ISL1 is necessary for auditory neuron development and contributes toward tonotopic organization.

A cardinal feature of the auditory pathway is frequency selectivity, represented in a tonotopic map from the cochlea to the cortex. The molecular determinants of the auditory frequency map are unknown. Here, we discovered that the transcription factor ISL1 regulates the molecular and cellular features of auditory neurons, including the formation of the spiral ganglion and peripheral and central processes that shape the tonotopic representation of the auditory map. We selectively knocked out Isl1 in auditory neurons using Neurod1Cre strategies. In the absence of Isl1, spiral ganglion neurons migrate into the central cochlea and beyond, and the cochlear wiring is profoundly reduced and disrupted. The central axons of Isl1 mutants lose their topographic projections and segregation at the cochlear nucleus. Transcriptome analysis of spiral ganglion neurons shows that Isl1 regulates neurogenesis, axonogenesis, migration, neurotransmission-related machinery, and synaptic communication patterns. We show that peripheral disorganization in the cochlea affects the physiological properties of hearing in the midbrain and auditory behavior. Surprisingly, auditory processing features are preserved despite the significant hearing impairment, revealing central auditory pathway resilience and plasticity in Isl1 mutant mice. Mutant mice have a reduced acoustic startle reflex, altered prepulse inhibition, and characteristics of compensatory neural hyperactivity centrally. Our findings show that ISL1 is one of the obligatory factors required to sculpt auditory structural and functional tonotopic maps. Still, upon Isl1 deletion, the ensuing central plasticity of the auditory pathway does not suffice to overcome developmentally induced peripheral dysfunction of the cochlea.

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.

Overexpression of Isl1 under the Pax2 Promoter, Leads to Impaired Sound Processing and Increased Inhibition in the Inferior Colliculus.

The LIM homeodomain transcription factor ISL1 is essential for the different aspects of neuronal development and maintenance. In order to study the role of ISL1 in the auditory system, we generated a transgenic mouse (Tg) expressing Isl1 under the Pax2 promoter control. We previously reported a progressive age-related decline in hearing and abnormalities in the inner ear, medial olivocochlear system, and auditory midbrain of these Tg mice. In this study, we investigated how Isl1 overexpression affects sound processing by the neurons of the inferior colliculus (IC). We recorded extracellular neuronal activity and analyzed the responses of IC neurons to broadband noise, clicks, pure tones, two-tone stimulation and frequency-modulated sounds. We found that Tg animals showed a higher inhibition as displayed by two-tone stimulation; they exhibited a wider dynamic range, lower spontaneous firing rate, longer first spike latency and, in the processing of frequency modulated sounds, showed a prevalence of high-frequency inhibition. Functional changes were accompanied by a decreased number of calretinin and parvalbumin positive neurons, and an increased expression of vesicular GABA/glycine transporter and calbindin in the IC of Tg mice, compared to wild type animals. The results further characterize abnormal sound processing in the IC of Tg mice and demonstrate that major changes occur on the side of inhibition.

Neurod1 Is Essential for the Primary Tonotopic Organization and Related Auditory Information Processing in the Midbrain.

Hearing depends on extracting frequency, intensity, and temporal properties from sound to generate an auditory map for acoustical signal processing. How physiology intersects with molecular specification to fine tune the developing properties of the auditory system that enable these aspects remains unclear. We made a novel conditional deletion model that eliminates the transcription factor NEUROD1 exclusively in the ear. These mice (both sexes) develop a truncated frequency range with no neuroanatomically recognizable mapping of spiral ganglion neurons onto distinct locations in the cochlea nor a cochleotopic map presenting topographically discrete projections to the cochlear nuclei. The disorganized primary cochleotopic map alters tuning properties of the inferior colliculus units, which display abnormal frequency, intensity, and temporal sound coding. At the behavioral level, animals show alterations in the acoustic startle response, consistent with altered neuroanatomical and physiological properties. We demonstrate that absence of the primary afferent topology during embryonic development leads to dysfunctional tonotopy of the auditory system. Such effects have never been investigated in other sensory systems because of the lack of comparable single gene mutation models.SIGNIFICANCE STATEMENT All sensory systems form a topographical map of neuronal projections from peripheral sensory organs to the brain. Neuronal projections in the auditory pathway are cochleotopically organized, providing a tonotopic map of sound frequencies. Primary sensory maps typically arise by molecular cues, requiring physiological refinements. Past work has demonstrated physiologic plasticity in many senses without ever molecularly undoing the specific mapping of an entire primary sensory projection. We genetically manipulated primary auditory neurons to generate a scrambled cochleotopic projection. Eliminating tonotopic representation to auditory nuclei demonstrates the inability of physiological processes to restore a tonotopic presentation of sound in the midbrain. Our data provide the first insights into the limits of physiology-mediated brainstem plasticity during the development of the auditory system.

