Show Summary Details

Page of

PRINTED FROM OXFORD HANDBOOKS ONLINE ( © Oxford University Press, 2018. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Handbooks Online for personal use (for details see Privacy Policy and Legal Notice).

date: 26 May 2019

Molecular and Structural Changes in the Cochlear Nucleus in Response to Hearing Loss

Abstract and Keywords

Hearing loss is the third most common health problem in the United States. It can affect the quality of life and relationships. About 48 million Americans have lost some hearing. Age, illness, and genetics contribute to the generation of hearing loss. During development, auditory synaptic circuitries are highly plastic and able to adapt to fluctuations in auditory experience. Whether this is so for mature auditory nerve synapses and circuitries within nuclei along the central auditory pathway is less understood. Daily fluctuations in auditory experience can lead to hearing deficits, including hearing loss and/or deafness, Therefore, understanding the cellular mechanisms that occur in mature central auditory synaptic circuitries that lead and/or contribute to hearing loss is important. This chapter focuses on published studies using animal models describing structural and molecular changes that occur in the cochlear nucleus in response to hearing loss, the first gateway of sound processing in the brain.

Keywords: cochlear nucleus, hearing loss, cellular mechanisms, deafening, presynaptic, postsynaptic

Introduction to the Cochlear Nucleus: Anatomy and Function

The cochlear nucleus is located in the lower brainstem in the angle formed by the lower pons, upper medulla, and the cerebellum (angle ponto-medular-cerebellosum), and it is composed of two main regions: the ventral cochlear nucleus (VCN) and dorsal cochlear nucleus (DCN). The auditory nerve (the central branch of spiral ganglion neurons) enters into the brainstem and divides the VCN in two additional regions: the anteroventral (AVCN) and posteroventral (PVCN) cochlear nucleus. The myelinated Type I auditory nerve fibers are the major source of excitation to the cochlear nucleus, carrying information from inner hair cells of the cochlea and innervating principal neurons in each of the regions (Figure 1; Lorente de Nó, 1981). The neurons of the cochlear nucleus are the first central processors of auditory information, and they provide inputs to all the major brainstem and midbrain auditory nuclei. The VCN represents the beginning of the binaural pathway through its projections to the superior olivary complex in the lower medulla. The synaptic circuitry of the VCN specializes in the precise and rapid representation of the incoming signals from the cochlear afferents (Young & Oertel, 2003, 2010). The DCN initiates the monaural pathway through its projections to the inferior colliculus in the midbrain and is key for up and down (vertical) sound processing. Apart from the primary sensory axons, the cochlear nucleus receives afferents from other auditory sources, among them the contralateral cochlear nucleus (Alibardi, 1998; Cant & Benson, 2003), as well as important modulatory inputs via descending projections from upper auditory regions, including the superior olivary complex (Cant & Benson, 2003), the inferior colliculus (Shore et al., 1991), and the auditory cortex (Meltzer & Ryugo, 2006), but also from non-auditory regions (somatosensory nuclei; Haenggeli et al., 2005; Shore et al., 2000; Heeringa et al., 2018). There exists an extended intrinsic synaptic circuitry in the cochlear nucleus complex not discussed in this chapter (see for details Cant, 1992; Rubio, 2018; Trussell & Oertel, 2018).

In the cochlear nucleus, there is an additional layer, the granular cell domain (GCD) that is an external shell of small neurons and neuropil that surrounds the magnocellular regions of the VCN (Figure 1; Osen, 1969). The GCD is not a major target of Type I auditory nerve fibers, although it does receive terminal branches of low spontaneous rate auditory nerve fibers (Liberman, 1991; Ryugo, 2008), as well as unmyelinated Type II auditory nerve fibers, that carry information from outer hair cells of the cochlea (Benson & Brown, 2004; Brown et al., 1988a;). This region is the target for a variety of nonprimary inputs (superior olivary complex; inferior colliculus; auditory cortex) (Brown et al., 1988b; Caicedo & Herbert, 1993; Saldaña, 1993) and nonauditory projections from somatosensory nuclei (cuneate: Weinberg & Rustioni, 1989; trigeminal nuclei: Itoh et al., 1987; Shore et al., 2000; vestibular organ: Burian & Goesttner, 1988; Kevetter & Parachio, 1989). Neurons within the GCD are in a position to integrate a wide spectrum of information carrying cues about attention, head position, sound localization, or sound recognition (Shore et al., 2000). Granule cell axons project into the superficial layer of the DCN (Rubio & Wenthold, 1997; Waterlood & Mugnaini, 1984).

The cochlear nucleus represents the first station of sound processing in the brainstem. Therefore, it is important to understand the cellular mechanisms in the neurons within the cochlear nucleus that lead and/or contribute to hearing loss. This book chapter will focus on the structural and molecular changes in the cochlear nucleus in response to hearing loss. For functional aspects of hearing loss in the cochlear nucleus, see chapter 6 by Manis in this volume.

Molecular and Structural Changes in the Cochlear Nucleus in Response to Hearing LossClick to view larger

Figure. 1. Schematic of three main subdivisions of the cochlear nucleus (CN) and principal neurons [bushy cells (BC), T stellate cells (T-s), and D stellate cells (D-s), within the anteroventral cochlear nucleus (AVCN) and the anterior posteroventral cochlear nucleus (PVCN); octopus cells (OC) within the posterior PVCN; and fusiform cells (FC) within the dorsal cochlear nucleus (DCN)]. The pale gray background represents the area of the ventral cochlear nucleus (VCN): the AVCN and anterior PVCN. Axonal projections from the principal cells and their targets are represented. The auditory nerve (AN) is represented entering the cochlear nucleus and dividing into descending and ascending branches. Middle frequency fibers (8 KHz) have a more caudal location within the AN, whereas lower frequency fibers (4 KHz) are more rostral. The extrinsic inputs to the AVCN from the superior olivary complex (SOC), cuneatus, spinal trigeminal nucleus (sp5), and contralateral cochlear nucleus are represented with three arrows. (GCD, granular cell domain; IC, inferior colliculus; LSO, lateral superior olive; MNTB, medial nucleus of the trapezoid body; MSO, medial superior olive; SPON: superior olivary nucleus).

The Effect of Cochlear Synaptic Activity on the Gross Anatomy of the Cochlear Nucleus and Neuronal Death

The volume and number of neurons in the cochlear nucleus depend on input from the auditory nerve for survival during the critical period of development (usually before or at postnatal day 9) in a variety of vertebrate species (see for review, Harris & Rubel, 2006; Tierney et al., 1997). Removing afferent input by ablating peripheral sensory receptors (deafferentation) in embryonic or young animals before hearing onset results in a variety of changes, including a reduced size of the cochlear nucleus, largely due to fast and dramatic degeneration of auditory nerve fibers and death of target neurons. In contrast, peripheral deafferentation after the onset of hearing does not lead to a major decrease in the size of the cochlear nucleus or to neuronal death (Tierney et al., 1997); apoptotic markers show up only in microglial cells (Campos Torres et al., 1999). One study used microarray technology to survey for differences in baseline gene expression over three postnatal ages that define a critical period of afferent-dependent neuron survival in the mouse cochlear nucleus (Harris et al., 2005). In this study, findings support the concept that multiple neuroprotective mechanisms increase and pro-apoptotic factors decrease over development to protect mature neurons from stressful insults, thus making them less dependent on afferent input for survival. More studies are needed to underpin the cellular mechanisms that occur during maturation to render cochlear nucleus neurons less susceptible to loss of afferent input. Nonsyndromic deafness studies in animals have shown that spontaneous synaptic activity in hair cells of the organ of Corti in the cochlea before onset of hearing affects the size of the cochlear nuclei. In these animals, death of principal neurons has not been reported (Lee et al., 2003; Ryugo et al., 1997; Seal et al., 2008; Youssoufian et al., 2008), but it is likely that there was death that caused the shrinkage. The topographic organization of auditory nerve axons and those intrinsic within the cochlear nucleus are well organized in the deaf otoferlin mice as compared to normal-hearing mice (Wright et al., 2014), indicating that at least in the cochlear nucleus of mice, the gross topographic organization develops independently of activity before and after the onset of hearing. In contrast, studies of neonatal deafness in cats (Leake et al., 2006), together with findings in the superior olivary complex using acetylcholine receptor α9 knockout mice (Clause et al., 2014), argue that the precise temporal pattern of spontaneous activity before hearing onset is crucial for establishment of precise tonotopy.

