Mice prone to tinnitus after acoustic trauma show increased pre-exposure sensitivity to background noise.

Noise-induced tinnitus is generally associated with hearing impairment caused by traumatic acoustic overexposure. Previous studies in laboratory animals and human subjects, however, have observed differences in tinnitus susceptibility, even among individuals with similar hearing loss. The mechanisms underlying increased sensitivity or, conversely, resistance to tinnitus are still incompletely understood. Here, we used behavioral tests and ABR audiometry to compare the sound-evoked responses of mice that differed in the presence of noise-induced tinnitus. The aim was to find a specific pre-exposure neurophysiological marker that would predict the development of tinnitus after acoustic trauma. Noise-exposed mice were screened for tinnitus-like behavior with the GPIAS paradigm and subsequently divided into tinnitus (+T) and non-tinnitus (-T) groups. Both groups showed hearing loss after exposure, manifested by elevated audiometric thresholds along with reduced amplitudes and prolonged latencies of ABR waves. Prior to exposure, except for a slightly increased slope of growth function for ABR amplitudes in +T mice, the two groups did not show significant audiometric differences. Behavioral measures, such as the magnitude of the acoustic startle response and its inhibition by gap pre-pulse, were also similar before exposure in both groups. However, +T mice showed significantly increased suppression of the acoustic startle response in the presence of background noise of moderate intensity. Thus, increased modulation of startle by background sounds may represent a behavioral correlate of susceptibility to noise-induced tinnitus, and its measurement may form the basis of a simple non-invasive method for predicting tinnitus development in laboratory rodents.

Acoustically Enriched Environment during the Critical Period of Postnatal Development Positively Modulates Gap Detection and Frequency Discrimination Abilities in Adult Rats.

Throughout life, sensory systems adapt to the sensory environment to provide optimal responses to relevant tasks. In the case of a developing system, sensory inputs induce changes that are permanent and detectable up to adulthood. Previously, we have shown that rearing rat pups in a complex acoustic environment (spectrally and temporally modulated sound) from postnatal day 14 (P14) to P28 permanently improves the response characteristics of neurons in the inferior colliculus and auditory cortex, influencing tonotopical arrangement, response thresholds and strength, and frequency selectivity, along with stochasticity and the reproducibility of neuronal spiking patterns. In this study, we used a set of behavioral tests based on a recording of the acoustic startle response (ASR) and its prepulse inhibition (PPI), with the aim to extend the evidence of the persistent beneficial effects of the developmental acoustical enrichment. The enriched animals were generally not more sensitive to startling sounds, and also, their PPI of ASR, induced by noise or pure tone pulses, was comparable to the controls. They did, however, exhibit a more pronounced PPI when the prepulse stimulus was represented either by a change in the frequency of a background tone or by a silent gap in background noise. The differences in the PPI of ASR between the enriched and control animals were significant at lower (55 dB SPL), but not at higher (65-75 dB SPL), intensities of background sound. Thus, rearing pups in the acoustically enriched environment led to an improvement of the frequency resolution and gap detection ability under more difficult testing conditions, i.e., with a worsened stimulus clarity. We confirmed, using behavioral tests, that an acoustically enriched environment during the critical period of development influences the frequency and temporal processing in the auditory system, and these changes persist until adulthood.

Effect of Kv3 channel modulators on auditory temporal resolution in aged Fischer 344 rats.

AUT00063 and AUT00202 are novel pharmaceutical modulators of the Kv3 subfamily of voltage-gated K+ channels. Kv3.1 channels, which control fast firing of many central auditory neurons, have been shown to decline with age and this may contribute to age-related deficits in central auditory processing. In the present study, the effects of the two novel compounds that specifically modulate Kv3 channels on auditory temporal processing were examined in aged (19-25-month-old) and young-adult (3-5 month-old) Fischer 344 rats (F344) using a behavioral gap-prepulse inhibition (gap-PPI) paradigm. The acoustic startle response (ASR) and its inhibition induced by a gap in noise were measured before and after drug administration. Hearing thresholds in tested rats were evaluated by the auditory brainstem response (ABR). Aged F344 rats had significantly higher ABR thresholds, lower amplitudes of ASR, and weaker gap-PPI compared with young-adult rats. No influence of AUT00063 and AUT00202 administration was observed on ABR hearing thresholds in rats of both age groups. AUT00063 and AUT00202 had suppressive effect on ASR of F344 rats that was more pronounced with AUT00063. The degree of suppression depended on the dose and age of the rats. Both compounds significantly improved the gap-PPI performance in gap detection tests in aged rats. These results indicate that AUT00063 and AUT00202 may influence intrinsic firing properties of neurons in the central auditory system of aged animals and have the potential to treat aged-related hearing disorders.

