Publications using the RP2.1

Effective personalized therapeutic treatment for hearing loss is currently not available. Cochlear oxidative stress is commonly identified in the pathogenesis of hearing loss based upon findings from excised tissue, thus suggesting a promising druggable etiology. However, the timing and site(s) to target for anti-oxidant treatment in vivo are not clear. Here, we address this long-standing problem with QUEnch-assiSTed Magnetic Resonance Imaging (QUEST MRI), which non-invasively measures excessive production of free radicals without an exogenous contrast agent. QUEST MRI is hypothesized to be sensitive to noise-evoked cochlear oxidative stress in vivo . Rats exposed to a loud noise event that resulted in hair cell loss and reduced hearing capability had a supra-normal MRI R1 value in their cochleae that could be corrected with anti-oxidants, thus non-invasively indicating cochlear oxidative stress. A gold-standard oxidative damage biomarker [heme oxidase 1 (HO-1)] supported the QUEST MRI result. The results from this study highlight QUEST MRI as a potentially transformative measurement of cochlear oxidative stress in vivo that can be used as a biomarker for improving individual evaluation of anti-oxidant treatment efficacy in currently incurable oxidative stress-based forms of hearing loss.

The weakly electric gymnotiform fish produce a rhythmic electric organ discharge (EOD) used for communication and active electrolocation. The EOD frequency is entrained to a medullary pacemaker nucleus. During communication and exploration, this rate can be modulated by a pre-pacemaker network, resulting in specific patterns of rate modulation, including stereotyped communication signals and dynamic interactions with conspecifics known as a Jamming Avoidance Response (JAR). One well-known stereotyped signal is the chirp, a brief upward frequency sweep usually lasting less than 500 ms. The abrupt change in frequency has dramatic effects on phase precession between two signalers. We report here on chirping in Brachyhypopmus cf. sullivani, Microsternarchus cf. bilineatus Lineage C, and Steatogenys cf. elegans during conspecific playback experiments. Microsternarchus also exhibits two behaviors that include chirp-like extreme frequency modulations, EOD interruptions with hushing silence and tumultuous rises, and these are described in terms of receiver impact. These behaviors all have substantial impact on interference caused by conspecifics and may be a component of the JAR in some species. Chirps are widely used in electronic communications systems, sonar, and other man-made active sensing systems. The brevity of the chirp, and the phase disruption it causes, makes chirps effective as attention-grabbing or readiness signals. This conforms to the varied assigned functions across gymnotiforms, including pre-combat aggressive or submissive signals or during courtship and mating. The specific behavioral contexts of chirp expression vary across species, but the physical structure of the chirp makes it extremely salient to conspecifics. Chirps may be expected in a wide range of behavioral contexts where their function depends on being noticeable and salient. Further, in pulse gymnotiforms, the chirp is well structured to comprise a robust jamming signal to a conspecific receiver if specifically timed to the receiver's EOD cycle. Microsternarchus and Steatogenys exploit this feature and include chirps in dynamic jamming avoidance behaviors. This may be an evolutionary re-use of a circuitry for a specific signal in another context.

Interaural time differences (ITD) and interaural level differences (ILD) are physical cues that enable the auditory system to pinpoint the position of a sound source in space. This ability is crucial for animal communication and predator-prey interactions. The barn owl has evolved an exceptional sense of hearing and shows abilities of sound localisation that outperform most other species. So far, behavioural studies in the barn owl often used reflexive responses to investigate aspects of sound localisation. Furthermore, they predominately probed the higher frequencies of the owl's hearing range (> 3 kHz). In the present study we used a Go/NoGo paradigm to measure the barn owl's behavioural sound localisation acuity (expressed as the Minimum Audible Angle, MAA) as a function of stimulus type (narrow-band noise centred at 500, 1000, 2000, 4000 and 8000 Hz, and broad-band noise) and sound source position. We found significant effects of both stimulus type and sound source position on the barn owls' MAA. The MAA improved with increasing stimulus frequency, from 14° at 500 Hz to 6° at 8000 Hz. The smallest MAA of 4° was found for broadband noise stimuli. Comparing different sound source positions revealed smaller MAAs for frontal compared to lateral stimulus presentation, irrespective of stimulus type. These results are consistent with both the known variations in physical ITDs and variation in the width of neural ITD tuning curves with azimuth and frequency. Physical and neural characteristics combine to result in better spatial acuity for frontal compared to lateral sounds and reduced localisation acuity at lower frequencies.

Our sensory environment changes constantly. Accordingly, neural systems continually adapt to the concurrent stimulus statistics to remain sensitive over a wide range of conditions. Such dynamic range adaptation (DRA) is assumed to increase both the effectiveness of the neuronal code and perceptual sensitivity. However, direct demonstrations of DRA-based efficient neuronal processing that also produces perceptual benefits are lacking. Here, we investigated the impact of DRA on spatial coding in the rodent brain and the perception of human listeners. Complex spatial stimulation with dynamically changing source locations elicited prominent DRA already on the initial spatial processing stage, the Lateral Superior Olive (LSO) of gerbils. Surprisingly, on the level of individual neurons, DRA diminished spatial tuning because of large response variability across trials. However, when considering single-trial population averages of multiple neurons, DRA enhanced the coding efficiency specifically for the concurrently most probable source locations. Intrinsic LSO population imaging of energy consumption combined with pharmacology revealed that a slow-acting LSO gain-control mechanism distributes activity across a group of neurons during DRA, thereby enhancing population coding efficiency. Strikingly, such "efficient cooperative coding" also improved neuronal source separability specifically for the locations that were most likely to occur. These location-specific enhancements in neuronal coding were paralleled by human listeners exhibiting a selective improvement in spatial resolution. We conclude that, contrary to canonical models of sensory encoding, the primary motive of early spatial processing is efficiency optimization of neural populations for enhanced source separability in the concurrent environment.

Regeneration of mature mammalian inner ear hair cells remains to be a challenge. This study aims to evaluate the ability of DNA methyltransferase (Dnmt) inhibitor 5-azacytidine (5-aza) to generate outer hair cells (OHCs) in a chemically-deafened adult mouse model. 5-aza was administrated into the mouse inner ear via the round window. Immunofluorescence was used to examine the expression of hair cell specific proteins following 5-aza treatment. The results showed that in the chemically-deafened mouse cochlea, new OHCs were found post 5-aza treatment, whereas OHCs were completely lost in saline-treated mice. New hair cells expressed multiple hair cell markers included Myosin VIIa, Pou4f3 and Myosin VI. Newly-generated hair cells presented in three cochlear turns and were able to survive for at least six weeks. The effects of new hair cells generation by 5-aza were concentration dependent. Quantitative PCR study indicates that 5-aza may function through Dnmt1 inhibition. The results of this report suggest that the Dnmt inhibitor 5-aza may promote hair cell regeneration in a chemically-deafened mouse model.

The auditory brainstem compares sound-evoked excitation and inhibition from both ears to compute sound source location. Although alterations to the anatomy and physiology of the auditory brainstem have been demonstrated in Fragile X Syndrome (FXS) it is not known whether these changes cause sound localization impairments in FXS. To test the hypothesis that FXS-related alterations to brainstem circuits impair spatial hearing abilities, a reflexive prepulse inhibition (PPI) task, with sound source location as the prepulse stimulus, was used to show that Fmr1 knockout mice have decreased inhibition of their startle responses. Specifically, Fmr1 mice show decreased PPI compared to wildtype during gap detection, changes in sound source location, and spatial release from masking with no alteration to their overall startle thresholds compared to wildtype. Lastly, Fmr1 mice have increased latency to respond in these tasks suggesting additional impairments in the pathway responsible for reacting to a startling sound.

Sound information is transduced into graded receptor potential by cochlear hair cells and encoded as discrete action potentials of auditory nerve fibers. In the cochlear nucleus, auditory nerve fibers convey this information through morphologically distinct synaptic terminals onto bushy cells (BCs) and stellate cells (SCs) for processing of different sound features. With expanding use of transgenic mouse models, it is increasingly important to understand the in vivo functional development of these neurons in mice. We characterized the maturation of spontaneous and acoustically evoked activity in BCs and SCs by acquiring single-unit juxtacellular recordings between hearing onset (P12) and young adulthood (P30) of anesthetized CBA/J mice. In both cell types, hearing sensitivity and characteristic frequency (CF) range are mostly adult-like by P14, consistent with rapid maturation of the auditory periphery. In BCs, however, some physiological features like maximal firing rate, dynamic range, temporal response properties, recovery from post-stimulus depression, first spike latency (FSL) and encoding of sinusoid amplitude modulation undergo further maturation up to P18. In SCs, the development of excitatory responses is even more prolonged, indicated by a gradual increase in spontaneous and maximum firing rates up to P30. In the same cell type, broadly tuned acoustically evoked inhibition is immediately effective at hearing onset, covering the low- and high-frequency flanks of the excitatory response area. Together, these data suggest that maturation of auditory processing in the parallel ascending BC and SC streams engages distinct mechanisms at the first central synapses that may differently depend on the early auditory experience.

Pitch perception is critical for recognizing speech, music and animal vocalizations, but its neurobiological basis remains unsettled, in part because of divergent results across species. We investigated whether species-specific differences exist in the cues used to perceive pitch and whether these can be accounted for by differences in the auditory periphery. Ferrets accurately generalized pitch discriminations to untrained stimuli whenever temporal envelope cues were robust in the probe sounds, but not when resolved harmonics were the main available cue. By contrast, human listeners exhibited the opposite pattern of results on an analogous task, consistent with previous studies. Simulated cochlear responses in the two species suggest that differences in the relative salience of the two pitch cues can be attributed to differences in cochlear filter bandwidths. The results support the view that cross-species variation in pitch perception reflects the constraints of estimating a sound’s fundamental frequency given species-specific cochlear tuning.

The auditory system relies on binaural differences and spectral pinna cues to localize sounds in azimuth and elevation. However, the acoustic input can be unreliable, due to uncertainty about the environment, and neural noise. A possible strategy to reduce sound-location uncertainty is to integrate the sensory observations with sensorimotor information from previous experience, to infer where sounds are more likely to occur. We investigated whether and how human sound localization performance is affected by the spatial distribution of target sounds, and changes thereof. We tested three different open-loop paradigms, in which we varied the spatial range of sounds in different ways. For the narrowest ranges, target-response gains were highly idiosyncratic and deviated from an optimal gain predicted by error-minimization; in the horizontal plane the deviation typically consisted of a response overshoot. Moreover, participants adjusted their behavior by rapidly adapting their gain to the target range, both in elevation and in azimuth, yielding behavior closer to optimal for larger target ranges. Notably, gain changes occurred without any exogenous feedback about performance. We discuss how the findings can be explained by a sub-optimal model in which the motor-control system reduces its response error across trials to within an acceptable range, rather than strictly minimizing the error.

A common method for measuring changes in temporal processing sensitivity in both humans and animals makes use of GaP-induced Inhibition of the Acoustic Startle (GPIAS). It is also the basis of a common method for detecting tinnitus in rodents. However, the link to tinnitus has not been properly established because GPIAS has not yet been used to objectively demonstrate tinnitus in humans. In guinea pigs, the Preyer (ear flick) myogenic reflex is an established method for measuring the acoustic startle for the GPIAS test, while in humans, it is the eye-blink reflex. Yet, humans have a vestigial remnant of the Preyer reflex, which can be detected by measuring skin surface potentials associated with the Post-Auricular Muscle Response (PAMR). A similar electrical potential can be measured in guinea pigs and we aimed to show that the PAMR could be used to demonstrate GPIAS in both species. In guinea pigs, we compare the GPIAS measured using the pinna movement of the Preyer reflex and the electrical potential of the PAMR to demonstrate that the two are at least equivalent. In humans, we establish for the first time that the PAMR provides a reliable way of measuring GPIAS that is a pure acoustic alternative to the multimodal eye-blink reflex. Further exploratory tests showed that while eye gaze position influenced the size of the PAMR response, it did not change the degree of GPIAS. Our findings confirm that the PAMR is a sensitive method for measuring GPIAS and suggest that it may allow direct comparison of temporal processing between humans and animals and may provide a basis for an objective test of tinnitus.

Predation risk induces broad behavioral and physiological responses that have traditionally been considered acute and transitory. However, prolonged or frequent exposure to predators and the sensory cues of their presence they broadcast to the environment impact long-term prey physiology and demographics. Though several studies have assessed acute and chronic stress responses in varied taxa, these attempts have often involved a priori expectations of the molecular pathways involved in physiological responses, such as glucocorticoid pathways and neurohormone production in vertebrates. While relatively little is known about physiological and molecular predator-induced stress in insects, many dramatic insect defensive behaviors have evolved to combat selection by predators. For instance, several moth families, such as Noctuidae, include members equipped with tympanic organs that allow the perception of ultrasonic bat calls and facilitate predation avoidance by eliciting evasive aerial flight maneuvers. In this study, we exposed adult male fall armyworm (Spodoptera frugiperda) moths to recorded ultrasonic bat foraging and attack calls for a prolonged period and constructed a de novo transcriptome based on brain tissue from predator cue-exposed relative to control moths kept in silence. Differential expression analysis revealed that 290 transcripts were highly up- or down-regulated among treatment tissues, with many annotating to noteworthy proteins, including a heat shock protein and an antioxidant enzyme involved in cellular stress. Though nearly 50% of differentially expressed transcripts were unannotated, those that were are implied in a broad range of cellular functions within the insect brain, including neurotransmitter metabolism, ionotropic receptor expression, mitochondrial metabolism, heat shock protein activity, antioxidant enzyme activity, actin cytoskeleton dynamics, chromatin binding, methylation, axonal guidance, cilia development, and several signaling pathways. The five most significantly overrepresented Gene Ontology terms included chromatin binding, macromolecular complex binding, glutamate synthase activity, glutamate metabolic process, and glutamate biosynthetic process. As a first assessment of transcriptional responses to ecologically relevant auditory predator cues in the brain of moth prey, this study lays the foundation for examining the influence of these differentially expressed transcripts on insect behavior, physiology, and life history within the framework of predation risk, as observed in ultrasound-sensitive Lepidoptera and other 'eared' insects.

It is well-known that outer hair cell (OHC) loss occurs in the cochlea of animal models of permanent hearing loss induced by intense noise exposure. Our earlier studies demonstrated the production of hydroxynonenal and peroxynitrite, as well as the disruption of gap junction-mediated intercellular communication (GJIC), in the cochlear spiral ligament prior to noise-induced sudden hearing loss. The goal of the present study was to evaluate the mechanism underlying cochlear OHC loss after sudden hearing loss induced by intense noise exposure. In organ of Corti explant cultures from mice, no significant OHC loss was observed after in vitro exposure to 4-hydroxynonenal (a product of lipid peroxidation), H2O2, SIN-1 (peroxynitrite generator), and carbenoxolone (a gap junction inhibitor). Interestingly, in vivo intracochlear carbenoxolone injection through the posterior semicircular canal caused marked OHC and hearing loss, as well as the disruption of gap junction-mediated intercellular communication in the cochlear spiral ligament. However, no significant OHC loss was observed in vivo in animals treated with 4-hydroxynonenal and SIN-1. Taken together, our data suggest that disruption of GJIC in the cochlear lateral wall structures is an important cause of cochlear OHC loss in models of hearing loss, including those induced by noise.

It is commonly assumed that the human auditory cortex is organized similarly to that of macaque monkeys, where the primary region, or "core," is elongated parallel to the tonotopic axis (main direction of tonotopic gradients), and subdivided across this axis into up to 3 distinct areas (A1, R, and RT), with separate, mirror-symmetric tonotopic gradients. This assumption, however, has not been tested until now. Here, we used high-resolution ultra-high-field (7 T) magnetic resonance imaging (MRI) to delineate the human core and map tonotopy in 24 individual hemispheres. In each hemisphere, we assessed tonotopic gradients using principled, quantitative analysis methods, and delineated the core using 2 independent (functional and structural) MRI criteria. Our results indicate that, contrary to macaques, the human core is elongated perpendicular rather than parallel to the main tonotopic axis, and that this axis contains no more than 2 mirror-reversed gradients within the core region. Previously suggested homologies between these gradients and areas A1 and R in macaques were not supported. Our findings suggest fundamental differences in auditory cortex organization between humans and macaques.

Learning drives behavioral adaptations necessary for survival. While plasticity of excitatory projection neurons during associative learning is studied extensively, little is known about the contributions of local interneurons. Using fear conditioning as a model for associative learning, we find that behaviorally relevant, salient stimuli cause learning by tapping into a local microcircuit consisting of precisely connected subtypes of inhibitory interneurons. By employing calcium imaging and optogenetics, we demonstrate that vasoactive intestinal peptide (VIP)-expressing interneurons in the basolateral amygdala are activated by aversive events and provide an instructive disinhibitory signal for associative learning. Notably, VIP interneuron responses are plastic and shift from the instructive to the predictive cue upon memory formation. We describe a novel form of adaptive disinhibitory gating by VIP interneurons that allows to discriminate unexpected, important from irrelevant information, and might be a general dynamic circuit motif to trigger stimulus-specific learning, thereby ensuring appropriate behavioral adaptations to salient events.

Neurons in the central nucleus of the inferior colliculus (ICC) receive ascending inputs from the ipsilateral and contralateral auditory pathway. However, the contributions of excitatory or inhibitory synaptic inputs evoked by ipsilateral and contralateral stimuli to auditory responses of ICC neurons remain unclear. Using in vivo whole-cell voltage-clamp recordings, we investigated excitatory and inhibitory synaptic currents in neurons of the ICC in response to binaural stimulation by performing an intensity-intensity scan. To systematically analyze the contribution of the ipsilateral and contralateral ear, the sound intensity was randomly delivered to each side from 0 dB sound pressure level (SPL) to 70 dB SPL. Although the synaptic responses were dominated by contralateral inputs at weak sound intensities, they could be increased (or decreased) by additional ipsilateral stimulation at higher intensities. Interestingly, the synaptic responses to contralateral acoustic inputs were not linearly superimposed with the ipsilateral ones. By contrast, the responses showed either a contralateral or ipsilateral profile, depending on which one was more dominant. This change occurred at a certain intensity "switch" point. Thus, the binaural auditory responses of the ICC neurons were not simply mediated by the summation of the inputs evoked by ipsilateral and contralateral stimulations. This suggested that the ICC might inherit the acoustic information integrated at the brainstem, causing the selectivity of monaural excitation and inhibition to underlie the neuronal binaural acoustic response.

Hyperbilirubinemia (jaundice) is caused by raised levels of unconjugated bilirubin in the blood. When severe, susceptible brain regions including the cerebellum and auditory brainstem are damaged causing neurological sequelae such as ataxia, hearing loss and kernicterus. The mechanism(s) by which bilirubin exerts its toxic effect have not been completely understood to date. In this study we investigated the acute mechanisms by which bilirubin causes the neurotoxicity that contributes to hearing loss. We developed a novel mouse model that exhibits the neurological features seen in human Bilirubin-Induced Neurological Dysfunction (BIND) syndrome that we assessed with a behavioural score and auditory brainstem responses (ABR). Guided by initial experiments applying bilirubin to cultured cells in vitro, we performed whole genome gene expression measurements on mouse brain tissue (cerebellum and auditory brainstem) following bilirubin exposure to gain mechanistic insights into biochemical processes affected, and investigated further using immunoblotting. We then compared the gene changes induced by bilirubin to bacterial lipopolysaccharide (LPS), a well characterized inducer of neuroinflammation, to assess the degree of similarity between them. Finally, we examined the extent to which genetic perturbation of inflammation and both known and novel anti-inflammatory drugs could protect hearing from bilirubin-induced toxicity. The in vitro results indicated that bilirubin induces changes in gene expression consistent with endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). These gene changes were similar to the gene expression signature of thapsigargin-a known ER stress inducer. It also induced gene expression changes associated with inflammation and NF-κB activation. The in vivo model showed behavioural impairment and a raised auditory threshold. Whole genome gene expression analysis confirmed inflammation as a key mechanism of bilirubin neurotoxicity in the auditory pathway and shared gene expression hallmarks induced by exposure to bacterial lipopolysaccharide (LPS) a well-characterized inducer of neuroinflammation. Interestingly, bilirubin caused more severe damage to the auditory system than LPS in this model, but consistent with our hypothesis of neuroinflammation being a primary part of bilirubin toxicity, the hearing loss was protected by perturbing the inflammatory response. This was carried out genetically using lipocalin-2 (LCN2)-null mice, which is an inflammatory cytokine highly upregulated in response to bilirubin. Finally, we tested known and novel anti-inflammatory compounds (interfering with NF-κB and TNFα signalling), and also demonstrated protection of the auditory system from bilirubin toxicity. We have developed a novel, reversible, model for jaundice that shows movement impairment and auditory loss consistent with human symptoms. We used this model to establish ER-stress and inflammation as major contributors to bilirubin toxicity. Because of the rapid and reversible onset of toxicity in this novel model it represents a system to screen therapeutic compounds. We have demonstrated this by targeting inflammation genetically and with anti-inflammatory small molecules that offered protection against bilirubin toxicity. This also suggests that anti-inflammatory drugs could be of therapeutic use in hyperbilirubinemia.

When stimuli from different sensory modalities are received, they may be combined by the brain to form a multisensory percept. One key mechanism for multisensory binding is the unity assumption under which multisensory stimuli that share certain physical properties like temporal and/or spatial correspondence are grouped together as deriving from one object. In humans, evidence for a role of the unity assumption has been found in spatial tasks and also in temporal tasks using stimuli that share physical properties (speech-related stimuli, musical and synesthetically congruent stimuli). In our study, we investigate the role of the unity assumption in an animal model in a temporal order judgment task. When subjects are asked to indicate which of two spatially separated visual stimuli appeared first in time, performance improves when the visual stimuli are paired (in time) with spatially non-informative acoustic cues, a phenomenon known as the temporal ventriloquism effect. Here, we show that European starlings perform better when one singleton acoustic cue is paired with the first visual stimulus as compared to pairing with the second visual stimulus. This shows, in combination with our previous study, that a non-informative singleton acoustic cue, when temporally paired with the first visual stimulus, triggers alerting while, when temporally pairing with the second visual stimulus, it prevents a temporal ventriloquism effect because the unity assumption is violated. Thus, the unity assumption influences sensory perception not only in humans but also in an animal model. The importance of the unity assumption in this task supports the idea that the temporal ventriloquism effect, similar to the spatial ventriloquism effect, is based on multisensory binding and integration but not on alerting effects.

Significance Early linguistic experience affects perception and cortical processing of speech, even in infants. The current study examined whether linguistic effects extend to brainstem speech encoding, where responses are rapid, automatic, and preattentive. We focused on transient consonants and measured perception behaviorally and the corresponding complex auditory brainstem response (cABR) onset using simultaneous electroencephalography/magnetoencephalography (EEG/MEG) in native Spanish and English speakers. We demonstrate that the latency of an EEG-cABR onset peak predicts consonant perception and that the perception differs according to language background. MEG-cABR analysis demonstrates deep sources for the onset, providing complimentary support for a brainstem origin. Effects of early linguistic experience on speech perception can be observed at the earlier stage of speech encoding at the brainstem.

Cisplatin, a small platinum-containing molecule, is a widely used, highly effective anticancer drug. However, severe side effects have been found in cancer patients treated with cisplatin, including nephrotoxicity, neurotoxicity, and ototoxicity. These cisplatin-induced side effects can have a major impact on patient quality of life, including social development problems in pediatric patients that develop hearing loss. Previous studies have suggested that the major cause of cisplatin-induced ototoxicity is abnormal accumulation of reactive oxygen species (ROS) and oxidative stress. Alpha-lipoic acid (ALA), one of the most effective antioxidants, is known to be involved in the cellular antioxidant system and may have a protective effect on cisplatin-induced ototoxicity. However, the therapeutic effect of ALA on damaged hearing function and its detailed mechanism of action are not fully understood. This study focused on determining whether ALA has a potential as a protective and/or therapeutic agent for cisplatin-induced ototoxicity. Histological and physiological analyses were performed using cisplatin-treated mouse cochlea and HEI-OC1 culture cells in pre- and post-treatment with ALA in vitro and in vivo. We found that ALA contributes to protecting mitochondrial function by preventing ROS accumulation and inhibiting apoptotic cell death. Importantly, post-treatment with ALA consistently showed an almost equal restorative effect to pretreatment, in vitro and in vivo, supporting the possible use of ALA as a therapeutic agent for cisplatin-induced ototoxicity. This study is the first report on a strong therapeutic potential of ALA to rescue ototoxic hearing loss caused by cisplatin, and our data provide key evidence that ALA may act as a reducing agent for glutathione disulfide to increase glutathione levels on behalf of glutathione reductase. This result was consistent in both cultured cells and the mouse model, which improves the clinical value of ALA for therapy of cisplatin-induced ototoxicity.

Noise exposure is one of the most common causes of hearing loss and peripheral damage to the auditory system. A growing literature suggests that the auditory system can compensate for peripheral loss through increased central neural activity. The current study sought to investigate the link between noise exposure, increases in central gain, synaptic reorganization, and auditory function. All axons of the auditory nerve project to the cochlear nucleus, making it a requisite nucleus for sound detection. As the first synapse in the central auditory system, the cochlear nucleus is well positioned to respond plastically to loss of peripheral input. To investigate noise-induced compensation in the central auditory system, we measured auditory brainstem responses (ABRs) and auditory perception and collected tissue from mice exposed to broadband noise. Noise-exposed mice showed elevated ABR thresholds, reduced ABR wave 1 amplitudes, and spiral ganglion neuron loss. Despite peripheral damage, noise-exposed mice were hyperreactive to loud sounds and showed nearly normal behavioral sound detection thresholds. Ratios of late ABR peaks (2–4) relative to the first ABR peak indicated that brainstem pathways were hyperactive in noise-exposed mice, while anatomical analysis indicated there was an imbalance between expression of excitatory and inhibitory proteins in the ventral cochlear nucleus. The results of the current study suggest that a reorganization of excitation and inhibition in the ventral cochlear nucleus may drive hyperactivity in the central auditory system. This increase in central gain can compensate for peripheral loss to restore some aspects of auditory function.