Hearing loss mainly occurs in adulthood and during aging, with the exception of nonsyndromic deafness. The following sections focus on the structural and molecular effects of hearing loss in animal models when synaptic circuitries in the cochlear nucleus are mature as well as during ageing.

Hearing Loss: Structural and Molecular Presynaptic Effects in the Cochlear Nucleus

Hearing loss after the onset of hearing leads to a decrease in the number of afferent synapses on inner hair cells, which alters auditory transmission from the inner ear to the cochlear nucleus. The auditory nerve makes synaptic contact on principal neurons of the VCN, including bushy, stellate, and octopus cells. In the DCN, the auditory nerve innervates fusiform and multipolar cells (Figure 1). The synapse of the auditory nerve on principal neurons is a secure and strong glutamatergic synapse. For these reasons and in contrast to excitatory synapses in other parts of the central nervous system, auditory nerve synapses lack the classical activity-dependent synaptic plasticity mechanisms (Fujino & Oertel, 2003; Zhao et al., 2011). This raises the question of whether mature auditory nerve synapses are able to adapt to changes in auditory experience. Studies have reported structural and molecular changes at auditory nerve endings in response to hearing loss. The effects are considered a response to a decrease in auditory nerve activity, although it is unclear whether the response of cochlear nucleus neurons is compensatory or pathological.

The first evidence of the existence of structural plasticity at auditory nerve synapses was reported in studies from congenital deaf white cats and mice (Baker et al., 2010; Redd et al., 2002; Ryugo et al., 2005; O’Neil et al., 2010) and more recently from otoferlin knockout mice (Wright et al., 2014). Although in these studies it is not easy to distinguish developmental effects from those that occur at a later age, they did show that in congenital deafness the auditory nerve terminals including the endbulb of Held in the VCN shrunk. Moreover, after cochlear implant and electrical stimulation of 3-month-old white deaf cats for 3 months, the size of the endbulbs recovers (Ryugo et al., 2005; O’Neil et al., 2010), thus suggesting that auditory nerve activity maintains the size of endbulb terminals. These results may have clinical relevance because they suggest that reestablishing auditory nerve activity after prolonged deafness may restore the presynaptic terminal of the auditory nerve, which may lead to a recovery of function. However, it remains unclear whether the smaller size of endbulb endings of congenital deaf animals is totally or partially due to developmental effects or to a lack of synaptic activity of the auditory nerve at more mature stages. A decrease in size of endbulb endings was also observed in animal models with an early onset of hearing loss and during aging (Frisina & Walton, 2006; McGuire et al., 2015; Connelly et al., 2017). On the other hand, a decrease in size of endbulb endings was not observed in rodents when hearing loss occurs after hearing onset and in response to milder forms of hearing loss such as conductive hearing loss (Clarkson et al., 2016).

Few studies have addressed the molecular changes of auditory nerve endings following hearing loss. Studies focused on determining changes in excitatory (glutamate) neurotransmitters in the cochlear nucleus after cochlear ablation or after middle ear ossicle removal in rodents (Godfrey et al., 2015; Suneja et al., 1998). The auditory nerve is a glutamatergic synapse, thus the general thought was that finding a decrease or increase in glutamate concentration could reflect a change in the demands for synaptic transmission at the auditory nerve in response to cochlear deafferentation and hearing loss. In general, these biochemical studies showed a decrease in glutamate concentration in the cochlear nucleus. If glutamate was located exclusively at synaptic auditory nerve endings, the most logical conclusion from these studies would be that an intact cochlea is needed to maintain normal levels of glutamate at auditory nerve endings. However, there are intrinsic (i.e., parallel fibers from the granule cells) as well as other extrinsic (i.e., mossy fibers from somatosensory origin) inputs within the cochlear nucleus where synaptic endings contain and release glutamate (Gómez-Nieto & Rubio, 2009; Manis, 1989; Rubio & Juiz, 1998, 2004; Rubio et al., 2008). In addition, glutamate is an amino acid that is widely expressed in all-neuronal types (excitatory and inhibitory), as well as in glial cells (Zhou & Danbolt, 2014). Therefore, a decrease in glutamate may not directly reflect a decrease of glutamate concentration in auditory nerve terminals.

More recent studies used other markers for glutamate release such as vesicular glutamate transporters 1 and/or 2 (vGluT1, vGluT2), which fill synaptic vesicles with glutamate (Takamori et al., 2002; Weston et al., 2011). Mature auditory nerve endings contain only vGluT1 (Zhou et al., 2007; Gómez-Nieto & Rubio, 2009; Fyk-Kolodziej et al., 2011). Following reports in the brain (Erickson et al., 2006; Liguz-Lecznar & Skangiel-Kramska, 2007), vGluT1 expression levels could reflect the average presynaptic activity of auditory nerve endings. Evidence has shown that deafening after peripheral damage or kanamycin injection, the expression levels of vGluT1 at auditory nerve endings decreased when compared to non-deafened animals (Fyk-Kolodziej et al., 2011; Zeng et al., 2009). A similar decrease was also observed in milder forms of hearing loss such as unilateral and bilateral conductive hearing loss (Clarkson et al., 2016; Zhuang et al., 2017). Ultrastructurally, the decrease in vGluT1 expression correlated with a decrease in synaptic vesicle size and volume but not in the surface area of auditory nerve terminals, thus indicating that conductive hearing loss reduces the number of glutamate molecules per synaptic vesicle, which is likely to lead to a decrease in vesicular glutamate release (Clarkson et al., 2016; Herman et al., 2014). However, other studies investigating the effects of hearing loss on auditory nerve synapses in the cochlear nucleus reported contradictory results. For example, one study found an increase in vGluT1 expression levels (Ngodup et al., 2015), while in another study from a different research group, a decrease in vGluT1 expression was observed (Kurioka et al., 2016). In both studies, a broadband noise was used to inflict cochlear damage, so it is unclear whether the difference in these results is due to the duration of the noise exposure, the different strain or age of mice, and/or the time of analysis after noise exposure. A decrease in vGluT1 expression in the cochlear nucleus was also reported after acoustic overstimulation (Barker et al., 2012). Morphological results from various laboratories suggest either up- or down-regulation of glutamate release, which may reflect that the auditory nerve reacts differently to various forms of deafening. Further functional studies are needed to determine whether the changes in vGluT1 expression at auditory nerve endings in response to hearing loss correlate with physiological responses at the synapse.

