Surround suppression in mouse auditory cortex underlies auditory edge detection.

Surround suppression (SS) is a fundamental property of sensory processing throughout the brain. In the auditory system, the early processing stream encodes sounds using a one dimensional physical space-frequency. Previous studies in the auditory system have shown SS to manifest as bandwidth tuning around the preferred frequency. We asked whether bandwidth tuning can be found around frequencies away from the preferred frequency. We exploited the simplicity of spectral representation of sounds to study SS by manipulating both sound frequency and bandwidth. We recorded single unit spiking activity from the auditory cortex (ACx) of awake mice in response to an array of broadband stimuli with varying central frequencies and bandwidths. Our recordings revealed that a significant portion of neuronal response profiles had a preferred bandwidth that varied in a regular way with the sound's central frequency. To gain insight into the possible mechanism underlying these responses, we modelled neuronal activity using a variation of the "Mexican hat" function often used to model SS. The model accounted for response properties of single neurons with high accuracy. Our data and model show that these responses in ACx obey simple rules resulting from the presence of lateral inhibitory sidebands, mostly above the excitatory band of the neuron, that result in sensitivity to the location of top frequency edges, invariant to other spectral attributes. Our work offers a simple explanation for auditory edge detection and possibly other computations of spectral content in sounds.

An automated, low-latency environment for studying the neural basis of behavior in freely moving rats.

BACKGROUND: Behavior consists of the interaction between an organism and its environment, and is controlled by the brain. Brain activity varies at sub-second time scales, but behavioral measures are usually coarse (often consisting of only binary trial outcomes). RESULTS: To overcome this mismatch, we developed the Rat Interactive Foraging Facility (RIFF): a programmable interactive arena for freely moving rats with multiple feeding areas, multiple sound sources, high-resolution behavioral tracking, and simultaneous electrophysiological recordings. The paper provides detailed information about the construction of the RIFF and the software used to control it. To illustrate the flexibility of the RIFF, we describe two complex tasks implemented in the RIFF, a foraging task and a sound localization task. Rats quickly learned to obtain rewards in both tasks. Neurons in the auditory cortex as well as neurons in the auditory field in the posterior insula had sound-driven activity during behavior. Remarkably, neurons in both structures also showed sensitivity to non-auditory parameters such as location in the arena and head-to-body angle. CONCLUSIONS: The RIFF provides insights into the cognitive capabilities and learning mechanisms of rats and opens the way to a better understanding of how brains control behavior. The ability to do so depends crucially on the combination of wireless electrophysiology and detailed behavioral documentation available in the RIFF.

Context-Dependent Inhibitory Control of Stimulus-Specific Adaptation.

Stimulus-specific adaptation (SSA) is the reduction in responses to frequent stimuli (standards) that does not generalize to rare stimuli (deviants). We investigated the contribution of inhibition in auditory cortex to SSA using two-photon targeted cell-attached recordings and optogenetic manipulations in male mice. We characterized the responses of parvalbumin (PV)-, somatostatin (SST)-, and vasoactive intestinal polypeptide (VIP)-expressing interneurons of layer 2/3, and of serotonin receptor 5HT3a-expressing interneurons of layer 1. All populations showed early-onset SSA. Unexpectedly, the PV, SST, and VIP populations exhibited a substantial late component of evoked activity, often stronger for standard than for deviant stimuli. Optogenetic suppression of PV neurons facilitated pyramidal neuron responses substantially more (approximately ×10) for deviants than for standards. VIP suppression decreased responses of putative PV neurons, specifically for standard but not for deviant stimuli. Thus, the inhibitory network does not generate cortical SSA, but powerfully controls its expression by differentially affecting the responses to deviants and to standards.SIGNIFICANCE STATEMENT Stimulus-specific adaptation (SSA) reflects the growing complexity of auditory processing along the ascending auditory system. In the presence of SSA, neuronal responses depend not only on the stimulus itself but also on the history of stimulation. Strong SSA in the fast, ascending auditory pathway first occurs in cortex. Here we studied the role of the cortical inhibitory network in shaping SSA, showing that while cortical inhibition does not generate SSA, it powerfully controls its expression. We deduce that the cortical network contributes in crucial ways to the properties of SSA.

