushy cells averages ~30 APs/s in vivo (Kopp-Scheinpflug, Fuchs, Lippe, Tempel, & Rübsamen, 2003), it is almost absent in LSO neurons and averages only 2.5 APs/s in cells that are spontaneously active (Karcz et al., 2011; Tsuchitani & Boudreau, 1966). In order to suppress AP firing, inhibition needs to be ~2-fold stronger than excitation, which can be achieved by few, but strong unitary IPSPs.
During brief stimulus trains, APs are faithfully elicited when only the ipsilateral input is activated, and concurrent activation of the contralateral input blocks preferably the latter-occurring APs (Figure 7B; Sanes, 1990). In vitro experiments also show sensitivity of LSO neurons to bilateral time differences (Figure 7C; Wu & Kelly, 1992a), thus confirming data from in vivo studies. Upon repetitive activation of the afferent fibers from the ipsilateral AVCN (10 pulses), an average LSO neuron can fire APs with ~90% fidelity when stimulated at 125 Hz (Wu & Kelly, 1993). The failure rate increases with the pulse number, indicating short-term plasticity (STP) in form of short-term depression (STD) at SBC-LSO synapses in the range of tens of milliseconds. A 90% fidelity at 125 Hz is remarkable, yet GBC-MNTB synapses do even better and are able to fire with 90% fidelity to a much higher stimulation frequency, up to 677 Hz (Wu & Kelly, 1993). Noticeably, one must consider that GBC-MNTB synapses employ calyces of Held, whereas AVCN-LSO and MNTB-LSO synapses employ conventional axon boutons. During prolonged stimulation periods (40 s), MNTB-LSO connections sustain virtually failure-free transmission up to frequencies of 100 Hz (Kramer et al., 2014). A high quantal content (i.e., number of vesicles released with a single AP) and effective vesicle replenishment form the basis for this synaptic reliability (Krächan et al., 2017). Two Ca2+ sensors, the synaptotagmin (Syt) proteins Syt1 and Syt2, mediate synaptic vesicle fusion at the fast-releasing MNTB-LSO synapses (Bouhours, Gjoni, Kochubey, & Schneggenburger, 2017). Syt2 is generally regarded as the main fast Ca2+ sensor (Chen, Arai, Satterfield, Young, & Jonas, 2017) and is more abundant than Syt1 in the LSO (Cooper & Gillespie, 2011). However, analysis of conditional Syt1-Syt2 single and double knockout (KO) mice at P12–15 has demonstrated a redundant cooperation of Syt2 with Syt1 at MNTB-LSO synapses (Bouhours et al., 2017). In this context, it is remarkable that excitatory calyces of Held undergo a change from Syt1 to Syt2 between P3 and P14 (Kochubey, Babai, & Schneggenburger, 2016). Whether a similar shift occurs in inhibitory MNTB axons after P15 or whether the Sy1/Syt2 redundancy lasts into adulthood remains to be shown.
An interesting aspect revealed by in vitro recordings is that the balance between excitation and inhibition in the LSO can be achieved via feedback signaling (Magnusson, Park, Pecka, Grothe, & Koch, 2008). The retrograde process involves GABA release from LSO neurons during AP firing activity and the activation of GABAB receptors on excitatory and inhibitory terminals. It may put the LSO neurons into a position to rapidly fine-tune their sound localization sensitivity in an activity-dependent manner.
In vitro recordings have also contributed substantially to our knowledge about biophysical properties of LSO neurons, which are very difficult to obtain through in vivo experiments (see, however, Franken et al., 2018). In response to sustained depolarizing current pulses, the majority of LSO principal neurons fires a single short latency AP (Figure 8A left; Barnes-Davies, Barker, Osmani, & Forsythe, 2004; Sterenborg et al., 2010). By contrast, LOC neurons display a delayed 1st AP and tonic firing behavior (Figure 8A right; Fujino et al., 1997; Sterenborg et al., 2010). In response to depolarizing voltage pulses, principal LSO neurons exhibit a fast-activating Na+ current (Na+ fast) and a sustained K+ current (K+ sust; Figure 8B left). Moreover, they show a slowly activating inward current in response to hyperpolarization (Ih), which is mediated through hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels (Figure 8C left; Leao, Leao, Sun, Fyffe, & Walmsley, 2006; Sterenborg et al., 2010). Ih controls the resting potential, dampens dendritic excitability, and temporal AP acuity (He, Chen, Li, & Hu, 2014; Rothman & Manis, 2003). In contrast to principal cells, LOC neurons exhibit a prominent, rapidly inactivating outward K+ current of the A-type (IA) when depolarized, yet lack the Ih current when hyperpolarized (Figure 8B,C right). Thus, one can physiologically distinguish principal and LOC neurons by their differences in voltage-gated currents. The firing pattern and channel properties of LSO neurons also correlate with the input resistance (Rin); low and high Rin are associated with single and multiple firing patterns, respectively. In the rat LSO, single-spiking neurons appear to be more abundant in the low-frequency region, whereas multiple-spiking neurons predominate in the high-frequency region (Barnes-Davies et al., 2004). The first group shows higher levels of a low-threshold K+ current (ILT). Blocking ILT with α-dendrotoxin converts the single-firing pattern into a multiple-firing one, which is indicative of the presence of voltage-gated potassium 1 (Kv1) channels, which play important roles in determining the latency of the 1st AP and AP repolarization (Fischl et al., 2016; Kole, Letzkus, & Stuart, 2007). Indeed, immunolabeling has demonstrated the presence of Kv1.1 in the rat LSO (Barnes-Davies et al., 2004), but the subcellular location and the development (Kim & Rutherford, 2016) have not been revealed. It is interesting that the LSO of naked mole rats, which live in subterranean habitats and have poor sound localization capabilities (Heffner & Heffner, 1993), lacks HCN channels (Gessele, Garcia-Pino, Omerbasic, Park, & Koch, 2016). The functional significance of IA has been described in a variety of neurons displaying repetitive firing (Rudy, 1988). Being an outward current, IA counteracts depolarizing effects of excitatory synapses and modulates the rate of such repetitive firing (Manis, 2008; Rothman & Manis, 2003). Taken together, ILT and IA may act in concert to modulate the rate of repetitive firing in LOC neurons.
Fetal Development of the LSO
Neurogenesis, cell fate determination, axon outgrowth, and target finding are major steps in early circuit assembly. To yield a functional ILD circuit, the generation of proper input circuits (MNTB-LSO; CN-LSO) and output circuits (LSO-IC) is crucial. In this chapter, we summarize both normal and disturbed fetal development of the LSO. As most studies focused on rodents, particularly mice, we also focus on these species in the following discussion.
Neurogenesis and Differentiation of LSO Neurons
During fetal development, the hindbrain becomes segregated in morphologically defined bulges along the antero-posterior axis (Kiecker & Lumsden, 2005; Lumsden & Krumlauf, 1996). These bulges appear as spatially distinct segments or compartments (rhombomeres) and contain progenitor cells (Figure 9A; Schneider-Maunoury, Gilardi-Hebenstreit, & Charnay, 1998). Segmentation genes, that is, genes whose inactivation results in the elimination of hindbrain territories or a modification of their extent, govern the process of segment formation and encode transcription factors. Overlapping or nested patterns of gene expression in the prospective hindbrain provide environmental signals that lead to the unique characteristics of individual rhombomeres and ultimately determines cell fate.
Eight rhombomeres (r1–8) give rise to different cell lineages and cell fates in rodents (Figure 9B; Kiecker & Lumsden, 2005). Auditory brainstem neurons are derived from progenitor cells of the lower rhombic lip, a structure located at the dorsal portion of the hindbrain that spans the whole antero-posterior hindbrain axis (Wullimann et al., 2011). AVCN neurons are mainly derived from r3 and partially from r2 (Farago, Awatramani, & Dymecki, 2006). In contrast, LSO neurons are derived from r5, while MNTB principal neurons are derived from r3 and r5 (Marrs, Morgan, Howell, Spirou, & Mathers, 2013). LOC neurons are derived from r4 (Di Bonito et al., 2013; Karis et al., 2001). VCN neurons are born between embryonic days (E) 11 and 14 (Altman & Bayer, 1980; Farago et al., 2006; Pierce, 1967; Willaredt, Schluter, & Nothwang, 2015). MNTB neurons are born during a very brief period from E11–12 (Kudo, Sakurai, Kurokawa, & Yamada, 2000; Willaredt et al., 2015), whereas LSO neurons are born over a longer period, namely from E9–16 (Figure 9C; Kudo, Kitao, Okoyama, Moriya, & Kawano, 1996; Kudo et al., 2000; Willaredt et al., 2015).
What are the underlying mechanisms that identify these cells as “auditory neurons” specific for their target region? Key regulators in this process are the transcription factors encoded by the genes Egr2 (Krox20) and Mafb (Kreisler). In r5, expression of these transcription factors begins at early embryonic stages (Egr2: E8; MafB: E9; Figure 9C; Willaredt et al., 2015). Egr2 encodes a zinc finger transcription factor, which is specifically expressed in areas that later coincide with r3 and r5 (Chavrier et al., 1990; Gilardi, Schneider-Maunoury, & Charnay, 1991; Wilkinson, Bhatt, Chavrier, Bravo, & Charnay, 1989). Accordingly, genetic deletion of Egr2 eliminates r3 and r5 (Figure 9B; Schneider-Maunoury et al., 1993). Mafb is expressed in r5 and r6 (Willaredt et al., 2015) and encodes a basic leucine zipper transcription factor (Cordes & Barsh, 1994). Similar to Egr2 deletion, Mafb KO leads to an abnormal shape of the hindbrain, especially to a loss of rhombomeric segmentation (r4–r7) and missing r5 and r6 (Figure 9B; McKay et al., 1994).
Atoh1 (Math1) is a basic helix-loop-helix transcription factor, which is involved in neuronal specification of cell derivatives from the rhombic lip (Ben-Arie et al., 1996). Conditional deletion of Atoh1 from r3 and r5 results in nearly complete neuronal loss in the AVCN and subsequently in the MNTB and LSO, likely due to a lack of trophic support (Figure 9E; Maricich et al., 2009).
Whereas the Atoh1 lineage gives rise to excitatory neurons (Rose, Ahmad, Thaller, & Zoghbi, 2009), the cell lineage of the transcription factor Engrailed 1 (En1) is required for normal positioning and survival of glycinergic MNTB and LSO neurons (Figure 9D, E; Altieri, Jalabi, Zhao, Romito-DiGiacomo, & Maricich, 2015; Jalabi et al., 2013). As expected, sound source localization performance is impaired in En1 cKOs although functional glycinergic input to the remaining LSO neurons was still observed. The source of this inhibition is unclear. Taken together, the data demonstrate the importance of En1 for the survival of glycinergic MNTB and LSO neurons.
Even more severe disruption of SOC nuclei occurs in Dicer1 cKOs (Rosengauer et al., 2012). Dicer1 is involved in the generation of mature microRNAs, which are involved in translational repression (Bernstein, Caudy, Hammond, & Hannon, 2001; Song & Rossi, 2017). Dicer1 cKOs display severely disrupted microRNA pathways, resulting in complete neuron loss in the MNTB and dramatic neuron loss in the VCN and LSO, in which principal cells are completely absent and only LOC cells persist (Rosengauer et al., 2012). This argues for a critical involvement of microRNAs in the histogenesis of SOC nuclei, further underlined in mir96—null mice, showing a 35% reduced volume in the VCN, MNTB, and LSO (Figure 9E; Schlüter et al., 2018).
Little is known about the spatiotemporal migration patterns after neurons of the ILD circuit are born. Cells of the Atoh1 lineage migrate superficially from the rhombic lip to their target region (Rose et al., 2009; Wang, Rose, & Zoghbi, 2005). For the VCN, cells mainly migrate tangentially between E11–15 (Hossain, D'Sa, & Morest, 2006; Wang et al., 2005), indicating that migration starts soon after neurons are born, since timeframes of neurogenesis and migration overlap. The MNTB and the LSO emerge between E16.5–17.5 (Marrs et al., 2013). At E17.5, both nuclei can be identified as a cell dense structure by marker labeling. Diffuse labeling is already apparent at E14.5, suggesting that migration has already started earlier. Hence, MNTB and LSO migration presumably occurs between E14–E18. Detailed spatiotemporal migration patterns for MNTB and LSO cells are yet to be resolved.
After neurogenesis and migration, neurons grow out axons to their target regions. In the auditory brainstem, axon outgrowth begins very shortly after neurons are born (Howell et al., 2007; Kandler & Friauf, 1993; Niblock, Brunso-Bechtold, & Henkel, 1995). Already at E13, rat CN axons grow along the ventral edge of the brainstem anlage (Niblock et al., 1995). At this time, only a few axons have crossed the midline and growth cones (axon endpoints) have a simple structure, lacking filopodia. Two days later, midline crossing is frequent and growth cones do contain several filopodia (Figure 9C; Kandler & Friauf, 1993; Niblock et al., 1995). CN axons innervate the ipsilateral LSO as early as E15.5, shown by the formation of axon branches (Howell et al., 2007). Functional CN-LSO and MNTB-LSO connectivity exist at E18, the earliest age examined (Kandler & Friauf, 1995b). LSO-IC axons grow out between E12–16 (Kudo et al., 1996). Interestingly, LSO axons innervate the contralateral IC about two days earlier than the ipsilateral IC (E12–13 vs. E14–16; Figure 9C).
Strikingly, VCN-LSO and MNTB-LSO projections are topographically organized already at postnatal day (P)0 and P2, respectively (Kil, Kageyama, Semple, & Kitzes, 1995; Sanes & Siverls, 1991). What might be the molecules involved in early circuit assembly and topographic organization in the auditory brainstem? We know from the topographical retino-geniculate projection that Eph receptors and their ephrin ligands play a critical role in establishing topographic maps (Triplett & Feldheim, 2012). One key function of Eph/ephrin signaling is axon guidance by forward and reverse signaling, providing attractive or repulsive cues (Cramer & Gabriele, 2014). Indeed, several Ephs and ephrins are expressed in the SOC from E13.5 until early postnatal stages (Abdul-Latif, Salazar, Marshak, Dinh, & Cramer, 2015; Nakamura, Hsieh, & Cramer, 2012), a period which largely coincides with the time window of axonal outgrowth from SOC nuclei (Figure 9C). Reverse signaling mediated through EphB2/EphB3-ephrin-B2 interaction is crucial for the normal development of the VCN-MNTB circuit (Hsieh et al., 2010; Nakamura et al., 2012). EphB2 KOs, EphB3 Kos, and ephrin-B2 KOs project a subset of VCN axons collaterals to the ipsilateral MNTB, resulting in a miswired VCN-MNTB circuitry virtually never observed in normal development. A similar phenotype exists in Ephrin-A2 or Ephrin-A5 single Kos, and Ephrin-A2/A5 double KOs, which all show aberrant ipsilateral VCN-MNTB axon collaterals. Interestingly, topographic wiring is unaffected in these KOs, both in normal contralateral axons and in miswired ipsilateral axons (Figure 9E; Abdul-Latif et al., 2015), indicating that different molecules regulate midline crossing and topographic organization. Indeed, VCN-MNTB axons in EphA4 and Ephrin-B2 KOs are laterally shifted compared to wildtypes (Miko, Nakamura, Henkemeyer, & Cramer, 2007). Taken together, Eph/ephrin signaling plays multiple roles in axon guidance, tonotopic map formation, and assembly of the ILD circuit (reviews: Cramer, 2005; Cramer & Gabriele, 2014).
Slit-robo and netrin-DCC interactions are also involved in axon guidance during ILD circuitry assembly (DCC = Deleted in Colorectal Cancer). Deletion of Robo3 from r3 and r5 disrupts midline crossing of AVCN axons and results in an ectopic innervation of the ipsilateral MNTB (Figure 9E; Michalski et al., 2013; Renier et al., 2010). Mice lacking Netrin-1 display a similar phenotype like Robo3-KOs, whereas KOs of the netrin-1 receptor DCC display almost no axonal outgrowth from the AVCN (Howell et al., 2007).
Development and Plasticity before Hearing Onset (P0–P12)
The auditory system of many altricial rodents, such as mice and rats, does not respond to airborne sound before ~P12 (Echteler, Arjmand, & Dallos, 1989; Ehret, 1976; Woolf & Ryan, 1984), as their ear canals are still closed (an exception are precocial guinea pigs). The altricial animals are therefore useful model organisms for developmental studies of the auditory system. At birth, ILD circuit assembly and initial topographic alignment by guidance molecules are largely complete (Friauf & Kandler, 1993; Kandler & Friauf, 1993; Kil et al., 1995; Sanes & Siverls, 1991). However, the LSO is still immature in many terms, namely inputs, dendritic morphology, biophysical properties, ion channels, synaptic kinetics, and transmitter phenotypes. Until hearing onset, enormous structural and functional changes lead to further maturation of the ILD circuitry. In this section, we highlight the most important changes required to yield a functional ILD circuit at the onset of hearing.
Before hearing onset, that is, in the absence of sensory input, spontaneous AP firing activity is present in the auditory system (Lippe, 1994; Sonntag, Englitz, Kopp-Scheinpflug, & Rübsamen, 2009; Sonntag, Englitz, Typlt, & Rübsamen, 2011; Tritsch, Yi, Gale, Glowatzki, & Bergles, 2007). The spontaneous activity is triggered by supporting cells, which periodically excite inner hair cells (IHCs) and induce Ca2+ APs (Tritsch et al., 2007; Wang et al., 2015). This results in activity propagation to central auditory targets, such as the SOC, with a conserved temporal AP pattern (Tritsch et al., 2010). Spontaneous AP activity can be recorded in vivo in the prehearing MNTB as early as P1 (Tritsch et al., 2010). However, synapses are generally weak in immature auditory circuits (Kandler & Friauf, 1995b; Marrs & Spirou, 2012). This raises the following question: What mechanisms ensure that the patterned AP firing of IHCs is efficiently conveyed synaptically to downstream nuclei like the LSO?
A strategy to ensure faithful AP generation in response to weak excitation is a high Rin (Mongiat, Esposito, Lombardi, & Schinder, 2009). Indeed, biophysical properties of neurons in the developing ILD circuit (VCN, MNTB, LSO) differ drastically from properties in the mature circuit (Figure 10). At birth, the Rin amounts to ~1 GΩ in VCN neurons (Marrs & Spirou, 2012), ~600 MΩ in MNTB neurons (Hoffpauir, Kolson, Mathers, & Spirou, 2010; Rusu & Borst, 2011), and ~200 MΩ in LSO neurons (Kandler & Friauf, 1995a). Consequently, weak excitatory input currents are sufficient to generate APs. Between P1–6, Rin stays constant in LSO neurons but declines thereafter (Kandler & Friauf, 1995a; Walcher, Hassfurth, Grothe, & Koch, 2011), which is coincident with a shortening of the membrane time constant (τmem; Figures 10; 11). Neurons decrease their Rin by adding ion channels into their plasma membrane that are active close to the resting membrane potential (Vrest). Candidates for such conductances are HCN channels and ILT channels. Indeed, both are highly abundant in the auditory brainstem (Barnes-Davies et al., 2004; Kopp-Scheinpflug, Pigott, & Forsythe, 2015).