Behavioral evaluation of auditory function abnormalities in adult rats with normal hearing thresholds that were exposed to noise during early development.

Noise-exposed rat pups provide a model of early deprivation of sensory input to the central auditory system, allowing the study of developmental neuroplasticity. Our previous results have demonstrated that a brief exposure of rats to broadband noise (125 dB SPL 8 min, 14th postnatal day) at the onset of hearing resulted in an altered intensity perception and frequency discrimination in adulthood despite normal hearing thresholds. In this study, we assessed the gap-detection ability and possible presence of tinnitus- and hyperacusis-like behavior in adult rats after the same neonatal acoustic trauma, using measurements of the acoustic startle response (ASR) in quiet and noisy environments and its prepulse inhibition by gaps in noise (gap-PPI). A significant deficit in the ability to detect gap was observed in the exposed rats when 55 dB SPL broadband noise was used as background. An increase of noise intensity to 65-75 dB SPL led to strengthening of the gap-PPI in exposed animals, which approached the gap-PPI values of control animals at these levels. Behavioral signs of tinnitus (gap detection deficits in 10 kHz narrow band noise) were found in 25% of exposed rats. An increased sensitivity to continuous noise was manifested in all exposed rats by suppression of the ASR at significantly lower background noise levels than in the controls. This effect was particularly pronounced in rats with tinnitus-like behavior. Our results indicate that neonatal acoustic trauma, producing only a transient threshold shift, may produce permanent abnormalities in suprathreshold auditory functions and the development of tinnitus and hyperacusis-like behavior.

Age-Related Differences in Hearing Function and Cochlear Morphology between Male and Female Fischer 344 Rats.

Fischer 344 (F344) rats represent a strain that is frequently used as a model for fast aging. In this study, we systematically compare the hearing function during aging in male and female F344 rats, by recording auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs). In addition to this, the functional parameters are correlated with the cochlear histology. The parameters of the hearing function were not different in the young (3-month-old) male and female F344 rats; the gender differences occurred only in adult and aged animals. In 8-24-month-old males, the ABR thresholds were higher and the ABR amplitudes were smaller than those measured in females of the same age. There were no gender differences in the neural adaptation tested by recording ABRs, elicited by a series of clicks with varying inter-click interval (ICI). Amplitudes of DPOAEs in both the males and females decreased with age, but in the males, the decrease of DPOAE amplitudes was faster. In males older than 20 months, the DPOAEs were practically absent, whereas in 20-24-month-old females, the DPOAEs were still measurable. There were no gender differences in the number of surviving outer hair cells (OHC) and the number of inner hair cell ribbon synapses in aged animals. The main difference was found in the stria vascularis (SV). Whereas the SV was well preserved in females up to the age of 24 months, in most of the age-matched males the SV was evidently deteriorated. The results demonstrate more pronounced age-related changes in the cochlear morphology, hearing thresholds, ABR amplitudes and DPOAE amplitudes in F344 males compared with females.

Development of the acoustic startle response in rats and its change after early acoustic trauma.

Even brief acoustic trauma during the critical period of development that results in no permanent hearing threshold shift may lead to altered auditory processing in adulthood. By monitoring the acoustic startle response (ASR), we examined the development of auditory function in control rats and in rats exposed to intense noise at the 14th postnatal day (P14). First ASRs appeared on P10-P11 to intense low-frequency tones. By P14, the range of sound intensities and frequencies eliciting ASRs extended considerably, the ASR reactivity being similar at all frequencies (4-32 kHz). During the subsequent two weeks, ASR amplitudes to low-frequency stimuli (4-8 kHz) increased, whereas the ASRs to high-frequency tones were maintained (16 kHz) or even decreased (32 kHz). Compared to controls, noise exposure on P14 (125 dB SPL for 8, 12, or 25 min) produced transient hyper-reactivity to startle stimuli, manifested by a decrease of ASR thresholds and an increase of ASR amplitudes. ASR enhancement occurred regardless of permanent hearing loss and was more pronounced at high frequencies. The hyper-reactivity of ASRs declined by P30; the ASR amplitudes in adult exposed rats were lower than in controls. The histological control did not reveal loss of hair cells in adult exposed rats, however, the number of inner hair cell ribbon synapses was significantly decreased, especially in the high-frequency part of the cochlea. The results indicate that early acoustic trauma may result in complex changes of ASRs during development.

Frequency discrimination in rats exposed to noise as juveniles.

Sound exposure during the early postnatal period can significantly influence the function of the auditory system in rats during adulthood. In the present study, rat pups (strain Long-Evans) were exposed to broad-band noise at 125dB SPL for 8, 12 or 25min on postnatal day 14 and then at the age of 3-5months their frequency discrimination at 4 and 16kHz was assessed using a modified method of the prepulse inhibition of the acoustic startle reflex. In all groups of exposed rats, an altered frequency discrimination of the tonal stimuli was observed, in comparison with controls, at 70dB SPL. A worsening of frequency discrimination was observed even in animals exposed for 8min, the auditory thresholds of which were almost identical to that of control animals. The individual auditory thresholds did not correlate with frequency discrimination. The difference in frequency discrimination between the exposed and control animals disappeared at 85-90dB SPL. Our data suggests that brief noise exposure during the critical period of development results in the altered frequency discrimination at moderate sound intensities in adult rats, which may appear even in individuals with normal hearing thresholds.

The effect of parvalbumin deficiency on the acoustic startle response and prepulse inhibition in mice.

The strength of the acoustic startle response (ASR) to short bursts of broadband noise or tone pips (4, 8 and 16 kHz) and the prepulse inhibition (PPI) of the ASR elicited by prepulse tones (4, 8 and 16 kHz) were measured in parvalbumin-deficient (PV-/-) mice and in age-matched PV+/+ mice as controls. Hearing thresholds as determined from recordings of auditory brainstem responses were found to be similar in both genotypes. The ASRs to broadband noise and tones of low and middle frequencies were stronger than the ASRs in response to high-frequency tones in both groups. In PV-/- mice, we observed smaller ASR amplitudes in response to relatively weak startling stimuli (80-90 dB sound pressure level (SPL)) of either broadband noise or 8-kHz tones compared to those recorded in PV+/+ mice. For these startling stimuli, PV-/- mice had higher ASR thresholds and longer ASR latencies. PPI of the ASR in PV-/- mice was less effective than in PV+/+ mice, for all tested prepulse frequencies (4, 8 or 16 kHz) at 70 dB SPL. Our findings demonstrate no effect of PV deficiency on hearing thresholds in PV-/- mice. However, the frequency-specific differences in the ASR and the significant reduction of PPI of ASR likely reflect specific changes of neuronal circuits, mainly inhibitory, in the auditory centers in PV-deficient mice.

Early poststroke rehabilitation using a robotic tilt-table stepper and functional electrical stimulation.

Background. Stroke frequently leaves survivors with hemiparesis. To prevent persistent deficits, rehabilitation may be more effective if started early. Early training is often limited because of orthostatic reactions. Tilt-table stepping robots and functional electrical stimulation (FES) may prevent these reactions. Objective. This controlled convenience sample study compares safety and feasibility of robotic tilt-table training plus FES (ROBO-FES) and robotic tilt-table training (ROBO) against tilt-table training alone (control). A preliminary assessment of efficacy is performed. Methods. Hemiparetic ischemic stroke survivors (age 58.3 ± 1.2 years, 4.6 ± 1.2 days after stroke) were assigned to 30 days of ROBO-FES (n = 38), ROBO (n = 35), or control (n = 31) in addition to conventional physical therapy. Impedance cardiography and transcranial doppler sonography were performed before, during, and after training. Hemiparesis was assessed using the British Medical Research Council (MRC) strength scale. Results. No serious adverse events occurred; 8 patients in the tilt-table group prematurely quit the study because of orthostatic reactions. Blood pressure and CBFV dipped <10% during robot training. In 52% of controls mean arterial pressure decreased by ≥20%. ROBO-FES increased leg strength by 1.97 ± 0.88 points, ROBO by 1.50 ± 0.85 more than control (1.03 ± 0.61, P < 0.05). CBFV increased in both robotic groups more than in controls (P < 0.05). Conclusions. Robotic tilt-table exercise with or without FES is safe and may be more effective in improving leg strength and cerebral blood flow than tilt table alone.

Age-related changes in the acoustic startle reflex in Fischer 344 and Long Evans rats.

The behavioral consequences of age-related changes in the auditory system were studied in Fischer 344 (F344) rats as a model of fast aging and in Long Evans (LE) rats as a model of normal aging. Hearing thresholds, the strength of the acoustic startle responses (ASRs) to noise and tonal stimuli, and the efficiency of the prepulse inhibition (PPI) of ASR were assessed in young-adult, middle-aged, and aged rats of both strains. Compared with LE rats, F344 rats showed larger age-related hearing threshold shifts, and the amplitudes of their startle responses were mostly lower. Both rat strains demonstrated a significant decrease of startle reactivity during aging. For tonal stimuli, this decrease occurred at an earlier age in the F344 rats: middle-aged F344 animals expressed similar startle reactivity as aged F344 animals, whereas middle-aged LE animals had similar startle reactivity as young-adult LE animals. For noise stimuli, on the other hand, a similar progression of age-related ASR changes was found in both strains. No significant relationship between the hearing thresholds and the ASR amplitudes was found within any age group. Auditory PPI was less efficient in F344 rats than in LE rats. An age-related reduction of the PPI of ASR was observed in rats of both strains; however, a significant reduction of PPI occurred only in aged rats. The results indicate that the ASR may serve as an indicator of central presbycusis.

Age-related changes in auditory temporal processing in the rat.

Presbycusis, as the deterioration of hearing ability occurring with aging, can be manifested not only in a shift of hearing thresholds, but also in a deterioration of the temporal processing of acoustical signals, which may in elderly people result in degraded speech comprehension. In this study we assessed the age-related changes in the temporal processing of acoustical signals in the auditory system of pigmented rats (Long Evans strain). The temporal resolution was investigated in young adult (3-4 months) and old (30-34 months) rats by behavioral and electrophysiological methods: the rats' ability to detect and discriminate gaps in a continuous noise was examined behaviorally, and the amplitude-rate function was assessed for the middle latency response (MLR) to clicks. A worsening of the temporal resolution with aging was observed in the results of all tests. The values of the gap detection threshold (GDT) and the gap duration difference limen (GDDL) in old rats increased about two-fold in comparison with young adult rats. The MLR to a click train in old rats exhibited a significantly faster reduction in amplitude with an increasing stimulation rate in comparison with young adult rats. None of the age-related changes in the parameters characterizing temporal resolution (GDT, GDDL and MLR to a click train) correlated with the degree of the age-related hearing loss. However, the age-related changes in MLR amplitude-rate function correlated with the age-related changes in GDDL, but not with the changes in GDT. The behavioral and electrophysiological data clearly show that aging in rats is accompanied with a pronounced deficit in the temporal processing of acoustical signals that is associated with the deteriorated function of the central auditory system.

Noise exposure during early development influences the acoustic startle reflex in adult rats.

Noise exposure during the critical period of postnatal development in rats results in anomalous processing of acoustic stimuli in the adult auditory system. In the present study, the behavioral consequences of an acute acoustic trauma in the critical period are assessed in adult rats using the acoustic startle reflex (ASR) and prepulse inhibition (PPI) of ASR. Rat pups (strain Long-Evans) were exposed to broad-band noise of 125 dB SPL for 8 min on postnatal day 14; at the age of 3-5 months, ASR and PPI of ASR were examined and compared with those obtained in age-matched controls. In addition, hearing thresholds were measured in all animals by means of auditory brainstem responses. The results show that although the hearing thresholds in both groups of animals were not different, a reduced strength of the startle reflex was observed in exposed rats compared with controls. The efficacy of PPI in exposed and control rats was also markedly different. In contrast to control rats, in which an increase in prepulse intensity was accompanied by a consistent increase in the efficacy of PPI, the PPI function in the exposed animals was characterized by a steep increase in inhibitory efficacy at low prepulse intensities of 20-30 dB SPL. A further increase of prepulse intensity up to 60-70 dB SPL caused only a small and insignificant change of PPI. Our findings demonstrate that brief noise exposure in rat pups results in altered behavioral responses to sounds in adulthood, indicating anomalies in intensity coding and loudness perception.

Inactivation of the left auditory cortex impairs temporal discrimination in the rat.

The left auditory cortex (AC) in humans is involved in the processing of the temporal parameters of acoustical signals, specifically in speech perception, whereas the right AC plays the dominant role in pitch and melody perception. The hemispheric lateralization of acoustical signal processing in non-human mammals is less explored. The present study examined the ability of rats to detect or discriminate a series of gaps in continuous noise under conditions of unilateral or bilateral reversible inactivation of the AC. The results showed that muscimol-induced reversible inactivation of the left AC suppresses the ability of rats to discriminate between acoustical stimuli of different temporal parameters (duration or repetition rate), whereas inactivation of the right AC results in no change or only a mild decrease in discrimination ability. Hemispheric asymmetry was observed only in the case of gap discrimination tasks, but not in a gap detection task. Our findings demonstrate that, similarly as in humans, the left AC in the rat plays the dominant role in temporal discrimination. These data provide further evidence for the functional asymmetry of the mammalian brain, which appears in a relatively early phase of evolution.

Comparison of noise-induced changes of auditory brainstem and middle latency response amplitudes in rats.

Auditory brainstem responses (ABRs) and middle latency responses (MLRs) were compared after noise exposure to elucidate the specific effects of a loud sound on the central auditory system in rats. Rats were exposed twice for 1 h to broad-band noise (BBN) of 118 dB SPL (first exposure) and 122 dB SPL (second exposure) with an interval between the exposures of three weeks. The first noise exposure produced threshold shifts (TSs) amounting to 5-45 dB, and the second exposure resulted in 40-70 dB TSs. The slope of MLR amplitude-intensity functions (AIFs) increased significantly in correlation with the TS, resembling loudness recruitment. However, maximal MLR amplitudes measured at 8 kHz increased after the first and second noise exposures to almost equal values in individual animals regardless of the TS. In addition, maximum MLR amplitude enhancement was dependent on pre-exposure MLR voltage, probably reflecting the level of metabolic activity or neurotransmitter processes in individual animals. In contrast to MLR amplitudes, ABR amplitudes were suppressed after noise exposure without changing the slope of ABR AIFs. The MLR changes reflect the specific effects of noise exposure on the central auditory system.

Effect of auditory cortex lesions on the discrimination of frequency-modulated tones in rats.

The lateralization of functions to individual hemispheres of the mammalian brain remains, with the exception of the human brain, unresolved. The aim of this work was to investigate the ability to discriminate between falling and rising frequency-modulated (FM) stimuli in rats with unilateral or bilateral lesions of the auditory cortex (AC). Using an avoidance conditioning procedure, thirsty rats were trained to drink in the presence of a rising FM tone and to stop drinking when a falling FM tone was presented. Rats with a lesion of the AC were able to learn to discriminate between rising and falling FM tones; however, they performed significantly worse than did control rats. A greater deficit in the ability to discriminate the direction of frequency modulation was observed in rats with a right or bilateral AC lesion. The discrimination performance (DP) in these rats was significantly worse than the DP in rats with a left AC lesion. Animals with a right or bilateral AC lesion improved their DP mainly by recognizing the pitch at the beginning of the stimuli. The lesioning of the AC in trained animals caused a significant decrease in DP, down to chance levels. Retraining resulted in a significant increase in DP in rats with a left AC lesion; animals with a right lesion improved only slightly. The results demonstrate a hemispheric asymmetry of the rat AC in the recognition of FM stimuli and indicate the dominance of the right AC in the discrimination of the direction of frequency modulation.