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Spontaneous activity in the developing auditory system is required for neuronal survival as well as the refinement and maintenance of tonotopic maps in the brain. However, the mechanisms responsible for initiating auditory nerve firing in the absence of sound have not been determined. Here we show that supporting cells in the developing rat cochlea spontaneously release ATP, which causes nearby inner hair cells to depolarize and release glutamate, triggering discrete bursts of action potentials in primary auditory neurons. This endogenous, ATP-mediated signalling synchronizes the output of neighbouring inner hair cells, which may help refine tonotopic maps in the brain. Spontaneous ATP-dependent signalling rapidly subsides after the onset of hearing, thereby preventing this experience-independent activity from interfering with accurate encoding of sound. These data indicate that supporting cells in the organ of Corti initiate electrical activity in auditory nerves before hearing, pointing to an essential role for peripheral, non-sensory cells in the development of central auditory pathways.

Learning causes a change in how information is processed by neuronal circuits. Whereas synaptic plasticity, an important cellular mechanism, has been studied in great detail, we know much less about how learning is implemented at the level of neuronal circuits and, in particular, how interactions between distinct types of neurons within local networks contribute to the process of learning. Here we show that acquisition of associative fear memories depends on the recruitment of a disinhibitory microcircuit in the mouse auditory cortex. Fear-conditioning-associated disinhibition in auditory cortex is driven by foot-shock-mediated cholinergic activation of layer 1 interneurons, in turn generating inhibition of layer 2/3 parvalbumin-positive interneurons. Importantly, pharmacological or optogenetic block of pyramidal neuron disinhibition abolishes fear learning. Together, these data demonstrate that stimulus convergence in the auditory cortex is necessary for associative fear learning to complex tones, define the circuit elements mediating this convergence and suggest that layer-1-mediated disinhibition is an important mechanism underlying learning and information processing in neocortical circuits. Stimulus convergence and concomitant auditory cortex disinhibition are essential for fear learning. Sounds like fear It is generally recognized that learned behavioural responses, such as those associated with sound, involve changes within specific neural circuits. However, we are only beginning to understand how those changes are implemented and what interactions between different types of neurons within the circuits contribute to the learning process. Using classical sound-based fear-conditioning in mice as a model system, Andreas Lüthi and colleagues identify a distinct disinhibition-based circuit that is critical to learning. The neural circuit involved is not specific to auditory cortex, and may represent a general mechanism through which cholinergic neuromodulation gates cortical activity.

Two types of human ES-cell-derived otic progenitors are shown to have the ability to differentiate in vitro into hair-cell-like cells and auditory neurons, and to engraft, differentiate and improve auditory-evoked response thresholds when transplanted into an auditory neuropathy model; this indicates that it may be possible to use cell-based therapeutic strategies to recover damaged sensory circuitry in deafness. Stem cells counter hearing loss Auditory neuropathy is a form of hearing loss in which the sensory-hair cells of the inner ear are often relatively unscathed, making cochlear implants alone ineffective as therapy. Rather, it is the next step in the auditory pathway that is impaired by damage sustained by the spiral ganglion neurons, and there are no routine treatments available to counter sensory-neuron loss. This paper reports the generation of ear-cell progenitors from human embryonic stem cells, and shows that these otic progenitor cells can differentiate into functional cells involved in auditory response. Transplant of the otic progenitor cells into chemically damaged gerbil ears restores auditory evoked response in the brainstem, suggesting that this type of procedure, combined with cochlear implants, could form the basis of a cell-based therapy for some types of deafness. Deafness is a condition with a high prevalence worldwide, produced primarily by the loss of the sensory hair cells and their associated spiral ganglion neurons (SGNs). Of all the forms of deafness, auditory neuropathy is of particular concern. This condition, defined primarily by damage to the SGNs with relative preservation of the hair cells 1 , is responsible for a substantial proportion of patients with hearing impairment 2 . Although the loss of hair cells can be circumvented partially by a cochlear implant, no routine treatment is available for sensory neuron loss, as poor innervation limits the prospective performance of an implant 3 . Using stem cells to recover the damaged sensory circuitry is a potential therapeutic strategy. Here we present a protocol to induce differentiation from human embryonic stem cells (hESCs) using signals involved in the initial specification of the otic placode. We obtained two types of otic progenitors able to differentiate in vitro into hair-cell-like cells and auditory neurons that display expected electrophysiological properties. Moreover, when transplanted into an auditory neuropathy model, otic neuroprogenitors engraft, differentiate and significantly improve auditory-evoked response thresholds. These results should stimulate further research into the development of a cell-based therapy for deafness.

