Publications using TDT

Animal behaviours that are superficially similar can express different intents in different contexts, but how this flexibility is achieved at the level of neural circuits is not understood. For example, males of many species can exhibit mounting behaviour towards same- or opposite-sex conspecifics1, but it is unclear whether the intent and neural encoding of these behaviours are similar or different. Here we show that female- and male-directed mounting in male laboratory mice are distinguishable by the presence or absence of ultrasonic vocalizations (USVs)2-4, respectively. These and additional behavioural data suggest that most male-directed mounting is aggressive, although in rare cases it can be sexual. We investigated whether USV+ and USV- mounting use the same or distinct hypothalamic neural substrates. Micro-endoscopic imaging of neurons positive for oestrogen receptor 1 (ESR1) in either the medial preoptic area (MPOA) or the ventromedial hypothalamus, ventrolateral subdivision (VMHvl) revealed distinct patterns of neuronal activity during USV+ and USV- mounting, and the type of mounting could be decoded from population activity in either region. Intersectional optogenetic stimulation of MPOA neurons that express ESR1 and vesicular GABA transporter (VGAT) (MPOAESR1∩VGAT neurons) robustly promoted USV+ mounting, and converted male-directed attack to mounting with USVs. By contrast, stimulation of VMHvl neurons that express ESR1 (VMHvlESR1 neurons) promoted USV- mounting, and inhibited the USVs evoked by female urine. Terminal stimulation experiments suggest that these complementary inhibitory effects are mediated by reciprocal projections between the MPOA and VMHvl. Together, these data identify a hypothalamic subpopulation that is genetically enriched for neurons that causally induce a male reproductive behavioural state, and indicate that reproductive and aggressive states are represented by distinct population codes distributed between MPOAESR1 and VMHvlESR1 neurons, respectively. Thus, similar behaviours that express different internal states are encoded by distinct hypothalamic neuronal populations.

Neurophysiological biomarkers that correlate with motor symptoms or disease severity are vital to improve our understanding of the pathophysiology in Parkinson’s disease (PD) and for the development of more effective treatments, including deep brain stimulation (DBS). This work provides direct insight into the application of these biomarkers in training classifiers to discriminate between brain states, which is a first step toward developing closed-loop DBS systems.

Many individuals with seemingly normal hearing abilities struggle to understand speech in noisy backgrounds. To understand why this might be the case, we investigated the neural representation of speech in the auditory midbrain of gerbils with "hidden hearing loss" through noise exposure that increased hearing thresholds only temporarily. In noise-exposed animals, we observed significantly increased neural responses to speech stimuli, with a more pronounced increase at moderate than at high sound intensities. Noise exposure reduced discriminability of neural responses to speech in background noise at high sound intensities, with impairment most severe for tokens with relatively greater spectral energy in the noise-exposure frequency range (2-4 kHz). At moderate sound intensities, discriminability was surprisingly improved, which was unrelated to spectral content. A model combining damage to high-threshold auditory nerve fibers with increased response gain of central auditory neurons reproduced these effects, demonstrating that a specific combination of peripheral damage and central compensation could explain listening difficulties despite normal hearing thresholds.

Auditory brain stem response (ABR) is more commonly used to evaluate cochlear lesions than cochlear compound action potential (CAP). In a noise-induced cochlear damage model, we found that the reduced CAP and enhanced ABR caused the threshold difference. In a unilateral cochlear destruction model, a shadow curve of the ABR from the contralateral healthy ear masked the hearing loss in the destroyed ear.

ML neurons synchronized less than A1 neurons, consistent with a hierarchical temporal-to-rate transformation. Both A1 and ML had a class of modulation transfer functions previously unreported in the cortex with a low-modulation-frequency (MF) peak, a middle-MF trough, and responses similar to unmodulated noise responses at high MFs. The results support a hierarchical shift toward a two-pool opponent code, where subtraction of neural activity between two populations of oppositely tuned neurons encodes AM.

Exposure to loud noise causes damage to the inner ear, including but not limited to outer and inner hair cells (OHCs and IHCs) and IHC ribbon synapses. This cochlear damage impairs auditory processing and increases audiometric thresholds (noise-induced hearing loss, NIHL). However, the exact relationship between the perceptual consequences of NIHL and its underlying cochlear pathology are poorly understood. This study used a nonhuman primate model of NIHL to relate changes in frequency selectivity and audiometric thresholds to indices of cochlear histopathology. Three macaques (one Macaca mulatta and two Macaca radiata) were trained to detect tones in quiet and in noises that were spectrally notched around the tone frequency. Audiograms were derived from tone thresholds in quiet; perceptual auditory filters were derived from tone thresholds in notched-noise maskers using the rounded-exponential fit. Data were obtained before and after a four-hour exposure to a 50-Hz noise centered at 2 kHz at 141 or 146 dB SPL. Noise exposure caused permanent audiometric threshold shifts and broadening of auditory filters at and above 2 kHz, with greater changes observed for the 146-dB-exposed monkeys. The normalized bandwidth of the perceptual auditory filters was strongly correlated with audiometric threshold at each tone frequency. While changes in audiometric threshold and perceptual auditory filter widths were primarily determined by the extent of OHC survival, additional variability was explained by including interactions among OHC, IHC, and ribbon synapse survival. This is the first study to provide within-subject comparisons of auditory filter bandwidths in an animal model of NIHL and correlate these NIHL-related perceptual changes with cochlear histopathology. These results expand the foundations for ongoing investigations of the neural correlates of NIHL-related perceptual changes.

Background: The auditory brainstem response (ABR), specifically wave I, is widely used to noninvasively measure auditory nerve (AN) function. Recent work in humans has introduced novel electrocochleographic measures to comprehensively characterize AN function that emphasize suprathreshold processing and estimate neural synchrony. New method: This study establishes new tools for evaluating AN function in vivo in adult mice using tone-evoked ABRs obtained from young-adult CBA/CaJ mice, adapting the approach previously introduced in humans. Six metrics are obtained from ABR wave I at suprathreshold stimulus levels. Results: Change-point analyses show that the metrics' rate of change with stimulus level differs between moderate and high suprathreshold levels, suggesting that this approach can potentially characterize the presence of heterogeneous AN fiber types. Comparison with existing methods: Traditional ABR approaches focus on response thresholds and averaged amplitudes/latencies. In contrast, our multi-metric approach, which uses single-trial data and suprathreshold stimuli, provides novel information and identifies evidence of neural synchrony deficits and changes in the heterogeneity of AN fibers underlying AN behavior. Conclusion: The techniques reported here provide a novel tool to assess changes in AN function in vivo in a commonly used animal model. A benchmark of most current hearing research is the transition from animal to human studies. Here we established a translational objective approach, applying methods that were first developed in humans to animals. This approach enables researchers to identify changes in AN function arising from the animal models with well-characterized pathology, and predict similar pathological changes in human AN dysfunction and hearing loss.

Age-related hearing loss is a very common sensory disability, affecting one in three older adults. Establishing a link between anatomical, physiological, and behavioral markers of presbycusis in a mouse model can improve the understanding of this disorder in humans. We measured age-related hearing loss for a variety of acoustic signals in quiet and noisy environments using an operant conditioning procedure and investigated the status of peripheral structures in CBA/CaJ mice. Mice showed the greatest degree of hearing loss in the last third of their lifespan, with higher thresholds in noisy than in quiet conditions. Changes in auditory brainstem response thresholds and waveform morphology preceded behavioral hearing loss onset. Loss of hair cells, auditory nerve fibers, and signs of stria vascularis degeneration were observed in old mice. The present work underscores the difficulty in ascribing the primary cause of age-related hearing loss to any particular type of cellular degeneration. Revealing these complex structure-function relationships is critical for establishing successful intervention strategies to restore hearing or prevent presbycusis.

Radio telemetry systems are a useful way to continuously monitor broad electrical neuronal activity in behaving animals. It can also be used to study sleep disturbances or monitor seizure activity. Many different telemeter styles are available, but the more versatile and cost-efficient ones are the head mounted systems. They permit long-term recordings and allow more flexibility in the recordings. However, there are currently no such system available for non-human primate (NHP). In fact, the choices for NHP telemetry solutions are very limited. Here, we present a chronically implantable 3D printed chamber specifically designed to accommodate a rodent head-mounted system (RodentPACK) onto a NHP's head. We recorded EEG signal for more than a year, confirmed quality of the signal, and the ability to use the data to monitor sleep activity. We also used two of our epileptic animals to validate the embedded alarm system for real time seizure monitoring. While initially not designed for NHP, but with a minimum number of adaptions, this telemeter is in fact perfectly suitable for NHP experiments. Since early medical intervention during seizures is critical to avoid status epilepticus and to save the animal's life, real time seizures monitoring is becoming a safety requirement in many NHP studies. This method refines the current seizure monitoring methods for NHP and creates a flexible telemetry solution.

Usher syndrome is a syndromic form of hereditary hearing impairment that includes sensorineural hearing loss and delayed-onset retinitis pigmentosa (RP). Type 1 Usher syndrome (USH1) is characterized by congenital profound sensorineural hearing impairment and vestibular areflexia, with adolescent-onset RP. Systemic treatment with antisense oligonucleotides (ASOs) targeting the human USH1C c.216G>A splicing mutation in a knockin mouse model of USH1 restores hearing and balance. Herein, we explore the effect of delivering ASOs locally to the ear to treat hearing and vestibular dysfunction associated with Usher syndrome. Three localized delivery strategies were investigated in USH1C mice: inner ear injection, trans-tympanic membrane injection, and topical tympanic membrane application. We demonstrate, for the first time, that ASOs delivered directly to the ear correct Ush1c expression in inner ear tissue, improve cochlear hair cell transduction currents, restore vestibular afferent irregularity, spontaneous firing rate, and sensitivity to head rotation, and successfully recover hearing thresholds and balance behaviors in USH1C mice. We conclude that local delivery of ASOs to the middle and inner ear reach hair cells and can rescue both hearing and balance. These results also demonstrate the therapeutic potential of ASOs to treat hearing and balance deficits associated with Usher syndrome and other ear diseases.

Although the activity from the dentate gyrus is known to have strong connections with other hippocampal layers, the functionality of these connections, that is, the degree to which it drives activity in the downstream regions of the hippocampus, is not well understood. This question is particularly relevant for mesoscale localfield potential (LFP) rhythms such as gamma oscillations. Following the hypothesis that fundamental features of the LFP are consistent with turbulent dynamics, we investigate the crosslayer relationship between the CA1 layers and the dentate gyrus as a function of running speed. In agreement with previous studies, same-layer spectral and bispectral analyses show that increasing input (rat speed) results in an increase of power and nonlinearity (phase coupling) between theta and gamma. The effectiveness of the connection between the 2 regions is investigated using cross-bicoherence analysis. Based on the turbulence interpretation of the evolution of spectra and bispectra as a function of the power input rate, we propose a measure for estimating the strength of the cross-frequency, cross-layer nonlinear forcing, that compares the magnitude of bicoherence (same-layer) and cross-bicoherence (cross-layer). Our results suggest that at moderate speeds gamma in CA1 is mainly driven by local theta, while the coupling of the CA1 gamma to the dentate-gyrus gamma becomes significant. Overall, these data are consistent with the hypothesis of theta-to-gamma energy cascade model for the organization of hippocampal LFP, with theta playing the role of a global pacemaker across the entire hippocampus while gamma is a local oscillation generated by through local anatomical connections. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Understanding the cytoarchitecture and wiring of the brain requires improved methods to record and stimulate large groups of neurons with cellular specificity. This requires miniaturized neural interfaces that integrate into brain tissue without altering its properties. Existing neural interface technologies have been shown to provide high-resolution electrophysiological recording with high signal-to-noise ratio. However, with single implantation, the physical properties of these devices limit their access to one, small brain region. To overcome this limitation, we developed a platform that provides three-dimensional coverage of brain tissue through multisite multifunctional fiber-based neural probes guided in a helical scaffold. Chronic recordings from the spatially expandable fiber probes demonstrate the ability of these fiber probes capturing brain activities with a single-unit resolution for long observation times. Furthermore, using Thy1-ChR2-YFP mice we demonstrate the application of our probes in simultaneous recording and optical/chemical modulation of brain activities across distant regions. Similarly, varying electrographic brain activities from different brain regions were detected by our customizable probes in a mouse model of epilepsy, suggesting the potential of using these probes for the investigation of brain disorders such as epilepsy. Ultimately, this technique enables three-dimensional manipulation and mapping of brain activities across distant regions in the deep brain with minimal tissue damage, which can bring new insights for deciphering complex brain functions and dynamics in the near future.

Action and perception are closely linked in many behaviors necessitating a close coordination between sensory and motor neural processes so as to achieve a well-integrated smoothly evolving task performance. To investigate the detailed nature of these sensorimotor interactions, and their role in learning and executing the skilled motor task of speaking, we analyzed ECoG recordings of responses in the high-γ band (70–150 Hz) in human subjects while they listened to, spoke, or silently articulated speech. We found elaborate spectrotemporally modulated neural activity projecting in both “forward” (motor-to-sensory) and “inverse” directions between the higher-auditory and motor cortical regions engaged during speaking. Furthermore, mathematical simulations demonstrate a key role for the forward projection in “learning” to control the vocal tract, beyond its commonly postulated predictive role during execution. These results therefore offer a broader view of the functional role of the ubiquitous forward projection as an important ingredient in learning, rather than just control, of skilled sensorimotor tasks.

Reduced tolerance to sound stimuli (hyperacusis) is commonly seen in tinnitus patients. Dysfunction of limbic systems, such as the nucleus accumbens (NAc), may be involved in emotional reactions to the sound stimuli in tinnitus patients. To study the functional changes in the NAc in hyperacusis, we have examined the neural activity changes of the NAc using c-Fos staining in an animal model of hyperacusis. The c-Fos staining was also examined in the medial geniculate nucleus (MGN), a central auditory pathway which has neural projections to the NAc. Postnatal rats (14 days) were exposed to loud noise (115 dB SPL, 4 hours for two consecutive days) to induce hyperacusis ( n = 4 ). Rats without noise exposure were used as the controls ( n = 4 ). After P35, rats in both groups were put in a behavioral training for sound detection. After they were trained to detect sound stimuli, their reaction time to noise bursts centered at 2 kHz (40-110 dB SPL) was measured. Rats in the noise group showed a significantly shorter reaction time than those in the control group to the noise bursts at high intensities, suggesting the noise exposure induced hyperacusis behavior. The c-Fos expressions in the NAc and the MGNs of the noise group were significantly higher than those of the control group. Our results suggested that early-age noise exposure caused hyperactivity in the NAc and the MGNs which may induce the loudness increase in these rats.

Key points Mechanoelectrical transduction at auditory hair cells requires highly specialized stereociliary bundles that project from their apical surface, forming a characteristic graded ‘staircase’ structure. The morphogenesis and maintenance of these stereociliary bundles is a tightly regulated process requiring the involvement of several actin‐binding proteins, many of which are still unidentified. We identify a new stereociliary protein, the I‐BAR protein BAIAP2L2, which localizes to the tips of the shorter transducing stereocilia in both inner and outer hair cells (IHCs and OHCs). We find that Baiap2l2 deficient mice lose their second and third rows of stereocilia, their mechanoelectrical transducer current, and develop progressive hearing loss, becoming deaf by 8 months of age. We demonstrate that BAIAP2L2 localization to stereocilia tips is dependent on the motor protein MYO15A and its cargo EPS8. We propose that BAIAP2L2 is a new key protein required for the maintenance of the transducing stereocilia in mature cochlear hair cells. Abstract The transduction of sound waves into electrical signals depends upon mechanosensitive stereociliary bundles that project from the apical surface of hair cells within the cochlea. The height and width of these actin‐based stereocilia is tightly regulated throughout life to establish and maintain their characteristic staircase‐like structure, which is essential for normal mechanoelectrical transduction. Here, we show that BAIAP2L2, a member of the I‐BAR protein family, is a newly identified hair bundle protein that is localized to the tips of the shorter rows of transducing stereocilia in mouse cochlear hair cells. BAIAP2L2 was detected by immunohistochemistry from postnatal day 2.5 (P2.5) throughout adulthood. In Baiap2l2 deficient mice, outer hair cells (OHCs), but not inner hair cells (IHCs), began to lose their third row of stereocilia and showed a reduction in the size of the mechanoelectrical transducer current from just after P9. Over the following post‐hearing weeks, the ordered staircase structure of the bundle progressively deteriorates, such that, by 8 months of age, both OHCs and IHCs of Baiap2l2 deficient mice have lost most of the second and third rows of stereocilia and become deaf. We also found that BAIAP2L2 interacts with other key stereociliary proteins involved in normal hair bundle morphogenesis, such as CDC42, RAC1, EPS8 and ESPNL. Furthermore, we show that BAIAP2L2 localization to the stereocilia tips depends on the motor protein MYO15A and its cargo EPS8. We propose that BAIAP2L2 is key to maintenance of the normal actin structure of the transducing stereocilia in mature mouse cochlear hair cells.

Noise induces oxidative stress in the cochlea followed by sensory cell death and hearing loss. The proof of principle that injections of antioxidant vitamins and Mg2+ prevent noise-induced hearing loss (NIHL) has been established. However, effectiveness of oral administration remains controversial and otoprotection mechanisms are unclear. Using auditory evoked potentials, quantitative PCR, and immunocytochemistry, we explored effects of oral administration of vitamins A, C, E, and Mg2+ (ACEMg) on auditory function and sensory cell survival following NIHL in rats. Oral ACEMg reduced auditory thresholds shifts after NIHL. Improved auditory function correlated with increased survival of sensory outer hair cells. In parallel, oral ACEMg modulated the expression timeline of antioxidant enzymes in the cochlea after NIHL. There was increased expression of glutathione peroxidase-1 and catalase at 1 and 10 days, respectively. Also, pro-apoptotic caspase-3 and Bax levels were diminished in ACEMg-treated rats, at 10 and 30 days, respectively, following noise overstimulation, whereas, at day 10 after noise exposure, the levels of anti-apoptotic Bcl-2, were significantly increased. Therefore, oral ACEMg improves auditory function by limiting sensory hair cell death in the auditory receptor following NIHL. Regulation of the expression of antioxidant enzymes and apoptosis-related proteins in cochlear structures is involved in such an otoprotective mechanism.

Exposure to loud noises results in neuroinflammatory responses in the central auditory pathway. Noise-induced neuroinflammation is implicated in auditory processing deficits such as impairment in gap detection. In this study, we examined whether strain differences between the FVB and C57BL/6 mice in noise-induced impairment in gap detection are correlated with strain differences in neuroinflammatory responses. We found that noise induced more robust TNF-α expression in C57BL/6 than in FVB mice. Noise-induced microglial deramification was observed in C57BL/6 mice, but not in FVB mice. Furthermore, noise exposure resulted in a reduction in parvalbumin-positive (PV+) neuron density in the C57BL/6 mice, but not in FVB mice. These results suggest that neuroinflammatory responses and loss of PV+ neurons may contribute to strain differences in noise-induced impairment in gap detection.

Perception is sensitive to statistical regularities in the environment, including temporal characteristics of sensory inputs. Interestingly, temporal patterns implicitly learned within one modality can also be recognised in another modality. However, it is unclear how cross-modal learning transfer affects neural responses to sensory stimuli. Here, we recorded neural activity of human volunteers (N=24, 12 females, 12 males) using electroencephalography (EEG), while participants were exposed to brief sequences of randomly-timed auditory or visual pulses. Some trials consisted of a repetition of the temporal pattern within the sequence, and subjects were tasked with detecting these trials. Unknown to the participants, some trials reappeared throughout the experiment, enabling implicit learning. Replicating previous behavioural findings, we showed that participants benefit from temporal information learned in audition, and that they can apply this information to stimuli presented in vision. Such memory transfer was not observed from vision to audition. However, using an analysis of EEG response learning curves, we showed that learning temporal structures both within and across modalities modulates single-trial EEG response amplitudes in both conditions (audition to vision and vision to audition). Interestingly, the neural correlates of temporal learning within modalities relied on modality-specific brain regions, while learning transfer affected activity in frontal regions, suggesting distinct mechanisms. The cross-modal effect could be linked to frontal beta-band activity. The neural effects of learning transfer were similar both when temporal information learned in audition was transferred to visual stimuli and vice versa. Thus, both modality-specific mechanisms for learning of temporal information, and general mechanisms which mediate learning transfer across modalities, have distinct physiological signatures that are observable in the EEG.

Significance The noise pollution accompanying industrialization is a risk factor to human health. Here, we show in a rodent model that even moderate-level noise at ∼65 dB SPL that has little effect on stress status can substantially impair hippocampus-related learning and memory by altering the plasticity of synaptic transmission. It is possible that because moderately loud noise does not affect peripheral hearing per se, the negative impacts of chronic exposure to such noise are currently not well characterized. Our results indicate the importance of more thoroughly defining these possibly hitherto unappreciated hazards of noise pollution in modern human environments.

Aging of the auditory system is associated with the incremental production of reactive oxygen species (ROS) and the accumulation of oxidative damage in macromolecules, which contributes to cellular malfunction, compromises cell viability, and, ultimately, leads to functional decline. Cellular detoxification relies in part on the production of NADPH, which is an important cofactor for major cellular antioxidant systems. NADPH is produced principally by the housekeeping enzyme glucose‐6‐phosphate dehydrogenase (G6PD), which catalyzes the rate‐limiting step in the pentose phosphate pathway. We show here that G6PD transgenic mice ( G6PD ‐Tg), which show enhanced constitutive G6PD activity and NADPH production along life, have lower auditory thresholds than wild‐type mice during aging, together with preserved inner hair cell (IHC) and outer hair cell (OHC), OHC innervation, and a conserved number of synapses per IHC. Gene expression of antioxidant enzymes was higher in 3‐month‐old G6PD ‐Tg mice than in wild‐type counterparts, whereas the levels of pro‐apoptotic proteins were lower. Consequently, nitration of proteins, mitochondrial damage, and TUNEL + apoptotic cells were all lower in 9‐month‐old G6PD ‐Tg than in wild‐type counterparts. Unexpectedly, G6PD overexpression triggered low‐grade inflammation that was effectively resolved in young mice, as shown by the absence of cochlear cellular damage and macrophage infiltration. Our results lead us to propose that NADPH overproduction from an early stage is an efficient mechanism to maintain the balance between the production of ROS and cellular detoxification power along aging and thus prevents hearing loss progression.