Psychoacoustics publications

Optogenetic stimulation is widely used to establish causal links between neural activity, behavior, and sensory perception, yet animals may also perceive the neural stimulation itself, a phenomenon termed “optoception.” We hypothesized that cortical optogenetic stimulation would generate an artificial percept that could be distinguished from externally evoked sensations and characterized psychometrically in an operant task. We tested this hypothesis using mesoscale cortical photostimulation delivered by a 3 mm, 459 nm LED implanted over auditory cortex. Four mice expressing Channelrhodopsin-2 (ChR2) in excitatory neurons learned a head-fixed go/no-go task in which 20 Hz cortical photostimulation served as the target. ChR2-positive mice detected cortical photostimulation relative to LED-off catch trials, distinguished it from both an external LED matched in wavelength and pulse rate and from an acoustic noise matched in amplitude-modulation rate, and discriminated between 20- and 10-Hz cortical photostimulation. Reducing implanted-LED optical power initially lowered rate-discrimination sensitivity, which then increased across training sessions, demonstrating perceptual learning. In two mice tested with 11 randomly interleaved rates spanning 10-20 Hz, lick probability followed a saturating rate-dependent function. Two ChR2-negative littermates failed to acquire photostimulation-locked behavioral responding. Together, these findings show that mesoscale cortical optogenetic stimulation generates a graded, learnable artificial percept whose behavioral readout depends on photostimulation rate and optical power. This single-LED preparation provides a cost-efficient and wavelength-extensible platform for psychometric analysis of optoception. SIGNIFICANCE STATEMENT Optogenetic stimulation can alter sensory processing, but the neural perturbation itself may also become a perceptual cue. We show that mice detect mesoscale cortical photostimulation delivered by a 3 mm implanted LED, distinguish it from matched external light and sound, and discriminate differences in photostimulation rate. When implanted-LED optical power was reduced, discrimination sensitivity initially declined and then increased across training sessions, revealing perceptual learning of optoception. Thus, mesoscale cortical photostimulation generates a graded internal signal whose behavioral readout depends on stimulation rate, optical power, and experience. A single implanted LED provides a cost- efficient and wavelength-extensible assay for measuring optogenetic perception.

Cochlear damage triggers compensatory primary auditory cortex (A1) plasticity that amplifies responses to residual sensory inputs, thereby contributing to the restoration of both cortical responsiveness to sound and perceptual sound detection threshold. However, this adaptation can become maladaptive, producing neuronal hyperactivity that contributes to tinnitus and hyperacusis. The neuromodulatory mechanisms governing these adaptive and maladaptive changes remain unknown. Here, we demonstrate that noise-induced cochlear injury triggers bidirectional synaptic zinc signaling plasticity that potentiates activity in excitatory principal neurons and parvalbumin-expressing interneurons, while suppressing activity in somatostatin-expressing interneurons. These cell-type-specific effects of synaptic zinc plasticity contribute to restoring A1 responsiveness to sound and perceptual detection thresholds, while being necessary for neural hyperactivity. Together, our findings establish synaptic zinc as a pivotal neuromodulator that shapes both adaptive and maladaptive cortical plasticity and identify a promising therapeutic target for improving perceptual recovery after cochlear damage and mitigating tinnitus and hyperacusis.

Through learning and memory, the cortex dynamically forms sensory associations to guide our behavior in an ever-changing environment. How memory-related brain regions, such as the medial-temporal lobe, influence sensory cortex to support this process remains unclear. Here, we used two-photon calcium imaging of axonal projections from the perirhinal (PRh) cortex to the auditory cortex during learning and generalization of an auditory discrimination task. PRh input in the auditory cortex increased during learning and influenced performance in a categorization task. Chemogenetically silencing PRh input selectively disrupted the activity of auditory cortex layer 2/3 pyramidal neurons, and PRh photoactivation drove behavior toward overgeneralization. These findings highlight PRh input as a key modulatory pathway that shapes cortical dynamics underlying auditory learning and memory-guided sensory perception.

Pitch perception is fundamental to speech and music, yet the neural representation of pitch in auditory cortex remains poorly understood. We hypothesized that mice rely on temporal cues for pitch perception because of their wide auditory filters and high-frequency hearing. To investigate, we developed a mouse auditory filter bank model that estimates the temporal pitch salience of complex tones. We then trained mice to discriminate low vs. high fundamental frequencies (F0s) in complex tones and found that modeled temporal pitch salience was highly correlated with behavioral discrimination sensitivity. Widefield calcium imaging showed that the organization of periodotopy in auditory cortex predicts how well mice recognize temporal pitch cues. Mice trained on an F0 discrimination task had larger periodotopic maps with greater vector strengths than naïve mice, demonstrating experience-dependent expansion and refinement of temporal pitch maps in auditory cortex. Our findings establish mice as a robust model for studying the neural basis of temporal pitch perception.

Adolescence is a developmental period characterized by heightened plasticity. Yet, how ongoing development affects sensory processing and cognitive function is unclear. We investigated how adolescent (postnatal day 20–42) and adult (postnatal day 60–82) mice differ in performance on a pure tone Go/No-Go auditory discrimination task of varying difficulty. Using dense electrophysiological recordings, we measured spiking activity at single neuron resolution in the auditory cortex while mice were engaged in the task. As compared to adults, adolescent mice showed lower auditory discrimination performance in a difficult task. This difference in performance was due to higher response variability and weaker cognitive control expressed as higher lick bias. Adolescent and adult neuronal responses differed only slightly in representations of pure tones when measured outside the context of learning and the task. However, cortical representations after learning within the context of the task were markedly different. We found differences in stimulus- and choice-related activity at the single neuron level representations, as well as lower population-level decoding of the difficult task in adolescents. Overall, cortical decoding in adolescents was lower and slower, especially for difficult sound discrimination, reflecting immature cortical representations of sounds and choices. Notably, we found age-related differences, which were more pronounced after learning, reflecting the combined impact of age and learning. Our findings highlight distinct neurophysiological and behavioral profiles in adolescence, underscoring the ongoing development of cognitive control mechanisms and cortical plasticity during this sensitive developmental period.

Many animal training paradigms rely on head-fixation. Head-fixation training is typically laborious and can benefit from automation to relieve the workload and reduce the variability in the training outcome. Several groups have reported successful implementations of such systems, but throughput varied greatly across groups. In addition, most studies relied on brief periods of head-fixation sessions (≤ 1 minute) to reduce the potential stress on the animal. Here, we report the design of a new system that could achieve head-fixation sessions on the order of minutes with a high participation rate from the animal (100%). Throughout the training period, each mouse performed a total of close to 40 minutes of head-fixation training on average each day and learned common psychoacoustic tasks, i.e., tone detection and tone discrimination. Our system can achieve highly efficient training with minimum idling time, allowing combinations with high-end neural recording equipment to achieve maximum training and data collection efficiency.

While evolutionary cortical expansion is thought to underlie the evolution of human cognitive capabilities, excessive developmental expansion can lead to megalencephaly, often found in neurodevelopmental disorders. Still, little is known about how the overproduction of cortical neurons during development affects cortical processing and behavior in later life. Here we show that developmental overproduction of cortical superficial neurons impairs auditory processing in adult mice. We applied XAV939 to overproduce cortical superficial excitatory neurons during development. XAV939-treated adult mice exhibited auditory behavioral deficits and abnormal auditory cortical processing. Furthermore, we found fewer functional monosynaptic connections between cortical putative excitatory neurons. Altogether, our results suggest that abnormal auditory cortical processing contributes to the atypical auditory detectability in XAV939-treated mice. Although the expansion of cortical size is evolutionarily advantageous, an abnormal expansion during development can result in detrimental effects on cortical processing and perceptual behavior in adulthood.

