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date: 21 January 2019

Aging Processes in the Subcortical Auditory System

Abstract and Keywords

As arguably the third most common malady of industrialized populations, age-related hearing loss is associated with social isolation and depression in a subset of the population that will approach 25% by 2050. Development of behavioral or pharmacotherapeutic approaches to prevent or delay the onset of age-related hearing loss and mitigate the impact of hearing loss of speech understanding requires a better understanding of age-related changes that occur in the central auditory processor. This chapter critically reviews and discusses changes that occur in the auditory brainstem and thalamus with increased age. It briefly discusses age-related cellular changes that occur de novo within the central auditory system versus deafferentation plasticity and animal models of aging. Subsections discuss the cochlear nucleus, superior olivary complex, inferior colliculus, and the medial geniculate body with an emphasis on age-related changes in neurotransmission and how these changes could underpin the observed loss of precise temporal processing with increased age.

Keywords: age-related hearing loss, presbycusis, brainstem aging, central auditory system, dorsal cochlear nucleus, superior olivary complex, inferior colliculus, medial geniculate body

The Importance of Age-Related Hearing Loss

United States epidemiological studies suggest that the prevalence of age-related hearing loss and its significant companion, loss of speech understanding, doubles with every decade of life, affecting 30% of the US population aged 65 to 74 years, and 50% of the population over 75 years of age (F. R. Lin, Thorpe, Gordon-Salant, & Ferrucci, 2011). US census data predict that the over age 65 population will increase from 14% in 2014 to near 21% by 2040 (, substantially increasing the number of individuals with age-related declines in speech understanding. Age-related hearing loss is socially debilitating, decreasing quality of life and leading to social isolation and depression in a substantial number of older adults (Dalton et al., 2003). Even older adults with mild-to-moderate age-related hearing loss can show substantially impaired processing of speech, especially in complex listening environments (Dalton et al., 2003; Gordon-Salant, 2014; Humes et al., 2012). Human and animal models of presbycusis show large variations in the age-related loss of cochlear hair cells and auditory nerve fibers. Peripheral changes only partially correlate with the observed age-related loss of temporal discrimination/speech processing and with the ability to attend to acoustic stimuli. This suggests a significant contribution of central auditory changes to presbycusis (Alain & Woods, 1999; S. Anderson, Parbery-Clark, White-Schwoch, & Kraus, 2012; Caspary, Ling, Turner, & Hughes, 2008; de Villers-Sidani et al., 2010; Gordon-Salant & Fitzgibbons, 1993; Humes, Kewley-Port, Fogerty, & Kinney, 2010; Juarez-Salinas, Engle, Navarro, & Recanzone, 2010; Lister, Besing, & Koehnke, 2002; Pichora-Fuller, Alain, & Schneider, 2017; Snell, 1997; Takahashi & Bacon, 1992; Tremblay, Piskosz, & Souza, 2003). Here we review subcortical age-related changes, which likely underpin degraded up-stream/ascending temporal processing attributed, in part, to increased temporal jitter at successive nuclei along the ascending auditory neuraxis. Age-related auditory brainstem changes in the timing of coded environmental acoustic information also impact the ability of older adults to accurately localize sound, which further degrades their ability to extract speech signals in cluttered acoustic environments (Dubno, Ahlstrom, & Horwitz, 2008; Eddins & Hall, 2010; King, Hopkins, & Plack, 2014; Pichora-Fuller et al., 2017; Pichora-Fuller, Schneider, Macdonald, Pass, & Brown, 2007).

The ability to code rapidly time-varying signals such as speech is facilitated by time-locked and tonic inhibition at multiple levels of the auditory brainstem. Age-related loss of speech understanding, in part, likely reflects maladaptive age-related plastic changes in inhibitory neurotransmission in response to a loss of ascending glutamatergic excitatory drive (Caspary et al., 2008; Godfrey, Chen, O'Toole, & Mustapha, 2017; Gold & Bajo, 2014).

Each section of this chapter will focus on age-related changes in (1) anatomical and structural features, (2) excitatory (glutamate) and inhibitory (GABA and glycine) amino acid neurotransmitters and their ionotropic and metabotropic receptors. (3) neuromodulators and calcium homeostasis, and (4) functional/physiological properties, and how these changes may be reflected in the behavior of the whole organism.

Successive chapter sections will detail observed age-related changes in dorsal cochlear nucleus (DCN), superior olivary complex (SOC), inferior colliculus (IC), and auditory thalamus/medial geniculate body (MGB). Layered upon the age-related changes in primary auditory neurotransmission affecting temporal processing are age-related changes in auditory vigilance, which are performed less well by older adults, especially those individuals with cognitive and attentional declines (Harris, Wilson, Eckert, & Dubno, 2012; Humes et al., 2012).

Cellular Mechanisms of Aging and Age-Related Hearing Loss

At the tissue level, aging is generally characterized by an accumulation of cellular damage over time. Cellular aging was once thought to be caused by a stochastic decline in function (i.e., “wearing out”) of cellular components (Abernethy, 1979). However, we now know that aging is driven by specific sets of genetically or epigenetically programmed sequences of events which cause both adaptive and non-adaptive changes in cellular function (reviewed in López-Otín, Blasco, Partridge, Serrano, & Kroemer, 2013). Here, we briefly review the major cellular changes thought to occur with aging, and how they relate to the auditory system.

DNA damage, both nuclear and mitochondrial, is one hallmark of aging. In the nucleus, DNA damage often leads to an adaptive cellular or replicative senescence response, which diminishes the replication of damaged cells or induces apoptosis (Grimes & Chandra, 2009; Rodriguez-Brenes, Wodarz, & Komarova, 2015). Concomitant with the age-related DNA changes is the shortening of telomeres, which are short strands of DNA that help protect chromosomes from damage or fusion with nearby chromosomes. Mitochondrial DNA contains diminished endogenous repair mechanisms relative to nuclear DNA and therefore is more vulnerable to age-related insults than nuclear DNA (López-Otín et al., 2013). Further, mitochondria are the source of oxygen-based free radical production, further exposing cells to threats over time. This age-related increase in free radicals has led to hypotheses suggesting that mitochondrial dysfunction underpins the aging process. In addition, aging is associated with the diminished ability of mitochondria to both produce ATP and to control the production of free radical molecules. Aging mitochondria also produce superoxide anion and hydrogen peroxide at increased rates compared to younger mitochondria (Lass, Sohal, Weindruch, Forster, & Sohal, 1998; Sohal, Agarwal, Candas, Forster, & Lal, 1994). Compounding this problem, the levels of endogenous anti-oxidant molecules diminish with aging (Rebrin, Forster, & Sohal, 2007; Rebrin, Kamzalov, & Sohal, 2003).

Efforts to extend the lifespans of experimental animals have led to the discovery of molecules that function, in part, to detect ambient cellular nutrient levels, and diminished function of these molecules may also lead to an aging phenotype. For example, sirtuins, which detect levels of NAD+, function as deacetylase inhibitors, thereby altering age-related epigenetic modifications of nuclear DNA (Longo & Kennedy, 2006). Other molecules that are sensitive to nutrient levels are mTOR (mammalian target of rapamycin; Kapahi et al., 2010) and AMP-activated protein kinase (Salminen & Kaarniranta, 2012). These proteins have been implicated in the beneficial effects of caloric restriction on aging, which has been shown to protect against age-related hearing loss in experimental animals (Someya, Yamasoba, Weindruch, Prolla, & Tanokura, 2007).

