Modulation of presbycusis: current status and future directions.

Literature and ideas are reviewed concerning the modulation of presbycusis - the influence of variables that can alter the severity and/or time course of presbycusis or counteract its negative aspects. Eleven topics are identified: variables related to biological aging; genetics; noise-induced hearing loss; moderately augmented acoustic environment; neural plasticity and the central auditory system; neural plasticity and hearing aids; socioeconomic and cultural barriers to hearing aid use; lifestyle (diet, exercise, etc.); medical variables; pharmaceutical interventions for presbycusis, and cognitive variables. It is concluded that the field of otogerontology will best be served by a comprehensive, integrative interaction among basic researchers and clinical scientists who will continue to learn how the auditory problems associated with presbycusis can be intentionally modulated in beneficial ways.

The total number of neurons and calcium binding protein positive neurons during aging in the cochlear nucleus of CBA/CaJ mice: a quantitative study.

The quantitative stereological method, the optical fractionator, was used for determining the total number of neurons and the total number of neurons immunostained with parvalbumin, calbindin-D28k (calbindin), and calretinin in the dorsal and posteroventral cochlear nucleus (DCN and PVCN) in CBA/CaJ (CBA) mice during aging (1-39 months old). CBA mice have only a modest sensorineural pathology late in life. An age-related decrease of the total number of neurons was demonstrated in the DCN (r=-0.54, P<0.03), while the total number of neurons in the PVCN did not show any significant age-related differences (r=0.16, P=0.57). In the DCN 5.5% of neurons were parvalbumin positive in the very old (30-39 months) mice, vs. 2.2% in the 1 month old mice. In the DCN 3% of the neurons were calbindin immunopositive in the 30-39 months mice compared to 1.9% in the 1 month old group. In the PVCN, 20% of the neurons in the very old mice were parvalbumin immunopositive, compared to 12% in the young mice. Calbindin did not show any significant age-related differences in the PVCN. The total number of calretinin immunopositive neurons both in the DCN and PVCN did not show any significant change with increasing age. In conclusion, the total neuronal number in the DCN and PVCN was age-related and region-specific. While the neuronal number in the DCN and PVCN was decreased or unchanged, respectively, the calcium binding protein positive neuronal number showed a graded increase during aging in a region-specific and protein-specific manner.

Genetic analysis reveals different functions for the products of the thyroid hormone receptor alpha locus.

Thyroid hormone receptors are encoded by the TRalpha (NR1A1) and TRbeta (NR1A2) loci. These genes are transcribed into multiple variants whose functions are unclear. Analysis by gene inactivation in mice has provided new insights into the functional complexity of these products. Different strategies designed to modify the TRalpha locus have led to strikingly different phenotypes. In order to analyze the molecular basis for these alterations, we generated mice devoid of all known isoforms produced from the TRalpha locus (TRalpha(0/0)). These mice are viable and exhibit reduced linear growth, bone maturation delay, moderate hypothermia, and reduced thickness of the intestinal mucosa. Compounding TRalpha(0) and TRbeta(-) mutations produces viable TRalpha(0/0)beta(-/-) mice, which display a more severe linear growth reduction and a more profound hypothermia as well as impaired hearing. A striking phenotypic difference is observed between TRalpha(0/0) and the previously described TRalpha(-/-) mice, which retain truncated TRDeltaalpha isoforms arising from a newly described promoter in intron 7. The lethality and severe impairment of the intestinal maturation in TRalpha(-/-) mice are rescued in TRalpha(0/0) animals. We demonstrate that the TRDeltaalpha protein isoforms, which are natural products of the TRalpha locus, are the key determinants of these phenotypical differences. These data reveal the functional importance of the non-T3-binding variants encoded by the TRalpha locus in vertebrate postnatal development and homeostasis.

Modulation of prepulse inhibition by an augmented acoustic environment in DBA/2J mice.

DBA/2J (DBA) mice exhibit progressive hearing loss, evident for high frequencies (>20 kHz) at age 3-4 weeks and severe by 12-16 weeks. From age 25 days to 12 weeks, DBA mice were exposed for 12 hr nightly to an augmented acoustic environment (AAE): moderately intense broadband noise bursts. After AAE treatment, prepulse inhibition (PPI) to tone prepulses (4-24 kHz, 70 dB SPL) was stronger, and baseline acoustic startle responses were larger, compared with results for age-matched DBA mice (testing performed with AAE off). Nightly AAE treatment was then terminated, and both AAE effects were largely gone 1 week later. Reinstatement of AAE treatment after the 4-week period had no significant effect on startle magnitude, but PPI improved significantly, with the AAE effect reacquired after 3 weeks. It is proposed that AAE modulates neural plasticity induced by high-frequency hearing loss in auditory system components of the PPI pathway.

