Abstract Subjective tinnitus is the most common auditory phantom perception in the absence of an acoustic stimulus yet there is no cure nor widely effective treatment to date. Previously, we suggested that sleep may contribute to tinnitus development after a triggering event, such as noise overexposure (NOE). Here, we investigated the effect of natural sleep on tinnitus development following NOE in mice. One group of mice was kept awake for 6 hours immediately after NOE, whereas a control group could sleep ad libitum . Tinnitus and hearing loss were assessed before and after NOE by determining gap prepulse inhibition of the acoustic startle reflex (GPIAS) and by recording auditory brainstem responses (ABRs). Only mice that were allowed to sleep in the first six hours after NOE developed a significant change in the GPIAS ratio one week after NOE, indicative of tinnitus. Habituation to the startle stimulus was largely similar between both groups, except that at eight weeks after NOE, when GPIAS ratio had returned to baseline levels in both groups, the sleep deprived group showed less habituation to the startle stimulus. Notably, animals in neither group showed significantly elevated ABR thresholds after NOE, yet the control group showed signs of elevated evoked activity in the auditory brainstem one week after NOE. These findings demonstrate that sleep early after noise overexposure may amplify subsequent tinnitus development. Our results suggest that sleep represents a temporal window that may be harnessed for potential modulation or mitigation of noise-induced hearing loss and tinnitus-related impairments.

N,N-Diisopropyltryptamine (DiPT) is a frequency-selective pitch-distorting psychedelic drug that induces a downward shift in perception where the auditory world of the subject sounds lower in pitch than in a sober state of consciousness. Hurst and Bajo propose the neural mechanisms for this effect and its use as potential therapeutic for tinnitus.

Background: In the auditory domain, temporal resolution is the ability to respond to rapid changes in the envelope of a sound over time. Silent gap-in-noise detection tests assess temporal resolution. Whether temporal resolution is impaired in tinnitus and whether those tests are useful for identifying the condition is still debated. We have revisited these questions by assessing the silent gap-in-noise detection performance of human participants. Methods: Participants were seventy-one young adults with normal hearing, separated into preliminary, tinnitus and matched-control groups. A preliminary group (n = 18) was used to optimise the silent gap-in-noise detection two-alternative forced-choice paradigm by examining the effect of the position and the salience of the gap. Temporal resolution was tested in case-control observational study of tinnitus (n = 20) and matched-control (n = 33) groups using the previously optimized silent gap-in-noise behavioral paradigm. These two groups were also tested using silent gap prepulse inhibition of the auditory startle reflex (GPIAS) and Auditory Brain Responses (ABRs). Results: In the preliminary group, reducing the predictability and saliency of the silent gap increased detection thresholds and reduced gap detection sensitivity (slope of the psychometric function). In the case-control study, tinnitus participants had higher gap detection thresholds than controls for narrowband noise stimuli centred at 2 and 8 kHz, with no differences in GPIAS or ABRs. In addition, ABR data showed latency differences across the different tinnitus subgroups stratified by subject severity. Conclusions: Operant silent gap-in-noise detection is impaired in tinnitus when the paradigm is optimized to reduce the predictability and saliency of the silent gap and to avoid the ceiling effect. Our behavioral paradigm can distinguish tinnitus and control groups suggesting that temporal resolution is impaired in tinnitus. However, in young adults with normal hearing, the paradigm is unable to objectively identify tinnitus at the individual level. The GPIAS paradigm was unable to differentiate the tinnitus and control groups, suggesting that operant, as opposed to reflexive, silent gap-in-noise detection is a more sensitive measure for objectively identifying tinnitus.

Subjective tinnitus is a phantom auditory perception in the absence of an actual acoustic stimulus that affects 15% of the global population. In humans, tinnitus is often associated with disturbed sleep and, interestingly, there is an overlap between the brain areas involved in tinnitus and regulation of NREM sleep. We used eight adult ferrets exposed to mild noise trauma as an animal model of tinnitus. We assessed the phantom percept using two operant paradigms sensitive to tinnitus, silent gap detection and silence detection, before and, in a subset of animals, up to six months after the mild acoustic trauma. The integrity of the auditory brainstem was assessed over the same period using auditory brainstem response recordings. Following noise overexposure, ferrets developed lasting, frequency-specific impairments in operant behaviour and evoked brainstem activity. To explore the interaction between sleep and tinnitus, in addition to tracking the behavioural markers of noise-induced tinnitus and hearing impairment after noise overexposure, we evaluated sleep-wake architecture and spontaneous and auditory-evoked EEG activity across vigilance states. Behavioural performance and auditory-evoked activity measurements after noise overexposure suggested distinct degrees of tinnitus and hearing impairment between individuals. Animals that developed signs of tinnitus consistently developed sleep impairments, suggesting a link between the emergence of noise-induced hearing loss and/or tinnitus and sleep disruption. However, neural markers of tinnitus were reduced during sleep, suggesting that sleep may transiently mitigate tinnitus. These results reveal the importance of sleep-wake states in tinnitus and suggest that understanding the neurophysiological link between sleep and tinnitus may provide a new angle for research into the causes of phantom percepts and inform future treatments.

Cortical acetylcholine (ACh) release has been linked to various cognitive functions, including perceptual learning. We have previously shown that cortical cholinergic innervation is necessary for accurate sound localization in ferrets, as well as for their ability to adapt with training to altered spatial cues. To explore whether these behavioral deficits are associated with changes in the response properties of cortical neurons, we recorded neural activity in the primary auditory cortex (A1) of anesthetized ferrets in which cholinergic inputs had been reduced by making bilateral injections of the immunotoxin ME20.4-SAP in the nucleus basalis (NB) prior to training the animals. The pattern of spontaneous activity of A1 units recorded in the ferrets with cholinergic lesions (NB ACh-) was similar to that in controls, although the proportion of burst-type units was significantly lower. Depletion of ACh also resulted in more synchronous activity in A1. No changes in thresholds, frequency tuning or in the distribution of characteristic frequencies were found in these animals. When tested with normal acoustic inputs, the spatial sensitivity of A1 neurons in the NB ACh- ferrets and the distribution of their preferred interaural level differences also closely resembled those found in control animals, indicating that these properties had not been altered by sound localization training with one ear occluded. Simulating the animals' previous experience with a virtual earplug in one ear reduced the contralateral preference of A1 units in both groups, but caused azimuth sensitivity to change in slightly different ways, which may reflect the modest adaptation observed in the NB ACh- group. These results show that while ACh is required for behavioral adaptation to altered spatial cues, it is not required for maintenance of the spectral and spatial response properties of A1 neurons.

Abstract The medial geniculate body (MGB) or auditory thalamus comprises both first-order and higher-order subdivisions, each of which has a distinct pattern of thalamocortical connections. Pyramidal neurons in layer 6 link each area of the auditory cortex with the region of the thalamus from which it receives most of its ascending input, forming a series of modulatory feedback loops, whereas layer 5 pyramidal neurons have non-reciprocal corticothalamic projections that may be involved in transferring information between cortical areas. Although auditory corticothalamic pathways have been described in detail anatomically, their physiological properties are less well understood. Stimulation or deactivation of these cortical projections can alter the way MGB neurons respond to sound, effects that are mediated through a combination of their direct excitatory inputs and disynaptic inhibition via the thalamic reticular nucleus. It seems likely that corticothalamic modulation allows the sensitivity and selectivity of thalamocortical neurons in the MGB to be dynamically updated, shaping their responses depending on the behavioral and sensory context in which particular sounds are heard. The availability of methods for targeting specific populations of projection neurons during behavior is starting to reveal the crucial role these descending circuits play in auditory learning, active listening, and in the way the brain adjusts to the degraded inputs associated with hearing loss.

IntroductionSound localization relies on the neural processing of binaural and monaural spatial cues generated by the physical properties of the head and body. Hearing loss in one ear compromises binaural computations, impairing the ability to localize sounds in the horizontal plane. With appropriate training, adult individuals can adapt to this binaural imbalance and largely recover their localization accuracy. However, it remains unclear how long this learning is retained or whether it generalizes to other stimuli.MethodsWe trained ferrets to localize broadband noise bursts in quiet conditions and measured their initial head orienting responses and approach-to-target behavior. To evaluate the persistence of auditory spatial learning, we tested the sound localization performance of the animals over repeated periods of monaural earplugging that were interleaved with short or long periods of normal binaural hearing. To explore learning generalization to other stimulus types, we measured the localization accuracy before and after adaptation using different bandwidth stimuli presented against constant or amplitude-modulated background noise.ResultsRetention of learning resulted in a smaller initial deficit when the same ear was occluded on subsequent occasions. Each time, the animals’ performance recovered with training to near pre-plug levels of localization accuracy. By contrast, switching the earplug to the contralateral ear resulted in less adaptation, indicating that the capacity to learn a new strategy for localizing sound is more limited if the animals have previously adapted to conductive hearing loss in the opposite ear. Moreover, the degree of adaptation to the training stimulus for individual animals was significantly correlated with the extent to which learning extended to untrained octave band target sounds presented in silence and to broadband targets presented in background noise, suggesting that adaptation and generalization go hand in hand.ConclusionsTogether, these findings provide further evidence for plasticity in the weighting of monaural and binaural cues during adaptation to unilateral conductive hearing loss, and show that the training-dependent recovery in spatial hearing can generalize to more naturalistic listening conditions, so long as the target sounds provide sufficient spatial information.

Sensory disconnection from the environment is a hallmark of sleep and is crucial for sleep maintenance. It remains unclear, however, whether internally generated percepts-phantom percepts-may overcome such disconnection and, in turn, how sleep and its effect on sensory processing and brain plasticity may affect the function of the specific neural networks underlying such phenomena. A major hurdle in addressing this relationship is the methodological difficulty to study sensory phantoms, due to their subjective nature and lack of control over the parameters or neural activity underlying that percept. Here, we explore the most prevalent phantom percept, subjective tinnitus-or tinnitus for short-as a model to investigate this. Tinnitus is the permanent perception of a sound with no identifiable corresponding acoustic source. This review offers a novel perspective on the functional interaction between brain activity across the sleep-wake cycle and tinnitus. We discuss characteristic features of brain activity during tinnitus in the awake and the sleeping brain and explore its effect on sleep functions and homeostasis. We ask whether local changes in cortical activity in tinnitus may overcome sensory disconnection and prevent the occurrence of global restorative sleep and, in turn, how accumulating sleep pressure may temporarily alleviate the persistence of a phantom sound. Beyond an acute interaction between sleep and neural activity, we discuss how the effects of sleep on brain plasticity may contribute to aberrant neural circuit activity and promote tinnitus consolidation. Tinnitus represents a unique window into understanding the role of sleep in sensory processing. Clarification of the underlying relationship may offer novel insights into therapeutic interventions in tinnitus management.

Sensory disconnection from the environment is a hallmark of sleep and is crucial for sleep maintenance. It remains unclear, however, whether internally generated percepts-phantom percepts-may overcome such disconnection and, in turn, how sleep and its effect on sensory processing and brain plasticity may affect the function of the specific neural networks underlying such phenomena. A major hurdle in addressing this relationship is the methodological difficulty to study sensory phantoms, due to their subjective nature and lack of control over the parameters or neural activity underlying that percept. Here, we explore the most prevalent phantom percept, subjective tinnitus-or tinnitus for short-as a model to investigate this. Tinnitus is the permanent perception of a sound with no identifiable corresponding acoustic source. This review offers a novel perspective on the functional interaction between brain activity across the sleep-wake cycle and tinnitus. We discuss characteristic features of brain activity during tinnitus in the awake and the sleeping brain and explore its effect on sleep functions and homeostasis. We ask whether local changes in cortical activity in tinnitus may overcome sensory disconnection and prevent the occurrence of global restorative sleep and, in turn, how accumulating sleep pressure may temporarily alleviate the persistence of a phantom sound. Beyond an acute interaction between sleep and neural activity, we discuss how the effects of sleep on brain plasticity may contribute to aberrant neural circuit activity and promote tinnitus consolidation. Tinnitus represents a unique window into understanding the role of sleep in sensory processing. Clarification of the underlying relationship may offer novel insights into therapeutic interventions in tinnitus management.

Sound information is transmitted from the ear to central auditory stations of the brain via several nuclei. In addition to these ascending pathways there exist descending projections that can influence the information processing at each of these nuclei. A major descending pathway in the auditory system is the feedback projection from layer VI of the primary auditory cortex (A1) to the ventral division of medial geniculate body (MGBv) in the thalamus. The corticothalamic axons have small glutamatergic terminals that can modulate thalamic processing and thalamocortical information transmission. Corticothalamic neurons also provide input to GABAergic neurons of the thalamic reticular nucleus (TRN) that receives collaterals from the ascending thalamic axons. The balance of corticothalamic and TRN inputs has been shown to refine frequency tuning, firing patterns, and gating of MGBv neurons. Therefore, the thalamus is not merely a relay stage in the chain of auditory nuclei but does participate in complex aspects of sound processing that include top-down modulations. In this review, we aim (i) to examine how lemniscal corticothalamic feedback modulates responses in MGBv neurons, and (ii) to explore how the feedback contributes to auditory scene analysis, particularly on frequency and harmonic perception. Finally, we will discuss potential implications of the role of corticothalamic feedback in music and speech perception, where precise spectral and temporal processing is essential.

For decades, the corticofugal descending projections have been anatomically well described but their functional role remains a puzzling question. In this review, we will first describe the contributions of neuronal networks in representing communication sounds in various types of degraded acoustic conditions from the cochlear nucleus to the primary and secondary auditory cortex. In such situations, the discrimination abilities of collicular and thalamic neurons are clearly better than those of cortical neurons although the latter remain very little affected by degraded acoustic conditions. Second, we will report the functional effects resulting from activating or inactivating corticofugal projections on functional properties of subcortical neurons. In general, modest effects have been observed in anesthetized and in awake, passively listening, animals. In contrast, in behavioral tasks including challenging conditions, behavioral performance was severely reduced by removing or transiently silencing the corticofugal descending projections. This suggests that the discriminative abilities of subcortical neurons may be sufficient in many acoustic situations. It is only in particularly challenging situations, either due to the task difficulties and/or to the degraded acoustic conditions that the corticofugal descending connections bring additional abilities. Here, we propose that it is both the top-down influences from the prefrontal cortex, and those from the neuromodulatory systems, which allow the cortical descending projections to impact behavioral performance in reshaping the functional circuitry of subcortical structures. We aim at proposing potential scenarios to explain how, and under which circumstances, these projections impact on subcortical processing and on behavioral responses.

Integration of information across the senses is critical for perception and is a common property of neurons in the cerebral cortex, where it is thought to arise primarily from corticocortical connections. Much less is known about the role of subcortical circuits in shaping the multisensory properties of cortical neurons. We show that stimulation of the whiskers causes widespread suppression of sound-evoked activity in mouse primary auditory cortex (A1). This suppression depends on the primary somatosensory cortex (S1), and is implemented through a descending circuit that links S1, via the auditory midbrain, with thalamic neurons that project to A1. Furthermore, a direct pathway from S1 has a facilitatory effect on auditory responses in higher-order thalamic nuclei that project to other brain areas. Crossmodal corticofugal projections to the auditory midbrain and thalamus therefore play a pivotal role in integrating multisensory signals and in enabling communication between different sensory cortical areas.

Neural adaptation enables sensory information to be represented optimally in the brain despite large fluctuations over time in the statistics of the environment. Auditory contrast gain control represents an important example, which is thought to arise primarily from cortical processing. We find, however, that neurons in both the auditory thalamus and midbrain of mice show robust contrast gain control, and that this is implemented independently of cortical activity. Although neurons at each level exhibit contrast gain control to similar degrees, adaptation time constants become longer at later stages of the processing hierarchy, resulting in progressively more stable representations. We also show that auditory discrimination thresholds in human listeners compensate for changes in contrast, and that the strength of this perceptual adaptation can be predicted from physiological measurements. Contrast adaptation is therefore a robust property of both the subcortical and cortical auditory system and accounts for the short-term adaptability of perceptual judgments.

Neural adaptation enables sensory information to be represented optimally in the brain despite large fluctuations over time in the statistics of the environment. Auditory contrast gain control represents an important example, which is thought to arise primarily from cortical processing. Here we show that neurons in the auditory thalamus and midbrain of mice show robust contrast gain control, and that this is implemented independently of cortical activity. Although neurons at each level exhibit contrast gain control to similar degrees, adaptation time constants become longer at later stages of the processing hierarchy, resulting in progressively more stable representations. We also show that auditory discrimination thresholds in human listeners compensate for changes in contrast, and that the strength of this perceptual adaptation can be predicted from physiological measurements. Contrast adaptation is therefore a robust property of both the subcortical and cortical auditory system and accounts for the short-term adaptability of perceptual judgments.

The brain has a remarkable capacity to adapt to changes in sensory inputs and to learn from experience. However, the neural circuits responsible for this flexible processing remain poorly understood. Using optogenetic silencing of ArchT-expressing neurons in adult ferrets, we show that within-trial activity in primary auditory cortex (A1) is required for training-dependent recovery in sound-localization accuracy following monaural deprivation. Because localization accuracy under normal-hearing conditions was unaffected, this highlights a specific role for cortical activity in learning. A1-dependent plasticity appears to leave a memory trace that can be retrieved, facilitating adaptation during a second period of monaural deprivation. However, in ferrets in which learning was initially disrupted by perturbing A1 activity, subsequent optogenetic suppression during training no longer affected localization accuracy when one ear was occluded. After the initial learning phase, the reweighting of spatial cues that primarily underpins this plasticity may therefore occur in A1 target neurons.

Ray Guillery was a neuroscientist known primarily for his ground-breaking studies on the development of the visual pathways and subsequently on the nature of thalamocortical processing loops. The legacy of his work, however, extends well beyond the visual system. Thanks to Ray Guillery's pioneering anatomical studies, the ferret has become a widely used animal model for investigating the development and plasticity of sensory processing. This includes our own work on the auditory system, where experiments in ferrets have revealed the role of sensory experience during development in shaping the neural circuits responsible for sound localization, as well as the capacity of the mature brain to adapt to changes in inputs resulting from hearing loss. Our research has also built on Ray Guillery's ideas about the possible functions of the massive descending projections that link sensory areas of the cerebral cortex to the thalamus and other subcortical targets, by demonstrating a role for corticothalamic feedback in the perception of complex sounds and for corticollicular projection neurons in learning to accommodate altered auditory spatial cues. Finally, his insights into the organization and functions of transthalamic corticocortical connections have inspired a raft of research, including by our own laboratory, which has attempted to identify how information flows through the thalamus.

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.

Enhanced detection and discrimination, along with faster reaction times, are the most typical behavioural manifestations of the brain's capacity to integrate multisensory signals arising from the same object. In this study, we examined whether multisensory behavioural gains are observable across different components of the localization response that are potentially under the command of distinct brain regions. We measured the ability of ferrets to localize unisensory (auditory or visual) and spatiotemporally coincident auditory-visual stimuli of different durations that were presented from one of seven locations spanning the frontal hemifield. During the localization task, we recorded the head movements made following stimulus presentation, as a metric for assessing the initial orienting response of the ferrets, as well as the subsequent choice of which target location to approach to receive a reward. Head-orienting responses to auditory-visual stimuli were more accurate and faster than those made to visual but not auditory targets, suggesting that these movements were guided principally by sound alone. In contrast, approach-to-target localization responses were more accurate and faster to spatially congruent auditory-visual stimuli throughout the frontal hemifield than to either visual or auditory stimuli alone. Race model inequality analysis of head-orienting reaction times and approach-to-target response times indicates that different processes, probability summation and neural integration, respectively, are likely to be responsible for the effects of multisensory stimulation on these two measures of localization behaviour.

The harmonic structure of sounds is an important grouping cue in auditory scene analysis. The ability of ferrets to detect mistuned harmonics was measured using a go/no-go task paradigm. Psychometric functions plotting sensitivity as a function of degree of mistuning were used to evaluate behavioral performance using signal detection theory. The mean (± standard error of the mean) threshold for mistuning detection was 0.8 ± 0.1 Hz, with sensitivity indices and reaction times depending on the degree of mistuning. These data provide a basis for investigation of the neural basis for the perception of complex sounds in ferrets, an increasingly used animal model in auditory research.