Age-Related and Noise-Induced Hearing Loss: Central Consequences in the Ventral Cochlear Nucleus
Abstract and Keywords
Hearing loss generally occurs in the auditory periphery but leads to changes in the central auditory system. Noise-induced hearing loss (NIHL) and age-related hearing loss (ARHL) affect neurons in the ventral cochlear nucleus (VCN) at both the cellular and systems levels. In response to a decrease in auditory nerve activity associated with hearing loss, the large synaptic endings of the auditory nerve, the endbulbs of Held, undergo simplification of their structure and the volume of the postsynaptic bushy neurons decreases. A major functional change shared by NIHL and ARHL is the development of asynchronous transmitter release at endbulb synapses during periods of high afferent firing. Compensatory adjustements in transmitter release, including changes in release probability and quantal content, have also been reported. The excitability of the bushy cells undergoes subtle changes in the long-term, although short-term, reversible changes in excitability may also occur. These changes are not consistently observed across all models of hearing loss, suggesting that the time course of hearing loss, and potential developmental effects, may influence endbulb transmission in multiple ways. NIHL can alter the representation of the loudness of tonal stimuli by VCN neurons and is accompanied by changes in spontaneous activity in VCN neurons. However, little is known about the representation of more complex stimuli. The relationship between mechanistic changes in VCN neurons with noise-induced or age-related hearing loss, the accompanying change in sensory coding, and the reversibility of changes with the reintroduction of auditory nerve activity are areas that deserve further thoughtful exploration.
(p. 164) The cochlear nuclear complex (CNC) is the sole target of the auditory nerve. The CNC performs the initial computations that transform auditory information into separate representational streams, or distinct “parallel” pathways (Cant & Benson, 2003). These initial computations depend on auditory nerve targets, local circuit innervation patterns, and the physiological properties of different cell types across the CNC. Specific processing mechanisms within the CNC are in turn essential for the other centers of the ascending auditory pathways to precisely and effectively perform their sensory integration tasks. The processing mechanisms at each stage, including in the CNC, are also sensitive to the status of the auditory periphery as it is modified by noise-induced hearing loss (NIHL) or age-related hearing loss (ARHL). Hearing-loss induces changes in excitatory and inhibitory synaptic function, network structure, and the intrinsic electrical excitability of neurons.
The pathology of the auditory system that leads to hearing loss has been most extensively studied in the auditory periphery. Damage to the peripheral end organ, the cochlea, can affect the functional organization of the central auditory system by altering the activity patterns in the auditory nerve. Changes in central function include the organization of central neural circuits, the dynamic operation of synapses, and the excitability of cells. All of these contribute to how sensory stimuli are represented in the spike firing population code in terms of both rate and timing. Synapses in the CNC are the first in the central auditory pathway to experience anatomical and physiological changes, and activity-dependent changes in their function can degrade the information available to the rest of the central auditory system. For this reason, the response of the central auditory system to peripheral auditory pathology, including auditory neuropathies (Moser & Starr, 2016) is now recognized as an important consideration when evaluating and treating hearing loss (Atcherson, Nagaraj, Kennett, & Levisee, 2015; Moore et al., 2014).
In this chapter, we focus on the consequences of noise-induced and age-related hearing loss, and some select preclinical genetic deafness models, on processing in one region of the CNC, the ventral cochlear nucleus (VCN). We discuss the consequences of hearing loss for target neurons that form the major output pathways of the ventral cochlear nucleus (VCN). A particular focus of the existing literature is on the consequences for the specialized synapses of the auditory nerve, the endbulbs of Held (Manis, Xie, Wang, Marrs, & Spirou, 2012), that terminate on VCN bushy neurons. This chapter considers how the total loss of auditory nerve input affects VCN neurons; outlines potential and distinct consequences of peripheral hearing loss that may influence how VCN cells respond to that loss; reviews studies that have examined the consequences of noise-induced hearing loss (NIHL) and age-related hearing loss (ARHL) at both the systems and cellular levels; and reviews studies of hearing loss resulting from genetic causes, at the cellular level. Other kinds of hearing loss, such as caused by ototoxic drugs and conductive mechanism failures, are not discussed, but it is important to recognize that these types of loses are likely to involve related mechanistic changes in the central auditory system.
(p. 165) Cells of the VCN
Bushy (BCs) and planar multipolar cells (pMCs, also known as “T-stellate cells”) are two of the four neuronal types that project from the VCN to other auditory centers (Cant & Benson, 2003). BCs project to the superior olivary complex, where they innervate cells involved in binaural processing and facilitate sound localization. BCs can be divided into two major populations based on the shape of their soma and on their projections: spherical bushy cells (sBCs) and globular bushy cells (gBCs). sBCs receive synaptic input from 2–4 auditory nerve fibers via large endings called endbulbs of Held (Manis et al., 2012). Each endbulb has up to 100 individual release sites. This synaptic configuration facilitates strong and very rapid release of neurotransmitter for each spike in the presynaptic auditory nerve fiber. sBCs project to the lateral superior olive and, in animals with good low-frequency hearing, to the medial superior olive. It is unclear whether the sBCs are present in mice (Lauer, Connelly, Graham, & Ryugo, 2013). gBCs receive convergent input from 10 to 70 auditory nerve fibers (ANFs) in cat (Liberman, 1991; Spirou, Rager, & Manis, 2005) and project to the lateral superior olive, as well as the medial nucleus of the trapezoid body. All bushy cell types spike precisely in response to rapid fluctuations in sound intensity at low frequencies (in cells with characteristic frequencies (CF) up to 3 kHz in cats and guinea pigs), and can report the phase of a tone with high temporal precision. Very low frequency bushy cells (CF < 500 Hz) can improve the temporal precision of spiking relative to auditory nerve fibers (Joris, Carney, Smith, & Yin, 1994). Consequently, the bushy cell pathways are important for both azimuthal sound localization (which depends on temporal differences between the ears) and for pitch discrimination (which depends on frequency-specific firing to a sound). When representing higher frequencies, bushy cells convey other kinds of temporal cues, including onsets and envelope information and may provide information useful for aspects of auditory scene analysis (Keine, Rubsamen, & Englitz, 2017).
The other major cell population in the VCN, the pMCs (“T-stellate cells”), project to the inferior colliculus (Adams, 1983) and additionally have collaterals in the VCN and the dorsal cochlear nucleus (DCN; Doucet & Ryugo, 1997; Oertel, Wu, Garb, & Dizack, 1990). pMCs encode acoustic cues, such as sound intensity and amplitude modulation, in their firing rate and spike timing (Frisina, Smith, & Chamberlain, 1990; Rhode & Greenberg, 1994). Like BCs, pMCs receive strong direct AN input, but pMCs have poor temporal firing precision relative to the fine structure of the acoustic waveform. pMCs are also thought to be part of a pathway that is involved in early stages of analyzing narrow-band signals embedded in wideband maskers (Pressnitzer, Meddis, Delahaye, & Winter, 2001; Xie & Manis, 2013b), a process known as comodulation masking release (Hall, Haggard, & Fernandes, 1984).
Two other smaller populations of cells found in the CNC are the octopus and radiate multipolar cells (rMC, also known as “D-stellate cells”). Both of these cell types (p. 166) receive convergent input from auditory nerve fibers representing a wide range of cochlear locations by virtue of the orientation of their dendrites (Oertel, Bal, Gardner, Smith, & Joris, 2000; Oertel et al., 1990; Xie & Manis, 2017a), and thus have very broad sensitivity to sound frequency (Godfrey, Kiang, & Norris, 1975; Jiang, Palmer, & Winter, 1996; Palmer, Jiang, & Marshall, 1996; Rhode & Smith, 1986; Ritz & Brownell, 1982). The octopus cells are found in the posteroventral cochlear nucleus and are highly specialized to provide detection of coincident activity across a population of auditory nerve fibers (McGinley, Liberman, Bal, & Oertel, 2012; Spencer, Grayden, Bruce, Meffin, & Burkitt, 2012). They respond transiently with an “onset” response to tones, but can represent low-frequency pitch information with high precision (Rhode, 1998). The rMCs are inhibitory neurons that project widely within the CNC (Arnott, Wallace, Shackleton, & Palmer, 2004; Doucet, Ross, Gillespie, & Ryugo, 1999; Oertel et al., 1990), and also to the contralateral CNC (Doucet & Ryugo, 2006; Schofield & Cant, 1996; Smith, Massie, & Joris, 2005). For these two cell types, there is a very limited literature about the consequences of hearing loss on their responses to sound.
Physiological and Anatomical Changes in Following Total Loss of AN Activity
Long-term damage to auditory structures causes pronounced changes in VCN cellular and anatomical properties. To understand the role of auditory nerve spike activity in the auditory nerve, two different approaches are taken to abolish responses to sound. The most direct is cochlear ablation, where the cochlea is removed, destroying the dendrites (and often somas, depending on the technique used) of the spiral ganglion cells (SGCs). Loss of the cochlea and SGC dendrites silences the activity of the auditory nerve, leaving spontaneous and trophic activity intact; death of SGC somas destroys the auditory nerve eliminating even spontaneous and trophic activity. The other approach is to apply tetrodotoxin (TTX) to block voltage-gated sodium channels. TTX silences the spiking activity of the nerve, eliminating all but spontaneous quantal release of neurotransmitter and trophic signaling at central ANF terminals.
Similar to TTX, cochlear ablation in cats immediately decreases the spontaneous firing rates of VCN neurons, but not dorsal cochlear nucleus neurons (Koerber, Pfeiffer, Warr, & Kiang, 1966). Spontaneous rates in the VCN do not recover up to 77 days after cochlear destruction. Both cochlear ablation and TTX application to the cochlea cause rapid compensatory changes in VCN neurons within hours after cessation of auditory nerve activity (Pasic, Moore, & Rubel, 1994; Pasic & Rubel, 1989; Sie & Rubel, 1992). Unilateral cochlear removal in p7 mouse and gerbil results in quantitative neuronal cell loss in the anterior VCN (aVCN) within 48 hours, while in mouse, TUNEL labeling (indicative of apoptosis) is seen as soon as 12 hours after cochlea removal. In older animals, (p. 167) cochlear ablation after a “critical period” (about p7 in rodents), leads to no neuronal cell loss (Hashisaki & Rubel, 1989; Mostafapour, Cochran, Del Puerto, & Rubel, 2000); however, neuronal cell size in aVCN is reduced after cochlear removal in older mice (Pasic et al., 1994; Pasic & Rubel, 1989). Decreases in aVCN cell size, but not in number, are seen when inner hair cells are acutely ablated in genetically engineered adult mice with a diphtheria toxin receptor (Tong et al., 2015). Overall, these studies are consistent in observing that acute loss of auditory nerve activity causes neuronal apoptosis in aVCN in animals before the onset of hearing, whereas older animals demonstrate changes in aVCN morphology and physiology.
Many neurons, including those in the auditory pathways, undergo homeostatic adjustments in their excitability in response to long-term synaptic input and firing changes (Desai, Rutherford, & Turrigiano, 1999; Kotak et al., 2005; Leao, Berntson, Forsythe, & Walmsley, 2004; Ngodup et al., 2015; Rao et al., 2010). In general, long-term decreases in excitatory synaptic drive lead to increased electrical excitability. In chickens, cochlear ablation leads to a transient decrease in immunoreactivity for Kv1.1 and Kv3.1 potassium channels, but protein levels of both channels recover to near normal levels by 2 weeks (Lu, Monsivais, Tempel, & Rubel, 2004). In rats, a short-term block of auditory nerve activity by TTX results in a loss of immunoreactivity for presynaptic KCNQ5 (a ligand-regulated voltage-sensitive potassium conductance (Schroeder, Hechenberger, Weinreich, Kubisch, & Jentsch, 2000)) in endbulbs within 2 hours (Caminos, Garcia-Pino, & Juiz, 2015); whether this is a persistent or transient loss is not clear. In order to determine whether destruction of the SGCs and removal of the ANF input also affects the electrical excitability of aVCN neurons, Francis and Manis (2000) performed bilateral cochlear ablations in 4-week old rats, including a substantial invasion of the modiolus to remove the SGCs. The intrinsic excitability of VCN neurons (including both BCs and MCs) showed only modest changes two weeks after the ablation. Presumed BCs, specifically those showing only single spike responses to depolarizing current injection, were slightly depolarized, had smaller action potentials with smaller spike after-hyperpolarizations, and had shorter membrane time constants. The population of BCs that fired 2–3 spikes in response to intracellular current injection were not significantly affected. Presumed MCs (largely pMCs) nearly doubled their input resistance on average but showed no other changes.
Taken together, these results indicate that in adult animals after loss of peripheral activity and input, not only do VCN cells survive, but they also largely retain their fundamental physiological identities.
Noise-Induced Hearing Loss
Overexposure to noise, particularly at extreme loudness or for a prolonged time, can severely injure the auditory periphery (D’Sa, Gross, Francone, & Morest, 2007; Feng, (p. 168) Bendiske, & Morest, 2012; Guthrie, 2017; Valero et al., 2017; Wang, Hirose, & Liberman, 2002) and lead to permanent noise-induced hearing loss (NIHL). The consequences of NIHL are complex and depend on the level, duration, and pattern of exposure (Wang et al., 2002). Thus, it is difficult to assign a single consequence for central processing to NIHL. However, consideration of the types of peripheral pathology induced by noise can help to set the conceptual framework for studying central consequences of NIHL. Intense noise exposure can damage hair cell stereocilia, resulting in elevated thresholds at the level of the ANF, but responses to sound can still occur (Liberman, 1987; Liberman & Dodds, 1984). Modest noise can also eliminate the response to sound in individual ANFs by damaging the inner hair cells or the SGC terminals (Kujawa & Liberman, 2009). More extensive damage to cochlear structures can reduce the sensory response by damaging the lateral wall of the cochlea (Wang et al., 2002). If damaged inner hair cells remain functionally connected to SGCs, the auditory nerve can still possess spontaneous activity, because the spontaneous firing is driven by vesicular (quantal) release from inner hair cells (Chapochnikov et al., 2014; Kiang, Liberman, & Levine, 1976; Rutherford, Chapochnikov, & Moser, 2012; Siegel, 1992). However, damage to inner hair cell synaptic mechanisms, the SGC afferent synapses or dendrites, or to the stria vascularis can lead to silencing of the auditory nerve or death of nerve fibers. The integrity of the stereocilary bundle may determine whether there is any sensory activity in an individual auditory nerve. Damage to the reticular lamina, tectorial membrane, or the stria vascularis may affect large numbers of ANFs. In many studies of NIHL, sound responses are not completely abolished, but individual ANFs may exhibit high thresholds and low average firing rates for the same sound intensity (Heinz, Issa, & Young, 2005; Heinz & Young, 2004), while other ANFs may be silent. The recognition that the high-threshold, low-spontaneous population of ANFs is particularly vulnerable to noise damage (Furman, Kujawa, & Liberman, 2013; Kujawa & Liberman, 2006, 2009) and aging (Sergeyenko, Lall, Liberman, & Kujawa, 2013) increases the complexity of interpreting central responses to hearing loss. All of these factors need to be considered when evaluating the effects of NIHL on VCN neurons.
NIHL: VCN Neuroanatomy
Extremely loud noise damages the peripheral auditory system leading to hearing loss and degeneration of synapses and neurons in the CNC (D’Sa et al., 2007; Feng et al., 2012; Kim, Gross, Morest, & Potashner, 2004; Kim, Gross, Potashner, & Morest, 2004a, 2004b; Sekiya et al., 2012). In adult mice (F1 C57BL/6J X CBA), 6 hours of exposure to broadband noise at 115 dB SPL destroys essentially all outer hair cells, and damages a majority of the inner hair cells and auditory nerve fibers (Feng et al 2012). The exposure results in a decrease in the synaptic vesicle protein SV2 in synapses in the posteroventral cochlear nucleus (PVCN) and a reduction of the total volume of the PVCN, as measured eight weeks after exposure. In adult Sprague-Dawley rats, a one-minute exposure (p. 169) to an octave-band noise centered at 4 kHz at 137 dB SPL produced similar damage in the cochlea but only a selective loss of neurons in aVCN (Sekiya et al., 2012).
The damaging effect of a single traumatic noise exposure can be long lasting in the VCN and may be followed by a period of axonal sprouting and re-innervation from non-cochlear sources. In chinchillas exposed to 108 dB SPL octave-band noise for 3 hours (Kim, Gross, Morest et al., 2004; Kim, Gross et al., 2004a, 2004b), there was long-term neurodegeneration with substantial loss of axons and synaptic terminals in the first 16–24 weeks after exposure. The degenerated VCN synapses included excitatory endings belonging to both the auditory nerve, and endings that are presumably local collaterals between VCN neurons (Kim, Gross, Morest et al., 2004; Kim, Gross et al., 2004a).
Following the noise exposure, the number of synapses in the VCN recovers, apparently by new growth of synaptic endings as observed at 24–32 weeks after noise exposure. The recovery was more pronounced for excitatory synapses, possibly as an adaptive compensation for decreased auditory nerve inputs (Kim, Gross, Morest et al., 2004). Some of the new synapses, including axo-somatic terminals onto gBCs, appear to come from central neurons instead of the terminals from the SGCs, suggesting a dynamic reorganization of synaptic connections following NIHL (Kim, Gross, Morest et al., 2004; Kim, Gross et al., 2004b). Indeed, following noise exposure, the expression of growth-associated protein 43 (GAP-43), a protein found in neuronal growth cones (Skene, 1989) and in synapses undergoing remodeling (Holahan, 2017), is increased in the VCN (Kraus et al., 2011; Michler & Illing, 2002).
While the precise origin of these new synapses is unclear, cochlear ablation experiments suggest these synapses might be collaterals of olivocochlear fibers (Meidinger, Hildebrandt-Schoenfeld, & Illing, 2006). In rats, cholinergic inputs to the VCN are thought to arise from collaterals of the olivocochlear system (~20%), from small neurons in the ventral nucleus of the trapezoid body (~65%), and from sources within the CNC (~15%; Jin, Godfrey, & Sun, 2005). Consistent with new or additional innervation by a cholinergic component of the olivocochlear system, there is an increase in the activity of ChAT, the synthetic enzyme for acetylcholine, in the VCN following cochlear ablation (Jin et al., 2005). Two other potential sources of non-cholinergic terminals are the pMCs, which normally have collaterals within the VCN (Oertel et al., 1990) and trigeminal ganglion afferents, which also sparsely innervate the central VCN (Shore, Vass, Wys, & Altschuler, 2000). Overall, these results suggest that the loss of auditory nerve input to the VCN may be associated with a compensatory innervation by other central auditory, and potentially non-auditory, pathways that already project into the VCN. However, whether this also occurs with NIHL or aging is not yet certain.
NIHL: System-Level Functional Studies
Acoustic trauma has immediate effect on the response properties of VCN cells. Boettcher and Salvi (1993) recorded peristimulus histograms (PSTH) before and after (p. 170) an acute exposure in rats. The exposure stimulus was a three to five-minute continuous tone at 90–105 dB SPL, positioned a half-octave above the unit characteristic frequency (CF). Noise exposure increased compound action potential thresholds above the exposure frequency by ~15 dB. Although there were no clear changes in the PSTH patterns, they found that the effect of the tone exposure varied within the response area of the cell. For cells whose spontaneous activity was inhibited by the sound exposure (27% of recorded cells), suppression of inhibition was seen, and most (64%) cells also exhibited increased firing at CF. In the remainder of the cells, overt inhibition was not observed at or near the frequency of the exposure stimulus. However, most (66%) of these cells showed a broadening of tuning with increased sound level concurrent with a general decrease in firing rate. The decrease in firing rate was observed independently at CF or above CF, or both at and above CF, in 66% of the recorded cells. Interestingly, spontaneous rates of most of the cells remained largely unchanged after the noise exposure, although a subset of cells showed changes in spontaneous rate despite no overt evidence for a change in inhibition. The mechanisms underlying these changes are not entirely clear. Some of the effects can be explained by the increase in thresholds in the cochlear region affected by the tone exposure, but some of the effects may result from a short-term suppression of excitability of local inhibitory neurons or depression of inhibitory synapses. It is unclear whether these short-term effects are reversible.
Cai, Ma, and Young (2009) examined long-term changes in the response properties of cells in the VCN after noise exposure. Measurements were made between 33 and 121 days after exposing cats to a narrowband noise centered at 2 kHz at 111–112 dB SPL for four hours. This exposure paradigm produces a permanent threshold shift across low frequencies, while maintaining relatively normal thresholds in the high frequency response areas. Although individual VCN units mirrored the effects of the cochlear threshold shift, the general physiological response characteristics across units were similar to those seen in unexposed animals. All of the expected response patterns, including primary-like, primary-like with notch and choppers were observed. Measures of discharge regularity and first spike latency were also not different between normal and exposed cats; however, neurons with chopper PSTHs (from pMCs; (Rhode, Oertel, & Smith, 1983; Rouiller & Ryugo, 1984; Smith & Rhode, 1989)) exhibited increased firing rates for suprathreshold sounds, even though their thresholds were elevated. In contrast, neurons with primary-like and primary-like with notch responses (BCs) had lower firing rates to BF tones, more closely reflecting the pattern of activity in the noise-impaired auditory nerve (Heinz et al., 2005; Heinz & Young, 2004). Neurons in noise-exposed animals also tended to have broader tuning, as determined by smaller Q10 values relative to normal units, irrespective of PSTH shape. The mechanism that causes the increase in firing rates of MCs is not clear, although weakened inhibition from the two main inhibitory sources, the tuberculoventral cells or the rMP cells, are prime candidates.
Vogler, Robertson, and Mulders (2011) compared the effects of a sham noise exposure, a mechanical lesion of the basal cochlear region, and acoustic trauma from a 10 (p. 171) kHz, 124 dB SPL tone for 2 hours in adult guinea pigs. Recordings were made 2 weeks after exposure. All PSTH types (primary-like, chopper and onset) could be identified in the noise exposed and mechanical trauma animals, and the frequency of occurrence was not different from the sham exposure animals. Neurons from both the low and high frequency regions of the VCN showed increased spontaneous firing, although this was most pronounced in the primary-like and onset cells, and less clear in the chopper class (although the transient choppers appeared to show a larger increase in spontaneous firing than the sustained choppers). Rate-intensity functions were not reported in this study.
These studies differ considerably in their noise exposure paradigms, species and recovery times. However, they are consistent in noting that NIHL does not substantially affect the fundamental response properties of VCN neurons of different classes, in that all of the expected PSTH patterns are present in similar proportions as in control subjects. Thresholds increase in parallel with threshold shifts in auditory nerve. In terms of possibly pathological changes in the VCN, NIHL induced by intense stimuli appears to increase spontaneous firing rates, at least in some cell populations, and selectively increases the steepness of the tone rate-intensity function in MCs, which may contribute to loudness recruitment.
NIHL: Synaptic Changes in the CN
In addition to the well documented anatomical changes across CN synapses and cells after NIHL, notable changes in synaptic physiology were also observed in mature animals. Synaptic transmission was studied at the endbulb of Held in mature CBA/CaJ mice at 2–4 months of age, under normal hearing and NIHL (Xie & Manis, 2012). NIHL was induced by a 2-hour exposure to 8-16kHz band noise at 106 dB SPL at postnatal day 25. As shown in Figure 7.1A, auditory nerve stimulation evoked EPSCs in BCs of normal hearing mice throughout the 400 Hz stimulus train, with reliable synchronous EPSCs during the latter half of the train (inset). In age-matched young mice with NIHL, the EPSCs were similar only during the initial phase of the train. EPSCs deteriorated in the second half of the train, showing long-lasting asynchronous EPSCs and reduced peak amplitude (Figure 7.1B). The results indicate that synaptic transmission at the endbulb of Held is compromised during high rate activity after NIHL. In a separate study (Rich, Xie, & Manis, 2010), synaptic quantal release frequency and amplitude were increased at auditory nerve synapses onto VCN stellate neurons (mostly pMCs) in mice with a permanent NIHL produced by octave band noise exposure for 2 hours at 114 dB SPL. A more modest exposure (98 dB SPL) that produced a temporary threshold shift only increased event frequency, but not amplitude. It is unclear whether the increased frequency is a consequence of additional innervation in response to cochlear damage or represents a compensatory response of synaptic release mechanisms. (p. 172)
(p. 173) NIHL: Synaptic Changes in the CN after “Benign” Noise Exposure
The intense, long duration noise exposures described earlier are not commonly encountered in the environment. Recent studies on NIHL have focused on noise exposure at moderate levels that only cause temporary threshold-shift in hearing, as evaluated by auditory brainstem response measurements. Surprisingly, Kujawa and Liberman (2009) found that exposure to noise at moderate levels can cause permanent cochlear synaptopathy, involving damage of the synapses between the inner hair cells and the peripheral terminal of the SGCs, even while the inner hair cells remain intact. SGC somata can survive for a long time after such deafferentation (Kujawa & Liberman, 2009) and the same is likely true for SGC central branches (the auditory nerve) and the synaptic terminals in CNC. The degeneration of endbulb and other CNC synapses seen after intense noise trauma (Kim, Gross, Morest et al., 2004; Kim, Gross et al., 2004a, 2004b) has not been reported following exposure to noise at moderate levels.
Physiologically, moderate noise exposure modifies sensory inputs to CN and leads to homeostatic regulation of vesicle release at CN synapses (Ngodup et al., 2015; Rich et al., 2010). At the endbulb of Held synapse, the high release probability of the synaptic transmission measured in normal hearing CBA/Caj mice was reduced after the mice were reared between 6 and 50 days in noise (1.6–39 kHz) at 90-94 dB SPL (Ngodup et al., 2015). The number of release sites at the endbulb of Held was significantly increased in noise-reared mice, which is consistent with larger vesicular glutamate transporter type 1 (vGluT1) labeled puncta at the terminals. The decreased release probability recovered to normal levels after the noise-reared mice were returned to quiet, suggesting that there is a homeostatic regulation of vesicle release at the endbulb of Held that relies on the activity levels of the auditory nerve input. Interestingly, in these experiments, the intrinsic excitability of the BCs as reflected by spike threshold, action potential height, and action potential width, showed small but significant changes. These results suggest that noise exposure, even if it is not overtly damaging, can dynamically adjust the operating points of central synapses and cells.
Age-Related Hearing Loss
When considering the effects of age, it is important to recognize that the majority of SGCs survive throughout the lifetime of the organism (Makary, Shin, Kujawa, Liberman, & Merchant, 2011; Sergeyenko et al., 2013; Sha et al., 2008). The integrity and functionality of SGC central synapses in the CNC will therefore play an essential role in the development of ARHL. Indeed, during aging SGC synapses show anatomical and physiological modifications that could contribute to ARHL.
(p. 174) AHRL: System Level Functional Studies
There are surprisingly few studies of the effects of aging on the responses of VCN neurons in vivo. The progression of hearing loss in 7–12 month old C57BL/6J mice (Willott, Parham, & Hunter, 1991) in part replicates the age-related cochlear pathology that often accompanies aging. The peripheral loss of high frequency hearing is also reflected in the sensitivity of neurons in the VCN. Single unit and multi-unit recordings in C57BL/6J mice, 7–12 months old, show an elevation in thresholds in the VCN with age as compared to young mice of the same strain or CBA/J mice (which show a much slower ARHL) of the same age. Multi-unit recordings suggest a loss of neurons with high frequency tuning, as no neurons were responsive to frequencies above 32 kHz in aged mice. This is accompanied by an increase in neurons with BFs between 8 and 32 kHz. Surprisingly, these elevations in threshold in the C57BL/6J mice are not as pronounced in recordings from the dorsal cochlear nucleus and inferior colliculus in the same strain, suggesting compensatory mechanisms downstream of the VCN. Although no differentiation of unit types by PSTH or regularity was attempted, the results in the VCN suggest that BCs and MCs likely have similar patterns of threshold shifts. Frisina and Walton (2006) reported that there is little change in gap duration recovery curves using near-field evoked potentials in the VCN of old (24 mo) as compared to young (7 mo) CBA mice.
ARHL: Synaptic Changes
In normal aging CBA/J mice, the aVCN cell number and packing density remains stable in the first year of life but shows a reduction during the second year of life (Willott, Jackson, & Hunter, 1987). The densities and the numbers of synaptic terminals in aVCN did not change with age in Fischer-344 rats up to 28 months (Helfert, Krenning, Wilson, & Hughes, 2003); however, aged rats demonstrated reduced synaptic terminal size that may reflect a reduction in neurotransmitter levels (Banay-Schwartz, Lajtha, & Palkovits, 1989a, 1989b). In a separate study, VCN synapses in 25–26 month Fischer-344 rats showed more complex endings than young rats, indicative of possible collateralization of CN neuronal processes to offset degenerative losses of SGC terminals (Keithley & Croskrey, 1990). In 18–20 month-old Wistar rats, VCN synapses showed significant decline in the immunostaining of both VGluT1 and VGAT synaptic markers, consistent with an overall decline in both excitatory and inhibitory synaptic endings during aging (Alvarado, Fuentes-Santamaria, Gabaldon-Ull, Blanco, & Juiz, 2014).
The extension of brain slice methods to record from increasingly older mice has enabled more precise analysis of synaptic transmission and excitability, revealing how specific cellular mechanisms are affected by ARHL. During ARHL, the physiological function of VCN synapses declines. In 20–26 month-old CBA/CaJ mice (Xie & Manis, 2017b), synaptic transmission at the endbulb of Held synapse was compromised by (p. 175) decreased synchronous release with a simultaneous increase in asynchronous release during the later phase of the 400 Hz stimulus train. In aged mice, auditory nerve stimulation evoked spikes in postsynaptic BCs with a significantly higher failure rate and decreased temporal precision (Figure 7.2). This suggests that endbulb of Held synapses cannot effectively and faithfully transmit sound information from the periphery to the VCN in aged mice (Xie, 2016). Both studies reveal two functionally important findings about the synaptic changes under ARHL (Xie, 2016; Xie & Manis, 2017b). First, synaptic transmission at the endbulb of Held in aged mice was found to be relatively normal during the onset phase of the stimulus train, but the synapses were unable to sustain ongoing activity during prolonged trains of stimulation. This finding predicts that the hearing of these aged mice with ARHL would be relatively normal for brief sound signals but may be challenged to carry information for long-duration or ongoing sounds, especially in the presence of background noise. These observations provide an additional predicted neural explanation for “hidden hearing loss,” in which responses would be similar to those in normal hearing to traditional brief tone burst assessments (which rely predominantly on the early part of the stimulus), but would reveal deficits during complex auditory tasks that depend more on sustained responses (Xie, 2016). Second, deterioration of synaptic transmission with ARHL was more profound for high rates of ANF firing (400 Hz stimulation) than for low rates (100 Hz stimulation). This indicates that aged VCN synapses are functionally challenged when processing high rate auditory nerve inputs. For example, cochlear implants can stimulate the auditory nerve at rates up to and beyond 300 Hz, and the failure of high-rate stimuli to further improve temporal pitch discrimination (Shannon, 1983; Zeng, 2002) might partly be due to these limitations of synaptic transmission. From a mechanistic standpoint, the degradation of synaptic release at high rates appears to be linked to abnormal calcium signaling in the endbulb of Held terminals in aged mice during high rate activities, as the age effect could be largely reversed by acute addition of an exogenous calcium buffer (Xie & Manis, 2017b). Whether this reflects a change in overall cell calcium handling (such as by mitochondrial uptake, calcium binding proteins or plasma membrane pumps) or an age-related change in the calcium-dependent mechanisms involved in transmitter release (Foster, 2007) remains unclear.
In studies of ARHL, it is often hard to differentiate contributions that are due to normal aging versus those that are due to hearing loss. Phenomenologically similar changes in sustained synaptic transmission are evident at the endbulb of Held in NIHL at 2–4 months of age (Figure 7.1B), in ARHL at 25–30 months of age (Figure 7.1C), and in dn/dn mice at ~13 days of age (Oleskevich & Walmsley, 2002), consistent with the idea that the compromised synaptic transmission is a pathological response to the change in ANF activity associated with hearing loss. However, “normal” aging of the auditory system almost never exists because of the continuous exposure to environmental sounds throughout life. In this sense, ARHL might be better described as the result of a lifetime accumulation of “noise” exposure. Indeed, hearing loss early in life due to noise exposure accelerates the aging of the auditory system in mice (Fernandez, Jeffers, Lall, Liberman, & Kujawa, 2015; Kujawa & Liberman, 2006). In summary, noise exposure (p. 176) and aging are intermingled in the development of ARHL, and more carefully controlled experiments are required to parse out these two factors.
Synaptic Changes in the CN during Hearing Loss Related to Genetic Causes
Besides NIHL and ARHL, hearing loss is also frequently observed in the form of congenital deafness or other early onset progressive hearing losses that associate with genetic causes (Angeli, Lin, & Liu, 2012). These hearing impairments can lead to substantial anatomical and physiological changes at CN synapses. In particular these impairments may affect normal cochlear development and affect early activity-dependent development and refinement of central connections. At the endbulb of Held, the generalized (p. 177) response to genetic deafness often consists of synaptic atrophy and a compensatory enhancement in synaptic transmission that promotes increased central gain. Here we consider selected studies that have examined the effects of congenital deafness and early onset deafness.
In congenitally deaf white cats, the CN is 50% smaller in volume than that of hearing cats (Saada, Niparko, & Ryugo, 1996), accompanied by reduced synaptic size and branching of the endbulb of Held synapses, increased synaptic vesicle density, and elongated postsynaptic density (Baker, Montey, Pongstaporn, & Ryugo, 2010; Ryugo, Pongstaporn, Huchton, & Niparko, 1997). The synaptic pathology could be rescued by stimulating the congenitally deaf cats with cochlear implants for three months (Ryugo, Kretzmer, & Niparko, 2005), consistent with the idea that the morphological changes of CN synapses are significantly influenced by auditory nerve activity (Ryugo, Rosenbaum, Kim, Niparko, & Saada, 1998). Similar patterns of morphological changes of the endbulb of Held synapse were also observed in congenital deaf shaker-2 mice (Connelly, Ryugo, & Muniak, 2017; Limb & Ryugo, 2000).
In congenitally deaf dn/dn mouse, the volume of aVCN endbulb of Held synapses was significantly smaller than normal mouse (Youssoufian, Couchman, Shivdasani, Paolini, & Walmsley, 2008), consistent with synaptic atrophy due to sensory inactivity of the auditory nerve. The synaptic transmission at the endbulb of Held was enhanced in deaf dn/dn mouse, showing increased transmitter release probability and larger evoked EPSCs, possibly as a compensatory mechanism to the reduced activity (Oleskevich & Walmsley, 2002). This study also showed the presence of asynchronous release at the endbulb synapse, similar to what is seen in NIHL and ARHL. Interestingly, spontaneous activity was recorded from unidentified cells in the CNC in these mice, indicating that the prolonged absence of sound-evoked activity in the nerve does not necessarily lead to an electrically silent central system (Youssoufian et al., 2008). Notably, no anatomical change was found in the downstream calyx of Held synapses in the nucleus of the trapezoid body of the same dn/dn mouse. Unlike the endbulb of Held, synaptic transmission at the calyx of Held in the MNTB showed no differences between normal hearing and deaf dn/dn mouse (Oleskevich, Youssoufian, & Walmsley, 2004; Youssoufian, Oleskevich, & Walmsley, 2005), although acute manipulations have revealed alterations in calyx function (Weatherstone et al., 2017).
In congenitally deaf mice that carry a mutation in otoferlin, which is an essential protein in the transmitter release process in hair cells (Michalski et al., 2017; Roux et al., 2006), the volume of the VCN was decreased by 46%, with smaller endbulb of Held synapses than hearing mice (Wright, Hwang, & Oertel, 2014). Postsynaptic bushy neurons in deaf mice receive more auditory nerve terminals, with increased amplitude of both quantal and evoked EPSCs (Wright et al., 2014). Similarly, in congenitally deaf jerker mice the cochlear nucleus is smaller in size, but develops normal topography in its auditory nerve innervation (Cao, McGinley, & Oertel, 2008). Endbulb of Held synapses near the nerve root in jerker mice were smaller than in hearing mice. The light-microscopic morphology of synaptic terminals in PVCN multipolar and octopus cell areas was not different between jerker and hearing mice. However, the deaf jerker mice showed an (p. 178) increased spontaneous event frequency and enhanced synaptic depression as measured onto both octopus and T-stellate neurons (Cao et al., 2008).
