Central auditory plasticity in mouse models of progressive sensorineural hearing loss
Central auditory plasticity in mouse models of progressive sensorineural hearing loss
Abstract and Keywords
This chapter presents data from mice, expressing genes which cause cochlear lesions, indicating possible consequences for hearing loss-induced plasticity. It also discusses data indicating that an augmented acoustic environment can modulate hearing loss-induced plasticity.
Several inbred strains of mice possess genes that invariably result in progressive sensorineural cochlear pathology. Such strains, including C57BL/6J (B6) and DBA/2J (D2), have advantageous characteristics for research on hearing-loss induced (HLI) plasticity in the central auditory system. Because the lesions are progressive and encompass substantial segments of the basal cochlea, they are likely to have significant, measurable effects on hearing and auditory behaviors. Moreover, the development of cochlear lesions follows a reliable course that is slow enough for a variety of behavioral and other procedures to be performed and this can be done using an unlimited number of genetically identical inbred mice. Finally, progressive sensorineural hearing loss is the most prevalent type of hearing disorder, often associated with aging (presbycusis), ototoxicity, diseases, genetic defects, and noise trauma (Schuknecht 1974; Willott 1991). Consequently, the mouse models may have great relevance for HLI plasticity in humans.
The sensorineural damage exhibited by B6 and D2 mice differs in a number of ways from that incurred by surgical or sound-induced lesions (see Willott 1996b). Most notably, the damage is progressive. Initially only the basal cochlea is affected; less severe apical damage occurs later; and middle turns usually remain relatively healthy. The lesion extends basalward from its border, with no islands of spared tissue. As damage progresses, the lesion border becomes more gradual in transition from healthy to severely damaged tissue. In the early phases of degeneration the lesion border is sharpest. The distance from healthy cochlea to an 80 per cent loss of outer hair cells (OHCs) encompasses 20–25 per cent of the cochlea. As the lesion progresses, a large extent of cochlea may have at least minor damage. Damage to inner hair cells (IHCs) and OHCs usually differs, with OHC injury being worse. Other cochlear tissue exhibits some degenerative changes as well. Spiral ganglion cell (SGC) damage typically lags behind OHC damage but is probably not secondary to IHC damage. The loss of SGCs alters the quantity and spatial pattern of afferent input to the cochlear nucleus (CN) and beyond. The age of onset and the time course of hearing loss vary among strains. In D2 mice, high-frequency hearing loss is evident at three weeks of age and becomes severe by 3–5 months of age (Ralls 1967; Erway et al. 1993; Parham et al. 1997; Willott 1981; Willott et al. 1995). Indeed, D2 pups probably never hear very high frequencies. In B6 mice the beginnings of damage to the extreme basal cochlea may be observed as early as two months of age, but hearing is normal for most of the mouse 's hearing range. By 5–6 months of age, however, high-frequency hearing loss is substantial in B6 mice, and by 12 months, it is severe (p.182) (Henry and Chole 1980; Li and Borg 1991; Mikaelian 1979). Thus, HLI plasticity in D2 mice occurs rapidly during adolescence, whereas in B6 it occurs more gradually during adulthood.
