Cortical implants are a proven clinical neurotechnology with the potential to transform our understanding of cognitive processes. These processes rely on complex neuronal networks that are difficult to selectively probe or stimulate. Optogenetics offers cell-type specificity, but achieving the density and coverage required for chronic, high-resolution modulation remains a challenge. We fabricated 100-element μLED arrays (200 μm pixel pitch, 2 × 2 mm2 footprint) coupled into chronically implantable systems for optogenetic stimulation of the mouse cortex. The μLEDs remain stable for over 300 hours continuous operation time in vivo, allowing for months-long chronic experiments. Simultaneous electrophysiology recordings confirmed robust neuronal responses at low μLED drive currents (< 5 mA), minimising thermal effects. Here we show that our device can be chronically implanted in freely-behaving mice and drive behavioural outcomes from spatiotemporal, patterned, optogenetic stimulation of auditory cortical circuits. Achieving high resolution with optical neural interfaces is challenging. Here, the authors developed and chronically implanted 100-pixel microLED arrays on the surface of the mouse auditory cortex for optogenetic behavioural experiements.

Background DFNB16, the second most common genetic cause of hearing loss, is caused by mutations of the STRC gene encoding stereocilin, a protein essential for the effective functioning of outer hair cells (OHCs) as cochlear amplifiers. Strc-/- mice, which lack stereocilin, display severe to profound deafness and constitute a relevant preclinical model for DFNB16.Methods Using Strc-/- mice, we developed a gene therapy strategy based on the use of dual AAV9-PHP.eB vectors to deliver the full-length Strc cDNA. Therapeutic efficacy was assessed by evaluating stereocilin expression, OHC bundle architecture, and their attachment to the tectorial membrane, together with functional recovery using distortion product otoacoustic emissions (DPOAEs), auditory brainstem responses (ABR) measurements and Go/No-Go behavioral testing with psychometric analysis.Results Dual-AAV-mediated Strc gene delivery restored stereocilin expression, OHC bundle architecture and their attachment to the tectorial membrane, leading to the recovery of cochlear amplification and hearing to near normal thresholds, as confirmed by distortion product otoacoustic emission (DPOAE) and auditory brainstem response measurements. Behavioural assessment showed that treated Strc-/- mice regained normal frequency discrimination, indicating a restoration of higher-order auditory processing, up to 100 days post-treatment.Conclusion These findings provide the first proof-of-principle that peripheral gene therapy can restore OHC function, cochlear amplification and central auditory perception in a DFNB16 model.Key points Dual AAV-mediated gene delivery restored peripheral hearing in a DFNB16 preclinical mouse model. The same treatment also restored central auditory processing. AAV-mediated gene therapy represents a promising curative strategy for DFNB16. These results reinforce the translational potential for treating human genetic deafness.

The integration of olfactory and spatial information is critical for guiding animal behavior. The lateral entorhinal cortex (LEC) is reciprocally interconnected with cortical areas for olfaction and the hippocampus and thus ideally positioned to encode odor-place associations. Here, we used miniendoscopes to record neural activity in the mouse piriform cortex (PCx) and LEC. We show that in head-fixed mice, odor identity could be decoded from LEC ensembles but less accurately than from PCx. In male mice freely navigating a linear track, LEC ensemble activity at the odor ports was dominated by spatial information. Spatial position along the linear track could be decoded from LEC and PCx activity; however, PCx but not LEC exhibited strong behavior-driven modulation of positional information. Together, our data reveal that information about odor cues and spatial context is differentially encoded along the PCx-LEC axis.

Early studies on orientation selectivity in the visual cortex have suggested that sensory systems generate new feature representations at specific processing stages. Many observations challenge this view, but in the absence of systematic, multistage measurements, the logic of how feature tuning emerges remains elusive. Here, using a generic approach based on representational similarity analysis with a noise-corrected population metric, we demonstrate in the mouse auditory system that feature representations evolve gradually with, in some cases, major, feature-specific improvements at particular stages. We observe that single frequency tuning is already fully developed in the cochlear nucleus, the first stage of processing, while tuning to higher-order features improves up to the auditory cortex, with major steps in the inferior colliculus for amplitude modulation frequency or noise bandwidth tuning and in the cortex for frequency modulation direction and for complex sound identity or direction. Moreover, we observe that intensity tuning is established in a feature-dependent manner, earlier for pure frequencies than for more complex sounds. This indicates that auditory feature computations are a mix of stepwise and gradual processes which together contribute to decorrelate sound representations.