A simple model of the attentional blink and its modulation by mental training.

The attentional blink (AB) effect is the reduced probability of reporting a second target (T2) that appears shortly after a first one (T1) within a rapidly presented sequence of distractors. The AB effect has been shown to be reduced following intensive mental training in the form of mindfulness meditation, with a corresponding reduction in T1-evoked P3b brain potentials. However, the mechanisms underlying these effects remain unknown. We propose a dynamical-systems model of the AB, in which attentional load is described as the response of a dynamical system to incoming impulse signals. Non-task related mental activity is represented by additive noise modulated by meditation. The model provides a parsimonious computational framework relating behavioral performance, evoked brain potentials and training through the concept of reduced mental noise.

Extrinsic rewards, intrinsic rewards, and non-optimal behavior.

The optimality of behavior in experimental settings is usually determined with respect to an extrinsic reward defined by the experimenters. However, actions that do not lead to reward are ubiquitous in many species and in many experimental paradigms. Modern research on decision processes commonly treat non-optimal behaviors as noise, often excluding from analysis animals that do not reach behavioral performance criteria. However, non-optimal behaviors can be a window on important brain processes. Here we explore the evidence that non-optimal behaviors are the consequence of intrinsically motivated actions, related to drives that are different from that of obtaining extrinsic reward. One way of operationally characterizing these drives is by postulating intrinsic rewards associated with them. Behaviors that are apparently non-optimal can be interpreted as the consequence of optimal decisions whose goal is to optimize a combination of intrinsic and extrinsic rewards. We review intrinsic rewards that have been discussed in the literature, and suggest ways of testing their existence and role in shaping animal behavior.

Context Sensitivity across Multiple Time scales with a Flexible Frequency Bandwidth.

Everyday auditory streams are complex, including spectro-temporal content that varies at multiple timescales. Using EEG, we investigated the sensitivity of human auditory cortex to the content of past stimulation in unattended sequences of equiprobable tones. In 3 experiments including 82 participants overall, we found that neural responses measured at different latencies after stimulus onset were sensitive to frequency intervals computed over distinct timescales. Importantly, early responses were sensitive to a longer history of stimulation than later responses. To account for these results, we tested a model consisting of neural populations with frequency-specific but broad tuning that undergo adaptation with exponential recovery. We found that the coexistence of neural populations with distinct recovery rates can explain our results. Furthermore, the adaptation bandwidth of these populations depended on spectral context-it was wider when the stimulation sequence had a wider frequency range. Our results provide electrophysiological evidence as well as a possible mechanistic explanation for dynamic and multiscale context-dependent auditory processing in the human cortex.

Value-complexity tradeoff explains mouse navigational learning.

We introduce a novel methodology for describing animal behavior as a tradeoff between value and complexity, using the Morris Water Maze navigation task as a concrete example. We develop a dynamical system model of the Water Maze navigation task, solve its optimal control under varying complexity constraints, and analyze the learning process in terms of the value and complexity of swimming trajectories. The value of a trajectory is related to its energetic cost and is correlated with swimming time. Complexity is a novel learning metric which measures how unlikely is a trajectory to be generated by a naive animal. Our model is analytically tractable, provides good fit to observed behavior and reveals that the learning process is characterized by early value optimization followed by complexity reduction. Furthermore, complexity sensitively characterizes behavioral differences between mouse strains.

Synaptic Recruitment Enhances Gap Termination Responses in Auditory Cortex.

The ability to detect short gaps in noise is an important tool for assessing the temporal resolution in the auditory cortex. However, the mere existence of responses to temporal gaps bounded by two short broadband markers is surprising, because of the expected short-term suppression that is prevalent in auditory cortex. Here, we used in-vivo intracellular recordings in anesthetized rats to dissect the synaptic mechanisms that underlie gap-related responses. When a gap is bounded by two short markers, a gap termination response was evoked by the onset of the second marker with minimal contribution from the offset of the first marker. Importantly, we show that the gap termination response was driven by a different (potentially partially overlapping) synaptic population than that underlying the onset response to the first marker. This recruitment of additional synaptic resources is a novel mechanism contributing to the important perceptual task of gap detection.