Developmental changes of HCN conductances have not been demonstrated directly for LSO neurons before hearing onset. However, 92% of LSO neurons show a linear I-V relationship at hyperpolarizing potentials before P6 (Figure 10; Kandler & Friauf, 1995a), which argues against the expression of HCN conductances at this age. At P11, robust conductances mediated via the fast HCN1 isoform are present (Hassfurth, Magnusson, Grothe, & Koch, 2009; Leao et al., 2006), suggesting a developmental increase between P6–10. This is a likely scenario as the adjacent MSO shows a 13-fold increase in HCN conductance from P6-20, with a similar developmental decrease of the Rin and τmem as observed in the LSO (Khurana et al., 2012).
Similarly to HCN channels, IL channels (like Kv1.1 and Kv1.2) are activated close to Vrest (Barnes-Davies et al., 2004; Hassfurth et al., 2009), and they are involved in the typical single-firing behavior found in auditory brainstem neurons (Brew & Forsythe, 1995). At P4, IL gene expression is low in the SOC and upregulated during postnatal week 2 (Ehmann et al., 2013), consistent with a robust and topographically aligned IL staining of the LSO at P9 (Barnes-Davies et al., 2004). The combination of a high Rin and low IL abundance during postnatal week 1 predicts that at this age, LSO neurons have sustained firing properties, but a developmental switch in AP firing pattern needs to be shown. At P11, the majority of LSO neurons (~60–80%) fire a single AP upon prolonged current injection (Barnes-Davies et al., 2004; Ebbers et al., 2015; Hirtz et al., 2011).
Decreased Rin by addition of channel conductances and acceleration of τmem yields fast repolarization of the membrane. Consequently, kinetics of inhibitory and excitatory LSO inputs also show a developmental acceleration from P6 onwards (Figure 10; Figure 11B; Kandler & Friauf, 1995b). Synaptic kinetics are further accelerated by reorganization of the GlyR and AMPA receptor (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor [AMPAR]) subunit composition (Pilati et al., 2016). Between P8 and P11, the transcript levels of the GlyRα1 subunit increase ~5-fold, while the GluA4 subunit of the AMPAR is upregulated by ~25% (Pilati et al., 2016). Both α1 subunits and GluA4 subunits are associated with fast kinetics (Takahashi et al., 1992; Yang et al., 2011).
Spike kinetics in LSO neurons speed up drastically during development (Figure 10; Figure 11; Kandler & Friauf, 1995a; own unpublished observations). In neonatal rodents, APs are broad with a half-width of ~3 ms but shorten ~5-fold until hearing onset (Ebbers et al., 2015; Hirtz et al., 2011; Kandler & Friauf, 1995a). Fast AP repolarization is mainly associated to high-threshold potassium channels (IHT channels; Johnston, Forsythe, & Kopp-Scheinpflug, 2010). We know virtually nothing about IHT function in the LSO before hearing onset. In the whole brain, IHT channel transcripts increase over the first two postnatal weeks (Perney, Marshall, Martin, Hockfield, & Kaczmarek, 1992), and this may also hold for the LSO per se.
Do the normal development of biophysical parameters and the increase in channel conductance depend on spontaneous prehearing activity? Mice systemically lacking voltage-gated calcium channels 1.3 (Cav1.3 KOs), VGluT3 KO mice, and dn/dn mice show flat auditory brainstem responses (ABRs), thus implying a lack of correlated auditory activity (Bock, Frank, & Steel, 1982; Durham, Rubel, & Steel, 1989; Platzer et al., 2000; Seal et al., 2008). The deafness of these KOs is suggestive of impaired spontaneous activity. In VGluT3 KOs, however, this is not the case (Babola et al., 2018; Sun et al., 2018). Although in VGluT3 KOs, glutamate release from IHCs is abolished (Seal et al., 2008), spontaneous activity persists in spiral ganglion neurons (SGNs) and propagates to the IC, albeit with a changed temporal pattern. This is the case because hyperexcitable SGNs are activated directly by supporting cells (Babola et al., 2018), a scenario which could generate spontaneous pre-hearing activity in other KO models as well (Sun et al., 2018).
LSO neurons in systemic Cav1.3 KOs display increased Rin values, reflecting an immature state (Hirtz et al., 2011). Moreover, ILT channel labeling in the LSO of systemic Cav1.3 KOs is sparse, whereas age-matched wildtype mice show strong somatic labeling. Consequently, 80% of LSO neurons in P11 systemic Cav1.3 KOs fire multiple APs upon current injection. Furthermore, the AP half width is increased due to altered expression of ILT channels and, probably, IHT channels as well. In contrast to systemic Cav1.3 KOs, systemic VGluT3 KOs have normal membrane properties (Noh, Seal, Garver, Edwards, & Kandler, 2010). In dn/dn mice, the percentage of single and multiple firing LSO neurons is shifted towards more single firing neurons (Couchman et al., 2011). Whereas the Rin of multiple-firing dn/dn LSO neurons does not differ from that of multiple firing wildtype neurons, it is increased in single-firing neurons. Interestingly, HCN channel conductances are upregulated in dn/dn mice. In general, deficits in biophysical properties are most severe in systemic Cav1.3 KOs, milder in dn/dn mice, and absent in systemic VGluT3 KOs. A potential explanation is the difference in spontaneous activity propagation and the on-site expression of Cav1.3 in LSO neurons (Hirtz et al., 2011). Ca2+ influx through L-type calcium channels, for example Cav1.3, is involved in triggering genetic cascades (Greer & Greenberg, 2008), potentially necessary for normal development of LSO neurons. Indeed, brainstem-specific Cav1.3 KO reproduces the sparse labeling pattern of ILT channels seen in systemic Cav1.3 KOs (Satheesh et al., 2012). Therefore, a combination of peripheral (missing spontaneous activity) and central effects (missing Cav1.3 in the SOC) may explain the more severe deficits seen in systemic Cav1.3 KOs. Further studies in brainstem-specific KOs should resolve this open issue.
Taken together, biophysical properties change drastically in ILD nuclei between P0–12 and adapt to the developmental needs of the system (Figure 10; Figure 11). At P0, a high Rin ensures high excitability from weak inputs to promote activity propagation through the immature system, likely enabling activity-dependent maturation processes. From ~P5 until hearing onset, the channel conductance increases in LSO neurons. This results in a gradual decrease in Rin and τmem and, consequently, increases the temporal precision, an attribute crucial for ILD computation.
Neurotransmitter Phenotype of LSO Input and D/H Shift
During postnatal week 1, MNTB-LSO synapses are special toward their transmitter phenotype, as they release (at least) three types of transmitter, namely GABA (Kotak et al., 1998), glycine (Nabekura et al., 2004), and glutamate (Figure 11A; Gillespie et al., 2005). Glycine and GABA appear to be released from the same synaptic vesicles (Nabekura et al., 2004), yet glutamate release likely occurs from other vesicles (Case & Gillespie, 2011; Cooper & Gillespie, 2011). GABA release is most prominent at P3–5 (reportedly ~75% of the total inhibitory current), after which the GABAergic proportion gradually drops until hearing onset (~10%; Kotak et al., 1998). At hearing onset, the main inhibitory neurotransmitter is glycine (90%; Figure 11A). The developmental neurotransmitter switch is disturbed in systemic Cav1.3 KOs, as shown by an increased number of GABAergic and a decreased number of glycinergic MNTB boutons, paralleled by a higher incidence of GABAergic miniature IPSCs (Hirtz et al., 2012). Between P0–8, virtually every LSO neuron shows glutamate responses from MNTB inputs (Gillespie et al., 2005). After P8, glutamate release diminishes, such that at hearing onset glutamate responses occur in only ~25% of LSO neurons. In deaf cir/cir mice, glutamate release from MNTB terminals persists and contributes largely to the total MNTB-mediated transmission, even after P8 (Hong, Kim, & Ahn, 2008). A similar pattern of results occurs after kanamycin-induced cochlea damage or unilateral cochlea ablation. Both manipulations lead to an increased glutamatergic component in MNTB-LSO transmission and higher VGluT3 immunoreactivity in MNTB terminals (Lee et al., 2011).
Interestingly, immature LSO neurons show a high internal Cl– concentration ([Cl]i) during postnatal week 1 (Balakrishnan et al., 2003; Ehrlich, Löhrke, & Friauf, 1999; Löhrke et al., 2005). The high [Cl]i is due to low activity of the Cl–-extruding potassium-chloride cotransporter 2 (KCC2; Balakrishnan et al., 2003; Friauf, Rust, Schulenborg, & Hirtz, 2011). It results in a Cl– reversal potential more positive than Vrest (Balakrishnan et al., 2003; Ehrlich et al., 1999). Consequently, the “inhibitory” neurotransmitters GABA and glycine are depolarizing in the LSO during postnatal week 1 (Kandler & Friauf, 1995b), whereas they become “classically” hyperpolarizing during postnatal week 2 (Figure 11; Kandler & Friauf, 1995b; Kullmann, Ene, & Kandler, 2002), a process named D/H shift. The early depolarizing period does not cause shunting inhibition (Friauf et al., 2011). It is indeed excitatory, because MNTB fiber stimulation in neonates can elicit APs in LSO perforated-patch recordings, a technique which maintains the native [Cl–]i (Kullmann & Kandler, 2001; Löhrke et al., 2005). Furthermore, MNTB-mediated APs and application of GABA and glycine increase [Ca2+]i of LSO neurons (Kullmann, Ene, & Kandler, 2002), possibly inducing genetic cascades. Taken together, the immature MNTB-LSO projection shows several transient features during postnatal week 1, such as GABA release, GABA/glycine-mediated depolarization, and glutamate corelease (Figure 11A). These features coincide temporally with the structural and functional reorganization in the immature ILD circuit. A potential involvement of glutamate corelease and glycinergic/GABAergic depolarization in these processes will be discussed in the section, “Structural and Functional Circuit Refinement.”
Upon repetitive activation, LSO inputs undergo STP (Friauf, Fischer, & Fuhr, 2015), that is, they dynamically adapt the strength of synaptic transmission (Zucker & Regehr, 2002). All LSO inputs respond to repetitive activation with STD. Thereby, the level of depression can depend on the activation frequency and the maturation state. In general, STD level decrease between birth and hearing onset and synaptic transmission becomes more robust (Case & Gillespie, 2011; Case, Zhao, & Gillespie, 2011; Krächan et al., 2017; Kramer et al., 2014). Developmental adaptions are coincident with a transition of presynaptic Ca2+ channels. During postnatal week 1, synaptic MNTB-LSO transmission in rats relies on L-type, N-type and P/Q-type Ca2+ channels to a similar extent, while P/Q type channels predominantly (> 90%) mediate transmission at hearing onset (Figure 10; Alamilla & Gillespie, 2013). Forty percent P/Q type channels are present at hearing onset in mice (Giugovaz-Tropper et al., 2011), potentially showing species-dependent differences. In contrast, the CN-LSO transmission employs mainly P/Q type (45%) and N-type channels (35%) in the first postnatal week, only increasing the percentage of P/Q type channels slightly (55%) until hearing onset (Alamilla & Gillespie, 2013).
Structural and Functional Circuit Refinement
As stated in section “Circuit Formation”, the ILD circuit shows topographic features at birth. Nevertheless, the initial topography of MTNB-LSO inputs is coarse and further sharpened between P4–8 (Clause, Kim, et al., 2014; Hirtz et al., 2012; Kandler, Clause, & Noh, 2009; Kim & Kandler, 2003). Sharpening is ~2-fold and achieved by functional elimination of synaptic inputs, resulting in reduced MNTB-LSO input areas (Figure 11C; Kim & Kandler, 2003, 2010). At P3, fibers of 20–25 MNTB neurons converge on a single LSO neuron, while only 3–10 remain by P11 (Hirtz et al., 2012; Kim & Kandler, 2003, 2010; Noh et al., 2010; Walcher et al., 2011). In parallel to functional elimination, there is a 10–12-fold strengthening of the remaining MNTB fibers (Figure 10; Figure 11C; Hirtz et al., 2012; Kim & Kandler, 2003; Noh et al., 2010). The strengthening comprises a 2-fold increase in quantal size (i.e., postsynaptic current elicited by fusion of a single vesicle), but the main contribution is the increase in quantal content, very likely due to the addition of release sites to MNTB fibers (Kim & Kandler, 2010). Addition of release sites is supported by structural data from MNTB terminals, which show a 3-fold increase in bouton number of single MNTB fibers between P4 and P13 (Figure 10; Figure 11C; Clause, Kim, et al., 2014). In accordance with the topographical sharpening of MNTB inputs during postnatal week 1, dendrites of LSO neurons undergo pruning during the same period (Figure 11C; Rietzel & Friauf, 1998).
We know little about the molecular mechanisms of synaptic refinement. Ca2+-dependent signaling may be involved in refinement, and LSO neurons possess several candidate molecules, such as NMDARs (Figure 11A; Case & Gillespie, 2011; Gillespie et al., 2005; Hirtz et al., 2011; Kalmbach, Kullmann, & Kandler, 2010) and functional L-type voltage-gated Ca2+ channels (Figure 10; Hirtz et al., 2011; Jurkovicova-Tarabova et al., 2012; Kullmann et al., 2002). Both molecules are involved in synaptic plasticity and genetic cascades (Citri & Malenka, 2008). NMDAR conductance peaks between P4–8, coincident with synaptic refinement. A causal link between synaptic elimination and long-term depression (LTD) and synaptic strengthening and long-term potentiation (LTP) is discussed (Kandler, 2004) and causality is likely when considering the visual system and the hippocampus (Lee et al., 2014; Wiegert & Oertner, 2013). Such causality remains to be shown for the ILD circuit. Both LTP and LTD have been demonstrated in the MNTB-LSO projection (Chang, Kotak, & Sanes, 2003; Kotak & Sanes, 2014; Pradhan, Maskey, & Ahn, 2012).
Compared with MNTB-LSO, we know less about CN-LSO synaptic refinement, mainly because the projection is difficult to preserve in slice preparations (Kronander, Michalski, Lebrand, Hornung, & Schneggenburger, 2017; Lohmann, Ilic, & Friauf, 1998). The CN-LSO projection refines roughly during the same period as the MNTB-LSO projection (Figure 10; Figure 11C; Case et al., 2011). At P3, ~5 fibers from CN neurons converge on a single LSO neuron, while ~3 fibers remain at P12 (Figure 10; Figure 11C; Case et al., 2011). Remaining CN-LSO fibers are also developmentally strengthened (~6-fold) within postnatal week 1–2. In contrast to the MNTB-LSO projections, CN-LSO fibers undergo further strengthening after the period of functional elimination (> P8; Case et al., 2011). Strengthening mechanisms for the CN-LSO projection are less clear. Quantal and structural analysis of CN-LSO terminals could clarify this open topic.
Are the temporally coincident features of the developing ILD circuit, such as prehearing spontaneous activity (CN-LSO; MNTB-LSO), glutamate corelease (MNTB-LSO), GABAergic transmission, and glycine and GABA mediated depolarization (MNTB-LSO) involved in ILD circuit refinement? To address this question, several studies have employed genetic approaches. They thus overcome invasive procedures such as surgical cochlea ablation, which often have severe side effects. VGluT3 KO mice are deaf (Seal et al., 2008), but spontaneous activity persists with a slightly changed temporal pattern (Babola et al., 2018; Sun et al., 2018). Furthermore, glutamate corelease from glycinergic MNTB terminals is abolished (Noh et al., 2010). VGluT3 KOs also show an impaired synaptic elimination and strengthening of the MNTB-LSO pathway (2-fold broader MNTB input width, 3-fold weaker MNTB fiber strength). Interestingly, the CN-LSO projection shows normal refinement (Noh et al., 2010), indicating a specific role of glutamate corelease for tonotopic refinement and strengthening of inhibitory (MNTB) synapses. Both synaptic elimination and strengthening of the MNTB-LSO projection are similarly impaired in systemic Cav1.3 KOs, which display a ~2-fold broader MNTB input width and a ~2-fold higher MNTB-LSO convergence (Hirtz et al., 2012). Single MNTB fiber strength is ~5-fold weaker, resulting from a reduced quantal size and a lower bouton number (Hirtz et al., 2012). A potential caveat of systemic Cav1.3 KOs is the on-site presence of Cav1.3 in the wildtype LSO, which makes it impossible to pinpoint the origin of the impairments to spontaneous peripheral activity, on-site effects or a combination of both. Cochlea—and brainstem-specific Cav1.3 KOs should clarify the respective role of Cav1.3 in the peripheral and the central auditory system.
In contrast to the harsh reduction of spontaneous peripheral activity in systemic Cav1.3 KOs, a genetic deletion of the α9 subunit of the acetylcholine receptor causes only modest activity alterations. Prehearing α9 KOs display a normal overall frequency of spontaneous activity, but shorter spike bursts and increased spiking between bursts, leading to a changed temporal fine structure. This subtle manipulation is sufficient to impair synaptic elimination and strengthening at the MNTB-LSO projection (Clause, Kim, et al., 2014). The results imply that spontaneous prehearing activity carries information that is crucial for normal synaptic refinement. The impact of glycine1 and GABA-mediated depolarization on synaptic refinement is not well known. First steps to disentangle the importance of the D/H shift (cf. section “Neurotransmitter Phenotype of LSO Input and D/H Shift”) were performed by using KCC2 knockdown mice in which GABA and glycine neurotransmission remains depolarizing (Lee, Bach, Noh, Delpire, & Kandler, 2016). Synaptic elimination and strengthening of the MNTB-LSO pathway was normal in these animals. This result underlines that the D/H shift itself is not required for synaptic refinement, but it still leaves the impact of the transient GABAergic and glycinergic depolarizing period unclear.
As mentioned previously, we know relatively little about CN-LSO refinement. During early development, LSO neurons are innervated by noradrenergic afferents which originate from the locus coeruleus (Mulders & Robertson, 2001). Pharmacological blockade of adrenoceptors between P2–8 strongly impairs functional synaptic elimination and strengthening of the CN-LSO connection, thus arguing for a crucial role of noradrenergic signaling (Hirao et al., 2015). It is very likely that molecules other than noradrenaline also play a modulatory role during CN-LSO refinement. For example, somatostatin is heavily present in the CN-LSO connection of rats, yet only between P1–11 (Kungel & Friauf, 1995). Somatostatin depletion during this period results in less complex dendritic trees (Kungel, Piechotta, Rietzel, & Friauf, 1997), providing evidence for a trophic role during CN-LSO refinement.
