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