Thalamic brain areas play an important role in adaptive behaviors. Nevertheless, the population dynamics of thalamic relays during learning across sensory modalities remain unknown. Using a cross-modal sensory reward-associative learning paradigm combined with deep brain two-photon calcium imaging of large populations of auditory thalamus (medial geniculate body, MGB) neurons in male mice, we identified that MGB neurons are biased towards reward predictors independent of modality. Additionally, functional classes of MGB neurons aligned with distinct task periods and behavioral outcomes, both dependent and independent of sensory modality. During non-sensory delay periods, MGB ensembles developed coherent neuronal representation as well as distinct co-activity network states reflecting predicted task outcome. These results demonstrate flexible cross-modal ensemble coding in auditory thalamus during adaptive learning and highlight its importance in brain-wide cross-modal computations during complex behavior.

Salicylate is commonly used to induce tinnitus in animals, but its underlying mechanism of action is still debated. We therefore tested its effects on the firing properties of neurons in the mouse inferior colliculus (IC). Salicylate induced a large decrease in the spontaneous activity and an increase of ∼20 dB SPL in the minimum threshold of single units. In response to sinusoidally modulated noise (SAM noise) single units showed both an increase in phase locking and improved rate coding. Mice also became better at detecting amplitude modulations, and a simple threshold model based on the IC population response could reproduce this improvement. The responses to dynamic random chords (DRCs) suggested that the improved AM encoding was due to a linearization of the cochlear output, resulting in larger contrasts during SAM noise. These effects of salicylate are not consistent with the presence of tinnitus, but should be taken into account when studying hyperacusis.

Changes in sound-evoked responses in the auditory cortex (ACtx) occur during learning, but how learning alters neural responses in different ACtx subregions and changes their interactions is unclear. To address these questions, we developed an automated training and widefield imaging system to longitudinally track the neural activity of all mouse ACtx subregions during a tone discrimination task. We find that responses in primary ACtx are highly informative of learned stimuli and behavioral outcomes throughout training. In contrast, representations of behavioral outcomes in the dorsal posterior auditory field, learned stimuli in the dorsal anterior auditory field, and inter-regional correlations between primary and higher-order areas are enhanced with training. Moreover, ACtx response changes vary between stimuli, and such differences display lag synchronization with the learning rate. These results indicate that learning alters functional connections between ACtx subregions, inducing region-specific modulations by propagating behavioral information from primary to higher-order areas.

While animals navigating the real world face a barrage of sensory input, their brains evolved to perceptually compress multidimensional information by selectively extracting the features relevant for survival. Notably, communication signals supporting social interactions in several mammalian species consist of acoustically complex sequences of vocalisations. However, little is known about what information listeners extract from such time-varying sensory streams. Here, we utilise female mice’s natural behavioural response to male courtship songs to identify the relevant acoustic dimensions used in their social decisions. We found that females were highly sensitive to disruptions of song temporal regularity and preferentially approached playbacks of intact over rhythmically irregular versions of male songs. In contrast, female behaviour was invariant to manipulations affecting the songs’ sequential organisation or the spectro-temporal structure of individual syllables. The results reveal temporal regularity as a key acoustic cue extracted by mammalian listeners from complex vocal sequences during goal-directed social behaviour.

Introduction Autism spectrum disorder (ASD) is characterized by deficits in communication and social interaction, restricted interests, repetitive behaviors, and sensory alterations, with auditory hypersensitivity being one of the most commonly reported sensory–perceptual abnormalities. Several candidate genes for involvement in this disorder have emerged from patient studies, including SHANK3 , a gene that encodes a protein (SHANK3) in the postsynaptic density of excitatory synapses. Previous work has shown that mutant mice carrying a human ASD mutation in the Shank3 gene ( InsG3680 ) exhibit repetitive behaviors and social interaction deficits, indicating important construct and face validity for this genotype as an animal model of ASD. Methods To further address whether these mice also present auditory sensory–perceptual alterations, we developed a novel behavioral test in which mice can choose between different soundscapes. Results Our results reveal that, in comparison to wild-type mice, Shank3 mutants display a strong behavioral preference toward silent regions of the arena. Discussion These data suggest that Shank3 - mutant mice might express an auditory hypersensitivity phenotype, further adding to the face validity of this genotype as an animal model of ASD.