In an auditory frequency discrimination task in rats, channelrhodopsin-2-mediated stimulation of corticostriatal neurons biases decisions in the direction predicted by the frequency tuning of the stimulated neurons, whereas archaerhodopsin-3-mediated inactivation biases decisions in the opposite direction. Sound decisions in the auditory cortex Many studies have established how sounds are represented in the auditory cortex, but the processes by which that coded information is transformed into action are less well understood. Petr Znamenskiy and Anthony Zador study one output of auditory cortex — the projections to the striatum — and explore the consequences of changing the activity of these neurons on rats' perceptions in an auditory task. Optogenetically manipulating neuronal activity biased decisions in a manner consistent with the properties of the stimulated neurons, implicating corticostriatal activity in sensorimotor transformations. As cortical areas corresponding to all sensory modalities project to the striatum, this work also has implications beyond the auditory system. The neural pathways by which information about the acoustic world reaches the auditory cortex are well characterized, but how auditory representations are transformed into motor commands is not known. Here we use a perceptual decision-making task in rats to study this transformation. We demonstrate the role of corticostriatal projection neurons in auditory decisions by manipulating the activity of these neurons in rats performing an auditory frequency-discrimination task. Targeted channelrhodopsin-2 (ChR2) 1 , 2 -mediated stimulation of corticostriatal neurons during the task biased decisions in the direction predicted by the frequency tuning of the stimulated neurons, whereas archaerhodopsin-3 (Arch) 3 -mediated inactivation biased decisions in the opposite direction. Striatal projections are widespread in cortex and may provide a general mechanism for the control of motor decisions by sensory cortex.

The neural correlates of how attended speech is internally represented are described, shedding light on the ‘cocktail party problem’. Heard instinct The 'cocktail-party problem' — the question of what goes on in our brains when we listen selectively for one person's voice while ignoring many others — has puzzled researchers from various disciplines for years. Using electrophysiological recordings from neurosurgery patients listening to two speakers simultaneously, Nima Mesgarani and Edward Chang determine the neural correlates associated with the internal representation of attended speech. They find that the neural responses in the auditory cortex represent the attended voice robustly, almost as if the second voice were not there. With these patterns established, a simple algorithm trained on various speakers predicts which stimulus a subject is attending to, on the basis of the patterns emerging in the secondary auditory cortex. These results suggest that speech representation in the brain reflects not only the acoustic environment, but also the listener's understanding of these signals. As well as shedding light on a long-standing neurobiological problem, this work may give clues as to how automatic speech recognition might be improved to cope with more than one talker. Humans possess a remarkable ability to attend to a single speaker’s voice in a multi-talker background 1 , 2 , 3 . How the auditory system manages to extract intelligible speech under such acoustically complex and adverse listening conditions is not known, and, indeed, it is not clear how attended speech is internally represented 4 , 5 . Here, using multi-electrode surface recordings from the cortex of subjects engaged in a listening task with two simultaneous speakers, we demonstrate that population responses in non-primary human auditory cortex encode critical features of attended speech: speech spectrograms reconstructed based on cortical responses to the mixture of speakers reveal the salient spectral and temporal features of the attended speaker, as if subjects were listening to that speaker alone. A simple classifier trained solely on examples of single speakers can decode both attended words and speaker identity. We find that task performance is well predicted by a rapid increase in attention-modulated neural selectivity across both single-electrode and population-level cortical responses. These findings demonstrate that the cortical representation of speech does not merely reflect the external acoustic environment, but instead gives rise to the perceptual aspects relevant for the listener’s intended goal.

We used functional magnetic resonance imaging to investigate neural processes when music gains reward value the first time it is heard. The degree of activity in the mesolimbic striatal regions, especially the nucleus accumbens, during music listening was the best predictor of the amount listeners were willing to spend on previously unheard music in an auction paradigm. Importantly, the auditory cortices, amygdala, and ventromedial prefrontal regions showed increased activity during listening conditions requiring valuation, but did not predict reward value, which was instead predicted by increasing functional connectivity of these regions with the nucleus accumbens as the reward value increased. Thus, aesthetic rewards arise from the interaction between mesolimbic reward circuitry and cortical networks involved in perceptual analysis and valuation.

