Developmental hearing loss-induced perceptual deficits are rescued by genetic restoration of cortical inhibition.

Even a transient period of hearing loss during the developmental critical period can induce long-lasting deficits in temporal and spectral perception. These perceptual deficits correlate with speech perception in humans. In gerbils, these hearing loss-induced perceptual deficits are correlated with a reduction of both ionotropic GABAA and metabotropic GABAB receptor-mediated synaptic inhibition in auditory cortex, but most research on critical period plasticity has focused on GABAA receptors. Therefore, we developed viral vectors to express proteins that would upregulate gerbil postsynaptic inhibitory receptor subunits (GABAA, Gabra1; GABAB, Gabbr1b) in pyramidal neurons, and an enzyme that mediates GABA synthesis (GAD65) presynaptically in parvalbumin-expressing interneurons. A transient period of developmental hearing loss during the auditory critical period significantly impaired perceptual performance on two auditory tasks: amplitude modulation depth detection and spectral modulation depth detection. We then tested the capacity of each vector to restore perceptual performance on these auditory tasks. While both GABA receptor vectors increased the amplitude of cortical inhibitory postsynaptic potentials, only viral expression of postsynaptic GABAB receptors improved perceptual thresholds to control levels. Similarly, presynaptic GAD65 expression improved perceptual performance on spectral modulation detection. These findings suggest that recovering performance on auditory perceptual tasks depends on GABAB receptor-dependent transmission at the auditory cortex parvalbumin to pyramidal synapse and point to potential therapeutic targets for developmental sensory disorders.

Transformation of acoustic information to sensory decision variables in the parietal cortex.

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.

SLEAP: A deep learning system for multi-animal pose tracking.

The desire to understand how the brain generates and patterns behavior has driven rapid methodological innovation in tools to quantify natural animal behavior. While advances in deep learning and computer vision have enabled markerless pose estimation in individual animals, extending these to multiple animals presents unique challenges for studies of social behaviors or animals in their natural environments. Here we present Social LEAP Estimates Animal Poses (SLEAP), a machine learning system for multi-animal pose tracking. This system enables versatile workflows for data labeling, model training and inference on previously unseen data. SLEAP features an accessible graphical user interface, a standardized data model, a reproducible configuration system, over 30 model architectures, two approaches to part grouping and two approaches to identity tracking. We applied SLEAP to seven datasets across flies, bees, mice and gerbils to systematically evaluate each approach and architecture, and we compare it with other existing approaches. SLEAP achieves greater accuracy and speeds of more than 800 frames per second, with latencies of less than 3.5 ms at full 1,024 × 1,024 image resolution. This makes SLEAP usable for real-time applications, which we demonstrate by controlling the behavior of one animal on the basis of the tracking and detection of social interactions with another animal.

A Redundant Cortical Code for Speech Envelope.

Animal communication sounds exhibit complex temporal structure because of the amplitude fluctuations that comprise the sound envelope. In human speech, envelope modulations drive synchronized activity in auditory cortex (AC), which correlates strongly with comprehension (Giraud and Poeppel, 2012; Peelle and Davis, 2012; Haegens and Zion Golumbic, 2018). Studies of envelope coding in single neurons, performed in nonhuman animals, have focused on periodic amplitude modulation (AM) stimuli and use response metrics that are not easy to juxtapose with data from humans. In this study, we sought to bridge these fields. Specifically, we looked directly at the temporal relationship between stimulus envelope and spiking, and we assessed whether the apparent diversity across neurons' AM responses contributes to the population representation of speech-like sound envelopes. We gathered responses from single neurons to vocoded speech stimuli and compared them to sinusoidal AM responses in auditory cortex (AC) of alert, freely moving Mongolian gerbils of both sexes. While AC neurons displayed heterogeneous tuning to AM rate, their temporal dynamics were stereotyped. Preferred response phases accumulated near the onsets of sinusoidal AM periods for slower rates (<8 Hz), and an over-representation of amplitude edges was apparent in population responses to both sinusoidal AM and vocoded speech envelopes. Crucially, this encoding bias imparted a decoding benefit: a classifier could discriminate vocoded speech stimuli using summed population activity, while higher frequency modulations required a more sophisticated decoder that tracked spiking responses from individual cells. Together, our results imply that the envelope structure relevant to parsing an acoustic stream could be read-out from a distributed, redundant population code.SIGNIFICANCE STATEMENT Animal communication sounds have rich temporal structure and are often produced in extended sequences, including the syllabic structure of human speech. Although the auditory cortex (AC) is known to play a crucial role in representing speech syllables, the contribution of individual neurons remains uncertain. Here, we characterized the representations of both simple, amplitude-modulated sounds and complex, speech-like stimuli within a broad population of cortical neurons, and we found an overrepresentation of amplitude edges. Thus, a phasic, redundant code in auditory cortex can provide a mechanistic explanation for segmenting acoustic streams like human speech.