Quantitative and mechanistic understanding of learning and long-term memory at the level of single neurons in living brains require highly demanding techniques. A specific need is to precisely label one cell whose firing output property is pinpointed amidst a functionally characterized large population of neurons through the learning process and then investigate the distribution and properties of dendritic inputs. Here, we disseminate an integrated method of daily two-photon neuronal population Ca 2+ imaging through an auditory associative learning course, followed by targeted single-cell loose-patch recording and electroporation of plasmid for enhanced chronic Ca 2+ imaging of dendritic spines in the targeted cell. Our method provides a unique solution to the demand, opening a solid path toward the hard-cores of how learning and long-term memory are physiologically carried out at the level of single neurons and synapses.

Tinnitus is the phantom perception of sound that has no external source. A neurological signature of tinnitus, and the frequently associated hyperacusis, is an imbalance between excitatory and inhibitory activity in the central auditory system (CAS), leading to dysregulated network excitability. The large conductance, calcium-activated potassium (BK) channel is a key player in pre- and post-synaptic excitability through its mediation of K + currents. Changes in BK channel activity are associated with aberrant network activity in sensory regions of the CNS, raising the possibility that BK channel modulation could regulate activity associated with tinnitus and hyperacusis. To test whether BK channel openers are able to suppress biomarkers of drug-induced tinnitus and hyperacusis, the 1,3,4 oxadiazole BMS-191011 was given to young adult CBA mice that had been administered 250 mg/kg sodium salicylate (SS). Systemic treatment with BMS-191011 reduced behavioral manifestations of SS-induced tinnitus, but not hyperacusis, probed via the gap-in-noise startle response method. Systemic BMS-191011 treatment did not influence SS-induced increases in auditory brainstem response functions, but local application at the inferior colliculus did reverse SS-suppressed spontaneous activity, particularly in the frequency region of the tinnitus percept. Thus, action of BMS-191011 in the inferior colliculus may contribute to the reduction in behaviorally measured tinnitus. Together, these findings support the utility of BK channel openers in reducing central auditory processing changes associated with the formation of the tinnitus percept.

In everyday behavior, sensory systems are in constant competition for attentional resources, but the cellular and circuit-level mechanisms of modality-selective attention remain largely uninvestigated. We conducted translaminar recordings in mouse auditory cortex (AC) during an audiovisual (AV) attention shifting task. Attending to sound elements in an AV stream reduced both pre-stimulus and stimulus-evoked spiking activity, primarily in deep-layer neurons and neurons without spectrotemporal tuning. Despite reduced spiking, stimulus decoder accuracy was preserved, suggesting improved sound encoding efficiency. Similarly, task-irrelevant mapping stimuli during inter-trial intervals evoked fewer spikes without impairing stimulus encoding, indicating that attentional modulation generalized beyond training stimuli. Importantly, spiking reductions predicted trial-to-trial behavioral accuracy during auditory attention, but not visual attention. Together, these findings suggest auditory attention facilitates sound discrimination by filtering sound-irrelevant background activity in AC, and that the deepest cortical layers serve as a hub for integrating extramodal contextual information.

Aging leads to degeneration of the peripheral and central auditory systems, hearing loss, and difficulty understanding sounds in noise. Aging is also associated with changes in susceptibility to or recovery from damaging noise exposures, although the effects of the interaction between acute noise exposure and age on the perception of sounds are not well studied. We tested these effects in the CBA/CaJ mouse model of age-related hearing loss using operant conditioning procedures before and after noise exposure and longitudinally measured changes in their sensitivity for detecting tones in quiet or noise backgrounds. Cochleae from a subset of the behaviorally tested mice were immunolabeled to examine organ of Corti damage relative to what is expected based on aging alone. Mice tested in both quiet and noise background conditions experienced worse behavioral sensitivity immediately after noise exposure, but mice exposed at older ages generally showed greater threshold shifts and reduced recovery over time. Surprisingly, day-to-day stability in thresholds was markedly higher for mice detecting signals in the presence of a noise masker compared with detection in quiet conditions. Cochlear analysis revealed decreases in the total number of outer hair cells (OHCs) and the number of ribbons per inner cell in high-frequency regions in aged, noise-exposed mice relative to aging alone. Our findings build on previous work showing interactions between age and noise exposure and add that background noise can increase the stability of behavioral hearing sensitivity after noise damage.

Big brown bats emit wideband frequency modulated (FM) ultrasonic pulses for echolocation. They perceive target range from echo delay and target size from echo amplitude. Their sounds contain two prominent down-sweeping harmonic sweeps (FM1, ∼55-22 kHz; FM2, ∼100-55 kHz), which are affected differently by propagation out to the target and back to the bat. FM2 is attenuated more than FM1 during propagation. Bats anchor target ranging asymmetrically on the low frequencies in FM1, while FM2 only contributes if FM1 is present as well. These experiments tested whether the bat’s ability to discriminate target size from the amplitude of echoes is affected by selectively attenuating upper or lower frequencies. Bats were trained to perform an echo amplitude discrimination task with virtual echo targets 83 cm away. While echo delay was held constant and echo amplitude was varied to estimate threshold, either lower FM1 frequencies or higher FM2 frequencies were attenuated. The results parallel effects seen in echo delay experiments; bats’ performance was significantly poorer when the lower frequencies in echoes were attenuated, compared to higher frequencies. The bat’s ability to distinguish between virtual targets at the same simulated range from echoes arriving at the same delay indicates a high level of focused attention for perceptual isolation of one and suppression of the other.

Although auditory harmonic distortion has been demonstrated psychophysically in humans and electrophysiologically in experimental animals, the cellular origin of the mechanical harmonic distortion remains unclear. To demonstrate the outer hair cell-generated harmonics within the organ of Corti, we measured sub-nanometer vibrations of the reticular lamina from the apical ends of the outer hair cells in living gerbil cochleae using a custom-built heterodyne low-coherence interferometer. The harmonics in the reticular lamina vibration are significantly larger and have broader spectra and shorter latencies than those in the basilar membrane vibration. The latency of the second harmonic is significantly greater than that of the fundamental at low stimulus frequencies. These data indicate that the mechanical harmonics are generated by the outer hair cells over a broad cochlear region and propagate from the generation sites to their own best-frequency locations.

Integration of multi-frequency sounds into a unified perceptual object is critical for recognizing syllables in speech. This “feature binding” relies on the precise synchrony of each component’s onset timing, but little is known regarding its neural correlates. We find that multi-frequency sounds prevalent in vocalizations, specifically harmonics, preferentially activate the mouse secondary auditory cortex (A2), whose response deteriorates with shifts in component onset timings. The temporal window for harmonics integration in A2 was broadened by inactivation of somatostatin-expressing interneurons (SOM cells), but not parvalbumin-expressing interneurons (PV cells). Importantly, A2 has functionally connected subnetworks of neurons preferentially encoding harmonic over inharmonic sounds. These subnetworks are stable across days and exist prior to experimental harmonics exposure, suggesting their formation during development. Furthermore, A2 inactivation impairs performance in a discrimination task for coincident harmonics. Together, we propose A2 as a locus for multi-frequency integration, which may form the circuit basis for vocal processing.