HLI plasticity in B6 mice
As high-frequency hearing declines in B6 mice, reorganization of frequency representation occurs in the inferior colliculus (IC) and auditory cortex (Willott 1984; 1986; Willott et al. 1993). Obviously, neurons in high-frequency tonotopic regions that normally respond to high-frequency tones can no longer do so. HLI plasticity is manifest here by an emerging, improved ability of such neurons to respond to still-audible, lower frequency tones. The IC has been most throughly studied in this respect. Events in the IC, of course, are closely related to what occurs in auditory cortex via afferent and/or efferent communication. Changes in the IC of B6 mice include the following, none of which are observed in like-aged CBA mice that retain normal hearing (Willott 1986, 1996a): The ‘tails ’ of multiple-unit tuning curves (MTCs) in the high-frequency, ventral IC normally have very high thresholds (> 80 dB SPL) for low-frequency tones. In middle-aged B6 mice with high-frequency impairment, ventral IC neurons now respond to low frequency sounds at intensities of less than 70 or even 60 dB SPL (i.e., activity from more apical regions of the cochlea now influences responses of these neurons). The ‘best frequencies’ (BFs, the frequency for which a neuron or multiple-unit cluster has the lowest threshold) of ventral IC neurons shifts from high to middle frequencies (10 to 15 kHz), so that BFs and their thresholds tend to be similar throughout the IC. Thus, the tonotopic gradient is severely disrupted. As high-frequency hearing loss progresses, the lowering of thresholds in MTCs progresses downward, as well. For example, in the dorsoventral midpoint of the IC, mean thresholds for 4–8 kHz tones (in the tuning curve tails) changes from about 75 dB in one-month-olds to 65–70 dB in seven-month-olds, to around 50 dB in nine-month-olds. Consistent with the study on MTCs, the single-unit BFs and rate BFs (the frequency for which the greatest discharge level occurs) show significant shifts in the ventral half of the IC. For example, Willott, Parham, and Hunter (1988) found that the mean rate BF decreases from more than 20 kHz in the ventral region of young mice to less than 15 kHz in 7-month-olds. In the ventral IC of middle-aged C57 mice, robust suprathreshold discharges are now evoked by lower frequencies than normal. The sensitivity to lower frequencies is presumably beholden to healthy regions of the cochlea whose responses were not previously exhibited in the ventral IC.
HLI plasticity in the auditory cortex and comparison with IC and CN
In B6 mice, the sorts of response changes described for IC appear to occur earlier and more dramatically in auditory cortex. Willott, Aitkin, and McFadden (1993) mapped primary auditory cortex in B6 mice aged 1, 2, 3, 6, and 12 months of age. Figures 9.1 and 9.2 show examples of auditory cortex frequency maps in two-month-old B6 mice that have near-normal hearing and in older mice with high-frequency hearing loss. In the two-month-olds (Figure 9.1), many neurons have BFs of more than 40 kHz dorsally, with lower BFs ventrally and caudally. In three-month-olds (Figure 9.2), BFs greater than 20 kHz are not seen, and most BFs are between 11–13 kHz. In the six-month-old almost all BFs are between 11–13 kHz. The distribution of BFs by frequency is shown in Figure 9.3, and the change is quite evident.
In sharp contrast, no evidence of HLI plasticity is observed in the ventral CN (VCN) of B6 mice aged 6 -12 months (Willott et al. 1991). As high-frequency sensitivity wanes, there is no sensitization of tuning curve tails in VCN neurons, and ‘new BFs’ in the high-frequency tonotopic regions appear to be little more than the remnants of original tuning curve tails. Moreover, former high-frequency VCN neurons do not respond robustly to lower frequencies as is the case (p.183)
Onset of hearing loss in adolescent (D2 mice) vs adulthood (B6)
We have no data on the auditory cortex of D2 mice, but the findings in VCN and IC are relevant because they undoubtedly affect auditory cortex. Three-week-old D2 mice and middle-aged B6 mice are similar in that both exhibit comparable high-frequency hearing loss. However, whereas no HLI plasticity is observed in the B6 mouse VCN, tonotopic organization is abnormal in young D2 mice (Willott et al. 1982). Indeed, tonotopicity in the VCN of young D2 mice is similar to what is observed in the auditory cortex of middle-aged B6 mice: virtually all parts have BFs between 10–15 kHz, with tuning curves of neurons in high-frequency regions resembling those typical of middle-frequency regions. The IC of D2 mice likewise responds strongly to middle frequencies throughout, and presumably this is also the case in auditory cortex. With respect to D2 mice, then, all levels of the central auditory apparently express greatly abnormal tonotopic organization. The ‘cortical enhancement’ of HLI plasticity observed in B6 mice may be moot.