Contrary to the auditory nerve endings and the endings of the parallel fibers of the granule cells, the extrinsic glutamatergic inputs from somatosensory origin within the cochlear nucleus contains vGluT2 (Zhou et al., 2007). Remarkably, after cochlear deafferentation or noise-induced hearing loss, vGluT2 expression levels increases in the GCD region (Barker et al., 2012; Zeng et al., 2009). What triggers this upregulation of vGluT2, together with its functional consequences, remains to be determined. In the DCN, it is well established that fusiform cells integrate auditory information through its basal dendrites and somatosensory information through its apical dendrites via the granule cells within the GCD (Fujino & Oertel, 2003; Kanold et al., 2011). Neural hyperactivity is induced in fusiform cells of the DCN following intense sound exposure. Researchers suggest that fusiform cells may be implicated as major generators of noise-induced tinnitus (see for review, Kaltenbach, 2007; Wu et al., 2016). Furthermore, new evidence shows that somatosensory signals influence auditory processing in the VCN. This appears to occur in the GCD, the major target region of somatosensory inputs and type II auditory nerve fibers, and also within the core, where collaterals of somatosensory axons distribute on principal neurons receiving Type I cochlear afferents (Heeringa et al., 2018). To understand the putative convergence of cochlear and somatosensory information within the GCD and the core of the VCN requires a better understanding of the role of the GCD in auditory processing. In addition, it requires the identification of the neuronal targets and the role of Type II unmyelinated auditory nerve fibers within the VCN, as well as determining the subset of principal neurons that receive both cochlear and somatosensory inputs. This convergence of auditory and somatosensory inputs in the VCN is of relevance, considering new evidence in animal models after noise exposure (Heeringa et al., 2018; Vogler et al., 2011) and clinical studies in humans (Gu et al., 2012) indicating that in addition to the DCN, the VCN is involved in the genesis of tinnitus.

Hearing loss has been suggested to unbalance the ratio of excitation and inhibition in the cochlear nucleus and along the auditory pathway. However, contrary to the glutamatergic synapses, we know less of the molecular and structural effects of hearing loss in presynaptic inhibitory endings. Biochemical and immunohistochemical studies after peripheral damage focused on investigating the effects of hearing loss in glycine and GABA (gamma-amino-butyric-acid) neurotransmitter content in the cochlear nucleus of the same side (Lee & Godfrey, 2014; Suneja et al., 1998). These studies showed a decrease in glycine but not in GABA concentration. Further studies need to focus in determining the structural and molecular effects of hearing loss in identified inhibitory inputs within the cochlear nucleus. It would be worthy to investigate whether hearing loss alters the expression levels of vesicular inhibitory neurotransmitter transporters, as a putative indication of changes in glycine release.

Hearing Loss: Structural and Molecular Postsynaptic Effects in the Cochlear Nucleus

In addition to presynaptic responses, studies in animals after deafening and with hearing loss have shown structural effects on the postsynaptic principal neurons within the VCN (bushy cells) and DCN (fusiform cells). Remarkably, these responses have been found in the same side of the deafening as well as in the contralateral side. The models of hearing loss used to study postsynaptic changes include congenital deafness, peripheral deafferentation, and conductive hearing loss. Structural and/or molecular responses of the other principal neurons of the cochlear nucleus (stellate and octopus cells in the VCN, and multipolar cells in the DCN) have not been performed.

Ultrastructural studies of congenitally deaf white cats and mice showed hypertrophy of the postsynaptic density (PSD) of bushy cells in apposition to auditory nerve endings (Lee et al. 2003; Redd et al., 2000; Ryugo et al. 1997). Interestingly, after cochlear implant and electrical stimulation for 3 months, the hypertrophy reversed and the postsynaptic densities were similar to those of normal-hearing cats (Ryugo et al. 2005; O’Neil et al. 2010). Deafening can have fast-acting consequences. After only 4 hours of peripheral deafening and before visible structural signs of degeneration at auditory nerve endings and synapses, the PSD of fusiform cells basal dendrites apposed to auditory nerve endings becomes thicker (Rubio, 2006). This, together with others reports in other systems (see for review Dosemeci et al., 2016) suggest that the PSD is a highly plastic structure strongly influenced by presynaptic activity (Gulley et al., 1977; Dosemeci et al., 2001). Biochemical binding studies have shown that the absence of auditory nerve inputs affects the amount and activity of glutamate receptors in the cochlear nucleus (Suneja et al., 2000). In addition, in vitro electrophysiological recordings reported larger excitatory postsynaptic current (EPSC) amplitude in bushy cells of congenitally deaf mice than in those with normal-hearing (Oleskevich & Walmsley, 2002). These two lines of evidence suggest, that the number and/or subunit composition of glutamate receptors at the auditory nerve synapse is altered in response to peripheral damage or congenital deafening. After peripheral damage and before subcellular signs of degeneration, one ultrastructural study showed that at the synapse of auditory nerve on fusiform cells basal dendrites, there was a redistribution of the GluA2, GluA3 and GluA4 subunits of the AMPA glutamate receptors (Rubio, 2006). Although these results are remarkable and suggest a fast response of the postsynaptic neurons to hearing loss, these effects in AMPA receptors expression were observed after peripheral cochlear damage. In this situation, it is difficult to separate the effects of damaging the nerve from those related to a decrease in the sensory input.

Milder forms of hearing loss also affect principal neurons receiving auditory nerve synapses. Sound reduction by unilateral conductive hearing loss (ossicle removal) alters the neuronal metabolic rates and protein synthesis in principal neurons of the ipsilateral VCN (Tucci et al., 1999; Huston et al., 2007). Transient unilateral conductive hearing loss (ear plugging) for one day led to a reversible increase in hearing thresholds and to reversible synaptic up-regulation of GluA3 AMPA receptors at the synapse of the auditory nerve on bushy cells in the VCN and fusiform cells in the DCN. The same neurons showed a down regulation of the α1 subunit of the glycine receptor (GlyR α1) at inhibitory synapses that also reversed once hearing levels were restored (Whiting et al., 2009), suggesting the existence of a homeostatic response to compensate for reduced acoustic stimulation. Longer periods (more than one week) of transient conductive hearing loss by unilateral ear plugging altered the cytoplasmic receptor pool of excitatory and inhibitory receptors in those same neuronal types (Wang et al., 2011). This study showed an increase in the expression of the GluA3 subunit of the AMPA receptors, and a decrease in the GlyR α1 subunit on the cell bodies of bushy cells and fusiform cells of the ipsilateral ventral and dorsal cochlear nucleus, respectively. On the other hand, the cytoplasmic expression levels of GABAA β2/3 subunits were unchanged (Wang et al., 2011). This up-regulation of GluA3 and down-regulation of GlyR α1 observed at the cell bodies, is similar to the synaptic changes mentioned previously after one-day ear plugging (Whiting et al., 2009). At the synaptic level, unilateral ear plugging for more than one week showed long lasting post-synaptic structural and molecular effects at the endbulb of the Held synapse, including larger postsynaptic densities and a sustained up-regulation of synaptic GluA3 (Clarkson et al., 2016). The same study showed that conductive hearing loss led to an increase in the central gain upstream the cochlear nucleus at level of the lateral lemniscus. This suggests that upper auditory nuclei compensate for the decrease signal from the cochlear nucleus. All together, these findings show that sensory dependent evoked plasticity is more complex than what might be predicted from experiments in reduced systems such as neuronal cultured cells or brain slices (see for review, Turrigiano, 2011). Future studies could investigate in the adult, long-term hearing sensitivities following conductive hearing loss, which is prevalent in children. Such studies will settle the central mechanisms of deficits in auditory perception, language acquisition or educational disabilities that occur after inadequate or abnormal sensory experience.