Aging Mechanisms in the Auditory System

Although these mechanisms have been extensively studied in organisms ranging from yeast to humans, few studies have systematically examined their role in age-related hearing loss outside of the cochlea. Within the cochlea, multiple studies have revealed evidence for roles of mitochondrial dysfunction and oxidative stress (Fischel-Ghodsian et al., 1997; D. W. Hoffman, Whitworth, Jones-King, & Rybak, 1988; Someya & Prolla, 2010; Yamasoba et al., 2007), proteostatic dysfunction (W. Wang et al., 2015), and diminished sirtuin levels (Xiong et al., 2014; Zeng et al., 2014) with aging. However, very little work, to our knowledge, has been done to examine the relevance of these mechanisms in the central auditory system. At the level of the IC, and as reviewed in the next section, homogenates from aged Fischer 344 rats showed diminished levels of antioxidant enzymes superoxide dismutase and catalase and increased levels of lipid peroxidation (Mei, Gawai, Nie, Ramkumar, & Helfert, 1999). Electron microscopy also revealed a decrease in mitochondrial number with aging that was more pronounced in GABAergic neurons (Mei et al., 1999). The investigators also documented an increase in mitochondrial morphological abnormalities in the aged group (Mei et al., 1999). Supporting a potential age-related loss of proteostasis at the level of the IC is the finding that levels of heat-shock protein (Hsp) 72 are decreased by more than 50% in the aged Fischer 344 rat (Helfert, Glatz, Wilson, Ramkumar, & Hughes, 2002). At the level of the auditory cortex, aging in rodent models has been associated with a drop in sirtuin levels, as well as drops in superoxide dismutase and increases in mitochondrial DNA mutation rates (Xiong et al., 2014; Zeng et al., 2014). Further work is clearly needed to explore the potential contribution of cellular aging mechanisms to central auditory processing deficits in aging, described next.

The Auditory Periphery, Peripheral Deafferentation, and Age-Related Hearing Loss

A number of chapters in the present volume examine plastic compensatory changes in central auditory structures following loss of normal adult peripheral input due to damage/dysfunctional changes in the middle ear, cochlea, and/or acoustic nerve (see chapters by Trussell, Manis, Rubio, Kaltenbach, and Shore, in this volume). Age-related peripheral changes have been a focus of a considerable number of recent studies providing for an update of the elegant historic work described in Schuknecht and Gacek (1993). These recent studies find that age-related hearing loss or presbycusis likely consists of some combination of sensory, neural, strial, and conductive elements resulting in a net loss in the quality and intensity of environmental and communication sounds reaching the central auditory processor (Altschuler et al., 2015; Kujawa & Liberman, 2015; Liberman, 2017; Ohlemiller, 2004). Recently a series of studies suggest that even profound acoustic nerve fiber losses may not substantially alter pure tone thresholds (Cai, Montgomery, Graves, Caspary, & Cox, 2017; Kujawa & Liberman, 2009; H. W. Lin, Furman, Kujawa, & Liberman, 2011; Sergeyenko, Lall, Liberman, & Kujawa, 2013). However, it has long been understood that elderly individuals with near-normal pure-tone thresholds may show significant deficits in speech understanding especially in complex acoustic environments (Harris et al., 2012; Humes et al., 2012; Pichora-Fuller et al., 2017). As extensively reviewed by Gold and Bajo as well as Syka (Gold & Bajo, 2014; Syka, 2002), when comparing aging to hearing loss with sound exposure (Godfrey et al., 2017; Godfrey et al., 2012), there are similarities in the central neurotransmitter and functional changes irrespective of the source/cause of the peripheral deafferentation (also see Bauer, Turner, Caspary, Myers, & Brozoski, 2008). A series of studies by Wang and colleagues found that aging and mild acoustic trauma result in similar losses in glycine receptors and functional inhibition in the rat DCN (Brozoski, Bauer, & Caspary, 2002; Caspary, Schatteman, & Hughes, 2005; H. Wang, Brozoski, & Caspary, 2011; H. Wang, Brozoski, et al., 2009; H. Wang, Turner, et al., 2009). Superb early studies by Suneja and Potashner (Suneja, Benson, & Potashner, 1998; Suneja, Potashner, & Benson, 1998) examined neurochemical markers of neurotransmission at different levels of the brainstem auditory pathway and at different times following disarticulation or cochlear ablation. They found compensatory changes similar to aging and sound exposure with the milder disarticulation and less similar with complete ablation of the cochlea. A study that examined three different cochlear insults found similar levels of single unit hyperactivity in the chinchilla IC with all three insult types and concluded that cochlear trauma in general, rather than its specific features, leads to multiple changes in central activity (Bauer et al., 2008). Many other examples of the similarity of brainstem neurotransmission changes following partial peripheral deafferentation due to aging or other peripheral insults are described in the reviews just noted. It appears that over a wide range of degraded peripheral acoustic input, conceptually ranging between 10% and 80%, a remarkably similar set of compensatory changes in the balance between excitatory and inhibitory neurotransmission develops in the auditory brainstem over time.

Beyond the plastic downregulation of GABA neurotransmission following partial deafferentation, GABAergic neurons may also be selectively vulnerable to metabolic changes associated with aging. For example, clinical data involving syndromes presumably related to deafferentation-related maladaptive plasticity (e.g., tinnitus, phantom pain syndromes, Charles-Bonnet syndrome) suggest that many of these plastic changes are exacerbated in the aged brain (H. J. Hoffman & Reed, 2004; Rozycka & Liguz-Lecznar, 2017; Teunisse, Cruysberg, Verbeek, & Zitman, 1995; Werhagen, Budh, Hultling, & Molander, 2004). In addition, GABAergic neurons are particularly susceptible to metabolic insults such as ischemia (Francis & Pulsinelli, 1982; Ross & Duhaime, 1989; Smith, Auer, & Siesjö, 1984), hypoxia (Sloper, Johnson, & Powell, 1980), traumatic brain injury (Erb & Povlishock, 1991), induced seizures (Houser & Esclapez, 1996), and application of amyloid beta (Pakaski et al., 1998), which may be related to the high metabolic demands of inhibitory neurons relative to their excitatory counterparts (Kann, Papageorgiou, & Draguhn, 2014). These findings suggest that a combination of deafferentation-related plastic changes and age-related cellular factors conspire to produce changes in central auditory function with aging.

Rodent and Non-human Primate Models of Aging

Several species have been used in studies of the aging auditory system, though rats and mice have been the most commonly used. Aging studies have examined two mouse strains in particular: C57BL/6J and CBA/CaJ. The C57BL/6J strain shows early onset presbycusis and 50% survival over 27 months. Hair cell loss occurs as soon as 3–6 months of age in C57BL/6J mice due to a mutation in cadherin 23 (Johnson, Erway, Cook, Willott, & Zheng, 1997), a protein expressed in the tip links of hair cells. Studies of age-related hearing loss in this model are complicated by the expression of cadherin 23 in the brain (Di Palma et al., 2001; Diez-Roux et al., 2011). However, the majority of genetically modified mouse lines are made on a C57BL/6J background, making this strain important for study. The CBA strain shows mild progressive age-related hearing loss across the life span (Hunter & Willott, 1987; Parham, Sun, & Kim, 1999; Willott, Parham, & Hunter, 1991). Rat strains utilized in auditory aging studies include the Fischer 344 (F344) rat, developed for cancer research at Colombia University in the early 1960s and then adopted as a model of aging by the National Institute on Aging (NIA) with 50% survival at 22 months. Eventually the NIA Rodent Resource Group began providing a back-crossed Fischer-Brown Norway (F344xBN F1 or FBN) strain which was a Brown Norway male crossed with a F344 female. The FBN strain shows 50% mortality at 34 months of age (Lipman, Chrisp, Hazzard, & Bronson, 1996). Other common rat strains, including Sprague Dawley (SD), Wistar, and Long-Evans have also been used in numerous aging studies. Gerbils are an excellent rodent model of aging and have been used in peripheral and in central studies, as we will describe (Boettcher, Mills, Swerdloff, & Holley, 1996; Gratton, Schmiedt, & Schulte, 1996; Gratton, Smyth, Schulte, & Vincent, 1995). Finally, recent detailed series of non-human primate studies, using the macaque, have added to the aging animal literature, which we will also review.

Aging and the Cochlear Nucleus

The cochlear nucleus is the first nucleus of the central auditory neuroaxis. Glutamatergic acoustic nerve fibers enter the internal acoustic meatus and bifurcate into an ascending branch which innervates the anteroventral cochlear nucleus (AVCN), and a descending branch, which innervates the posteroventral (PVCN) and dorsal (DCN) cochlear nucleus. The anatomical circuitry and physiology of the cochlear nuclei are richly reviewed in the chapters by Oertel et al., Trussell, Manis, Rubio, Kaltenbach, and Shore, in this volume. This section will focus on age-related change in the anatomy, neurochemistry and physiology of the DCN with some references to aging in ventral cochlear nucleus (VCN) reviewed (see also Manis, this volume).

