Publications using TDT

The midbrain map of auditory space commands sound-orienting responses in barn owls. Owls precisely localize sounds in frontal space but underestimate the direction of peripheral sound sources. This bias for central locations was proposed to be adaptive to the decreased reliability in the periphery of sensory cues used for sound localization by the owl. Understanding the neural pathway supporting this biased behavior provides a means to address how adaptive motor commands are implemented by neurons. Here we find that the sensory input for sound direction is weighted by its reliability in premotor neurons of the midbrain tegmentum of owls (male and female), such that the mean population firing rate approximates the head-orienting behavior. We provide evidence that this coding may emerge through convergence of upstream projections from the midbrain map of auditory space. We further show that manipulating the sensory input yields changes predicted by the convergent network in both premotor neural responses and behavior. This work demonstrates how a topographic sensory representation can be linearly read out to adjust behavioral responses by the reliability of the sensory input.SIGNIFICANCE STATEMENT This research shows how statistics of the sensory input can be integrated into a behavioral command by readout of a sensory representation. The firing rate of midbrain premotor neurons receiving sensory information from a topographic representation of auditory space is weighted by the reliability of sensory cues. We show that these premotor responses are consistent with a weighted convergence from the topographic sensory representation. This convergence was also tested behaviorally, where manipulation of stimulus properties led to bidirectional changes in sound localization errors. Thus a topographic representation of auditory space is translated into a premotor command for sound localization that is modulated by sensory reliability.

Cochlear inner hair cell (IHC) ribbon synapses play an important role in sound encoding and neurotransmitter release. Previous reports show that both noise and aminoglycoside exposures lead to reduced numbers and morphologic changes of synaptic ribbons. In this work, we determined the distribution of N-methyl-D-aspartate receptors (NMDARs) and their role in the gentamicin-induced pathological changes of cochlear IHC ribbon synaptic elements. In normal mature mouse cochleae, the majority of NMDARs were distributed on the modiolar side of IHCs and close to the IHC nuclei region, while most of synaptic ribbons and α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) were located on neural terminals closer to the IHC basal poles. After gentamicin exposure, the NMDARs increased and moved towards the IHC basal poles. At the same time, synaptic ribbons and AMPARs moved toward the IHC bundle poles on the afferent dendrites. The number of ribbon synapse decreased, and this was accompanied by increased auditory brainstem response thresholds and reduced wave I amplitudes. NMDAR antagonist MK801 treatment reduced the gentamicin-induced hearing loss and the pathological changes of IHC ribbon synapse, suggesting that NMDARs were involved in gentamicin-induced ototoxicity by regulating the number and distribution of IHC ribbon synapses.

Objective . Optogenetic modulation of neural activity is a ubiquitous tool for basic investigation of brain circuits. While the majority of optogenetic paradigms rely on short light pulses to evoke synchronized activity of optically sensitized cells, many neurobiological processes are associated with slow local field potential (LFP) oscillations. Therefore, we developed a hybrid fiber probe capable of simultaneous electrophysiological recording and optical stimulation and used it to investigate the utility of sinusoidal light stimulation for evoking oscillatory neural activity in vivo across a broad frequency range. Approach . We fabricated hybrid fiber probes comprising a hollow cylindrical array of 9 electrodes and a flexible optical waveguide integrated within the core. We implanted these probes in the hippocampus of transgenic Thy1-ChR2-YFP mice that broadly express the blue-light sensitive cation channel channelrhodopsin 2 (ChR2) in excitatory neurons across the brain. The effects of the sinusoidal light stimulation were characterized and contrasted with those corresponding to pulsed stimulation in the frequency range of physiological LFP rhythms (3–128 Hz). Main results . Within hybrid probes, metal electrode surfaces were vertically aligned with the waveguide tip, which minimized optical stimulation artifacts in neurophysiological recordings. Sinusoidal stimulation resulted in reliable and coherent entrainment of LFP oscillations up to 70 Hz, the cutoff frequency of ChR2, with response amplitudes inversely scaling with the stimulation frequencies. Effectiveness of the stimulation was maintained for two months following implantation. Significance . Alternative stimulation patterns complementing existing pulsed protocols, in particular sinusoidal light stimulation, are a prerequisite for investigating the physiological mechanisms underlying brain rhythms. So far, studies applying sinusoidal stimulation in vivo were limited to single stimulation frequencies. We show the feasibility of sinusoidal stimulation in vivo to induce coherent LFP oscillations across the entire frequency spectrum supported by the gating dynamics of ChR2 and introduce a hybrid fiber probe tailored to continuous light stimulation.

Myo3a is expressed in cochlear hair cells and retinal cells and is responsible for human recessive hereditary nonsyndromic deafness (DFNB30). To investigate the mechanism of DFNB30-type deafness, we established a mouse model of Myo3a kinase domain Y137C mutation by using CRISPR/Cas9 system. No difference in hearing between 2-month-old Myo3a mutant mice and wild-type mice was observed. The hearing threshold of the ≥6-month-old mutant mice was significantly elevated compared with that of the wild-type mice. We observed degeneration in the inner ear hair cells of 6-month-old Myo3a mutant mice, and the degeneration became more severe at the age of 12 months. We also found structural abnormality in the cochlear hair cell stereocilia. Our results showed that Myo3a is essential for normal hearing by maintaining the intact structure of hair cell stereocilia, and the kinase domain plays a critical role in the normal functions of Myo3a. This mouse line is an excellent model for studying DFNB30-type deafness in humans.

Recently, a least-squares-based method has been proposed to decode auditory attention from single-trial EEG recordings for an acoustic scenario with two competing speakers. This method aims at reconstructing the attended speech envelope from the EEG recordings using a trained spatio-temporal filter. While the performance of this method has been mainly studied for noiseless and anechoic acoustic conditions, it is important to fully understand its performance in realistic noisy and reverberant acoustic conditions. In this paper, we investigate auditory attention decoding (AAD) using EEG recordings for different acoustic conditions (anechoic, reverberant, noisy, and reverberant-noisy). In particular, we investigate the impact of different acoustic conditions for AAD filter training and for decoding. In addition, we investigate the influence on the decoding performance of the different acoustic components (i.e. reverberation, background noise and interfering speaker) in the reference signals used for decoding and the training signals used for computing the filters. First, we found that for all considered acoustic conditions it is possible to decode auditory attention with a decoding performance larger than 90%, even when the acoustic conditions for AAD filter training and for decoding are different. Second, when using reference signals affected by reverberation and/or background noise, a comparable decoding performance as when using clean reference signals can be obtained. In contrast, when using reference signals affected by the interfering speaker, the decoding performance significantly decreases. Third, the experimental results indicate that it is even feasible to use training signals affected by reverberation, background noise and/or the interfering speaker for computing the filters.

Electrical stimulation of the auditory nerve with a penetrating intraneural (IN) electrode in acutely deafened cats produces much more restricted spread of excitation than is obtained in that preparation with a conventional cochlear implant (CI) as reported by Middlebrooks and Snyder (J Assoc Res Otolaryngol 8:258-279, 2007). That suggests that a future auditory prosthesis employing IN stimulation might offer human patients greater frequency selectivity than is available with a present-day CI. Nevertheless, it is a concern that the electrical field produced by an IN electrode might be too restricted to produce adequate stimulation of the partially depopulated auditory nerve of a deaf patient. We evaluated this by testing responses to IN and CI stimulation in adult-deafened cats. Activation of the auditory pathway was monitored by recording from the central nucleus of the inferior colliculus (ICC). Cats deaf for 153-277 days exhibited a ~ 30 % loss of auditory nerve fibers compared to cats deaf for < 18 h. Contrary to our concern, measures of thresholds and dynamic ranges showed no significant deafness-related impairment of excitation by IN or CN stimulation. Surprisingly, however, temporal acuity decreased dramatically in these adult-deafened cats, as demonstrated by a marked decrease in the maximum rate of electrical cochlear stimulation to which ICC neurons synchronized to IN or CI stimulation. For instance, half of ICC neurons synchronized to IN stimulation up to 203 pulses per second (pps) in acute deafness, whereas that number dropped to 79 pps for chronic deafness. Such a loss of temporal acuity might contribute to the poor sensitivity to temporal fine structure that has been reported in human CI users. Seemingly, the degraded temporal acuity that we observed in cats was even worse than the fine-structure sensitivity of human CI users, suggesting that most patients experience some improvement of temporal acuity resulting from restoration of patterned auditory nerve stimulation by a CI.

Detection of salient objects in the visual scene is a vital aspect of an animal’s interactions with its environment. Here, we show that neurons in the mouse superior colliculus (SC) encode visual saliency by detecting motion contrast between stimulus center and surround. Excitatory neurons in the most superficial lamina of the SC are contextually modulated, monotonically increasing their response from suppression by the same-direction surround to maximal potentiation by an oppositely-moving surround. The degree of this potentiation declines with depth in the SC. Inhibitory neurons are suppressed by any surround at all depths. These response modulations in both neuronal populations are much more prominent to direction contrast than to phase, temporal frequency, or static orientation contrast, suggesting feature-specific saliency encoding in the mouse SC. Together, our findings provide evidence supporting locally generated feature representations in the SC, and lay the foundations towards a mechanistic and evolutionary understanding of their emergence.

Critical animal behaviors, especially among rodents, are guided by odors in remarkably well-coordinated manners, yet many extramodal sensory cues compete for cognitive resources in these ecological contexts. That rodents can engage in such odor-guided behaviors suggests that they can selectively attend to odors. Indeed, higher-order cognitive processes-such as learning, memory, decision making, and action selection-rely on the proper filtering of sensory cues based on their relative salience. We developed a behavioral paradigm to reveal that rats are capable of selectively attending to odors in the presence of competing extramodal stimuli. We found that this selective attention facilitates accurate odor-guided decisions, which become further strengthened with experience. Further, we uncovered that selective attention to odors adaptively sharpens their representation among neurons in the olfactory tubercle, an olfactory cortex region of the ventral striatum that is considered integral for evaluating sensory information in the context of motivated behaviors. Odor-directed selective attention exerts influences during moments of heightened odor anticipation and enhances odorant representation by increasing stimulus contrast in a signal-to-noise-type coding scheme. Together, these results reveal that rats engage selective attention to optimize olfactory outcomes. Further, our finding of attention-dependent coding in the olfactory tubercle challenges the notion that a thalamic relay is integral for the attentional control of sensory coding.

In a Dutch consanguineous family with recessively inherited nonsyndromic hearing impairment (HI), homozygosity mapping combined with whole-exome sequencing revealed a MPZL2 homozygous truncating variant, c.72del (p.Ile24Metfs∗22). By screening a cohort of phenotype-matched subjects and a cohort of HI subjects in whom WES had been performed previously, we identified two additional families with biallelic truncating variants of MPZL2. Affected individuals demonstrated symmetric, progressive, mild to moderate sensorineural HI. Onset of HI was in the first decade, and high-frequency hearing was more severely affected. There was no vestibular involvement. MPZL2 encodes myelin protein zero-like 2, an adhesion molecule that mediates epithelial cell-cell interactions in several (developing) tissues. Involvement of MPZL2 in hearing was confirmed by audiometric evaluation of Mpzl2-mutant mice. These displayed early-onset progressive sensorineural HI that was more pronounced in the high frequencies. Histological analysis of adult mutant mice demonstrated an altered organization of outer hair cells and supporting cells and degeneration of the organ of Corti. In addition, we observed mild degeneration of spiral ganglion neurons, and this degeneration was most pronounced at the cochlear base. Although MPZL2 is known to function in cell adhesion in several tissues, no phenotypes other than HI were found to be associated with MPZL2 defects. This indicates that MPZL2 has a unique function in the inner ear. The present study suggests that deleterious variants of Mplz2/MPZL2 affect adhesion of the inner-ear epithelium and result in loss of structural integrity of the organ of Corti and progressive degeneration of hair cells, supporting cells, and spiral ganglion neurons.

CaBPs are a family of Ca2+ binding proteins related to calmodulin. Two CaBP family members, CaBP1 and CaBP2, are highly expressed in the cochlea. Here, we investigated the significance of CaBP1 and CaBP2 for hearing in mice lacking expression of these proteins (CaBP1 KO and CaBP2 KO) using auditory brain responses (ABRs) and distortion product otoacoustic emissions (DPOAEs). In CaBP1 KO mice, ABR wave I was larger in amplitude, and shorter in latency and faster in decay, suggestive of enhanced synchrony of auditory nerve fibers. This interpretation was supported by the greater excitability of CaBP1 KO than WT neurons in whole-cell patch clamp recordings of spiral ganglion neurons in culture, and normal presynaptic function of CaBP1 KO IHCs. DPOAEs and ABR thresholds were normal in 4-week old CaBP1 KO mice, but elevated ABR thresholds became evident at 32 kHz at 9 weeks, and at 8 and 16 kHz by 6 months of age. In contrast, CaBP2 KO mice exhibited significant ABR threshold elevations at 4 weeks of age that became more severe in the mid-frequency range by 9 weeks. Though normal at 4 weeks, DPOAEs in CaBP2 KO mice were significantly reduced in the mid-frequency range by 9 weeks. Our results reveal requirements for CaBP1 and CaBP2 in the peripheral auditory system and highlight the diverse modes by which CaBPs influence sensory processing.

Identification of comparable biomarkers in humans and validated animal models will facilitate pre-clinical to clinical therapeutic pipelines to treat neurodevelopmental disorders. Fragile X Syndrome (FXS) is a leading known genetic cause of intellectual disability with symptoms that include increased anxiety, social and sensory processing deficits. Recent EEG studies in humans with FXS have identified neural oscillation deficits that include enhanced resting state gamma power and reduced inter-trial coherence of sound evoked gamma oscillations. To determine if analogous phenotypes are present in an animal model of FXS, we recorded EEGs in awake, freely moving Fmr1 knock out (KO) mice using similar stimuli as in the human studies. We report remarkably similar neural oscillation phenotypes in the Fmr1 KO mouse including enhanced resting state gamma power and reduced evoked gamma synchronization. The gamma band inter-trial coherence of neural response was reduced in both auditory and frontal cortex of Fmr1 KO mice stimulated with a sound whose envelope was modulated from 1 to 100 Hz, similar to that seen in humans with FXS. These deficits suggest a form of enhanced 'resting state noise' that interferes with the ability of the circuit to mount a synchronized response to sensory input, predicting specific sensory and cognitive deficits in FXS. The abnormal gamma oscillations are consistent with parvalbumin neuron and perineuronal net deficits seen in the Fmr1 KO mouse auditory cortex indicating that the EEG biomarkers are not only clinically relevant, but could also be used to probe cellular and circuit mechanisms of sensory hypersensitivity in FXS.

Introduction: Methicillin-resistant staphylococcus aureus is an emerging problem for the treatment of chronic suppurative otitis media, and also for pediatric tympanostomy tube otorrhea. To date, there are no effective topical antibiotic drugs to treat methicillin-resistant staphylococcus aureus otorrhea. Objective: In this study, we evaluated the ototoxicity of topical KR-12-a2 solution on the cochlea when it is applied topically in the middle ear of guinea pigs. Methods: The antimicrobial activity of KR-12-a2 against methicillin-resistant staphylococcus aureus strains was examined by using the inhibition zone test. Topical application of KR-12-a2 solution, gentamicin and phosphate buffered saline were applied in the middle ear of the guinea pigs after inserting ventilation tubes. Ototoxicity was assessed by auditory brainstem evoked response and scanning electron microscope examination. Results: KR-12-a2 produced an inhibition zone against methicillin-resistant staphylococcus aureus from 6.25 μg. Hearing threshold in the KR-12-a2 and PBS groups were similar to that before ventilation tube insertion. However, the gentamicin group showed elevation of the hearing threshold and there were statistically significant differences compared to the phosphate buffered saline or the KR-12-a2 group. In the scanning electron microscope findings, the KR-12-a2 group showed intact outer hair cells. However, the gentamicin group showed total loss of outer hair cells. In our experiment, topically applied KR-12-a2 solution did not cause hearing loss or cochlear damage in guinea pigs. Conclusion: In our experiment, topically applied KR-12-a2 solution did not cause hearing loss or cochlear damage in guinea pigs. The KR-12-a2 solution can be used as ototopical drops for treating methicillin-resistant staphylococcus aureus otorrhea; however, further evaluations, such as the definition of optimal concentration and combination, are necessary.

Whether via cuff or intrafascicular electrode, peripheral neural stimulations often rely on symmetric, charge balanced paradigms. To date, few investigations have been carried out which systematically decompose the features of a stimulus waveform. Factors such as pulse-width, amplitude, and the timing with which they are presented may have significant effects on the quality of the stimuli. This work seeks to fill this gap in knowledge and share insight into how selection of electrical stimuli may affect the resultant neural activation in peripheral nerves. In particular, we found that, although there is some variance, over the parameter range tested there was not a significant effect on neural fiber recruitment percent due to waveform selection.

A human variant in the BDNF gene (Val66Met; rs6265) is associated with impaired fear extinction. Using super-resolution imaging, we demonstrate that the BDNF Met prodomain disassembles dendritic spines and eliminates synapses in hippocampal neurons. In vivo, ventral CA1 (vCA1) hippocampal neurons undergo similar morphological changes dependent on their transient co-expression of a SorCS2/p75NTR receptor complex during peri-adolescence. BDNF Met prodomain infusion into the vCA1 during this developmental time frame reduces dendritic spine density and prelimbic (PL) projections, impairing cued fear extinction. Adolescent BdnfMet/Met mice display similar spine and PL innervation deficits. Using fiber photometry, we found that, in wild-type mice, vCA1 neurons projecting to the PL encode extinction by enhancing neural activity in threat anticipation and rapidly subsiding their response. This adaptation is absent in BDNFMet/Met mice. We conclude that the BDNF Met prodomain renders vCA1-PL projection neurons underdeveloped, preventing their capacity for subsequent circuit modulation necessary for fear extinction. VIDEO ABSTRACT.

During early developmental windows known as critical periods (CPs) of plasticity, passive alterations in the quality and quantity of sensory inputs are sufficient to induce profound and long-lasting distortions in cortical sensory representations. With CP closure, those representations are stabilized, a process requiring the maturation of inhibitory networks and the maintenance of sufficient GABAergic tone in the cortex. In humans and rodents, however, cortical inhibition progressively decreases with advancing age, raising the possibility that the regulation of plasticity could be altered in older individuals. Here we tested the hypothesis that aging results in a destabilization of sensory representations and maladaptive dysregulated plasticity in the rat primary auditory cortex (A1). Consistent with this idea, we found that passive tone exposure is sufficient to distort frequency tuning in the A1 of older but not younger adult rats. However, we also found that these passive distortions decayed rapidly, indicating an ongoing instability of A1 tuning in the aging cortex. These changes were associated with a decrease in GABA neurotransmitter concentration and a reduction in parvalbumin and perineuronal net expression in the cortex. Finally, we show that artificially increasing GABA tone in the aging A1 is sufficient to restore representational stability and improve the retention of learning.

In realistic listening environments, speech perception requires grouping together audible fragments of speech, filling in missing information, and segregating the glimpsed target from the background. The purpose of this study was to determine the extent to which age-related difficulties with these tasks can be explained by declines in glimpsing, phonemic restoration, and/or speech segregation. Younger and older adults with normal hearing listened to sentences interrupted with silence or envelope-modulated noise, presented either in quiet or with a competing talker. Older adults were poorer than younger adults at recognizing keywords based on short glimpses but benefited more when envelope-modulated noise filled silent intervals. Recognition declined with a competing talker but this effect did not interact with age. Results of cognitive tasks indicated that faster processing speed and better visual-linguistic closure were predictive of better speech understanding. Taken together, these results suggest that age-related declines in speech recognition may be partially explained by difficulty grouping short glimpses of speech into a coherent message.

Hypothesis: Insertion of cochlear implant electrodes generates transient pressure spikes within the vestibular labyrinth equivalent to high-intensity acoustic stimuli. Background: Though cochlear implant (CI) surgery is regarded as having low risk of impacting the vestibular system, several studies have documented changes in vestibular function after implantation. The mechanism of these changes is not understood. We have previously established that large, potentially damaging pressure transients can be generated in the cochlea during electrode insertion, but whether pressure transients occur within the vestibular labyrinth has yet to be determined. Here, we quantify the exposure of the vestibular system to potentially damaging pressure transients during CI surgery. Methods: Five human cadaveric heads were prepared with an extended facial recess and implanted sequentially with eight different CI electrode styles via a round window approach. Fiber-optic sensors measured intralabyrinthine pressures in scala vestibuli, scala tympani, and the lateral semicircular canal during insertions. Results: Electrode insertion produced a range of high-intensity pressure spikes simultaneously in the cochlea and lateral semicircular canal with all electrodes tested. Pressure transients recorded were found to be significantly higher in the vestibular labyrinth than the cochlea and occurred at peak levels known to cause acoustic trauma. Conclusion: Insertion of CI electrodes can produce transients in intralabyrinthine fluid pressure levels equivalent to high-intensity, impulsive acoustic stimuli. Results from this investigation affirm the importance of atraumatic surgical techniques and suggest that in addition to the cochlea, the vestibular system is potentially exposed to damaging fluid pressure waves during cochlear implantation.

Until recently, hypocretin (Hcrt) neurons were the only known wake-promoting neuronal population in the lateral hypothalamus (LH), but subpopulations of inhibitory neurons in this area and glutamatergic neurons in the nearby supramammillary nucleus (SuM) have recently been found that also promote wakefulness. We performed chemogenetic excitation of LH neurons in mice and observed increased wakefulness that lasted more than 4 h without unusual behavior or EEG anomalies. The increased wakefulness was similar in the presence or absence of the dual orexin receptor blocker almorexant (ALM). Analysis of hM3Dq transfection and c-FOS expression in LH inhibitory neurons and in the SuM failed to confirm that the increased wakefulness was due to these wake-promoting populations, although this possibility cannot be completely excluded. To evaluate the relationship to the Hcrt system, we repeated the study in Orexin-tTA mice in the presence or absence of dietary doxycycline (DOX), which enabled us to manipulate the percentage of Hcrt neurons that expressed hM3Dq. In DOX-fed mice, 18% of Hcrt neurons as well as many other LH neurons expressed hM3Dq; these mice showed a profound increase in wake after hM3Dq activation even in the presence of ALM. In mice switched to normal chow, 62% of Hcrt neurons expressed hM3Dq along with other LH cells; chemogenetic activation produced even more sustained arousal which could be reduced to previous levels by ALM treatment. Together, these results indicate an LH neuron population that promotes wakefulness through an Hcrt-independent pathway that can act synergistically with the Hcrt system to prolong arousal.

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

Vocal communication is a sensory-motor process requiring auditory self-monitoring to correct errors and to ensure accurate vocal production. When presented with altered speech feedback, humans rapidly change their speech to compensate. Although previous evidence has demonstrated suppression of auditory cortex during both speech and animal vocalization, the specific role of auditory cortex in such feedback-dependent control is unknown. Here we show the relationship between neural activity in the auditory cortex and feedback-dependent vocal control in marmoset monkeys. We demonstrate that marmosets, like humans, exhibit feedback control of vocal acoustics. We further show that feedback-sensitive activity of auditory cortex neurons predict such compensatory vocal changes. Finally, we demonstrate that electrical microstimulation of auditory cortex rapidly evokes similar changes in vocal production. These results are evidence for a causal role of auditory cortex in vocal self-monitoring and feedback-dependent control, and have implications for understanding human speech motor control.