Hearing Loss Effects in the Contralateral Side

Reports exist of molecular effects of conductive hearing loss in neurons of the cochlear nucleus of the contralateral side to the affected ear. In particular, contralateral neurons of the cochlear nucleus have increased metabolic rates and protein synthesis (Hutson et al., 2007; Tucci et al., 1999). In addition, by immunohistochemistry at the light and electron microscopy level it has been reported that conductive hearing loss alters synaptic proteins. Bushy cells and fusiform cells of the contralateral side up-regulate the GluA3 subunits of AMPA receptors while they down-regulate the GlyRα1 in response unilateral conductive hearing loss (Wang et al., 2011; Whiting et al., 2009,), changes similar to what has been observed in the ipsilateral cochlear nucleus (Wang et al., 2011; Whiting et al., 2009). The pathways by which changes in neuronal activity in one cochlear nucleus influence activity in the other cochlear nucleus is still an open question. The cochlear nucleus complex is the first site at which binaural information converses in the CNS (for review, see Cant & Benson, 2003). Communication between cochlear nuclei can occur through glutamatergic and glycinergic commissural projections (Alibardi, 1998, 2000, 2003; Bledsoe et al., 2009; Shore et al., 2003) or via descending inputs from upper auditory nuclei, particularly descending cholinergic inputs (Darrow et al., 2006; Liberman & Brown, 1986; Spangler et al., 1987; Shore et al., 1991; Warren & Liberman, 1989a, b). Functional connections between the cochlear nuclei have been also shown (Davis, 2005; Ingham et al., 2006; Needham & Paolini, 2006; Shore et al., 2003; Sumner et al., 2005). Thus, unilateral conductive hearing loss could create an imbalance in the neuronal synaptic circuitry of the contralateral cochlear nucleus through two pathways—the commissural fibers and descending cholinergic inputs. More efforts are needed to determine the contribution of each pathway in normal hearing and in response to hearing loss.

Age-Related Hearing Loss: Structural and Molecular Changes

Prebycussis (age-related-hearing loss) is a widespread communication disorder and chronic medical condition in our aged population. Relatively few studies have examined age-related structural and molecular changes in the cochlear nucleus. The neurophysiological studies are very few and suggest a decline in glutamate and glycine-mediated excitation and inhibition, respectively (see for details chapter 6 by Manis in this volume). Biochemical studies of glycine inhibition in the cochlear nucleus are consistent with age-related functional declines of this neurotransmitter system that affect complex sound processing (Mildbrandt & Caspary, 1995). Biochemical studies investigating the effect of aging in glutamatergic synapses are also lacking.

Gross Morphological and Structural Changes during Aging

Studies investigating a population of young, middle, and old C57BL/J6 (C57) and CBA/CaJ (CBA) mice revealed changes in the dimensions and volumes of the AVCN as well as the number, density, and size of neurons (Frisina & Walton, 2006; Willot et al., 1987). The idea was to compare these parameters in a mouse strain with an early onset of hearing loss (C57) with those of CBA mice that have a “normal” age-induced hearing loss. The authors found that AVCN volumes did not change significantly with age in either strain. However, neuron number and density declined in C57s during the first 7 months, but they remained stable thereafter. In CBAs, reductions in neuron number and packing were not observed until the second year. Changes in neuronal sizes were observed but varied depending on the neuronal type and strain. Aging affected principally the caudal (high-frequency) area of the AVCN. DBA mice exhibit similar changes as C57s even if this strain exhibits a congenital accelerated, high-frequency cochlear hearing loss occurring at a rate even faster than C57s. Ultrastructurally, principal neurons in the AVCN (bushy cells and multipolar cells) displayed an increase in the incidence of heterochromatic nuclei and in the percentage of the soma occupied by lipofuscin, indicating an aging process (Briner & Willott, 1989). Additionally, multipolar cells showed a decrease in roundness and an increase in the number of nuclear invaginations. The PVCN, the area of octopus cells, decreased in overall volume, number of octopus cells, neuron size, and dendrite number and size. Interestingly, there was an increase in glial cell density. In the DCN of C57s and CBA mice, and unlike the AVCN, the nucleus volume, cell number, and size declined with age for C57s, particularly in deep layers. In CBA mice, the volume of the DCN increased in the first years and declined in old age. Taken together, these studies show that in aged mice the VCN is more affected than DCN, perhaps because the VCN has a higher proportion of direct inputs from the cochlea than the DCN, and the cochlear inputs show declines with age, especially in C57 mice due to their early onset of hearing loss.

Molecular Changes during Aging

Previous research has shown that the rat cochlear nucleus undergoes several molecular changes during aging. There are significant reductions in the levels of glutamate and glycine, without similar changes in the level of GABA (Banay-Schwartz et al., 1989a,b). GABA or any enzyme or protein involved in the synthesis of GABA remained stable with age in the cochlear nucleus. Biochemical studies showed a decline in glycine receptor binding in DCN and VCN of aged Fisher-344 rats (Milbrandt & Caspary, 1995); the decrease was due to an age-related decline in the number of binding sites, with little change in affinity. mRNA studies showed that GlyR α1 and β1 declined in AVCN of old rats, while subunit GlyR α2 increased (Krenning et al., 1998). The results from the rat DCN were confirmed in old C57, but not in middle age C57 or old CBA mice (Willott et al., 1997). Further studies are needed to tease apart the effects of species, hearing loss, and age and their impact in the cochlear nucleus regions.

Ultrastructural Synaptic Changes during Aging and in Mouse Models with an Early Onset of Hearing Loss

Only few studies determined how aging affects the number and ultrastructure of synapses in the cochlear nucleus (Fisher-344 rats: Helfert et al., 2003; CBA/Ca, heterozygous shaker-2+/-, homozygous shaker-2-/-, and DBA/2 mice: Connelly et al., 2017; DBA/J2 mice: McGuire et al., 2015). All these studies focused on the AVCN, where no synapse losses were observed in either rats or mice. This is in contrast with a dramatic degeneration of synaptic endings and dendrites in the inferior colliculus (Helfert et al., 1999). In rat AVCN, a decrease in size of synaptic endings of putative inhibitory and excitatory inputs was observed on dendrites that were < 2 μm in diameter (Helfert et al., 2003). The studies in mice investigated ultrastructural changes in the glutamatergic synapses of the auditory nerve (endbulb of Held) on bushy cells. Apart from a decrease in size of the endbulbs of mice with early onset of hearing loss (DBA/J2 and shaker-2-/-mice), no dramatic ultrastructural changes were observed in the mitochondria fraction and postsynaptic density size (Connelly et al., 2017; McGuire et al., 2015). The reduction in the neurotransmitter glutamate and glycine found in aged rodents surprisingly contrast with no major ultrastructural changes at endbulb synapses on bushy cell bodies or putative glycinergic endings on dendrites. Synaptic replacement may occur during aging through the collaterization by neighboring axons or endings; these new endings may be smaller in size and could therefore contain less neurotransmitter. Alternatively, synaptic vesicles could be smaller, and/or the expression of presynaptic calcium channels could decrease during aging. Additional anatomical, molecular, and functional studies are needed to elucidate the presynaptic and postsynaptic cellular mechanisms underlying the age-related changes in the AVCN, as well the other regions of the cochlear nucleus.