During wake, sound-evoked and spontaneous neural activity of the auditory cortex evolves in distinct subspaces, whereas anesthesia disrupts sound responses and merges these spaces. To evaluate if similar modifications of sound representation geometry explain sensory disconnection during sleep, large neural populations of the mouse auditory cortex are followed across slow-wave sleep and wakefulness. It is observed that sleep dampens sound responses but preserves the geometry of sound representations such that they remain separate from spontaneous activity. Moreover, response dampening is strongly coordinated across neurons and varied throughout sleep, spanning from fully preserved response patterns to population response failures on a fraction of sound presentations. These failures rarely occurred in wakefulness and are more common during high spindle-band activity. Therefore, in sleep, the auditory system preserves sound feature selectivity up to the cortex for detailed acoustic surveillance but concurrently implements an intermittent gating mechanism leading to local sensory disconnections.

The claustrum is thought to be one of the most highly interconnected forebrain structures but its organizing principles have yet to be fully explored at the level of single neurons. Here, we investigated the identity, connectivity, and activity of identified claustrum neurons to understand how the structure's unique convergence of input and divergence of output support binding information streams. We found that neurons in the claustrum communicate with each other across efferent projection-defined modules which were differentially innervated by sensory and frontal cortical areas. Individual claustrum neurons were responsive to inputs from more than one cortical region in a cell-type and projection-specific manner, particularly between areas of frontal cortex. In vivo imaging of claustrum axons revealed responses to both unimodal and multimodal sensory stimuli. Finally, chronic claustrum silencing specifically reduced animals' sensitivity to multimodal stimuli. These findings support the view that the claustrum is a fundamentally integrative structure, consolidating information from around the cortex and redistributing it following local computations.

The temporal structure of sensory inputs contains essential information for their interpretation. Sensory cortex represents these temporal cues through two codes: the temporal sequences of neuronal activity and the spatial patterns of neuronal firing rate. However, it is unknown which of these coexisting codes causally drives sensory decisions. To separate their contributions, we generated in the mouse auditory cortex optogenetically driven activity patterns differing exclusively along their temporal or spatial dimensions. Mice could rapidly learn to behaviorally discriminate spatial but not temporal patterns. Moreover, large-scale neuronal recordings across the auditory system revealed that the auditory cortex is the first region in which spatial patterns efficiently represent temporal cues on the timescale of several hundred milliseconds. This feature is shared by the deep layers of neural networks categorizing time-varying sounds. Therefore, the emergence of a spatial code for temporal sensory cues is a necessary condition to efficiently associate temporally structured stimuli with decisions.

Human-specific cognitive abilities depend on information processing in the cerebral cortex, where neurons are significantly larger and sparser compared to rodents. We found that, in synaptically-connected layer 2/3 pyramidal cells (L2/3 PCs), soma-to-soma signal propagation delay is similar in humans and rodents. Thus, to compensate for the increase in neurons’ size, membrane potential changes must propagate faster in human axons and/or dendrites. Dual somato-dendritic and somato-axonal patch recordings show that action potentials (APs) propagation speed is similar in human and rat axons, but the forward propagation of the EPSPs and the back-propagating APs are ∼ 26 and 47% faster in human dendrites respectively. Faithful biophysical models of human and rat L2/3 PCs, combined with pharmacological manipulations of membrane properties, showed both the larger diameter of the apical dendrite and the larger conductance load imposed by the basal tree in human, combined with differences in cable properties, underlie the accelerated signal propagation in human cortical circuits.

During wake, sound-evoked and spontaneous neural activity of the auditory cortex evolve in distinct subspaces whereas anesthesia disrupts sound responses and merges these spaces. To evaluate if similar modifications of the sound representation geometry explain sensory disconnection during sleep, we followed large neural populations of the mouse auditory cortex across slow wave sleep and wakefulness. We observed that sleep dampens sound responses but preserves the geometry of sound representations which remain separate from spontaneous activity. Moreover, response dampening was strongly coordinated across neurons and varied throughout sleep spanning from fully preserved response patterns to population response failures on a fraction of sound presentations. These failures are more common during high spindle-band activity and more rarely observed in wakefulness. Therefore, in sleep, the auditory system preserves sound feature selectivity up to the cortex for detailed acoustic surveillance, but concurrently implements an intermittent gating mechanism leading to local sensory disconnections. ### Competing Interest Statement The authors have declared no competing interest. Fondation pour l’Audition, RD-2023-1, FPA IDA02, APA 2016-03 Fondation pour la Recherche Médicale, SPF202005011970 Agence Nationale pour la Recherche, AudioDream, ANR-23-IAHU-0003 European Research Council, ERC CoG 770841 DEEPEN

Early studies on orientation selectivity in the visual cortex have suggested that sensory systems generate new feature representations at specific processing stages. Many observations challenge this view, but in the absence of systematic, multistage measurements, the logic of how feature tuning emerges remains elusive. Here, using a generic approach based on representational similarity analysis with a noise-corrected population metric, we demonstrate in the mouse auditory system that feature representations evolve gradually with, in some cases, major, feature-specific improvements at particular stages. We observe that single frequency tuning is already fully developed in the cochlear nucleus, the first stage of processing, while tuning to higher-order features improves up to the auditory cortex, with major steps in the inferior colliculus for amplitude modulation frequency or noise bandwidth tuning and in the cortex for frequency modulation direction and for complex sound identity or direction. Moreover, we observe that intensity tuning is established in a feature-dependent manner, earlier for pure frequencies than for more complex sounds. This indicates that auditory feature computations are a mix of stepwise and gradual processes which together contribute to decorrelate sound representations. ### Competing Interest Statement The authors have declared no competing interest.

The entire auditory system downstream of the cochlea features pronounced offset responses that follow the termination of sounds. Because of their ubiquity, it remains an unsolved question whether offset responses are generated early in the auditory system and subsequently propagated downstream or recomputed at each processing stage. Here, we analysed large-scale sound response datasets acquired in the cochlear nucleus, inferior colliculus, medial geniculate nucleus and auditory cortex of awake mice. All brain regions showed a significant proportion of offset responses, often combined with onset and sustained responses in the same neuron. However, using population activity decoders, we observed that neural representations after the sound offset show a three-fold increase in sound encoding accuracy in the cortex relative to subcortical areas. This result indicates that cortical offsets encode a more precise short-term memory of the elapsed sound than subcortical offsets and that they probably result from specific computational steps. KEY POINTS: Offset responses are found throughout the central auditory system. Offset responses are often combined with sustained and onset responses at all central auditory system stages. Offset responses provide richer information about elapsed sounds in the auditory cortex.

Auditory neuropathies affect the spiral ganglion neurons of the auditory nerve or their synapses with the sensory hair cells, distorting the sound information transmitted from the ear to the brain. Deciphering the underlying pathophysiological mechanisms remains challenging owing to the diversity of spiral ganglion neuron subtypes and associated central auditory circuits. An auditory neuropathy mechanism is unraveled by investigating the origin of auditory hyperexcitability in a mouse model for hereditary congenital deafness. Otogl encodes the large Otogelin-like protein, which is related to secreted epithelial mucins and is implicated in the mechanical stimulation of cochlear outer hair cells. Heterozygous Otogl+/- mutant mice display auditory hyperexcitability, highlighted by their susceptibility to audiogenic seizures induced by loud sounds. It is shown that Otogl is transiently expressed in a subpopulation of spiral ganglion neurons during cochlear development. Despite their apparently normal hearing, Otogl+/- mice display poor activation of the spiral ganglion neurons processing loud sounds and an elevation of the activation threshold of the middle the ear muscle reflex that attenuates loud sounds. The findings reveal how a neuropathy affecting spiral ganglion neurons specialized in loud sound processing and associated with the middle the ear muscle reflex can manifest itself as auditory hyperexcitability.