Impact of Aging on the Structure of the DCN

Willott and colleagues (Willott, Bross, & McFadden, 1992) working in CBA mouse, found no age-related changes in the number or volume of DCN neurons, while a second study in CBA mice described small, but significant losses in the number of DCN neurons with age (Idrizbegovic, Canlon, Bross, Willott, & Bogdanovic, 2001). In CBA mouse DCN a significant age-related decrease in the number of labeled projection neurons was observed following injection of a retrograde tracer into the contralateral IC (Frisina & Walton, 2001, 2006).

The FBN rat shows a parallel 20–30 dB age-related threshold shift across life span (Cai & Caspary, 2015; Cai et al., 2017; Caspary et al., 2005; H. Wang, Turner et al., 2009). Godfrey and colleagues (2017) found modest, but significant changes in DCN volume in the FBN rat across the life span with increases in the middle age group (22 months), but returns toward the young (6 months) volumes at the oldest age (33 months) examined. These authors found no significant reduction/change in dry weight for any layer of the DCN across lifespan. In addition, no age-related changes in the number of DCN neurons were observed across layers when comparing 3 and 24 month-old SD rats (Jalenques, Albuisson, Despres, & Romand, 1995). While mice show age-related decreases in DCN cell number, rats show a more complex set of age-related DCN changes, which include volume changes across life span with little or no changes in neuron number or DCN dry-weight.

Impact of Aging on Neurotransmitters in the DCN

Whether the association between age-related pre- and postsynaptic changes at inhibitory, glycinergic synapses in cochlear nuclei are due solely to deafferentation or in part to de novo aging, as discussed earlier, has not been conclusively established. It is reasonable to suggest that an age-related loss of ascending excitatory drive due to the loss of acoustic nerve fibers, loss of inner and outer hair cells, decreased metabolic/endocochlear potential, and/or loss of mechanical efficiency collectively result in activity-dependent changes at acoustic nerve synapses within cochlear nuclei (Cai et al., 2017; Sergeyenko et al., 2013). Age-related reductions in acoustic nerve input may be reflected in the profound age-related decline in ambient glutamate levels in cochlear nucleus (Banay-Schwartz, Lajtha, & Palkovits, 1989; Godfrey et al., 2017). Studies, in FBN and SD rats, report a greater than 20% age-related decrease in glutamate levels throughout the cochlear nucleus, where glutamate functions as the neurotransmitter released at acoustic nerve synapses and as the transmitter released at parallel fibers synapses in the DCN (Caspary, Havey, & Faingold, 1981; Martin & Adams, 1979; Petralia, Rubio, Wang, & Wenthold, 2000; Raman & Trussell, 1995). Glutamate is the most prevalent amino acid in the brain and has multiple roles in cellular metabolism as well as neurotransmission (Cooper, Bloom, & Roth, 2003). Although it has been established that both AMPA and NMDA type glutamate receptors are negatively impacted by aging (Wenk & Barnes, 2000), few, if any studies have examined the effects of aging on postsynaptic AMPA or NMDA receptors in the aging DCN. Additional studies by Manis (this volume), have shown age-related dysfunction at the endbulb/acoustic nerve synapses in AVCN (Y. Wang & Manis, 2005; Xie & Manis, 2017).

The primary inhibitory neurotransmitter in the cochlear nucleus is glycine (Caspary, Backoff, Finlayson, & Palombi, 1994; Caspary, Havey, & Faingold, 1979; Kolston, Osen, Hackney, Ottersen, & Storm-Mathisen, 1992). GABA may be a neurotransmitter at a minority of VCN synapses, primarily in PVCN, and there are likely GABAergic neurons in the superficial layers of the DCN which may project onto the apical dendrites of fusiform cells (Rubio & Juiz, 2004). It appears that at many glycinergic terminals/synapses, GABA is co-released along with glycine, where glycine functions as the primary postsynaptic inhibitory transmitter acting at ionotropic chloride fluxing glycine receptors (GlyRs) to inhibit the target neuron, while co-released GABA acts presynaptically at GABAB autoreceptors and possibly as a weak at GlyRs to shorten postsynaptic glycinergic currents (Caspary, Rybak, & Faingold, 1984; Kolston et al., 1992; Lim, Alvarez, & Walmsley, 2000; T. Lu, Rubio, & Trussell, 2008). Presynaptic GABAB receptors also modulate excitatory neurotransmitter release in the cochlear nucleus (Caspary et al., 1984; Irie & Ohmori, 2008; Lujan, Shigemoto, Kulik, & Juiz, 2004). In DCN, glycinergic projections from neighboring vertical cells profoundly depress near-characteristic frequency (CF) tone-evoked responses by acting at GlyRs on the basal dendrites and somata of fusiform DCN projection neurons (Caspary, Pazara, Ko, & Faingold, 1987; Davis & Young, 2000; Rhode, 1999; Rhode, Smith, & Oertel, 1983; Voigt & Young, 1990). This micro-circuit controls near-CF discharge rate/dynamic range and gain while having only minor effects on the sharpness of tuning (Caspary et al., 1987). Glycine receptor radioligand binding studies have been carried out in mice and rats using the high affinity α1 GlyR subunit ligand, strychnine (Frostholm & Rotter, 1985; Milbrandt & Caspary, 1995; H. Wang, Turner, et al., 2009; Willott, Milbrandt, Bross, & Caspary, 1997). These rodent studies show significant age-related losses of strychnine binding throughout the fusiform cell layer with the largest age-related losses in the medial or high frequency limb of DCN (Milbrandt & Caspary, 1995; H. Wang, Turner, et al., 2009; Willott et al., 1997). Age-related changes in GlyR subunit message and protein suggest an age-related change in the makeup of aged GlyRs in the DCN (Krenning, Hughes, Caspary, & Helfert, 1998; H. Wang, Turner, et al., 2009; Willott et al., 1997). Specifically, the wild-type α1 GlyR subunit shows significant age-related declines in the fusiform cell layer with a paradoxical increase in the GlyR anchoring protein, gephrin (H. Wang, Turner et al., 2009). These age-related changes in near-CF inhibition significantly alter the temporal processing ability of DCN output neurons, as discussed next.

Impact of Aging on Calcium Binding Proteins, Glia, and Trophic Factors in DCN

Many theories of generalized aging have focused on dysfunctional calcium signaling because normal adult brain function, including synaptic transmission, transmitter and endocrine secretion, excitability, learning, and memory, rely on calcium homeostasis. A number of mouse DCN studies have shown age-related increases in levels of the major calcium binding proteins: calbindin, calretinin, and parvalbumin (Idrizbegovic, Bogdanovic, Viberg, & Canlon, 2003; Idrizbegovic, Bogdanovic, Willott, & Canlon, 2004; Idrizbegovic, Salman, Niu, & Canlon, 2006; Zettel, O’Neill, Trang, & Frisina, 2003). Contrary to these findings, a non-human primate aging study found no age-related change in parvalbumin in macaque DCN (Gray, Engle, & Recanzone, 2014). A postmortem human DCN study examined calcium-binding proteins across nine decades of life and found no age-related changes in calbindin1 and calretinin, but significant reductions in parvalbumin-positive neurons in the 6th and 8th decade with a nonsignificant trend in the 9th decade, likely due to the small number of subjects (Sharma, Nag, Thakar, Bhardwaj, & Roy, 2014). These investigators also examined age-related changes in glial fibrillary acidic protein (GFAP), considered a marker of gliosis and possibly for impaired synaptic plasticity (Finch, 2003). Few changes in GFAP across life span were found in human DCN (Sharma et al., 2014) unlike an earlier rat study which found significant increases in GFAP-positive cell numbers and density with aging (Jalenques et al., 1995). Wang and colleagues (2011) described no significant age-related changes in brain-derived neurotrophic factor (BDNF) or its receptor in rat DCN.