Multiple Timescales Account for Adaptive Responses across Sensory Cortices.

Sensory systems encounter remarkably diverse stimuli in the external environment. Natural stimuli exhibit timescales and amplitudes of variation that span a wide range. Mechanisms of adaptation, a ubiquitous feature of sensory systems, allow for the accommodation of this range of scales. Are there common rules of adaptation across different sensory modalities? We measured the membrane potential responses of individual neurons in the visual, somatosensory, and auditory cortices of male and female mice to discrete, punctate stimuli delivered at a wide range of fixed and nonfixed frequencies. We find that the adaptive profile of the response is largely preserved across these three areas, exhibiting attenuation and responses to the cessation of stimulation, which are signatures of response to changes in stimulus statistics. We demonstrate that these adaptive responses can emerge from a simple model based on the integration of fixed filters operating over multiple time scales.SIGNIFICANCE STATEMENT Our recent sensations affect our current expectations and perceptions of the environment. Neural correlates of this process exist throughout the brain and are loosely termed adaptation. Adaptive processes have been described across sensory cortices, but direct comparisons of these processes have not been possible because paradigms have been tailored specifically for each modality. We developed a common stimulus set that was used to characterize adaptation in somatosensory, visual, and auditory cortex. We describe here the similarities and differences in adaptation across these cortical areas and demonstrate that adaptive responses may emerge from a set of static filters that operate over a broad range of timescales.

BACE inhibition-dependent repair of Alzheimer's pathophysiology.

Amyloid-ß (Aß) is thought to play an essential pathogenic role in Alzheimer´s disease (AD). A key enzyme involved in the generation of Aß is the ß-secretase BACE, for which powerful inhibitors have been developed and are currently in use in human clinical trials. However, although BACE inhibition can reduce cerebral Aß levels, whether it also can ameliorate neural circuit and memory impairments remains unclear. Using histochemistry, in vivo Ca2+ imaging, and behavioral analyses in a mouse model of AD, we demonstrate that along with reducing prefibrillary Aß surrounding plaques, the inhibition of BACE activity can rescue neuronal hyperactivity, impaired long-range circuit function, and memory defects. The functional neuronal impairments reappeared after infusion of soluble Aß, mechanistically linking Aß pathology to neuronal and cognitive dysfunction. These data highlight the potential benefits of BACE inhibition for the effective treatment of a wide range of AD-like pathophysiological and cognitive impairments.

Evidence for Linear but Not Helical Automatic Representation of Pitch in the Human Auditory System.

The perceptual organization of pitch is frequently described as helical, with a monotonic dimension of pitch height and a circular dimension of pitch chroma, accounting for the repeating structure of the octave. Although the neural representation of pitch height is widely studied, the way in which pitch chroma representation is manifested in neural activity is currently debated. We tested the automaticity of pitch chroma processing using the MMN-an ERP component indexing automatic detection of deviations from auditory regularity. Musicians trained to classify pure or complex tones across four octaves, based on chroma-C versus G (21 participants, Experiment 1) or C versus F# (27, Experiment 2). Next, they were passively exposed to MMN protocols designed to test automatic detection of height and chroma deviations. Finally, in an "attend chroma" block, participants had to detect the chroma deviants in a sequence similar to the passive MMN sequence. The chroma deviant tones were accurately detected in the training and the attend chroma parts both for pure and complex tones, with a slightly better performance for complex tones. However, in the passive blocks, a significant MMN was found only to height deviations and complex tone chroma deviations, but not to pure tone chroma deviations, even for perfect performers in the active tasks. These results indicate that, although height is represented preattentively, chroma is not. Processing the musical dimension of chroma may require higher cognitive processes, such as attention and working memory.

Blocking c-Fos Expression Reveals the Role of Auditory Cortex Plasticity in Sound Frequency Discrimination Learning.

The behavioral changes that comprise operant learning are associated with plasticity in early sensory cortices as well as with modulation of gene expression, but the connection between the behavioral, electrophysiological, and molecular changes is only partially understood. We specifically manipulated c-Fos expression, a hallmark of learning-induced synaptic plasticity, in auditory cortex of adult mice using a novel approach based on RNA interference. Locally blocking c-Fos expression caused a specific behavioral deficit in a sound discrimination task, in parallel with decreased cortical experience-dependent plasticity, without affecting baseline excitability or basic auditory processing. Thus, c-Fos-dependent experience-dependent cortical plasticity is necessary for frequency discrimination in an operant behavioral task. Our results connect behavioral, molecular and physiological changes and demonstrate a role of c-Fos in experience-dependent plasticity and learning.

Early multisensory integration of self and source motion in the auditory system.

Discriminating external from self-produced sensory inputs is a major challenge for brains. In the auditory system, sound localization must account for movements of the head and ears, a computation likely to involve multimodal integration. Principal neurons (PNs) of the dorsal cochlear nucleus (DCN) are known to be spatially selective and to receive multimodal sensory information. We studied the responses of PNs to body rotation with or without sound stimulation, as well as to sound source rotation with stationary body. We demonstrated that PNs are sensitive to head direction, and, in the presence of sound, they differentiate between body and sound source movement. Thus, the output of the DCN provides the brain with enough information to disambiguate the movement of a sound source from an acoustically identical relative movement produced by motion of the animal.

Stimulus-specific adaptation in a recurrent network model of primary auditory cortex.

Stimulus-specific adaptation (SSA) occurs when neurons decrease their responses to frequently-presented (standard) stimuli but not, or not as much, to other, rare (deviant) stimuli. SSA is present in all mammalian species in which it has been tested as well as in birds. SSA confers short-term memory to neuronal responses, and may lie upstream of the generation of mismatch negativity (MMN), an important human event-related potential. Previously published models of SSA mostly rely on synaptic depression of the feedforward, thalamocortical input. Here we study SSA in a recurrent neural network model of primary auditory cortex. When the recurrent, intracortical synapses display synaptic depression, the network generates population spikes (PSs). SSA occurs in this network when deviants elicit a PS but standards do not, and we demarcate the regions in parameter space that allow SSA. While SSA based on PSs does not require feedforward depression, we identify feedforward depression as a mechanism for expanding the range of parameters that support SSA. We provide predictions for experiments that could help differentiate between SSA due to synaptic depression of feedforward connections and SSA due to synaptic depression of recurrent connections. Similar to experimental data, the magnitude of SSA in the model depends on the frequency difference between deviant and standard, probability of the deviant, inter-stimulus interval and input amplitude. In contrast to models based on feedforward depression, our model shows true deviance sensitivity as found in experiments.

Detection of Tones Masked by Fluctuating Noise in Rat Auditory Cortex.

Sounds in natural settings always appear over a noisy background. The masked threshold of a pure tone in white noise (the lowest sound level at which the tone can be detected in the presence of masking noise) is largely determined by energy masking in the peripheral auditory system: when the signal-to-noise ratio within a frequency band centered at the target tone frequency is large enough, the tone can be detected. However, when additional information is supplied to the auditory system, for example in the presence of slow and coherent modulations of a broadband masker (often found in natural sounds), masked thresholds can be reduced substantially below the values expected from pure energy masking. Here, we used intracellular recordings in vivo in rat auditory cortex in order to study neuronal responses to pure tones masked by broadband maskers and amplitude-modulated broadband maskers. When tones were embedded in amplitude-modulated noise, detection thresholds were substantially lower than when embedded in unmodulated noise. The main cue for tone detection in modulated noise consisted of the suppression of the locking of the neuronal responses to the amplitude modulation of the noise by low-level tones.

Primary Auditory Cortex is Required for Anticipatory Motor Response.

The ability of the brain to predict future events based on the pattern of recent sensory experience is critical for guiding animal's behavior. Neocortical circuits for ongoing processing of sensory stimuli are extensively studied, but their contributions to the anticipation of upcoming sensory stimuli remain less understood. We, therefore, used in vivo cellular imaging and fiber photometry to record mouse primary auditory cortex to elucidate its role in processing anticipated stimulation. We found neuronal ensembles in layers 2/3, 4, and 5 which were activated in relationship to anticipated sound events following rhythmic stimulation. These neuronal activities correlated with the occurrence of anticipatory motor responses in an auditory learning task. Optogenetic manipulation experiments revealed an essential role of such neuronal activities in producing the anticipatory behavior. These results strongly suggest that the neural circuits of primary sensory cortex are critical for coding predictive information and transforming it into anticipatory motor behavior.

The Representation of Prediction Error in Auditory Cortex.

To survive, organisms must extract information from the past that is relevant for their future. How this process is expressed at the neural level remains unclear. We address this problem by developing a novel approach from first principles. We show here how to generate low-complexity representations of the past that produce optimal predictions of future events. We then illustrate this framework by studying the coding of 'oddball' sequences in auditory cortex. We find that for many neurons in primary auditory cortex, trial-by-trial fluctuations of neuronal responses correlate with the theoretical prediction error calculated from the short-term past of the stimulation sequence, under constraints on the complexity of the representation of this past sequence. In some neurons, the effect of prediction error accounted for more than 50% of response variability. Reliable predictions often depended on a representation of the sequence of the last ten or more stimuli, although the representation kept only few details of that sequence.

Functional mapping of single spines in cortical neurons in vivo.

The individual functional properties and spatial arrangement of afferent synaptic inputs on dendrites have a critical role in the processing of information by neurons in the mammalian brain. Although recent work has identified visually-evoked local dendritic calcium signals in the rodent visual cortex, sensory-evoked signalling on the level of dendritic spines, corresponding to individual afferent excitatory synapses, remains unexplored. Here we used a new variant of high-resolution two-photon imaging to detect sensory-evoked calcium transients in single dendritic spines of mouse cortical neurons in vivo. Calcium signals evoked by sound stimulation required the activation of NMDA (N-methyl-D-aspartate) receptors. Active spines are widely distributed on basal and apical dendrites and pure-tone stimulation at different frequencies revealed both narrowly and widely tuned spines. Notably, spines tuned for different frequencies were highly interspersed on the same dendrites: even neighbouring spines were mostly tuned to different frequencies. Thus, our results demonstrate that NMDA-receptor-dependent single-spine synaptic inputs to the same dendrite are highly heterogeneous. Furthermore, our study opens the way for in vivo mapping of functionally defined afferent sensory inputs with single-synapse resolution.

The Representation of Interaural Time Differences in High-Frequency Auditory Cortex.

Early representations of auditory features often involve neuronal populations whose tuning is substantially wider than behavioral discrimination thresholds. Although behavioral discrimination performance can be sometimes achieved by single neurons when using the appropriate part of their (wide) tuning curves, neurons that encode the resulting high-acuity representations have rarely been described. Here we demonstrate the existence of neurons with extremely narrow tuning for interaural time differences (ITDs), a major physical cue for the azimuth of sound sources. The tuning width of ITD-tuned brainstem neurons is mostly determined by the properties of their acoustic input, and may be 10-100 times wider than behavioral thresholds. In contrast, we show that tuning widths of some neurons in the primary auditory cortex in the cat high-frequency auditory cortex (measured using transposed stimulus) can be very sharp and approach behavioral thresholds. Furthermore, while best ITDs of brainstem neurons often lie outside the range of naturally encountered ITDs (the ethological range), the range of best ITDs of the narrowly tuned cortical neurons corresponds well to the ethological range. Thus, our results suggest that the auditory cortex contains a high-resolution representation of ITDs that explicitly decodes the widely tuned brainstem representations.

Auditory cortical processing in real-world listening: the auditory system going real.

The auditory sense of humans transforms intrinsically senseless pressure waveforms into spectacularly rich perceptual phenomena: the music of Bach or the Beatles, the poetry of Li Bai or Omar Khayyam, or more prosaically the sense of the world filled with objects emitting sounds that is so important for those of us lucky enough to have hearing. Whereas the early representations of sounds in the auditory system are based on their physical structure, higher auditory centers are thought to represent sounds in terms of their perceptual attributes. In this symposium, we will illustrate the current research into this process, using four case studies. We will illustrate how the spectral and temporal properties of sounds are used to bind together, segregate, categorize, and interpret sound patterns on their way to acquire meaning, with important lessons to other sensory systems as well.