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.

Extensive representation of sensory deviance in the responses to auditory gaps in unanesthetized rats.

Unexpected changes in incoming sensory streams are associated with large errors in predicting the deviant stimulus relative to a memory trace of past stimuli. Mismatch negativity (MMN) in human studies and the release from stimulus-specific adaptation (SSA) in animal models correlate with prediction errors and deviance detection.1 In human studies, violation of expectations elicited by an unexpected stimulus omission resulted in an omission MMN.2,3,4,5 These responses are evoked after the expected occurrence time of the omitted stimulus, implying that they reflect the violation of a temporal expectancy.6 Because they are often time locked to the end of the omitted stimulus,4,6,7 they resemble off responses. Indeed, suppression of cortical activity after the termination of the gap disrupts gap detection, suggesting an essential role for offset responses.8 Here, we demonstrate that brief gaps in short noise bursts in the auditory cortex of unanesthetized rats frequently evoke offset responses. Importantly, we show that omission responses are elicited when these gaps are expected but are omitted. These omission responses, together with the release from SSA of both onset and offset responses to rare gaps, form a rich and varied representation of prediction-related signals in the auditory cortex of unanesthetized rats, extending substantially and refining the representations described previously in anesthetized rats.

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.

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.

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.

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.

Emergence of abstract sound representations in the ascending auditory system.

Auditory processing begins by decomposing sounds into their frequency components, raising the question of where the representation of sounds as wholes emerges in the auditory system. To address this question, we used stimulus-specific adaptation (SSA), the reduction in the responses of a neuron to a common sound (standard) which does not generalize to another, rare sound (deviant). SSA to tone frequency has been demonstrated in multiple stations of the auditory pathway, including the inferior colliculus (IC), medial geniculate body (MGB) and auditory cortex. We designed wideband stimuli (tone clouds) that have identical frequency components but are nevertheless distinct. Tone clouds evoked early and substantial SSA in primary auditory cortex (A1) but only late and minor SSA in IC and MGB. These results imply that while in IC and MGB sounds are largely represented in terms of their frequency components, in A1 they are represented as abstract entities.

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.

Single-neuron representation of learned complex sounds in the auditory cortex.

The sensory responses of cortical neuronal populations following training have been extensively studied. However, the spike firing properties of individual cortical neurons following training remain unknown. Here, we have combined two-photon Ca2+ imaging and single-cell electrophysiology in awake behaving mice following auditory associative training. We find a sparse set (~5%) of layer 2/3 neurons in the primary auditory cortex, each of which reliably exhibits high-rate prolonged burst firing responses to the trained sound. Such bursts are largely absent in the auditory cortex of untrained mice. Strikingly, in mice trained with different multitone chords, we discover distinct subsets of neurons that exhibit bursting responses specifically to a chord but neither to any constituent tone nor to the other chord. Thus, our results demonstrate an integrated representation of learned complex sounds in a small subset of cortical neurons.

Immunohistological and Ultrastructural Study of the Inflammatory Response to Perforated Polyimide Cortical Implants: Mechanisms Underlying Deterioration of Electrophysiological Recording Quality.

The deterioration of field potential (FP) recording quality and yield by in vivo multielectrode arrays (MEA) within days to weeks of implantation severely limits progress in basic and applied brain research. The prevailing hypothesis is that implantation of MEA platforms initiate and perpetuate inflammatory processes which culminate in the formation of scar tissue (the foreign body response, FBR) around the implant. The FBR leads to progressive degradation of the recording qualities by displacing neurons away from the electrode surfaces, increasing the resistance between neurons (current source) and the sensing pads and by reducing the neurons' excitable membrane properties and functional synaptic connectivity through the release of pro-inflammatory cytokines. Meticulous attempts to causally relate the cellular composition, cell density, and electrical properties of the FBR have failed to unequivocally correlate the deterioration of recording quality with the histological severity of the FBR. Based on confocal and electron microscope analysis of thin sections of polyimide based MEA implants along with the surrounding brain tissue at different points in time after implantation, we propose that abrupt FP amplitude attenuation occurs at the implant/brain-parenchyma junction as a result of high seal resistance insulation formed by adhering microglia to the implant surfaces. In contrast to the prevailing hypothesis, that FP decrease occurs across the encapsulating scar of the implanted MEA, this mechanism potentially explains why no correlations have been found between the dimensions and density of the FBR and the recording quality. Recognizing that the seal resistance formed by adhering-microglia to the implant constitutes a downstream element undermining extracellular FP recordings, suggests that approaches to mitigate the formation of the insulating glial could lead to improved recording quality and yield.

Author Correction: Functional organization and population dynamics in the mouse primary auditory cortex.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Stimulus-specific adaptation to behaviorally-relevant sounds in awake rats.

Stimulus-specific adaptation (SSA) is the reduction in responses to a common stimulus that does not generalize, or only partially generalizes, to other stimuli. SSA has been studied mainly with sounds that bear no behavioral meaning. We hypothesized that the acquisition of behavioral meaning by a sound should modify the amount of SSA evoked by that sound. To test this hypothesis, we used fear conditioning in rats, using two word-like stimuli, derived from the English words "danger" and "safety", as well as pure tones. One stimulus (CS+) was associated with a foot shock whereas the other stimulus (CS-) was presented without a concomitant foot shock. We recorded neural responses to the auditory stimuli telemetrically, using chronically implanted multi-electrode arrays in freely moving animals before and after conditioning. Consistent with our hypothesis, SSA changed in a way that depended on the behavioral role of the sound: the contrast between standard and deviant responses remained the same or decreased for CS+ stimuli but increased for CS- stimuli, showing that SSA is shaped by experience. In most cases the sensory responses underlying these changes in SSA increased following conditioning. Unexpectedly, the responses to CS+ word-like stimuli showed a specific, large decrease, which we interpret as evidence for substantial inhibitory plasticity.

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.

In Vivo Functional Mapping of a Cortical Column at Single-Neuron Resolution.

The cerebral cortex is organized in vertical columns that contain neurons with similar functions. The cellular micro-architecture of such columns is an essential determinant of brain dynamics and cortical information processing. However, a detailed understanding of columns is incomplete, even in the best studied cortical regions, and mostly restricted to the upper cortical layers. Here, we developed a two-photon Ca2+-imaging-based method for the serial functional mapping of all pyramidal layers of the mouse primary auditory cortex at single-neuron resolution in individual animals. We demonstrate that the best frequency-responsive neurons are organized in all-layers-crossing narrow columns, with fuzzy boundaries and a bandwidth of about one octave. This micro-architecture is, in many ways, different from what has been reported before, indicating the region and stimulus specificity of functional cortical columns in vivo.

Filters: When, Why, and How (Not) to Use Them.

Filters are commonly used to reduce noise and improve data quality. Filter theory is part of a scientist's training, yet the impact of filters on interpreting data is not always fully appreciated. This paper reviews the issue and explains what a filter is, what problems are to be expected when using them, how to choose the right filter, and how to avoid filtering by using alternative tools. Time-frequency analysis shares some of the same problems that filters have, particularly in the case of wavelet transforms. We recommend reporting filter characteristics with sufficient details, including a plot of the impulse or step response as an inset.

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.

Tau impairs neural circuits, dominating amyloid-ß effects, in Alzheimer models in vivo.

The coexistence of amyloid-ß (Aß) plaques and tau neurofibrillary tangles in the neocortex is linked to neural system failure and cognitive decline in Alzheimer's disease. However, the underlying neuronal mechanisms are unknown. By employing in vivo two-photon Ca2+ imaging of layer 2/3 cortical neurons in mice expressing human Aß and tau, we reveal a dramatic tau-dependent suppression of activity and silencing of many neurons, which dominates over Aß-dependent neuronal hyperactivity. We show that neurofibrillary tangles are neither sufficient nor required for the silencing, which instead is dependent on soluble tau. Surprisingly, although rapidly effective in tau mice, suppression of tau gene expression was much less effective in rescuing neuronal impairments in mice containing both Aß and tau. Together, our results reveal how Aß and tau synergize to impair the functional integrity of neural circuits in vivo and suggest a possible cellular explanation contributing to disappointing results from anti-Aß therapeutic trials.

Acoustic recordings data from an echoic environment and a toolkit for its analysis.

The primary data are the impulse responses that were recorded in an echoic environment, using a set of twelve loudspeakers and a microphone. They were used as a part of an acoustic calibration process of large environments, as presented by Kazakov and Nelken (DOI: 10.1016/j.jneumeth.2018.08.025; Kazakov and Nelken, 2018). The impulse responses can be also used to localize the microphone in 3D (multi-lateration). The required audio files and the MATLAB code allows a complete reproduction of the experiment.