Impact of Aging on the Physiology of the DCN

DCN fusiform or pyramidal neurons represent the primary output to the contralateral IC (Cant & Benson, 2003; Oertel & Young, 2004; Rhode et al., 1983). These neurons show unique temporal response properties and areas of profound inhibition, which focused near the CF within their excitatory response areas (Young & Brownell, 1976). Thus, fusiform cell CF rate-level functions display a profound non-monotonicity reflecting the glycinergic input from neighboring vertical cells onto their basal dendrites and somata (Caspary et al., 1987; Caspary et al., 2005). Iontophoretic application of the GlyR antagonist strychnine transforms the non-monotonic rate-level function into more monotonic functions (Caspary et al., 1987; Davis & Young, 2000). One would predict that if aging negatively impacted glycinergic circuits within the DCN, rate-level functions from aged fusiform cells would show more monotonic functions. That is exactly what was found when comparing recordings from aged fusiform cells with fusiform cells from young adult DCN in FBN rat (Caspary et al., 2005). Likely reflecting age-related peripheral changes, aged fusiform cells showed significantly elevated CF thresholds, increased spontaneous activity, and higher driven rates at supra-threshold intensities. As might be predicted by the age-related loss of inhibition, this same population of fusiform cells showed significantly reduced ability to accurately code rapidly time varying modulated signals similar to speech sounds (Figure 1). Human studies show that loss of temporal processing is a hallmark of age-related hearing loss (Pichora-Fuller et al., 2007; Pichora-Fuller & Souza, 2003; Schatteman, Hughes, & Caspary, 2008). Thus when sinusoidally amplitude modulated (SAM) stimuli were used as a surrogate for speech, group data showed an age-related decrease in the peak vector-strength at the best modulation frequency (BMF) at different depths of modulation for aged fusiform cells relative to the young fusiform cells examined (Schatteman et al., 2008); Figure 1).

Aging Processes in the Subcortical Auditory SystemClick to view larger

Figure 1. Age-related loss of temporal processing in dorsal cochlear nucleus

Temporal modulation transfer functions (tMTFs: vector strength) from young (n = 93; 4–6 mos) and aged (n = 88; 28–30 mos) fusiform cells at 50% and 20% depth of modulation. Note the clear band-pass nature of the young tMTFs at 50% and 20% modulation depth. With aging, fusiform cell tMTFs are flatter and broader likely reflecting an age-related loss of glycinergic inhibition. Error bars represent the S.E.M.

Reproduced from Schatteman, Hughes, & Caspary (2008), with permission from Elsevier.

Cartwheel cells located in the superficial, molecular layer of the DCN, are excited by parallel fibers and likely project glycinergic/GABAergic inhibition onto the apical dendrites of fusiform cells and neighboring cartwheel cells (He, Wang, Petralia, & Brenowitz, 2014; Mancilla & Manis, 2009; Portfors & Roberts, 2007; Rubio & Juiz, 2004). Single unit recordings from aged cartwheel cells in FBN rat showed significantly higher thresholds, modestly increased spontaneous activity, and significantly altered rate-level functions characterized by hyperexcitability at higher intensities (Caspary, Hughes, Schatteman, & Turner, 2006). Aged cartwheel cells also showed reduced off-set suppression, suggesting a loss of tonic and perhaps sound-evoked inhibition.

In AVCN, markers for excitatory and inhibitory neurotransmission show age-related decreases in the mouse VCN and are reviewed in the chapter by Manis in this volume (Y. Wang & Manis, 2005; Xie & Manis, 2013, 2017).

Aging and the SOC

Cluttered acoustic environments such as restaurants and social settings represent a challenge to speech understanding for elderly adults, even those with relatively normal hearing (Gordon-Salant, 2014; Harris & Dubno, 2017; Pichora-Fuller et al., 2017; Pichora-Fuller & Souza, 2003). The ability to utilize binaural cues enables separation of relevant communication signals from irrelevant background distractors (Eddins & Hall, 2010; Ozmeral, Eddins, & Eddins, 2016). A key set of brainstem nuclei receiving time locked information primarily from VCN projection neurons comprise the SOC. Important nuclei for processing interaural time differences (ITDs) and interaural intensity differences (IIDs) include the medial superior olive (MSO) for low frequency ITD detection and the lateral superior olive (LSO)/medial nucleus of the trapezoid body (MNTB) for processing IIDs but also ITDs (see Grothe; Friauf; Kaczmarek; this volume). Human psychoacoustic studies have shown age-related binaural deficits negatively impact signal detection under a number of different listening conditions (Eddins & Hall, 2010; Pichora-Fuller et al., 2017).

Impact of Aging on the Structure of the SOC

Godfrey and colleagues (2017) found no significant differences in regional volume or dry weight for LSO, MSO, or MNTB between 6 month and 33 month-old FBN rat SOC. A series of anatomical aging studies in the 1980s focused on cellular changes in the MNTB of young and aged Sprague Dawley (SD) rats (Casey, 1990; Casey & Feldman, 1982, 1988). The MNTB provides contralateral inhibitory glycinergic input primarily to the LSO, but also to MSO and other nuclei within the SOC (Grothe & Pecka, 2014; Moore & Caspary, 1983). These studies initially used SD rats and showed a 34% loss of MNTB neurons between 2–3 months and 24 months of age (Casey & Feldman, 1982). Casey (1990) also counted the number of MNTB neuron in the F344 rat model of aging and found a significantly smaller 8% loss of principal neurons in this strain relative to the 34% loss in SD rats. A companion study in SD rats found that the volume density ratio of capillaries significantly decreased between 6 and 33 months of age (Casey & Feldman, 1985b). Aged SD rats showed degeneration of nerve endings including alterations in the endbulb input terminals from AVCN onto the principal neurons of the MNTB. The effect of aging on axosomatic MNTB synaptic terminals was measured using quantitative electron microscopy and revealed that the mean percentage of the principal cell surface areas contacted by synaptic terminals showed an age-related decrease from ~61% in young 3 month-old to ~43% in 27–33 month-old SD rats (Casey & Feldman, 1985a, 1988). Likewise, between 3 and 27–33 months of age, the average number of synaptic terminals present along a 100 micron length of principal cell surface decreases significantly, from 28.3 to 18.9. Only terminals derived from calyces of Held were lost in the aged animals described above (Casey & Feldman, 1988). These data support a partial age-related deafferentation of MNTB principal cells, potentially reducing both accurate IID and ITD coding in aged animals (discussed next).

Impact of Aging on Neurotransmitters in the SOC

Glutamate serves as the primary excitatory neurotransmitter providing well-timed drive from the VCN to endbulbs on MNTB neurons and onto the dendrites of ipsilateral LSO neurons and ipsi- and contralateral MSO neurons. The MNTB represents a large group of glycinergic neurons providing binaural/contralateral inhibition onto the medial dendrites of LSO neurons for IID detection and refining ITD coding in the MSO (see Grothe; Friauf, this volume; Grothe & Pecka, 2014; Myoga, Lehnert, Leibold, Felmy, & Grothe, 2014). Age-related changes in the magnitude or the timing of excitation or inhibition would certainly alter one’s ability to accurately localize signals in the azimuthal plane. Age-related reductions in glutamate levels in areas of AVCN which project to SOC as well as all SOC subnuclei examined show significant age-related losses of ambient glutamate (Banay-Schwartz et al., 1989; Godfrey et al., 2017). Early SOC aging studies described above found a 34% loss of putative glycinergic principal cells in MNTB of SD rats but only an 8% loss in F344 rat MNTB (Casey, 1990; Casey & Feldman, 1982). Godfrey and colleagues (2017) show significant age-related decreases in glycine levels throughout the SOC with losses in the LSO and MNTB likely to directly impact azimuthal coding in the elderly. Functional studies described next tested the possible loss of IID coding due to the loss of glycinergic input onto LSO neurons in F344 and SD rats.

Impact of Aging on Calcium Binding Proteins and Neuromodulators in the SOC

A number of studies have examined age-related changes in calcium binding proteins, calbindin1, calretinin, parvalbumin, and nitric oxide synthase NADPH-diaphorase (NADPHd) in rodent, non-human primates, and humans. Gray et al (Gray, Engle, & Recanzone, 2013; Gray, Engle, Rudolph, & Recanzone, 2014) observed an increase in parvalbumin-positive and calbindin1-positive cells with age in macaque MSO, LSO, and nonsignificant changes in the MNTB. Calbindin1-positive cells that co-localized with glutamic acid decarboxylase (GAD)-67 increased with age. NADPH showed a similar pattern of increase in MSO and LSO with aging (Gray, Engle, et al., 2013). Non-human primate results differed from results in certain mouse strains where calcium-binding proteins were seen to decrease in the SOC (O'Neill, Zettel, Whittemore, & Frisina, 1997).

