Publications using TDT

Background: Mice produce ultrasonic vocalizations in various inter-individual encounters and with high call rates. However, it is so far virtually unknown how these vocal patterns are generated. On the one hand, these vocal patterns could be embedded into the normal respiratory cycle, as happens in bats and other mammals that produce similar call rates and frequencies. On the other, mice could possess distinct vocal pattern generating systems that are capable of modulating the respiratory cycle, which is what happens in non-human and human primates. In the present study, we investigated the temporal call patterns of two different mammalian species, bats and mice, in order to differentiate between these two possibilities for mouse vocalizations. Our primary focus was on comparing the mechanisms for the production of rapid, successive ultrasound calls of comparable frequency ranges in the two species. Results: We analyzed the temporal call pattern characteristics of mice, and we compared these characteristics to those of ultrasonic echolocation calls produced by horseshoe bats. We measured the distributions of call durations, call intervals, and inter-call intervals in the two species. In the bat, and consistent with previous studies, we found that call duration was independent of corresponding call intervals, and that it was negatively correlated with the corresponding inter-call interval. This indicates that echolocation call production mechanisms in the bat are highly correlated with the respiratory cycle. In contrast, call intervals in the mouse were directly correlated with call duration. Importantly, call duration was not, or was only slightly, correlated with inter-call intervals, consistent with the idea that vocal production in the mouse is largely independent of the respiratory cycle. Conclusions: Our findings suggest that ultrasonic vocalizations in mice are produced by call-pattern generating mechanisms that seem to be similar to those that have been found in primates. This is in contrast to the production mechanisms of ultrasonic echolocation calls in horseshoe bats. These results are particularly interesting, especially since mouse vocalizations have recently attracted increased attention as potential indicators for the degree of progression of several disease patterns in mouse models for neurodegenerative and neurodevelopmental disorders of humans.

Disruption of neuronal migration in humans is associated with a wide range of behavioral and cognitive outcomes including severe intellectual disability, language impairment, and social dysfunction. Furthermore, malformations of cortical development have been observed in a number of neurodevelopmental disorders (e.g. autism and dyslexia), where boys are much more commonly diagnosed than girls (estimates around 4 to 1). The use of rodent models provides an excellent means to examine how sex may modulate behavioral outcomes in the presence of comparable abnormal neuroanatomical presentations. Initially characterized by Rosen et al. 2012, the BXD29- Tlr4(lps-2J) /J mouse mutant exhibits a highly penetrant neuroanatomical phenotype that consists of bilateral midline subcortical nodular heterotopia with partial callosal agenesis. In the current study, we confirm our initial findings of a severe impairment in rapid auditory processing in affected male mice. We also report that BXD29- Tlr4(lps-2J) /J (mutant) female mice show no sparing of rapid auditory processing, and in fact show deficits similar to mutant males. Interestingly, female BXD29- Tlr4(lps-2J) /J mice do display superiority in Morris water maze performance as compared to wild type females, an affect not seen in mutant males. Finally, we report new evidence that BXD29- Tlr4(lps-2J) /J mice, in general, show evidence of hyper-social behaviors. In closing, the use of the BXD29- Tlr4(lps-2J) /J strain of mice - with its strong behavioral and neuroanatomical phenotype - may be highly useful in characterizing sex independent versus dependent mechanisms that interact with neural reorganization, as well as clinically relevant abnormal behavior resulting from aberrant neuronal migration.

A psychophysical matching paradigm has been used to better quantify voice quality under laboratory conditions. The goals of this study were to establish which of two candidate comparison stimuli would best ensure that the range of perceived vocal roughness could be adequately bracketed using a matching task and to provide a general solution to the problem of estimating vocal roughness. Psychometric functions for roughness matching indicated that a speech-like sawtooth-plus-noise complex (20 dB signal-to-noise ratio) amplitude modulated by a sinusoidal function raised to the 4th power yielded a comparison stimulus with a perceptual dynamic range well suited for roughness matching.

Normal hearing depends on the ability to distinguish self-generated sounds from other sounds, and this ability is thought to involve neural circuits that convey copies of motor command signals to various levels of the auditory system. Although such interactions at the cortical level are believed to facilitate auditory comprehension during movements and drive auditory hallucinations in pathological states, the synaptic organization and function of circuitry linking the motor and auditory cortices remain unclear. Here we describe experiments in the mouse that characterize circuitry well suited to transmit motor-related signals to the auditory cortex. Using retrograde viral tracing, we established that neurons in superficial and deep layers of the medial agranular motor cortex (M2) project directly to the auditory cortex and that the axons of some of these deep-layer cells also target brainstem motor regions. Using in vitro whole-cell physiology, optogenetics, and pharmacology, we determined that M2 axons make excitatory synapses in the auditory cortex but exert a primarily suppressive effect on auditory cortical neuron activity mediated in part by feedforward inhibition involving parvalbumin-positive interneurons. Using in vivo intracellular physiology, optogenetics, and sound playback, we also found that directly activating M2 axon terminals in the auditory cortex suppresses spontaneous and stimulus-evoked synaptic activity in auditory cortical neurons and that this effect depends on the relative timing of motor cortical activity and auditory stimulation. These experiments delineate the structural and functional properties of a corticocortical circuit that could enable movement-related suppression of auditory cortical activity.

A growing interest in sensory system plasticity in the natural context of motherhood has created the need to investigate how intrinsic physiological state (e.g., hormonal, motivational, etc.) interacts with sensory experience to drive adaptive cortical plasticity for behaviorally relevant stimuli. Using a maternal mouse model of auditory cortical inhibitory plasticity for ultrasonic pup calls, we examined the role of pup care versus maternal physiological state in the long-term retention of this plasticity. Very recent experience caring for pups by Early Cocarers, which are virgins, produced stronger call-evoked lateral-band inhibition in auditory cortex. However, this plasticity was absent when measured post-weaning in Cocarers, even though it was present at the same time point in Mothers, whose pup experience occurred under a maternal physiological state. A two-alternative choice phonotaxis task revealed that the same animal groups (Early Cocarers and Mothers) demonstrating stronger lateral-band inhibition also preferred pup calls over a neutral sound, a correlation consistent with the hypothesis that this inhibitory mechanism may play a mnemonic role and is engaged to process sounds that are particularly salient. Our electrophysiological data hint at a possible mechanism through which the maternal physiological state may act to preserve the cortical plasticity: selectively suppressing detrimental spontaneous activity in neurons that are responsive to calls, an effect observed only in Mothers. Taken together, the maternal physiological state during the care of pups may help maintain the memory trace of behaviorally salient infant cues within core auditory cortex, potentially ensuring a more rapid induction of future maternal behavior.

For over a century epileptic seizures have been known to cluster at specific times of the day. Recent studies have suggested that the circadian regulatory system may become permanently altered in epilepsy, but little is known about how this affects neural activity and the daily pattern of seizures. To investigate, we tracked long-term changes in the rate of spontaneous hippocampal EEG spikes (SPKs) in a rat model of temporal lobe epilepsy. In healthy animals, SPKs oscillated with near 24-h period; however, after injury by status epilepticus, a persistent phase shift of ∼12 h emerged in animals that later went on to develop chronic spontaneous seizures. Additional measurements showed that global 24-h rhythms, including core body temperature and theta state transitions, did not phase shift. Instead, we hypothesized that locally impaired circadian input to the hippocampus might be responsible for the SPK phase shift. This was investigated with a biophysical computer model in which we showed that subtle changes in the relative strengths of circadian input could produce a phase shift in hippocampal neural activity. MRI provided evidence that the medial septum, a putative circadian relay center for the hippocampus, exhibits signs of damage and therefore could contribute to local circadian impairment. Our results suggest that balanced circadian input is critical to maintaining natural circadian phase in the hippocampus and that damage to circadian relay centers, such as the medial septum, may disrupt this balance. We conclude by discussing how abnormal circadian regulation may contribute to the daily rhythms of epileptic seizures and related cognitive dysfunction.

Gamma oscillations (∼30-120Hz) are considered to be a reflection of coordinated neuronal activity, linked to processes underlying synaptic integration and plasticity. Increases in gamma power within the cerebral cortex have been found during many cognitive processes such as attention, learning, memory and problem solving in both humans and animals. However, the specificity of gamma to the detailed contents of memory remains largely unknown. We investigated the relationship between learning-induced increased gamma power in the primary auditory cortex (A1) and the strength of memory for acoustic frequency. Adult male rats (n=16) received three days (200 trials each) of pairing a tone (3.66 kHz) with stimulation of the nucleus basalis, which implanted a memory for acoustic frequency as assessed by associatively-induced disruption of ongoing behavior, viz., respiration. Post-training frequency generalization gradients (FGGs) revealed peaks at non-CS frequencies in 11/16 cases, likely reflecting normal variation in pre-training acoustic experiences. A stronger relationship was found between increased gamma power and the frequency with the strongest memory (peak of the difference between individual post- and pre-training FGGs) vs. behavioral responses to the CS training frequency. No such relationship was found for the theta/alpha band (4-15 Hz). These findings indicate that the strength of specific increased neuronal synchronization within primary sensory cortical fields can determine the specific contents of memory.

Dynamic range compression is widely used to reduce the difference between the most and least intense portions of a signal. Such compression distorts the shape of the amplitude envelope of a signal, but it is unclear to what extent such distortions are actually perceivable by listeners. Here, the ability to distinguish between compressed and uncompressed versions of a noise vocoded sentence was initially measured in listeners with normal hearing while varying the threshold, ratio, attack, and release parameters. This narrow condition was selected in order to characterize perception under the most favorable listening conditions. The average behavioral sensitivity to compression was highly correlated to several acoustical indices of modulation depth. In particular, performance was highly correlated to the Euclidean distance between the modulation spectra of the uncompressed and compressed signals. Suggesting that this relationship is not restricted to the initial test conditions, the correlation remained largely unchanged both (1) when listeners with normal hearing were tested using a time-compressed version of the original signal, and (2) when listeners with impaired hearing were tested using the original signal. If this relationship generalizes to more ecologically valid conditions, it will provide a straightforward method for predicting the detectability of compression-induced distortions.

Assessment of network connectivity across multiple brain regions is critical to understanding the mechanisms underlying various neurological disorders. Conventional methods for assessing dynamic interactions include cross-correlation and coherence analysis. However, these methods do not reveal the direction of information flow, which is important for studying the highly directional neurological system. Granger causality (GC) analysis can characterize the directional influences between two systems. We tested GC analysis for its capability to capture directional interactions within both simulated and in vivo neural networks. The simulated networks consisted of Hindmarsh-Rose neurons; GC analysis was used to estimate the causal influences between two model networks. Our analysis successfully detected asymmetrical interactions between these networks ( , t -test). Next, we characterized the relationship between the "electrical synaptic strength" in the model networks and interactions estimated by GC analysis. We demonstrated the novel application of GC to monitor interactions between thalamic and cortical neurons following ischemia induced brain injury in a rat model of cardiac arrest (CA). We observed that during the post-CA acute period the GC interactions from the thalamus to the cortex were consistently higher than those from the cortex to the thalamus ( 1.983±0.278 times higher, p = 0.021). In addition, the dynamics of GC interactions between the thalamus and the cortex were frequency dependent. Our study demonstrated the feasibility of GC to monitor the dynamics of thalamocortical interactions after a global nervous system injury such as CA-induced ischemia, and offers preferred alternative applications in characterizing other inter-regional interactions in an injured brain.

Cortical sensory representation is highly adaptive to the environment, and prevalent or behaviorally important stimuli are often overrepresented. One class of such stimuli is species-specific vocalizations. Rats vocalize in the ultrasonic range >30 kHz, but cortical representation of this frequency range has not been systematically examined. We recorded in vivo cortical electrophysiological responses to ultrasonic pure-tone pips, natural ultrasonic vocalizations, and pitch-shifted vocalizations to assess how rats represent this ethologically relevant frequency range. We find that nearly 40% of the primary auditory cortex (AI) represents an octave-wide band of ultrasonic vocalization frequencies (UVFs; 32–64 kHz) compared with <20% for other octave bands <32 kHz. These UVF neurons respond preferentially and reliably to ultrasonic vocalizations. The UVF overrepresentation matures in the cortex before it develops in the central nucleus of inferior colliculus, suggesting a cortical origin and corticofugal influences. Furthermore, the development of cortical UVF overrepresentation depends on early acoustic experience. These results indicate that natural sensory experience causes large-scale cortical map reorganization and improves representations of species-specific vocalizations.

Acoustic trauma, a leading cause of sensorineural hearing loss in adults, induces a complex degenerative process in the cochlea. Although previous investigations have identified multiple stress pathways, a comprehensive analysis of cochlear responses to acoustic injury is still lacking. In the current study, we used the next-generation RNA-sequencing (RNA-Seq) technique to sequence the whole transcriptome of the normal and noise-traumatized cochlear sensory epithelia (CSE). CSE tissues were collected from rat inner ears 1d after the rats were exposed to a 120-dB (sound pressure level) noise for 2 h. The RNA-Seq generated over 176 million sequence reads for the normal CSE and over 164 million reads for the noise-traumatized CSE. Alignment of these sequences with the rat Rn4 genome revealed the expression of over 17,000 gene transcripts in the CSE, over 2000 of which were exclusively expressed in either the normal or noise-traumatized CSE. Seventy-eight gene transcripts were differentially expressed (70 upregulated and 8 downregulated) after acoustic trauma. Many of the differentially expressed genes are related to the innate immune system. Further expression analyses using quantitative real time PCR confirmed the constitutive expression of multiple complement genes in the normal organ of Corti and the changes in the expression levels of the complement factor I (Cfi) and complement component 1, s subcomponent (C1s) after acoustic trauma. Moreover, protein expression analysis revealed strong expression of Cfi and C1s proteins in the organ of Corti. Importantly, these proteins exhibited expression changes following acoustic trauma. Collectively, the results of the current investigation suggest the involvement of the complement components in cochlear responses to acoustic trauma.

Exogenous tumor necrosis factor-alpha (TNF-α) plays a role in auditory hair cell death by altering the expression of apoptosis-related genes in response to noxious stimuli. Little is known, however, about the function of TNF-α in normal hair cell physiology. We, therefore, investigated the cochlear morphology and auditory function of TNF-α-deficient mice. Auditory evoked brainstem response showed significantly higher thresholds, especially at higher frequencies, in 1-month-old TNF-α(-/-) mice as compared to TNF-α(+/-) and wild type (WT); hearing loss did not progress further from 1 to 4 months of age. There was no difference in the gross morphology of the organ of Corti, lateral wall, and spiral ganglion cells in TNF-α(-/-) mice compared to WT mice at 4 months of age, nor were there differences in the anatomy of the auditory ossicles. Outer hair cells were completely intact in surface preparations of the organ of Corti of TNF-α(-/-) mice, and synaptic ribbon counts of TNF-α(-/-) and WT mice at 4 months of age were similar. Reduced amplitudes of distortion product otoacoustic emissions, however, indicated dysfunction of outer hair cells in TNF-α(-/-) mice. Scanning electron microscopy revealed that stereocilia were sporadically absent in the basal turn and distorted in the middle turn. In summary, our results demonstrate that TNF-α-mutant mice exhibit early hearing loss, especially at higher frequencies, and that loss or malformation of the stereocilia of outer hair cells appears to be a contributing factor.

Objective: Brain machine interfaces (BMIs) that decode control signals from motor cortex have developed tremendously in the past decade, but virtually all rely exclusively on vision to provide feedback. There is now increasing interest in developing an afferent interface to replace natural somatosensation, much as the cochlear implant has done for the sense of hearing. Preliminary experiments toward a somatosensory neuroprosthesis have mostly addressed the sense of touch, but proprioception, the sense of limb position and movement, is also critical for the control of movement. However, proprioceptive areas of cortex lack the precise somatotopy of tactile areas. We showed previously that there is only a weak tendency for neighboring neurons in area 2 to signal similar directions of hand movement. Consequently, stimulation with the relatively large currents used in many studies is likely to activate a rather heterogeneous set of neurons. Approach: Here, we have compared the effect of single-electrode stimulation at subthreshold levels to the effect of stimulating as many as seven electrodes in combination. Main results: We found a mean enhancement in the sensitivity to the stimulus (d') of 0.17 for pairs compared to individual electrodes (an increase of roughly 30%), and an increase of 2.5 for groups of seven electrodes (260%). Significance: We propose that a proprioceptive interface made up of several hundred electrodes may yield safer, more effective sensation than a BMI using fewer electrodes and larger currents.

Activation of the medial olivocochlear reflex (MOCR) can be assessed indirectly using transient-evoked otoacoustic emissions (TEOAEs). The change in TEOAE amplitudes when the MOCR is activated (medial olivocochlear (MOC) shift) has most often been quantified as the mean value in groups of subjects. The usefulness of MOC shift measurements may be increased by the ability to quantify significant shifts in individuals. This study used statistical resampling to quantify significant MOC shifts in 16 subjects. TEOAEs were obtained using transient stimuli containing energy from 1 to 10 kHz. A nonlinear paradigm was used to extract TEOAEs. Transient stimuli were presented at 30 dB sensation level (SL) with suppressor stimuli presented 12 dB higher. Contralateral white noise, used to activate the MOCR, was presented at 30 dB SL and was interleaved on and off in 30-s intervals during a 7-min recording period. Confounding factors of middle ear muscle reflex and slow amplitude drifts were accounted for. TEOAEs were analyzed in 11 1/3-octave frequency bands. The statistical significance of each individual MOC shift was determined using a bootstrap procedure. The minimum detectable MOC shifts ranged from 0.10 to 3.25 dB and were highly dependent on signal-to-noise ratio at each frequency. Subjects exhibited a wide range of magnitudes of significant MOC shifts in the 1.0-3.2-kHz region (median = 1.94 dB, range = 0.34-6.51 dB). There was considerable overlap between the magnitudes of significant and nonsignificant shifts. While most subjects had significant MOC shifts in one or more frequency bands below 4 kHz, few had significant shifts in all of these bands. Above 4 kHz, few significant shifts were seen, but this may have been due to lower signal-to-noise ratios. The specific frequency bands containing significant shifts were variable across individuals. Further work is needed to determine the clinical usefulness of examining MOC shifts in individuals.

The distinctive planar polarity of auditory hair cells is evident in the polarized organization of the stereociliary bundle. Mutations in the core planar cell polarity gene Van Gogh-like 2 (Vangl2) result in hair cells that fail to properly orient their stereociliary bundles along the mediolateral axis of the cochlea. The severity of this phenotype is graded along the length of the cochlea, similar to the hair cell differentiation gradient, suggesting that an active refinement process corrects planar polarity phenotypes in Vangl2 knock-out (KO) mice. Because Vangl2 gene deletions are lethal, Vangl2 conditional knock-outs (CKOs) were generated to test this hypothesis. When crossed with Pax2-Cre, Vangl2 is deleted from the inner ear, yielding planar polarity phenotypes similar to Vangl2 KOs at late embryonic stages except that Vangl2 CKO mice are viable and do not have craniorachischisis like Vangl2 KOs. Quantification of planar polarity deficits through postnatal development demonstrates the activity of a Vangl2-independent refinement process that rescues the planar polarity phenotype within 10 d of birth. In contrast, the Pax2-Cre;Vangl2 CKO has profound changes in the shape and distribution of outer pillar cell and Deiters' cell phalangeal processes that are not corrected during the period of planar polarity refinement. Auditory brainstem response analyses of adult mice show a 10-15 dB shift in auditory threshold, and distortion product otoacoustic emission measurements indicate that this mild hearing deficit is of cochlear origin. Together, these data demonstrate a Vangl2-independent refinement mechanism that actively reorients auditory stereociliary bundles and reveals an unexpected role of Vangl2 during supporting cell morphogenesis.

Intranasal trigeminal sensory input, often perceived as a burning, tingling, or stinging sensation, is well known to affect odor perception. While both anatomical and functional imaging data suggest that the influence of trigeminal stimuli on odor information processing may occur within the olfactory cortex, direct electrophysiological evidence for the encoding of trigeminal information at this level of processing is unavailable. Here, in agreement with human functional imaging studies, we found that 26% of neurons in the mouse piriform cortex (PCX) display modulation in firing to carbon dioxide (CO 2 ), an odorless stimulant with known trigeminal capacity. Interestingly, CO 2 was represented within the PCX by distinct temporal dynamics, differing from those evoked by odor. Experiments with ascending concentrations of isopentyl acetate, an odorant known to elicit both olfactory and trigeminal sensations, resulted in morphing of the temporal dynamics of stimulus-evoked responses. Whereas low concentrations of odorant evoked responses upon stimulus onset, high concentrations of odorant and/or CO 2 often evoked responses structured to stimulus offset. These physiological experiments in mice suggest that PCX neurons possess the capacity to encode for stimulus modality (olfactory vs trigeminal) by differential patterns of firing. These data provide mechanistic insights into the influences of trigeminal information on odor processing and place constraints on models of olfactory-trigeminal sensory integration.

Nonmuscle myosin heavy chain IIA (NMMHCIIA) encoded by MYH9 is associated with autosomal dominantly inherited diseases called MYH9 disorders. MYH9 disorders are characterized by macrothrombocytopenia and very characteristic inclusion bodies in granulocytes. MYH9 disorders frequently cause nephritis, sensorineural hearing disability and cataracts. One of the most common and deleterious mutations causing these disorders is the R702C missense mutation. We generated knock-in mice expressing the Myh9 R702C mutation. R702C knock-in hetero mice (R702C+/- mice) showed macrothrombocytopenia. We studied megakaryopoiesis of cultured fetal liver cells of R702C+/- mice and found that proplatelet formation was impaired: the number of proplatelet tips was decreased, proplatelet size was increased, and proplatelet shafts were short and enlarged. Although granulocyte inclusion bodies were not visible by May-Grünwald Giemsa staining, immunofluorescence analysis indicated that NMMHCIIA proteins aggregated and accumulated in the granulocyte cytoplasm. In other organs, R702C+/- mice displayed albuminuria which increased with age. Renal pathology examination revealed glomerulosclerosis. Sensory hearing loss was indicated by lowered auditory brainstem response. These findings indicate that Myh9 R702C knock-in mice mirror features of human MYH9 disorders arising from the R702C mutation.

This study investigates the temporal properties of adaptation in the late auditory-evoked potentials in humans. The results are used to make inferences about the mechanisms of adaptation in human auditory cortex. The first experiment measured adaptation by single adapters as a combined function of the adapter duration and the stimulus onset asynchrony (SOA) and interstimulus interval (ISI) between the adapter and the adapted sound (“probe”). The results showed recovery from adaptation with increasing ISI, as would be expected, but buildup of adaptation with increasing adapter duration and thus SOA. This suggests that adaptation in auditory cortex is caused by the ongoing, rather than the onset, response to the adapter. Quantitative modeling indicated that the rate of buildup of adaptation is almost an order of magnitude faster than the recovery rate of adaptation. The recovery rate suggests that cortical adaptation is caused by synaptic depression and slow afterhyperpolarization. The P2 was more strongly affected by adaptation than the N1, suggesting that the two deflections originate from different cortical generators. In the second experiment, the single adapters were replaced by trains of two or four identical adapters. The results indicated that adaptation decays faster after repeated presentation of the adapter. This increase in the recovery rate of adaptation might contribute to the elicitation of the auditory mismatch negativity response. It may be caused by top-down feedback or by local processes such as the buildup of residual Ca 2+ within presynaptic neurons.

A Bayesian adaptive procedure for estimating the auditory-filter shape was proposed and evaluated using young, normal-hearing listeners at moderate stimulus levels. The resulting quick-auditory-filter (qAF) procedure assumed the power spectrum model of masking with the auditory-filter shape being modeled using a spectrally symmetric, two-parameter rounded-exponential (roex) function. During data collection using the qAF procedure, listeners detected the presence of a pure-tone signal presented in the spectral notch of a noise masker. Dependent on the listener's response on each trial, the posterior probability distributions of the model parameters were updated, and the resulting parameter estimates were then used to optimize the choice of stimulus parameters for the subsequent trials. Results showed that the qAF procedure gave similar parameter estimates to the traditional threshold-based procedure in many cases and was able to reasonably predict the masked signal thresholds. Additional measurements suggested that occasional failures of the qAF procedure to reliably converge could be a consequence of incorrect responses early in a qAF track. The addition of a parameter describing lapses of attention reduced the likelihood of such failures.

'Ecstasy' or 3,4-methylenedioxy-N-methamphetamine (MDMA) is an amphetamine abused for its euphoric, empathogenic, hallucinatory, and stimulant effects. It is also used to treat certain psychiatric disorders. Common settings for Ecstasy use are nightclubs and "rave" parties where participants consume MDMA and dance to loud music. One concern with the club setting is that exposure to loud sounds can cause permanent sensorineural hearing loss. Another concern is that consumption of MDMA may enhance such hearing loss. Whereas this latter possibility has not been investigated, this study tested the hypothesis that MDMA enhances noise-induced hearing loss (NIHL) by exposing rats to either MDMA, noise trauma, both MDMA and noise, or neither treatment. MDMA was given in a binge pattern of 5 mg/kg per intraperitoneal injections every 2 h for a total of four injections to animals in the two MDMA-treated groups (MDMA-only and Noise + MDMA). Saline injections were given to the animals in the two non-MDMA groups (Control and Noise-only). Following the final injection, noise trauma was induced by a 10 kHz tone at 120 dB SPL for 1 h to animals in the two noise trauma-treated groups (Noise-only and Noise + MDMA). Hearing loss was assessed by the auditory brainstem response (ABR) and cochlear histology. Results showed that MDMA enhanced NIHL compared to Noise-only and that MDMA alone caused no hearing loss. This implies that "clubbers" and "rave-goers" are exacerbating the amount of NIHL when they consume MDMA and listen to loud sounds. In contrast to earlier reports, the present study found that MDMA by itself caused no changes in the click-evoked ABR's wave latencies or amplitudes.