Fear-potentiated startle, but not prepulse inhibition of startle, is impaired in CREBalphadelta-/- mutant mice.

Fear-potentiated startle was assessed in mice with a targeted disruption of the alpha and delta isoforms of the transcription factor cAMP response element binding protein (CREB) 24 hr after 5 tone + shock training trials. Whereas wild-type mice showed fear-potentiated startle that persisted up to 45 days after training, CREBalphadelta-/- mice failed to show fear-potentiated startle. However, CREBalphadelta-/- and wild-type mice had similar startle amplitudes and similar magnitudes of prepulse inhibition of startle, suggesting that CREBalphadelta-/- mice have no obvious sensory or motor deficits. These results add to the literature indicating that CREB-activated transcription plays a critical role in the formation of long-term memory and illustrate the utility of the fear-potentiated startle paradigm for assessing cognition in genetically altered mice.

Purkinje cell degeneration and control mice: responses of single units in the dorsal cochlear nucleus and the acoustic startle response.

The cartwheel cell is the most numerous inhibitory interneuron of the dorsal cochlear nucleus (DCN). It is expected to be an important determinant of DCN function. To assess the contribution of the cartwheel cell, we examined the discharge characteristics of DCN neurons and behavioral measures in the Purkinje cell degeneration (pcd) mice, which lack cartwheel cells, and compared them to those of the control mice. Distortion product otoacoustic emissions and auditory brainstem-evoked response thresholds were similar between the two groups. Extracellularly recorded DCN single units in ketamine/xylazine-anesthetized mice were classified according to post-stimulus time histogram (PSTH) and excitatory-inhibitory response area (EI-area) schemes. PSTHs recorded in mouse DCN included chopper, pauser/buildup, onset, inhibited and nondescript types. EI-areas recorded included Types I, II, III, I/III, IV and V. There were no significant differences in the proportions of various unit types between the pcd and control mice. The pcd units had slightly lower thresholds to characteristic frequency tones; however, they had spontaneous rates, thresholds to noise, and maximum driven rates to noise that were similar to those of the control units. Pcd mice had smaller startle amplitudes, but startle latency, prepulse inhibition/augmentation and facilitation by a background tone were comparable between the two groups. From these results, we conclude that DCN function in response to relatively simple acoustic stimuli is minimally affected by the absence of the cartwheel cells. Future studies employing more complex and/or multimodal stimuli should help assess the role of the cartwheel cells.

Posttraining lesions of the amygdala interfere with fear-potentiated startle to both visual and auditory conditioned stimuli in C57BL/6J mice.

The fear-potentiated startle paradigm has been used with great success to examine conditioned fear in both rats and humans. The purpose of the present experiment was to extend the authors' previous findings and further validate the fear-potentiated startle paradigm in mice. In Experiments 1 and 2, C57BL/6J mice were given Pavlovian fear conditioning with either an auditory or a visual conditioned stimulus. Similar to data collected with rats, fear-potentiated startle was observed for both stimulus modalities. In Experiment 3, posttraining lesions of the amygdala disrupted fear-potentiated startle in both conditioned stimulus modalities. These data are consistent with amygdala lesion studies in rats and suggest that fear-potentiated startle in mice requires an intact amygdala. Together, these results extend the authors' previous results and provide the basis for using this well-understood behavioral paradigm for examining the molecular mechanisms of conditioned fear in transgenic and knockout mice.

Neural plasticity in the mouse inferior colliculus: relationship to hearing loss, augmented acoustic stimulation, and prepulse inhibition.

C57BL/6J (C57) and DBA/2J (DBA) mice exhibit progressive high-frequency hearing loss. Extracellular recordings of responses of neurons in the inferior colliculus (IC) evoked by 70-dB SPL tones indicated that normal tonotopic organization was greatly disrupted in both strains: still-audible lower frequencies (4-12 kHz) evoked responses in a large percentage of recording sites in ventral tonotopic regions that normally respond strongly to high frequencies only. To relate the IC responses to an auditory behavior, prepulse inhibition (PPI) was measured using 70-dB tones as prepulses. As high-frequency hearing loss progressed in C57 mice, prepulses of 4-12 kHz elicited stronger PPI, and this was significantly correlated with changes in the percentage of IC recording sites responding to 70-dB tones (the neural pathway for PPI includes the IC). The analysis was extended to DBA mice that had been exposed to an augmented acoustic environment (AAE) - a procedure that improves PPI. In these mice, a higher percentage of IC recording sites responded to 70-dB tones, and this was correlated with improved PPI. The data suggest that responses of IC neurons reflect both hearing loss-induced plasticity and changes induced by exposure to an AAE, and these neural changes are correlated with the magnitude of PPI.

