Auditory Research publications

Background: Commonly encountered nontraumatic, moderate noise is increasingly implicated in anxiety; however, the neural substrates underlying this process remain unclear. Objectives: We investigated the neural circuit mechanism through which chronic exposure to moderate-level noise causes anxiety-like behaviors. Methods: Mice were exposed to chronic, moderate white noise [85 decibel (dB) sound pressure level (SPL)], 4 h/d for 4 wk to induce anxiety-like behaviors, which were assessed by open field, elevated plus maze, light-dark box, and social interaction tests. Viral tracing, immunofluorescence confocal imaging, and brain slice patch-clamp recordings were used to characterize projections from auditory brain regions to the lateral amygdala. Neuronal activities were characterized by in vivo multielectrode and fiber photometry recordings in awake mice. Optogenetics and chemogenetics were used to manipulate specific neural circuitry. Results: Mice chronically (4 wk) exposed to moderate noise (85 dB SPL, 4 h/d) demonstrated greater neuronal activity in the lateral amygdala (LA), and the LA played a critical role in noise-induced anxiety-like behavior in these model mice. Viral tracing showed that the LA received monosynaptic projections from the medial geniculate body (MG) and auditory cortex (ACx). Optogenetic excitation of the MG→LA or ACx→LA circuits acutely evoked anxiety-like behaviors, whereas their chemogenetic inactivation abolished noise-induced anxiety-like behavior. Moreover, mice chronically exposed to moderate noise were more susceptible to acute stress, with more neuronal firing in the LA, even after noise withdrawal. Discussion: Mice exposed to 4 wk of moderate noise (85 dB SPL, 4 h/d) demonstrated behavioral and physiological differences compared to controls. The neural circuit mechanisms involved greater excitation from glutamatergic neurons of the MG and ACx to LA neurons under chronic, moderate noise exposure, which ultimately promoted anxiety-like behaviors. Our findings support the hypothesis that nontraumatic noise pollution is a potentially serious but unrecognized public health concern. https://doi.org/10.1289/EHP12532.

Social learning (SL) through experience with conspecifics can facilitate the acquisition of many behaviors. Thus, when Mongolian gerbils are exposed to a demonstrator performing an auditory discrimination task, their subsequent task acquisition is facilitated, even in the absence of visual cues. Here, we show that transient inactivation of auditory cortex (AC) during exposure caused a significant delay in task acquisition during the subsequent practice phase, suggesting that AC activity is necessary for SL. Moreover, social exposure induced an improvement in AC neuron sensitivity to auditory task cues. The magnitude of neural change during exposure correlated with task acquisition during practice. In contrast, exposure to only auditory task cues led to poorer neurometric and behavioral outcomes. Finally, social information during exposure was encoded in the AC of observer animals. Together, our results suggest that auditory SL is supported by AC neuron plasticity occurring during social exposure and prior to behavioral performance.

Psilocybin and its active metabolite psilocin have been shown to elicit rapid and long-lasting symptom improvements in a variety of affective psychiatric illnesses. However, the region-specific alterations underlying these therapeutic effects remain relatively unknown. The central amygdala (CeA) is a primary output region within the extended amygdala that is dysregulated in affective psychiatric disorders. Here, we measured CeA activity using the activity marker c-Fos and CeA reactivity using fiber photometry paired with an aversive air-puff stimulus. We found that psilocin administration acutely increased CeA activity in both males and females and increased stimulus specific CeA reactivity in females, but not males. In contrast, psilocin produced time-dependent decreases in reactivity in males, but not in females, as early as 2 days and lasting to 28 days post administration. We also measured behavioral responses to the air-puff stimulus and found sex-dependent changes in threat responding but not exploratory behavior or general locomotion. Repeated presentations of the auditory component of the air-puff were also performed and sex-specific effects of psilocin on CeA reactivity to the auditory-alone stimulus were also observed. This study provides new evidence that a single dose of psilocin produces sex-specific, time-dependent, and enduring changes in CeA reactivity and behavioral responding to specific components of an aversive stimulus.

The process by which sensory evidence contributes to perceptual choices requires an understanding of its transformation into decision variables. Here, we address this issue by evaluating the neural representation of acoustic information in the auditory cortex-recipient parietal cortex, while gerbils either performed a two-alternative forced-choice auditory discrimination task or while they passively listened to identical acoustic stimuli. During task engagement, stimulus identity decoding performance from simultaneously recorded parietal neurons significantly correlated with psychometric sensitivity. In contrast, decoding performance during passive listening was significantly reduced. Principal component and geometric analyses revealed the emergence of low-dimensional encoding of linearly separable manifolds with respect to stimulus identity and decision, but only during task engagement. These findings confirm that the parietal cortex mediates a transition of acoustic representations into decision-related variables. Finally, using a clustering analysis, we identified three functionally distinct subpopulations of neurons that each encoded task-relevant information during separate temporal segments of a trial. Taken together, our findings demonstrate how parietal cortex neurons integrate and transform encoded auditory information to guide sound-driven perceptual decisions.

Animal research focused on chronic tinnitus associated with noise-induced hearing loss can be expensive and time-consuming as a result of the behavioral training required. Although there exist a number of behavioral tests for tinnitus; there have been few formal direct comparisons of these tests. Here, we evaluated animals in two different tinnitus assessment methods. CBA/CaJ mice were trained in an operant conditioning, active avoidance (AA) test, and a reflexive, gap-induced pre-pulse inhibition of acoustic startle (GPIAS) test, or both. Tinnitus was induced in awake mice by unilateral continuous sound exposure using a 2-kHz- or 1 2 octave-wide noise centered at 16 kHz and presented at 113- or 116-dB SPL. Tinnitus was assessed 8 weeks after sound overexposure. Most mice had evidence of tinnitus behavior in at least one of the two behaviors. Of the mice evaluated in AA, over half (55%) had tinnitus positive behavior. In GPIAS, fewer animals (13%) were positive than were identified using the AA test. Few mice were positive in both tests (10%), and only one was positive for tinnitus behavior at the same spectral frequency in both tests. When the association between tinnitus behavior and spontaneous activity recorded in the inferior colliculus was compared, animals with tinnitus behavior in AA exhibited increased spontaneous activity, while those positive in GPIAS did not. Thus, it appears that operant conditioning tests, like AA, maybe more reliable and accurate tests for tinnitus than reflexive tests.

The nucleus reuniens (RE) is necessary for memories dependent on the interaction between the medial prefrontal cortex (mPFC) and hippocampus (HPC). One example is trace eyeblink conditioning, in which the mPFC exhibits differential activity to neutral conditioned stimuli (CS) depending on their contingency with an aversive unconditioned stimulus (US). To test if this relevancy signal is routed to the RE, we photometrically recorded mPFC axon terminals within the RE and tracked their changes with learning. As a comparison, we measured prefrontal terminal activity in the mediodorsal thalamus (MD), which lacks connectivity with the HPC. In naïve male rats, prefrontal terminals within the RE were not strongly activated by tone or light. As the rats associated one of the stimuli (CS+) with the US, terminals gradually increased their response to the CS+ but not the other stimulus (CS-). In contrast, stimulus-evoked responses of prefrontal terminals within the MD were strong even before conditioning. They also became augmented only to the CS+ in the first conditioning session; however, the degree of activity differentiation did not improve with learning. These findings suggest that associative learning selectively increased mPFC output to the RE, signaling the behavioral relevance of sensory stimuli.

The inferior colliculus (IC) is at the midpoint of the auditory system and integrates virtually all information ascending from the auditory brainstem, organizes it, and transmits the results to the auditory forebrain. Its abundant, excitatory local connections are crucial for this task. This study describes a long duration sound (LDS)-induced potentiation in the IC that changes both subsequent tone-evoked responses and spontaneous activity. Afterdischarges, changes of spontaneous spiking following an LDS, were seen previously in single neurons. Here, we used multi-channel probes to record activity before and after a single, tetanic sound and describe the changes in a population of IC neurons. Following a 60 s narrowband-noise stimulation, a subset of recording channels (∼16%) showed afterdischarges. A facilitated response spike rate to tone pips following an LDS was also observed in ∼16% of channels. Both channels with an afterdischarge and channels with facilitated tone responses had higher firing rates in response to LDS, and the magnitude of the afterdischarges increased with increased responses to the LDS. This is the first study examining the effect of LDS stimulation on tone-evoked responses. This observed facilitation in vivo has similarities to post-tetanic potentiation in vitro as both manner of induction (strong stimulation for several seconds) as well as time-course of the facilitation (second to minute range) are comparable. Channels with and without facilitation appear to be intermixed and distributed widely in the central nucleus of IC, and this suggests a heretofore unknown property of some IC neurons or their circuits. Consequently, this sound-evoked facilitation may enhance the sound-evoked output of these neurons, while, simultaneously, most other IC neurons have reduced or unchanged output in response to the same stimulus.

The contactin-associated protein-like 2 gene, CNTNAP2, is a highly penetrant risk gene thought to play a role in the genetic etiology of language-related disorders, such as autism spectrum disorder and developmental language disorder. Despite its candidacy for influencing language development, few preclinical studies have examined the role of CNTNAP2 in auditory processing. Using in vivo and in vitro electrophysiological recordings in a rat model with translational validity, we report that a loss of the Cntnap2 gene function caused immature-like cortical evoked potentials, delayed multiunit response latencies to acoustic stimuli, impaired temporal processing, and led to a pattern of hyperexcitability in both multiunit and single cell recordings in adulthood. These collective results provide direct evidence that a constitutive loss of Cntnap2 gene function in rats can cause auditory processing impairments similar to those seen in language-related human disorders, indicating that its contribution in maintaining cortical neuron excitability may underlie the cortical activity alterations observed in Cntnap2−/− rats.

Sensory hypersensitivity, especially in the auditory system, is a common symptom in Fragile X syndrome (FXS), the most common monogenic form of intellectual disability. However, linking phenotypes across genetic background strains of mouse models has been a challenge and could underly some of the issues with translatability of drug studies to the human condition. This study is the first to characterize the auditory brain stem response (ABR), a minimally invasive physiological readout of early auditory processing that is also used in humans, in a commonly used mouse background strain model of FXS, C57BL/6J. We measured morphological features of pinna and head and used ABR to measure the hearing range, and monaural and binaural auditory responses in hemizygous males, homozygous females, and heterozygous females compared with those in wild-type mice. Consistent with previous study, we showed no difference in morphological parameters across genotypes or sexes. There was no significant difference in hearing range between the sexes or genotypes, however there was a trend towards high frequency hearing loss in male FXS mice. In contrast, female mice with homozygous FXS had a decreased amplitude of wave IV of the monaural ABR, while there was no difference in males for amplitudes and no change in latency of ABR waveforms across sexes and genotypes. Finally, males with FXS had an increased latency of the binaural interaction component (BIC) at 0 interaural timing difference compared with that in wild-type males. These findings further clarify auditory brain stem processing in FXS by adding more information across genetic background strains allowing for a better understanding of shared phenotypes.

Offset responses in auditory processing appear after a sound terminates. They arise in neuronal circuits within the peripheral auditory system, but their role in the central auditory system remains unknown. Here, we ask what the behavioral relevance of cortical offset responses is and what circuit mechanisms drive them. At the perceptual level, our results reveal that experimentally minimizing auditory cortical offset responses decreases the mouse performance to detect sound termination, assigning a behavioral role to offset responses. By combining in vivo electrophysiology in the auditory cortex and thalamus of awake mice, we also demonstrate that cortical offset responses are not only inherited from the periphery but also amplified and generated de novo. Finally, we show that offset responses code more than silence, including relevant changes in sound trajectories. Together, our results reveal the importance of cortical offset responses in encoding sound termination and detecting changes within temporally discontinuous sounds crucial for speech and vocalization.

Obesity remains prevalent in the US. One potential treatment is vagus nerve stimulation (VNS), which activates the sensory afferents innervating the stomach that convey stomach volume and establish satiety. However, current VNS approaches and stimulus optimization could benefit from additional understanding of the underlying neural response to stomach distension. In this study, obesity-prone Sprague Dawley rats consumed a standard, high-carbohydrate, or high-fat diet for several months, leading to diet-induced obesity in the latter two groups. Under anesthesia, the neural activity in the vagus nerve was recorded with a penetrating microelectrode array while the stomach was distended with an implanted balloon. Vagal tone during distension was compared to baseline tone prior to distension. Responses were strongly correlated with stomach distension, but the sensitivity to distension was significantly lower in animals that had been fed the nonstandard diets. The results indicate that both high fat and high carbohydrate diets impair vagus activity.

Brain injury affecting the isocortical frontal cortex is a common pathological occurrence. Many patients report severe deficits to functions of daily living. However, there is a variable degree of motor recovery that occurs with some individuals recovering astounding degrees of motor recovery while others have not. This variability has led researchers into investigating the possible mechanisms for this variability. Recently, several non-human primate studies have shed light on the possibility of spared, ipsilesional motor area taken over the lost function to the damaged cortex. Unfortunately, these studies have focused on long-term adaption ranging from 5months to one year post injury. In this present study, we are the first use rigorous stereological quantification to show that significant neuroplastic changes in the form of changes to neuroanatomical connections between distant cortical area occurs at a very early time point of 4 weeks post injury. Much like the Dancause study in 2005, we found that ishemic damage to the distal forelimb area (DFL) of the primary motor cortex (M1) induced plastic changes between the DFL of the ventral premotor cortex (PMv) and area 1/2 of the somatosensory cortex. Indeed, we found a nearly 2 fold increase in the number of boutons between PMV and area 1/2. Additionally, labeled fibers from PMv change direction from their normal termination within M1 and traveled in a ventral posterior direction toward the somatosensory cortex. Also of interest, several labeled fibers actually traveled through the glial scar of M1 toward the somatosensory cortex. These data demonstrate that a massive neuroplastic response has occurred following an ischemic insult to the DFL of M1. These data may suggest that the brain may be undergoing an attempt to re-establish a degree of motor and or sensory control to compensate for the lost function due to the injury.

The auditory brainstem compares sound-evoked excitation and inhibition from both ears to compute sound source location and determine spatial acuity. Although alterations to the anatomy and physiology of the auditory brainstem have been demonstrated in fragile X syndrome (FXS), it is not known whether these changes cause spatial acuity deficits in FXS. To test the hypothesis that FXS-related alterations to brainstem circuits impair spatial hearing abilities, a reflexive prepulse inhibition (PPI) task, with variations in sound (gap, location, masking) as the prepulse stimulus, was used on Fmr1 knock-out mice and B6 controls. Specifically, Fmr1 mice show decreased PPI compared with wild-type mice during gap detection, changes in sound source location, and spatial release from masking with no alteration to their overall startle thresholds compared with wild-type mice. Last, Fmr1 mice have increased latency to respond in these tasks, suggesting additional impairments in the pathway responsible for reacting to a startling sound. This study further supports data in humans with FXS that show similar deficits in PPI.

Neuronal circuits are shaped by experience during time windows of increased plasticity in postnatal development. In the auditory system, the critical period for the simplest sounds—pure frequency tones—is well defined. Critical periods for more complex sounds remain to be elucidated. We used in vivo electrophysiological recordings in the mouse auditory cortex to demonstrate that passive exposure to frequency modulated sweeps (FMS) from postnatal day 31 to 38 leads to long-term changes in the temporal representation of sweep directions. Immunohistochemical analysis revealed a decreased percentage of layer 4 parvalbumin-positive (PV+) cells during this critical period, paralleled with a transient increase in responses to FMS, but not to pure tones. Preventing the PV+ cell decrease with continuous white noise exposure delayed the critical period onset, suggesting a reduction in inhibition as a mechanism for this plasticity. Our findings shed new light on the dependence of plastic windows on stimulus complexity that persistently sculpt the functional organization of the auditory cortex.

Although information theoretic approaches have been used extensively in the analysis of the neural code, they have yet to be used to describe how information is accumulated in time while sensory systems are categorizing dynamic sensory stimuli such as speech sounds or visual objects. Here, we present a novel method to estimate the cumulative information for stimuli or categories. We further define a time-varying categorical information index that, by comparing the information obtained for stimuli versus categories of these same stimuli, quantifies invariant neural representations. We use these methods to investigate the dynamic properties of avian cortical auditory neurons recorded in zebra finches that were listening to a large set of call stimuli sampled from the complete vocal repertoire of this species. We found that the time-varying rates carry 5 times more information than the mean firing rates even in the first 100 ms. We also found that cumulative information has slow time constants (100-600 ms) relative to the typical integration time of single neurons, reflecting the fact that the behaviorally informative features of auditory objects are time-varying sound patterns. When we correlated firing rates and information values, we found that average information correlates with average firing rate but that higher-rates found at the onset response yielded similar information values as the lower-rates found in the sustained response: the onset and sustained response of avian cortical auditory neurons provide similar levels of independent information about call identity and call-type. Finally, our information measures allowed us to rigorously define categorical neurons; these categorical neurons show a high degree of invariance for vocalizations within a call-type. Peak invariance is found around 150 ms after stimulus onset. Surprisingly, call-type invariant neurons were found in both primary and secondary avian auditory areas.

Vocal learners use early social experience to develop auditory skills specialized for communication. However, it is unknown where in the auditory pathway neural responses become selective for vocalizations or how the underlying encoding mechanisms change with experience. We used a vocal tutoring manipulation in two species of songbird to reveal that tuning for conspecific song arises within the primary auditory cortical circuit. Neurons in the deep region of primary auditory cortex responded more to conspecific songs than to other species' songs and more to species-typical spectrotemporal modulations, but neurons in the intermediate (thalamorecipient) region did not. Moreover, birds that learned song from another species exhibited parallel shifts in selectivity and tuning toward the tutor species' songs in the deep but not the intermediate region. Our results locate a region in the auditory processing hierarchy where an experience-dependent coding mechanism aligns auditory responses with the output of a learned vocal motor behavior.

In the rodent auditory system, the primary cortex is subdivided into two regions, both receiving direct inputs from the auditory thalamus: the primary auditory cortex (A1) and the anterior auditory field (AAF). Although neurons in the two regions display different response properties, like response latency, firing threshold or tuning bandwidth, it is still not clear whether they process sound in a distinct way. Using in vivo electrophysiological recordings in the mouse auditory cortex, we found that AAF neurons have significantly stronger responses to tone offset than A1 neurons. AAF neurons also display faster and more transient responses than A1 neurons. Additionally, offset responses in AAF – unlike in A1, increase with sound duration. Local field potential (LFP) and laminar analyses suggest that the differences in sound responses between these two primary cortices are both of subcortical and intracortical origin. These results emphasize the potentially critical role of AAF for temporal processing. Our study reveals a distinct role of two primary auditory cortices in tone processing and highlights the complexity of sound encoding at the cortical level.

Cortical layers (L) 5 and 6 are populated by intermingled cell-types with distinct inputs and downstream targets. Here, we made optogenetically guided recordings from L5 corticofugal (CF) and L6 corticothalamic (CT) neurons in the auditory cortex of awake mice to discern differences in sensory processing and underlying patterns of functional connectivity. Whereas L5 CF neurons showed broad stimulus selectivity with sluggish response latencies and extended temporal non-linearities, L6 CTs exhibited sparse selectivity and rapid temporal processing. L5 CF spikes lagged behind neighboring units and imposed weak feedforward excitation within the local column. By contrast, L6 CT spikes drove robust and sustained activity, particularly in local fast-spiking interneurons. Our findings underscore a duality among sub-cortical projection neurons, where L5 CF units are canonical broadcast neurons that integrate sensory inputs for transmission to distributed downstream targets, while L6 CT neurons are positioned to regulate thalamocortical response gain and selectivity.

Fifty percent of inner ear disorders are caused by genetic mutations. To develop treatments for genetic inner ear disorders, we designed gene replacement therapies using synthetic adeno-associated viral vectors to deliver the coding sequence for Transmembrane Channel-Like ( Tmc ) 1 or 2 into sensory hair cells of mice with hearing and balance deficits due to mutations in Tmc1 and closely related Tmc2 . Here we report restoration of function in inner and outer hair cells, enhanced hair cell survival, restoration of cochlear and vestibular function, restoration of neural responses in auditory cortex and recovery of behavioral responses to auditory and vestibular stimulation. Secondarily, we find that inner ear Tmc gene therapy restores breeding efficiency, litter survival and normal growth rates in mouse models of genetic inner ear dysfunction. Although challenges remain, the data suggest that Tmc gene therapy may be well suited for further development and perhaps translation to clinical application.

Tinnitus and hyperacusis are life-disrupting perceptual abnormalities that are often preceded by acoustic overexposure. Animal models of overexposure have suggested a link between these phenomena and neural hyperactivity, i.e., elevated spontaneous rates (SRs) and sound-evoked responses. Prior work has focused on changes in central auditory responses, with less attention paid to the exact nature of the associated cochlear damage. The demonstration that acoustic overexposure can cause cochlear neuropathy without permanent threshold elevation suggests cochlear neuropathy per se may be a key elicitor of neural hyperactivity. We addressed this hypothesis by recording responses in the mouse inferior colliculus (IC) following a bilateral, neuropathic noise exposure. One to three weeks post-exposure, mean SRs were unchanged in mice recorded while awake, or under anesthesia. SRs were also unaffected by more intense, or unilateral exposures. These results suggest that neither neuropathy nor hair cell loss are sufficient to raise SRs in the IC, at least in 7-week-old mice, 1-3 weeks post exposure. However, it is not clear whether our mice had tinnitus. Tone-evoked rate-level functions at the CF were steeper following exposure, specifically in the region of maximal neuropathy. Furthermore, suppression driven by off-CF tones and by ipsilateral noise were reduced. Both changes were especially pronounced in neurons of awake mice. This neural hypersensitivity may manifest as behavioral hypersensitivity to sound - prior work reports that this same exposure causes elevated acoustic startle. Together, these results indicate that neuropathy may initiate a compensatory response in the central auditory system leading to the genesis of hyperacusis.