Impact of Aging on the Physiology of the SOC

Few studies have examined age-related changes in the physiology of the SOC. Two studies evolved from the anatomical SOC studies described earlier and tested whether the age-related loss of putative glycinergic principal neurons of the MNTB would result in a shift in the interaural intensity functions derived from LSO neurons (Finlayson & Caspary, 1993). However, as might be predicted from the minor 8% age-related loss of MNTB neurons in the F344 rat, no significant asymmetrical aging changes were observed, although a trend toward loss of contralateral inhibition was noted (Finlayson & Caspary, 1993). When the SD rat LSO was similarly examined, the 34% age-related decrease in the numbers of MNTB neurons observed anatomically was not reflected in any age-related change in LSO IID coding. Despite these electrophysiological findings, age-related loss of azimuthal coding is well supported by psychoacoustic studies.

Aging and the IC

As reviewed in the chapters by Cant, Oliver et al., and Rees & Orton, in this volume, major inputs to the IC include ascending glutamatergic excitatory inputs from the cochlear nucleus, SOC, and descending from cortex, thalamus, and brachium of the IC. The IC comprises three subdivisions: the central nucleus, generally considered to be the lemniscal division, and two non-lemniscal divisions: the lateral nucleus (sometimes referred to as the lateral cortex or external cortex) and the dorsal cortex. Each division has a distinct synaptic and biochemical profile, which is potentially important since many studies have grouped segments of the IC together, potentially obscuring age-related differences between IC subdivisions.

Impact of Aging on the Structure of the IC

An early study by Willott et al. (1994) employed light microscopy to measure the volume of the IC, packing density and cellular volumes in mice ranging from 1.5 to 30 months of age. No differences in the IC were seen across ages in either CBA/J or C57BL/6J mice despite brainstem spongiform changes being observed in aged C57BL/6J mice (Willott et al., 1994). Similarly, Kazee et al. (1995) used a combination of light and electron microscopy to show preserved cellular volumes and synaptic numbers and types in aging CBA mice (Kazee & West, 1999), but dramatic drops in synaptic number and somatic size in the central nucleus of IC neurons in C57BL/6 mice (Kazee et al., 1995). Consistent with these findings, using electron microscopy in the F344 rat, Helfert et al. (1999) observed no changes in cellular density across 3 to 28 months of age, but did report age-related decreases in excitatory and inhibitory synaptic number and proceeded to model how these changes might correlate with aging dendritic structure of IC disc shaped neurons. Specifically, they speculated that there is loss of GABAergic and non-GABAergic terminals on distal dendrites of both GABAergic and non-GABAergic neurons, but that there is a shift of these terminals to the proximal regions of GABAergic cells (Figure 2; Helfert et al., 1999). To our knowledge, only two studies examined age-related changes in connectivity between the IC and other brain regions (Frisina & Walton, 2001; Willott, Pankow, Hunter, & Kordyban, 1985). Willott et al. (1985) placed a retrograde tracer into the central nucleus of the IC of young and aged C57BL/6 mice and found no differences in the projection of the AVCN to the IC across the lifespan. A second study used a similar approach and found significant declines of inputs to the dorsomedial IC from all three divisions of the contralateral CN in aged CBA mice relative to young animals (Frisina & Walton, 2001). Taken together, these data suggest that gross morphological features of the IC (cell size and packing density) are relatively unchanged with aging, but neuropil features (synaptic number and density) decline with aging, and, given the accentuated synaptic loss in C57BL/J mice compared to CBA/J mice, loss of peripheral hearing likely contributes to this loss of synaptic density. This loss in synaptic density is consistent with the many age-related changes in markers for both excitatory glutamate and inhibitory GABA neurotransmission in IC (Caspary et al., 1999; Caspary et al., 2008; Godfrey et al., 2017; Gold & Bajo, 2014; Ouda, Profant, & Syka, 2015) reviewed next.

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Figure 2. Models of age-related synaptic changes in the inferior colliculus

Impact of aging on the synaptic contacts of disc-shaped IC neurons. (A) Cartoon of a young IC neuron shows GABA– (excitatory) and GABA+ (inhibitory) terminals ending on secondary and tertiary dendrites. Both types of terminals are also located on the small numbers of dendritic spines and very thin dendrites throughout the dendritic arbor. (B) Cartoon of aged GABA– IC neuron shows GABA– and GABA+ synaptic terminals on remaining distal dendrites. (C) Cartoon of an aged GABA+ IC neuron showing loss of inhibitory and excitatory synaptic contacts on distal dendrites, with a shift of terminals onto more proximal portions of the dendritic tree.

Reproduced from Helfert, Sommer, Meeks, Hofstetter, & Hughes (1999), with permission from John Wiley & Sons.

Impact of Aging on Metabolism in the IC

The IC is one of the most metabolically active structures in the brain (Gross, Sposito, Pettersen, Panton, & Fenstermacher, 1987; Hevner, Liu, & Wong-Riley, 1995; Sokoloff et al., 1977). Given its high metabolic demand, one would predict that the IC may be particularly vulnerable to age-related metabolic stressors. This prediction is supported by data showing age-related decreases in the levels of antioxidant enzymes superoxide dismutase and catalase, as well as increases in lipid peroxidation in the aging rat IC (Mei et al., 1999). In addition, electron microscopic studies in the aging rat IC show decreases in mitochondrial density across both inhibitory and excitatory neurons when compared to younger animals (Mei et al., 1999), suggesting that metabolic energy failure may play a role in age-related IC dysfunction. Further, the aging F344 rat IC shows diminished levels of Hsp-72 (Helfert et al., 2002), which is an inducible heat-shock protein whose levels normally increase under conditions of environmental stress and function to chaperone misfolded proteins. Finally, expression of the BDNF receptor (tyrosine-kinase B or TrkB), is diminished in the aging F344 rat IC. Given the role of BDNF in supporting synaptic health and its antioxidant function (Sato et al., 2001), the authors speculated that this diminishment in TrkB receptor activity may tie together the age-related synaptic losses and loss of antioxidant function already described.

In contrast, more direct measurements of neuronal metabolism using 2-deoxyglucose autoradiography have not revealed significant age-related changes in IC metabolic rate. Resting 2-deoxyglucose uptake in the aging rat and mouse IC appears to be unchanged relative to young controls (Clerici & Coleman, 1987; Willott, Hunter, & Coleman, 1988). In response to pure-tone stimulation, the sharpness of frequency tuning, as determined by the spatial spread of 2-deoxyglucose uptake, is diminished with aging in an SD rat model (Clerici & Coleman, 1987; Keithley, Lo, & Ryan, 1994). This finding is consistent with the in vivo single unit frequency tuning recordings that we shall review . The lack of overall metabolic changes at rest suggests that either compensatory mechanisms have permitted overall metabolic stability to occur despite the biochemical change noted previously, or that differences can only be seen with more sensitive techniques or under conditions of environmental stress. Further work is needed to elucidate these possibilities.

Impact of Aging on Neurotransmitters in the IC

The impact of aging on inhibitory neurotransmission in the IC has been extensively studied (Caspary et al., 2008; Godfrey et al., 2017; Gold & Bajo, 2014; Ouda et al., 2015). Resting GABA levels are significantly reduced in rodent models and human aging studies (Banay-Schwartz et al., 1989; Banay-Schwartz, Palkovits, & Lajtha, 1993; Caspary, Raza, Armour, Pippin, & Arneric, 1990). Consistent with these findings are studies showing significant age-related loss in IC of both forms of GAD, the rate-limiting metabolic enzyme required for the production of both metabolic and neurotransmitter GABA in rodents and humans (Burianova, Ouda, Profant, & Syka, 2009; Caspary et al., 1990; Gutierrez, Khan, & De Blas, 1994; McGeer & McGeer, 1975; Milbrandt, Albin, & Caspary, 1994; Milbrandt, Holder, Wilson, Salvi, & Caspary, 2000; Raza, Milbrandt, Arneric, & Caspary, 1994). These age-related changes are observed in both the somata and terminals throughout the central nucleus of the IC (Caspary et al., 1990; Helfert et al., 1999). As one would predict, there is a commensurate reduction in potassium-evoked calcium mediated release of GABA from IC punches from the aged F344 rat IC (Caspary et al., 1990). GABAB receptors acting as presynaptic autoreceptors are known to control release of GABA from presynaptic terminals in the IC (C. L. Ma, Kelly, & Wu, 2002). Milbrandt and colleagues found a significant age-related loss of GABAB receptors in the IC of F344 rats (Milbrandt et al., 1994). Whether presynaptic age-related changes in production and release of GABA reflect a compensatory down-regulation of inhibition due to a loss of glutamatergic excitatory drive or age-related intrinsic changes has not been established, but as delineated later in the chapter, glutamate levels and excitatory terminals are also significantly reduced in aged rodent IC (Banay-Schwartz et al., 1989; Godfrey et al., 2017; Helfert et al., 1999).

The function and pharmacology of the heteromeric, pentameric chloride-fluxing GABAA receptor are determined by its subunit composition with different combinations of the 19 available subunits determining the magnitude/amplitude, and duration of evoked inhibitory post-synaptic potentials and ligand affinity (Rudolph & Möhler, 2006; Whiting, 2003). Thus, age-related changes in the subunit makeup of the primary excitatory and inhibitory neurotransmitters can have a profound effect on normal young adult physiology and the ability to accurately code acoustic information. Young-adult, wild-type GABAARs are made up of 2α12γ2 subunits. Significant age-related changes in the message and protein of the GABAAR subunits have been reported in the IC and its subregions in two rat models (Caspary et al., 1999; Milbrandt, Hunter, & Caspary, 1997). The trend across all regions of the IC was for a decrease in wild-type GABAAR constructs which are replaced by constructs containing more developmental subunits, γ1 and α3, which have slower temporal kinetics (Caspary et al., 1999; Whiting, 2003). In addition to age-related changes in the subunit makeup of GABAARs, there is a significant loss in the number of metabotropic GABABRs within the F344 rat IC (Milbrandt et al., 1994).

Glutamatergic signaling has been found to change in the aging IC. Glutamate levels were measured across multiple regions of the IC of young and aged rats, using quantitative microchemical analysis and high-performance liquid chromatography (HPLC; Godfrey et al., 2017). Working with FBN rats, Godfrey and colleagues found a roughly 20% decrease in glutamate levels throughout the IC, and that this drop was most prominent in the central nucleus of the IC (Figure 3), the most metabolically active part of the IC (Godfrey et al., 2017). This work in FBN rat is consistent with an early study which used HPLC to measure amino acid levels across whole structures in F344 rats (Banay-Schwartz et al., 1989). Perhaps in response to an age-related decrease in glutamate levels, Osumi et al. (2012) found diminished expression of the NMDA zeta1 subunit throughout the IC of middle-aged (12–15 months) compared to juvenile (1 month) C57BL/6J mice. Since “aged” animals in this study were relatively young, but had significant hearing loss, the authors speculated that such declines in NMDA receptor subunits may be related to loss of synaptic input from afferent fibers. It is possible that NMDA receptor subunit downregulation functions to diminish potential glutamate toxicity, given the metabolic vulnerability of this structure with aging (reviewed earlier). Consistent with this idea, Tadros et al. (2007) observed upregulation of the high-affinity glutamate transporter in the IC of aging CBA mice with advanced hearing loss, possibly functioning to clear excess glutamate. Thus, both the biochemical and structural data point to age-related decreases in both glutamatergic and GABAergic function in the IC with aging, but that GABAergic maybe dominant, tilting the balance in favor of excitation.

Aging Processes in the Subcortical Auditory SystemClick to view larger

Figure 3. Age-related loss of glutamate in inferior colliculus

Map of the left inferior colliculus of 33-month-old rat with color coded percentages of glutamate levels in similarly located samples of 6-month-old rat. Young and old samples were microdissected on the same day and included in the same HPLC assay. Percentage values are coded as shown in the key.

Modified from Godfrey, Chen, O'Toole, & Mustapha (2017), with permission from Elsevier.

Impact of Aging on Calcium Binding Proteins and Neuromodulators in the IC

Expression of calcium-binding proteins is altered in the aging IC and aging effects appear to be species- and strain-specific. Normally, parvalbumin is strongly expressed in the central nucleus, as well as in discrete GABA-rich regions (containing both GABAergic somata and terminals) in the external cortex (Chernock, Larue, & Winer, 2004; Lesicko, Hristova, Maigler, & Llano, 2016). Calretinin, on the other hand, is present outside the GABA-rich regions of the external cortex (Dillingham, Gay, Behrooz, & Gabriele, 2017) while calbindin1 is only expressed in the nucleus of the commissure (Zettel, Frisina, Haider, & O'Neill, 1997). Zettel et al. (1997) observed substantial age-related increases in calretinin staining in the non-leminscal portions of the CBA/CaJ IC, but not the C57BL/6J mice. Given the complementary staining for GABA and calretinin in the external cortex, the age-related increase in IC calretinin signal may reflect a relative decrease in GABA staining. Subsequent work on the CBA/CaJ mouse demonstrated that this calretinin increase is dependent on ongoing acoustic information processing and suggests that the difference between two strains maybe related to the poor hearing in C57BL/6 mice (Zettel, O’Neill, Trang, & Frisina, 2001). Data from rat have shown both increases (Hong et al., 2009) and decreases (Ouda, Burianova, & Syka, 2012) in calretinin staining in the IC with aging. Differences here may be related to strain as Wistar rats (24 months) were used in the Hong et al. (2009) study while Long-Evans and F344 rats (18-33 months) were used in the Ouda et al. (2012) study. Age-related upregulation was also seen in parvalbumin-positive neurons in the non-human primate IC with aging, and this increase correlated with peripheral hearing loss (Engle, Gray, Turner, Udell, & Recanzone, 2014). In the rat, the number of parvalbumin-positive neurons increases in the IC of aging Long-Evans rats, while the mean size of parvalbumin-positive neurons decreases in the IC of F344 rats (Ouda, Druga, & Syka, 2008). Given the disparate species and approaches used to examine the pattern of calcium binding proteins in the IC with aging, a unified picture of these proteins has yet to emerge.

In contrast to GABA and glutamate, where a number of studies provide a relatively coherent picture of age-related loss of both neurotransmitters in the IC, most studies of other neuroactive species have yet to provide consistent results. For example, the synthetic enzyme for nitric oxide, a gaseous neurotransmitter which has been implicated in toxicity associated with brain aging (Indo et al., 2015; McCann, 1997), is strongly expressed in the non-lemniscal portions of the IC (Coote & Rees, 2008). Two studies have measured changes in NADPH diaphorase staining (a marker for nitric oxide synthase-containing neurons) across young and aged Wistar rats, and found different results. Huh et al. (2008) observed a doubling of NADPH diaphorase-positive neurons in the IC in 24-month-old rats relative to 4-month-old rats. In contrast, Sánchez-Zuriaga and colleagues observed a significant drop (at least 50% in all IC subdivisions) in 28–30-month-old rats relative to 6–9-month-old rats (Sánchez‐Zuriaga, Martí‐Gutiérrez, La Cruz, Pérez, & Peris‐Sanchis, 2007). Given the age differences between the control and the aged rats in these two studies, these results may point to a transient middle age increase in nitric oxide production, followed by a late-life decrease. Complicating the interpretation of these rodent findings is the finding of no age-related changes in the number of NADPH-positive cells in the non-human primate IC (Engle et al., 2014). More work is needed to add clarity in this area.

A single study probed changes in IC serotonergic function with aging. Expression of the 5HT2B receptor was found to be upregulated in the external cortex of the IC of the aging CBA/J mouse (Tadros, D'Souza, Zettel, Zhu, Lynch-Erhardt, et al., 2007). This increased expression of 5HT2B receptors has been correlated with hearing loss, and given the role of these receptors in inflammation, local blood flow, mitochondrial function, and calcium regulation, the authors speculated that the increase in 5HT2B receptors may be a compensatory response to damage at the auditory periphery.

Impact of Aging on the Physiology of the IC

One of the most notable differences between young and aged IC neurons is the increase in average response threshold observed in aged animals (Leong, Barsz, Allen, & Walton, 2011; Palombi & Caspary, 1996b; Willott, 1986; Willott, Parham, & Hunter, 1988a, 1988b), likely reflecting peripheral hearing loss. Several studies also noted increases in spontaneous activity and/or reduction of the proportion of sound-responsive neurons in the aged IC (Chiu, Poon, Chan, & Yew, 2003; Palombi & Caspary, 1996b; Willott, Parham, et al., 1988a, 1988b). Increases in spontaneous firing rate have also been noted after acute hearing loss, and may reflect decreases in inhibitory tone (Bauer et al., 2008; Jastreboff, 1995; W. D. Ma, Hidaka, & May, 2006), as reviewed earlier. A majority of IC neurons across species are characterized by strongly non-monotonic CF input-output/rate-level functions likely reflecting GABAergic inhibition with their receptive fields (Palombi & Caspary, 1996a). The significant loss of markers for normal adult GABAergic inhibition in IC predicts the observed age-related loss of rate-level function non-monotonicity for IC neurons (Palombi & Caspary, 1996b). The combination of the increase in spontaneous firing, relative decrease of sound-responsive units and loss of damping at higher stimulus intensities would likely introduce temporal jitter and serve to diminish the overall signal-to-noise ratio of coded acoustic information in the IC of aged animals. Frequency representations in the aging IC tend to reflect changes in peripheral hearing, such that aged animals with high-frequency hearing loss have a lowered proportion of neurons representing this frequency range in the IC (Palombi & Caspary, 1996b; Willott, 1984, 1986). Sharpness of tuning functions also tends to be diminished with aging (Leong et al., 2011; Palombi & Caspary, 1996b; Willott, 1986). However, despite the age-related changes noted above, most investigators commented that, besides threshold shifts, increased spontaneous activity, and loss of non-monotonicity for rate-level functions, many basic response properties between young and aged IC were more similar than expected.

In contrast to the relatively subtle changes in the responses of IC neurons to simple stimuli, more robust age-related changes have been observed when temporally patterned stimuli are used. A number of studies have employed amplitude-modulated stimuli to probe the temporal processing characteristics of neurons in the young and aged IC. For example, Palombi et al. observed a significant shift in the proportion of band-pass neurons towards more low-pass neurons (i.e., a shift in toward neurons responding maximally to lower amplitude modulation rates) in aged F344 rats (Palombi, Backoff, & Caspary, 2001). A similar shift to lower rates of amplitude modulation was also seen in IC neurons of CBA mice (Walton, Simon, & Frisina, 2002). An age-related shift to more low-pass functions would also be seen with a drop in peak modulation frequency essentially turning a bandpass modulation transfer function into a more low-pass function. A study of young and aged Mongolian gerbils, Khouri et al. (2011) computed the selectivity to combinations of temporal parameters (“pulse matrix receptive field”) when neurons were presented trains of pulses at varying rates and pulse durations. They found that aging was associated with a decline in temporal selectivity, and this drop in selectivity diminished the population encoding human speech sounds (Khouri et al., 2011).

Another commonly used paradigm to investigate temporal processing is gap detection, which is significantly compromised in behavioral studies of aged humans and rodents (Dubno, Horwitz, & Ahlstrom, 2003; Gordon-Salant & Fitzgibbons, 1993; Schneider, 1997; Snell, 1997; Strouse, Ashmead, Ohde, & Grantham, 1998; Walton, Frisina, Ison, & O'Neill, 1997; H. Wang, Brozoski, et al., 2009). Two studies in aging mice demonstrated impaired gap detection in aged IC neurons. In 24–28-month-old CBA/CaJ mice, Walton et al. observed both a shift in the minimal gap detection thresholds and a pronounced shift in the gap duration required to recover neuronal onset responses. More dramatically, in young mice, nearly all neurons recovered to 75% of their baseline responsiveness with gaps less than 10 msec, whereas very few aged IC neurons returned to 75% of baseline, even at gap widths of 50 msec (Walton, Frisina, & O’Neill, 1998). In addition, in 20 month-old Long Evans rats, Finlayson used paired tone stimuli to probe the effects of aging on forward masking recovery (Finlayson, 2002). They found that the median time constant for suppression increased from 71.6 msec in young to 101.1 msec in aged IC neurons. This increase was not dependent on hearing loss, suggesting that the change was of central origin. Finally, a recent computational modeling study explored potential mechanisms by which the age-related temporal processing deficits described above may occur (Rabang et al., 2012). The authors constructed biologically realistic models of IC neurons based on anatomical and physiological data. They found that the shift from band-pass to low-pass neurons in response to SAM stimuli occurred as GABAergic inhibition was downregulated.

Humans show age-related loss in the ability to localize sound, which may well correlate to a loss in the ability to understand speech in complex acoustic environments (for review see (Eddins & Hall, 2010; Freigang, Richter, Rübsamen, & Ludwig, 2015). Two studies measured binaural or free-field properties of IC neurons in aging rodent models. McFadden and Willott (1994) examined azimuthal tuning functions in C57BL/6J mice, which showed behavioral evidence of age-related declines in sound localization performance (Heffner & Donnal, 1993). In most respects, IC neurons showed similar azimuthal functions in young and aged mice. However, with aging, there was a shift in bias toward more neurons being ipsilaterally tuned, and this shift was not restricted to high-frequency sounds (where most hearing is lost), suggesting that the changes were due to central aging effects- and not purely hearing-loss related (McFadden & Willott, 1994). Similarly, in the F344 rat, only subtle differences (not reaching statistical significance) were seen in the binaural responses properties of aged IC neurons (Palombi & Caspary, 1996c). These data suggest that overall, sound localization properties of IC neurons are not substantially altered in aging rodents, but may reflect some minor loss of binaural inhibitory coding.

Taken together, the data suggest that the aged IC provides a lower fidelity representation of the external acoustic world, and that this representation is particularly vulnerable when temporally patterned stimuli are required. The computational work by Rabang et al. (2012) suggests that the biochemical and anatomical data demonstrating decreases in GABAergic tone in the aging IC described earlier may be, at least in part, responsible for age-related changes in temporal resolving power of IC neurons. Given that most real-life acoustic stimuli, such as speech and species-specific sounds, contain strong modulations in amplitude and frequency over time, the aging IC is likely to provide its target, the auditory thalamus, with a temporally smeared representation of the real-life acoustic world, relative to the young IC.

Aging and the Auditory Thalamus

The auditory thalamus, also known as the MGB, receives its main excitatory glutamatergic input from the IC and sends excitatory glutamatergic projections to the auditory cortex and the thalamic reticular nucleus (TRN). The MGB can be subdivided into a lemniscal ventral division (MGBv), and two non-lemniscal divisions: the dorsal division (MGBd), medial division (MGBm), as well as several paralaminar structures (suprageniculate, posterior intralaminar, and peripeduncular). The MGBv is the only tonotopically organized region and gets its main input from the central nucleus of the IC and projects to primary auditory cortical fields, whereas the other regions get their main input from the non-lemniscal portions of the IC and auditory cortex and project to non-primary auditory cortical fields as well as to the upper layers of the primary auditory cortex (reviewed in Lee, 2013).

GABAergic inhibitory input to the MGB stems from several sources. In non-rodent species, approximately 20% of MGB neurons are GABAergic, while in rodents as few as 1% of MGB neurons are GABAergic (Winer & Larue, 1988). In rodents, there is a major ascending GABAergic input from the IC (Peruzzi, Bartlett, Smith, & Oliver, 1997; Winer, Saint Marie, Larue, & Oliver, 1996). In addition, there is GABAergic input from the TRN, which partially surrounds the thalamus. Finally, there is a small GABAergic component from the zona incerta (Barthó, Freund, & Acsády, 2002). There is no known glycinergic input to the MGB.

Impact of Aging on Neurotransmitters in the MGB

Two carefully done rodent studies show significant reductions in ambient glutamate levels but unlike the IC, where GABA levels show significant age-related reductions, these same studies show nonsignificant reduction of endogenous GABA levels (Banay-Schwartz et al., 1989; Godfrey et al., 2017). Richardson et al. (2013) found small, but significant changes in GAD67 protein in Western blots from FBN rat MGB. This study also assessed whole-cell chloride currents in young (3-8 month) and aged (28-32 month) rat MGB neurons in a brain slice preparation. While age-related changes in synaptic chloride GABA currents were small, the authors observed a pronounced drop (~50%) in tonic chloride, extrasynaptic, currents from neurons in both the MGBv and MGBd with aging (see Figure 4). Given the multiple sources of GABAergic inhibition in the MGB, it is not clear if age-related changes in GABA release from one or more of these sources serve as the trigger for the compensatory decrease in extrasynaptic GABAARs. Down-regulation of extrasynaptic GABAARs could be due to a loss of ambient GABA in response to an age-related decrease in GABA release, age-related changes in neuroactive steroids, or de novo aging.

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Figure 4. Age-related loss of extrasynaptic GABAARs in rat MGB

GABAAR-mediated tonic inhibitory currents are reduced with age. (A) Raw sample trace from a young adult MGB neuron (top, black) and an aged MGB neuron (bottom, gray) in response to application of gaboxidal (an agonist with high affinity for α4δ containing GABAARs). Addition of gabazine blocked all GABAA currents. Calibration applies to both traces. (B and C) Histogram (open bars, young adult; gray bars, aged rats) shows age-related differences between gaboxadol-activated (B) and endogenous (C) high-affinity GABAAR-mediated tonic current amplitudes from MGd, MGv, and all MGB (MGTot) neurons. (B) Shows age-related tonic current amplitude difference in 1.5μM gaboxadol-evoked current GABAAR blockade. (C) Shows age-related tonic current amplitude difference between the baseline/endogenous current after blockade of GABAARs. *p < 0.05; **p < 0.01 (independent-sample t tests).

From Richardson, Hancock, & Caspary (2013), with permission from Journal of Neuroscience.

Impact of Aging on Calcium Binding Proteins and Neuromodulators in the MGB

Three main calcium binding proteins (parvalbumin, calbindin1, and calretinin) have different distributions within the MGB such that parvalbumin is primarily found in the MGBv, whereas calbindin1 and calretinin are found throughout the non-leminscal divisions (Cruikshank, Killackey, & Metherate, 2001; E. Lu, Llano, & Sherman, 2009; Molinari et al., 1995). To date, three studies have examined age-related changes of these proteins in rat MGB and one in monkey MGB, and have yielded conflicting results. Ouda and colleagues found drops in calbindin1-positive cell density and cell volume in the rat MGBv (a structure with very little calbindin1 staining) and no changes in parvalbumin and calretinin (Ouda et al., 2012; Ouda et al., 2008). In contrast, to the calbindin1 findings from Ouda et al., (2008; 2012) in F344 and Long-Evans rats, Hong et al. (2009) found no change in the numbers of calbindin1-positive neurons in the aging MGB in Wistar rat. They also found no changes in calretinin neurons. Also in contrast to the Ouda parvalbumin study in rats, Gray et al. (2013) observed an increase in parvalbumin-positive cell density in the monkey MGBv with aging. The differences here likely relate to species differences since the rat MGBv has very few parvalbumin-positive cell bodies (most staining is in neuropil), whereas strong parvalbumin cellular staining was seen in the Gray et al. study in monkeys (see their figures 2A and B). The origin of the differences in calbindin1 changes with aging between the Ouda et al. (2008, 2012) and Hong et al. (2009) studies is not known, though it should be noted that the Hong et al. study did not parse MGB by subdivision. Clearly, more work is needed to resolve these differences across studies and to derive a coherent view of thalamic calcium homeostasis with aging.

Two recent studies examined the impact of aging on cholinergic function in the MGB. Using a combination of radioligand binding studies and whole-cell patch recordings from brain slices in FBN rats, findings from Sottile et al. (2017) are consistent with a reduction in β2-subunit containing post-synaptic neuronal nicotinic acetylcholine receptors on MGB neurons in the aging rat MGB (Figure 4 Sottile, Ling, et al., 2017). Sottile et al. (2017) also observed that pre-synaptic neuronal nicotinic acetylcholine receptors on corticothalamic fibers and inhibitory tectothalamic fibers showed diminished effectiveness to applied acetylcholine and decreased epibatidine binding in the aged rat MGB. Given the evidence of cholinergic influences on attention (Klinkenberg, Sambeth, & Blokland, 2011), these data suggest that age-related changes in auditory attention may be mediated by pre- and post-synaptic changes in cholinergic function at the level of the MGB.

Impact of Aging on the Physiology of the MGB

To date, no studies have been published that examine basic response properties of MGB neurons with aging, though a recent abstract suggests that no differences exist in basic tuning properties between young (3 month) and aged (18 month) anesthetized CBA mice (L. A. Anderson, Quraishe, & Newman, 2017). A small number of studies examined changes in single MGB neurons in young and aged rodents and focused on selectivity for frequency modulation (Mendelson & Lui, 2004), amplitude modulation (Cai, Richardson, & Caspary, 2016), and novelty detection (Richardson, Hancock, & Caspary, 2013). In terms of responses to time-varying signals, Mendelson and Lui (2004) recorded from the MGBv of young (3-4 month) and aged (23-30 month) anesthetized Long Evans rats and found no differences in tuning for speed or directionality of frequency-modulated signals. The absence of a difference between groups contrasted with their previous work showing age-related changes in the auditory cortex using a similar experimental paradigm (Mendelson & Ricketts, 2001), suggesting that the negative result was not a result of lack of sensitivity of their approach, and that an age-related shift to preference for slow frequency modulation rates in the cortex was not inherited from the MGB.

Stimulus-specific adaptation (SSA) is a phenomenon reported in single units of the IC, MGB, and auditory cortex whereby units respond preferentially to novel stimuli (Malmierca, Cristaudo, Pérez-González, & Covey, 2009; Ulanovsky, Las, & Nelken, 2003). Although SSA is diminished in the auditory cortex of aged FBN rats (de Villers-Sidani et al., 2010), no age-related changes in SSA recorded from MGB neurons in awake FBN rats were found (Richardson, Hancock, et al., 2013).In a subsequent study, a more demanding, temporally complex novelty stimulus set was used in single unit recordings from young (4-6 month) and aged (28-30 month) awake FBN rat MGB neurons (Cai et al., 2016). SAM stimuli were modulated between 2 and 1024 Hz with the modulation frequency changing randomly across trials or presented in a predictable sequence. Units were found to be random-preferring, predictable-preferring, or non-selective based on total firing rate. When random versus predictable differences were examined across different modulation frequencies, the largest age-related differences were found at higher modulation frequencies, with aged MGB units preferring predictably presented SAM stimuli (see Figure 5, Cai et al., 2016). Figure 5, here, looks at the entire population of young and aged MGB neurons from Cai et al., (2016), in response to predictable presentation of a 512 Hz modulated carrier. While MGB neurons from young FBN rats are seen to adapt to repetitions of the SAM stimulus, neurons from the aged MGB increase their discharge rate across successive presentations (Figure 5). These findings suggest that aged MGB units/animals may employ increased top-down resources to enhance processing of “expected” temporally rich stimuli, especially at more challenging higher modulation rates These results suggest a neuronal substrate for an age-related increase in experience/attentional-based influences in processing temporally complex auditory information in the MGB. These findings are consistent with the body of psychophysical literature showing increasing dependence on top-down cues with aging, given the degradation in the processing of bottom-up signals (reviewed in Lesicko & Llano, 2017).

Aging Processes in the Subcortical Auditory SystemClick to view larger

Figure 5. Aged MGB neurons show increasing responses to predictable stimuli

Trial-by-trial responses to a repeating SAM stimulus modulated at 512 Hz. Group data (mean ± SE) show statistically different trend lines slopes, when plotting average spikes against each successive presentation of the SAM stimulus, recorded from 60 old MGB neurons and 72 young MGB neurons (ANCOVA, 2-tailed, p < 0.01).

Modified from ––Cai, Richardson, & Caspary (2016), with permission from Journal of Neuroscience.


Age-related hearing loss, is arguably the third major malady of industrialized populations causing social isolation and depression among a significant subset of this demographic. With the proportion of the elderly population approaching 25% by 2050, it is imperative that efforts be made to ameliorate this socially debilitating condition. It is accepted from human studies that presbycusis is multifactorial and that amplification of the input alone (i.e., hearing aids) frequently does not resolve issues of speech understanding especially in challenging acoustic environments.

It is our hope that this review has presented some of the many changes which occur in response to age-related peripheral deafferentation, as well as de novo central cellular aging. Many of issues highlighted in this review illustrate the disproportional downregulation of inhibitory processes and loss of temporal precision with aging. Development of non-sedating subunit selective GABA-related compounds to upregulate inhibition and training strategies shown to improve temporal processing in older individuals are indicative of future pharmacological and behavioral approaches toward ameliorating loss of speech understanding in the elderly.


This work was supported by the National Institute on Deafness and Other Communication Disorders: DC000151-DMC; DC012125 & DC013073-DAL.


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