Effects of exposure to an augmented acoustic environment on auditory function in mice: roles of hearing loss and age during treatment.

The effects of exposure to an augmented acoustic environment (AAE) on auditory function were evaluated in mouse strains that exhibit various degrees and time courses of progressive hearing loss (BXD-22, BXD-12, BXD-16, BXD-14, BALB/cJ), and in normal-hearing CBA/CaJ mice. Beginning at age 25 days, mice were exposed 12 h every night to a 70 dB SPL broadband noise AAE. The AAE was maintained for at least 30 days in each strain. Same-strain control mice were age-matched and maintained under normal vivarium acoustic conditions. The auditory brainstem response (ABR), acoustic startle response amplitude, and prepulse inhibition (PPI) were used to assess the auditory system. Exposure to the AAE resulted in improved auditory performance (better PPI, lower ABR thresholds) when hearing impairment was present, but not when hearing was normal. The ameliorative effects occurred irrespective of a mouse's age at the onset of hearing loss, as long as initiation of AAE treatment preceded the occurrence of severe hearing loss. If AAE treatment was delayed beyond such a point, loss of threshold sensitivity progressed as usual, although PPI could still benefit. Finally, AAE treatment can slow, but not prevent, the occurrence of severe genetically determined hearing loss.

Prolonged exposure to an augmented acoustic environment ameliorates age-related auditory changes in C57BL/6J and DBA/2J mice.

The effects of exposure to an augmented acoustic environment (AAE) on auditory function were evaluated in mouse strains that exhibit high-frequency hearing loss beginning during young adulthood (the C57BL/6J strain [C57]) or around the time of weaning/ adolescence (the DBA/2J strain [DBA]). Beginning at age 25 days, mice were exposed 12 h every night to a 70 dB SPL broad-band noise AAE. The AAE was maintained until age 14 months in C57 mice and 9 months in DBA mice. Control mice were age-matched and maintained under normal vivarium acoustic conditions. The auditory brainstem response (ABR), acoustic startle response amplitude, and prepulse inhibition (PPI) were used to assess the auditory system. Exposure to the AAE resulted in improved auditory performance in both strains (better PPI, lower ABR thresholds, bigger startle amplitudes).

Genetics of age-related hearing loss in mice. IV. Cochlear pathology and hearing loss in 25 BXD recombinant inbred mouse strains.

The effects of three putative genes which contribute to age-related hearing loss (AHL genes) were evaluated using auditory brainstem response (ABR) thresholds and post-mortem cochlear histopathology in 25 recombinant BXD inbred mouse strains, originally derived from C57BL/6J (B6) and DBA/2J (D2) progenitor strains. All BXD strains showed substantial elevation of ABR thresholds and loss of spiral ganglion cells (SGCs) during the first year of life. The findings are consistent with our genetic model in which D2 and B6 inbred strains both possess the Ahl (age-related hearing loss) gene, whereas D2 possesses two additional chromosomal loci with AHL genes (Ahl2 and Ahl3). The between-strain distribution in the severity of SGC loss and ABR threshold elevations suggests that the severity of hearing loss is determined in large part by the number of AH L genes an animal possesses and by additional genetic background effects. The present findings also demonstrate that, because BXD strains vary substantially in the rate and severity of progressive hearing loss (but are genetically closely related), they can provide powerful animal models for developmental studies of AHL.

Exposure to an augmented acoustic environment alters auditory function in hearing-impaired DBA/2J mice.

The effects of exposure to an augmented acoustic environment (AAE) on auditory function were evaluated using DBA/2J (DBA) mice, a strain that exhibits high-frequency hearing loss beginning around the time of weaning/adolescence (between 3-4 weeks of age) and becoming severe by 2-3 months of age. Mice were exposed 12 h per night for 10 nights to a 70 dB SPL broad-band noise AAE at one of three age periods ranging from the onset of hearing loss (25-35 days of age) to more severe degrees of hearing loss (35-45 days and 45-55 days); control mice did not receive the AAE. C57BL/6J (C57) mice of the same ages provided normal-hearing. age-matched mice in both exposed and control conditions. The auditory brainstem response (ABR), acoustic startle response amplitude, and prepulse inhibition (PPI) were used to assess the auditory system. The AAE had significant effects on DBA mice, but had no effect on normal-hearing C57 mice. For the most part, AAE exposure resulted in improved auditory performance in DBA mice (better PPI, lower ABR thresholds, bigger startle amplitudes). However, the age of the mice and/or severity of hearing loss proved to be an important variable; improvement of PPI occurred only when the AAE was initiated later in the course of hearing loss (35 days of age or older); in contrast to this, beneficial effects on ABR thresholds occurred only when the AAE was initiated early in the course of hearing loss (< 45 days of age).

Caudal pontine reticular formation of C57BL/6J mice: responses to startle stimuli, inhibition by tones, and plasticity.

C57BL/6J (C57) mice were used to examine relationships between the behavioral acoustic startle response (ASR) and the responses of neurons in the caudal pontine reticular formation (PnC) in three contexts: 1) responses evoked by basic startle stimuli; 2) the prepulse inhibition (PPI) paradigm; and 3) the effects of high-frequency hearing loss and concomitant neural plasticity that occurs in middle-aged C57 mice. 1) Responses (evoked action potentials) of PnC neurons closely paralleled the ASR with respect to latency, threshold, and responses to rapidly presented stimuli. 2) "Neural PPI" (inhibition of responses evoked by a startle stimulus when preceded by a tone prepulse) was observed in all PnC neurons studied. 3) In PnC neurons of 6-mo-old mice with high-frequency (>20 kHz) hearing loss, neural PPI was enhanced with 12- and 4-kHz prepulses, as it is behaviorally. These are frequencies that have become "overrepresented" in the central auditory system of 6-mo-old C57 mice. Thus neural plasticity in the auditory system, induced by high-frequency hearing loss, is correlated with increased salience of the inhibiting tones in both behavioral and neural PPI paradigms.

The BALB/c mouse as an animal model for progressive sensorineural hearing loss.

To develop the BALB/c mouse strain as an animal model for the study of progressive sensorineural hearing loss, mice ranging in age from young adult through middle age were studied. Auditory brainstem response thresholds, histopathology [cytocochleograms for hair cells, the packing density of spiral ganglion cells (SGCs), the number of neurons and overall size of the anterior ventral cochlear nucleus (AVCN)], and behavioral paradigms (prepulse inhibition, fear-potentiated startle) were compared with previous data from C57BL/6J (C57) and DBA/2J (DBA) mouse strains. Progressive high frequency hearing loss in BALB/c mice was generally more rapid than C57 and slower than DBA (e.g. mean thresholds for 16 kHz: 10-month-old BALB/c mice = 71 dB SPL; 55-day-old DBA mice = 79 dB SPL; 12-month-old C57 mice = 50 dB SPL). Like the other strains, BALB/c exhibited a progressive loss of hair cells and SGCs that was most severe in the cochlear base and least severe in the middle turns; however, BALB/c mice had relatively more SGC loss in the apex. Unlike C57 and DBA, no loss of neurons was observed in the AVCN following cochlear pathology (although AVCN volume was reduced). Like the other strains, successful fear conditioning was obtained with a 12 kHz conditioned stimulus. Prepulse inhibition showed that middle and low frequency tones (4-12 kHz) became more salient as high frequency hearing declined. Similar results had been previously obtained with C57 and DBA mice and were interpreted as reflecting hearing-loss-induced plasticity in the central auditory system.

Glycine immunoreactivity and receptor binding in the cochlear nucleus of C57BL/6J and CBA/CaJ mice: effects of cochlear impairment and aging.

Glycinergic neurons in the cochlear nucleus (CN) of C57BL/6J (C57) and CBA/CaJ (CBA) mice were studied by using immunocytochemical and receptor-binding techniques. Adult C57 mice exhibit progressive cochlear pathology as they age, whereas aging CBA mice retain good hearing. In the CN of old C57 mice (18 months) with severe hearing loss, the number of glycine-immunoreactive neurons decreased significantly. The number (Bmax) of strychnine-sensitive glycine receptors (GlyR) decreased significantly in the dorsal CN of old C57 mice. Significant effects were not observed in the CN of middle-aged C57 mice (with less-severe hearing loss) or in very old CBA mice (which do not exhibit severe hearing loss). The data suggest that the combination of severe hearing loss and old age results in deficits in one or more inhibitory glycinergic circuits in the CN.

Fear-potentiated startle in two strains of inbred mice.

The fear-potentiated startle paradigm has been used with great success to examine conditioned fear in both rats and humans. The purpose of this study was to examine fear-potentiated startle in inbred mice. One-month-old C57BL/6J (C57) and DBA/2J (DBA) mice were given tone + foot shock training trials. The amplitude of the acoustic startle reflex was measured in the presence and absence of the tone both before and after training. Both strains showed fear-potentiated startle after training as evidenced by larger startle amplitudes in the presence of the tone than in its absence. However, the magnitude of fear-potentiated startle was greater in DBA mice than in C57 mice. These results not only demonstrate fear-potentiated startle in mice for the first time but also suggest that fear-potentiated startle can be influenced by characteristics of the mouse strain.

A major gene affecting age-related hearing loss in C57BL/6J mice.

A major gene responsible for age-related hearing loss (AHL) in C57BL/6J mice was mapped by analyses of a (C57BL/6J x CAST/Ei) x C57BL/6J backcross. AHL, as measured by elevated auditory-evoked brainstem response (ABR) thresholds, segregated among backcross mice as expected for a recessive, primarily single-gene trait. Both qualitative and quantitative linkage analyses gave the same genetic map position for the AHL gene (Ahl on chromosome 10, near D10Mit5. Marker assisted selection was then used to produce congenic lines of C57BL/6J that contain different CAST-derived segments of chromosome 10. ABR test results and cochlear histopathology of aged progenitors of these congenic lines are presented. Ahl is the first gene causing late-onset, non-syndromic hearing loss that has been reported in the mouse.

The behavioral salience of tones as indicated by prepulse inhibition of the startle response: relationship to hearing loss and central neural plasticity in C57BL/6J mice.

Adult C57BL/6J mice exhibit high-frequency, sensorineural hearing loss accompanied by physiological changes in the upper auditory brainstem and cortex, referred to as hearing-loss induced (HLI) plasticity: as high-frequency sensitivity declines, many neurons come to respond better to still-audible, middle-frequency tones (especially 12-16 kHz). We used prepulse inhibition (PPI) to assess the relationship between the behavioral salience of tones and HLI plasticity. The ability of a tone 'prepulse' (S1), presented 100 ms before a startle-eliciting tone (S2), to 'inhibit' startle responses was measured in normal-hearing 1-month-olds and 5-month-olds with high-frequency hearing loss. Tone bursts of 4, 8, 12, 16, and 24 kHz were used as S1s and S2s in all possible combinations. PPI was significantly improved (more inhibition) in 5-month-olds with 12 or 16 kHz S1s. This effect was not influenced by S2 frequency or the size of the startle evoked by S2-only stimuli (smaller for high-frequency S2s in older mice). The increased salience of 12-16 kHz S1s in 5-month-old C57 mice parallels changes in the central representation of tone frequency and implies a behavioral effect of HLI plasticity.

Anatomic and physiologic aging: a behavioral neuroscience perspective.

Because hearing is accomplished by the brain (with neural input from the cochlea), presbyacusis can be ultimately accounted for by changes in brain activity that accompany aging. The anatomic and physiologic changes that accompany aging are of two basic types: the central effects of biological aging (CEBA) and the central effects of peripheral pathology (CEPP). Research using inbred mice and other animal models has provided insights into both CEPP and CEBA, and some implications of this research are reviewed, including the following. Age-related cochlear pathology results in changes in how frequency is "mapped" in the central auditory system (CAS), especially at higher anatomic levels, and this has potentially negative consequences for hearing. Aging and/or age-related hearing loss may impair neural inhibition in the CAS. CEPP may result in abnormalities in neural responses involved in binaural hearing and cause exaggerated "masking" of neural responses by noise. The extent of age-related anatomic change (CEBA and CEPP) varies among CAS subdivisions and accelerates during the terminal phase of life. Genes have been found to influence the time course and severity of presbyacusis as well as the role dietary restriction plays in ameliorating age-related hearing loss in mice.

Physiological plasticity in the auditory system and its possible relevance to hearing aid use, deprivation effects, and acclimatization.

Alterations in the physiological and/or the anatomical properties of the central auditory system (neural plasticity) can be induced by unilateral or bilateral sensorineural hearing loss, auditory stimulation, and conditioning in which sounds are used as conditioned stimuli. These types of neural plasticity have implications for hearing aid use, acclimatization, and deprivation effects. The occurrence of hearing-loss-induced plasticity suggests that the organization of the central auditory system may be altered by the time a hearing aid is fitted. The success of hearing aids may depend, therefore, on how the auditory system responds to the reintroduction of certain sounds by amplification. For example, enhanced auditory stimulation provided by hearing aids may induce "secondary" plasticity in the auditory system, which might contribute to acclimatization and/or deprivation effects. Such functional changes might be further modulated by reinforcing responses to reintroduced sounds using conditioning techniques. This article reviews relevant literature on auditory system plasticity--drawn largely from animal research--with the goal of providing insight into possible mechanisms of acclimatization and deprivation effects.