Behavioral correlates of HLI plasticity
Does plasticity in the auditory system matter with respect to auditory perception or behavior? Several lines of research suggest that it does.
Prepulse inhibition (PPI) is widely viewed as a behavioral measure of ‘sensory gating,’ a type of central processing related to the perceptual impact or salience of sensory stimuli. PPI by auditory stimuli is manifested as follows: An audible ‘prepulse’ stimulus (S1) is presented about 100 ms before an intense startle-eliciting stimulus (S2). The S1 is processed by the central auditory system, and neural output from the auditory system then activates other components of the PPI neural circuitry, including pathways that ultimately descend to the reticular formation and inhibit the neurons that trigger the startle reflex (e.g. Carlson and Willott 1998; Davis 1984; Hoffman and Ison 1980; Ison 2001; Koch 1999; Leitner and Cohen 1985; Li et al. 1998a, b; Willott et al. 1994). Activation of the PPI circuit inhibits the startle pathway for a period lasting several hundred ms, resulting in an ‘inhibited’ startle response (reduced amplitude) when evoked during this period. Because the initial portion of the PPI neural circuit is the auditory system, the qualitative and/or quantitative aspects of neural responses to S1 tones determine whether PPI is weak or strong. Thus, PPI reflects the behavioral salience of sounds used as S1s. For example, in humans, sounds that are psychophysically salient make the most effective pre-pulses (Hoffman and Ison 1980; Ison 2001; Reiter and Ison 1979; Swerdlow and Geyer 1999; Willott 1996a). It follows, therefore, that HLI plasticity – changes in the responses of central auditory neurons to tones – should modulate PPI when prepulses are tones affected by frequency reorganization. Indeed, studies of C57 mice have shown that the magnitude of PPI changes in a manner that is correlated with hearing loss and HLI plasticity (Carlson and Willott 1996; Willott and Carlson 1995; Willott et al. 1994). As discussed above, responses of IC neurons to low- and middle-frequency tones become stronger as high-frequency threshold elevations occur. Thus, as high-frequency sensitivity declines in aging B6 mice, the salience of a 24 kHz S1 in PPI wanes as well. However, improved PPI is produced by lower frequency S1s. Figure 9.4 shows this relationship for 1- and 12-month-old B6 mice (from Willott and Turner 2000). Because tone bursts of 70 dB SPL were used as S1s, the percentage of IC neurons responding to five S1 frequencies at 70 dB is shown (upper panels). It is evident that a greater percentage of IC neurons respond to 4 kHz tones in 12-month-olds compared to 1-month-olds. Likewise, PPI produced by 4 kHz tones is stronger in the 12-month-olds (lower panels). In contrast, 24 kHz tones become ineffective stimuli in the IC and PPI. The IC plays a key role in PPI (Carlson and Willott 1998; Koch 1999; Li et al. 1998; Willott et al. 1994), so the PPI changes may be most relevant to HLI plasticity in the midbrain. However, as mentioned earlier, changes in frequency organization in IC are undoubtedly related to those in auditory cortex. In any event, the PPI data suggest that HLI plasticity has consequences for hearing: ‘over-represented’ frequencies become more salient.
Frequency difference limens
In an avoidance conditioning paradigm, D2 mice have smaller frequency difference limens (DLs) for 12 kHz tones, compared to young, normal-hearing B6 mice (Kulig and Willott 1984). DLs for 16 kHz tones, near the lesion ‘edge’ (i.e., upper range for D2 mice) are also quite good in D2 mice. Young B6 mice have smaller DLs at 8 kHz. The size of frequency DLs is correlated with the relative proportions of central auditory neurons that respond to the test frequencies. Because of the early abnormalities in frequency representation in D2 mice, relatively more neurons respond to moderately intense tones of 12 and 16 kHz in D2 than in B6 mice; similarly, fewer neurons respond to 8 kHz tones in D2 mice. The data suggest that when more neurons respond to a tone frequency discrimination is better in these mice. In turn, the number of neurons responding is, in part, a function of HLI plasticity.