Protective Mechanisms in the Cochlear Nucleus to Hearing Loss via Descending Inputs

There is increasing interest in determining whether the descending projections to the cochlear nucleus have a protective role in response to hearing loss (Kirk & Smith, 2003; Reiter & Liberman, 1995). In contrast to the ascending auditory pathway, less is known about the anatomy and function of the descending auditory pathways in the normal-hearing and in the hearing impaired. Immunohistochemical studies one week after cochlear ablation showed a massive increase in growth-associated protein 43 (GAP-43) expression levels in the VCN of the side of the lesion. GAP-43 immunoreactivity was found in axons and synaptic endings that made synaptic contacts with glutamatergic and glycinergic neurons. These endings had their origin in the contralateral ventral superior olive (VSO) in the lower brainstem (Hildebrandt et al., 2011; Illing & Resich, 2006; Meidinger et al., 2006). Neurons in the VSO, including the medial olivocochlear neurons, employ acetylcholine as a neurotransmitter (Vetter et al., 1991; Yao & Godfrey, 1996). Studies after noise-induced hearing loss have also reported that over time (8 months) after noise exposure, auditory nerve synapses degenerate, but in addition there is rewiring of the VCN synaptic circuitry (Kim et al. 2004). It is still undetermined what this rewiring means in terms of VCN function, and whether this rewiring correlates with new cholinergic endings from the VSO or other descending inputs from upper auditory nuclei.


Normal auditory nerve activity is key for maintaining fundamental structural, molecular, and functional parameters of auditory nerve synapses, as well as the postsynaptic excitatory or inhibitory neurons within the cochlear nucleus, and that hearing deficits alter those parameters. The studies summarized in this in chapter show that there are multiple ways through which neurons in the cochlear nucleus respond to fluctuations in their inputs and that probably these responses relate to the etiology of hearing loss. Studies of different models of hearing loss are necessary to underpin the cellular mechanisms, as well as determining common features, that will help us to understand whether the synaptic modifications compensate for the hearing deficits or represent pathological responses to hearing loss. However, it is also important to study the same model of hearing loss by a variety of approaches. Most of the anatomical and molecular studies are performed in mature animals, whereas most of the in vitro electrophysiological studies have been performed at early ages. For this reason, anatomical and molecular studies lack functional studies and, vice versa electrophysiological studies lack of anatomical and molecular verification. Progress of the field would thus profit from closer interactions between anatomists, electrophysiologists, and molecular biologists.


Support was provided by the National Institute for Deafness and Other Communication Disorders (grant DC013048).

Author Note

Maria E. Rubio declares that she has no conflict of interest.


Alibardi, L. (1998). Ultrastructural and immunocytochemical characterization of commissural neurons in the ventral cochlear nucleus of the rat. Annals of Anatomy, 180(5), 427–438.Find this resource:

Alibardi, L. (2000). Cytology, synaptology and immunocytochemistry of commissural neurons and their putative axonal terminals in the dorsal cochlear nucleus of the rat. Annals of Anatomy, 182, 207–220.Find this resource:

Alibardi, L. (2003). Ultrastructural immunocytochemistry for glycine in neurons of the dorsal cochlear nucleus of the guinea pig. Journal of Submicroscopy Biology, 5(4), 373–387.Find this resource:

Baker, C. A., Montey, K. L., Pongstapom, T., & Ryugo, D. K. (2010). Postnatal development of the endbulb of Held in congenitally deaf cats. Frontiers in Neuroanatomy, 4, 19.Find this resource:

Banay-Schwartz, M., Lajhta, A., & Palovits, M. (1989a). Changes with aging in the levels of amino acids in rat CNS structural elements I. Glutamate and related amino acids. Neurochemical Research, 14, 555–562.Find this resource:

Banay-Schwartz, M., Lajhta, A., & Palovits, M. (1989b). Changes with aging in the levels of amino acids in rat CNS structural elements. II. Taurine and small neutral amino acids. Neurochemical Research, 14, 563–570.Find this resource:

Barker, M., Solinski, H. J., Hashimoto, H., Tagoe, T., Pilati, N., & Hamann, M. H. (2012). Acoustic overexposure increases the expression of VGLUT-2 mediated projections from the lateral vestibular nucleus to the dorsal cochlear nucleus. PlosOne, this resource:

Benson, T. E., & Brown, M. C. (2004). Postsynaptic targets of type II auditory nerve fibers in the cochlear nucleus. Journal of the Association for Research in Otolaryngology, 5(2), 111–125.Find this resource:

Bledsoe, S. C., Jr., Koehler, S., Tucci, D. L., Zhou, J., Le Prell, C., & Shore, S. E. (2009). Ventral cochlear nucleus responses to contralateral sound are mediated by commissural and olivocochlear pathways. Journal of Neurophysiology, 102(2), 886–900.Find this resource:

Briner W., & Willott J. F. (1989). Ultrastructural features of neurons in the C57BL/6J mouse anteroventral cochlear nucleus: Young mice versus old mice with chronic presbycusis. Neurobiology of Aging, 10(4), 295–303.Find this resource:

Brown, M. C., Berglund, A. M., Kiang, N. Y., & Ryugo, D. K. (1988a). Central trajectories of type II spiral ganglion neurons. Journal of Comparative Neurology, 278(4), 581–590.Find this resource:

Brown, M. C., Liberman, M. C., Benson T. E., & Ryugo, D. K. (1988b). Brainstem branches from olivocochlear axons in cats and rodents. Journal of Comparative Neurology, 278(4), 591–603.Find this resource:

Burian, M., & Goesttner, W. (1988). Projection of primary vestibular afferent fibres to the cochlear nucleus in the guinea pig. Neuroscience Letters, 84(1), 13–17.Find this resource:

Caicedo, A., & Herbert, H. (1993). Topography of descending projections from the inferior colliculus to auditory brainstem nuclei in the rat. Journal of Comparative Neurology, 328(3), 377–392.Find this resource:

Campos Torres, A., Vidal, P. P., & de Waele, C. (1999). Evidence for microglial reaction within the vestibular and cochlear nuclei following inner ear lesion in the rat. Neuroscience, 92, 1475–1490.Find this resource:

Cant, N. B. (1992). The cochlear nucleus: Neural types and their synaptic organization. In D. B. Webster, A. N. Popper, & R. R. Fay (Eds.), The mammalian auditory pathway: Neuroanatomy (pp.66–116). New York, NY: Springer.Find this resource:

Cant, N. B., & Benson, C. G. (2003). Parallel auditory pathways: Projection patterns of the different neuronal populations in the dorsal and ventral cochlear nuclei. Brain Research Bulletin, 60(5–6), 457–474.Find this resource:

Clarkson, C., Antunes, F., Rubio, M. E. (2016). Conductive hearing loss has long-lasting structural and molecular effects on pre- and post-synaptic structures of the auditory nerve in the cochlear nucleus. Journal of Neuroscience, 36(39), 10214–10227.Find this resource:

Clause, A., Kim, G., Sonntag, M., Weisz, C. J. C., Vetter, D. E., Rübsamen, R., & Kandler, K. (2014). The precise temporal pattern of prehearing spontaneous activity is necessary for tonotopic map refinement. Neuron, 82, 822–835.Find this resource:

Connelly, C. J., Ryugo, D. K., & Muniak, M. A. (2017). The effect of progressive hearing loss on the morphology of endbulbs of Held and bushy cells. Hearing Research, 343, 14–33.Find this resource:

Darrow, K. N., Maison, S. F., & Liberman, M.C. (2006). Cochlear efferent feedback balances interaural sensitivity. Nature Neuroscience, 9(12), 1474–1476.Find this resource:

Davis, K. A. (2005). Contralateral effects and binaural interactions in dorsal cochlear nucleus. Journal of the Association in Research in Otolaryngology, 6, 280–296.Find this resource:

Dosemeci, A., Tao-Cheng, J. H., Vinade, L., Winters, C. A., Pozzo-Miller, L., & Reese, T. S. (2001). Glutamate-induced transient modification of the postsynaptic density. Proceedings National Academy Sciences U S A, 98(18), 10428–10432.Find this resource:

Dosemeci, A., Weinberg, R. J., Reese, T. S., & Tao-Cheng, J-H. (2016) The postsynaptic density: There is more than meets the eye. Frontiers in Synaptic Neuroscience, 8, 23.Find this resource:

Erickson J. D., De Gois S., Varoqui H., Schafer M. K., & Weihe, E. (2006). Activity-dependent regulation of vesicular glutamate and GABA transporters: A means to scale quantal size. Neurochemistry International, 48(6–7), 643–649. Review.Find this resource:

Frisina, R. D., & Walton, J. P. (2006). Age-related structural and functional changes in the cochlear nucleus. Hearing Research, 216217, 216–223.Find this resource:

Fujino, K., & Oertel, D. (2003). Bidirectional synaptic plasticity in the cerebellum-like mammalian dorsal cochlear nucleus. Proceedings of the National Academy of Sciences of the United States of America, 100(1), 265–270.Find this resource:

Fyk-Kolodziej, B., Shimano, T., Gong, T. W., & Holt, A. G. (2011). Vesicular glutamate transporters: Spatio-temporal plasticity following hearing loss. Neuroscience, 178, 218–239.Find this resource:

Gómez-Nieto, R., Rubio, & M. E. (2009). A bushy cell network in the rat ventral cochlear nucleus. Journal of Comparative Neurology, 516(4), 241–263.Find this resource:

Godfrey, D. A., Chen, K., Godfrey, M. A., Lee, A. C., Crass, S. P., Shipp, D., Simo, H., & Robinson, K. T. (2015). Cochlear ablation effects on amino acid levels in the chinchilla cochlear nucleus. Neuroscience, 297, 137–159.Find this resource:

Gu, J. W., Hermann, B. S., Levine, R. A., & Melcher, J. R. (2012). Brainstem auditory evoked potentials suggest a role for the ventral cochlear nucleus in tinnitus. Journal of the Association for Research in Otolaryngology, 13(6), 819–833.Find this resource:

Gulley, R. L., Wenthold, R. J., Neises, G. R. (1977). Remodeling of neuronal membranes as an early response to deafferentation. A freeze-fracture study. Journal Cell Biology, 75(3), 837–850.Find this resource:

Haenggeli, C. A., Pongstaporn, T., Doucet, J. R., & Ryugo, D. K. (2005). Projections from the spinal trigeminal nucleus to the cochlear nucleus in the rat. Journal of Comparative Neurology, 484(2), 191–205.Find this resource:

Harris, J. A., Hardie, N. A., Bermingham-McDonogh, O., & Rubel, E. W. (2005). Gene expression differences over a critical period of afferent-dependent neuron survival in the mouse auditory brainstem. Journal of Comparative Neurology, 491, 460–474.Find this resource:

Harris, J. A., & Rubel, E. W. (2006). Afferent regulation of neuron number in the cochlear nucleus: Cellular and molecular analysis of a critical period. Hearing Research, 2162017, 127–137.Find this resource:

Heeringa, A. N., Wu, W., & Shore, S. E. (2018). Multisensory integration enhances temporal coding in the ventral cochlear nucleus. Journal of Neuroscience, 38(11), 2832–2843.Find this resource:

Herman, M. A., Ackermann, F., Trimbuch, T., & Rossenmund, C. (2014). Vesicular glutamate transporter expression levels affects synaptic release probability at hippocampal synapses in culture. Journal of Neuroscience, 34(35), 11781–11791.Find this resource:

Helfert, R. H., Krenning, J., Wilson, T. S., & Hughes, L. F. (2003). Age-related synaptic changes in the anteroventral cochlear nucleus of Fisher-344 rats. Hearing Research, 183, 18–28.Find this resource:

Helfert, R. H., Sommer, T. J., Meeks, J., Hofstetter, P., & Hughes, L. F. (1999). Age-related synaptic changes in the central nucleus of the inferior colliculus of the Fisher-344 rat. Journal of Comparative Neurology, 406, 285–298.Find this resource:

Hildebrandt, H., Hoffmann, N. A., & Illing, R. B. (2011). Synaptic reorganization in the adult rat’s ventral cochlear nucleus following its total sensory deafferentation. PlosOne, 6(8), e23686.Find this resource:

Hutson, K. A., Durham, D., & Tucci, D. L. (2007). Consequences of unilateral hearing loss: Time dependent regulation of protein synthesis in auditory brainstem nuclei. Hearing Research, 233(1–2), 124–134.Find this resource:

Illing R. B., & Resich, A. (2006). Specific plasticity responses to unilaterally decreased or increased hearing intensity in the adult cochlear nucleus and beyond. Hearing Research, 216217, 189–197.Find this resource:

Ingham, N. J., Bleeck, S., & Winter, I. M. (2006). Contralateral inhibitory and excitatory frequency response maps in the mammalian cochlear nucleus. European Journal of Neuroscience, 24, 2515–2529.Find this resource:

Itoh, K., Kamiya, H., Mitani, A., & Yasui, Y. (1987). Direct projections from the dorsal column nuclei and the spinal trigeminal nuclei to the cochlear nuclei in the cat. Brain Research, 400(1), 145–150.Find this resource:

Kaltenbach, J. A. (2007). The dorsal cochlear nucleus as a contributor to tinnitus: Mechanisms underlying the induction of hyperactivity. Progress in Brain Research, 166, 89–106.Find this resource:

Kanold, P., Davis, K. A., & Young, E. (2011). Somatosensory context alters auditory responses in the cochlear nucleus. Journal of Neurophysiology, 105(3): 1063–1070.Find this resource:

Kevetter, G. A., & Parachio, A. A. (1989). Projections from the saccules to the cochlear nuclei in the Mongolian gerbil. Brain, Behavior and Evolution, 34(4), 193–200.Find this resource:

Kim, J. J., Gross, S. J., Potashner, S. J., & Morest, D. K. (2004). Fine structure of long-term changes in the cochlear nucleus after acoustic overstimulation: Chronic degeneration and new growth of synaptic endings. Journal of Neuroscience Research, 77(6), 817–828.Find this resource:

Kirk, E. C., & Smith, D. W. (2003). Protection from acoustic trauma is not a primary function of the medial olivocochlear efferent system. Journal of the Association for Research in Otolaryngology, 4, 445–465.Find this resource:

Krenning, J., Hughes, L. F., Caspary, D. M., & Helfert, R. H. (1998). Age-related glycine receptor subunit changed in the cochlear nucleus of Fisher-344 rats. Laryngoscope, 108, 26–31.Find this resource:

Kurioka, T., Lee, M. Y., Heeringa, A. N., Beyer, L. A., Swiderski, D. L., Kanicki, A. C., … Raphael, Y. (2016). Selective hair cell ablation and noise exposure lead to different patterns of changes in the cochlea and the cochlear nucleus. Neuroscience, 332, 242–257.Find this resource:

Leake, P. A., Hradek, G. T., Chair, L., & Snyder, R. L. (2006). Neonatal deafness results in degraded topographic specificity of auditory nerve projections to the cochlear nucleus in cats. Journal of Comparative Neurology, 497(1), 13–31.Find this resource:

Lee, A. C., Godfrey, D. A. (2014). Cochlear damage affects neurotransmitter chemistry in the central auditory system. Frontiers in Neurology, 5, 227. doi: 10.3389/fneur.2014.00227Find this resource:

Lee, D. J., Cahill, H. B., & Ryugo, D. K. (2003). Effects of congenital deafness in the cochlear nuclei of Shaker-2 mice: An ultrastructural analysis of synapse morphology in the endbulbs of Held. Journal of Neurocytology, 32(3), 229–243.Find this resource:

Liberman, M. C. (1991). Central projections of auditory-nerve fibers of differing spontaneous rate. I. Anteroventral cochlear nucleus. The Journal of Comparative Neurology, 313(2), 240–258.Find this resource:

Liberman, M. C., & Brown, C. (1986). Physiology and anatomy of single olivocochlear neurons in the cat. Hearing Research, 24(1), 17–36.Find this resource:

Liguz-Lecznar M., & Skangiel-Kramska J. (2007). Vesicular glutamate transporters (VGLUTs): The three musketeers of glutamatergic system. Acta Neurobiologiae Experimentalis 67(3):207–218. Review.Find this resource:

Lorente de Nó, R. (1981). The primary acoustic nuclei. New York, NY: Raven Press.Find this resource:

Manis, P. B. (1989). Responses to parallel fiber stimulation in the guinea pig dorsal cochlear nucleus in vitro. Journal of Neurophysiology, 61, 149–161.Find this resource:

McGuire, B., Fiorillo B., Ryugo, D. K., & Lauer, A. M. (2015). Auditory nerve synapses persist in ventral cochlear nucleus after loss of acoustic input in mice with early-onset progressive hearing loss. Brain Research, 1605, 22–30.Find this resource:

Meidinger, M. A., Hidebrandt-Schoenfeld, H., & Illing R. B. (2006). Cochlear damage induces GAP-43 expression in cholinergic synapses of the cochlear nucleus in the adult rat: a light and electron micriscipy study. European Journal of Neuroscience, 23, 3187–3199.Find this resource:

Meltzer, N. E., & Ryugo, D. K. (2006). Projections from auditory cortex to cochlear nucleus: A comparative analysis of rat and mouse. The Anatomical Record. Discoveries in Molecular Cellular Evolutionary Biology, 288, 397–408.Find this resource:

Milbrandt, J. C., & Caspary, D. M. (1995). Age-related reduction of [3H]strychnine binding sites in the cochlear nucleus of the Fisher 344 rat. Neuroscience, 67(3), 713–719.Find this resource:

Needham, K., & Paolini, A. G. (2006). Neural timing, inhibition and the nature of stellate cell interaction in the ventral cochlear nucleus. Hearing Research, 216, 31–42.Find this resource:

Ngodup, T., Goetz, J. A., McGuire, B. C., Sun, W., Lauer, A. M., & Xu-Friedman, M. A. (2015). Activity-dependent, homeostatic regulation of neurotransmitter release from auditory nerve fibers. Proceedings of the National Academy of Sciences USA, 112, 6479–6484.Find this resource:

Oleskevich, S., & Walmsley, B. (2002). Synaptic transmission in the auditory brainstem of normal and congenitally deaf mice. Journal of Physiology, 540(2), 447–455.Find this resource:

O’Neil, J. N., Limb, C. J., Baker, C. A., & Ryugo, D. K. (2010). Bilateral effects of unilateral cochlear implantation in congenitally deaf cats. Journal of Comparative Neurology, 518(12), 2382–23404.Find this resource:

Osen, K. K. (1969). Cytoarchitecture of the cochlear nuclei in the cat. Journal of Comparative Neurology, 136(4), 453–484.Find this resource:

Redd, E. E., Cahill, Pongstaporn, T., & Ryugo, D. K. (2002). The effects of congenital deafness on auditory nerve synapses: Type I and Type II multipolar cells in the anteroventral cochlear nucleus of cats. Journal of the Association for Research in Otolaryngology, 3, 403–417.Find this resource:

Redd, E. E., Pongstaporn, T., & Ryugo, D. K. (2000). The effects of congenital deafness on auditory nerve synapses and globular bushy cells in cats. Hearing Research, 147, 160–174.Find this resource:

Reiter, E. R., & Liberman, M. C. (1995). Efferent-mediated protection from acoustic overexposure: Relation to slow effects of olivocochlear stimulation. Journal of Neurophysiology, 73(2), 506–514.Find this resource:

Rubio, M. E. (2006). Redistribution of synaptic AMPA receptors at glutamatergic synapses in the dorsal cochlear nucleus as an early response to cochlear ablation in the rat. Hearing Research, 216217, 154–167.Find this resource:

Rubio, M. E. (2018). Microcircuits of the anteroventral cochlear nucleus. In D. L. Oliver et al. (Eds.), Springer handbook of auditory research. The mammalian auditory pathways (65, 41–71). New York, NY: Springer International Publishing AG 2018 41. this resource:

Rubio, M. E., Gudsnuk K. A., Smith Y., & Ryugo D. K. (2008). Revealing the molecular layer of the primate dorsal cochlear nucleus. Neuroscience, 154, 99–113.Find this resource:

Rubio, M. E., & Juiz, J. M. (1998). Chemical anatomy of excitatory endings in the dorsal cochlear nucleus: Synaptic distribution of aspartate amino-transferase, glutamate and zinc. Journal of Comparative Neurology, 399, 341–358.Find this resource:

Rubio, M. E., & Juiz, J. M. (2004). Differential distribution of synaptic endings containing glutamate, glycine, and GABA in the rat dorsal cochlear nucleus. Journal of Comparative Neurology, 477(3), 253–272.Find this resource:

Rubio, M. E., & Wenthold, R. J. (1997). Glutamate receptors are selectively targeted to postsynaptic sites in neurons. Neuron, 18(6), 939–950.Find this resource:

Ryugo, D. K. (2008). Projections of low spontaneous rate, high threshold auditory nerve fibers to the small cell cap of the cochlear nucleus in cats. Neuroscience, 154(1), 114–126.Find this resource:

Ryugo, D. K., Kretzmer, E. A., & Niparko, J. K. (2005). Restoration of auditory nerve synapses in cats by cochlear implants. Science, 310(5753), 1490–1492.Find this resource:

Ryugo, D. K., Pongstaporn, T., Huchton, D. M., & Niparko, J. K. (1997). Ultrastructural analysis of primary endings in deaf white cats: Morphologic alterations in endbulbs of Held. The Journal of Comparative Neurology, 385(2), 230–244.Find this resource:

Saldaña, E. (1993). Descending projections from the inferior colliculus to the cochlear nuclei in mammals. In M. A. Merchán, J. M. Juiz, D. A. Godfrey, & E. Mugnaini (Eds.), The mammalian cochlear nuclei: Organization and function (pp. 153–165). New York, NY: Plenum Publishing Corporation.Find this resource:

Seal, P. A., 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.Find this resource:

Shore, S. E., El Kashlan, H., & Lu, J. (2003). Effects of trigeminal ganglion stimulation on unit activity of ventral cochlear nucleus neurons. Neuroscience, 119, 1085–1101.Find this resource:

Shore, S. E., Helfert, R. H., Bledsoe, S. C. Jr., Altschuler, R. A., & Godfrey, D. A. (1991). Descending projections to the ventral and dorsal divisions of the cochlear nucleus in guinea pig. Hearing Research, 52, 255–268.Find this resource:

Shore, S. E., Vass, Z., Wys, N. L., & Altschuler, R. A. (2000). Trigeminal ganglion innervates the auditory brainstem. Journal of Comparative Neurology, 419(3), 271–285.Find this resource:

Spangler, K. M., Cant, N. B., Henkel, C.K., Farley, G.R., & Warr, W. B. (1987). Descending projections from the superior olivary complex to the cochlear nucleus of the cat. The Journal of Comparative Neurology, 259(3), 452–465.Find this resource:

Sumner, C. J., Tucci, D. L., & Shore, S. E. (2005). Responses of the ventral cochlear nucleus to contralateral sound following conductive hearing loss. Journal of Neurophysiology, 94, 4234–4343.Find this resource:

Suneja, S. K., Potashner, S. J., & Benson, C. G. (1998). Plastic changes in glycine and GABA release and uptake in adult brain stem auditory nuclei after unilateral middle ear ossicle removal and cochlear ablation. Experimental Neurology, 151, 273–288.Find this resource:

Suneja, S. K., Potashner, S. J., & Benson, C. G. (2000). AMPA receptor binding in adult guinea pig brain stem after unilateral ablation. Experimental Neurology, 165, 355–389.Find this resource:

Takamori, S., Malherbe, P., Broger, C., & Jahn, R. (2002). Molecular cloning and functional characterization of human vesicular glutamate transporter 3. EMBO Reports, 3(8), 798–803.Find this resource:

Tierney, T. S., Russell, F. A., & Moore, D. R. (1997). Susceptibility of developing cochlear nucleus neurons to deafferentation-induced death abruptly ends just before the onset of hearing. Journal of Comparative Neurology, 378, 295–306.Find this resource:

Trussell, L. O., & Oertel, D. (2018). Microcircuits of the dorsal cochlear nucleus. In D. L. Oliver et al. (Eds.), The mammalian auditory pathways, Springer handbook of auditory research (65, pp.73–99). New York, NY: Springer International Publishing AG 2018 41.Find this resource:

Tucci, D. L., Cant, N. B., & Durham, D. (1999). Conductive hearing loss results in a decrease in central auditory system activity in the young gerbil. Laryngoscope, 109(9), 1359–1371.Find this resource:

Turrigiano, G. (2011). Too many cooks? Intrinsic and synaptic homeostatic mechanisms in cortical circuit refinement. Annual Review in Neuroscience, 34, 89–103.Find this resource:

Vetter, D. E., Adams, J. C., & Mugnaini, E. (1991). Chemically distinct rat olivocochlear neurons. Synapse, 7, 21–43.Find this resource:

Vogler, D. P., Roberston, D., & Mulders, W. H. A.M. (2011). Hyperactivity in the ventral cochlear nucleus after cochlear trauma. Journal of Neuroscience, 31(18), 6639–6645.Find this resource:

Wang, H., Yin, G., Rogers, K., Miralles, C., De Blas, A. L., & Rubio, M. E. (2011). Monaural conductive hearing loss alters the general expression of the GluA3 AMPA and glycine receptor α1 subunits in bushy and fusiform cells of the cochlear nucleus. Neuroscience, 199, 438–451.Find this resource:

Warren, E. H. 3rd, & Liberman, M. C. (1989a). Effects of contralateral sound on auditory-nerve responses. I. Contributions of cochlear efferents. Hearing Research, 37(2), 89–104.Find this resource:

Warren, E. H. 3rd., & Liberman, M. C. (1989b). Effects of contralateral sound on auditory-nerve responses. II. Dependence on stimulus variables. Hearing Research, 37(2), 105–121.Find this resource:

Waterlood, F. G., & Mugnaini, E. (1984). Cartwheel neurons of the dorsal cochlear nucleus: A Golgi-electron microscopic study in rat. Journal of Comparative Neurology, 227(1), 136–157.Find this resource:

Weinberg, R. J., & Rustioni, A. (1989). Brainstem projections to the rat cuneate nucleus. Journal of Comparative Neurology, 282(1), 142–156.Find this resource:

Weston, M.C., Nehring, R. B., Wojcik, S. M., & Rosendmund C. (2011). Interplay between VGLUT isoforms and endophilin A1 regulates neurotransmitter release and short-term plasticity. Neuron, 69, 1147–1159.Find this resource:

Whiting, B., Moiseff, A., & Rubio, M. E. (2009). Cochlear nucleus neurons redistribute synaptic AMPA and glycine receptors in response to monaural conductive hearing loss. Neuroscience, 163(4), 1264–1276.Find this resource:

Willott J. F., Milbrandt, J. C., Bross, L. S., & Caspary, D. M. (1997). Glycine immunoreactivity and receptor binding in the cochlear nucleus of C57BL/6J and CBA/CaJ mice: effects of cochlear impairment and aging. Journal of Comparative Neurology, 385, 405–414.Find this resource:

Willot, J. F., Parham, K., & Hunter, P. K. (1987). Comparison of the auditory sensitivity of neurons of the ventral cochlear nucleus and inferior colliculus of young and aging C57/BL and CBA/J mice. Hearing Research, 53, 78–94.Find this resource:

Wright, S., Hwang, Y., & Oertel, D. (2014). Synaptic transmission between end bulbs of Held and bushy cells in the cochlear nucleus of mice with a mutation in Otoferlin. Journal of Neurophysiology, 112(12), 3173–3188.Find this resource:

Wu, C., Martel, D. T., & Shore, S. E. (2016). Increased synchrony and bursting of dorsal cochlear nucleus fusiform cells correlate with tinnitus. Journal of Neuroscience, 36(6), 2068–2073.Find this resource:

Yao, W., & Godfrey, D.A. (1996). Autoradiographic distribution of muscarinic acetylcholine receptor subtypes in rat cochlear nucleus. Auditory Neuroscience, 2, 241–255.Find this resource:

Young, E. D., & Oertel, D. (2003). Cochlear nucleus. In G. M. Shepherd (Ed.), The synaptic organization of the brain (5th ed., ch. 4, pp.125–163). Oxford, England: Oxford University Press.Find this resource:

Young, E. D., Oertel, D. (2010). Cochlear nucleus. In G. M. Shepherd & S. Grillner (Eds.), Handbook of Brain Microcircuits (pp. 215–223). New York, NY: Oxford.Find this resource:

Youssoufian, M., Oleskevich, S., & Walmsley, B. (2008). Maturation of auditory brainstem projections and calyces in the congenitally deaf (dn/dn) mouse. The Journal of Comparative Neurology, 506(3), 442–451.Find this resource:

Zhao, Y., Rubio, M. E., & Tzounopoulos, T. (2011). Mechanisms underlying input-specific synaptic plasticity in the dorsal cochlear nucleus. Hearing Research, 279(1–2), 67–73.Find this resource:

Zeng, C., Nannapaneni, N., Zhou, J., Hughes, L. F., & Shore, S. (2009). Cochlear damage changes the distribution of vesicular glutamate transporters associated with auditory and nonauditory inputs to the cochlear nucleus. Journal of Neuroscience, 29(13), 4210–4217.Find this resource:

Zhou, J., Nannapaneni, N., & Shore, S. (2007). Vessicular glutamate transporters 1 and 2 are differentially associated with auditory nerve and spinal trigeminal inputs to the cochlear nucleus. Journal of Comparative Neurology, 500(4), 777–787.Find this resource:

Zhou, Y., & Danbolt, N. C. (2014). Glutamate as a neurotransmitter in the healthy brain. Journal of Neural Transmission, 121(8), 799–817.Find this resource:

Zhuang, X., Sun, W., & Xu-Friedman, M. A. (2017). Changes in properties of auditory nerve synapses following conductive hearing loss. Journal of Neuroscience, 37(2), 323–332.Find this resource: