Animal Models Of Deafness Research Articles

Connectome alterations following perinatal deafness in the cat

Following sensory deprivation, areas and networks in the brain may adapt and reorganize to compensate for the loss of input. These adaptations are manifestations of compensatory crossmodal plasticity, which has been documented in both human and animal models of deafness–including the domestic cat. Although there are abundant examples of structural plasticity in deaf felines from retrograde tracer-based studies, there is a lack of diffusion-based knowledge involving this model compared to the current breadth of human research. The purpose of this study was to explore white matter structural adaptations in the perinatally-deafened cat via tractography, increasing the methodological overlap between species. Plasticity was examined by identifying unique group connections and assessing altered connectional strength throughout the entirety of the brain. Results revealed a largely preserved connectome containing a limited number of group-specific or altered connections focused within and between sensory networks, which is generally corroborated by deaf feline anatomical tracer literature. Furthermore, five hubs of cortical plasticity and altered communication following perinatal deafness were observed. The limited differences found in the present study suggest that deafness-induced crossmodal plasticity is largely built upon intrinsic structural connections, with limited remodeling of underlying white matter.

Knockdown and mutation of Pou4f3 gene mutation promotes pyroptosis of cochleae in cisplatin-induced deafness mice by NLRP3/caspase-3/GSDME pathway

ObjectiveTo investigate the effect and mechanism of Pou4f3 gene mutation on pyroptosis in cochleae of cisplatin-induced deafness mice. Methods: Mice were intraperitoneally injected with cisplatin to construct an animal model of deafness, and sh-Pou4f3 and mutant vector were injected to alter gene expression. TUNEL staining was used to assess the apoptosis level of cochlear hair cells, ELISA was used to detect the secretion of inflammatory factors, and immunofluorescence and Western Blot were used to detect the expression of pyroptosis related factors. Results: Cisplatin induced pyroptosis through NLRP3/Caspase-3/GSDME pathway and significantly down-regulated Pou4f3 level. Pou4f3 mutations promote cochlear hair cell pyroptosis by activating the NLRP3/Caspase-3/GSDME pathway. Knockdown of Pou4f3 can superimpose cisplatin treatment to induce pyroptosis of cochlear hair cells through NLRP3/Caspase-3/GSDME pathway. Conclusion: Pou4f3 gene mutation promotes pyroptosis of cochleae in cisplatin-induced deafness mice through NLRP3/Caspase-3/GSDME pathway.

Therapeutic Efficacy of Bone Marrow Derived Mesenchymal Stem Cells in Ototoxic Sensorineural Hearing Loss

Background and Objectives Ototoxic sensorineural hearing loss causes permanent hearing loss in most cases. Recently there have been many reports describing cell base therapy with stem cells that has some effect on hearing recovery. We evaluated the efficacy of clinical grade, pre-made, human bone marrow derived mesenchymal stem cells (BM-MSCs) in ototoxic deaf animal model.Materials and Method BM-MSCs were cultured in a clinical grade laboratory. The animals were divided into 2 groups as follows: a saline injected control group and a stem cell injected group (MSC-group). Cultured MSCs were transplanted into the brachial vein of the deaf mice model. We recorded auditory brainstem response (ABR) and conducted immunohistochemistry at 1, 3, and 5 weeks.Results After the transplantation of MSC, a significant improvement in the hearing threshold of ABR was observed in the MSC transplanted group. Five weeks after transplantation of MSCs, hair cell regeneration was confirmed from the basal to the apex of the cochlea in fluorescent dyed image under the microscope compared to the control group.Conclusion BM-MSCs were effective in an acute ototoxic deaf animal model. These results show that stem cell transplantation mediate inner ear regeneration.

Gene therapy development in hearing research in China.

Sensorineural hearing loss, the most common form of hearing impairment, is mainly attributable to genetic mutations or acquired factors, such as aging, noise exposure, and ototoxic drugs. In the field of gene therapy, advances in genetic and physiological studies and profound increases in knowledge regarding the underlying mechanisms have yielded great progress in terms of restoring the auditory function in animal models of deafness. Nonetheless, many challenges associated with the translation from basic research to clinical therapies remain to be overcome before a total restoration of auditory function can be expected. In recent years, Chinese research teams have promoted various developmental efforts in this field, including gene sequencing to identify additional potential loci that cause deafness, studies to elucidate the underlying molecular mechanisms, and research to optimize vectors and delivery routes. In this review, we summarize the state of the field and focus mainly on the progress of gene therapy in animal model studies and the optimization of therapeutic strategies in China.

Differential deletion of GDNF in the auditory system leads to altered sound responsiveness.

Glial-derived neurotrophic factor (GDNF) has been proposed as a potent neurotrophic factor with the potential to cure neurodegenerative diseases. In the cochlea, GDNF has been detected in auditory neurons and sensory receptor cells and its expression is upregulated upon trauma. Moreover, the application of GDNF in different animal models of deafness has shown its capacity to prevent hearing loss and promoted its future use in therapeutic trials in humans. In the present study we have examined the endogenous requirement of GDNF during auditory development in mice. Using a lacZ knockin allele we have confirmed the expression of GDNF in the cochlea including its sensory regions during development. Global inactivation of GDNF throughout the hearing system using a Foxg1-Cre line causes perinatal lethality but reveals no apparent defects during formation of the cochlea. Using TrkC-Cre and Atoh1-Cre lines, we were able to generate viable mutants lacking GDNF in auditory neurons or both auditory neurons and sensory hair cells. These mutants show normal frequency-dependent auditory thresholds. However, mechanoelectrical response properties of outer hair cells (OHCs) in TrkC-Cre GDNF mutants are altered at low thresholds. Furthermore, auditory brainstem wave analysis shows an abnormal increase of wave I. On the other hand, Atoh1-Cre GDNF mutants show normal OHC function but their auditory brainstem wave pattern is reduced at the levels of wave I, III and IV. These results show that GDNF expression during the development is required to maintain functional hearing at different levels of the auditory system.

Regenerative efficacy of mesenchymal stromal cells from human placenta in sensorineural hearing loss

IntroductionHearing loss is a common chronic disorder characterized by decline of auditory function. The global population have suffered from deafness and the transplantation of stem cells is regarded as a therapeutic strategy for this disease. MethodsWe collected placenta from a total of 13 samples of full term pregnant women and isolated MSCs derived from human placenta and transplanted MSCs on deaf animal model. The normal group and the sensorineural hearing loss (SNHL) group and the experimental (transplanted MSCs) group were compared and estimated hearing level using auditory brainstem response (ABR) recordings and the otoacoustic emission (OAE) test. ResultsABR threshold value and DPOAE level showed that MSCs transplantation groups was improved than the SNHL group. And the number of spiral ganglion neurons were increased in all turn of the cochlea. And there was no evidence of acute immunological rejection and inflammation response was not observed. DiscussionThis study is to evaluate regenerative efficacy of hearing loss by transplanting mesenchymal stromal cells (MSCs) derived from human placenta (amnion and chorion) in deaf animal model. We identified that MSCs transplantation restored auditory impairment and promoted cell regeneration. We hope to overcome sensorineural hearing loss by transplanting stem cells such as mesenchymal stromal cells (MSCs) from easily accessible adult stem cell source in placenta.

Asymmetric Hearing During Development: The Aural Preference Syndrome and Treatment Options

Deafness affects ∼2 in 1000 children and is one of the most common congenital impairments. Permanent hearing loss can be treated by fitting hearing aids. More severe to profound deafness is an indication for cochlear implantation. Although newborn hearing screening programs have increased the identification of asymmetric hearing loss, parents and caregivers of children with single-sided deafness are often hesitant to pursue therapy for the deaf ear. Delayed intervention has consequences for recovery of hearing. It has long been reported that asymmetric hearing loss/single-sided deafness compromises speech and language development and educational outcomes in children. Recent studies in animal models of deafness and in children consistently show evidence of an "aural preference syndrome" in which single-sided deafness in early childhood reorganizes the developing auditory pathways toward the hearing ear, with weaker central representation of the deaf ear. Delayed therapy consequently compromises benefit for the deaf ear, with slow rates of improvement measured over time. Therefore, asymmetric hearing needs early identification and intervention. Providing early effective stimulation in both ears through appropriate fitting of auditory prostheses, including hearing aids and cochlear implants, within a sensitive period in development has a cardinal role for securing the function of the impaired ear and for restoring binaural/spatial hearing. The impacts of asymmetric hearing loss on the developing auditory system and on spoken language development have often been underestimated. Thus, the traditional minimalist approach to clinical management aimed at 1 functional ear should be modified on the basis of current evidence.

Regenerative Cell Therapy for the Sensorineural Hearing Loss

Sensorineural hearing loss is the most common disability in the world and nearly one third of all individuals over the age of 65 are affected. For hearing handicapped people, many devices (hearing aid, cochlear implant, middle ear implant etc.) have been developed to reduce or overcome the disability. But these devices do not give perfect benefit to the patients functionally and there are aesthetic problems. That is why researchers have interest in regenerative measures to restore or prevent hearing loss. Recently there were fruitful results from gene and stem cell therapy research for hearing loss. Gene therapy with Atoh 1 gene and transplantation of stem cells into the cochlea regenerate damaged hair cells and morphologically restore spiral ganglion neurons allowing functional hearing in the deaf animal model. Based on these results, many countries including Korea have done clinical trials in deaf patients. The past ten years have shown an incredible advancement in medical biotechnology in the otologic field and this progress may someday substitute the medical devices for the hard of hearing patients.

An efficient strategy for establishing a model of sensorineural deafness in rats.

Ototoxic drugs can be used to produce a loss of cochlear hair cells to create animal models of deafness. However, to the best of our knowledge, there is no report on the establishment of a rat deafness model through the combined application of aminoglycosides and loop diuretics. The aim of this study was to use single or combined administration of furosemide and kanamycin sulfate to establish rat models of deafness. The rats received intravenous injections of different doses of furosemide and/or intramuscular injections of kanamycin sulfate. The auditory brainstem response was measured to determine the hearing threshold after drug application. Immunocytochemistry and confocal microscopy were performed to evaluate inner ear morphology. In the group receiving combined administration of furosemide and kanamycin, the auditory brainstem response threshold showed significant elevation 3 days after administration, higher than that produced by furosemide or kanamycin alone. The hair cells showed varying degrees of injury, from the apical turn to the basal turn of the cochlea and from the outer hair cells to the inner hair cells. The spiral ganglion cells maintained a normal morphology during the first week after the hair cells completely disappeared, and then gradually degenerated. After 2 months, the majority of spiral ganglion cells disappeared, but a few remained. These findings demonstrate that the combined administration of furosemide and kanamycin has a synergistic ototoxic effect, and that these drugs can produce hair cell loss and hearing loss in rats. These findings suggest that even in patients with severe deafness, electronic cochlear implants may partially restore hearing.

Regenerative Stem Cell Therapy with Umbilical Cord Mesenchymal Stromal Cells in Deaf Animal Model

Objectives: This study was performed to confirm the effect of transplantation of human umbilical cord blood mesenchymal stem cells (UCB-MSCs) on hearing restoration in deaf animal model. Methods: UCB was collected from pregnant women after obtaining consent, and mesenchymal stem cells (MSCs) were extracted. We established deaf animal model and transplanted UCB-MSCs through the brachial vein of the guinea pigs. The animals were divided into 4 groups: animals with normal hearing, animals with sensorineural hearing loss (SNHL), animals with SNHL and injected with saline, and animals with SNHL and transplanted with UCB-MSCs. Hearing tests were conducted at 1, 3, and 5 weeks, and the results were compared by grading auditory brainstem response (ABR) recordings and distortion product otoacoustic emissions (DPOAEs) for each treatment. Lastly, cochlear pathological features were examined. Results: In SNHL group, decreased DPOAEs and increased ABR threshold were noted. And ABR hearing thresholds were unconverted and were similar to those observed in deafness. The transplanted UCB-MSC group showed a significant improvement in hearing threshold (40 dB). Examination of the SNHL animals’ cochlear morphological features demonstrated a noticeable lack of spiral ganglion cells and also showed degenerated outer hair cells. However, the transplanted UCB-MSCs showed an increase in spiral ganglion and hair cells. Conclusions: Intravenous transplantation of UCB-MSCs can enhance hearing thresholds, and regenerate inner ear hair cells and spiral ganglion neurons (SGNs).

Hearing restoration in a deaf animal model with intravenous transplantation of mesenchymal stem cells derived from human umbilical cord blood

ObjectiveThis study was performed to confirm the effect of transplantation of human umbilical cord blood mesenchymal stem cells (UCB-MSCs) on hearing restoration in a sensorineural hearing loss (SNHL) animal model. Material and methodsUCB was collected from pregnant women after obtaining consent, and mesenchymal stem cells (MSCs) were extracted. We established an SNHL model and transplanted UCB-MSCs through the brachial vein of the guinea pigs. The animals were divided into 4 groups: animals with normal hearing, animals with SNHL, animals with SNHL and injected with saline, and animals with SNHL and transplanted with UCB-MSCs. Hearing tests were conducted at 1, 3, and 5weeks, and the results were compared by grading auditory brainstem response (ABR) recordings and distortion product otoacoustic emissions (DPOAEs) for each treatment. Lastly, cochlear pathological features were examined, and surface preparations and morphological changes in each animal model were compared using hematoxylin and eosin staining and light microscopy studies. ResultsIn SNHL group, decreased DPOAEs and increased ABR threshold were noted. Furthermore, in the SNHL group, ABR hearing thresholds were unconverted and were similar to those observed in deafness. The transplanted UCB-MSC group showed a significant improvement in hearing threshold (40dB) compared to that in all the SNHL group (80–90dB). Examination of the SNHL animals′ cochlear morphological features demonstrated a noticeable lack of spiral ganglion cells and also showed degenerated outer hair cells. However, the transplanted UCB-MSCs showed an increase in spiral ganglion and hair cells. ConclusionIntravenous transplantation of UCB-MSCs can enhance hearing thresholds, outer-hair cells and increase the number of spiral ganglion neurons (SGNs).

New Route for Stem Cell Transplantation into the Cochlea

Objective: Cell transplantation provides a potential method to replace the irreversible loss of auditory hair cells and neurons. In this study, we will prove the intravenous route of stem cell transplantation to the inner ear and the efficacy of the umbilical cord blood-derived mesenchymal stem cell transplantation in hearing restoration of deaf animal model. Method: About 100,000 umbilical cord blood-derived mesenchymal stem cells which were tagged as PKH26 were infused to deaf guinea pigs intravenously. After 1 week and 3 weeks, auditory brainstem response test was checked and we obtained a guinea pig cochlea. A cryosection of each cochlea every 120 μm was obtained and we calculated stem cells for 3 sections of each animal. Results: No hearing gain was shown after stem cell transplantation, but PKH26 tagging mesenchymal stem cell was found in Modiolus, Rosenthal’s canals and organ of Corti. Cells were not found in scala tympani, scala media, and scala vestibuli. Average number of cells in the inner ear was about 88 cells (59-123 cells/section). Most cells were found in spiral ganglion and migrated into the organ of Corti. Conclusion: In this study, we demonstrated that cord blood-derived mesenchymal stem cells could be delivered into the inner ear with intravenous infusion. Based on these results, intravenous injection of stem cells may be used in the treatment of sensorineural hearing loss, regeneration of the auditory hair cells, and neurons.

Drug Delivery to the Inner Ear: Strategies and Their Therapeutic Implications for Sensorineural Hearing Loss

Hearing aids or cochlear implants constitute almost exclusively the treatment options currently available to patients suffering from sensorineural hearing loss and related conditions, such as noise-induced hearing loss, ototoxicity or autoimmune inner ear disease. While some systemic treatments exist, they generally exert adverse secondary effects and their efficacy is hampered by the blood-cochlear barrier that limits drug access to the inner ear. Hence, the new therapies that are being developed for hearing loss focus on strategies for direct drug delivery to the inner ear. The passive and active methods for local delivery can be categorized into two general groups: intratympanic or intracochlear. The intratympanic approach is a non-invasive method that preserves hearing and takes advantage of the permeability of the round window to gain access to the cochlea. However, this technique is limited by not knowing the dose of the drug that reaches the cochlea, (a handicap which might be overcome by the use of tagged drugs). While direct access to the inner ear by intracochlear administration avoids this problem, this method requires surgery. Currently, laboratory animals are being used to explore which therapeutic approaches are best suited to address this problem. These include cochleostomy and the insertion of devices that pump drugs into the inner ear without inducing cochlear damage. In this article, we review the different techniques under evaluation in animal models of deafness, and their potential use for drug delivery and treatment of human inner ear diseases.

Use It or Lose It? Lessons Learned from the Developing Brains of Children Who are Deaf and Use Cochlear Implants to Hear

In the present paper, we review what is currently known about the effects of deafness on the developing human auditory system and ask: Without use, does the immature auditory system lose the ability to normally function and mature? Any change to the structure or function of the auditory pathways resulting from a lack of activity will have important implications for future use through an auditory prosthesis such as a cochlear implant. Data to date show that deafness in children arrests and disrupts normal auditory development. Multiple changes to the auditory pathways occur during the period of deafness with the extent and type of change being dependent upon the age and stage of auditory development at onset of deafness, the cause or type of deafness, and the length of time the immature auditory pathways are left without significant input. Structural changes to the auditory nerve, brainstem, and cortex have been described in animal models of deafness as well in humans who are deaf. Functional changes in deaf auditory pathways have been evaluated by using a cochlear implant to stimulate the auditory nerve with electrical pulses. Studies of electrically evoked activity in the immature deaf auditory system have demonstrated that auditory brainstem development is arrested and that thalamo-cortical areas are vulnerable to being taken over by other competitive inputs (cross-modal plasticity). Indeed, enhanced peripheral sight and detection of visual movement in congenitally deaf cats and adults have been linked to activity in specific areas of what would normally be auditory cortex. Cochlear implants can stimulate developmental plasticity in the auditory brainstem even after many years of deafness in childhood but changes in the auditory cortex are limited, at least in part, by the degree of reorganization which occurred during the period of deafness. Consequently, we must identify hearing loss rapidly (i.e., at birth for congenital deficits) and provide cochlear implants to appropriate candidates as soon as possible. Doing so has facilitated auditory development in the thalamo-cortex and allowed children who are deaf to perceive and use spoken language.

Specification of Sensory Fates in the Vertebrate Inner Ear

The otic placode gives rise to the inner sensory organs subserving hearing and balance, along with the associated auditory and vestibular ganglion neurons that supply their afferent innervation. Our lab is using both chicken and zebrafish to study the molecular basis of cell fate specification within the otic neurosensory lineages. In chicken embryos, Wnt/β-catenin signaling can promote vestibular over auditory sensory organ fates at early stages if the pathway is manipulated by retrovirus-mediated overexpression. As the organs begin to differentiate into hair cells and supporting cells, the miR-183 family of microRNAs can control the number of HCs that form in the zebrafish, as shown by gene knockdown and overexpression. We are currently studying whether these microRNAs play a similar role in the chicken ear. Somewhat later in development, Wnt overexpression can influence the differentiation of distinct hair cell types (tall vs. short) in the auditory sensory organ of the bird. These findings may offer therapeutic strategies to induce the regeneration of supporting cells into the appropriate types of hair cells in animal models of deafness.

Immunohistochemical localization of calbindin D28-k, parvalbumin, and calretinin in the cerebellar cortex of the circling mouse

The spontaneous mutant circling mouse has an autosomal recessive pattern of inheritance and is an animal model for deafness, which is characterized by circling, head tossing, and hyperactivity. Since the main pathology in circling mice lies in the organ of Corti, most studies on deaf mice have focused on auditory brain stem nuclei. No studies regarding behavior-related CNS changes in circling mice have been reported. The major center of sensory input for modulation of motor activity is best-studied in the cerebellum. Considering the importance of calcium homeostasis in numerous processes, calcium-binding proteins (CaBPs), such as calbindin D-28k (CB), parvalbumin (PV), and calretinin (CR), may play crucial roles in preserving cerebellar coordinated motor function. Thus, the distribution of CB, PV, and CR was determined in the cerebellum using immunohistochemical methods to compare immunoreactivity (IR) of CaBPs between wild-type (+/+), heterozygous (+/cir), and homozygous (cir/cir) mice. The IR of CB and PV was predominantly observed in the Purkinje cell layer of all three genotypes. Compared with the +/+ genotype, the relative mean density of CB and PV IR in the Purkinje cell layer and CR IR in the granular layer was significantly decreased in the cir/cir genotype. Changes in calcium homeostasis in parallel fiber/Purkinje cell synapses could diminish cerebellar control of motor coordination. A number of deficiencies among the CaBPs lead to distinct alterations in brain physiology, which may affect normal behavior.

A Claudin-9–Based Ion Permeability Barrier Is Essential for Hearing

Hereditary hearing loss is one of the most common birth defects, yet the majority of genes required for audition is thought to remain unidentified. Ethylnitrosourea (ENU)–mutagenesis has been a valuable approach for generating new animal models of deafness and discovering previously unrecognized gene functions. Here we report on the characterization of a new ENU–induced mouse mutant (nmf329) that exhibits recessively inherited deafness. We found a widespread loss of sensory hair cells in the hearing organs of nmf329 mice after the second week of life. Positional cloning revealed that the nmf329 strain carries a missense mutation in the claudin-9 gene, which encodes a tight junction protein with unknown biological function. In an epithelial cell line, heterologous expression of wild-type claudin-9 reduced the paracellular permeability to Na+ and K+, and the nmf329 mutation eliminated this ion barrier function without affecting the plasma membrane localization of claudin-9. In the nmf329 mouse line, the perilymphatic K+ concentration was found to be elevated, suggesting that the cochlear tight junctions were dysfunctional. Furthermore, the hair-cell loss in the claudin-9–defective cochlea was rescued in vitro when the explanted hearing organs were cultured in a low-K+ milieu and in vivo when the endocochlear K+-driving force was diminished by deletion of the pou3f4 gene. Overall, our data indicate that claudin-9 is required for the preservation of sensory cells in the hearing organ because claudin-9–defective tight junctions fail to shield the basolateral side of hair cells from the K+-rich endolymph. In the tight-junction complexes of hair cells, claudin-9 is localized specifically to a subdomain that is underneath more apical tight-junction strands formed by other claudins. Thus, the analysis of claudin-9 mutant mice suggests that even the deeper (subapical) tight-junction strands have biologically important ion barrier function.

Time course of cochlear electrophysiology and morphology after combined administration of kanamycin and furosemide

In animal models of deafness, administration of an aminoglycoside in combination with a loop diuretic is often applied to produce a rapid loss of cochlear hair cells. However, the extent to which surviving hair cells remain functional after such a deafening procedure varies. In a longitudinal electrocochleographical study, we investigated the variability of cochlear function between and within guinea pigs after combined administration of kanamycin and furosemide. Concurrently, histological data were obtained at 1, 2, 4 and 8 weeks after deafening treatment. The main measures in our study were compound action potential (CAP) thresholds, percentage of surviving hair cells and packing density of spiral ganglion cells (SGCs). One day after deafening treatment, we found threshold shifts widely varying among animals from 0 to 100 dB. The variability decreased after 2 days, and in 18 out of 20 animals threshold shifts greater than 55 dB were found 4–7 days after deafening. Remarkably, in the majority of animals, thresholds decreased by up to 25 dB after 7 days indicating functional recovery. As expected, final thresholds were negatively correlated to the percentage of surviving hair cells. Notably, the percentage of surviving hair cells might be predicted on the basis of thresholds observed one day after deafening. SGC packing density, which rapidly decreased with the period after deafening treatment and correlated to the percentage of surviving inner hair cells, was not a determining factor for the CAP thresholds.

Clinical application of neurotrophic factors: the potential for primary auditory neuron protection.

Sensorineural hearing loss, as a result of damage to or destruction of the sensory epithelia within the cochlea, is a common cause of deafness. The subsequent degeneration of the neural elements within the inner ear may impinge upon the efficacy of the cochlear implant. Experimental studies have demonstrated that neurotrophic factors can prevent this degeneration in animal models of deafness, and can even provide functional benefits. Neurotrophic factor therapy may therefore provide similar protective effects in humans, resulting in improved speech perception outcomes among cochlear implant patients. There are, however, numerous issues pertaining to delivery techniques and treatment regimes that need to be addressed prior to any clinical application. This review considers these issues in view of the potential therapeutic application of neurotrophic factors within the auditory system.

Auditory Detection and Discrimination in Deaf Cats: Psychophysical and Neural Thresholds for Intracochlear Electrical Signals

More than 30,000 hearing-impaired human subjects have learned to use cochlear implants for speech perception and speech discrimination. To understand the basic mechanisms underlying the successful application of contemporary speech processing strategies, it is important to investigate how complex electrical stimuli delivered to the cochlea are processed and represented in the central auditory system. A deaf animal model has been developed that allows direct comparison of psychophysical thresholds with central auditory neuronal thresholds to temporally modulated intracochlear electrical signals in the same animals. Behavioral detection thresholds were estimated in neonatally deafened cats for unmodulated pulse trains (e.g., 30 pulses/s or pps) and sinusoidal amplitude-modulated (SAM) pulse trains (e.g., 300 pps, SAM at 30 Hz; 300/30 AM). Animals were trained subsequently in a discrimination task to respond to changes in the modulation frequency of successive SAM signals (e.g., 300/8 AM vs. 300/30 AM). During acute physiological experiments, neural thresholds to pulse trains were estimated in the inferior colliculus (IC) and the primary auditory cortex (A1) of the anesthetized animals. Psychophysical detection thresholds for unmodulated and SAM pulse trains were virtually identical. Single IC neuron thresholds for SAM pulse trains showed a small but significant increase in threshold (0.4 dB or 15.5 microA) when compared with thresholds for unmodulated pulse trains. The mean difference between psychophysical and minimum neural thresholds within animals was not significant (mean = 0.3 dB). Importantly, cats also successfully discriminated changes in the modulation frequencies of the SAM signals. Performance on the discrimination task was not affected by carrier rate (100, 300, 500, 1,000, or 1,500 pps). These findings indicate that 1) behavioral and neural response thresholds are based on detection of the peak pulse amplitudes of the modulated and unmodulated signals, and 2) discrimination of successive SAM pulse trains is based on temporal resolution of the envelope frequencies. Overall, our animal model provides a robust framework for future studies of behavioral discrimination and central neural temporal processing of electrical signals applied to the deaf cochlea by a cochlear implant.