The fear-potentiated startle response
Fear-potentiated startle (FPS) is a behavior that is widely used to investigate the neurobiological basis of anxiety, as well as the neurobiological basis of learning and memory. In FPS a mouse learns to fear an auditory or visual cue – the conditioned stimulus – (CS) that was paired with footshock; later, when startled in the presence of the cue, startle amplitude is increased as a function of the learned fear. Auditory cortex and auditory thalamus play key roles in FPS, sending auditory information about the CS to the amygdala (e.g. Campeau and Davis 1995a, b; Falls et al. 1997a, b; Romanski and LeDoux 1992; Rosen et al. 1991). The magnitude of FPS, then, reflects the salience of a tone CS. As is the case for PPI, if the salience of tones is increased by HLI plasticity, FPS should be affected. This appears to be the case. When a 12 kHz tone is the CS, D2 mice exhibit stronger FPS than young B6 mice (Falls et al. 1997). Moreover, as B6 mice age from one to six months, FPS becomes stronger for the 12 kHz CS (Willott et al. 1996). Thus for both young D2 versus young B6 and young B6 versus older B6, increased salience of a 12 kHz tone CS is correlated with an over-representation of 12 kHz in the central auditory system. It is important to note that a light CS does not become more effective in six-month-old B6, indicating that there is no general change in FPS behavior with age (Heldt et al. 2000). The experiments with B6 mice are summarized in Figure 9.5.
Modulation of HLI plasticity by an augmented acoustic environment
An augmented acoustic environment (AAE), consisting of moderately intense (70 dB SPL), middle-frequency (4–25 kHz) noise bursts presented 12 hours per night, modulates PPI in B6, D2, and other strains of mice exhibiting hearing loss. In normal-hearing mice such as CBA/CaJ, PPI is not affected by exposure to the AAE. Because, as we have argued, PPI appears to mirror HLI plasticity, we interpret these findings as evidence that HLI plasticity is being modulated by the AAE.
Willott and Turner (1999) exposed B6 mice to the nightly AAE from age 25 days (weaning) to 12 or 14 months. PPI was evaluated periodically. The improvement in PPI that accompanies HLI plasticity was again evident in non-exposed control mice. However, mice exposed to the AAE have even stronger PPI and this is still evident at 12 or 14 months of age (progressive hearing loss is also slowed by the AAE, but that is another story and does not account for the PPI data). Some of these findings are shown in Figure 9.6.
‘Acquisition’ of AAE-induced enhancement of PPI parallels the development of high-frequency hearing loss. In B6 and BALB/c mice, high-frequency hearing loss progresses relatively slowly (several months), as does the emergence of AAE-induced strengthening of PPI elicited by still-audible, lower-frequency prepulse tones (Willott and Turner 1999; Willott et al. 2000). In strains like D2, rapid progression of hearing loss is accompanied by a more rapid development of AAE effects (10 days or less).
Additional properties of AAE-induced changes were explored by Jeskey and Willott (2000). They established the behavioral AAE effects by exposing D2 mice from age 25 days to 12 weeks, with control mice maintained in the vivarium. Subsequently, mice were kept in normal acoustic conditions and tested weekly for four weeks, as were age-matched controls (testing was always during the day in quiet). The study found that enhanced PPI effect declines within 1–2 weeks after termination of the AAE (age 13 weeks), as PPI is no longer significantly different from that observed in like-aged control mice (Figure 9.7). When the AAE is reinstated for three weeks, PPI (p.188)
The evidence indicates that AAE exposure modulated PPI up and down in D2 mice, much like the introduction and removal of stimuli modulate behavior in other forms of centrally mediated behavioral plasticity. However, the AAE effect on PPI does not fit neatly into other categories of (p.189) behavioral plasticity (see Jeskey and Willott 2000 for a full discussion). We have hypothesized that exposure to the AAE facilitates or reinforces synaptic mechanisms of HLI plasticity. It is thought that HLI plasticity occurs because high-frequency hearing loss allows pathways stimulated by low- and middle-frequency sounds in the typical (non-AAE) ambient environment to encroach upon or compete for central synaptic sites occupied by diminished high-frequency pathways (see Willott 1996a for a review). Whether this involves strengthening of existing excitatory synapses, weakening of existing inhibitory synapses, and/or synaptogenesis is unknown. In any event, chronic stimulation by the AAE must add to the ambient stimulation and increase the synaptic activity in the viable low- and middle-frequency pathways, giving them even more of a ‘competitive edge’ over pathways weakened by high-frequency hearing loss. Because of the combined effects of HLI plasticity and AAE stimulation on auditory pathways, a middle-frequency S1 now excites more neurons in the IC and other structures that participate in or modulate the PPI circuit. This presumably strengthens PPI. Indeed, Willott and Turner (1999) have shown that more action potentials are evoked by low- and middle-frequency tones in the D2 mouse's IC after AAE treatment. If HLI plasticity per se strengthens PPI by allowing the S1 to excite more neurons, it follows that facilitation of this process by AAE treatment would further strengthen PPI, as shown in the studies cited above.
The AAE effect on PPI does not occur in normal-hearing CBA/CaJ mice or in young B6 mice before the onset of significant hearing loss (Turner and Willott 1998; Willott et al. 2000). Thus, it appears that the occurrence of high-frequency hearing loss is a necessary condition for improvement of PPI by AAE exposure; with too much or too little hearing loss, the AAE has no effect.
Summary and conclusions
Plasticity is a function of both the loss of sensitivity from cochlear damage and auditory stimulation of still-healthy cochlear segments. The data seem to comport well with the notion that neural plasticity may result from synaptic competition, whereby synapses activated by ‘lost’ frequencies give way to synapses activated by still-audible frequencies. This would result in reorganization when the intact synapses are activated by normal ambient sounds. By the same token, the process would be facilitated by enhanced activation of those synapses by an AAE.
The finding that auditory cortex is particularly well equipped to exhibit HLI plasticity is not surprising. A primary task of cortex (perhaps the primary task) is to use plasticity in the form of learning and a host of perceptual and cognitive processes in order to deal with a complex, ever-changing environment. By contrast, the low-level CN provides the interface with the cochlea and a relay for information, albeit with a certain degree of neural processing. Higher subcortical levels such as the IC still relay information to cortex, but this is done while also carrying out a number of sophisticated functions. The more complex neural circuitry allows for a substantial degree of reorganization, but it is at the cortical level where plasticity peaks.
We have presented evidence that HLI plasticity has consequences in mice, enhancing the salience of sounds in behaviors such as PPI, FPS, and frequency DLs. There is no reason to expect that HLI plasticity does not occur in humans and that auditory perceptual consequences would result. The probability that these phenomena occur in humans with presbycusis or other forms of progressive hearing loss begs the question as to whether HLI plasticity is beneficial or detrimental. As discussed elsewhere (Willott 1996a) this may depend on the circumstances. If the enhanced sound is a signal, this could be beneficial, but if the enhanced sound is noise, the opposite effect would occur. Or, as in D2 mice, frequency discrimination may be especially acute for certain frequencies while being sub-par for others. Moreover, the ‘rules’ have been changed with respect to which neurons respond to which frequencies, and this might confuse the auditory system, unless compensatory adjustments can be made. Indeed, many older people have difficulties (p.190) hearing in noise or other poor listening conditions that exceed what would be predicted from threshold elevations alone (see Willott 1991). Perhaps HLI plasticity has a negative impact in such cases. In any event, it seems very important for future research to clarify the consequences of HLI plasticity on hearing and learn to modulate it in ways that optimize hearing.
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