Acoustical Enrichment during Early Development Improves Response Reliability in the Adult Auditory Cortex of the Rat.

It is well known that auditory experience during early development shapes response properties of auditory cortex (AC) neurons, influencing, for example, tonotopical arrangement, response thresholds and strength, or frequency selectivity. Here, we show that rearing rat pups in a complex acoustically enriched environment leads to an increased reliability of responses of AC neurons, affecting both the rate and the temporal codes. For a repetitive stimulus, the neurons exhibit a lower spike count variance, indicating a more stable rate coding. At the level of individual spikes, the discharge patterns of individual neurons show a higher degree of similarity across stimulus repetitions. Furthermore, the neurons follow more precisely the temporal course of the stimulus, as manifested by improved phase-locking to temporally modulated sounds. The changes are persistent and present up to adulthood. The results document that besides basic alterations of receptive fields presented in our previous study, the acoustic environment during the critical period of postnatal development also leads to a decreased stochasticity and a higher reproducibility of neuronal spiking patterns.

Immediate manifestation of acoustic trauma in the auditory cortex is layer specific and cell type dependent.

Exposure to loud sounds damages the auditory periphery and induces maladaptive changes in central parts of the auditory system. Diminished peripheral afferentation and altered inhibition influence the processing of sounds in the auditory cortex. It is unclear, however, which types of inhibitory interneurons are affected by acoustic trauma. Here we used single-unit electrophysiological recording and two-photon calcium imaging in anesthetized mice to evaluate the effects of acute acoustic trauma (125 dB SPL, white noise, 5 min) on the response properties of neurons in the core auditory cortex. Electrophysiological measurements suggested the selective impact of acoustic trauma on inhibitory interneurons in the auditory cortex. To further investigate which interneuronal types were affected, we used two-photon calcium imaging to record the activity of neurons in cortical layers 2/3 and 4, specifically focusing on parvalbumin-positive (PV+) and somatostatin-positive (SST+) interneurons. Spontaneous and pure-tone-evoked firing rates of SST+ interneurons increased in layer 4 immediately after acoustic trauma and remained almost unchanged in layer 2/3. Furthermore, PV+ interneurons with high best frequencies increased their evoked-to-spontaneous firing rate ratios only in layer 2/3 and did not change in layer 4. Finally, acoustic trauma unmasked low-frequency excitatory inputs only in layer 2/3. Our results demonstrate layer-specific changes in the activity of auditory cortical inhibitory interneurons within minutes after acoustic trauma.

Age-related changes in the central auditory system.

Aging is accompanied by the deterioration of hearing that complicates our understanding of speech, especially in noisy environments. This deficit is partially caused by the loss of hair cells as well as by the dysfunction of the stria vascularis. However, the central part of the auditory system is also affected by processes accompanying aging that may run independently of those affecting peripheral receptors. Here, we review major changes occurring in the central part of the auditory system during aging. Most of the information that is focused on age-related changes in the central auditory system of experimental animals arises from experiments using immunocytochemical targeting on changes in the glutamic-acid-decarboxylase, parvalbumin, calbindin and calretinin. These data are accompanied by information about age-related changes in the number of neurons as well as about changes in the behavior of experimental animals. Aging is in principle accompanied by atrophy of the gray as well as white matter, resulting in the enlargement of the cerebrospinal fluid space. The human auditory cortex suffers not only from atrophy but also from changes in the content of some metabolites in the aged brain, as shown by magnetic resonance spectroscopy. In addition to this, functional magnetic resonance imaging reveals differences between activation of the central auditory system in the young and old brain. Altogether, the information reviewed in this article speaks in favor of specific age-related changes in the central auditory system that occur mostly independently of the changes in the inner ear and that form the basis of the central presbycusis.

Formation and disruption of tonotopy in a large-scale model of the auditory cortex.

There is ample experimental evidence describing changes of tonotopic organisation in the auditory cortex due to environmental factors. In order to uncover the underlying mechanisms, we designed a large-scale computational model of the auditory cortex. The model has up to 100 000 Izhikevich's spiking neurons of 17 different types, almost 21 million synapses, which are evolved according to Spike-Timing-Dependent Plasticity (STDP) and have an architecture akin to existing observations. Validation of the model revealed alternating synchronised/desynchronised states and different modes of oscillatory activity. We provide insight into these phenomena via analysing the activity of neuronal subtypes and testing different causal interventions into the simulation. Our model is able to produce experimental predictions on a cell type basis. To study the influence of environmental factors on the tonotopy, different types of auditory stimulations during the evolution of the network were modelled and compared. We found that strong white noise resulted in completely disrupted tonotopy, which is consistent with in vivo experimental observations. Stimulation with pure tones or spontaneous activity led to a similar degree of tonotopy as in the initial state of the network. Interestingly, weak white noise led to a substantial increase in tonotopy. As the STDP was the only mechanism of plasticity in our model, our results suggest that STDP is a sufficient condition for the emergence and disruption of tonotopy under various types of stimuli. The presented large-scale model of the auditory cortex and the core simulator, SUSNOIMAC, have been made publicly available.

Acoustical enrichment during early postnatal development changes response properties of inferior colliculus neurons in rats.

The structure and function of the auditory system may be influenced by acoustic stimulation, especially during the early postnatal period. This study explores the effects of an acoustically enriched environment applied during the third and fourth week of life on the responsiveness of inferior colliculus neurons in rats. The enrichment comprised a spectrally and temporally modulated complex sound reinforced with several target acoustic stimuli, one of which triggered a reward release. The exposure permanently influenced neuronal representation of the sound frequency and intensity, resulting in lower excitatory thresholds at neuronal characteristic frequency, an increased frequency selectivity, larger response magnitudes, steeper rate-intensity functions and an increased spontaneous activity. The effect was general and non-specific, spanning the entire hearing range - no changes specific to the frequency band of the target stimuli were found. The alterations depended on the activity of animals during the enrichment - a higher activity of rats in the stimulus-reward paradigm led to more profound changes compared with the treatment when the stimulus-reward paradigm was not used. Furthermore, the exposure in early life led to permanent changes in response parameters, whereas the application of the same environment in adulthood influenced only a subset of the examined parameters and had only a temporary effect. These findings indicate that a rich and stimulating acoustic environment during early development, particularly when reinforced by positive feedback, may permanently affect signal processing in the subcortical auditory nuclei, including the excitatory thresholds of neurons and their frequency and intensity resolution.

Reference hearing thresholds in an extended frequency range as a function of age.

The ISO 7029 (2000) standard defines normative hearing thresholds H (dB hearing level) as a function of age Y (years), given by H = α(Y - 18)(2), up to 8 kHz. The purpose of this study was to determine reference thresholds above 8 kHz. Hearing thresholds were examined using pure-tone audiometry over the extended frequency range 0.125-16 kHz, and the acquired values were used to specify the optimal approximation of the dependence of hearing thresholds on age. A sample of 411 otologically normal men and women 16-70 years of age was measured in both ears using a high-frequency audiometer and Sennheiser HDA 200 headphones. The coefficients of quadratic, linear, polynomial and power-law approximations were calculated using the least-squares fitting procedure. The approximation combining the square function H = α(Y - 18)(2) with a power-law function H = ß(Y - 18)(1.5), both gender-independent, was found to be the most appropriate. Coefficient α was determined at frequencies of 9 kHz (α = 0.021), 10 kHz (α = 0.024), 11.2 kHz (α = 0.029), and coefficient ß at frequencies of 12.5 kHz (ß = 0.24), 14 kHz (ß = 0.32), 16 kHz (ß = 0.36). The results could be used to determine age-dependent normal hearing thresholds in an extended frequency range and to normalize hearing thresholds when comparing participants differing in age.