Temporal Encoding is Required for Categorization, But Not Discrimination.

Core auditory cortex (AC) neurons encode slow fluctuations of acoustic stimuli with temporally patterned activity. However, whether temporal encoding is necessary to explain auditory perceptual skills remains uncertain. Here, we recorded from gerbil AC neurons while they discriminated between a 4-Hz amplitude modulation (AM) broadband noise and AM rates >4 Hz. We found a proportion of neurons possessed neural thresholds based on spike pattern or spike count that were better than the recorded session's behavioral threshold, suggesting that spike count could provide sufficient information for this perceptual task. A population decoder that relied on temporal information outperformed a decoder that relied on spike count alone, but the spike count decoder still remained sufficient to explain average behavioral performance. This leaves open the possibility that more demanding perceptual judgments require temporal information. Thus, we asked whether accurate classification of different AM rates between 4 and 12 Hz required the information contained in AC temporal discharge patterns. Indeed, accurate classification of these AM stimuli depended on the inclusion of temporal information rather than spike count alone. Overall, our results compare two different representations of time-varying acoustic features that can be accessed by downstream circuits required for perceptual judgments.

Neural Variability Limits Adolescent Skill Learning.

Skill learning is fundamental to the acquisition of many complex behaviors that emerge during development. For example, years of practice give rise to perceptual improvements that contribute to mature speech and language skills. While fully honed learning skills might be thought to offer an advantage during the juvenile period, the ability to learn actually continues to develop through childhood and adolescence, suggesting that the neural mechanisms that support skill learning are slow to mature. To address this issue, we asked whether the rate and magnitude of perceptual learning varies as a function of age as male and female gerbils trained on an auditory task. Adolescents displayed a slower rate of perceptual learning compared with their young and mature counterparts. We recorded auditory cortical neuron activity from a subset of adolescent and adult gerbils as they underwent perceptual training. While training enhanced the sensitivity of most adult units, the sensitivity of many adolescent units remained unchanged, or even declined across training days. Therefore, the average rate of cortical improvement was significantly slower in adolescents compared with adults. Both smaller differences between sound-evoked response magnitudes and greater trial-to-trial response fluctuations contributed to the poorer sensitivity of individual adolescent neurons. Together, these findings suggest that elevated sensory neural variability limits adolescent skill learning.SIGNIFICANCE STATEMENT The ability to learn new skills emerges gradually as children age. This prolonged development, often lasting well into adolescence, suggests that children, teens, and adults may rely on distinct neural strategies to improve their sensory and motor capabilities. Here, we found that practice-based improvement on a sound detection task is slower in adolescent gerbils than in younger or older animals. Neural recordings made during training revealed that practice enhanced the sound sensitivity of adult cortical neurons, but had a weaker effect in adolescents. This latter finding was partially explained by the fact that adolescent neural responses were more variable than in adults. Our results suggest that one mechanistic basis of adult-like skill learning is a reduction in neural response variability.

Preserving Inhibition during Developmental Hearing Loss Rescues Auditory Learning and Perception.

Transient periods of childhood hearing loss can induce deficits in aural communication that persist long after auditory thresholds have returned to normal, reflecting long-lasting impairments to the auditory CNS. Here, we asked whether these behavioral deficits could be reversed by treating one of the central impairments: reduction of inhibitory strength. Male and female gerbils received bilateral earplugs to induce a mild, reversible hearing loss during the critical period of auditory cortex development. After earplug removal and the return of normal auditory thresholds, we trained and tested animals on an amplitude modulation detection task. Transient developmental hearing loss induced both learning and perceptual deficits, which were entirely corrected by treatment with a selective GABA reuptake inhibitor (SGRI). To explore the mechanistic basis for these behavioral findings, we recorded the amplitudes of GABAA and GABAB receptor-mediated IPSPs in auditory cortical and thalamic brain slices. In hearing loss-reared animals, cortical IPSP amplitudes were significantly reduced within a few days of hearing loss onset, and this reduction persisted into adulthood. SGRI treatment during the critical period prevented the hearing loss-induced reduction of IPSP amplitudes; but when administered after the critical period, it only restored GABAB receptor-mediated IPSP amplitudes. These effects were driven, in part, by the ability of SGRI to upregulate α1 subunit-dependent GABAA responses. Similarly, SGRI prevented the hearing loss-induced reduction of GABAA and GABAB IPSPs in the ventral nucleus of the medial geniculate body. Thus, by maintaining, or subsequently rescuing, GABAergic transmission in the central auditory thalamocortical pathway, some perceptual and cognitive deficits induced by developmental hearing loss can be prevented.SIGNIFICANCE STATEMENT Even a temporary period of childhood hearing loss can induce communication deficits that persist long after auditory thresholds return to normal. These deficits may arise from long-lasting central impairments, including the loss of synaptic inhibition. Here, we asked whether hearing loss-induced behavioral deficits could be reversed by reinstating normal inhibitory strength. Gerbils reared with transient hearing loss displayed both learning and perceptual deficits. However, when animals were treated with a selective GABA reuptake inhibitor during or after hearing loss, behavioral deficits were entirely corrected. This behavioral recovery was correlated with the return of normal thalamic and cortical inhibitory function. Thus, some perceptual and cognitive deficits induced by developmental hearing loss were prevented with a treatment that rescues a central synaptic property.

Top-down modulation of sensory cortex gates perceptual learning.

Practice sharpens our perceptual judgments, a process known as perceptual learning. Although several brain regions and neural mechanisms have been proposed to support perceptual learning, formal tests of causality are lacking. Furthermore, the temporal relationship between neural and behavioral plasticity remains uncertain. To address these issues, we recorded the activity of auditory cortical neurons as gerbils trained on a sound detection task. Training led to improvements in cortical and behavioral sensitivity that were closely matched in terms of magnitude and time course. Surprisingly, the degree of neural improvement was behaviorally gated. During task performance, cortical improvements were large and predicted behavioral outcomes. In contrast, during nontask listening sessions, cortical improvements were weak and uncorrelated with perceptual performance. Targeted reduction of auditory cortical activity during training diminished perceptual learning while leaving psychometric performance largely unaffected. Collectively, our findings suggest that training facilitates perceptual learning by strengthening both bottom-up sensory encoding and top-down modulation of auditory cortex.

De novo sequencing and initial annotation of the Mongolian gerbil (Meriones unguiculatus) genome.

The Mongolian gerbil (Meriones unguiculatus) is a member of the rodent family that displays several features not found in mice or rats, including sensory specializations and social patterns more similar to those in humans. These features have made gerbils a valuable animal for research studies of auditory and visual processing, brain development, learning and memory, and neurological disorders. Here, we report the whole gerbil annotated genome sequence, and identify important similarities and differences to the human and mouse genomes. We further analyze the chromosomal structure of eight genes with high relevance for controlling neural signaling and demonstrate a high degree of homology between these genes in mouse and gerbil. This homology increases the likelihood that individual genes can be rapidly identified in gerbil and used for genetic manipulations. The availability of the gerbil genome provides a foundation for advancing our knowledge towards understanding evolution, behavior and neural function in mammals. ACCESSION NUMBER: The Whole Genome Shotgun sequence data from this project has been deposited at DDBJ/ENA/GenBank under the accession NHTI00000000. The version described in this paper is version NHTI01000000. The fragment reads, and mate pair reads have been deposited in the Sequence Read Archive under BioSample accession SAMN06897401.

A Decline in Response Variability Improves Neural Signal Detection during Auditory Task Performance.

The detection of a sensory stimulus arises from a significant change in neural activity, but a sensory neuron's response is rarely identical to successive presentations of the same stimulus. Large trial-to-trial variability would limit the central nervous system's ability to reliably detect a stimulus, presumably affecting perceptual performance. However, if response variability were to decrease while firing rate remained constant, then neural sensitivity could improve. Here, we asked whether engagement in an auditory detection task can modulate response variability, thereby increasing neural sensitivity. We recorded telemetrically from the core auditory cortex of gerbils, both while they engaged in an amplitude-modulation detection task and while they sat quietly listening to the identical stimuli. Using a signal detection theory framework, we found that neural sensitivity was improved during task performance, and this improvement was closely associated with a decrease in response variability. Moreover, units with the greatest change in response variability had absolute neural thresholds most closely aligned with simultaneously measured perceptual thresholds. Our findings suggest that the limitations imposed by response variability diminish during task performance, thereby improving the sensitivity of neural encoding and potentially leading to better perceptual sensitivity. SIGNIFICANCE STATEMENT: The detection of a sensory stimulus arises from a significant change in neural activity. However, trial-to-trial variability of the neural response may limit perceptual performance. If the neural response to a stimulus is quite variable, then the response on a given trial could be confused with the pattern of neural activity generated when the stimulus is absent. Therefore, a neural mechanism that served to reduce response variability would allow for better stimulus detection. By recording from the cortex of freely moving animals engaged in an auditory detection task, we found that variability of the neural response becomes smaller during task performance, thereby improving neural detection thresholds.

GABAergic inhibition gates excitatory LTP in perirhinal cortex.

The perirhinal cortex (PRh) is a key region downstream of auditory cortex (ACx) that processes familiarity linked mnemonic signaling. In gerbils, ACx-driven EPSPs recorded in PRh neurons are largely shunted by GABAergic inhibition (Kotak et al., 2015, Frontiers in Neural Circuits, 9). To determine whether inhibitory shunting prevents the induction of excitatory long-term potentiation (e-LTP), we stimulated ACx-recipient PRh in a brain slice preparation using theta burst stimulation (TBS). Under control conditions, without GABA blockers, the majority of PRh neurons exhibited long-term depression. A very low concentration of bicuculline increased EPSP amplitude, but under this condition TBS did not significantly increase e-LTP induction. Since PRh synaptic inhibition included a GABAB receptor-mediated component, we added a GABAB receptor antagonist. When both GABAA and GABAB receptors were blocked, TBS reliably induced e-LTP in a majority of PRh neurons. We conclude that GABAergic transmission is a vital mechanism regulating e-LTP induction in the PRh, and may be associated with auditory learning.

Sustained Perceptual Deficits from Transient Sensory Deprivation.

Sensory pathways display heightened plasticity during development, yet the perceptual consequences of early experience are generally assessed in adulthood. This approach does not allow one to identify transient perceptual changes that may be linked to the central plasticity observed in juvenile animals. Here, we determined whether a brief period of bilateral auditory deprivation affects sound perception in developing and adult gerbils. Animals were reared with bilateral earplugs, either from postnatal day 11 (P11) to postnatal day 23 (P23) (a manipulation previously found to disrupt gerbil cortical properties), or from P23-P35. Fifteen days after earplug removal and restoration of normal thresholds, animals were tested on their ability to detect the presence of amplitude modulation (AM), a temporal cue that supports vocal communication. Animals reared with earplugs from P11-P23 displayed elevated AM detection thresholds, compared with age-matched controls. In contrast, an identical period of earplug rearing at a later age (P23-P35) did not impair auditory perception. Although the AM thresholds of earplug-reared juveniles improved during a week of repeated testing, a subset of juveniles continued to display a perceptual deficit. Furthermore, although the perceptual deficits induced by transient earplug rearing had resolved for most animals by adulthood, a subset of adults displayed impaired performance. Control experiments indicated that earplugging did not disrupt the integrity of the auditory periphery. Together, our results suggest that P11-P23 encompasses a critical period during which sensory deprivation disrupts central mechanisms that support auditory perceptual skills. SIGNIFICANCE STATEMENT: Sensory systems are particularly malleable during development. This heightened degree of plasticity is beneficial because it enables the acquisition of complex skills, such as music or language. However, this plasticity comes with a cost: nervous system development displays an increased vulnerability to the sensory environment. Here, we identify a precise developmental window during which mild hearing loss affects the maturation of an auditory perceptual cue that is known to support animal communication, including human speech. Furthermore, animals reared with transient hearing loss display deficits in perceptual learning. Our results suggest that speech and language delays associated with transient or permanent childhood hearing loss may be accounted for, in part, by deficits in central auditory processing mechanisms.

Cortical Synaptic Inhibition Declines during Auditory Learning.

Auditory learning is associated with an enhanced representation of acoustic cues in primary auditory cortex, and modulation of inhibitory strength is causally involved in learning. If this inhibitory plasticity is associated with task learning and improvement, its expression should emerge and persist until task proficiency is achieved. We tested this idea by measuring changes to cortical inhibitory synaptic transmission as adult gerbils progressed through the process of associative learning and perceptual improvement. Using either of two procedures, aversive or appetitive conditioning, animals were trained to detect amplitude-modulated noise and then tested daily. Following each training session, a thalamocortical brain slice was generated, and inhibitory synaptic properties were recorded from layer 2/3 pyramidal neurons. Initial associative learning was accompanied by a profound reduction in the amplitude of spontaneous IPSCs (sIPSCs). However, sIPSC amplitude returned to control levels when animals reached asymptotic behavioral performance. In contrast, paired-pulse ratios decreased in trained animals as well as in control animals that experienced unpaired conditioned and unconditioned stimuli. This latter observation suggests that inhibitory release properties are modified during behavioral conditioning, even when an association between the sound and reinforcement cannot occur. These results suggest that associative learning is accompanied by a reduction of postsynaptic inhibitory strength that persists for several days during learning and perceptual improvement.

Transient Hearing Loss Within a Critical Period Causes Persistent Changes to Cellular Properties in Adult Auditory Cortex.

Sensory deprivation can induce profound changes to central processing during developmental critical periods (CPs), and the recovery of normal function is maximal if the sensory input is restored during these epochs. Therefore, we asked whether mild and transient hearing loss (HL) during discrete CPs could induce changes to cortical cellular physiology. Electrical and inhibitory synaptic properties were obtained from auditory cortex pyramidal neurons using whole-cell recordings after bilateral earplug insertion or following earplug removal. Varying the age of HL onset revealed brief CPs of vulnerability for membrane and firing properties, as well as, inhibitory synaptic currents. These CPs closed 1 week after ear canal opening on postnatal day (P) 18. To examine whether the cellular properties could recover from HL, earplugs were removed prior to (P17) or after (P23), the closure of these CPs. The earlier age of hearing restoration led to greater recovery of cellular function, but firing rate remained disrupted. When earplugs were removed after the closure of these CPs, several changes persisted into adulthood. Therefore, long-lasting cellular deficits that emerge from transient deprivation during a CP may contribute to delayed acquisition of auditory skills in children who experience temporary HL.

Behaviorally gated reduction of spontaneous discharge can improve detection thresholds in auditory cortex.

Animals often listen selectively for particular sounds, a strategy that could alter neural encoding mechanisms to maximize the ability to detect the target. Here, we recorded auditory cortex neuron responses in well trained, freely moving gerbils as they performed a tone detection task. Each trial was initiated by the animal, providing a predictable time window during which to listen. No sound was presented on nogo trials, permitting us to assess spontaneous activity on trials in which a signal could have been expected, but was not delivered. Immediately after animals initiated a trial, auditory cortex neurons displayed a 26% reduction in spontaneous activity. Moreover, when stimulus-driven discharge rate was referenced to this reduced baseline, a larger fraction of auditory cortex neurons displayed a detection threshold within 10 dB of the behavioral threshold. These findings suggest that auditory cortex spontaneous discharge rate can be modulated transiently during task performance, thereby increasing the signal-to-noise ratio and enhancing signal detection.

A sensitive period for the impact of hearing loss on auditory perception.

Manipulations of the sensory environment typically induce greater changes to the developing nervous system than they do in adulthood. The relevance of these neural changes can be evaluated by examining the age-dependent effects of sensory experience on quantitative measures of perception. Here, we measured frequency modulation (FM) detection thresholds in adult gerbils and investigated whether diminished auditory experience during development or in adulthood influenced perceptual performance. Bilateral conductive hearing loss (CHL) of ≈30 dB was induced either at postnatal day 10 or after sexual maturation. All animals were then trained as adults to detect a 5 Hz FM embedded in a continuous 4 kHz tone. FM detection thresholds were defined as the minimum deviation from the carrier frequency that the animal could reliably detect. Normal-hearing animals displayed FM thresholds of 25 Hz. Inducing CHL, either in juvenile or adult animals, led to a deficit in FM detection. However, this deficit was greater for juvenile onset hearing loss (89 Hz) relative to adult onset hearing loss (64 Hz). The effects could not be attributed to sensation level, nor were they correlated with proxies for attention. The thresholds displayed by CHL animals were correlated with shallower psychometric function slopes, suggesting that hearing loss was associated with greater variance of the decision variable, consistent with increased internal noise. The results show that decreased auditory experience has a greater impact on perceptual skills when initiated at an early age and raises the possibility that altered development of CNS synapses may play a causative role.

Auditory midbrain processing is differentially modulated by auditory and visual cortices: An auditory fMRI study.

The cortex contains extensive descending projections, yet the impact of cortical input on brainstem processing remains poorly understood. In the central auditory system, the auditory cortex contains direct and indirect pathways (via brainstem cholinergic cells) to nuclei of the auditory midbrain, called the inferior colliculus (IC). While these projections modulate auditory processing throughout the IC, single neuron recordings have samples from only a small fraction of cells during stimulation of the corticofugal pathway. Furthermore, assessments of cortical feedback have not been extended to sensory modalities other than audition. To address these issues, we devised blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) paradigms to measure the sound-evoked responses throughout the rat IC and investigated the effects of bilateral ablation of either auditory or visual cortices. Auditory cortex ablation increased the gain of IC responses to noise stimuli (primarily in the central nucleus of the IC) and decreased response selectivity to forward species-specific vocalizations (versus temporally reversed ones, most prominently in the external cortex of the IC). In contrast, visual cortex ablation decreased the gain and induced a much smaller effect on response selectivity. The results suggest that auditory cortical projections normally exert a large-scale and net suppressive influence on specific IC subnuclei, while visual cortical projections provide a facilitatory influence. Meanwhile, auditory cortical projections enhance the midbrain response selectivity to species-specific vocalizations. We also probed the role of the indirect cholinergic projections in the auditory system in the descending modulation process by pharmacologically blocking muscarinic cholinergic receptors. This manipulation did not affect the gain of IC responses but significantly reduced the response selectivity to vocalizations. The results imply that auditory cortical gain modulation is mediated primarily through direct projections and they point to future investigations of the differential roles of the direct and indirect projections in corticofugal modulation. In summary, our imaging findings demonstrate the large-scale descending influences, from both the auditory and visual cortices, on sound processing in different IC subdivisions. They can guide future studies on the coordinated activity across multiple regions of the auditory network, and its dysfunctions.

On the localization of complex sounds: temporal encoding based on input-slope coincidence detection of envelopes.

Behavioral and neural findings demonstrate that animals can locate low-frequency sounds along the azimuth by detecting microsecond interaural time differences (ITDs). Information about ITDs is also available in the amplitude modulations (i.e., envelope) of high-frequency sounds. Since medial superior olivary (MSO) neurons encode low-frequency ITDs, we asked whether they employ a similar mechanism to process envelope ITDs with high-frequency carriers, and the effectiveness of this mechanism compared with the process of low-frequency sound. We developed a novel hybrid in vitro dynamic-clamp approach, which enabled us to mimic synaptic input to brain-slice neurons in response to virtual sound and to create conditions that cannot be achieved naturally but are useful for testing our hypotheses. For each simulated ear, a virtual sound, computer generated, was used as input to a computational auditory-nerve model. Model spike times were converted into synaptic input for MSO neurons, and ITD tuning curves were derived for several virtual-sound conditions: low-frequency pure tones, high-frequency tones modulated with two types of envelope, and speech sequences. Computational models were used to verify the physiological findings and explain the biophysical mechanism underlying the observed ITD coding. Both recordings and simulations indicate that MSO neurons are sensitive to ITDs carried by spectrotemporally complex virtual sounds, including speech tokens. Our findings strongly suggest that MSO neurons can encode ITDs across a broad-frequency spectrum using an input-slope-based coincidence-detection mechanism. Our data also provide an explanation at the cellular level for human localization performance involving high-frequency sound described by previous investigators.

Effects of spectral and temporal disruption on cortical encoding of gerbil vocalizations.

Animal communication sounds contain spectrotemporal fluctuations that provide powerful cues for detection and discrimination. Human perception of speech is influenced both by spectral and temporal acoustic features but is most critically dependent on envelope information. To investigate the neural coding principles underlying the perception of communication sounds, we explored the effect of disrupting the spectral or temporal content of five different gerbil call types on neural responses in the awake gerbil's primary auditory cortex (AI). The vocalizations were impoverished spectrally by reduction to 4 or 16 channels of band-passed noise. For this acoustic manipulation, an average firing rate of the neuron did not carry sufficient information to distinguish between call types. In contrast, the discharge patterns of individual AI neurons reliably categorized vocalizations composed of only four spectral bands with the appropriate natural token. The pooled responses of small populations of AI cells classified spectrally disrupted and natural calls with an accuracy that paralleled human performance on an analogous speech task. To assess whether discharge pattern was robust to temporal perturbations of an individual call, vocalizations were disrupted by time-reversing segments of variable duration. For this acoustic manipulation, cortical neurons were relatively insensitive to short reversal lengths. Consistent with human perception of speech, these results indicate that the stable representation of communication sounds in AI is more dependent on sensitivity to slow temporal envelopes than on spectral detail.