Cortical inhibitory interneurons expressing vasoactive intestinal polypeptide (VIP) are shown to specialize in suppressing the activity of other inhibitory interneurons and are activated by reinforcement signals, thus increasing the activity of excitatory neurons by releasing them from inhibition; these results reveal a cell-type-specific microcircuit that tunes cortical activity under certain behavioural conditions. Neuronal disinhibition in the cerebral cortex Disinhibition is a potentially powerful mechanism for controlling the activity and computation in neural circuits. Relatively little is known about neurons specializing in disinhibition and their specific function. Now Adam Kepecs and colleagues report that a cortical interneuron type defined by vasoactive intestinal polypeptide (VIP) expression inhibits the activity of other inhibitory interneurons, thereby adding an additional level of control over excitatory neurons. They further find that VIP interneurons are activated by rewards and punishments when rats perform a reinforcement learning task. These results reveal a cell-type-specific microcircuit that tunes cortical activity under certain behavioural conditions. In the mammalian cerebral cortex the diversity of interneuronal subtypes underlies a division of labour subserving distinct modes of inhibitory control 1 , 2 , 3 , 4 , 5 , 6 , 7 . A unique mode of inhibitory control may be provided by inhibitory neurons that specifically suppress the firing of other inhibitory neurons. Such disinhibition could lead to the selective amplification of local processing and serve the important computational functions of gating and gain modulation 8 , 9 . Although several interneuron populations are known to target other interneurons to varying degrees 10 , 11 , 12 , 13 , 14 , 15 , little is known about interneurons specializing in disinhibition and their in vivo function. Here we show that a class of interneurons that express vasoactive intestinal polypeptide (VIP) mediates disinhibitory control in multiple areas of neocortex and is recruited by reinforcement signals. By combining optogenetic activation with single-cell recordings, we examined the functional role of VIP interneurons in awake mice, and investigated the underlying circuit mechanisms in vitro in auditory and medial prefrontal cortices. We identified a basic disinhibitory circuit module in which activation of VIP interneurons transiently suppresses primarily somatostatin- and a fraction of parvalbumin-expressing inhibitory interneurons that specialize in the control of the input and output of principal cells, respectively 3 , 6 , 16 , 17 . During the performance of an auditory discrimination task, reinforcement signals (reward and punishment) strongly and uniformly activated VIP neurons in auditory cortex, and in turn VIP recruitment increased the gain of a functional subpopulation of principal neurons. These results reveal a specific cell type and microcircuit underlying disinhibitory control in cortex and demonstrate that it is activated under specific behavioural conditions.

Speech recognition is robust to background noise. One underlying neural mechanism is that the auditory system segregates speech from the listening background and encodes it reliably. Such robust internal representation has been demonstrated in auditory cortex by neural activity entrained to the temporal envelope of speech. A paradox, however, then arises, as the spectro-temporal fine structure rather than the temporal envelope is known to be the major cue to segregate target speech from background noise. Does the reliable cortical entrainment in fact reflect a robust internal “synthesis” of the attended speech stream rather than direct tracking of the acoustic envelope? Here, we test this hypothesis by degrading the spectro-temporal fine structure while preserving the temporal envelope using vocoders. Magnetoencephalography (MEG) recordings reveal that cortical entrainment to vocoded speech is severely degraded by background noise, in contrast to the robust entrainment to natural speech. Furthermore, cortical entrainment in the delta-band (1–4Hz) predicts the speech recognition score at the level of individual listeners. These results demonstrate that reliable cortical entrainment to speech relies on the spectro-temporal fine structure, and suggest that cortical entrainment to the speech envelope is not merely a representation of the speech envelope but a coherent representation of multiscale spectro-temporal features that are synchronized to the syllabic and phrasal rhythms of speech. •Cortical entrainment to vocoded speech is sensitive to background noise.•Robust cortical entrainment to speech relies on the spectro-temporal fine structure.•Delta-band entrainment predicts individual speech recognition score.

Transcranial direct current stimulation (tDCS) can systematically modify behavior by inducing changes in the underlying brain function. Objective electrophysiological evidence for tDCS-induced excitability changes has been demonstrated for the visual and somatosensory cortex, while evidence for excitability changes in the auditory cortex is lacking. In the present study, we applied tDCS over the left temporal as well as the left temporo-parietal cortex and investigated tDCS-induced effects on auditory evoked potentials after anodal, cathodal, and sham stimulation. Results show that anodal and cathodal tDCS can modify auditory cortex reactivity. Moreover, auditory evoked potentials were differentially modulated as a function of site of stimulation. While anodal tDCS over the temporal cortex increased auditory P50 amplitudes, cathodal tDCS over the temporo-parietal cortex induced larger N1 amplitudes. The results directly demonstrate excitability changes in the auditory cortex induced by active tDCS over the temporal and temporo-parietal cortex and might contribute to the understanding of mechanisms involved in the successful treatment of auditory disorders like tinnitus via tDCS.

Hearing impairment in older adults is independently associated in longitudinal studies with accelerated cognitive decline and incident dementia, and in cross-sectional studies, with reduced volumes in the auditory cortex. Whether peripheral hearing impairment is associated with accelerated rates of brain atrophy is unclear. We analyzed brain volume measurements from magnetic resonance brain scans of individuals with normal hearing versus hearing impairment (speech-frequency pure tone average>25dB) followed in the neuroimaging substudy of the Baltimore Longitudinal Study of Aging for a mean of 6.4years after the baseline scan (n=126, age 56–86years). Brain volume measurements were performed with semi-automated region-of-interest (ROI) algorithms, and brain volume trajectories were analyzed with mixed-effect regression models adjusted for demographic and cardiovascular factors. We found that individuals with hearing impairment (n=51) compared to those with normal hearing (n=75) had accelerated volume declines in whole brain and regional volumes in the right temporal lobe (superior, middle, and inferior temporal gyri, parahippocampus, p<.05). These results were robust to adjustment for multiple confounders and were consistent with voxel-based analyses, which also implicated right greater than left temporal regions. These findings demonstrate that peripheral hearing impairment is independently associated with accelerated brain atrophy in whole brain and regional volumes concentrated in the right temporal lobe. Further studies investigating the mechanistic basis of the observed associations are needed.