Differential distribution of glycine receptor subtypes at the rat calyx of Held synapse.

The properties of glycine receptors (GlyRs) depend upon their subunit composition. While the prevalent adult forms of GlyRs are heteromers, previous reports suggested functional α homomeric receptors in mature nervous tissues. Here we show two functionally different GlyRs populations in the rat medial nucleus of trapezoid body (MNTB). Postsynaptic receptors formed α1/ß-containing clusters on somatodendritic domains of MNTB principal neurons, colocalizing with glycinergic nerve endings to mediate fast, phasic IPSCs. In contrast, presynaptic receptors on glutamatergic calyx of Held terminals were composed of dispersed, homomeric α1 receptors. Interestingly, the parent cell bodies of the calyces of Held, the globular bushy cells of the cochlear nucleus, expressed somatodendritic receptors (α1/ß heteromers) and showed similar clustering and pharmacological profile as GlyRs on MNTB principal cells. These results suggest that specific targeting of GlyR ß-subunit produces segregation of GlyR subtypes involved in two different mechanisms of modulation of synaptic strength.

Two-Photon Processor and SeNeCA: a freely available software package to process data from two-photon calcium imaging at speeds down to several milliseconds per frame.

Two-Photon Processor (TPP) is a versatile, ready-to-use, and freely available software package in MATLAB to process data from in vivo two-photon calcium imaging. TPP includes routines to search for cell bodies in full-frame (Search for Neural Cells Accelerated; SeNeCA) and line-scan acquisition, routines for calcium signal calculations, filtering, spike-mining, and routines to construct parametric fields. Searching for somata in artificial in vivo data, our algorithm achieved better performance than human annotators. SeNeCA copes well with uneven background brightness and in-plane motion artifacts, the major problems in simple segmentation methods. In the fast mode, artificial in vivo images with a resolution of 256 × 256 pixels containing ≈ 100 neurons can be processed at a rate up to 175 frames per second (tested on Intel i7, 8 threads, magnetic hard disk drive). This speed of a segmentation algorithm could bring new possibilities into the field of in vivo optophysiology. With such a short latency (down to 5-6 ms on an ordinary personal computer) and using some contemporary optogenetic tools, it will allow experiments in which a control program can continuously evaluate the occurrence of a particular spatial pattern of activity (a possible correlate of memory or cognition) and subsequently inhibit/stimulate the entire area of the circuit or inhibit/stimulate a different part of the neuronal system. TPP will be freely available on our public web site. Similar all-in-one and freely available software has not yet been published.

Differences in auditory temporal processing in the left and right auditory cortices of the rat.

In the present study, we examined hemispheric differences in the representation and processing of temporally structured auditory stimuli. Neuronal responses evoked by sinusoidally frequency modulated (FM) tones, frequency sweeps, amplitude modulated (AM) tones and noise, click trains with constant inter-click intervals and natural vocalizations were recorded from the left (LAC) and right (RAC) auditory cortices in adult (4-6 months old) anaesthetized F344 rats. Using vector strength, modulation-transfer functions, van Rossum distances, or direction-selectivity index, representation and processing of structured auditory stimuli were compared in the LAC and the RAC. The RAC generally tended to exhibit a higher ability to synchronize with the stimulus, a higher reproducibility of responses, and a higher proportion of direction-selective units. The LAC, on the other hand, mostly had higher relative response magnitudes in the modulation transfer functions. Importantly, the hemispheric differences were dependent on the type of the stimulus and there was also a significant inter-individual variability. Our findings indicate that neural coding in the RAC is based more on timing of action potentials (temporal code), while the LAC uses more the response magnitudes (rate code). It is thus necessary to distinguish between the type of the neural code and the stimulus feature it encodes and reconsider the simple opinion about dominance of the LAC for temporal processing, as it may not hold in general for all types of temporally structured stimuli.