Taken together, prehearing development yields an ILD circuit in the auditory brainstem with a plethora of structural and functional hallmarks that are uncommon to many other brain areas. The hallmarks include topographically aligned projections and fast output and input kinetics, the latter with a high temporal precision and resistance to synaptic fatigue. Spontaneous activity is necessary for several maturation processes before hearing onset. Future research should aim at revealing the role of several transient features, for example high [Cl]i, GABA release, and high NMDA conductance. In addition, research needs to identify the molecular pathways controlling circuit maturation and to disentangle the impact of peripheral versus central activity.
Development and Plasticity after Hearing Onset
Hearing thresholds drop drastically around P12 in altricial rodents, coincident with hearing onset (Echteler et al., 1989; Woolf & Ryan, 1984, 1985). By this age, characteristic features of auditory brainstem circuits, such as temporal and topographical precision, synaptic reliability, and fast input and output kinetics are present in the ILD circuit (Trussell, 1999; von Gersdorff & Borst, 2002). Nevertheless, further developmental steps after hearing onset improve the aforementioned features. In this chapter, we will highlight the most important steps at the biophysical, structural, and functional level and discuss the impact of auditory experience on the maturation process.
Several biophysical parameters of LSO neurons continue to maturate after hearing onset (Figure 10). First, Rin declines from ~70 MΩ to 20 MΩ until P20 in gerbils (Walcher et al., 2011). Second, τmem accelerates ~4-fold in gerbils and ~2-fold in mice, reaching ~2 ms in both species (Garcia-Pino, Gessele, & Koch, 2017; Walcher et al., 2011). Third, HCN conductance increases ~3-fold in gerbils (Hassfurth et al., 2009). The HCN half-activation voltage decreases from ~-90 mV to –70–80 mV between P10–17 (Garcia-Pino et al., 2017; Hassfurth et al., 2009), yielding HCN-mediated conductances close to Vrest. A low Rin and large HCN channel conductance are characteristics of temporally precise circuits (Khurana et al., 2012). Functionally, an HCN conductance reduces τmem, resulting in local acceleration of EPSP kinetics, thus minimizing temporal summation of LSO inputs (Leao, Leao, & Walmsley, 2011). Pharmacological blockade of HCN channels hyperpolarize LSO neurons, increase the Rin and τmem (Hassfurth et al., 2009). This highlights the functional importance of the HCN channel conductance in the LSO as a basis of temporally precise processing and ILD computation.
Another key conductance for temporally precise computation is provided by ILT (Golding & Oertel, 2012). ILT is highly abundant in the LSO of P30 rats, increasing from medial to lateral (Barnes-Davies et al., 2004), suggesting different firing properties at different isofrequency bands. Indeed, single-firing LSO neurons are more abundant in the lateral limb (Barnes-Davies et al., 2004). Similar to the situation before hearing onset, little is known about IHT in the LSO after hearing onset. Robust staining for Kv3.3, but not Kv3.1, suggests a more prominent role of Kv3.3 (Grigg, Brew, & Tempel, 2000; Li, Kaczmarek, & Perney, 2001). AP kinetics of LSO neurons speed up drastically after hearing onset, characterized by a fast rising phase and a similarly fast repolarization, which results in a half width of ~200 µs at P21 (Figure 11B; Garcia-Pino et al., 2017).
Synaptic kinetics also accelerate further after hearing onset. The decay time of MNTB-mediated IPSCs is ~0.7 ms (Pilati et al., 2016), which is among the fastest glycinergic kinetics in the brain. Other studies report similar values (Kramer et al., 2014; Walcher et al., 2011). CN-mediated glutamatergic EPSCs also accelerate after hearing onset to 0.7 ms (Pilati et al., 2016). Consequently, they match IPSC kinetics (Figure 10; Figure 11). This contrasts with many other brain regions, in which kinetics of EPSCs are usually several-fold faster than IPSC kinetics (Xie & Manis, 2013). The fast, sub-ms kinetics are likely due a low Rin, which becomes manifested after hearing onset. Another contribution is the developmental reorganization of glycine and AMPAR subunits. The abundance of the fast GluA4 AMPAR subunit increases > 2-fold (Pilati et al., 2016).
The developmental EPSC acceleration in the LSO very likely depends on normal auditory experience. Acoustic trauma results in increased ABR thresholds and prolonged EPSCs in the LSO due to reorganization in the AMPAR subunit composition (Pilati et al., 2016). Because IPSC kinetics are unchanged, subunit composition of GlyRs is likely less plastic than that of AMPARs. Due to the prolonged EPSC kinetics, ILD functions are shifted toward the contralateral side after acoustic trauma. The effect is fully reversible after ~2 months, after which EPSC kinetics have returned to normal (Pilati et al., 2016). Taken together, biophysical parameters of LSO neurons maturate further after hearing onset. In combination, decrease of the Rin and acceleration of τmem, APs, and GlyR and AMPAR kinetics to an adult-like state are all crucial for temporally precise processing in the ILD circuit (Golding & Oertel, 2012).
Synapses in the auditory brainstem are active at a high rate. Spontaneous MNTB spike activity at P28 is ~30 Hz, reaching ~350 Hz upon sound stimulation (Sonntag et al., 2009). Synapses of the ILD circuit must be able to transmit such high frequencies in order to function properly. Indeed, MNTB-LSO and CN-LSO synapses show little synaptic failures upon repetitive high-frequency stimulation. At P21, the CN-LSO projection shows steady-state depression levels of 20–30% even at 200 Hz after 20 pulses (Garcia-Pino et al., 2017; Walcher et al., 2011). MNTB-LSO synapses depress to a steady-state level of ~15% at this frequency. Extending the stimulus duration to 60 s, steady-state depression is ~10% (Kramer et al., 2014). Thus, the MNTB-LSO and CN-LSO synapses can cope with high activation rates despite profound synaptic depression, and they are resistant to synaptic fatigue over prolonged periods. Highly efficient replenishment mechanisms are most likely at both MNTB-LSO and CN-LSO synapses, but the issue needs further investigation. Potential developmental specializations after hearing onset, such as nanodomain coupling, maturation of the readily releasable pool, or replenishment mechanisms are yet to be resolved.
Structural and Functional Refinement of the ILD Circuit
MNTB axon terminals in the LSO become pruned between P13–20, and the number of boutons per MNTB fiber is reduced by ~50%, accompanied by a ~50% reduction of the bouton area (Figure 11C; Clause, Kim, et al., 2014). As a result, the bouton spread along the tonotopic axis is reduced, further sharpening the topographic map (Clause, Kim, et al., 2014; Sanes & Siverls, 1991). The topographic sharpening is disrupted in gerbils upon unilateral cochlea ablation; these animals show a larger spread of boutons within the LSO (Sanes & Takacs, 1993). In parallel with bouton pruning during normal development, dendrites of LSO neurons undergo pruning after hearing onset as well (Figure 11C). For example, the number of primary dendrites is reduced from 6 to 4 between P11–36, and the number of dendritic endpoints is reduced even 5-fold, from ~150 to ~25 (Rietzel & Friauf, 1998).
Effects of deafferentation on the structural refinement in the ILD circuit have often been studied in deafened rodents. Early deafferentation by means of surgical ablation of the cochlea or treatment with ototoxins causes a variety of abnormalities, including neuronal loss (Moore, 1990, 1992; Moore, Rogers, & O’Leary, 1998), changed synaptic strength (Kotak & Sanes, 1996, 1997), and changed morphology (Sanes & Takacs, 1993). Unilateral cochlea ablation at P7 weakens excitatory VCN-LSO transmission on the ablated side and inhibitory MNTB-LSO transmission on the unablated side (Kotak & Sanes, 1996, 1997). Furthermore, ectopic VCN-MNTB projections form as VCN neurons of the non-ablated side project to previously inappropriate targets, including the ipsilateral MNTB and the contralateral LSO (Kitzes, Kageyama, Semple, & Kil, 1995; Russell & Moore, 1995). Another common denominator of such studies is a reduced topographic precision due to broader spread of axon terminals or LSO dendrites. For example, unilateral cochlea ablation at P7 results in more dendritic branch points in the LSO of the ablated side by P21 (Sanes & Chokshi, 1992; Sanes, Markowitz, Bernstein, & Wardlow, 1992). As a cautionary note, several early cochlea ablation studies (≤ P7) have a big drawback: if structural pruning is analyzed 1–2 weeks later, spontaneous prehearing as well as acoustically evoked activity is affected and, therefore, a clear causal conclusion toward the lacking activity cannot be drawn. Consequently, an important field of study will be to determine the impact of acoustic experience in isolation.
Little is known about critical periods during development of the ILD circuit. Sprouting of MNTB terminals is likely to be restricted to the time before hearing onset and hence does not depend on auditory experience, as cochlea ablation at P10, very shortly before hearing onset, does not yield de novo sprouting of AVCN-LSO projections (Russell & Moore, 1995). Nevertheless, even in adult rats, unilateral cochlea lesions or acoustic traumata induce several anatomical, cellular, and molecular changes in the brainstem, for example, a long-lasting (> 1 year) reappearance of the growth-associated protein 43 (GAP-43) in the LSO, as well as the CN and IC, the input and target nuclei of the LSO (Illing et al., 2000; Michler & Illing, 2002). The results corroborate earlier findings of a higher density of GlyRs in the contralateral LSO five months after unilateral cochleotopy (Suneja, Benson, & Potashner, 1998). They provide evidence for substantial adult auditory brainstem plasticity, possibly lasting throughout life, and can be interpreted toward reweighting synaptic inputs and readjusting neuronal tuning to prevent the ILD network from delivering false signals to higher auditory centers.
Does auditory experience yield further functional elimination or strengthening of inputs to the LSO? At P18, fibers of 3–4 MNTB neurons innervate a single LSO neuron in mice and gerbils, similar to P10. The data suggest no further functional elimination after hearing onset (Walcher et al., 2011). MNTB fiber strength also stays constant after hearing onset (Figure 10, Figure 11C). This contrasts with two reports of a developmental decline of the MNTB fiber conductance from prehearing until after hearing onset (Kramer et al., 2014; Pilati et al., 2016). The latter reports have not determined single fiber strength, which potentially explains the discrepancies. CN-LSO single fiber strength remains unchanged after hearing onset, but maximal CN-LSO strength increases. An unchanged quantal size after hearing onset suggests a developmental addition of release sites (Garcia-Pino et al., 2017). Interestingly, in a mouse model for Fragile X syndrome (fragile X mental retardation protein [FRMP] KOs), the maximal strength of CN-LSO synapses is abnormally high after hearing onset, whereas the MNTB-LSO strength develops normally. Increased excitation, combined with normal inhibition, results in shifted binaural sensitivity and increased firing rates in the LSO of FRMP KOs (Garcia-Pino et al., 2017). The changes potentially underlie the auditory hypersensitivity and processing deficits described in Fragile X patients.
As further functional refinement after hearing onset is not observed in the MNTB-LSO projection until P20, structural refinement appears to be temporally segregated from functional refinement (Clause, Kim, et al., 2014). Interestingly, disruption of the temporal pattern of spontaneous prehearing activity in α9 KOs affects not only the functional refinement before hearing onset, but also the structural refinement thereafter (Clause, Kim, et al., 2014). This is surprising because α9 KOs lack obvious hearing deficits (May, Prosen, Weiss, & Vetter, 2002; Vetter et al., 1999) besides a disturbed frequency discrimination (Clause, Lauer, & Kandler, 2017), consistent with a disturbed MNTB-LSO circuit refinement (Clause, Kim, et al., 2014). Axonal end branches of MNTB neurons stay unpruned after hearing onset in α9 KOs and thus remain in an immature state, exhibiting a higher bouton number and a larger topographic spread than normally. These results suggest that structural refinement after hearing onset is predefined by the functional elimination before hearing onset, even though both processes are temporally segregated.
Very little is known about structural and functional refinement after hearing onset in KO models. While several studies have investigated systemic Cav1.3, VGluT3, and α9 KOs during prehearing age, these models are thus far rarely employed after P20. This leaves a multitude of open questions about ILD circuit development in these models (Figure 11). Taken together, the ILD circuit further matures after hearing onset mainly by structural refinement, finally yielding an astonishing degree of topographic alignment.
In this monumental book chapter on the LSO, we aimed to provide an overview of our current knowledge about this fascinating nucleus in the auditory brainstem, in terms of organization, development, and plasticity—unlike previous reviews, which have tried to combine several seemingly diverse aspects of the ‘ILD detector’ in a single article. To our knowledge, this is the first attempt to do so. Our motto has been ‘All in one go what one ought to know about the LSO.’ Thus far, no review has put the LSO in the center of its work. It is our hope that the reader will find the insights provided by the chapters helpful in better understanding a major station of the central auditory system. For further reading and to the die-hard LSO aficionados, we recommend the following reviews published over the past 20 years or so. Structure and function of central auditory system: Altschuler & Shore, 2010; Malmierca & Hackett, 2010; Schofield, 2010. SOC: Schwartz, 1992. Binaural sound localization cues: Grothe, Pecka, & McAlpine, 2010; Middlebrooks, 2015; Tollin, 2003; Yin, 2013; Yin, 2002; Yin & Kuwada, 2010. Development of central auditory system: Cant, 1998; Sanes & Walsh, 1998. Development and plasticity of the SOC: Friauf, 2004; Moore & King, 2004. Development of sound localization circuits: Clause, Sturm, Altien, Maricich, & Kandler, 2014; Kandler & Gillespie, 2005.
Several structural and functional specializations in the ILD circuit place LSO neurons into the position to process binaural information with high speed, precision, and fidelity, even during sustained activity. The acquisition of these features is set via genetic programs and shaped by processes comprising activity-dependent remodeling. The latter make the LSO circuit crucially dependent on proper cochlea function. Although the mechanisms for sound localization are among the most thoroughly studied of central auditory information processing, many open issues remain and request future research. For example, there is compelling and growing evidence that LSO neurons have more diverse attributes than previously thought. It is therefore important to determine whether various cell types mediate complementary functions in binaural processing. Methods that combine morphology, physiology, and genetics will shed light on these issues. Likewise, it is mandatory to bring in vivo and in vitro data together. Finally, aging, with its various functional and behavioral changes, involves not only deterioration of the auditory periphery, but also deficits in central auditory processing. It will be interesting to investigate how much an impaired performance of the LSO contributes to this important issue.
This work was supported by the Priority Program 1608 “Ultrafast and temporally precise information processing: normal and dysfunctional hearing” of the Deutsche Forschungsgemeinschaft (grant Fr1784/17–1 to EF). Special thanks to Drs. Jan Hirtz and Karl Kandler for valuable comments on the manuscript and to Ulrike Eschbach for providing expert secretarial help.
Abdul-Latif, M. L., Salazar, J. A., Marshak, S., Dinh, M. L., & Cramer, K. S. (2015). Ephrin-A2 and ephrin-A5 guide contralateral targeting but not topographic mapping of ventral cochlear nucleus axons. Neural Development, 10, 27. doi:10.1186/s13064-015-0054-6Find this resource:
Adam, T. J., Finlayson, P. G., & Schwarz, D. W. (2001). Membrane properties of principal neurons of the lateral superior olive. Journal of Neurophysiology, 86(2), 922–934. doi:10.1152/jn.2001.86.2.922Find this resource:
Adam, T. J., Schwarz, D. W. F., & Finlayson, P. G. (1999). Firing properties of chopper and delay neurons in the lateral superior olive of the rat. Experimental Brain Research, 124(4), 489–502.Find this resource:
Akazawa, C., Ishibashi, M., Shimizu, C., Nakanishi, S., & Kageyama, R. (1995). A mammalian helix-loop-helix factor structurally related to the product of Drosophila proneural gene atonal is a positive transcriptional regulator expressed in the developing nervous system. Journal of Biological Chemistry, 270(15), 8730–8738.Find this resource:
Alamilla, J., & Gillespie, D. C. (2013). Maturation of calcium-dependent GABA, glycine, and glutamate release in the glycinergic MNTB-LSO pathway. PLoS One, 8(9), e75688. doi:10.1371/journal.pone.0075688Find this resource:
Alexander, S. P., Peters, J. A., Kelly, E., Marrion, N. V., Faccenda, E., Harding, S. D., … Davies, J. A.; CGTP Collaborators. (2017). The concise guide to pharmacology 2017/18: Ligand-gated ion channels. British Journal of Pharmacology, 174 Suppl. 1, S130–S159. doi:10.1111/bph.13879Find this resource:
Altieri, S. C., Jalabi, W., Zhao, T., Romito-DiGiacomo, R. R., & Maricich, S. M. (2015). En1 directs superior olivary complex neuron positioning, survival, and expression of FoxP1. Developmental Biology, 408(1), 99–108. doi:10.1016/j.ydbio.2015.10.008Find this resource:
Altman, J., & Bayer, S. A. (1980). Development of the brain stem in the rat. III. Thymidine-radiographic study of the time of origin of neurons of the vestibular and auditory nuclei of the upper medulla. Journal of Comparative Neurology, 194(4), 877–904. doi:10.1002/cne.901940410Find this resource:
Altschuler, R. A., & Shore, S. E. (2010). Central auditory neurotransmitters. In A. Rees & A. R. Palmer (Eds.), Oxford handbook of auditory science: The auditory brain (Vol. 2, pp. 965–989). Oxford, New York: Oxford University Press.Find this resource:
Aschoff, A., & Ostwald, J. (1987). Different origins of cochlear efferents in some bat species, rats, and guinea pigs. Journal of Comparative Neurology, 264(1), 56–72. doi:10.1002/cne.902640106Find this resource:
Azeredo, W. J., Kliment, M. L., Morley, B. J., Relkin, E., Slepecky, N. B., Sterns, A., … Woods, C. I. (1999). Olivocochlear neurons in the chinchilla: a retrograde fluorescent labelling study. Hearing Research, 134(1–2), 57–70. doi:10.1016/s0378-5955(99)00069-6Find this resource:
Babola, T. A., Li, S., Gribizis, A., Lee, B. J., Issa, J. B., Wang, H. C., … Bergles, D. E. (2018). Homeostatic control of spontaneous activity in the developing auditory system. Neuron, 99(3), 511–524. e515. doi:10.1016/j.neuron.2018.07.004Find this resource:
Balakrishnan, V., Becker, M., Löhrke, S., Nothwang, H. G., Güresir, E., & Friauf, E. (2003). Expression and function of chloride transporters during development of inhibitory neurotransmission in the auditory brainstem. Journal of Neuroscience, 23(10), 4134–4145.Find this resource:
Barnes-Davies, M., Barker, M. C., Osmani, F., & Forsythe, I. D. (2004). Kv1 currents mediate a gradient of principal neuron excitability across the tonotopic axis in the rat lateral superior olive. European Journal of Neuroscience, 19(2), 325–333.Find this resource:
Batra, R., Kuwada, S., & Fitzpatrick, D. C. (1997a). Sensitivity to interaural temporal disparities of low—and high-frequency neurons in the superior olivary complex. I. Heterogeneity of responses. Journal of Neurophysiology, 78(3), 1222–1236. doi:10.1152/jn.1922.214.171.1242Find this resource:
Batra, R., Kuwada, S., & Fitzpatrick, D. C. (1997b). Sensitivity to interaural temporal disparities of low—and high-frequency neurons in the superior olivary complex. II. Coincidence detection. Journal of Neurophysiology, 78(3), 1237–1247. doi:10.1152/jn.19126.96.36.1997Find this resource:
Bazwinsky, I., Bidmon, H. J., Zilles, K., & Hilbig, H. (2005). Characterization of the rhesus monkey superior olivary complex by calcium binding proteins and synaptophysin. Journal of Anatomy, 207(6), 745–761. doi:10.1111/j.1469-7580.2005.00491.xFind this resource:
Bazwinsky-Wutschke, I., Härtig, W., Kretzschmar, R., & Rübsamen, R. (2016). Differential morphology of the superior olivary complex of Meriones unguiculatus and Monodelphis domestica revealed by calcium-binding proteins. Brain Structure and Function, 221(9), 4505–4523. doi:10.1007/s00429-015-1181-xFind this resource:
Beiderbeck, B., Myoga, M. H., Müller, N. I. C., Callan, A. R., Friauf, E., Grothe, B., & Pecka, M. (2018). Precisely timed inhibition facilitates action potential firing for spatial coding in the auditory brainstem. Nature Communications, 9(1), 1771. doi:10.1038/s41467-018-04210-yFind this resource:
Ben-Arie, N., McCall, A. E., Berkman, S., Eichele, G., Bellen, H. J., & Zoghbi, H. Y. (1996). Evolutionary conservation of sequence and expression of the bHLH protein Atonal suggests a conserved role in neurogenesis. Human Molecular Genetics, 5(9), 1207–1216.Find this resource:
Bernstein, E., Caudy, A. A., Hammond, S. M., & Hannon, G. J. (2001). Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature, 409(6818), 363–366. doi:10.1038/35053110Find this resource:
Bledsoe, S. C., Snead, C. R., Helfert, R. H., Prasad, V., Wenthold, R. J., & Altschuler, R. A. (1990). Immunocytochemical and lesion studies support the hypothesis that the projection from the medial nucleus of the trapezoid body to the lateral superior olive Is glycinergic. Brain Research, 517(1–2), 189–194. doi:10.1016/0006-8993(90)91025-CFind this resource:
Bock, G. R., Frank, M. P., & Steel, K. P. (1982). Preservation of central auditory function in the deafness mouse. Brain Research, 239(2), 608–612.Find this resource:
Borst, J. G., & Soria van Hoeve, J. (2012). The calyx of Held synapse: From model synapse to auditory relay. Annual Review of Physiology, 74, 199–224. doi:10.1146/annurev-physiol-020911-153236Find this resource:
Boudreau, J. C., & Tsuchitani, C. (1968). Binaural interaction in the cat superior olive S segment. Journal of Neurophysiology, 31(3), 442–454. doi:10.1152/jn.19188.8.131.522Find this resource:
Bouhours, B., Gjoni, E., Kochubey, O., & Schneggenburger, R. (2017). Synaptotagmin2 (Syt2) drives fast release redundantly with Syt1 at the output synapses of parvalbumin-expressing inhibitory neurons. Journal of Neuroscience, 37(17), 4604–4617. doi:10.1523/jneurosci.3736-16.2017Find this resource:
Brew, H. M., & Forsythe, I. D. (1995). Two voltage-dependent K+ conductances with complementary functions in postsynaptic integration at a central auditory synapse. Journal of Neuroscience, 15(12), 8011–8022.Find this resource:
Brownell, W. E., Manis, P. B., & Ritz, L. A. (1979). Ipsilateral inhibitory responses in the cat lateral superior olive. Brain Research, 177(1), 189–193.Find this resource:
Brunso-Bechtold, J. K., Linville, M. C., & Henkel, C. K. (1994). Terminal types on ipsilaterally and contralaterally projecting lateral superior olive cells. Hearing Research, 77(1–2), 99–104.Find this resource:
Caicedo, A., & Eybalin, M. (1999). Glutamate receptor phenotypes in the auditory brainstem and mid-brain of the developing rat. European Journal of Neuroscience, 11(1), 51–74.Find this resource:
Caird, D., & Klinke, R. (1983). Processing of binaural stimuli by cat superior olivary complex neurons. Experimental Brain Research, 52(3), 385–399.Find this resource:
Cant, N. B. (1984). The fine structure of the lateral superior olivary nucleus of the cat. Journal of Comparative Neurology, 227(1), 63–77. doi:10.1002/cne.902270108Find this resource:
Cant, N. B. (1998). Structural development of the mammalian auditory pathways. In E. W. Rubel, A. N. Popper, & R. R. Fay (Eds.), Development of the Auditory System (pp. 315–413). New York: Springer.Find this resource:
Case, D. T., & Gillespie, D. C. (2011). Pre- and postsynaptic properties of glutamatergic transmission in the immature inhibitory MNTB-LSO pathway. Journal of Neurophysiology, 106(5), 2570–2579. doi:10.1152/jn.00644.2010Find this resource:
Case, D. T., Zhao, X., & Gillespie, D. C. (2011). Functional refinement in the projection from ventral cochlear nucleus to lateral superior olive precedes hearing onset in rat. PLoS One, 6(6), e20756. doi:10.1371/journal.pone.0020756Find this resource:
Casey, M. A. (1990). The effects of aging on neuron number in the rat superior olivary complex. Neurobiology of Aging, 11(4), 391–394.Find this resource:
Casey, M. A., & Feldman, M. L. (1982). Aging in the rat medial nucleus of the trapezoid body. I. Light microscopy. Neurobiology of Aging, 3(3), 187–195.Find this resource:
Casey, M. A., & Feldman, M. L. (1985). Aging in the rat medial nucleus of the trapezoid body. II. Electron microscopy. Journal of Comparative Neurology, 232(3), 401–413. doi:10.1002/cne.902320311Find this resource:
Caspary, D. M., & Faingold, C. L. (1989). Non-N-methyl-D-aspartate receptors may mediate ipsilateral excitation at lateral superior olivary synapses. Brain Research, 503(1), 83–90. doi:10.1016/0006-8993(89)91707-1Find this resource:
Caspary, D. M., & Finlayson, P. G. (1991). Superior olivary complex: Functional neuropharmacology of the principal cell types. In R. A. Altschuler, R. P. Bobbin, B. M. Clopton, & D. W. Hoffman (Eds.), Neurobiology of hearing: The central auditory system (Vol. 1, pp. 141–161). New York: Raven Press, Ltd.Find this resource:
Caspary, D. M., Ling, L., Turner, J. G., & Hughes, L. F. (2008). Inhibitory neurotransmission, plasticity and aging in the mammalian central auditory system. Journal of Experimental Biology, 211(Pt 11), 1781–1791. doi:10.1242/jeb.013581Find this resource:
Casseday, J. H., & Neff, W. D. (1973). Localization of pure tones. Journal of the Acoustical Society of America, 54(2), 365–372.Find this resource:
Chang, E. H., Kotak, V. C., & Sanes, D. H. (2003). Long-term depression of synaptic inhibition is expressed postsynaptically in the developing auditory system. Journal of Neurophysiology, 90(3), 1479–1488. doi:10.1152/jn.00386.2003Find this resource:
Chavrier, P., Vesque, C., Galliot, B., Vigneron, M., Dolle, P., Duboule, D., & Charnay, P. (1990). The segment-specific gene Krox-20 encodes a transcription factor with binding sites in the promoter region of the Hox-1.4 gene. EMBO Journal, 9(4), 1209–1218.Find this resource:
Chen, C., Arai, I., Satterfield, R., Young, S. M., Jr., & Jonas, P. (2017). Synaptotagmin 2 is the fast Ca2+ sensor at a central inhibitory synapse. Cell Reports, 18(3), 723–736. doi:10.1016/j.celrep.2016.12.067Find this resource:
Chen, Q. C., Cain, D., & Jen, P. H. (1995). Sound pressure transformation at the Pinna of Mus-Domesticus. Journal of Experimental Biology, 198(9), 2007–2023.Find this resource:
Citri, A., & Malenka, R. C. (2008). Synaptic plasticity: Multiple forms, functions, and mechanisms. Neuropsychopharmacology, 33(1), 18–41. doi:10.1038/sj.npp.1301559Find this resource:
Clause, A., Kim, G., Sonntag, M., Weisz, C. J., Vetter, D. E., Rübsamen, R., & Kandler, K. (2014). The precise temporal pattern of prehearing spontaneous activity is necessary for tonotopic map refinement. Neuron, 82(4), 822–835. doi:10.1016/j.neuron.2014.04.001Find this resource:
Clause, A., Lauer, A. M., & Kandler, K. (2017). Mice lacking the alpha9 subunit of the nicotinic acetylcholine receptor exhibit deficits in frequency difference limens and sound localization. Frontiers in Cellular Neuroscience, 11, 167. doi:10.3389/fncel.2017.00167Find this resource:
Clause, A., Sturm, J., Altien, S. C., Maricich, S. M., & Kandler, K. (2014). Development of mammalian primary sound localization circuits. In R. Romand & V.-N. I. (Eds.), Development of auditory and vestibular systems (4th ed., pp. 249–285). Amsterdam: Elsevier.Find this resource:
Coomes, D. L., & Schofield, B. R. (2004). Projections from the auditory cortex to the superior olivary complex in guinea pigs. European Journal of Neuroscience, 19(8), 2188–2200. doi:10.1111/j.0953-816X.2004.03317.xFind this resource:
Coomes Peterson, D., & Schofield, B. R. (2007). Projections from auditory cortex contact ascending pathways that originate in the superior olive and inferior colliculus. Hearing Research, 232(1–2), 67–77. doi:10.1016/j.heares.2007.06.009Find this resource:
Cooper, A. P., & Gillespie, D. C. (2011). Synaptotagmins I and II in the developing rat auditory brainstem: Synaptotagmin I is transiently expressed in glutamate-releasing immature inhibitory terminals. Journal of Comparative Neurology, 519(12), 2417–2433. doi:10.1002/cne.22634Find this resource:
Cordes, S. P., & Barsh, G. S. (1994). The mouse segmentation gene kr encodes a novel basic domain-leucine zipper transcription factor. Cell, 79(6), 1025–1034.Find this resource:
Couchman, K., Garrett, A., Deardorff, A. S., Rattay, F., Resatz, S., Fyffe, R., … Leao, R. N. (2011). Lateral superior olive function in congenital deafness. Hearing Research, 277(1–2), 163–175. doi:10.1016/j.heares.2011.01.012Find this resource:
Covey, E., Jones, D. R., & Casseday, J. H. (1984). Projections from the superior olivary complex to the cochlear nucleus in the tree shrew. Journal of Comparative Neurology, 226(2), 289–305. doi:10.1002/cne.902260212Find this resource:
Covey, E., Vater, M., & Casseday, J. H. (1991). Binaural properties of single units in the superior olivary complex of the mustached bat. Journal of Neurophysiology, 66(3), 1080–1094. doi:10.1152/jn.19184.108.40.2060Find this resource:
Cramer, K. S. (2005). Eph proteins and the assembly of auditory circuits. Hearing Research, 206(1–2), 42–51. doi:10.1016/j.heares.2004.11.024Find this resource:
Cramer, K. S., & Gabriele, M. L. (2014). Axon guidance in the auditory system: Multiple functions of Eph receptors. Neuroscience, 277, 152–162. doi:10.1016/j.neuroscience.2014.06.068Find this resource:
Darrow, K. N., Benson, T. E., & Brown, M. C. (2012). Planar multipolar cells in the cochlear nucleus project to medial olivocochlear neurons in mouse. Journal of Comparative Neurology, 520(7), 1365–1375. doi:10.1002/cne.22797Find this resource:
Darrow, K. N., Maison, S. F., & Liberman, M. C. (2006). Cochlear efferent feedback balances interaural sensitivity. Nature Neuroscience, 9(12), 1474–1476. doi:10.1038/nn1807Find this resource:
Deol, M. S. (1964). The abnormalities of the inner ear in kreisler mice. Journal of Embryology and Experimental Morphology, 12, 475–490.Find this resource:
Di Bonito, M., Narita, Y., Avallone, B., Sequino, L., Mancuso, M., Andolfi, G., … Studer, M. (2013). Assembly of the auditory circuitry by a Hox genetic network in the mouse brainstem. PLoS Genetics, 9(2), e1003249. doi:10.1371/journal.pgen.1003249Find this resource:
Doucet, J. R., & Ryugo, D. K. (2003). Axonal pathways to the lateral superior olive labeled with biotinylated dextran amine injections in the dorsal cochlear nucleus of rats. Journal of Comparative Neurology, 461(4), 452–465. doi:10.1002/cne.10722Find this resource:
Doucet, J. R., & Ryugo, D. K. (2006). Structural and functional classes of multipolar cells in the ventral cochlear nucleus. Anatomical Record, 288(4), 331–344. doi:10.1002/ar.a.20294Find this resource:
Durham, D., Rubel, E. W., & Steel, K. P. (1989). Cochlear ablation in deafness mutant mice: 2-deoxyglucose analysis suggests no spontaneous activity of cochlear origin. Hearing Research, 43(1), 39–46. doi:10.1016/0378-5955(89)90057-9Find this resource:
Ebbers, L., Satheesh, S. V., Janz, K., Rüttiger, L., Blosa, M., Hofmann, F., … Nothwang, H. G. (2015). L-type calcium channel Cav1.2 is required for maintenance of auditory brainstem nuclei. Journal of Biological Chemistry, 290(39), 23692–23710. doi:10.1074/jbc.M115.672675Find this resource:
Echteler, S. M., Arjmand, E., & Dallos, P. (1989). Developmental alterations in the frequency map of the mammalian cochlea. Nature, 341(6238), 147–149. doi:10.1038/341147a0Find this resource:
Ehmann, H., Hartwich, H., Salzig, C., Hartmann, N., Clement-Ziza, M., Ushakov, K., … Nothwang, H. G. (2013). Time-dependent gene expression analysis of the developing superior olivary complex. Journal of Biological Chemistry, 288(36), 25865–25879. doi:10.1074/jbc.M113.490508Find this resource:
Ehret, G. (1976). Development of absolute auditory thresholds in the house mouse (Mus musculus). Journal of the American Academy of Audiology, 1(5), 179–184.Find this resource:
Ehret, G., & Dreyer, A. (1984). Localization of tones and noise in the horizontal plane by unrestrained house mice (Mus musculus). Journal of Experimental Biology, 109, 163–174.Find this resource:
Ehrlich, I., Löhrke, S., & Friauf, E. (1999). Shift from depolarizing to hyperpolarizing glycine action in rat auditory neurons is due to age-dependent Cl- regulation. Journal of Physiology, 520, 121–137. doi:10.1111/j.1469-7793.1999.00121.xFind this resource:
Farago, A. F., Awatramani, R. B., & Dymecki, S. (2006). Assembly of the brainstem cochlear nuclear complex is revealed by intersectional and subtractive genetic fate maps. Neuron, 50(2), 205–218. doi:10.1016/j.neuron.2006.03.014Find this resource:
Fech, T., Calderon-Garciduenas, L., & Kulesza, R. J., Jr. (2017). Characterization of the superior olivary complex of Canis lupus domesticus. Hearing Research, 351, 130–140. doi:10.1016/j.heares.2017.06.010Find this resource:
Feliciano, M., Saldaña, E., & Mugnaini, E. (1995). Direct projections from the rat primary auditory neocortex to nucleus sagulum, paralemniscal regions, superior olivary complex and cochlear nuclei. Auditory Neuroscience, 1, 287–308.Find this resource:
Finlayson, P. G. (1995). Decreased inhibition to lateral superior olive neurons in young and aged Sprague-Dawley rats. Hearing Research, 87(1–2), 84–95.Find this resource:
Finlayson, P. G., & Caspary, D. M. (1989). Synaptic potentials of chinchilla lateral superior olivary neurons. Hearing Research, 38(3), 221–228.Find this resource:
Finlayson, P. G., & Caspary, D. M. (1991). Low-frequency neurons in the lateral superior olive exhibit phase-sensitive binaural inhibition. Journal of Neurophysiology, 65(3), 598–605. doi:10.1152/jn.19220.127.116.118Find this resource:
Finlayson, P. G., & Caspary, D. M. (1993). Response properties in young and old Fischer-344 rat lateral superior olive neurons: A quantitative approach. Neurobiology of Aging, 14(2), 127–139.Find this resource:
Fischl, M. J., Burger, R. M., Schmidt-Pauly, M., Alexandrova, O., Sinclair, J. L., Grothe, B., … Kopp-Scheinpflug, C. (2016). Physiology and anatomy of neurons in the medial superior olive of the mouse. Journal of Neurophysiology, 116(6), 2676–2688. doi:10.1152/jn.00523.2016Find this resource:
Franken, T. P., Joris, P. X., & Smith, P. H. (2018). Principal cells of the brainstem's interaural sound level detector are temporal differentiators rather than integrators. Elife, 7. doi:10.7554/eLife.33854Find this resource:
Franken, T. P., Smith, P. H., & Joris, P. X. (2016). In vivo whole-cell recordings combined with electron microscopy reveal unexpected morphological and physiological properties in the lateral nucleus of the trapezoid body in the auditory brainstem. Frontiers in Neural Circuits, 10, 69. doi:10.3389/fncir.2016.00069Find this resource:
Fredrich, M., Reisch, A., & Illing, R. B. (2009). Neuronal subtype identity in the rat auditory brainstem as defined by molecular profile and axonal projection. Experimental Brain Research, 195(2), 241–260. doi:10.1007/s00221-009-1776-7Find this resource:
Friauf, E. (2004). Developmental changes and cellular plasticity in the superior olivary complex. In T. N. Parks, E. W. Rubel, R. R. Fay, & A. N. Popper (Eds.), Plasticity of the auditory system (pp. 49–95). New York: Springer.Find this resource:
Friauf, E., Aragon, C., Löhrke, S., Westenfelder, B., & Zafra, F. (1999). Developmental expression of the glycine transporter GLYT2 in the auditory system of rats suggests involvement in synapse maturation. Journal of Comparative Neurology, 412(1), 17–37.Find this resource:
Friauf, E., Fischer, A. U., & Fuhr, M. F. (2015). Synaptic plasticity in the auditory system: a review. Cell and Tissue Research, 361(1), 177–213. doi:10.1007/s00441-015-2176-xFind this resource:
Friauf, E., Hammerschmidt, B., & Kirsch, J. (1997). Development of adult-type inhibitory glycine receptors in the central auditory system of rats. Journal of Comparative Neurology, 385(1), 117–134.Find this resource:
Friauf, E., & Herbert, H. (1985). Topographic organization of facial motoneurons to individual pinna muscles in rat (Rattus rattus) and bat (Rousettus aegyptiacus). Journal of Comparative Neurology, 240(2), 161–170. doi:10.1002/cne.902400206Find this resource:
Friauf, E., & Kandler, K. (1993). Cell birth, formation of efferent connections, and establishment of tonotopic order in the rat cochlear nucleus. In M. A. Merchán, J. M. Juiz, D. A. Godfrey, & E. Mugnaini (Eds.), The mammalian cochlear nuclei: Organization and function (Vol. 1, pp. 19–28). New York: Plenum.Find this resource:
Friauf, E., & Ostwald, J. (1988). Divergent projections of physiologically characterized rat ventral cochlear nucleus neurons as shown by intraaxonal injection of horseradish peroxidase. Experimental Brain Research, 73(2), 263–284.Find this resource:
Friauf, E., Rust, M. B., Schulenborg, T., & Hirtz, J. J. (2011). Chloride cotransporters, chloride homeostasis, and synaptic inhibition in the developing auditory system. Hearing Research, 279(1–2), 96–110. doi:10.1016/j.heares.2011.05.012Find this resource:
Frisina, D. R. (2010). Aging changes in the central auditory system. In A. Rees & A. R. Palmer (Eds.), Oxford handbook of auditory science: The auditory brain (Vol. 2, pp. 417–440). Oxford: Oxford University Press.Find this resource:
Fujino, K., Koyano, K., & Ohmori, H. (1997). Lateral and medial olivocochlear neurons have distinct electrophysiological properties in the rat brain slice. Journal of Neurophysiology, 77(5), 2788–2804.Find this resource:
Fukui, H., & Raphael, Y. (2013). Gene therapy for the inner ear. Hearing Research, 297, 99–105. doi:10.1016/j.heares.2012.11.017Find this resource:
Garcia-Pino, E., Gessele, N., & Koch, U. (2017). Enhanced excitatory connectivity and disturbed sound processing in the auditory brainstem of Fragile X mice. Journal of Neuroscience, 37(31), 7403–7419. doi:10.1523/jneurosci.2310-16.2017Find this resource:
Gessele, N., Garcia-Pino, E., Omerbasic, D., Park, T. J., & Koch, U. (2016). Structural changes and lack of HCN1 channels in the binaural auditory brainstem of the naked mole-rat (Heterocephalus glaber). PLoS One, 11(1), e0146428. doi:10.1371/journal.pone.0146428Find this resource:
Gilardi, P., Schneider-Maunoury, S., & Charnay, P. (1991). Krox-20: A candidate gene for the regulation of pattern formation in the hindbrain. Biochimie, 73(1), 85–91.Find this resource:
Gillespie, D. C., Kim, G., & Kandler, K. (2005). Inhibitory synapses in the developing auditory system are glutamatergic. Nature Neuroscience, 8(3), 332–338.Find this resource:
Giugovaz-Tropper, B., Gonzalez-Inchauspe, C., Di Guilmi, M. N., Urbano, F. J., Forsythe, I. D., & Uchitel, O. D. (2011). P/Q-type calcium channel ablation in a mice glycinergic synapse mediated by multiple types of Ca2+ channels alters transmitter release and short term plasticity. Neuroscience, 192, 219–230. doi:10.1016/j.neuroscience.2011.06.021Find this resource:
Gjoni, E., Aguet, C., Sahlender, D. A., Knott, G., & Schneggenburger, R. (2018). Ultrastructural basis of strong unitary inhibition in a binaural neuron. Journal of Physiology, 596(20), 4969–4982. doi:10.1113/jp276015Find this resource:
Gjoni, E., Zenke, F., Bouhours, B., & Schneggenburger, R. (2018). Specific synaptic input strengths determine the computational properties of excitation-inhibition integration in a sound localization circuit. Journal of Physiology, 596(20), 4945–4967. doi:10.1113/jp276012Find this resource:
Gleich, O., Weiss, M., & Strutz, J. (2004). Age-dependent changes in the lateral superior olive of the gerbil (Meriones unguiculatus). Hearing Research, 194(1–2), 47–59. doi:10.1016/j.heares.2004.03.016Find this resource:
Glendenning, K. K., & Baker, B. N. (1988). Neuroanatomical distribution of receptors for three potential inhibitory neurotransmitters in the brainstem auditory nuclei of the cat. Journal of Comparative Neurology, 275(2), 288–308. doi:10.1002/cne.902750210Find this resource:
Glendenning, K. K., Baker, B. N., Hutson, K. A., & Masterton, R. B. (1992). Acoustic chiasm V: Inhibition and excitation in the ipsilateral and contralateral projections of LSO. Journal of Comparative Neurology, 319(1), 100–122.Find this resource:
Glendenning, K. K., Hutson, K. A., Nudo, R. J., & Masterton, R. B. (1985). Acoustic chiasm II: Anatomical basis of binaurality in lateral superior olive of cat. Journal of Comparative Neurology, 232(2), 261–285. doi:10.1002/cne.902320210Find this resource:
Glendenning, K. K., & Masterton, R. B. (1983). Acoustic chiasm: Efferent projections of the lateral superior olive. Journal of Neuroscience, 3(8), 1521–1537.Find this resource:
Glendenning, K. K., & Masterton, R. B. (1998). Comparative morphometry of mammalian central auditory systems: Variation in nuclei and form of the ascending system. Brain, Behavior and Evolution, 51(2), 59–89. doi:10.1159/000006530Find this resource:
Glendenning, K. K., Masterton, R. B., Baker, B. N., & Wenthold, R. J. (1991). Acoustic chiasm. III: Nature, distribution, and sources of afferents to the lateral superior olive in the cat. Journal of Comparative Neurology, 310(3), 377–400. doi:10.1002/cne.903100308Find this resource:
Goldberg, J. M., & Brown, P. B. (1968). Functional organization of the dog superior olivary complex to dichotic tonal stimuli: An anatomical and electrophysiological study. Journal of Neurophysiology, 31(4), 639–655.Find this resource:
Goldberg, J. M., & Brown, P. B. (1969). Response of binaural neurons of dog superior olivary complex to dichotic tonal stimuli: Some physiological mechanism of sound localization. Journal of Neurophysiology, 32(4), 613–636.Find this resource:
Golding, N. L., & Oertel, D. (2012). Synaptic integration in dendrites: Exceptional need for speed. Journal of Physiology, 590(22), 5563–5569. doi:10.1113/jphysiol.2012.229328Find this resource:
Gomez-Alvarez, M., & Saldana, E. (2016). Different tonotopic regions of the lateral superior olive receive a similar combination of afferent inputs. Journal of Comparative Neurology, 524(11), 2230–2250. doi:10.1002/cne.23942Find this resource:
Gomez-Nieto, R., Rubio, M. E., & Lopez, D. E. (2008). Cholinergic input from the ventral nucleus of the trapezoid body to cochlear root neurons in rats. Journal of Comparative Neurology, 506(3), 452–468. doi:10.1002/cne.21554Find this resource:
Greene, N. T., Anbuhl, K. L., Williams, W., & Tollin, D. J. (2014). The acoustical cues to sound location in the guinea pig (Cavia porcellus). Hearing Research, 316, 1–15. doi:10.1016/j.heares.2014.07.004Find this resource:
Greene, N. T., Lomakin, O., & Davis, K. A. (2010). Monaural spectral processing differs between the lateral superior olive and the inferior colliculus: Physiological evidence for an acoustic chiasm. Hearing Research, 269(1–2), 134–145. doi:10.1016/j.heares.2010.06.018Find this resource:
Greer, P. L., & Greenberg, M. E. (2008). From synapse to nucleus: Calcium-dependent gene transcription in the control of synapse development and function. Neuron, 59(6), 846–860. doi:10.1016/j.neuron.2008.09.002Find this resource:
Grigg, J. J., Brew, H. M., & Tempel, B. L. (2000). Differential expression of voltage-grated potassium channel genes in auditory nuclei of the mouse brainstem. Hearing Research, 140(1–2), 77–90. doi:10.1016/S0378-5955(99)00187-2Find this resource:
Grothe, B., & Park, T. J. (1995). Time can be traded for intensity in the lower auditory system. Naturwissenschaften, 82(11), 521–523. doi:Doi 10.1007/Bf01134488Find this resource:
Grothe, B., & Park, T. J. (2000). Structure and function of the bat superior olivary complex. Microscopy Research and Technique, 51(4), 382–402. doi:10.1002/1097-0029(20001115)51:4<382::AID-JEMT7>3.0.CO;2–7Find this resource:
Grothe, B., & Pecka, M. (2014). The natural history of sound localization in mammals: A story of neuronal inhibition. Frontiers in Neural Circuits, 8, 116. doi:10.3389/fncir.2014.00116Find this resource:
Grothe, B., Pecka, M., & McAlpine, D. (2010). Mechanisms of sound localization in mammals. Physiological Reviews, 90(3), 983–1012. doi:10.1152/physrev.00026.2009Find this resource:
Guinan, J. J., Norris, B. E., & Guinan, S. S. (1972). Single auditory units in the superior olivary complex. II: Locations of unit categories and tonotopic organization. International Journal of Neuroscience, 4(4), 147–166. doi:10.3109/00207457209164756Find this resource:
Hackney, C. M. (1987). Anatomical features of the auditory pathway from cochlea to cortex. British Medial Bulletin, 43(4), 780–801.Find this resource:
Harnischfeger, G., Neuweiler, G., & Schlegel, P. (1985). Interaural time and intensity coding in superior olivary complex and inferior colliculus of the echolocating bat molossus ater. Journal of Neurophysiology, 53(1), 89–109.Find this resource:
Harrison, J. M., & Irving, R. (1966). Visual and nonvisual auditory systems in mammals. Anatomical evidence indicates two kinds of auditory pathways and suggests two kinds of hearing in mammals. Science, 154(3750), 738–743.Find this resource:
Harrison, J. M., & Warr, W. B. (1962). A study of the cochlear nuclei and ascending auditory pathways of the medulla. Journal of Comparative Neurology, 119, 341–380.Find this resource:
Hassfurth, B., Magnusson, A. K., Grothe, B., & Koch, U. (2009). Sensory deprivation regulates the development of the hyperpolarization-activated current in auditory brainstem neurons. European Journal of Neuroscience, 30(7), 1227–1238. doi:10.1111/j.1460-9568.2009.06925.xFind this resource:
He, C., Chen, F., Li, B., & Hu, Z. (2014). Neurophysiology of HCN channels: From cellular functions to multiple regulations. Progress in Neurobiology, 112, 1–23. doi:10.1016/j.pneurobio.2013.10.001Find this resource:
Heffner, R. S., & Heffner, H. E. (1993). Degenerate hearing and sound localization in naked mole rats (Heterocephalus glaber), with an overview of central auditory structures. Journal of Comparative Neurology, 331(3), 418–433. doi:10.1002/cne.903310311Find this resource:
Heffner, R. S., & Heffner, H. E. (2010). Explaining high-frequency hearing. Anatomical Record (Hoboken), 293(12), 2080–2082. doi:10.1002/ar.21292Find this resource:
Heffner, R. S., Koay, G., & Heffner, H. E. (2001). Audiograms of five species of rodents: Implications for the evolution of hearing and the perception of pitch. Hearing Research, 157(1–2), 138–152.Find this resource:
Helfert, R. H., Bonneau, J. M., Wenthold, R. J., & Altschuler, R. A. (1989). GABA and glycine immunoreactivity in the guinea pig superior olivary complex. Brain Research, 501(2), 269–286.Find this resource:
Helfert, R. H., Juiz, J. M., Bledsoe, S. C., Bonneau, J. M., Wenthold, R. J., & Altschuler, R. A. (1992). Patterns of glutamate, glycine, and GABA immunolabeling in four synaptic terminal classes in the lateral superior olive of the guinea pig. Journal of Comparative Neurology, 323(3), 305–325. doi:10.1002/cne.903230302Find this resource:
Helfert, R. H., & Schwartz, I. R. (1986). Morphological evidence for the existence of multiple neuronal classes in the cat lateral superior olivary nucleus. Journal of Comparative Neurology, 244(4), 533–549. doi:10.1002/cne.902440409Find this resource:
Helfert, R. H., & Schwartz, I. R. (1987). Morphological features of five neuronal classes in the gerbil lateral superior olive. American Journal of Anatomy, 179(1), 55–69. doi:10.1002/aja.1001790108Find this resource:
Henkel, C. K., & Gabriele, M. L. (1999). Organization of the disynaptic pathway from the anteroventral cochlear nucleus to the lateral superior olivary nucleus in the ferret. Anatomy and Embryology, 199, 149–160.Find this resource:
Hilbig, H., Beil, B., Hilbig, H., Call, J., & Bidmon, H. J. (2009). Superior olivary complex organization and cytoarchitecture may be correlated with function and catarrhine primate phylogeny. Brain Structure and Function, 213(4–5), 489–497. doi:10.1007/s00429-008-0201-5Find this resource:
Hirao, K., Eto, K., Nakahata, Y., Ishibashi, H., Nagai, T., & Nabekura, J. (2015). Noradrenergic refinement of glutamatergic neuronal circuits in the lateral superior olivary nucleus before hearing onset. Journal of Neurophysiology, 114(3), 1974–1986. doi:10.1152/jn.00813.2014Find this resource:
Hirtz, J. J., Boesen, M., Braun, N., Deitmer, J. W., Kramer, F., Lohr, C., … Friauf, E. (2011). Cav1.3 calcium channels are required for normal development of the auditory brainstem. Journal of Neuroscience, 31(22), 8280–8294. doi:10.1523/JNEUROSCI.5098-10.2011Find this resource:
Hirtz, J. J., Braun, N., Griesemer, D., Hannes, C., Janz, K., Löhrke, S., … Friauf, E. (2012). Synaptic refinement of an inhibitory topographic map in the auditory brainstem requires functional Cav1.3 calcium channels. Journal of Neuroscience, 32(42), 14602–14616. doi:10.1523/JNEUROSCI.0765-12.2012Find this resource:
Hoffpauir, B. K., Kolson, D. R., Mathers, P. H., & Spirou, G. A. (2010). Maturation of synaptic partners: functional phenotype and synaptic organization tuned in synchrony. Journal of Physiology, 588(Pt 22), 4365–4385. doi:10.1113/jphysiol.2010.198564Find this resource:
Hong, S. H., Kim, M. J., & Ahn, S. C. (2008). Glutamatergic transmission is sustained at a later period of development of medial nucleus of the trapezoid body-lateral superior olive synapses in circling mice. Journal of Neuroscience, 28(48), 13003–13007. doi:10.1523/Jneurosci.3002-08.2008Find this resource:
Hossain, W. A., D’Sa, C., & Morest, D. K. (2006). Site-specific interactions of neurotrophin-3 and fibroblast growth factor (FGF2) in the embryonic development of the mouse cochlear nucleus. Journal of Neurobiology, 66(9), 897–915. doi:10.1002/neu.20264Find this resource:
Howell, D. M., Morgan, W. J., Jarjour, A. A., Spirou, G. A., Berrebi, A. S., Kennedy, T. E., & Mathers, P. H. (2007). Molecular guidance cues necessary for axon pathfinding from the ventral cochlear nucleus. Journal of Comparative Neurology, 504(5), 533–549. doi:10.1002/cne.21443Find this resource:
Hsieh, C. Y., Nakamura, P. A., Luk, S. O., Miko, I. J., Henkemeyer, M., & Cramer, K. S. (2010). Ephrin-B reverse signaling is required for formation of strictly contralateral auditory brainstem pathways. Journal of Neuroscience, 30(29), 9840–9849. doi:10.1523/Jneurosci.0386-10.2010Find this resource:
Illing, R. B., Kraus, K. S., & Michler, S. A. (2000). Plasticity of the superior olivary complex. Microscopy Research and Technique, 51(4), 364–381. doi:10.1002/1097-0029(20001115)51:4<364::AID-JEMT6>3.0.CO;2-EFind this resource:
Irvine, D. R. F. (1992). Physiology of the auditory brainstem. In A. N. Popper & R. R. Fay (Eds.), The mammalian auditory pathway: Neurophysiology (pp. 153–231). New York: Springer.Find this resource:
Irving, R., & Harrison, J. M. (1967). The superior olivary complex and audition: A comparative study. Journal of Comparative Neurology, 130(1), 77–86. doi:10.1002/cne.901300105Find this resource:
Ito, T., & Oliver, D. L. (2010). Origins of glutamatergic terminals in the inferior colliculus identified by retrograde transport and expression of VGLUT1 and VGLUT2 genes. Frontiers in Neuroanatomy, 4, 135. doi:10.3389/fnana.2010.00135Find this resource:
Jalabi, W., Kopp-Scheinpflug, C., Allen, P. D., Schiavon, E., DiGiacomo, R. R., Forsythe, I. D., & Maricich, S. M. (2013). Sound localization ability and glycinergic innervation of the superior olivary complex persist after genetic deletion of the medial nucleus of the trapezoid body. Journal of Neuroscience, 33(38), 15044–15049. doi:10.1523/JNEUROSCI.2604-13.2013Find this resource:
Jenkins, S. A., & Simmons, D. D. (2006). GABAergic neurons in the lateral superior olive of the hamster are distinguished by differential expression of gad isoforms during development. Brain Research, 1111(1), 12–25. doi:10.1016/j.brainres.2006.06.067Find this resource:
Johnston, J., Forsythe, I. D., & Kopp-Scheinpflug, C. (2010). Going native: Voltage-gated potassium channels controlling neuronal excitability. Journal of Physiology, 588(Pt 17), 3187–3200. doi:10.1113/jphysiol.2010.191973Find this resource:
Joris, P. X. (1996). Envelope coding in the lateral superior olive. II. Characteristic delays and comparison with responses in the medial superior olive. Journal of Neurophysiology, 76(4), 2137–2156. doi:10.1152/jn.1918.104.22.1687Find this resource:
Joris, P. X., & Yin, T. C. (1995). Envelope coding in the lateral superior olive. I. Sensitivity to interaural time differences. Journal of Neurophysiology, 73(3), 1043–1062. doi:10.1152/jn.1922.214.171.1243Find this resource:
Joris, P. X., & Yin, T. C. (1998). Envelope coding in the lateral superior olive. III. Comparison with afferent pathways. Journal of Neurophysiology, 79(1), 253–269. doi:10.1152/jn.19126.96.36.199Find this resource:
Jurkovicova-Tarabova, B., Griesemer, D., Pirone, A., Sinnegger-Brauns, M. J., Striessnig, J., & Friauf, E. (2012). Repertoire of high voltage-activated Ca2+ channels in the lateral superior olive: Functional analysis in wild-type, Cav 1.3–/–, and Cav1.2DHP–/– mice. Journal of Neurophysiology, 108(2), 365–379. doi:10.1152/jn.00948.2011Find this resource:
Kalmbach, A., Kullmann, P. H., & Kandler, K. (2010). NMDAR-mediated calcium transients elicited by glutamate co-release at developing inhibitory synapses. Frontiers in Synaptic Neuroscience, 2, 27. doi:10.3389/fnsyn.2010.00027Find this resource:
Kandler, K. (2004). Activity-dependent organization of inhibitory circuits: lessons from the auditory system. Current Opinion in Neurobiology, 14(1), 96–104. doi:10.1016/j.conb.2004.01.017Find this resource:
Kandler, K., Clause, A., & Noh, J. (2009). Tonotopic reorganization of developing auditory brainstem circuits. Nature Neuroscience, 12(6), 711–717. doi:10.1038/nn.2332Find this resource:
Kandler, K., & Friauf, E. (1993). Pre- and postnatal development of efferent connections of the cochlear nucleus in the rat. Journal of Comparative Neurology, 328(2), 161–184. doi:10.1002/cne.903280202Find this resource:
Kandler, K., & Friauf, E. (1995a). Development of electrical membrane properties and discharge characteristics of superior olivary complex neurons in fetal and postnatal rats. European Journal of Neuroscience, 7(8), 1773–1790.Find this resource:
Kandler, K., & Friauf, E. (1995b). Development of glycinergic and glutamatergic synaptic transmission in the auditory brainstem of perinatal rats. Journal of Neuroscience, 15(10), 6890–6904.Find this resource:
Kandler, K., & Gillespie, D. C. (2005). Developmental refinement of inhibitory sound-localization circuits. Trends in Neurosciences, 28(6), 290–296. doi:10.1016/j.tins.2005.04.007Find this resource:
Karcz, A., Hennig, M. H., Robbins, C. A., Tempel, B. L., Rübsamen, R., & Kopp-Scheinpflug, C. (2011). Low-voltage activated Kv1.1 subunits are crucial for the processing of sound source location in the lateral superior olive in mice. Journal of Physiology, 589(Pt 5), 1143–1157. doi:10.1113/jphysiol.2010.203331Find this resource:
Karis, A., Pata, I., van Doorninck, J. H., Grosveld, F., De Zeeuw, C. I., de Caprona, D., & Fritzsch, B. (2001). Transcription factor GATA-3 alters pathway selection of olivocochlear neurons and affectrs morphogenesis of the ear. Journal of Comparative Neurology, 429(4), 615–630.Find this resource:
Kelly, J. B., Liscum, A., van Adel, B., & Ito, M. (1998). Projections from the superior olive and lateral lemniscus to tonotopic regions of the rat's inferior colliculus. Hearing Research, 116(1–2), 43–54.Find this resource:
Kelly, J. B., van Adel, B. A., & Ito, M. (2009). Anatomical projections of the nuclei of the lateral lemniscus in the albino rat (Rattus norvegicus). Journal of Comparative Neurology, 512(4), 573–593. doi:10.1002/cne.21929Find this resource:
Khurana, S., Liu, Z., Lewis, A. S., Rosa, K., Chetkovich, D., & Golding, N. L. (2012). An essential role for modulation of hyperpolarization-activated current in the development of binaural temporal precision. Journal of Neuroscience, 32(8), 2814–2823. doi:10.1523/JNEUROSCI.3882-11.2012Find this resource:
Kiecker, C., & Lumsden, A. (2005). Compartments and their boundaries in vertebrate brain development. Nature Reviews. Neuroscience, 6(7), 553–564. doi:10.1038/nrn1702Find this resource:
Kil, J., Kageyama, G. H., Semple, M. N., & Kitzes, L. M. (1995). Development of ventral cochlear nucleus projections to the superior olivary complex in gerbil. Journal of Comparative Neurology, 353(3), 317–340. doi:10.1002/cne.903530302Find this resource:
Kim, G., & Kandler, K. (2003). Elimination and strengthening of glycinergic/GABAergic connections during tonotopic map formation. Nature Neuroscience, 6(3), 282–290. doi:10.1038/nn1015Find this resource:
Kim, G., & Kandler, K. (2010). Synaptic changes underlying the strengthening of GABA/glycinergic connections in the developing lateral superior olive. Neuroscience, 171(3), 924–933. doi:10.1016/j.neuroscience.2010.09.054Find this resource:
Kim, K. X., & Rutherford, M. A. (2016). Maturation of NaV and KV channel topographies in the auditory nerve spike initiator before and after developmental onset of hearing function. Journal of Neuroscience, 36(7), 2111–2118. doi:10.1523/jneurosci.3437-15.2016Find this resource:
Kitzes, L. M., Kageyama, G. H., Semple, M. N., & Kil, J. (1995). Development of ectopic projections from the ventral cochlear nucleus to the superior olivary complex induced by neonatal ablation of the contralateral cochlea. Journal of Comparative Neurology, 353(3), 341–363. doi:10.1002/cne.903530303Find this resource:
Koay, G., Heffner, R. S., & Heffner, H. E. (1998). Hearing in a megachiropteran fruit bat (Rousettus aegyptiacus). Journal of Comparative Psychology, 112(4), 371–382.Find this resource:
Kochubey, O., Babai, N., & Schneggenburger, R. (2016). A synaptotagmin isoform switch during the development of an identified CNS synapse. Neuron, 90(5), 984–999. doi:10.1016/j.neuron.2016.04.038Find this resource:
Koka, K., Read, H. L., & Tollin, D. J. (2008). The acoustical cues to sound location in the rat: Measurements of directional transfer functions. Journal of the Acoustical Society of America, 123(6), 4297–4309. doi:10.1121/1.2916587Find this resource:
Kole, M. H., Letzkus, J. J., & Stuart, G. J. (2007). Axon initial segment Kv1 channels control axonal action potential waveform and synaptic efficacy. Neuron, 55(4), 633–647. doi:10.1016/j.neuron.2007.07.031Find this resource:
Kopp-Scheinpflug, C., Fuchs, K., Lippe, W. R., Tempel, B. L., & Rübsamen, R. (2003). Decreased temporal precision of auditory signaling in Kcna1-null mice: An electrophysiological study in vivo. Journal of Neuroscience, 23(27), 9199–9207.Find this resource:
Kopp-Scheinpflug, C., Pigott, B. M., & Forsythe, I. D. (2015). Nitric oxide selectively suppresses IH currents mediated by HCN1-containing channels. Journal of Physiology, 593(7), 1685–1700. doi:10.1113/jphysiol.2014.282194Find this resource:
Korada, S., & Schwartz, I. R. (1999). Development of GABA, glycine, and their receptors in the auditory brainstem of gerbil: A light and electron microscopic study. Journal of Comparative Neurology, 409(4), 664–681. doi:10.1002/(Sici)1096-9861(19990712)409:4<664::Aid-Cne10>3.0.Co;2-SFind this resource:
Kotak, V. C., Korada, S., Schwartz, I. R., & Sanes, D. H. (1998). A developmental shift from GABAergic to glycinergic transmission in the central auditory system. Journal of Neuroscience, 18(12), 4646–4655.Find this resource:
Kotak, V. C., & Sanes, D. H. (1996). Developmental influence of glycinergic transmission: regulation of NMDA receptor-mediated EPSPs. Journal of Neuroscience, 16(5), 1836–1843.Find this resource:
Kotak, V. C., & Sanes, D. H. (1997). Deafferentation weakens excitatory synapses in the developing central auditory system. European Journal of Neuroscience, 9(11), 2340–2347.Find this resource:
Kotak, V. C., & Sanes, D. H. (2014). Developmental expression of inhibitory synaptic long-term potentiation in the lateral superior olive. Frontiers in Neural Circuits, 8, 67. doi:10.3389/fncir.2014.00067Find this resource:
Krächan, E. G., Fischer, A. U., Franke, J., & Friauf, E. (2017). Synaptic reliability and temporal precision are achieved via high quantal content and effective replenishment: Auditory brainstem versus hippocampus. Journal of Physiology, 595(3), 839–864. doi:10.1113/JP272799Find this resource:
Kramer, F., Griesemer, D., Bakker, D., Brill, S., Franke, J., Frotscher, E., & Friauf, E. (2014). Inhibitory glycinergic neurotransmission in the mammalian auditory brainstem upon prolonged stimulation: Short-term plasticity and synaptic reliability. Frontiers in Neural Circuits, 8, 14. doi:10.3389/fncir.2014.00014Find this resource:
Kraus, K. S., & Illing, R. B. (2004). Superior olivary contributions to auditory system plasticity: Medial but not lateral olivocochlear neurons are the source of cochleotomy-induced GAP-43 expression in the ventral cochlear nucleus. Journal of Comparative Neurology, 475(3), 374–390. doi:10.1002/cne.20180Find this resource:
Kronander, E., Michalski, N., Lebrand, C., Hornung, J. P., & Schneggenburger, R. (2017). An organotypic slice culture to study the formation of calyx of Held synapses in-vitro. PLoS One, 12(4), e0175964. doi:10.1371/journal.pone.0175964Find this resource:
Kudo, M., Kitao, Y., Okoyama, S., Moriya, M., & Kawano, J. (1996). Crossed projection neurons are generated prior to uncrossed projection neurons in the lateral superior olive of the rat. Brain Research. Developmental Brain Research, 95(1), 72–78.Find this resource:
Kudo, M., Sakurai, H., Kurokawa, K., & Yamada, H. (2000). Neurogenesis in the superior olivary complex in the rat. Hearing Research, 139(1–2), 144–152.Find this resource:
Kulesza, R. J., Jr. (2007). Cytoarchitecture of the human superior olivary complex: Medial and lateral superior olive. Hearing Research, 225(1–2), 80–90. doi:10.1016/j.heares.2006.12.006Find this resource:
Kulesza, R. J., Jr. (2008). Cytoarchitecture of the human superior olivary complex: Nuclei of the trapezoid body and posterior tier. Hearing Research, 241(1–2), 52–63.Find this resource:
Kullmann, P. H., Ene, F. A., & Kandler, K. (2002). Glycinergic and GABAergic calcium responses in the developing lateral superior olive. European Journal of Neuroscience, 15(7), 1093–1104.Find this resource:
Kullmann, P. H., & Kandler, K. (2001). Glycinergic/GABAergic synapses in the lateral superior olive are excitatory in neonatal C57Bl/6J mice. Brain Research. Developmental Brain Research, 131(1–2), 143–147.Find this resource:
Kungel, M., & Friauf, E. (1995). Somatostatin and leu-enkephalin in the rat auditory brainstem during fetal and postnatal development. Anatomy and Embryology, 191(5), 425–443. doi:10.1007/BF00304428Find this resource:
Kungel, M., Piechotta, K., Rietzel, H. J., & Friauf, E. (1997). Influence of the neuropeptide somatostatin on the development of dendritic morphology: A cysteamine-depletion study in the rat auditory brainstem. Brain Research. Developmental Brain Research, 101(1–2), 107–114. doi:10.1016/S0165-3806(97)00053-9Find this resource:
Kuwabara, N., & Zook, J. M. (1991). Classification of the principal cells of the medial nucleus of the trapezoid body. Journal of Comparative Neurology, 314(4), 707–720. doi:10.1002/cne.903140406Find this resource:
Kuwabara, N., & Zook, J. M. (1992). Projections to the medial superior olive from the medial and lateral nuclei of the trapezoid body in rodents and bats. Journal of Comparative Neurology, 324(4), 522–538. doi:10.1002/cne.903240406Find this resource:
Leao, K. E., Leao, R. N., Sun, H., Fyffe, R. E., & Walmsley, B. (2006). Hyperpolarization-activated currents are differentially expressed in mice brainstem auditory nuclei. Journal of Physiology, 576(Pt 3), 849–864. doi:10.1113/jphysiol.2006.114702Find this resource:
Leao, K. E., Leao, R. N., & Walmsley, B. (2011). Modulation of dendritic synaptic processing in the lateral superior olive by hyperpolarization-activated currents. European Journal of Neuroscience, 33(8), 1462–1470. doi:10.1111/j.1460-9568.2011.07627.xFind this resource:
Lee, H., Bach, E., Noh, J., Delpire, E., & Kandler, K. (2016). Hyperpolarization-independent maturation and refinement of GABA/glycinergic connections in the auditory brain stem. Journal of Neurophysiology, 115(3), 1170–1182. doi:10.1152/jn.00926.2015Find this resource:
Lee, H., Brott, B. K., Kirkby, L. A., Adelson, J. D., Cheng, S., Feller, M. B., … Shatz, C. J. (2014). Synapse elimination and learning rules co-regulated by MHC class I H2-Db. Nature, 509(7499), 195–200. doi:10.1038/nature13154Find this resource:
Lee, J. H., Pradhan, J., Maskey, D., Park, K. S., Hong, S. H., Suh, M. W., … Ahn, S. C. (2011). Glutamate co-transmission from developing medial nucleus of the trapezoid body: Lateral superior olive synapses is cochlear dependent in kanamycin-treated rats. Biochemical and Biophysical Research Communications, 405(2), 162–167. doi:10.1016/j.bbrc.2010.12.129Find this resource:
Li, W., Kaczmarek, L. K., & Perney, T. M. (2001). Localization of two high-threshold potassium channel subunits in the rat central auditory system. Journal of Comparative Neurology, 437(2), 196–218.Find this resource:
Lippe, W. R. (1994). Rhythmic spontaneous activity in the developing avian auditory system. Journal of Neuroscience, 14(3 Pt 2), 1486–1495. doi:10.1523/JNEUROSCI.14-03-01486.1994Find this resource:
Lohmann, C., Ilic, V., & Friauf, E. (1998). Development of a topographically organized auditory network in slice culture is calcium dependent. Journal of Neurobiology, 34(2), 97–112. doi:10.1002/(Sici)1097-4695(19980205)34:2<97::Aid-Neu1>3.0.Co;2-6Find this resource:
Löhrke, S., Srinivasan, G., Oberhofer, M., Doncheva, E., & Friauf, E. (2005). Shift from depolarizing to hyperpolarizing glycine action occurs at different perinatal ages in superior olivary complex nuclei. The European Journal of Neuroscience, 22(11), 2708–2722. doi:10.1111/j.1460-9568.2005.04465.xFind this resource:
Lumsden, A., & Krumlauf, R. (1996). Patterning the vertebrate neuraxis. Science, 274(5290), 1109–1115.Find this resource:
Magnusson, A. K., Park, T. J., Pecka, M., Grothe, B., & Koch, U. (2008). Retrograde GABA signaling adjusts sound localization by balancing excitation and inhibition in the brainstem. Neuron, 59(1), 125–137. doi:10.1016/j.neuron.2008.05.011Find this resource:
Majorossy, K., & Kiss, A. (1990). Types of neurons and synaptic relations in the lateral superior olive of the cat: Normal structure and experimental observations. Acta Morphologica Hungarica, 38(3–4), 207–215.Find this resource:
Maki, K., & Furukawa, S. (2005). Acoustical cues for sound localization by the Mongolian gerbil, Meriones unguiculatus. Journal of the Acoustical Society of America, 118(2), 872–886.Find this resource:
Malmierca, M. S., & Hackett, T. A. (2010). Structural organization of the ascending auditory pathway. In A. Rees & A. R. Palmer (Eds.), Oxford handbook of auditory science: The auditory brain (Vol. 2, pp. 9–42). Oxford: Oxford University Press.Find this resource:
Malmierca, M. S., & Ryugo, D. (2012). Auditory system. In C. Watson, G. Paxinos, & L. Puelles (Eds.), The mouse nervous system (pp. 607–645). Amsterdam: Elsevier.Find this resource:
Manis, P. B. (2008). Biophysical specializations of neurons that encode timing. In P. Dallos & D. Oertel (Eds.), The senses: A comprehensive reference. Audition (Vol. 3, pp. 565–586). San Diego, Academic Press.Find this resource:
Maricich, S. M., Xia, A., Mathes, E. L., Wang, V. Y., Oghalai, J. S., Fritzsch, B., & Zoghbi, H. Y. (2009). Atoh1-lineal neurons are required for hearing and for the survival of neurons in the spiral ganglion and brainstem accessory auditory nuclei. Journal of Neuroscience, 29(36), 11123–11133. doi:10.1523/JNEUROSCI.2232-09.2009Find this resource:
Marrs, G. S., Morgan, W. J., Howell, D. M., Spirou, G. A., & Mathers, P. H. (2013). Embryonic origins of the mouse superior olivary complex. Developmental Neurobiology, 73(5), 384–398. doi:10.1002/dneu.22069Find this resource:
Marrs, G. S., & Spirou, G. A. (2012). Embryonic assembly of auditory circuits: Spiral ganglion and brainstem. Journal of Physiology, 590(10), 2391–2408. doi:10.1113/jphysiol.2011.226886Find this resource:
Masterton, B., Jane, J. A., & Diamond, I. T. (1967). Role of brainstem auditory structures in sound localization. I. Trapezoid body, superior olive, and lateral lemniscus. Journal of Neurophysiology, 30(2), 341–359. doi:10.1152/jn.19188.8.131.521Find this resource:
May, B. J., Prosen, C. A., Weiss, D., & Vetter, D. (2002). Behavioral investigation of some possible effects of the central olivocochlear pathways in transgenic mice. Hearing Research, 171(1–2), 142–157. doi:10.1016/S0378-5955(02)00495-1Find this resource:
McCullagh, E. A., Salcedo, E., Huntsman, M. M., & Klug, A. (2017). Tonotopic alterations in inhibitory input to the medial nucleus of the trapezoid body in a mouse model of Fragile X syndrome. Journal of Comparative Neurology, 525(16), 3543–3562. doi:10.1002/cne.24290Find this resource:
McKay, I. J., Mucharmore, I., Krumlauf, R., Maden, M., Lumsden, A., & Lewis, J. (1994). The kreisler mouse: A hindbrain segmentation mutant that lacks two rhombomeres. Development, 120(8), 2199–2211.Find this resource:
Michalski, N., Babai, N., Renier, N., Perkel, D. J., Chedotal, A., & Schneggenburger, R. (2013). Robo3-driven axon midline crossing conditions functional maturation of a large commissural synapse. Neuron, 78(5), 855–868. doi:10.1016/j.neuron.2013.04.006Find this resource:
Michler, S. A., & Illing, R. B. (2002). Acoustic trauma induces reemergence of the growth- and plasticity-associated protein GAP-43 in the rat auditory brainstem. Journal of Comparative Neurology, 451(3), 250–266. doi:10.1002/cne.10348Find this resource:
Middlebrooks, J. C. (2015). Sound localization. Handbook of Clinical Neurology, 129, 99–116. doi:10.1016/b978-0-444-62630-1.00006-8Find this resource:
Middlebrooks, J. C., & Green, D. M. (1991). Sound localization by human listeners. Annual Review of Psychology, 42, 135–159. doi:10.1146/annurev.ps.42.020191.001031Find this resource:
Middlebrooks, J. C., Makous, J. C., & Green, D. M. (1989). Directional sensitivity of sound-pressure levels in the human ear canal. Journal of the Acoustical Society of America, 86(1), 89–108.Find this resource:
Miko, I. J., Nakamura, P. A., Henkemeyer, M., & Cramer, K. S. (2007). Auditory brainstem neural activation patterns are altered in EphA4-and ephrin-B2-deficient mice. Journal of Comparative Neurology, 505(6), 669–681. doi:10.1002/cne.21530Find this resource:
Mongiat, L. A., Esposito, M. S., Lombardi, G., & Schinder, A. F. (2009). Reliable activation of immature neurons in the adult hippocampus. PLoS One, 4(4), e5320. doi:10.1371/journal.pone.0005320Find this resource:
Moore, D. R. (1990). Auditory brainstem of the ferret: early cessation of developmental sensitivity of neurons in the cochlear nucleus to removal of the cochlea. Journal of Comparative Neurology, 302(4), 810–823. doi:10.1002/cne.903020412Find this resource:
Moore, D. R. (1992). Trophic influences of excitatory and inhibitory synapses on neurones in the auditory brain stem. Neuroreport, 3(3), 269–272.Find this resource:
Moore, D. R., & King, A. J. (2004). Plasticity of binaural systems. In T. N. Parks (Ed.), Plasticity of the Auditory System (pp. 98–172). New York: Springer.Find this resource:
Moore, D. R., Rogers, N. J., & O’Leary, S. J. (1998). Loss of cochlear nucleus neurons following aminoglycoside antibiotics or cochlear removal. Annals of Otology, Rhinology, and Laryngology, 107(4), 337–343. doi:10.1177/000348949810700413Find this resource:
Moore, D. R., Russell, F. A., & Cathcart, N. C. (1995). Lateral superior olive projections to the inferior colliculus in normal and unilaterally deafened ferrets. Journal of Comparative Neurology, 357(2), 204–216. doi:10.1002/cne.903570203Find this resource:
Moore, J. K. (2000). Organization of the human superior olivary complex. Microscopy Research and Technique, 51(4), 403–412. doi:10.1002/1097-0029(20001115)51:4<403::AID-JEMT8>3.0.CO;2-QFind this resource:
Moore, M. J., & Caspary, D. M. (1983). Strychnine blocks binaural inhibition in lateral superior olivary neurons. Journal of Neuroscience, 3(1), 237–242.Find this resource:
Moritz, C. P., Eckstein, E., Tenzer, S., & Friauf, E. (2015). Neuroproteomics in the auditory brainstem: Candidate proteins for ultrafast and precise information processing. Molecular and Cellular Neurosciences, 64, 9–23. doi:10.1016/j.mcn.2014.08.006Find this resource:
Mulders, W. H., & Robertson, D. (2001). Origin of the noradrenergic innervation of the superior olivary complex in the rat. Journal of Chemical Neuroanatomy, 21(4), 313–322.Find this resource:
Munemoto, Y., Kuriyama, H., Doi, T., Sato, K., Matsumoto, A., Sugatani, J., … Yamashita, T. (1998). Auditory pathway and auditory brainstem response in mice lacking NMDA receptor epsilon 1 and epsilon 4 subunits. Neuroscience Letters, 251(2), 101–104.Find this resource:
Musicant, A. D., Chan, J. C., & Hind, J. E. (1990). Direction-dependent spectral properties of cat external ear: New data and cross-species comparisons. Journal of the Acoustical Society of America, 87(2), 757–781.Find this resource:
Nabekura, J., Katsurabayashi, S., Kakazu, Y., Shibata, S., Matsubara, A., Jinno, S., … Ishibashi, H. (2004). Developmental switch from GABA to glycine release in single central synaptic terminals. Nature Neuroscience, 7(1), 17–23. doi:10.1038/nn1170Find this resource:
Nakagawa, H., Sato, K., Shiraishi, Y., Kuriyama, H., & Altschuler, R. A. (2000). NMDAR1 isoforms in the rat superior olivary complex and changes after unilateral cochlear ablation. Brain Research. Molecular Brain Research, 77(2), 246–257.Find this resource:
Nakamura, P. A., Hsieh, C. Y., & Cramer, K. S. (2012). EphB signaling regulates target innervation in the developing and deafferented auditory brainstem. Developmental Neurobiology, 72(9), 1243–1255. doi:10.1002/dneu.20990Find this resource:
Niblock, M. M., Brunso-Bechtold, J. K., & Henkel, C. K. (1995). Fiber outgrowth and pathfinding in the developing auditory brainstem. Brain Research. Developmental Brain Research, 85(2), 288–292.Find this resource:
Noh, J., Seal, R. P., Garver, J. A., Edwards, R. H., & Kandler, K. (2010). Glutamate co-release at GABA/glycinergic synapses is crucial for the refinement of an inhibitory map. Nature Neuroscience, 13(2), 232–238. doi:10.1038/nn.2478Find this resource:
Nordeen, K. W., Killackey, H. P., & Kitzes, L. M. (1983). Ascending auditory projections to the inferior colliculus in the adult gerbil, Meriones unguiculatus. Journal of Comparative Neurology, 214(2), 131–143. doi:10.1002/cne.902140203Find this resource:
Nothwang, H. G. (2016). Evolution of mammalian sound localization circuits: A developmental perspective. Progress in Neurobiology, 141, 1–24. doi:10.1016/j.pneurobio.2016.02.003Find this resource:
Oertel, D., Wright, S., Cao, X. J., Ferragamo, M., & Bal, R. (2011). The multiple functions of T stellate/multipolar/chopper cells in the ventral cochlear nucleus. Hearing Research, 276(1–2), 61–69. doi:10.1016/j.heares.2010.10.018Find this resource:
Oliver, D. L. (2000). Ascending efferent projections of the superior olivary complex. Microscopy Research and Technique, 51(4), 355–363. doi:10.1002/1097-0029(20001115)51:4<355::AID-JEMT5>3.0.CO;2-JFind this resource:
Ollo, C., & Schwartz, I. R. (1979). The superior olivary complex in C57BL/6 mice. American Journal of Anatomy, 155(3), 349–374. doi:10.1002/aja.1001550306Find this resource:
O’Neill, W. E., Zettel, M. L., Whittemore, K. R., & Frisina, R. D. (1997). Calbindin D-28k immunoreactivity in the medial nucleus of the trapezoid body declines with age in C57BL/6, but not CBA/CaJ, mice. Hearing Research, 112(1–2), 158–166. doi:10.1016/S0378-5955(97)00116-0Find this resource:
Osmanski, M. S., & Wang, X. (2011). Measurement of absolute auditory thresholds in the common marmoset (Callithrix jacchus). Hearing Research, 277(1–2), 127–133. doi:10.1016/j.heares.2011.02.001Find this resource:
Paoletti, P., Bellone, C., & Zhou, Q. (2013). NMDA receptor subunit diversity: Impact on receptor properties, synaptic plasticity and disease. Nature Reviews. Neuroscience, 14(6), 383–400. doi:10.1038/nrn3504Find this resource:
Park, T. J., Grothe, B., Pollak, G. D., Schuller, G., & Koch, U. (1996). Neural delays shape selectivity to interaural intensity differences in the lateral superior olive. Journal of Neuroscience, 16(20), 6554–6566.Find this resource:
Park, T. J., Monsivais, P., & Pollak, G. D. (1997). Processing of interaural intensity differences in the LSO: role of interaural threshold differences. Journal of Neurophysiology, 77(6), 2863–2878. doi:10.1152/jn.19184.108.40.20663Find this resource:
Perney, T. M., Marshall, J., Martin, K. A., Hockfield, S., & Kaczmarek, L. K. (1992). Expression of the mRNAs for the Kv3.1 potassium channel gene in the adult and developing rat brain. Journal of Neurophysiology, 68(3), 756–766. doi:10.1152/jn.19220.127.116.116Find this resource:
Pickles, J. O. (1982). An introduction to the physiology of hearing. London, New York, Paris, San Diego, San Francisco, Sao Paulo, Sydney, Tokyo, Toronto: Academic Press.Find this resource:
Pierce, E. T. (1967). Histogenesis of the dorsal and ventral cochlear nuclei in the mouse. An autoradiographic study. Journal of Comparative Neurology, 131(1), 27–54. doi:10.1002/cne.901310104Find this resource:
Pilati, N., Linley, D. M., Selvaskandan, H., Uchitel, O., Hennig, M. H., Kopp-Scheinpflug, C., & Forsythe, I. D. (2016). Acoustic trauma slows AMPA receptor-mediated EPSCs in the auditory brainstem, reducing GluA4 subunit expression as a mechanism to rescue binaural function. Journal of Physiology, 594(13), 3683–3703. doi:10.1113/JP271929Find this resource:
Platzer, J., Engel, J., Schrott-Fischer, A., Stephan, K., Bova, S., Chen, H., … Striessnig, J. (2000). Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+ channels. Cell, 102(1), 89–97.Find this resource:
Populin, L. C., & Yin, T. C. (1998). Behavioral studies of sound localization in the cat. Journal of Neuroscience, 18(6), 2147–2160.Find this resource:
Pradhan, J., Maskey, D., & Ahn, S. C. (2012). Long term depression of MNTB-LSO synapses is expressed postsynaptically in developing circling mice. Neuroscience Letters, 531(1), 30–34. doi:10.1016/j.neulet.2012.09.049Find this resource:
Radtke-Schuller, S., Seeler, S., & Grothe, B. (2015). Restricted loss of olivocochlear but not vestibular efferent neurons in the senescent gerbil (Meriones unguiculatus). Frontiers in Aging Neuroscience, 7, 4. doi:10.3389/fnagi.2015.00004Find this resource:
Raman, I. M., Zhang, S., & Trussell, L. O. (1994). Pathway-specific variants of AMPA receptors and their contribution to neuronal signaling. Journal of Neuroscience, 14(8), 4998–5010.Find this resource:
Rayleigh, L. (1907). XII. On our perception of sound direction. The London, Edinburgh, and Dublin Philosophical Magazine and Journal of Science, 13(74), 214–232. doi:10.1080/14786440709463595Find this resource:
Renier, N., Schonewille, M., Giraudet, F., Badura, A., Tessier-Lavigne, M., Avan, P., … Chedotal, A. (2010). Genetic dissection of the function of hindbrain axonal commissures. PLoS Biology, 8(3), e1000325. doi:10.1371/journal.pbio.1000325Find this resource:
Reuss, S., Disque-Kaiser, U., Antoniou-Lipfert, P., Gholi, M. N., Riemann, E., & Riemann, R. (2009). Neurochemistry of olivocochlear neurons in the hamster. Anatomical Record (Hoboken), 292(4), 461–471. doi:10.1002/ar.20881Find this resource:
Rietzel, H. J., & Friauf, E. (1998). Neuron types in the rat lateral superior olive and developmental changes in the complexity of their dendritic arbors. Journal of Comparative Neurology, 390(1), 20–40.Find this resource:
Rooney, B. J., Kavanagh, G. L., & Kelly, J. B. (1991). Kainic acid lesions of the superior olivary complex: A horseradish peroxidase study of surviving brain-stem projections. Journal of Neuroscience Methods, 39(1), 65–75.Find this resource:
Rose, M. F., Ahmad, K. A., Thaller, C., & Zoghbi, H. Y. (2009). Excitatory neurons of the proprioceptive, interoceptive, and arousal hindbrain networks share a developmental requirement for Math1. Proceedings of the National Academy of Sciences of the United States of America, 106(52), 22462–22467. doi:10.1073/pnas.0911579106Find this resource:
Rosengauer, E., Hartwich, H., Hartmann, A. M., Rudnicki, A., Satheesh, S. V., Avraham, K. B., & Nothwang, H. G. (2012). Egr2::cre mediated conditional ablation of dicer disrupts histogenesis of mammalian central auditory nuclei. PLoS One, 7(11), e49503. doi:10.1371/journal.pone.0049503Find this resource:
Rothman, J. S., & Manis, P. B. (2003). The roles potassium currents play in regulating the electrical activity of ventral cochlear nucleus neurons. Journal of Neurophysiology, 89(6), 3097–3113. doi:10.1152/jn.00127.2002Find this resource:
Rudy, B. (1988). Diversity and ubiquity of K channels. Neuroscience, 25(3), 729–749.Find this resource:
Ruhland, J. L., Jones, A. E., & Yin, T. C. (2015). Dynamic sound localization in cats. Journal of Neurophysiology, 114(2), 958–968. doi:10.1152/jn.00105.2015Find this resource:
Russell, F. A., & Moore, D. R. (1995). Afferent reorganisation within the superior olivary complex of the gerbil: Development and induction by neonatal, unilateral cochlear removal. Journal of Comparative Neurology, 352(4), 607–625. doi:10.1002/cne.903520409Find this resource:
Rusu, S. I., & Borst, J. G. (2011). Developmental changes in intrinsic excitability of principal neurons in the rat medial nucleus of the trapezoid body. Developmental Neurobiology, 71(4), 284–295. doi:10.1002/dneu.20856Find this resource:
Ryugo, D. K., & Fekete, D. M. (1982). Morphology of primary axosomatic endings in the anteroventral cochlear nucleus of the cat: a study of the endbulbs of Held. Journal of Comparative Neurology, 210(3), 239–257. doi:10.1002/cne.902100304Find this resource:
Saint Marie, R. L., & Baker, R. A. (1990). Neurotransmitter-specific uptake and retrograde transport of [3H]glycine from the inferior colliculus by ipsilateral projections of the superior olivary complex and nuclei of the lateral lemniscus. Brain Research, 524(2), 244–253.Find this resource:
Saint Marie, R. L., Ostapoff, E. M., Morest, D. K., & Wenthold, R. J. (1989). Glycine-immunoreactive projection of the cat lateral superior olive: possible role in midbrain ear dominance. Journal of Comparative Neurology, 279(3), 382–396. doi:10.1002/cne.902790305Find this resource:
Saldana, E., & Berrebi, A. S. (2000). Anisotropic organization of the rat superior paraolivary nucleus. Anatomy and Embryology, 202(4), 265–279. doi:10.1007/s004290002020265.429Find this resource:
Sanes, D. H. (1990). An in vitro analysis of sound localization mechanisms in the gerbil lateral superior olive. Journal of Neuroscience, 10(11), 3494–3506.Find this resource:
Sanes, D. H., & Chokshi, P. (1992). Glycinergic transmission influences the development of dendrite shape. Neuroreport, 3(4), 323–326.Find this resource:
Sanes, D. H., Geary, W. A., Wooten, G. F., & Rubel, E. W. (1987). Quantitative distribution of the glycine receptor in the auditory brain stem of the gerbil. Journal of Neuroscience, 7(11), 3793–3802.Find this resource:
Sanes, D. H., Markowitz, S., Bernstein, J., & Wardlow, J. (1992). The influence of inhibitory afferents on the development of postsynaptic dendritic arbors. Journal of Comparative Neurology, 321(4), 637–644. doi:10.1002/cne.903210410Find this resource:
Sanes, D. H., Merickel, M., & Rubel, E. W. (1989). Evidence for an alteration of the tonotopic map in the gerbil cochlea during development. Journal of Comparative Neurology, 279(3), 436–444. doi:10.1002/cne.902790308Find this resource:
Sanes, D. H., & Rubel, E. W. (1988). The ontogeny of inhibition and excitation in the gerbil lateral superior olive. Journal of Neuroscience, 8(2), 682–700.Find this resource:
Sanes, D. H., & Siverls, V. (1991). Development and specificity of inhibitory terminal arborizations in the central nervous system. Journal of Neurobiology, 22(8), 837–854. doi:10.1002/neu.480220805Find this resource:
Sanes, D. H., Song, J., & Tyson, J. (1992). Refinement of dendritic arbors along the tonotopic axis of the gerbil lateral superior olive. Brain Research. Developmental Brain Research, 67(1), 47–55.Find this resource:
Sanes, D. H., & Takacs, C. (1993). Activity-dependent refinement of inhibitory connections. European Journal of Neuroscience, 5(6), 570–574.Find this resource:
Sanes, D. H., & Walsh, E. J. (1998). The development of central auditory processing. In E. W. Rubel, A. N. Popper, & R. R. Fay (Eds.), Development of the auditory system (pp. 271–314). New York: Springer.Find this resource:
Satheesh, S. V., Kunert, K., Rüttiger, L., Zuccotti, A., Schönig, K., Friauf, E., … Nothwang, H. G. (2012). Retrocochlear function of the peripheral deafness gene Cacna1d. Human Molecular Genetics, 21(17), 3896–3909. doi:10.1093/hmg/dds217Find this resource:
Sato, K., Nakagawa, H., Kuriyama, H., & Altschuler, R. A. (1999). Differential distribution of N-methyl-D-aspartate receptor-2 subunit messenger RNA in the rat superior olivary complex. Neuroscience, 89(3), 839–853.Find this resource:
Sato, K., Shiraishi, S., Nakagawa, H., Kuriyama, H., & Altschuler, R. A. (2000). Diversity and plasticity in amino acid receptor subunits in the rat auditory brain stem. Hearing Research, 147(1–2), 137–144.Find this resource:
Scheibel, M. E., & Scheibel, A. B. (1974). Neuropil organization in the superior olive of the cat. Experimental Neurology, 43(2), 339–348.Find this resource:
Schlüter, T., Berger, C., Rosengauer, E., Fieth, P., Krohs, C., Ushakov, K., … Nothwang, H. G. (2018). miR-96 is required for normal development of the auditory hindbrain. Human Molecular Genetics, 27(5), 860–874. doi:10.1093/hmg/ddy007Find this resource:
Schmid, S., Guthmann, A., Ruppersberg, J. P., & Herbert, H. (2001). Expression of AMPA receptor subunit flip/flop splice variants in the rat auditory brainstem and inferior colliculus. Journal of Comparative Neurology, 430(2), 160–171.Find this resource:
Schneggenburger, R., & Forsythe, I. D. (2006). The calyx of Held. Cell and Tissue Research, 326(2), 311–337.Find this resource:
Schneider-Maunoury, S., Gilardi-Hebenstreit, P., & Charnay, P. (1998). How to build a vertebrate hindbrain. Lessons from genetics. Comptes Rendus de l’Academie des Sciences Serie III-Sciences de la Vie-Life Sciences, 321(10), 819–834. doi:10.1016/S0764-4469(99)80022-5Find this resource:
Schneider-Maunoury, S., Topilko, P., Seitandou, T., Levi, G., Cohen-Tannoudji, M., Pournin, S., … Charnay, P. (1993). Disruption of Krox-20 results in alteration of rhombomeres 3 and 5 in the developing hindbrain. Cell, 75(6), 1199–1214.Find this resource:
Schofield, B. R. (2010). Structural organization of the descending auditory pathway. In A. Rees & A. R. Palmer (Eds.), Oxford handbook of auditory science: The auditory brain (Vol. 2, pp. 43–64). Oxford: Oxford University Press.Find this resource:
Schofield, B. R., & Cant, N. B. (1991). Organization of the superior olivary complex in the guinea pig. I. Cytoarchitecture, cytochrome oxidase histochemistry, and dendritic morphology. Journal of Comparative Neurology, 314(4), 645–670. doi:10.1002/cne.903140403Find this resource:
Schwartz, I. R. (1992). The superior olivary complex and lateral lemniscal nuclei. In D. B. Webster, A. N. Popper, & R. R. Fay (Eds.), The mammalian auditory pathway: Neuroanatomy (pp. 117–167). New York: Springer.Find this resource:
Seal, R. P., Akil, O., Yi, E., Weber, C. M., Grant, L., Yoo, J., … Edwards, R. H. (2008). Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3. Neuron, 57(2), 263–275. doi:10.1016/j.neuron.2007.11.032Find this resource:
Shaw, E. A., & Vaillancourt, M. M. (1985). Transformation of sound-pressure level from the free field to the eardrum presented in numerical form. Journal of the Acoustical Society of America, 78(3), 1120–1123.Find this resource:
Shneiderman, A., Stanforth, D. A., Henkel, C. K., & Saint Marie, R. L. (1999). Input-output relationships of the dorsal nucleus of the lateral lemniscus: Possible substrate for the processing of dynamic spatial cues. Journal of Comparative Neurology, 410(2), 265–276.Find this resource:
Smith, P. H., Joris, P. X., Carney, L. H., & Yin, T. C. (1991). Projections of physiologically characterized globular bushy cell axons from the cochlear nucleus of the cat. Journal of Comparative Neurology, 304(3), 387–407. doi:10.1002/cne.903040305Find this resource:
Sommer, I., Lingenhöhl, K., & Friauf, E. (1993). Principal cells of the rat medial nucleus of the trapezoid body: An intracellular in vivo study of their physiology and morphology. Experimental Brain Research, 95(2), 223–239.Find this resource:
Song, M. S., & Rossi, J. J. (2017). Molecular mechanisms of Dicer: Endonuclease and enzymatic activity. Biochemical Journal, 474(10), 1603–1618. doi:10.1042/BCJ20160759Find this resource:
Sonntag, M., Englitz, B., Kopp-Scheinpflug, C., & Rübsamen, R. (2009). Early postnatal development of spontaneous and acoustically evoked discharge activity of principal cells of the medial nucleus of the trapezoid body: An in vivo study in mice. Journal of Neuroscience, 29(30), 9510–9520. doi:10.1523/JNEUROSCI.1377-09.2009Find this resource:
Sonntag, M., Englitz, B., Typlt, M., & Rübsamen, R. (2011). The calyx of Held develops adult-like dynamics and reliability by hearing onset in the mouse in vivo. Journal of Neuroscience, 31(18), 6699–6709. doi:10.1523/JNEUROSCI.0575-11.2011Find this resource:
Spangler, K. M., Warr, W. B., & Henkel, C. K. (1985). The projections of principal cells of the medial nucleus of the trapezoid body in the cat. Journal of Comparative Neurology, 238(3), 249–262. doi:10.1002/cne.902380302Find this resource:
Spirou, G. A., & Berrebi, A. S. (1997). Glycine immunoreactivity in the lateral nucleus of the trapezoid body of the cat. Journal of Comparative Neurology, 383(4), 473–488.Find this resource:
Srinivasan, G., Friauf, E., & Löhrke, S. (2004). Functional glutamatergic and glycinergic inputs to several superior olivary nuclei of the rat revealed by optical imaging. Neuroscience, 128(3), 617–634.Find this resource:
Sterenborg, J. C., Pilati, N., Sheridan, C. J., Uchitel, O. D., Forsythe, I. D., & Barnes-Davies, M. (2010). Lateral olivocochlear (LOC) neurons of the mouse LSO receive excitatory and inhibitory synaptic inputs with slower kinetics than LSO principal neurons. Hearing Research, 270(1–2), 119–126. doi:10.1016/j.heares.2010.08.013Find this resource:
Sun, S., Babola, T., Pregernig, G., So, K. S., Nguyen, M., Su, S. M., … Müller, U. (2018). Hair cell mechanotransduction regulates spontaneous activity and spiral ganglion subtype specification in the auditory system. Cell, 174, 1247–1263 e15. doi:10.1016/j.cell.2018.07.008Find this resource:
Suneja, S. K., Benson, C. G., & Potashner, S. J. (1998). Glycine receptors in adult guinea pig brain stem auditory nuclei: Regulation after unilateral cochlear ablation. Experimental Neurology, 154(2), 473–488. doi:10.1006/exnr.1998.6946Find this resource:
Takahashi, T., Momiyama, A., Hirai, K., Hishinuma, F., & Akagi, H. (1992). Functional correlation of fetal and adult forms of glycine receptors with developmental changes in inhibitory synaptic receptor channels. Neuron, 9(6), 1155–1161.Find this resource:
Thompson, A. M., & Thompson, G. C. (1987). Efferent projections from posteroventral cochlear nucleus to lateral superior olive in guinea pig. Brain Research, 421(1–2), 382–386.Find this resource:
Tollin, D. J. (2003). The lateral superior olive: a functional role in sound source localization. Neuroscientist, 9(2), 127–143. doi:10.1177/1073858403252228Find this resource:
Tollin, D. J., & Yin, T. C. (2002). The coding of spatial location by single units in the lateral superior olive of the cat. II. The determinants of spatial receptive fields in azimuth. Journal of Neuroscience, 22(4), 1468–1479.Find this resource:
Tollin, D. J., & Yin, T. C. (2005). Interaural phase and level difference sensitivity in low-frequency neurons in the lateral superior olive. Journal of Neuroscience, 25(46), 10648–10657. doi:10.1523/JNEUROSCI.1609-05.2005Find this resource:
Tollin, D. J., & Yin, T. C. T. (2002). The coding of spatial location by single units in the lateral superior olive of the cat. I. Spatial receptive fields in azimuth. Journal of Neuroscience, 22(4), 1454–1467. doi:Doi 10.1523/Jneurosci.22-04-01454.2002Find this resource:
Triplett, J. W., & Feldheim, D. A. (2012). Eph and ephrin signaling in the formation of topographic maps. Seminars in Cell & Developmental Biology, 23(1), 7–15. doi:10.1016/j.semcdb.2011.10.026Find this resource:
Tritsch, N. X., Rodriguez-Contreras, A., Crins, T. T. H., Wang, H. C., Borst, J. G. G., & Bergles, D. E. (2010). Calcium action potentials in hair cells pattern auditory neuron activity before hearing onset. Nature Neuroscience, 13(9), 1050–1052. doi:10.1038/nn.2604Find this resource:
Tritsch, N. X., Yi, E., Gale, J. E., Glowatzki, E., & Bergles, D. E. (2007). The origin of spontaneous activity in the developing auditory system. Nature, 450(7166), 50–55. doi:10.1038/nature06233Find this resource:
Trussell, L. O. (1999). Synaptic mechanisms for coding timing in auditory neurons. Annual Review of Physiology, 61, 477–496. doi:10.1146/annurev.physiol.61.1.477Find this resource:
Tsuchitani, C. (1977). Functional organization of lateral cell groups of cat superior olivary complex. Journal of Neurophysiology, 40(2), 296–318. doi:10.1152/jn.1918.104.22.1686Find this resource:
Tsuchitani, C. (1988a). The inhibition of cat lateral superior olive unit excitatory responses to binaural tone bursts. I. The transient chopper response. Journal of Neurophysiology, 59(1), 164–183. doi:10.1152/jn.1922.214.171.124Find this resource:
Tsuchitani, C. (1988b). The inhibition of cat lateral superior olive unit excitatory responses to binaural tone bursts. II. The sustained discharges. Journal of Neurophysiology, 59(1), 184–211. doi:10.1152/jn.19126.96.36.199Find this resource:
Tsuchitani, C., & Boudreau, J. C. (1966). Single unit analysis of cat superior olive S segment with tonal stimuli. Journal of Neurophysiology, 29(4), 684–697. doi:10.1152/jn.19188.8.131.524Find this resource:
Tsuchitani, C., & Boudreau, J. C. (1967). Encoding of stimulus frequency and intensity by cat superior olive S-segment cells. Journal of the Acoustical Society of America, 42(4), 794–805.Find this resource:
Tsuchitani, C., & Johnson, D. H. (1991). Binaural cues and signal processing in the superior olivary complex. In R. A. Altschuler, R. P. Bobbin, B. M. Clopton, & D. W. Hoffman (Eds.), Neurobiology of hearing: The central auditory system (Vol. 1, pp. 163–193). New York: Raven Press.Find this resource:
van Adel, B. A., & Kelly, J. B. (1998). Kainic acid lesions of the superior olivary complex: Effects on sound localization by the albino rat. Behavioral Neuroscience, 112(2), 432–446.Find this resource:
Vetter, D. E., Adams, J. C., & Mugnaini, E. (1991). Chemically distinct rat olivocochlear neurons. Synapse, 7(1), 21–43. doi:10.1002/syn.890070104Find this resource:
Vetter, D. E., Liberman, M. C., Mann, J., Barhanin, J., Boulter, J., Brown, M. C., … Elgoyhen, A. B. (1999). Role of a9 nicotinic ACh receptor subunits in the development and function of cochlear efferent innervation. Neuron, 23(1), 93–103.Find this resource:
Vetter, D. E., & Mugnaini, E. (1992). Distribution and dendritic features of three groups of rat olivocochlear neurons. A study with two retrograde cholera toxin tracers. Anatomy and Embryology, 185(1), 1–16.Find this resource:
Vitten, H., Reusch, M., Friauf, E., & Löhrke, S. (2004). Expression of functional kainate and AMPA receptors in developing lateral superior olive neurons of the rat. Journal of Neurobiology, 59(3), 272–288. doi:10.1002/neu.10326Find this resource:
von Gersdorff, H., & Borst, J. G. (2002). Short-term plasticity at the calyx of Held. Nature Reviews. Neuroscience, 3(1), 53–64. doi:10.1038/nrn705Find this resource:
Walcher, J., Hassfurth, B., Grothe, B., & Koch, U. (2011). Comparative posthearing development of inhibitory inputs to the lateral superior olive in gerbils and mice. Journal of Neurophysiology, 106(3), 1443–1453. doi:10.1152/jn.01087.2010Find this resource:
Walker, V. A., Peremans, H., & Hallam, J. C. T. (1998). One tone, two ears, three dimensions: A robotic investigation of pinnae movements used by rhinolophid and hipposiderid bats. Journal of the Acoustical Society of America, 104(1), 569–579. doi:10.1121/1.423256Find this resource:
Wallace, M. M., Harris, J. A., Brubaker, D. Q., Klotz, C. A., & Gabriele, M. L. (2016). Graded and discontinuous EphA-ephrinB expression patterns in the developing auditory brainstem. Hearing Research, 335, 64–75. doi:10.1016/j.heares.2016.02.013Find this resource:
Wang, H. C., Lin, C. C., Cheung, R., Zhang-Hooks, Y., Agarwal, A., Ellis-Davies, G., … Bergles, D. E. (2015). Spontaneous activity of cochlear hair cells triggered by fluid secretion mechanism in adjacent support cells. Cell, 163(6), 1348–1359. doi:10.1016/j.cell.2015.10.070Find this resource:
Wang, V. Y., Rose, M. F., & Zoghbi, H. Y. (2005). Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum. Neuron, 48(1), 31–43. doi:10.1016/j.neuron.2005.08.024Find this resource:
Warr, W. B. (1992). Organization of olivocochlear efferent systems in mammals. In D. B. Webster, A. N. Popper, & R. R. Fay (Eds.), The mammalian auditory pathway: Neuroanatomy (Vol. 1, pp. 410–448). New York: Springer Verlag.Find this resource:
Warr, W. B., Beck Boche, J. E., Ye, Y., & Kim, D. O. (2002). Organization of olivocochlear neurons in the cat studied with the retrograde tracer cholera toxin-B. Journal of the Association for Research in Otolaryngology, 3(4), 457–478.Find this resource:
Warr, W. B., & Beck, J. E. (1996). Multiple projections from the ventral nucleus of the trapezoid body in the rat. Hearing Research, 93(1–2), 83–101.Find this resource:
Warr, W. B., & Boche, J. E. (2003). Diversity of axonal ramifications belonging to single lateral and medial olivocochlear neurons. Experimental Brain Research, 153(4), 499–513. doi:10.1007/s00221-003-1682-3Find this resource:
Weinrich, L., Sonntag, M., Arendt, T., & Morawski, M. (2018). Neuroanatomical characterization of perineuronal net components in the human cochlear nucleus and superior olivary complex. Hearing Research, 367, 32–47. doi:10.1016/j.heares.2018.07.005Find this resource:
Wenthold, R. J., Huie, D., Altschuler, R. A., & Reeks, K. A. (1987). Glycine immunoreactivity localized in the cochlear nucleus and superior olivary complex. Neuroscience, 22(3), 897–912.Find this resource:
Wiegert, J. S., & Oertner, T. G. (2013). Long-term depression triggers the selective elimination of weakly integrated synapses. Proceedings of the National Academy of Sciences of the United States of America, 110(47), E4510–4519. doi:10.1073/pnas.1315926110Find this resource:
Wilkinson, D. G., Bhatt, S., Chavrier, P., Bravo, R., & Charnay, P. (1989). Segment-specific expression of a zinc-finger gene in the developing nervous system of the mouse. Nature, 337(6206), 461–464. doi:10.1038/337461a0Find this resource:
Willard, F. H., & Martin, G. F. (1983). The auditory brainstem nuclei and some of their projections to the inferior colliculus in the North American opossum. Neuroscience, 10(4), 1203–1232.Find this resource:
Willaredt, M. A., Schluter, T., & Nothwang, H. G. (2015). The gene regulatory networks underlying formation of the auditory hindbrain. Cellular and Molecular Life Sciences, 72(3), 519–535. doi:10.1007/s00018-014-1759-0Find this resource:
Willott, J. F. (1997). Pathology of the aging mouse. Washington, DC: ILSI Press.Find this resource:
Winter, I. M., Robertson, D., & Cole, K. S. (1989). Descending projections from auditory brainstem nuclei to the cochlea and cochlear nucleus of the guinea pig. Journal of Comparative Neurology, 280(1), 143–157. doi:10.1002/cne.902800110Find this resource:
Woolf, N. K., & Ryan, A. F. (1984). The development of auditory function in the cochlea of the mongolian gerbil. Hearing Research, 13(3), 277–283.Find this resource:
Woolf, N. K., & Ryan, A. F. (1985). Ontogeny of neural discharge patterns in the ventral cochlear nucleus of the mongolian gerbil. Brain Research, 349(1–2), 131–147.Find this resource:
Wu, S. H., & Kelly, J. B. (1991). Physiological properties of neurons in the mouse superior olive: Membrane characteristics and postsynaptic responses studied in vitro. Journal of Neurophysiology, 65(2), 230–246. doi:10.1152/jn.19184.108.40.206Find this resource:
Wu, S. H., & Kelly, J. B. (1992a). Binaural interaction in the lateral superior olive: Time difference sensitivity studied in mouse brain slice. Journal of Neurophysiology, 68(4), 1151–1159. doi:10.1152/jn.19220.127.116.111Find this resource:
Wu, S. H., & Kelly, J. B. (1992b). Synaptic pharmacology of the superior olivary complex studied in mouse brain slice. Journal of Neuroscience, 12(8), 3084–3097.Find this resource:
Wu, S. H., & Kelly, J. B. (1993). Response of neurons in the lateral superior olive and medial nucleus of the trapezoid body to repetitive stimulation: Intracellular and extracellular recordings from mouse brain slice. Hearing Research, 68(2), 189–201.Find this resource:
Wu, S. H., & Kelly, J. B. (1995). Inhibition in the superior olivary complex: pharmacological evidence from mouse brain slice. Journal of Neurophysiology, 73(1), 256–269. doi:10.1152/jn.1918.104.22.1686Find this resource:
Wullimann, M. F., Mueller, T., Distel, M., Babaryka, A., Grothe, B., & Koster, R. W. (2011). The long adventurous journey of rhombic lip cells in jawed vertebrates: a comparative developmental analysis. Frontiers in Neuroanatomy, 5, 27. doi:10.3389/fnana.2011.00027Find this resource:
Xie, R., & Manis, P. B. (2013). Target-specific IPSC kinetics promote temporal processing in auditory parallel pathways. Journal of Neuroscience, 33(4), 1598–1614. doi:10.1523/JNEUROSCI.2541-12.2013Find this resource:
Xue, C., & Liu, F. (2014). Structured synaptic inhibition has a critical role in multiple-choice motion-discrimination tasks. Journal of Neuroscience, 34(40), 13444–13457. doi:10.1523/JNEUROSCI.0001-14.2014Find this resource:
Yang, Y. M., Aitoubah, J., Lauer, A. M., Nuriya, M., Takamiya, K., Jia, Z., … Wang, L. Y. (2011). GluA4 is indispensable for driving fast neurotransmission across a high-fidelity central synapse. Journal of Physiology, 589(17), 4209–4227. doi:10.1113/jphysiol.2011.208066Find this resource:
Yin, T. C. (2013). Physiological and behavioral studies of sound localization. Journal of the Acoustical Society of America, 133, 050050–050050. doi:10.1121/1.4799510Find this resource:
Yin, T. C. T. (2002). Neural mechanisms of encoding binaural localization cues in the auditory brainstem. In D. Oertel, R. R. Fay, & A. N. Popper (Eds.), Integrative functions in the mammalian auditory pathway (pp. 99–159). New York: Springer.Find this resource:
Yin, T. C. T., & Kuwada, S. (1983). Binaural interaction in low-frequency neurons in inferior colliculus of the cat. III. Effects of changing frequency. Journal of Neurophysiology, 50(4), 1020–1042. doi:10.1152/jn.1922.214.171.1240Find this resource:
Yin, T. C. T., & Kuwada, S. (2010). Binaural localization cues. In A. Rees & A. R. Palmer (Eds.), Oxford handbook of auditory science: The auditory brain. (Vol. 2, pp. 271–302). Oxford: Oxford University Press.Find this resource:
Young, E. D., Rice, J. J., & Tong, S. C. (1996). Effects of pinna position on head-related transfer functions in the cat. Journal of the Acoustical Society of America, 99(5), 3064–3076.Find this resource:
Zucker, R. S., & Regehr, W. G. (2002). Short-term synaptic plasticity. Annual Review of Physiology, 64, 355–405. doi:10.1146/annurev.physiol.64.092501.114547Find this resource: