Changes in the Inferior Colliculus Associated with Hearing Loss: Noise-Induced Hearing Loss, Age-Related Hearing Loss, Tinnitus and Hyperacusis
Abstract and Keywords
The inferior colliculus is an important auditory relay center that undergoes fundamental changes following hearing loss, whether noise induced (NIHL) or age related (ARHL). These changes may contribute to the induction or maintenance of phenomena such as tinnitus (phantom auditory sensations) and hyperacusis (increased sensitivity to sound). Here, we outline changes that can occur in the inferior colliculus following damage to the periphery and/or as a result of the ageing process, both immediate and long-term, and attempt to disentangle which changes relate to either tinnitus or hyperacusis, as opposed to solely hearing loss. Understanding these changes is ultimately important to reversing the underlying pathology and treating these conditions.
Trauma to the ear, either by ototoxic drugs or acoustic over-exposure (AOE) or simply as a result of ageing, can result in hearing loss. Age-related hearing loss (ARHL) or presbycusis is the major cause of hearing problems in elderly people. It is usually, but not always, associated with a progressive elevation in hearing thresholds and its prevalence increases with age so that it affects almost two-thirds of adults in their mid-70s (Gopinath et al., 2009). With or without elevation of thresholds, with ageing there can be a deterioration in speech intelligibility, temporal processing, and sound localization (Lee, 2013; Strouse, Ashmead, Ohde, & Grantham, 1998). Many factors may trigger or exacerbate ARHL, including lifetime exposure to environmental noise; exposure to ototoxic agents; or dietary, metabolic, hormonal or vascular changes (Masoro, 1991). There is, however, a considerable genetic component at least of ARHL of cochlear origin, with many genes that either contribute to noise-induced hearing loss (NIHL), promote ARHL, or promote both NIHL and ARHL (e.g., Ohlemiller, 2006). In humans, Schuknecht defined three forms of presbycusis (based on the analysis of human temporal bones) that affect different elements of the transduction process: sensory, neural, and metabolic (Schuknecht, 1955, 1964). A variety of aetiologies of ARHL has been described for different rodent models in the auditory periphery (Fetoni, Picciotti, Paludetti, & Troiani, 2011). In addition, ageing results in other widespread changes in morphology and neurochemistry of the whole brain (e.g., Banay-Schwartz, Lajtha, & Palkovits, 1989; McGeer & McGeer, 1975), and age-related changes have been documented at all stations of auditory processing within the central nervous system from cochlear nucleus to auditory cortex (Caspary, Ling, Turner, & Hughes, 2008).
Hearing loss (as a result of ageing or AOE) is considered the most common trigger for chronic tinnitus, a phantom auditory sensation in the absence of an external stimulus (Eggermont & Roberts, 2004). Tinnitus is extremely widespread, affecting 8–15% of the adult population (Shargorodsky, Curhan, & Farwell, 2010). Historically, the causes of tinnitus were assumed to be within the inner ear, although studies demonstrating its persistence following severance of the auditory nerve or ablation of the cochlea indicated that central auditory system changes must contribute to the phantom percept (House & Brackmann, 1981; Zacharek, Kaltenbach, Mathog, & Zhang, 2002). As an important center for binaural integration from the two ears, as well as a near-obligatory relay for ascending auditory information, the inferior colliculus (IC) has been proposed as a key structure in the generation and maintenance of subjective tinnitus (Robertson, Bester, Vogler, & Mulders, 2012).
Concurrently with the presence of tinnitus, hyperacusis—an oversensitivity to loud sounds—can also occur following cochlear trauma, and tinnitus is comorbid in up to 86% of patients with hyperacusis (Anari, Axelsson, Eliasson, & Magnusson, 1999), findings that suggest common underlying aetiologies. Here, we discuss immediate and early changes in the IC following different types of cochlear trauma and examine pathophysiology in the IC that could underlie hyperacusis. We then examine long-term changes and consider evidence linking these to tinnitus, attempting to identify alterations solely related to hearing loss wherever possible. We also assess how the IC changes as a result of age-related hearing loss (presbycusis). Finally, we discuss how pathological IC activity may be modulated by various interventions.
Noise-Induced Hearing Loss and Its Sequelae
Immediate and Short-Term Changes Following Cochlear Trauma
Here we describe immediate and short-term changes (defined as ≤ 30 days after the insult) that occur in the IC following damage to the cochlea. Spontaneous firing rates (neural activity during silence) appear either unchanged immediately after an acoustic trauma (Dong, Mulders, Rodger, Woo, & Robertson, 2010; Groschel, Ryll, Gotze, Ernst, & Basta, 2014; Wang, Salvi, & Powers, 1996) or even decreased (Niu, Kumaraguru, Wang, & Sun, 2013), but significant increases are usually evident within 12 hours (Mulders & Robertson, 2013). This increase in spontaneous firing is persistent and evident between 1 to 4 weeks later (Hesse et al., 2016; Manzoor, Gao, Licari, & Kaltenbach, 2013; Mulders & Robertson, 2013; Vogler, Robertson, & Mulders, 2014; Wang et al., 2013). Initially, increased spontaneous activity appears to occur over a broad range of frequencies and later narrows to frequencies corresponding to the region of hearing loss (Manzoor et al., 2013; Mulders & Robertson, 2013; Vogler et al., 2014). Such increased spontaneous activity may be caused by a shift in the balance of excitatory and inhibitory inputs to GABAergic and glutamatergic IC neurons observed after noise exposure (Sturm, Zhang-Hooks, Roos, Nguyen, & Kandler, 2017). Similar changes in spontaneous activity are found in recordings from mouse brain slices, but over different time courses—either no change or a reduction in IC spontaneous firing after 1 week, with hyperactivity only apparent 2 weeks after noise exposure (Basta & Ernst, 2005; Groschel et al., 2014). However, it is possible that these differences are a result of the type of recording (in vivo vs. in vitro), as in vivo neural responses may be affected by input from other auditory regions. Certainly, there is evidence that ablation or lesioning of the cochlea or dorsal cochlear nucleus (DCN) can reduce or prevent IC hyperactivity in the early stages of changes following noise exposure (Brozoski, Wisner, Sybert, & Bauer, 2012; Manzoor et al., 2012; Mulders & Robertson, 2009), thereby suggesting a dependence on ascending input.
A number of studies have examined evoked activity following an acoustic insult. Recently, Sheppard et al. (2017) demonstrated that long-term exposure to low-level noise produced enhanced evoked responses immediately after the exposure, despite a reduction in suprathreshold compound action potential (CAP) amplitudes. One week later, IC local field potential amplitudes were enhanced at frequencies corresponding to the noise exposure but suppressed at frequencies above, while CAP amplitudes were also enhanced at this time point. Wang et al. (2002) also demonstrated enhancements in IC responses within 24 hours after noise exposure, at frequencies below the hearing loss, possibly reflecting a decrease in inhibition at these frequencies (as observed in Heeringa & van Dijk, 2016). However, changes in IC-evoked firing rates following noise trauma, as with other changes, may depend on the specific subregion recorded from the central nucleus (CNIC), external nucleus (ICx), or dorsal cortex (ICd). Szczepaniak and Moller (1996b) demonstrated that during exposure to loud tones, generally considered non-traumatic (either 95 dB or 104 dB SPL), click-evoked responses recorded from neurons in the ICx in rats were reduced compared to pre-exposure. However, 15 minutes after exposure, the same responses were significantly larger than baseline recordings, possibly reflecting some degree of hypersensitivity. All such changes could indicate evidence of a neural basis for hyperacusis.
Contrary to these studies, both Popelar et al. (1987) and Sun et al. (2012) demonstrated decreases in IC sound-evoked activity 1 hour following acoustic trauma. Recordings were made from the CNIC in Popelar et al. (1987), while the precise recording location was not specified in Sun et al. (2012), although it is possible that these responses could be restricted to the CNIC. Therefore, extra-lemniscal IC regions, such as the ICx, are likely to exhibit responses different to those from the CNIC following noise exposure. This is perhaps unsurprising, as there are fundamental differences in input between the subregions: the CNIC receives much of its afferent input from the cochlear nucleus, superior olivary complex, and lateral lemniscus, while ICx has many multisensory connections and ICd primarily receives descending input (see Huffman & Henson, 1990).
Corresponding to and probably underlying such functional alterations, there are clear changes in neurotransmission in the short term following cochlear trauma. Extensive evidence indicates that GABAergic inhibition is altered rapidly following noise exposure, which could underlie changes in spontaneous firing rates, although the time courses over which these changes take place vary between studies. Levels of the glutamic acid decarboxylase (GAD) isoform GAD67, the primary enzyme in producing gamma-aminobutyric acid (GABA), were elevated immediately after noise exposure (Abbott, Hughes, Bauer, Salvi, & Caspary, 1999). Two to 30 days later, levels of GAD67 and another isoform, GAD65, were decreased compared to controls. Similarly, Argence et al. (2006) demonstrated that unilateral cochleotomy resulted in a decrease of GAD67 and glycine receptor α1 subunits in contralateral CNIC, starting one day after the procedure and continuing until 8 days later, at which point both measures remained low. Furthermore, Dong et al. (2010) observed that two weeks after noise exposure GABAAα1 subunit expression, which is related to fast inhibitory neurotransmission, decreased in areas of the IC corresponding to frequencies close to the exposure frequency. Complete destruction of the organ of Corti also downregulated GAD67 and GABAtp (another gene associated with inhibitory transmission), although downregulation was also apparent for VGLUT2, which is associated with excitatory neurotransmission (Fyk-Kolodziej et al., 2015). However, there are likely to be significant differences between changes induced by widespread mechanical trauma compared with noise exposure (which is more focused).
All of these studies indicate a net decrease in inhibition following trauma to the periphery. Although Suneja et al. (1998) actually found an increase in GABA release following both cochlear ablation and ossicle removal, this was combined with a decrease in GABA uptake, again suggesting that inhibition was pathologically altered. By contrast, Tan et al. (2007) found an increase in GABA-positive neurons, in conjunction with an elevation in brain-derived neurotrophic factor (BDNF) 6 days after noise exposure, which may be an indication of synaptic plasticity induced by the trauma. Shorter-term increases in BDNF activation were also evident 30 minutes following noise exposure (Meltser & Canlon, 2010), which coincides with an increase in c-fos expression (Saint Marie, Luo, & Ryan, 1999), although here increases in BDNF were no longer significant 24 hours later. Milbrandt et al. (2000) also demonstrated that GAD65 in IC was decreased following noise exposure, both immediately after and 48 hours later, but this completely recovered 30 days post-exposure. However, [3H]muscimol binding was increased at this time point, which is indicative of an increase in GABAA binding sites. Interestingly, Holt et al. (2010) demonstrated that the ICd was the only auditory area with an increase in manganese uptake two days after noise exposure, which is suggestive of increased glutamatergic activity (Takeda, 2003). Therefore, although there is a general consensus that IC neurotransmission is altered following cochlear trauma, there is clearly complexity in how these changes take place.
Long-Term Changes Following Cochlear Trauma
Spontaneous firing rates in the IC remain increased in the long term (> 30 days) following trauma to the cochlea (Berger, Coomber, Wells, Wallace, & Palmer, 2014; Coomber et al., 2014; Longenecker & Galazyuk, 2016; Mulders & Robertson, 2011; Ropp, Tiedemann, Young, & May, 2014; Vogler, Robertson, & Mulders, 2016). Given that evidence of chronic tinnitus-like behavior can take up to 5–8 weeks to emerge (e.g., Turner, Larsen, Hughes, Moechars, & Shore, 2012), this is a time at which it becomes important to differentiate between changes underlying tinnitus compared to those that are simply a result of the noise exposure. Although increases in spontaneous firing rate have classically been considered an underlying contributor to the perception of tinnitus, recent studies, demonstrating no differences between animals with behavioral evidence of tinnitus and those without, raise the possibility that these increases may simply be a product of the hearing loss but not necessarily associated with tinnitus (Coomber et al., 2014; Longenecker & Galazyuk, 2016; Ropp et al., 2014). Furthermore, one recent study demonstrated that repetitive transcranial magnetic stimulation in guinea pigs successfully eliminated behavioral evidence of tinnitus, although IC hyperactivity (increased spontaneous activity) remained unchanged (Mulders, Vooys, Makowiecki, Tang, & Rodger, 2016).
It appears that there is a time-dependent change in the way that increased spontaneous activity is maintained within the IC following noise exposure. Cochlear ablation within 6 weeks can reverse noise-induced hyperactivity (Mulders & Robertson, 2009) but is ineffective beyond this time (Mulders & Robertson, 2011). Furthermore, DCN ablation in the first few weeks following an acoustic insult significantly reduced noise-induced IC hyperactivity (Manzoor et al., 2012). This is supported by evidence indicating that bilateral DCN lesions prior to noise exposure prevented tinnitus-like behavior from emerging (Brozoski et al., 2012), although DCN ablation 3–5 months after acoustic trauma did not reverse preexisting tinnitus-like behavior (Brozoski & Bauer, 2005). However, it is possible that there may still be some dependence on peripheral input at this later stage, as Ropp et al. (2014) demonstrated that IC neurons receiving VCN input were hyperactive 1–4 months following noise exposure, whereas those receiving DCN input were not. Further research is required to determine whether the VCN modulates noise-induced changes in IC activity in the long term. In summary, the evidence just described suggests that IC hyperactivity is generally dependent on ascending input in the short term following noise exposure, but it may later become intrinsic.
There are distinct changes in the firing patterns of IC neurons following long-term recovery from noise exposure. Several weeks after noise exposure, patterns of burst firing emerge, which are associated with increased neural synchrony (Bauer, Turner, Caspary, Myers, & Brozoski, 2008; Coomber et al., 2014). These bursting patterns occur at the same time as a shift in the balance of response profiles, whereby the proportion of IC onset-type responses increases, along with a decrease in sustained responses (Berger et al., 2014), although these were evident regardless of the presence behavioral evidence of tinnitus. Furthermore, noise exposure in juvenile rats can impair sound processing (frequency selectivity) in adulthood: the dynamic range of IC neurons is reduced, inhibitory sidebands are reduced, and excitatory areas are expanded (Bures, Grecova, Popelar, & Syka, 2010; Grecova, Bures, Popelar, Suta, & Syka, 2009).
There is limited evidence for some form of tonotopic reorganization of the IC 1–10 months following noise exposure (Izquierdo, Gutierrez-Conde, Merchan, & Malmierca, 2008), although this reorganization does not occur in the same manner or to the same extent as in the auditory cortex and may simply be a passive process. There is also evidence of changes in IC neurotransmitters which persist following long-term recovery. Three to sixteen weeks following noise trauma, decreases in the density of serotonergic fibers in the CNIC are evident, an effect that is exacerbated in aging mice (Papesh & Hurley, 2012). Given that the neuromodulatory serotonergic system appears to be involved in regulating plasticity, this could reflect plastic changes, underlying alterations in neuronal firing rates, caused by the noise exposure.
Browne et al. (2012) demonstrated that although GAD67 levels were decreased in contralateral IC 4 days after noise exposure, these were at near-normal levels 32 days after. Expression of N-methyl-d-aspartate receptor subunit 2A in the IC, related to excitatory neurotransmission, was decreased at this later time point. Although this seems surprising, given the wealth of evidence showing that firing rates are increased, the authors suggested that reduced excitatory transmission might be to compensate for the hyperactivity. Five months after noise exposure, glutamate and aspartate (related to glutamate synthesis) levels were increased. At that time there was also an unexpected increase in GABA and decreased taurine production, possibly linked to GABA or glycine function (Godfrey et al., 2012). Therefore, while levels of GABA were increased, it is possible that inhibitory function in the IC may have decreased.
Age-Related Changes in the Inferior Colliculus
The standard paradigm for investigating ARHL has been to compare young and old individuals of the same strain. This has been facilitated by using rodent models with shorter lifespans and further by using strains that have accelerated ARHL (see Hazzard & Soban, 1988 for early examples). Most of these models exhibit a progressive hearing loss and this is particularly pronounced in the C57BL/6 strain investigated at the inferior colliculus level by Willott (1986). In this strain, the progressive hearing loss of cochlear origin starts at high-frequency and leads to broader frequency tuning and an enhancement of mid-frequency hearing in the IC, before almost total hearing loss at only 14 months of age. The hearing loss is of cochlear origin in these mice, but there are significant changes in the inferior colliculus of C57BL/6 mice that accompany the hearing loss, which include decrease in the size of principal neurons, reduced numbers of synapses on principal neurons, and a reduction in the area of the soma covered by synapses (Kazee et al., 1995). This very rapid and profound progression of hearing loss is a little extreme compared to other strains (Willott, 1986), and in subsequent work investigators have tended to use other models such as CBA mice or Fischer 344 rats, which do eventually show high-frequency hearing loss but not as early or as profoundly, more in keeping with most human presbycusis. Indeed, the changes in principal cells and synapses, found with ageing in C57BL/6 mice, appear not to occur in CBA mice (Kazee & West, 1999). This suggests that synaptic changes may be a result of the reduced afferent inflow rather than ageing per se. In rats, at least, it is unlikely that presbycusis is mainly associated with changes in the total number of neurons in the IC (Burianova, Ouda, & Syka, 2015).
Despite progressive hearing loss (reaching profound levels) with ageing, the projections from the ventral cochlear nucleus and superior olive to the IC remain stable (Byrd, Frisina, Lynch-Armour, & Walton, 1995; Willott, Pankow, Hunter, & Kordyban, 1985), although one report suggests that inputs from all divisions of the cochlear nucleus to the inferior colliculus decline with age (Lynch-Armour, Frisina, McReynolds, Byrd, & Walton, 1995). Clearly, any ARHL effects that are described at the level of the inferior colliculus can have several elements, some of which may be inherited from lower levels or result from descending influences from higher levels.
Changes to Neurotransmitter Systems with Ageing
As we described earlier, reduced afferent inflow to the inferior colliculus as a result of a variety of causes, including noise overexposure, manifests as significant changes, particularly in the inhibitory (GABAergic) neurotransmission systems. It is not yet known whether changes in the IC with ageing are occurring at this level for the first time or whether they are a consequence of the gradual loss of afferent input as result of age-related changes in the cochlea. However, there are age-related changes in the neurotransmitter systems that occur at the level of the inferior colliculus that may not necessarily reflect peripheral hearing loss, nor appear to simply mirror changes taking place in the rest of the brain. Some morphological changes occur with ageing such as a reorganization of the synaptic endings on the soma and dendrites (Helfert, Sommer, Meeks, Hofstetter, & Hughes, 1999). The exact functional significance of such alterations is unknown, but more obviously functional are a range of different indicators of GABAergic synaptic transmission that have all been shown to change with age. Presynaptically these include a reduction in the number of GABA immunostained neurons (Caspary et al., 1990); reductions in the levels of GABA (Banay-Schwartz et al., 1989; Caspary, Raza, Lawhorn Armour, Pippin, & Arneric, 1990) and in GABA receptor subunits (Gutierrez, Khan, Morris, & De Blas, 1994); reduction in GAD activity (Burianova, Ouda, Profant, & Syka, 2009; Gutierrez et al., 1994); and reduced GABAA and GABAB receptor binding (Milbrandt, Albin, & Caspary, 1994; Milbrandt, Albin, Turgeon & Caspary 1996).
There are also (possibly as a consequence of thepresynaptic changes already described) age-related alterations in the postsynaptic GABA receptor. The GABA receptor consists of pentameric subunit complexes, and with ageing there is a significant downregulation of the α1 subunit and an upregulation of the α3 and γ1 subunits (Caspary et al., 1999; Gutierrez et al., 1994; Milbrandt, Hunter, & Caspary, 1997). Co-expression of various subunits with the γ1 produces an increase in the GABA affinity (Caspary et al., 1999; Milbrandt et al., 1997), which is confirmed by oocyte expression studies and microsac/synapsosome preparations (Caspary et al., 1999; Ducic, Caruncho, Zhu, Vicini, & Costa, 1995). Aquaporin expression changes transiently with ageing in the IC, which may also have an effect on neurotransmitter cycling (Christensen, D'Souza, Zhu, & Frisina, 2009). A combination of all of these factors suggests an age-related reduction in inhibitory function in the inferior colliculus (Caspary, Milbrandt, & Helfert, 1995).
Excitatory neurotransmission in the IC is also altered in ageing. Subunits of the N-methyl-d-aspartate receptor are downregulated and nitric oxide signaling is reduced (Jung, Na, & Huh, 2012; Osumi et al., 2012; Sanchez-Zuriaga, Marti-Gutierrez, De La Cruz, & Peris-Sanchis, 2007). Glutamate related genes are also altered in expression with ageing and hearing loss, leading on the one hand to increased glutamate availability (and possibly toxicity) and, on the other, to an upregulation of a high affinity glutamate transporter that may be compensatory (Tadros et al., 2007).
While the relationship of various calcium-binding proteins to neurotransmission is not fully understood, these proteins are still useful markers of distinct neuronal types and have been shown to change in the ageing IC. Calbindin is present only in the nucleus of the commissure of the inferior colliculus but declines by up to 25% in ageing mice, whereas Calretinin is absent in the central nucleus of the IC but high in the pericentral regions (dorsal cortex and external nucleus), where there was a 40–60% increase in immunoreactivity for calretinin with ageing in CBA mice but not C57 mice (Zettel, Frisina, Haider, & O’Neill, 1997). Parvalbumin (co-expressed in GABAergic neurons) immunoreactivity changes in ageing, but in a strain-dependent manner such that an increase was found in Long Evans rat IC but a decrease in Fischer 344 rat cortex (Ouda, Druga, & Syka, 2008). Parvalbumin is also upregulated in the IC of ageing macaques (Engle, Gray, Turner, Udell, & Recanzone, 2014).
Age-Related Changes in Inferior Colliculus Physiological Responses
Mentioned earlier (Willott, 1986), are changes in responses in the IC in C57BL/6 mice that are consequent on threshold elevations due to peripheral pathology (Fetoni et al., 2011). These changes in frequency responsiveness and tuning affect the tonotopic arrangement in the IC, as also documented using 2-deoxyglucose labelling in rats (Keithley, Lo, & Ryan, 1994). In C57BL/6 mice there was an increase with age in the numbers of spontaneously active neurons, an increase in poorly responsive neurons and pronounced changes in frequency tuning (Willott, Parham, & Hunter, 1988). However, the effect of ageing is, perhaps not surprisingly, species and strain specific (given the different pathologies). In ageing CBA mice, major threshold elevation and changes in tonotopic organization do not occur, with mostly normal activity retained (Walton, Frisina, & O'Neill, 1994; Willott, 1986), although changes in spontaneous rates and the proportion of poorly responsive neurons have been reported (Willott et al., 1988). However, a detailed study of ageing CBA frequency response areas (FRAs; Leong, Barsz, Allen, & Walton, 2011) indicated broader and more symmetric FRAs in middle-aged and old mice, with fewer closed response areas and consequently an increase in monotonic rate level functions. Many of the usual response characteristics can be unchanged in ageing animals: for example in the inferior colliculus of Fischer 344 rats, with only modest threshold elevations of about 30 dB, spontaneous rate, first-spike latency, dynamic range, the proportion of non-monotonic rate level functions, and sensitivity to tone presentation rate show no differences with ageing (Palombi & Caspary, 1996). There were, however, somewhat more subtle changes with ageing in these rats: more units were unresponsive, the maximum discharge rate was lower (by 12%), 12% more units were onset responders, and the iso-intensity functions were 18% wider. Overall, however, neurons in these rats responded to most simple auditory stimuli like those in young animals.
Across a range of studies in different animal models, a consistent finding is that temporal coding measured by a variety of metrics is worse in the ageing inferior colliculus. Fine temporal coding is important for speech recognition and localization, both of which are poorer in elderly individuals (e.g., Gordon-Salant & Fitzgibbons, 1993; Strouse et al., 1998). In particular, the ability to identify gaps in sound is important and this has been the focus of several studies of neural responses in ageing mice. Interestingly, there are neurons in aged CBA mice that have minimal gap detection thresholds of only 1–2 ms, which matches the behaviorally measured ability (Walton, Frisina, Ison, & O'Neill, 1997, Walton, Frisina & Meierhans, 1995). The main difference is, however, that such neurons (which have onset or phasic responses to tone bursts) are much less common in the aged animals (Walton, Frisina, & O'Neill, 1998). In addition, the recovery of the response after the silent gap was generally slower and less complete in neurons from aged animals. A similar increased recovery time has been found using gross potentials such as the auditory brainstem response (Allen, Burkard, Ison, & Walton, 2003) and paired tones (Finlayson, 2002).
Equally important for the discrimination of species-specific vocalizations are fluctuations in amplitude and frequency. Sensitivity to such fluctuations has been studied with sinusoidal amplitude modulated signals and with frequency sweeps. Somewhat surprisingly, although there is a deterioration in sensitivity to the speed of frequency- modulated sweeps in the auditory cortex, this is not evident at the level of the inferior colliculus (Lee, Wallani, & Mendelson, 2002; Mendelson & Lui, 2004). Sensitivity to amplitude modulation in IC is, however, affected by the ageing process. Responses to amplitude modulation are usually quantified using modulation transfer functions (MTFs). These plot either the discharge rate (the rate MTF or rMTF) or the activity locked to the modulation envelope (the temporal MTF or tMTF) as a function of the modulation rate. In young Fischer 344 rats the tMTFs were more commonly band-pass in shape, whereas in older rats the tMTFs were more commonly low-pass in shape, while the proportions of rMTF shapes were similar across the ages, as was the response gain and median maximum discharge rate (Shaddock Palombi, Backoff, & Caspary, 2001).
In aged CBA mice, by using noise carriers the overall response rate to amplitude modulated stimuli was increased by a factor about two and the median upper cut-off frequency of the rMTFs was reduced to about half that in young mice (Walton, Simon, & Frisina, 2002).
In the ageing gerbil there is a decrease in the selectivity to temporally variable pulse trains leading to an increase in signal correlations such that the population response as a whole becomes more homogeneous and less efficient in coding complex sounds (Khouri, Lesica, & Grothe, 2011). A similar result has recently been shown in the auditory cortex of ageing Macaques (Chi-Wing & Recanzone, 2017).
Finally, middle-aged mice C57BL/6J are less able to benefit from spatial separation of signal and masker (McFadden & Willott, 1994) presumably again as a result of the loss of fine temporal coding.
Modulation of Pathological IC Activity
Despite the fact that there is no uniformly effective treatment for either tinnitus or hyperacusis, a number of studies have demonstrated modulation of noise-induced pathological activity related to these conditions in the IC. On the basis that inhibition is suppressed following cochlear trauma, Szczepaniak and Moller (1996a) successfully attenuated noise-induced sound-evoked hyperactivity by systemically administering a GABAB agonist, L-baclofen, to rats. Although L-baclofen, administered at a high dose, also diminished behavioral evidence of tinnitus in rats (Zheng, Vagal, McNamara, Darlington, & Smith, 2012), its efficacy as a treatment in humans is highly variable (Smith, Zheng, & Darlington, 2012), and in some cases it may actually induce tinnitus (Auffret et al., 2014). In a similar scenario, noise-induced hyperactivity in the IC and behavioral evidence of tinnitus have both been suppressed in guinea pigs by acute and chronic administration of the diuretic furosemide (Mulders, Barry, & Robertson, 2014; Mulders, McMahen, & Robertson, 2014). However, once again, although in some patients intravenous administration of furosemide reduced their symptoms of tinnitus (Risey, Guth, & Amedee, 1995), in high doses it may actually cause tinnitus (see Salvi, Lobarinas, & Sun, 2009 for a review).
A phenomenon known as residual inhibition, whereby tinnitus can be temporarily suppressed or eliminated following presentation of a particular auditory stimulus, is evident to some degree in approximately 70% of patients (Roberts, Moffat, & Bosnyak, 2006). Voytenko and Galazyuk (2011) proposed a possible underlying mechanism for residual inhibition, demonstrating that the spontaneous firing of single IC neurons may be suppressed following the presentation of a short stimulus, an effect that was mediated by metabotropic glutamate receptors. Furthermore, Galazyuk et al. (2017) recently demonstrated that this effect is present in approximately 40% of spontaneously active IC neurons, and is similarly evident in animals with behavioral evidence of noise-induced tinnitus, wherein IC neurons were hyperactive. While this method only provides temporary cessation of the phantom percept, it offers a promising tool for examining neuronal states with and without the presence of tinnitus, and further implies a possible role for the IC in the modulation of tinnitus.
A number of studies have examined electrical stimulation of the inferior colliculus as a potential basis for development of an auditory midbrain implant. Offutt et al. (2014) demonstrated that direct electrical stimulation of the ICd resulted in modulation of CNIC firing that persisted after stimulation had ceased, which they proposed as a possible methodology for treating tinnitus. In a follow-up to this study, Smit et al. (2016) found that stimulation of ICx in rats suppressed noise-induced deficits in behavioral gap detection, consistent with the reduction of tinnitus-like behavior. Furthermore, a recent study showed that electrical IC stimulation can result in frequency percepts that correlate with the frequency tuning of the IC (Pages et al., 2016), thus suggesting that this may also be an effective treatment for hearing loss in humans who would not be suitable candidates for cochlear implants. It has also been demonstrated that stimulation of the round window of the cochlea within two-to-three weeks after noise exposure can suppress hyperactivity in IC neurons (Mulders, Spencer, & Robertson, 2016; Norena, Mulders, & Robertson, 2015).
One consideration when examining modulation of noise-induced IC pathology is the time after noise exposure at which interventions are employed. As described earlier, there may be a particular temporal window following a traumatic event, during which time the dependence of the IC on peripheral activity allows treatments that target the cochlea, auditory nerve, or cochlear nucleus to also affect IC activity. However, if IC pathology underlies or contributes to tinnitus or hyperacusis, any treatments targeting the periphery at a later time may not be successful. Clearly, the complexity in the development of tinnitus over time, as well as the uncertainty in differentiating between noise-induced pathology and tinnitus-specific pathology, complicates this process.
Conclusions and Discussion
A finding common to NIHL and ARHL is that there are changes to the machinery of neurotransmitter release in the inferior colliculus. This has been extensively studied for the inhibitory neurotransmitter GABA, and it has been shown that several factors combine to make GABA less available in both NIHL and ARHL. It is somewhat surprising therefore that many studies of ARHL fail to reveal large changes in the physiological response profiles, although other detailed analyses do indeed reveal somewhat subtle changes. Such findings have prompted several authors to suggest that there are compensatory changes occurring in both excitatory and inhibitory neurotransmission (Caspary et al., 1999; Helfert, Sommer, Hughes, Jeffery, & Caspary, 1994; Mendelson & Lui, 2004). In the case of GABA, the presynaptic downregulation and other changes that make GABA less available are offset by a change in the subunit structure, which increases the efficacy of the GABA receptors in transporting chloride ions. In ageing there is also a downregulation in excitatory amino acids such that the balance of excitation and inhibition is less disrupted by the changes in GABA. It is unclear whether changes in neurotransmission due to NIHL and those due to ARHL are both initiated by reduction in afferent activity, since the changes in ARHL appear to occur in some instances without large threshold elevations. A consistent finding, at least in ARHL, is that the temporal coding in the IC is somewhat disrupted, which could provide some basis for the poorer discrimination and speech intelligibility shown by subjects with ARHL.
Hearing loss of cochlear origin that generates a profound high-frequency loss with a sharp frequency transition (beyond an “edge-frequency”) can result in long-term plastic changes in the tonotopic mapping in the auditory cortex (Eggermont & Komiya, 2000; Robertson & Irvine, 1989). This takes the form of a spread of the sensitivity to the edge-frequency across the deafferented cortex. This active reorganization of tonotopy has not been reported in the IC, despite experiments specifically designed to reveal such changes, although some degree of passive reorganization may occur (Irvine, Rajan, & Smith, 2003; Izquierdo et al., 2008).
NIHL has been reported to result in increased spontaneous discharge rates at a variety of levels in the auditory pathway, not least in the inferior colliculus (e.g., Coomber et al., 2014; Mulders & Robertson, 2009; Ropp et al., 2014). This increase has been linked to the changes in neurotransmission suggesting increased “gain” in the processing circuitry (Schaette & McAlpine, 2011). The higher spontaneous rates have been cited as a possible correlate of tinnitus. However, several studies have now shown that such changes in spontaneous rate can be found in all animals that have been subject to damaging levels of noise whether or not there is any behavioral evidence of tinnitus (Coomber et al., 2014; Longenecker & Galazyuk, 2016; Ropp et al., 2014).
Although changes in the IC after NIHL and ARHL seem to correlate in some instances with conditions such as tinnitus, hyperacusis, and presbycusis, it is unclear whether this is merely a correlation or causal. Are other changes taking place (for example, at the auditory cortex) more appropriate mechanisms of tinnitus and hyperacusis and therefore more appropriate targets for intervention? What is it in the ascending input to the IC that is initiating or driving the changes in neurotransmission that eventually become more permanent and independent of peripheral input?
It is known that an enriched auditory environment can alleviate reorganization of auditory cortex caused by severe high-frequency hearing loss (Norena & Eggermont, 2005). It is also clear that enrichment following noise trauma can prevent reorganization of the IC with concomitant alleviation of behavioral indices of pathology (Sturm et al., 2017). It is yet to be determined, however, whether any practical therapy involving acoustic enrichment immediately following acoustic insults will be effective in humans.
Further research is also required to determine whether the VCN modulates noise-induced changes in IC activity in the long term.
Abbott, S. D., Hughes, L. F., Bauer, C. A., Salvi, R., & Caspary, D. M. (1999). Detection of glutamate decarboxylase isoforms in rat inferior colliculus following acoustic exposure. Neuroscience, 93(4), 1375–1381. doi:S0306-4522(99)00300-0 [pii]Find this resource:
Allen, P. D., Burkard, R. F., Ison, J. R., & Walton, J. P. (2003). Impaired gap encoding in aged mouse inferior colliculus at moderate but not high stimulus levels. Hearing Research, 186(1–2), 17–29. doi:S0378595503003009 [pii]Find this resource:
Anari, M., Axelsson, A., Eliasson, A., & Magnusson, L. (1999). Hypersensitivity to sound—questionnaire data, audiometry and classification. Scandinavian Audiology, 28(4), 219–230.Find this resource:
Argence, M., Saez, I., Sassu, R., Vassias, I., Vidal, P. P., & de Waele, C. (2006). Modulation of inhibitory and excitatory synaptic transmission in rat inferior colliculus after unilateral cochleectomy: an in situ and immunofluorescence study. Neuroscience, 141(3), 1193–1207. doi:10.1016/j.neuroscience.2006.04.058Find this resource:
Auffret, M., Rolland, B., Deheul, S., Loche, V., Hennaux, C., Cottencin, O., … Team, C. (2014). Severe tinnitus induced by off-label baclofen. Annals of Pharmacotherapy, 48(5), 656–659. doi:10.1177/1060028014525594Find this resource:
Banay-Schwartz, M., Lajtha, A., & Palkovits, M. (1989). Changes with aging in the levels of amino acids in rat CNS structural elements. II. Taurine and small neutral amino acids. Neurochemical Research, 14(6), 563–570.Find this resource:
Basta, D., & Ernst, A. (2005). Erratum to “Noise-induced changes of neuronal spontaneous activity in mice inferior colliculus brain slices.” Neuroscience Letters, 374(1), 74–79.Find this resource:
Bauer, C. A., Turner, J. G., Caspary, D. M., Myers, K. S., & Brozoski, T. J. (2008). Tinnitus and inferior colliculus activity in chinchillas related to three distinct patterns of cochlear trauma. Journal of Neuroscience Research, 86(11), 2564–2578. doi:10.1002/jnr.21699Find this resource:
Berger, J. I., Coomber, B., Wells, T. T., Wallace, M. N., & Palmer, A. R. (2014). Changes in the response properties of inferior colliculus neurons relating to tinnitus. Frontiers of Neurology, 5, 203. doi:10.3389/fneur.2014.00203Find this resource:
Browne, C. J., Morley, J. W., & Parsons, C. H. (2012). Tracking the expression of excitatory and inhibitory neurotransmission-related proteins and neuroplasticity markers after noise induced hearing loss. PLOS One, 7(3). doi:10.1371/journal.pone.0033272Find this resource:
Brozoski, T. J., & Bauer, C. A. (2005). The effect of dorsal cochlear nucleus ablation on tinnitus in rats. Hearing Research, 206(1–2), 227–236. doi:10.1016/j.heares.2004.12.013Find this resource:
Brozoski, T. J., Wisner, K. W., Sybert, L. T., & Bauer, C. A. (2012). Bilateral dorsal cochlear nucleus lesions prevent acoustic-trauma induced tinnitus in an animal model. Journal of the Association for Research in Otolaryngology, 13(1), 55–66. doi:10.1007/s10162-011-0290-3Find this resource:
Bures, Z., Grecova, J., Popelar, J., & Syka, J. (2010). Noise exposure during early development impairs the processing of sound intensity in adult rats. European Journal of Neuroscience, 32(1), 155–164. doi:10.1111/j.1460-9568.2010.07280.xFind this resource:
Burianova, J., Ouda, L., Profant, O., & Syka, J. (2009). Age-related changes in GAD levels in the central auditory system of the rat. Experimental Gerontology, 44(3), 161–169. doi:10.1016/j.exger.2008.09.012Find this resource:
Burianova, J., Ouda, L., & Syka, J. (2015). The influence of aging on the number of neurons and levels of non-phosphorylated neurofilament proteins in the central auditory system of rats. Frontiers in Aging Neuroscience, 7, 27. doi:10.3389/fnagi.2015.00027Find this resource:
Byrd, J., Frisina, R. D., Lynch-Armour, M. A., & Walton, J. P. (1995). Superior olivary complex inputs to the dorsomedial inferior colliculus of the CBA mouse model of presbycusis remain stable with age. Journal of the Association for Research in Otolaryngology, Abstr. 18, 174.Find this resource:
Caspary, D. M., Holder, T. M., Hughes, L. F., Milbrandt, J. C., McKernan, R. M., & Naritoku, D. K. (1999). Age-related changes in GABA(A) receptor subunit composition and function in rat auditory system. Neuroscience, 93(1), 307–312. doi:S0306-4522(99)00121-9 [pii]Find this resource:
Caspary, D. M., Ling, L., Turner, J. G., & Hughes, L. F. (2008). Inhibitory neurotransmission, plasticity and aging in the mammalian central auditory system. Journal of Experimental Biology, 211(Pt 11), 1781–1791. doi:10.1242/jeb.013581Find this resource:
Caspary, D. M., Milbrandt, J. C., & Helfert, R. H. (1995). Central auditory aging: GABA changes in the inferior colliculus. Experimental Gerontology, 30(3–4), 349–360.Find this resource:
Caspary, D. M., Raza, A., Lawhorn Armour, B. A., Pippin, J., & Arneric, S. P. (1990). Immunocytochemical and neurochemical evidence for age-related loss of GABA in the inferior colliculus: Implications for neural presbycusis. Journal of Neuroscience, 10(7), 2363–2372.Find this resource:
Chi-Wing, N., & Recanzone, G. H. (2017). Age-related changes in temporal processing of rapidly-presented sound sequences in the Macaque auditory cortex. Cerebral Cortex, 13, 1–22.Find this resource:
Christensen, N., D'Souza, M., Zhu, X., & Frisina, R. D. (2009). Age-related hearing loss: Aquaporin 4 gene expression changes in the mouse cochlea and auditory midbrain. Brain Research, 1253, 27–34. doi:10.1016/j.brainres.2008.11.070Find this resource:
Coomber, B., Berger, J. I., Kowalkowski, V. L., Shackleton, T. M., Palmer, A. R., & Wallace, M. N. (2014). Neural changes accompanying tinnitus following unilateral acoustic trauma in the guinea pig. European Journal of Neuroscience, 40(2), 2427–2441. doi:10.1111/ejn.12580Find this resource:
Dong, S., Mulders, W. H., Rodger, J., Woo, S., & Robertson, D. (2010). Acoustic trauma evokes hyperactivity and changes in gene expression in guinea-pig auditory brainstem. European Journal of Neuroscience, 31(9), 1616–1628. doi:10.1111/j.1460-9568.2010.07183.xFind this resource:
Dong, S., Rodger, J., Mulders, W. H., & Robertson, D. (2010). Tonotopic changes in GABA receptor expression in guinea pig inferior colliculus after partial unilateral hearing loss. Brain Research, 1342, 24–32. doi:10.1016/j.brainres.2010.04.067Find this resource:
Ducic, I., Caruncho, H. J., Zhu, W. J., Vicini, S., & Costa, E. (1995). gamma-Aminobutyric acid gating of Cl- channels in recombinant GABAA receptors. Journal of Pharmacology and Experimental Therapeutics, 272(1), 438–445.Find this resource:
Eggermont, J. J., & Komiya, H. (2000). Moderate noise trauma in juvenile cats results in profound cortical topographic map changes in adulthood. Hearing Research, 142, 89–101.Find this resource:
Eggermont, J. J., & Roberts, L. E. (2004). The neuroscience of tinnitus. Trends in Neuroscience, 27(11), 676–682. doi:10.1016/j.tins.2004.08.010Find this resource:
Engle, J. R., Gray, D. T., Turner, H., Udell, J. B., & Recanzone, G. H. (2014). Age-related neurochemical changes in the rhesus macaque inferior colliculus. Frontiers in Aging Neuroscience, 6, 73. doi:10.3389/fnagi.2014.00073Find this resource:
Fetoni, A. R., Picciotti, P. M., Paludetti, G., & Troiani, D. (2011). Pathogenesis of presbycusis in animal models: A review. Experimental Gerontology, 46(6), 413–425. doi:10.1016/j.exger.2010.12.003Find this resource:
Finlayson, P. G. (2002). Paired-tone stimuli reveal reductions and alterations in temporal processing in inferior colliculus neurons of aged animals. Journal of the Association for Research in Otolaryngology, 3(3), 321–331. doi:10.1007/s101620020038Find this resource:
Fyk-Kolodziej, B. E., Shimano, T., Gafoor, D., Mirza, N., Griffith, R. D., Gong, T.-W., & Holt, A. G. (2015). Dopamine in the auditory brainstem and midbrain: Co-localization with amino acid neurotransmitters and gene expression following cochlear trauma. Frontiers in Neuroanatomy, 9, 88.Find this resource:
Galazyuk, A. V., Voytenko, S. V., & Longenecker, R. J. (2017). Long-lasting forward suppression of spontaneous firing in auditory neurons: Implication to the residual inhibition of tinnitus. Journal of the Association for Research in Otolaryngology, 18(2), 343–353. doi:10.1007/s10162-016-0601-9Find this resource:
Godfrey, D. A., Kaltenbach, J. A., Chen, K., Ilyas, O., Liu, X., Licari, F., … McKnight, D. (2012). Amino acid concentrations in the hamster central auditory system and long-term effects of intense tone exposure. Journal of Neuroscience Research, 90(11), 2214–2224. doi:10.1002/jnr.23095Find this resource:
Gopinath, B., Rochtchina, E., Wang, J. J., Schneider, J., Leeder, S. R., & Mitchell, P. (2009). Prevalence of age-related hearing loss in older adults: Blue Mountains Study. Archives of Internal Medicine, 169(4), 415–416. doi:10.1001/archinternmed.2008.597Find this resource:
Gordon-Salant, S., & Fitzgibbons, P. J. (1993). Temporal factors and speech recognition performance in young and elderly listeners. Journal of Speech and Hearing Research, 36(6), 1276–1285.Find this resource:
Grecova, J., Bures, Z., Popelar, J., Suta, D., & Syka, J. (2009). Brief exposure of juvenile rats to noise impairs the development of the response properties of inferior colliculus neurons. European Journal of Neuroscience, 29(9), 1921–1930. doi:10.1111/j.1460-9568.2009.06739.xFind this resource:
Groschel, M., Ryll, J., Gotze, R., Ernst, A., & Basta, D. (2014). Acute and long-term effects of noise exposure on the neuronal spontaneous activity in cochlear nucleus and inferior colliculus brain slices. Biomedical Research International, 2014, 909260. doi:10.1155/2014/909260Find this resource:
Gutierrez, A., Khan, Z. U., Morris, S. J., & De Blas, A. L. (1994). Age-related decrease of GABAA receptor subunits and glutamic acid decarboxylase in the rat inferior colliculus. Journal of Neuroscience, 14(12), 7469–7477.Find this resource:
Hazzard, D. G., & Soban, J. (1988). Studies of aging using genetically defined rodents: A bibliography. Experimental Aging Research, 14(2–3), 59–81. doi:10.1080/03610738808259727Find this resource:
Heeringa, A. N., & van Dijk, P. (2016). The immediate effects of acoustic trauma on excitation and inhibition in the inferior colliculus: A Wiener-kernel analysis. Hearing Research, 331, 47–56.Find this resource:
Helfert, R. H., Sommer, T. J., Hughes, L. F., Jeffery, C. M., & Caspary, D. M. (1994). Age-related changes in the organization of the central nucleus of the inferior colliculus of the Fischer 344 rat. Journal of the Association for Research in Otolaryngology, Abstr. 17, 11.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 Fischer-344 rats. Journal of Comparative Neurology, 406(3), 285–298. doi:10.1002/(SICI)1096-9861(19990412)406:3<285::AID-CNE1>3.0.CO;2-P [pii]Find this resource:
Hesse, L. L., Bakay, W., Ong, H.-C., Anderson, L., Ashmore, J., McAlpine, D., … Schaette, R. (2016). Non-monotonic relation between noise exposure severity and neuronal hyperactivity in the auditory midbrain. Frontiers in Neurology, 7, 133.Find this resource:
Holt, A. G., Bissig, D., Mirza, N., Rajah, G., & Berkowitz, B. (2010). Evidence of key tinnitus-related brain regions documented by a unique combination of manganese-enhanced MRI and acoustic startle reflex testing. PLOS One, 5(12). doi:ARTN e14260 10.1371/journal.pone.0014260Find this resource:
House, J. W., & Brackmann, D. E. (1981). Tinnitus: Surgical treatment. CIBA Foundation Symposium, 85, 204–216.Find this resource:
Huffman, R. F., & Henson, O. W. (1990). The descending auditory pathway and acousticomotor systems: Connections with the inferior colliculus. Brain Research Reviews, 15(3), 295–323.Find this resource:
Irvine, D. R. F., Rajan, R., & Smith, S. (2003). Effects of restricted cochlear lesions in adult cats on the frequency organization of the inferior colliculus Journal of Comparative Neurology, 467, 354–374.Find this resource:
Izquierdo, M. A., Gutierrez-Conde, P. M., Merchan, M. A., & Malmierca, M. S. (2008). Non-plastic reorganization of frequency coding in the inferior colliculus of the rat following noise-induced hearing loss. Neuroscience, 154(1), 355–369. doi:10.1016/j.neuroscience.2008.01.057Find this resource:
Jung, J., Na, C., & Huh, Y. (2012). Alterations in nitric oxide synthase in the aged CNS. Oxidative Medicine and Cellular Longevity, 2012, 718976. doi:10.1155/2012/718976Find this resource:
Kazee, A. M., Han, L. Y., Spongr, V. P., Walton, J. P., Salvi, R. J., & Flood, D. G. (1995). Synaptic loss in the central nucleus of the inferior colliculus correlates with sensorineural hearing loss in the C57BL/6 mouse model of presbycusis. Hearing Research, 89(1–2), 109–120.Find this resource:
Kazee, A. M., & West, N. R. (1999). Preservation of synapses on principal cells of the central nucleus of the inferior colliculus with aging in the CBA mouse. Hearing Research, 133(1–2), 98–106. doi:S0378-5955(99)00058-1 [pii]Find this resource:
Keithley, E. M., Lo, J., & Ryan, A. F. (1994). 2-Deoxyglucose uptake patterns in response to pure tone stimuli in the aged rat inferior colliculus. Hearing Research, 80(1), 79–85.Find this resource:
Khouri, L., Lesica, N. A., & Grothe, B. (2011). Impaired auditory temporal selectivity in the inferior colliculus of aged Mongolian gerbils. Journal of Neuroscience, 31(27), 9958–9970. doi:10.1523/JNEUROSCI.4509-10.2011Find this resource:
Lee, H. J., Wallani, T., & Mendelson, J. R. (2002). Temporal processing speed in the inferior colliculus of young and aged rats. Hearing Research, 174(1–2), 64–74. doi:S0378595502006391 [pii]Find this resource:
Lee, K. Y. (2013). Pathophysiology of age-related hearing loss (peripheral and central). Korean Journal of Audiology, 17(2), 45–49. doi:10.7874/kja.2013.17.2.45Find this resource:
Leong, U. C., Barsz, K., Allen, P. D., & Walton, J. P. (2011). Neural correlates of age-related declines in frequency selectivity in the auditory midbrain. Neurobiology of Aging, 32(1), 168–178. doi:10.1016/j.neurobiolaging.2009.01.006Find this resource:
Longenecker, R. J., & Galazyuk, A. V. (2016). Variable effects of acoustic trauma on behavioral and neural correlates of tinnitus in individual animals. Frontiers in Behavioral Neuroscience, 10, 207. doi:10.3389/fnbeh.2016.00207Find this resource:
Lynch-Armour, M. A., Frisina, R. D., McReynolds, E. E., Byrd, J., & Walton, J. P. (1995). Cochlear nucleus inputs to a functionally-characterized region of the inferior colliculus decline with age for the CBA mouse model of presbycusis. Journal of the Association for Research in Otolaryngology, Abstr. 18, 71.Find this resource:
Manzoor, N. F., Gao, Y., Licari, F., & Kaltenbach, J. A. (2013). Comparison and contrast of noise-induced hyperactivity in the dorsal cochlear nucleus and inferior colliculus. Hearing Research, 295, 114–123. doi:10.1016/j.heares.2012.04.003Find this resource:
Manzoor, N. F., Licari, F. G., Klapchar, M., Elkin, R. L., Gao, Y., Chen, G., & Kaltenbach, J. A. (2012). Noise-induced hyperactivity in the inferior colliculus: Its relationship with hyperactivity in the dorsal cochlear nucleus. Journal of Neurophysiology, 108(4), 976–988. doi:10.1152/jn.00833.2011Find this resource:
Masoro, E. J. (1991). Use of rodents as models for the study of “normal aging”: conceptual and practical issues. Neurobiology of Aging, 12(6), 639–643.Find this resource:
McFadden, S. L., & Willott, J. F. (1994). Responses of inferior colliculus neurons in C57BL/6J mice with and without sensorineural hearing loss: Effects of changing the azimuthal location of a continuous noise masker on responses to contralateral tones. Hearing Research, 78(2), 132–148.Find this resource:
McGeer, E. G., & McGeer, P. L. (1975). Age changes in the human for some enzymes associated with metabolism of catecholamines, GABA and ace- tylcholine. In J. M. Ordy. & K. R. Brizzee. (Eds.), Neurobiology of Aging (pp. 287–305). New York, NY: Plenum.Find this resource:
Meltser, I., & Canlon, B. (2010). The expression of mitogen-activated protein kinases and brain-derived neurotrophic factor in inferior colliculi after acoustic trauma. Neurobiology of Disease, 40(1), 325–330. doi:10.1016/j.nbd.2010.06.006Find this resource:
Mendelson, J. R., & Lui, B. (2004). The effects of aging in the medial geniculate nucleus: A comparison with the inferior colliculus and auditory cortex. Hearing Research, 191(1–2), 21–33. doi:10.1016/j.heares.2004.01.010Find this resource:
Milbrandt, J. C., Albin, R. L., & Caspary, D. M. (1994). Age-related decrease in GABAB receptor binding in the Fischer 344 rat inferior colliculus. Neurobiology of Aging, 15(6), 699–703.Find this resource:
Milbrandt, J. C., Albin, R. L., Turgeon, S. M., & Caspary, D. M. (1996). GABAA receptor binding in the aging rat inferior colliculus. Neuroscience, 73(2), 449–458. doi:0306-4522(96)00050-4 [pii]Find this resource:
Milbrandt, J. C., Holder, T. M., Wilson, M. C., Salvi, R. J., & Caspary, D. M. (2000). GAD levels and muscimol binding in rat inferior colliculus following acoustic trauma. Hearing Research, 147(1–2), 251–260.Find this resource:
Milbrandt, J. C., Hunter, C., & Caspary, D. M. (1997). Alterations of GABAA receptor subunit mRNA levels in the aging Fischer 344 rat inferior colliculus. Journal of Comparative Neurology, 379(3), 455–465. doi:10.1002/(SICI)1096-9861(19970317)379:3<455::AID-CNE10>3.0.CO;2-F [pii]Find this resource:
Mulders, W. H., Barry, K. M., & Robertson, D. (2014). Effects of furosemide on cochlear neural activity, central hyperactivity and behavioural tinnitus after cochlear trauma in guinea pig. PLOS One, 9(5), e97948. doi:10.1371/journal.pone.0097948Find this resource:
Mulders, W. H., McMahen, C., & Robertson, D. (2014). Effects of chronic furosemide on central neural hyperactivity and cochlear thresholds after cochlear trauma in Guinea pig. Frontiers of Neurology, 5, 146. doi:10.3389/fneur.2014.00146Find this resource:
Mulders, W. H., & Robertson, D. (2009). Hyperactivity in the auditory midbrain after acoustic trauma: Dependence on cochlear activity. Neuroscience, 164(2), 733–746. doi:10.1016/j.neuroscience.2009.08.036Find this resource:
Mulders, W. H., & Robertson, D. (2011). Progressive centralization of midbrain hyperactivity after acoustic trauma. Neuroscience, 192, 753–760. doi:10.1016/j.neuroscience.2011.06.046Find this resource:
Mulders, W. H., & Robertson, D. (2013). Development of hyperactivity after acoustic trauma in the guinea pig inferior colliculus. Hearing Research, 298, 104–108. doi:10.1016/j.heares.2012.12.008Find this resource:
Mulders, W. H., Spencer, T. C., & Robertson, D. (2016). Effects of pulsatile electrical stimulation of the round window on central hyperactivity after cochlear trauma in guinea pig. Hearing Research, 335, 128–137. doi:10.1016/j.heares.2016.03.001Find this resource:
Mulders, W. H., Vooys, V., Makowiecki, K., Tang, A. D., & Rodger, J. (2016). The effects of repetitive transcranial magnetic stimulation in an animal model of tinnitus. Scientific Reports, 6, 38234. doi:10.1038/srep38234Find this resource:
Niu, Y., Kumaraguru, A., Wang, R., & Sun, W. (2013). Hyperexcitability of inferior colliculus neurons caused by acute noise exposure. Journal of Neuroscience Research, 91(2), 292–299.Find this resource:
Norena, A. J., & Eggermont, J. J. (2005). Enriched acoustic environment after noise trauma reduces hearing loss and prevents cortical map reorganization. Journal of Neuroscience, 25(3), 699–705. doi:10.1523/JNEUROSCI.2226-04.2005Find this resource:
Norena, A. J., Mulders, W. H., & Robertson, D. (2015). Suppression of putative tinnitus-related activity by extra-cochlear electrical stimulation. Journal of Neurophysiology, 113(1), 132–143. doi:10.1152/jn.00580.2014Find this resource:
Offutt, S. J., Ryan, K. J., Konop, A. E., & Lim, H. H. (2014). Suppression and facilitation of auditory neurons through coordinated acoustic and midbrain stimulation: Investigating a deep brain stimulator for tinnitus. Journal of Neural Engineering, 11(6). doi:Artn 066001Find this resource:
Ohlemiller, K. K. (2006). Contributions of mouse models to understanding of age- and noise-related hearing loss. Brain Research, 1091(1), 89–102. doi:10.1016/j.brainres.2006.03.017Find this resource:
Osumi, Y., Shibata, S. B., Kanda, S., Yagi, M., Ooka, H., Shimano, T., … Tomoda, K. (2012). Downregulation of N-methyl-D-aspartate receptor zeta1 subunit (GluN1) gene in inferior colliculus with aging. Brain Research, 1454, 23–32. doi:10.1016/j.brainres.2012.03.018Find this resource:
Ouda, L., Druga, R., & Syka, J. (2008). Changes in parvalbumin immunoreactivity with aging in the central auditory system of the rat. Experimental Gerontology, 43(8), 782–789. doi:10.1016/j.exger.2008.04.001Find this resource:
Pages, D. S., Ross, D. A., Punal, V. M., Agashe, S., Dweck, I., Mueller, J., … Groh, J. M. (2016). Effects of electrical stimulation in the inferior colliculus on frequency discrimination by rhesus monkeys and implications for the auditory midbrain implant. Journal of Neuroscience, 36(18), 5071–5083. doi:10.1523/JNEUROSCI.3540-15.2016Find this resource:
Palombi, P. S., & Caspary, D. M. (1996). Physiology of the aged Fischer 344 rat inferior colliculus: Responses to contralateral monaural stimuli. Journal of Neurophysiology, 76(5), 3114–3125.Find this resource:
Papesh, M. A., & Hurley, L. M. (2012). Plasticity of serotonergic innervation of the inferior colliculus in mice following acoustic trauma. Hearing Research, 283(1–2), 89–97. doi:10.1016/j.heares.2011.11.004Find this resource:
Popelar, J., Syka, J., & Berndt, H. (1987). Effect of noise on auditory evoked responses in awake guinea pigs. Hearing Research, 26(3), 239–247.Find this resource:
Risey, J. A., Guth, P. S., & Amedee, R. G. (1995). Furosemide Distinguishes Central and Peripheral Tinnitus. The International Tinnitus Journal, 1(2), 99–103.Find this resource:
Roberts, L. E., Moffat, G., & Bosnyak, D. J. (2006). Residual inhibition functions in relation to tinnitus spectra and auditory threshold shift. Acta Oto-Laryngologica Supplementum (556), 27–33.Find this resource:
Robertson, D., Bester, C., Vogler, D., & Mulders, W. H. (2012). Spontaneous hyperactivity in the auditory midbrain: Relationship to afferent input. Hearing Research, 295, 124–129. doi:10.1016/j.heares.2012.02.002Find this resource:
Robertson, D., & Irvine, D. R. F. (1989). Plasticity of frequency organization in auditory cortex of guinea pigs with partial unilateral deafness. Journal of Comparative Neurology, 282, 456–471.Find this resource:
Ropp, T. J., Tiedemann, K. L., Young, E. D., & May, B. J. (2014). Effects of unilateral acoustic trauma on tinnitus-related spontaneous activity in the inferior colliculus. Journal of the Association for Research in Otolaryngology, 15(6), 1007–1022. doi:10.1007/s10162-014-0488-2Find this resource:
Saint Marie, R. L., Luo, L., & Ryan, A. F. (1999). Effects of stimulus frequency and intensity on c-fos mRNA expression in the adult rat auditory brainstem. Journal of Comparative Neurology, 404(2), 258–270.Find this resource:
Salvi, R., Lobarinas, E., & Sun, W. (2009). Pharmacological treatments for tinnitus: New and old. Drugs Future, 34(5), 381–400. doi:10.1358/dof.2009.034.05.1362442Find this resource:
Sanchez-Zuriaga, D., Marti-Gutierrez, N., De La Cruz, M. A., & Peris-Sanchis, M. R. (2007). Age-related changes of NADPH-diaphorase-positive neurons in the rat inferior colliculus and auditory cortex. Microscopy Research and Technique, 70(12), 1051–1059. doi:10.1002/jemt.20512Find this resource:
Schaette, R., & McAlpine, D. (2011). Tinnitus with a normal audiogram: Physiological evidence for hidden hearing loss and computational model. Journal of Neuroscience, 31(38), 13452–13457. doi:10.1523/JNEUROSCI.2156-11.2011Find this resource:
Schuknecht, H. F. (1955). Presbycusis. Laryngoscope, 65(6), 402–419. doi:10.1288/00005537-195506000-00002Find this resource:
Schuknecht, H. F. (1964). Further observations on the pathology of presbycusis. Archives of Otolaryngology, 80, 369–382.Find this resource:
Shaddock Palombi, P., Backoff, P. M., & Caspary, D. M. (2001). Responses of young and aged rat inferior colliculus neurons to sinusoidally amplitude modulated stimuli. Hearing Research, 153(1–2), 174–180. doi:S0378595500002641 [pii]Find this resource:
Shargorodsky, J., Curhan, G. C., & Farwell, W. R. (2010). Prevalence and characteristics of tinnitus among US adults. American Journal of Medicine, 123(8), 711–718. doi:10.1016/j.amjmed.2010.02.015Find this resource:
Sheppard, A. M., Chen, G. D., Manohar, S., Ding, D., Hu, B. H., Sun, W., … Salvi, R. (2017). Prolonged low-level noise-induced plasticity in the peripheral and central auditory system of rats. Neuroscience, 359, 159–171. doi:10.1016/j.neuroscience.2017.07.005Find this resource:
Smit, J. V., Janssen, M. L., van Zwieten, G., Jahanshahi, A., Temel, Y., & Stokroos, R. J. (2016). Deep brain stimulation of the inferior colliculus in the rodent suppresses tinnitus. Brain Research, 1650, 118–124. doi:10.1016/j.brainres.2016.08.046Find this resource:
Smith, P. F., Zheng, Y., & Darlington, C. L. (2012). Revisiting baclofen for the treatment of severe chronic tinnitus. Frontiers of Neurology, 3, 34. doi:10.3389/fneur.2012.00034Find this resource:
Strouse, A., Ashmead, D. H., Ohde, R. N., & Grantham, D. W. (1998). Temporal processing in the aging auditory system. Journal of the Acoustical Society of America, 104(4), 2385–2399.Find this resource:
Sturm, J. J., Zhang-Hooks, Y. X., Roos, H., Nguyen, T., & Kandler, K. (2017). Noise trauma-induced behavioral gap detection deficits correlate with reorganization of excitatory and inhibitory local circuits in the inferior colliculus and are prevented by acoustic enrichment. Journal of Neuroscience, 37(26), 6314–6330. doi:10.1523/JNEUROSCI.0602-17.2017Find this resource:
Sun, W., Deng, A., Jayaram, A., & Gibson, B. (2012). Noise exposure enhances auditory cortex responses related to hyperacusis behavior. Brain Research, 1485, 108–116. doi:10.1016/j.brainres.2012.02.008Find 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(2), 273–288. doi:10.1006/exnr.1998.6812Find this resource:
Szczepaniak, W. S., & Moller, A. R. (1996a). Effects of (–)-baclofen, clonazepam, and diazepam on tone exposure-induced hyperexcitability of the inferior colliculus in the rat: Possible therapeutic implications for pharmacological management of tinnitus and hyperacusis. Hearing Research, 97(1–2), 46–53.Find this resource:
Szczepaniak, W. S., & Moller, A. R. (1996b). Evidence of neuronal plasticity within the inferior colliculus after noise exposure: A study of evoked potentials in the rat. Electroencephalography and clinical neurophysiology, 100(2), 158–164.Find this resource:
Tadros, S. F., D'Souza, M., Zettel, M. L., Zhu, X., Waxmonsky, N. C., & Frisina, R. D. (2007). Glutamate-related gene expression changes with age in the mouse auditory midbrain. Brain Research, 1127(1), 1–9. doi:10.1016/j.brainres.2006.09.081Find this resource:
Takeda, A. (2003). Manganese action in brain function. Brain Research Reviews, 41(1), 79–87.Find this resource:
Tan, J., Ruttiger, L., Panford-Walsh, R., Singer, W., Schulze, H., Kilian, S. B., … Knipper, M. (2007). Tinnitus behavior and hearing function correlate with the reciprocal expression patterns of BDNF and Arg3.1/arc in auditory neurons following acoustic trauma. Neuroscience, 145(2), 715–726. doi:10.1016/j.neuroscience.2006.11.067Find this resource:
Turner, J., Larsen, D., Hughes, L., Moechars, D., & Shore, S. (2012). Time course of tinnitus development following noise exposure in mice. Journal of Neuroscience Research, 90(7), 1480–1488. doi:10.1002/jnr.22827Find this resource:
Vogler, D. P., Robertson, D., & Mulders, W. H. (2014). Hyperactivity following unilateral hearing loss in characterized cells in the inferior colliculus. Neuroscience, 265, 28–36. doi:10.1016/j.neuroscience.2014.01.017Find this resource:
Vogler, D. P., Robertson, D., & Mulders, W. H. A. M. (2016). Influence of the paraflocculus on normal and abnormal spontaneous firing rates in the inferior colliculus. Hearing Research, 333, 1–7. doi:10.1016/j.heares.2015.12.021Find this resource:
Voytenko, S. V., & Galazyuk, A. V. (2011). mGluRs modulate neuronal firing in the auditory midbrain. Neuroscience Letters, 492(3), 145–149. doi:10.1016/j.neulet.2011.01.075Find this resource:
Walton, J. P., Frisina, R. D., Ison, J. R., & O'Neill, W. E. (1997). Neural correlates of behavioral gap detection in the inferior colliculus of the young CBA mouse. Journal of Comparative Physiology A, 181(2), 161–176.Find this resource:
Walton, J. P., Frisina, R. D., & Meierhans, L. R. (1995). Sensorineural hearing loss alters recovery from short-term adaptation in the C57BL/6 mouse. Hearing Research, 88(1–2), 19–26.Find this resource:
Walton, J. P., Frisina, R. D., & O'Neill, W. E. (1994). Effects of age on single-unit processing in the inferior colliculus of the CBA mouse model of presbycusis. Journal of the Association for Research in Otolaryngology, Abstr. 17, 83.Find this resource:
Walton, J. P., Frisina, R. D., & O'Neill, W. E. (1998). Age-related alteration in processing of temporal sound features in the auditory midbrain of the CBA mouse. Journal of Neuroscience, 18(7), 2764–2776.Find this resource:
Walton, J. P., Simon, H., & Frisina, R. D. (2002). Age-related alterations in the neural coding of envelope periodicities. Journal of Neurophysiology, 88(2), 565–578.Find this resource:
Wang, F., Zuo, L., Hong, B., Han, D., Range, E. M., Zhao, L., … Liu, L. (2013). Tonotopic reorganization and spontaneous firing in inferior colliculus during both short and long recovery periods after noise overexposure. Journal of Biomedical Science, 20, 91. doi:10.1186/1423-0127-20-91Find this resource:
Wang, J., Ding, D., & Salvi, R. J. (2002). Functional reorganization in chinchilla inferior colliculus associated with chronic and acute cochlear damage. Hearing Research, 168(1–2), 238–249.Find this resource:
Wang, J., Salvi, R. J., & Powers, N. (1996). Plasticity of response properties of inferior colliculus neurons following acute cochlear damage. Journal of Neurophysiology, 75(1), 171–183.Find this resource:
Willott, J. F. (1986). Effects of aging, hearing loss, and anatomical location on thresholds of inferior colliculus neurons in C57BL/6 and CBA mice. Journal of Neurophysiology, 56(2), 391–408.Find this resource:
Willott, J. F., Pankow, D., Hunter, K. P., & Kordyban, M. (1985). Projections from the anterior ventral cochlear nucleus to the central nucleus of the inferior colliculus in young and aging C57BL/6 mice. Journal of Comparative Neurology, 237(4), 545–551. doi:10.1002/cne.902370410Find this resource:
Willott, J. F., Parham, K., & Hunter, K. P. (1988). Response properties of inferior colliculus neurons in middle-aged C57BL/6J mice with presbycusis. Hearing Research, 37(1), 15–27. doi:0378-5955(88)90074-3 [pii]Find this resource:
Zacharek, M. A., Kaltenbach, J. A., Mathog, T. A., & Zhang, J. (2002). Effects of cochlear ablation on noise induced hyperactivity in the hamster dorsal cochlear nucleus: Implications for the origin of noise induced tinnitus. Hearing Research, 172(1–2), 137–143. doi:S0378595502005750 [pii]Find this resource:
Zettel, M. L., Frisina, R. D., Haider, S. E., & O'Neill, W. E. (1997). Age-related changes in calbindin D-28k and calretinin immunoreactivity in the inferior colliculus of CBA/CaJ and C57Bl/6 mice. Journal of Comparative Neurology, 386(1), 92–110. doi:10.1002/(SICI)1096-9861(19970915)386:1<92::AID-CNE9>3.0.CO;2-8 [pii]Find this resource:
Zheng, Y., Vagal, S., McNamara, E., Darlington, C. L., & Smith, P. F. (2012). A dose-response analysis of the effects of L-baclofen on chronic tinnitus caused by acoustic trauma in rats. Neuropharmacology, 62(2), 940–946. doi:10.1016/j.neuropharm.2011.09.027Find this resource: