Publications using TDT

Echolocating bats use echoes of their sonar emissions to determine the position and distance of objects or prey. Target distance is represented as a map of echo delay in the auditory cortex (AC) of bats. During a bat’s flight through a natural complex environment, echo streams are reflected from multiple objects along its flight path. Separating such complex streams of echoes or other sounds is a challenge for the auditory system of bats as well as other animals. We investigated the representation of multiple echo streams in the AC of anesthetized bats ( Phyllostomus discolor) and tested the hypothesis that neurons can lock on echoes from specific objects in a complex echo-acoustic pattern while the representation of surrounding objects is suppressed. We combined naturalistic pulse/echo sequences simulating a bat’s flight through a virtual acoustic space with extracellular recordings. Neurons could selectively lock on echoes from one object in complex echo streams originating from two different objects along a virtual flight path. The objects were processed sequentially in the order in which they were approached. Object selection depended on sequential changes of echo delay and amplitude, but not on absolute values. Furthermore, the detailed representation of the object echo delays in the cortical target range map was not fixed but could be dynamically adapted depending on the temporal pattern of sonar emission during target approach within a simulated flight sequence. NEW & NOTEWORTHY Complex signal analysis is a challenging task in sensory processing for all animals, particularly for bats because they use echolocation for navigation in darkness. Recent studies proposed that the bat’s perceptional system might organize complex echo-acoustic information into auditory streams, allowing it to track specific auditory objects during flight. We show that in the auditory cortex of bats, neurons can selectively respond to echo streams from specific objects.

Tinnitus and hyperacusis are common and potentially serious hearing disorders associated with noise-, age- or drug-induced hearing loss. Accumulating evidence suggests that tinnitus and hyperacusis are linked to excessive neural activity in a distributed brain network that not only includes the central auditory pathway, but also brain regions involved in arousal, emotion, stress and motor control. Here we examine electrophysiological changes in two novel non-auditory areas implicated in tinnitus and hyperacusis: the caudal pontine reticular nucleus (PnC), involved in arousal, and the paraflocculus lobe of the cerebellum (PFL), implicated in head-eye coordination and gating tinnitus and we measure the changes in corticosterone stress hormone levels. Using the salicylate-induced model of tinnitus and hyperacusis, we found that long-latency (>10 ms) sound-evoked response components in both the brain regions were significantly enhanced after salicylate administration, while the short-latency responses were reduced, likely reflecting cochlear hearing loss. These results are consistent with the central gain model of tinnitus and hyperacusis, which proposes that these disorders arise from the amplification of neural activity in central auditory pathway plus other regions linked to arousal, emotion, tinnitus gating and motor control. Finally, we demonstrate that salicylate results in an increase in corticosterone level in a dose-dependent manner consistent with the notion that stress may interact with hearing loss in tinnitus and hyperacusis development. This increased stress response has the potential to have wide-ranging effects on the central nervous system and may therefore contribute to brain-wide changes in neural activity.

Animal models have demonstrated that tinnitus is a pathology of dysfunctional excitability in the central auditory system, in particular in the dorsal cochlear nucleus (DCN) of the brainstem. We used a murine model and studied whether acoustic over-exposure leading to hearing loss and tinnitus, affects long-term potentiation (LTP) at DCN multisensory synapses. Whole cell and field potential recordings were used to study the effects on release probability and synaptic plasticity, respectively in brainstem slices. Shifts in hearing threshold were quantified by auditory brainstem recordings, and gap-induced prepulse inhibition of the acoustic startle reflex was used as an index for tinnitus. An increased release probability that saturated LTP and thereby induced metaplasticity at DCN multisensory synapses, was observed 4-5days following acoustic over-exposure. Perfusion of an NMDA receptor antagonist or decreasing extracellular calcium concentration, decreased the release probability and restored LTP following acoustic over-exposure. In vivo administration of magnesium-threonate following acoustic over-exposure restored LTP at DCN multisensory synapses, and reduced gap detection deficits observed four months following acoustic over-exposure. These observations suggest that consequences of noise-induced metaplasticity could underlie the gap detection deficits that follow acoustic over-exposure, and that early therapeutic intervention could target metaplasticity and alleviate tinnitus.

Recent anecdotal reports from VA audiology clinics as well as a few published studies have identified a sub-population of Service Members seeking treatment for problems communicating in everyday, noisy listening environments despite having normal to near-normal hearing thresholds. Because of their increased risk of exposure to dangerous levels of prolonged noise and transient explosive blast events, communication problems in these soldiers could be due to either hearing loss (traditional or "hidden") in the auditory sensory periphery or from blast-induced injury to cortical networks associated with attention. We found that out of the 14 blast-exposed Service Members recruited for this study, 12 had hearing thresholds in the normal to near-normal range. A majority of these participants reported having problems specifically related to failures with selective attention. Envelope following responses (EFRs) measuring neural coding fidelity of the auditory brainstem to suprathreshold sounds were similar between blast-exposed and non-blast controls. Blast-exposed subjects performed substantially worse than non-blast controls in an auditory selective attention task in which listeners classified the melodic contour (rising, falling, or "zig-zagging") of one of three simultaneous, competing tone sequences. Salient pitch and spatial differences made for easy segregation of the three concurrent melodies. Poor performance in the blast-exposed subjects was associated with weaker evoked response potentials (ERPs) in frontal EEG channels, as well as a failure of attention to enhance the neural responses evoked by a sequence when it was the target compared to when it was a distractor. These results suggest that communication problems in these listeners cannot be explained by compromised sensory representations in the auditory periphery, but rather point to lingering blast-induced damage to cortical networks implicated in the control of attention. Because all study participants also suffered from post-traumatic disorder (PTSD), follow-up studies are required to tease apart the contributions of PTSD and blast-induced injury on cognitive performance.

Adult pair bonding involves dramatic changes in the perception and valuation of another individual. One key change is that partners come to reliably activate the brain's reward system, although the precise neural mechanisms by which partners become rewarding during sociosexual interactions leading to a bond remain unclear. Here we show, using a prairie vole (Microtus ochrogaster) model of social bonding, how a functional circuit from the medial prefrontal cortex to nucleus accumbens is dynamically modulated to enhance females' affiliative behaviour towards a partner. Individual variation in the strength of this functional connectivity, particularly after the first mating encounter, predicts how quickly animals begin affiliative huddling with their partner. Rhythmically activating this circuit in a social context without mating biases later preference towards a partner, indicating that this circuit's activity is not just correlated with how quickly animals become affiliative but causally accelerates it. These results provide the first dynamic view of corticostriatal activity during bond formation, revealing how social interactions can recruit brain reward systems to drive changes in affiliative behaviour.

The influence of experience with human speech sounds on speech perception in budgerigars, vocal mimics whose speech exposure can be tightly controlled in a laboratory setting, was measured. Budgerigars were divided into groups that differed in auditory exposure and then tested on a cue-trading identification paradigm with synthetic speech. Phonetic cue trading is a perceptual phenomenon observed when changes on one cue dimension are offset by changes in another cue dimension while still maintaining the same phonetic percept. The current study examined whether budgerigars would trade the cues of voice onset time (VOT) and the first formant onset frequency when identifying syllable initial stop consonants and if this would be influenced by exposure to speech sounds. There were a total of four different exposure groups: No speech exposure (completely isolated), Passive speech exposure (regular exposure to human speech), and two Speech-trained groups. After the exposure period, all budgerigars were tested for phonetic cue trading using operant conditioning procedures. Birds were trained to peck keys in response to different synthetic speech sounds that began with "d" or "t" and varied in VOT and frequency of the first formant at voicing onset. Once training performance criteria were met, budgerigars were presented with the entire intermediate series, including ambiguous sounds. Responses on these trials were used to determine which speech cues were used, if a trading relation between VOT and the onset frequency of the first formant was present, and whether speech exposure had an influence on perception. Cue trading was found in all birds and these results were largely similar to those of a group of humans. Results indicated that prior speech experience was not a requirement for cue trading by budgerigars. The results are consistent with theories that explain phonetic cue trading in terms of a rich auditory encoding of the speech signal.

Brain-machine interfaces (BMIs) promise to improve the quality of life of patients suffering from sensory and motor disabilities by creating a direct communication channel between the brain and the external world. Yet, their performance is currently limited by the relatively small amount of information that can be decoded from neural activity recorded form the brain. We have recently proposed that such decoding performance may be improved when using state-dependent decoding algorithms that predict and discount the large component of the trial-to-trial variability of neural activity which is due to the dependence of neural responses on the network's current internal state. Here we tested this idea by using a bidirectional BMI to investigate the gain in performance arising from using a state-dependent decoding algorithm. This BMI, implemented in anesthetized rats, controlled the movement of a dynamical system using neural activity decoded from motor cortex and fed back to the brain the dynamical system's position by electrically microstimulating somatosensory cortex. We found that using state-dependent algorithms that tracked the dynamics of ongoing activity led to an increase in the amount of information extracted form neural activity by 22%, with a consequently increase in all of the indices measuring the BMI's performance in controlling the dynamical system. This suggests that state-dependent decoding algorithms may be used to enhance BMIs at moderate computational cost.

The cochlea behaves like a bank of band-pass filters, segregating information into different frequency channels. Some aspects of perception reflect processing within individual channels, but others involve the integration of information across them. One instance of this is sound localization, which improves with increasing bandwidth. The processing of binaural cues for sound location has been studied extensively. However, although the advantage conferred by bandwidth is clear, we currently know little about how this additional information is combined to form our percept of space. We investigated the ability of cells in the auditory system of guinea pigs to compare interaural level differences (ILDs), a key localization cue, between tones of disparate frequencies in each ear. Cells in auditory cortex believed to be integral to ILD processing (excitatory from one ear, inhibitory from the other: EI cells) compare ILDs separately over restricted frequency ranges which are not consistent with their monaural tuning. In contrast, cells that are excitatory from both ears (EE cells) show no evidence of frequency-specific processing. Both cell types are explained by a model in which ILDs are computed within separate frequency channels and subsequently combined in a single cortical cell. Interestingly, ILD processing in all inferior colliculus cell types (EE and EI) is largely consistent with processing within single, matched-frequency channels from each ear. Our data suggest a clear constraint on the way that localization cues are integrated: cortical ILD tuning to broadband sounds is a composite of separate, frequency-specific, binaurally sensitive channels. This frequency-specific processing appears after the level of the midbrain.SIGNIFICANCE STATEMENT For some sensory modalities (e.g., somatosensation, vision), the spatial arrangement of the outside world is inherited by the brain from the periphery. The auditory periphery is arranged spatially by frequency, not spatial location. Therefore, our auditory perception of location must be synthesized from physical cues in separate frequency channels. There are multiple cues (e.g., timing, level, spectral cues), but even single cues (e.g., level differences) are frequency dependent. The synthesis of location must account for this frequency dependence, but it is not known how this might occur. Here, we investigated how interaural-level differences are combined across frequency along the ascending auditory system. We found that the integration in auditory cortex preserves the independence of the different-level cues in different frequency regions.

Significance A decline in organic brain health paralleled by degraded perceptual and cognitive abilities is a well-established aspect of human and animal aging. Here, in a rodent model, an elementary form of attention-demanding auditory training completed in young adulthood resulted in positive changes in modulation-rate discrimination abilities that carried forward into older age. These sustained behavioral impacts for processing speed were paralleled by enduring changes in physical and functional aspects of perceptual processing, documented at the level of the primary auditory cortex. Additionally, an important generalization of training impacts was recorded in the hippocampus, a brain structure for which physical and functional declines have been long associated with the progression to infirmity and dementia in aging.

Feedback signals from the primary auditory cortex (A1) can shape the receptive field properties of neurons in the ventral division of the medial geniculate body (MGBv). However, the behavioral significance of corticothalamic modulation is unknown. The aim of this study was to elucidate the role of this descending pathway in the perception of complex sounds. We tested the ability of adult female ferrets to detect the presence of a mistuned harmonic in a complex tone using a positive conditioned go/no-go behavioral paradigm before and after the input from layer VI in A1 to MGBv was bilaterally and selectively eliminated using chromophore-targeted laser photolysis. MGBv neurons were identified by their short latencies and sharp tuning curves. They responded robustly to harmonic complex tones and exhibited an increase in firing rate and temporal pattern changes when one frequency component in the complex tone was mistuned. Injections of fluorescent microbeads conjugated with a light-sensitive chromophore were made in MGBv, and, following retrograde transport to the cortical cell bodies, apoptosis was induced by infrared laser illumination of A1. This resulted in a selective loss of ∼60% of layer VI A1-MGBv neurons. After the lesion, mistuning detection was impaired, as indicated by decreased d' values, a shift of the psychometric curves toward higher mistuning values, and increased thresholds, whereas discrimination performance was unaffected when level cues were also available. Our results suggest that A1-MGBv corticothalamic feedback contributes to the detection of harmonicity, one of the most important grouping cues in the perception of complex sounds.SIGNIFICANCE STATEMENT Perception of a complex auditory scene is based on the ability of the brain to group those sound components that belong to the same source and to segregate them from those belonging to different sources. Because two people talking simultaneously may differ in their voice pitch, perceiving the harmonic structure of sounds is very important for auditory scene analysis. Here we demonstrate mistuning sensitivity in the thalamus and that feedback from the primary auditory cortex is required for the normal ability of ferrets to detect a mistuned harmonic within a complex sound. These results provide novel insight into the function of descending sensory pathways in the brain and suggest that this corticothalamic circuit plays an important role in scene analysis.

The mechanisms for acute pain regulation in the brain are not well understood. The prefrontal cortex (PFC) provides top-down control of emotional processes, and it projects to the nucleus accumbens (NAc). This corticostriatal projection forms an important regulatory pathway within the brain's reward system. Recently, this projection has been suggested to control both sensory and affective phenotypes specifically associated with chronic pain. As this projection is also known to play a role in the transition from acute to chronic pain, we hypothesized that this corticostriatal circuit can also exert a modulatory function in the acute pain state. Here, we used optogenetics to specifically target the projection from the PFC to the NAc. We tested sensory pain behaviors with Hargreaves' test and mechanical allodynia, and aversive pain behaviors with conditioned place preference (CPP) test. We found that the activation of this corticostriatal circuit gave rise to bilateral relief from peripheral nociceptive inputs. Activation of this circuit also provided important control for the aversive response to transient noxious stimulations. Hence, our results support a novel role for corticostriatal circuitry in acute pain regulation.

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions and its pathophysiological mechanisms are still poorly understood. Dominant mutations of the GNAL gene are a cause of isolated dystonia (DYT25) in patients. Some mutations result in a complete loss of function of the encoded protein, Gαolf, an adenylyl-cyclase-stimulatory G-protein highly enriched in striatal projection neurons, where it mediates the actions of dopamine and adenosine. We used male and female heterozygous Gnal knock-out mice (Gnal+/-) to study how GNAL haplodeficiency is implicated in dystonia. In basal conditions, no overt dystonic movements or postures or change in locomotor activity were observed. However, Gnal haploinsufficiency altered self-grooming, motor coordination, and apparent motivation in operant conditioning, as well as spine morphology and phospho-CaMKIIβ in the striatum. After systemic administration of oxotremorine, an unselective cholinergic agonist, Gnal+/- mice developed more abnormal postures and movements than WT mice. These effects were not caused by seizures as indicated by EEG recordings. They were prevented by the M1-preferring muscarinic antagonists, telenzepine, pirenzepine, and trihexyphenidyl, which alleviate dystonic symptoms in patients. The motor defects were worsened by mecamylamine, a selective nicotinic antagonist. These oxotremorine-induced abnormalities in Gnal+/- mice were replicated by oxotremorine infusion into the striatum, but not into the cerebellum, indicating that defects in striatal neurons favor the appearance of dystonia-like movement alterations after oxotremorine. Untreated and oxotremorine-treated Gnal+/- mice provide a model of presymptomic and symptomatic stages of DYT25-associated dystonia, respectively, and clues about the mechanisms underlying dystonia pathogenesis.SIGNIFICANCE STATEMENT Adult-onset dystonia DYT25 is caused by dominant loss-of-function mutations of GNAL, a gene encoding the stimulatory G-protein Gαolf, which is critical for activation of the cAMP pathway in the striatal projection neurons. Here, we demonstrate that Gnal-haplodeficient mice have a mild neurological phenotype and display vulnerability to developing dystonic movements after systemic or intrastriatal injection of the cholinergic agonist oxotremorine. Therefore, impairment of the cAMP pathway in association with an increased cholinergic tone creates alterations in striatal neuron functions that can promote the onset of dystonia. Our results also provide evidence that untreated and oxotremorine-treated Gnal-haplodeficient mice are powerful models with which to study presymptomic and symptomatic stages of DYT25-associated dystonia, respectively.

Liposome nanocarriers (LPNs) are potentially the future of inner ear therapy due to their high drug loading capacity and efficient uptake in the inner ear after a minimally invasive intratympanic administration. However, information on the biocompatibility of LPNs in the inner ear is lacking. The aim of the present study is to document the biocompatibility of LPNs in the inner ear after intratympanic delivery. LPNs with or without gadolinium-tetra-azacyclo-dodecane-tetra-acetic acid (Gd-DOTA) were delivered to the rats through transtympanic injection. The distribution of the Gd-DOTA-containing LPNs in the middle and inner ear was tracked in vivo using MRI. The function of the middle and inner ear barriers was evaluated using gadolinium-enhanced MRI. The auditory function was measured using auditory brainstem response (ABR). The potential inflammatory response was investigated by analyzing glycosaminoglycan and hyaluronic acid secretion and CD44 and TLR2 expression in the inner ear. The potential apoptosis was analyzed using terminal transferase (TdT) to label the free 3'OH breaks in the DNA strands of apoptotic cells with TMR-dUTP (TUNEL staining). As a result, LPNs entered the inner ear efficiently after transtympanic injection. The transtympanic injection of LPNs with or without Gd-DOTA neither disrupted the function of the middle and inner ear barriers nor caused hearing impairment in rats. The critical inflammatory biological markers in the inner ear, including glycosaminoglycan and hyaluronic acid secretion and CD44 and TLR2 expression, were not influenced by the administration of LPNs. There was no significant cell death associated with the administration of LPNs. The transtympanic injection of LPNs is safe for the inner ear, and LPNs may be applied as a drug delivery matrix in the clinical therapy of sensorineural hearing loss.

The dorsal and ventral premotor cortices (PMd and PMv, respectively) each take part in unique aspects for the planning and execution of hand movements. These premotor areas are components of complex anatomical networks that include the primary motor cortex (M1) of both hemispheres. One way that PMd and PMv could play distinct roles in hand movements is by modulating the outputs of M1 differently. However, patterns of effects from PMd and PMv on the outputs of M1 have not been compared systematically. Our goals were to study how PMd within the same (i.e., ipsilateral or iPMd) and in the opposite hemisphere (i.e., contralateral or cPMd) can shape M1 outputs and then compare these effects with those induced by PMv. We used paired-pulse protocols with intracortical microstimulation techniques in sedated female cebus monkeys while recording EMG signals from intrinsic hand and forearm muscles. A conditioning stimulus was delivered in iPMd or cPMd concurrently or before a test stimulus in M1. The patterns of modulatory effects from PMd were compared with those from PMv collected in the same animals. Striking differences were revealed. Conditioning stimulation in iPMd induced more frequent and powerful inhibitory effects on M1 outputs compared with iPMv. In the opposite hemisphere, cPMd conditioning induced more frequent and powerful facilitatory effects than cPMv. These contrasting patterns of modulatory effects could allow PMd and PMv to play distinct functions for the control of hand movements and predispose them to undertake different, perhaps somewhat opposite, roles in motor recovery after brain injury.SIGNIFICANCE STATEMENT The dorsal and ventral premotor cortices (PMd and PMv, respectively) are two specialized areas involved in the control of hand movements in primates. One way that PMd and PMv could participate in hand movements is by modulating or shaping the primary motor cortex (M1) outputs to hand muscles. Here, we studied the patterns of modulation from PMd within the same and in the opposite hemisphere on the outputs of M1 and compared them with those from PMv. We found that PMd and PMv have strikingly different effects on M1 outputs. These contrasting patterns of modulation provide a substrate that may allow PMd and PMv to carry distinct functions for the preparation and execution of hand movements and for recovery after brain injury.

Human listeners place greater weight on the beginning of a sound compared to the middle or end when determining sound location, creating an auditory illusion known as the Franssen effect. Here, we exploited that effect to test whether human auditory cortex (AC) represents the physical vs. perceived spatial features of a sound. We used functional magnetic resonance imaging (fMRI) to measure AC responses to sounds that varied in perceived location due to interaural level differences (ILD) applied to sound onsets or to the full sound duration. Analysis of hemodynamic responses in AC revealed sensitivity to ILD in both full-cue (veridical) and onset-only (illusory) lateralized stimuli. Classification analysis revealed regional differences in the sensitivity to onset-only ILDs, where better classification was observed in posterior compared to primary AC. That is, restricting the ILD to sound onset-which alters the physical but not the perceptual nature of the spatial cue-did not eliminate cortical sensitivity to that cue. These results suggest that perceptual representations of auditory space emerge or are refined in higher-order AC regions, supporting the stable perception of auditory space in noisy or reverberant environments and forming the basis of illusions such as the Franssen effect.

Sound stimuli are characterized by their rich spectral and temporal dynamic properties. Individual neurons in auditory cortex (ACX) encode both spectral and temporal aspects of sounds e.g. sound onset and/or offset. While the different fields of the ACX show gradients of frequency selectivity the large-scale organization of sound dynamics is unknown. We used widefield imaging of GCaMP6s in awake mouse ACX combined with a novel unsupervised image segmentation technique to investigate the spatiotemporal representation of sound onset and offset. Using this technique, we identified known auditory fields but also detected novel ACX areas. Furthermore, we found that ACX areas differed in their responses to tone onset and offset. Multiple areas were preferentially activated by tone offset, and on-response areas were more spatially localized than off-response areas. We also found tonotopy in off-responses. Together our results demonstrate a different spatial distribution of neurons across ACX for processing sound onsets versus offsets.

Purpose Our study aimed to explore the feasibility of manganese‐enhanced magnetic resonance imaging ( MEMRI ) combined with visual evoked potentials ( VEP ) and auditory evoked visual cortex responses ( AVR ) in evaluating for the establishment of visual/auditory compensatory pathways after monocular blindness. Materials and Methods A total of 14 healthy neonatal male Sprague‐Dawley rats were randomly divided into two groups ( n = 7 for Groups A and B). Right optic nerve ( ON ) transection was performed on the 7 rats of Group A to obtain a monocularly blind model, and the 7 rats of Group B were chosen as the control group. Four months later, 400 mmol MnCl 2 was injected into the left eye in both groups via intravitreal injection. The changes in the visual pathways projected from the blind eye and the remaining eye in Group A and the normal eyes in Group B were compared to determine if new visual compensatory pathways were established. Additionally, VEP tests were performed to determine complete blindness, and AVR examinations were performed to help identify the generation of auditory compensatory function. Results The VEP test indicated complete visual loss after ON transection. In the monocularly blind rats, the contrast‐to‐noise ratio ( CNR ) of ON , optic tract ( OT ), lateral geniculate nucleus ( LGN ), superior colliculus ( SC ), optic radiation ( OR ) and visual cortex ( VC ) of visual pathway projected from the left eye was significantly higher than that of the right pathway ( p < .001). Moreover, the CNR of ON , OT , LGN , SC , OR and VC in the visual pathway projected from the left eye of monocularly blind rats was significantly lower than those of normal rats ( p < .05). The AVR results revealed that the corresponding bilateral visual cortex in monocularly blind rats did not respond to the auditory stimulus or showed dissimilation with the low frequency. Conclusion MEMRI combined with electrophysiology, including VEP and AVR , may be potentially helpful in the evaluation of the possible generation of new visual/auditory compensatory pathways after monocular blindness.

Significance Word retrieval is essential to language production, relying on the activation of conceptual and word representations in memory followed by the selection of the correct word. The detailed spatiotemporal cortical dynamics of this core language process are not well-known. By using direct cortical recordings, we show that the activation of concepts or word representations and their selection co-occur in time and engage widespread brain networks and overlapping brain regions. In contrast with modular brain models of language production, our data do not support a clear division of labor between brain regions during these early stages of language production. Rather, we suggest that overlapping brain mechanisms optimize word retrieval.

Significance The capacity of a network of neurons to represent the sensory world depends not only on the way individual neurons respond to sensory stimuli but also on the similarity of activity across neurons comprising the network. This similarity can be quantified as the correlation of activity across neuronal pairs, or neural correlations. This work presents a unique finding, demonstrating that a neuromodulator, in this case acetylcholine, can produce specific changes in the correlation structure of the cortical network that ultimately increase the encoding capacity of the network.

Hair cells of the cochlea are mechanosensors for the perception of sound. Mutations in the LRTOMT gene, which encodes a protein with homology to the catecholamine methyltransferase COMT that is linked to schizophrenia, cause deafness. Here, we show that Tomt/Comt2, the murine ortholog of LRTOMT, has an unexpected function in the regulation of mechanotransduction by hair cells. The role of mTOMT in hair cells is independent of mTOMT methyltransferase function and mCOMT cannot substitute for mTOMT function. Instead, mTOMT binds to putative components of the mechanotransduction channel in hair cells and is essential for the transport of some of these components into the mechanically sensitive stereocilia of hair cells. Our studies thus suggest functional diversification between mCOMT and mTOMT, where mTOMT is critical for the assembly of the mechanotransduction machinery of hair cells. Defects in this process are likely mechanistically linked to deafness caused by mutations in LRTOMT/Tomt.