The effect of aging, hearing loss, and tinnitus on white matter in the human auditory system revealed with fixel-based analysis.

Introduction: Aging negatively influences the structure of the human brain including the white matter. The objective of our study was to identify, using fixel-based morphometry, the age induced changes in the pathways connecting several regions of the central auditory system (inferior colliculus, Heschl's gyrus, planum temporale) and the pathways connecting these structures with parts of the limbic system (anterior insula, hippocampus and amygdala). In addition, we were interested in the extent to which the integrity of these pathways is influenced by hearing loss and tinnitus. Methods: Tractographic data were acquired using a 3 T MRI in 79 volunteers. The participants were categorized into multiple groups in accordance with their age, auditory thresholds and tinnitus status. Fixel-based analysis was utilized to identify alterations in the subsequent three parameters: logarithm of fiber cross-section, fiber density, fiber density and cross-section. Two modes of analysis were used: whole brain analysis and targeted analysis using fixel mask, corresponding to the pathways connecting the aforementioned structures. Results: A significantly negative effect of aging was present for all fixel-based metrics, namely the logarithm of the fiber cross-section, (7 % fixels in whole-brain, 14% fixels in fixel mask), fiber density (5 % fixels in whole-brain, 15% fixels in fixel mask), fiber density and cross section (7 % fixels in whole-brain, 19% fixels in fixel mask). Expressed age-related losses, exceeding 30% fixels, were particularly present in pathways connecting the auditory structures with limbic structures. The effect of hearing loss and/or tinnitus did not reach significance. Conclusions: Our results show that although an age-related reduction of fibers is present in pathways connecting several auditory regions, the connections of these structures with limbic structures are even more reduced. To what extent this fact influences the symptoms of presbycusis, such as decreased speech comprehension, especially in noise conditions, remains to be elucidated.

Functional changes in the auditory cortex and associated regions caused by different acoustic stimuli in patients with presbycusis and tinnitus.

Presbycusis and tinnitus are the two most common hearing related pathologies. Although both of these conditions presumably originate in the inner ear, there are several reports concerning their central components. Interestingly, the onset of presbycusis coincides with the highest occurrence of tinnitus. The aim of this study was to identify age, hearing loss, and tinnitus related functional changes, within the auditory system and its associated structures. Seventy-eight participants were selected for the study based on their age, hearing, and tinnitus, and they were divided into six groups: young controls (Y-NH-NT), subjects with mild presbycusis (O-NH-NT) or expressed presbycusis (O-HL-NT), young subjects with tinnitus (Y-NH-T), subjects with mild presbycusis and tinnitus (O-NH-T), and subjects with expressed presbycusis and tinnitus (O-HL-T). An MRI functional study was performed with a 3T MRI system, using an event related design (different types of acoustic and visual stimulations and their combinations). The amount of activation of the auditory cortices (ACs) was dependent on the complexity of the stimuli; higher complexity resulted in a larger area of the activated cortex. Auditory stimulation produced a slightly greater activation in the elderly, with a negative effect of hearing loss (lower activation). The congruent audiovisual stimulation led to an increased activity within the default mode network, whereas incongruent stimulation led to increased activation of the visual cortex. The presence of tinnitus increased activation of the AC, specifically in the aged population, with a slight prevalence in the left AC. The occurrence of tinnitus was accompanied by increased activity within the insula and hippocampus bilaterally. Overall, we can conclude that expressed presbycusis leads to a lower activation of the AC, compared to the elderly with normal hearing; aging itself leads to increased activity in the right AC. The complexity of acoustic stimuli plays a major role in the activation of the AC, its support by visual stimulation leads to minimal changes within the AC. Tinnitus causes changes in the activity of the limbic system, as well as in the auditory AC, where it is bound to the left hemisphere.

The influence of developmental noise exposure on the temporal processing of acoustical signals in the auditory cortex of rats.

Previous experiments have acknowledged that inappropriate or missing auditory inputs during the critical period of development cause permanent changes of the structure and function of the auditory system (Bures et al., 2017). We explore in this study how developmental noise exposure influences the coding of temporally structured stimuli in the neurons of the primary auditory cortex (AC) in Long Evans rats. The animals were exposed on postnatal day 14 (P14) for 12 minutes to a loud (125 dB SPL) broad-band noise. The responses to an amplitude-modulated (AM) noise, frequency-modulated (FM) tones, and click trains, were recorded from the right AC of rats of two age groups: young-adult (ca. 6 months old) and adult (ca. 2 years old), both in the exposed animals and in control unexposed rats. The neonatal exposure resulted in a higher synchronization ability (phase-locking) of the AC neurons for all three stimuli; furthermore, the similarity of neuronal response patterns to repetitive stimulation was higher in the exposed rats. On the other hand, the exposed animals showed a steeper decline of modulation-transfer functions towards higher modulation frequencies/repetition rates. Differences between the two age groups were also apparent; in general, aging had qualitatively the same effect as the developmental exposure. The current results demonstrate that brief noise exposure during the maturation of the auditory system influences both the temporal and the rate coding of periodically modulated sounds in the AC of rats; the changes are permanent and observable up to late adulthood.

Age-related changes in the temporal processing of acoustical signals in the auditory cortex of rats.

Age-related hearing loss is manifested primarily by a decreased sensitivity to faint sounds, that is, by elevation of the hearing thresholds. Nevertheless, aging also affects the ability of the auditory system to process temporal parameters of the sound stimulus. To explore the precision and reliability of auditory temporal processing during aging, responses to several types of sound stimuli were recorded from neurons of the auditory cortex (AC) of young and aged anaesthetized Fischer 344 rats. In response to broad-band noise bursts, the aged rats exhibited larger response magnitudes, a higher proportion of monotonic units, and also a larger variability of response magnitudes, suggesting a lower stability of the rate code. Of primary interest were the responses to temporally structured stimuli (amplitude-modulated (AM) noise, frequency-modulated (FM) tones, and click trains) recorded separately in the right and left AC. Significant differences of temporal processing were already found between the neuronal responses in the left and right AC in the young animals: for the click trains, the left hemisphere exhibited a greater responsiveness to higher repetition rates, lower vector strength values, and a lower similarity of responses. The two hemispheres were also affected differently by aging. In the right hemisphere, neurons in the aged animals displayed worse synchronization with the AM noise and clicks, but better synchronization with the FM tone. In the left hemisphere, neuronal synchronization with the stimulus modulation improved at a higher age for all three stimuli. The results show that the ability of the aging auditory system to process temporal parameters of the stimulus strongly depends on the stimulus type and on laterality. Furthermore, the commonly reported age-related decline in the temporal processing ability cannot be regarded as general as, at least at the neuronal level in the AC, objective measures of the temporal representation often exhibit age-related improvement instead of deterioration.

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.

Noise exposure during early development impairs the processing of sound intensity in adult rats.

During the early postnatal development of rats, the structural and functional maturation of the central auditory nuclei strongly relies on the natural character of the incoming neural activity. Even a temporary deprivation in the critical period results in a deterioration of neuronal responsiveness in adult animals. We demonstrate that besides the poorer frequency selectivity of neurons in the impaired animals reported previously [Grecova et al. (2009)Eur. J. Neurosci. 29, 1921-1930], the neuronal representation of sound intensity is significantly affected. Rate-intensity functions of inferior colliculus neurons were recorded in anaesthetized adult rats that were exposed to intense noise at postnatal day 14, and compared with those obtained in age-matched controls. Although the response thresholds were similar in the exposed and control rats, the neurons in the exposed animals had a longer first-spike latency, a narrower dynamic range, lower maximum response magnitudes and a steeper slope of the rate-intensity functions. The percentage of monotonic neurons was significantly lower in the exposed animals. The observed anomalies were confined to the mid- and high-frequency regions, whereas no significant changes were found in the low-frequency neurons. The altered parameters of the individual rate-intensity functions led also to differences in the cumulative responses. We conclude that a brief noise exposure during the critical period leads to a frequency-dependent alteration of the sound intensity representation in the inferior colliculus of adult rats. The results suggest that such impairments may appear in individuals with normal hearing thresholds, but with a history of noise exposure very early in childhood.