DBA/2j mice carry multiple recessive alleles of hearing loss genes (Erway, Willott, Archer, & Harrison, 1993; Johnson, Longo-Guess, Gagnon, Yu, & Zheng, 2008) and develop early onset progressive hearing loss starting at 3 weeks of age and reach nearly complete deafness by 7 months (McGuire, Fiorillo, Ryugo, & Lauer, 2015; Willott & Erway, 1998; Xie & Manis, 2013a; Zheng, Johnson, & Erway, 1999). No significant changes were found in VCN volume, number of neurons or VGluT1-positive auditory nerve terminals between two age groups of DBA/2j mice at 1–2 months and 9–10 months (McGuire et al., 2015). However, endbulb of Held synapses were smaller in DBA/2j mice at 9–10 months (McGuire et al., 2015). Synaptic transmission at the endbulb of Held was significantly modified during the early stage of hearing loss in these mice (Wang & Manis, 2005). Compared to young DBA/2j mice at 22 days, quantal synaptic transmission in the high frequency region of the aVCN in 45-day-old mice was smaller in amplitude and decreased in frequency, and the release probability of evoked synaptic transmission was significantly reduced. Surprisingly, evoked glycinergic inhibition from the DCN onto BCs was transiently enhanced during the onset of the hearing loss at 20–35 days in DBA/2j mice, becoming weaker and unreliable by 6–7 months of age, when the mice exhibit a profound hearing loss (Xie & Manis, 2013a).
Changes of synaptic transmission at the endbulb of Held are also widely reported during hearing loss caused by other genetic mutations. In BCs from hearing impaired CPX-I (Complexin I; a protein involved in synaptic vesicle fusion with the presynaptic membrane) knockout mice, the resting release probability was significantly reduced, facilitation was increased, release was delayed, EPSC jitter was increased, and tone evoked steady-state (adapted) firing rates were increased (Strenzke et al., 2009). Mice with a targeted deletion of the CACNA2D3 gene, which encodes the auxiliary subunit α2δ3 of the voltage gated calcium channels, show distorted ABR waveforms and compromised temporal processing (Pirone et al., 2014). Endbulb of Held synapses were smaller in α2δ3-/- mice and synaptic transmission was impaired with reduced firing rate and increased first spike latency in response to tones in postsynaptic bushy neurons (Pirone et al., 2014). Mice with deletion of exons 4 and 5 of the Bassoon gene show reduced auditory nerve sensory inputs in the aVCN (Jing et al., 2013) without affecting the endbulb of Held synaptic structure (Mendoza Schulz et al., 2014); however, the readily releasable vesicle pool and vesicle replenishment were decreased at the endbulb. Compensation for these deficiencies include increased postsynaptic densities, quantal size and vesicular release probability, resulting in unaltered EPSC amplitude (Mendoza Schulz et al., 2014). Deletion of AMPA glutamate receptor subunit GluA3 impaired the hearing of mice without changing the ending profile area of the endbulb of Held synapse, but reduced the number and size of postsynaptic density in BCs (Garcia-Hernandez, Abe, Sakimura, & Rubio, 2017).
(p. 179) Summary
VCN synapses undergo both anatomical and physiological changes in response to noise-induced hearing loss and aging. These changes are generally considered to be secondary to degeneration of cochlear structure and reduced peripheral activity, but they have additional functional consequences for the representation of sound in the brain. Structurally, volume changes in postsynaptic cells and simplification of the structure of the surviving, activity deprived endbulbs are frequently associated with hearing loss. A major functional change shared by noise-induced hearing loss and aging is the development of asynchronous transmitter release at endbulb synapses during periods of high afferent firing, and this is also seen in at least one genetic model of hearing loss. In some cases, there appear to be compensatory responses in transmitter release, including changes in release probability and in the quantal content. These are not consistently observed across all models of hearing loss, suggesting that the time course of hearing loss and potential developmental effects may influence endbulb transmission in multiple ways. The electrical excitability of postsynaptic cells appears to undergo subtle changes, at least in the long-term, although studies that have examined ion channel expression in the VCN suggest that short-term, reversible changes in excitability may also occur. There is far less information about synaptic function and excitability of the pMCs and octopus cells, and none regarding the rMCs, in spite of their potentially critical role as providing inhibition to many principal cell types in the CNC (Arnott et al., 2004; Nelken & Young, 1994). Finally, there are clear indications that inhibition onto BCs and pMCs is reduced after hearing loss, although in most studies the exact sources of inhibition (rMCs, DCN vertical cells, or descending inputs from the olivary complex) are not clear. Overall, the relationship between the cellular and network changes and the consequences for auditory information processing are still unclear. The systems-level studies that have been done in the VCN with respect to hearing loss are limited.
A major question is whether changes in synaptic transmission or excitability in the VCN following NIHL or ARHL are reversible with the introduction of peripheral stimulation, as occurs when people are fitted with cochlear implants after a period of hearing loss, or which might occur with peripheral regeneration. So far this has only been studied in terms of the morphology of endbulbs of Held after electrical stimulation in two different models of deafness (Ryugo et al., 2010; Ryugo et al., 2005), with slightly different results. Whether other functional changes in synaptic transmission also occur, such as a reduction of the asynchronous release, and whether normalization of spontaneous rates and inhibitory tone can occur, could be important factors in designing effective stimulation patterns.
The relationship between the mechanistic changes and sensory coding by VCN neurons is an area that deserves further exploration. The studies we have discussed (p. 180) indicate that hearing loss is likely to alter how the loudness of tonal stimuli is represented centrally. Whether there are significant changes in coding for more complex stimuli, or for stimuli embedded in broadband sounds typical of many acoustic environments is not clear. Future studies should employ a careful categorization of cell types according to established criteria and should explore population responses to more naturalistic stimuli that better engage the networks of other excitatory and inhibitory cells that influence the firing of the principal neurons. In addition, such studies would benefit from an evaluation of the functional and morphological status of the auditory periphery in the same experimental subjects, to clarify the status of activity in the nerve.
This work was supported by NIDCD grants R01DC004551 to PBM, and R03DC013396 and R01DC016037 to RX. TFR was supported by T32DC005360.
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