The clustered gamma protocadherin PcdhγC4 isoform regulates cortical interneuron programmed cell death in the mouse cortex.

Cortical inhibitory interneurons (cINs) are born in the ventral forebrain and migrate into the cortex where they make connections with locally produced excitatory glutamatergic neurons. Cortical function critically depends on the number of cINs, which is also key to establishing the appropriate inhibitory/excitatory balance. The final number of cINs is determined during a postnatal period of programmed cell death (PCD) when ~40% of the young cINs are eliminated. Previous work shows that the loss of clustered gamma protocadherins (Pcdhgs), but not of genes in the Pcdha or Pcdhb clusters, dramatically increased BAX-dependent cIN PCD. Here, we show that PcdhγC4 is highly expressed in cINs of the mouse cortex and that this expression increases during PCD. The sole deletion of the PcdhγC4 isoform, but not of the other 21 isoforms in the Pcdhg gene cluster, increased cIN PCD. Viral expression of the PcdhγC4, in cIN lacking the function of the entire Pcdhg cluster, rescued most of these cells from cell death. We conclude that PcdhγC4 plays a critical role in regulating the survival of cINs during their normal period of PCD. This highlights how a single isoform of the Pcdhg cluster, which has been linked to human neurodevelopmental disorders, is essential to adjust cIN cell numbers during cortical development.

Basic Properties of Coordinated Neuronal Ensembles in the Auditory Thalamus.

Coordinated neuronal activity has been identified to play an important role in information processing and transmission in the brain. However, current research predominantly focuses on understanding the properties and functions of neuronal coordination in hippocampal and cortical areas, leaving subcortical regions relatively unexplored. In this study, we use single-unit recordings in female Sprague Dawley rats to investigate the properties and functions of groups of neurons exhibiting coordinated activity in the auditory thalamus-the medial geniculate body (MGB). We reliably identify coordinated neuronal ensembles (cNEs), which are groups of neurons that fire synchronously, in the MGB. cNEs are shown not to be the result of false-positive detections or by-products of slow-state oscillations in anesthetized animals. We demonstrate that cNEs in the MGB have enhanced information-encoding properties over individual neurons. Their neuronal composition is stable between spontaneous and evoked activity, suggesting limited stimulus-induced ensemble dynamics. These MGB cNE properties are similar to what is observed in cNEs in the primary auditory cortex (A1), suggesting that ensembles serve as a ubiquitous mechanism for organizing local networks and play a fundamental role in sensory processing within the brain.

Receptive-field nonlinearities in primary auditory cortex: a comparative perspective.

Cortical processing of auditory information can be affected by interspecies differences as well as brain states. Here we compare multifeature spectro-temporal receptive fields (STRFs) and associated input/output functions or nonlinearities (NLs) of neurons in primary auditory cortex (AC) of four mammalian species. Single-unit recordings were performed in awake animals (female squirrel monkeys, female, and male mice) and anesthetized animals (female squirrel monkeys, rats, and cats). Neuronal responses were modeled as consisting of two STRFs and their associated NLs. The NLs for the STRF with the highest information content show a broad distribution between linear and quadratic forms. In awake animals, we find a higher percentage of quadratic-like NLs as opposed to more linear NLs in anesthetized animals. Moderate sex differences of the shape of NLs were observed between male and female unanesthetized mice. This indicates that the core AC possesses a rich variety of potential computations, particularly in awake animals, suggesting that multiple computational algorithms are at play to enable the auditory system's robust recognition of auditory events.

On the Role of Theory and Modeling in Neuroscience.

In recent years, the field of neuroscience has gone through rapid experimental advances and a significant increase in the use of quantitative and computational methods. This growth has created a need for clearer analyses of the theory and modeling approaches used in the field. This issue is particularly complex in neuroscience because the field studies phenomena that cross a wide range of scales and often require consideration at varying degrees of abstraction, from precise biophysical interactions to the computations they implement. We argue that a pragmatic perspective of science, in which descriptive, mechanistic, and normative models and theories each play a distinct role in defining and bridging levels of abstraction, will facilitate neuroscientific practice. This analysis leads to methodological suggestions, including selecting a level of abstraction that is appropriate for a given problem, identifying transfer functions to connect models and data, and the use of models themselves as a form of experiment.

Offset responses in the auditory cortex show unique history dependence.

Sensory responses typically vary depending on the recent history of sensory experience. This is essential for processes including adaptation, efficient coding, and change detection. In the auditory cortex (AC), the short-term history-dependence of sound-evoked (onset) responses has been well characterized. Yet many AC neurons also respond to sound terminations, and little is known about the history-dependence of these "offset" responses, whether the short-term dynamics of onset and offset responses are correlated, or how these properties are distributed among cell types. Here we presented awake male and female mice with repeating noise burst stimuli while recording single unit activity from primary AC. We identified PV and SST interneurons through optotagging, and also separated narrow-spiking from broad-spiking units. We found that offset responses are typically less depressive than onset responses, and this result was robust to a variety of stimulus parameters, controls, measurement types, and selection criteria. Whether a cell's onset response facilitates or depresses does not predict whether its offset response facilitates or depresses. Cell types differed in the dynamics of their onset responses, and in the prevalence but not the dynamics of their offset responses. Finally, we clustered cells according to spiking responses and found that response clusters were associated with cell type. Each cluster contained cells of several types, but even within a cluster, cells often showed cell type specific response dynamics. We conclude that onset and offset responses are differentially influenced by recent sound history, and discuss the implications of this for the encoding of ongoing sound stimuli.SIGNIFICANCE STATEMENT:Sensory neuron responses depend on stimulus history. This history dependence is crucial for sensory processing, is precisely controlled at individual synapses and circuits, and is adaptive to the specific requirements of different sensory systems. In the auditory cortex, neurons respond to sound cessation as well as to sound itself, but how history dependence is utilized along this separate, "offset" information stream is unknown. We show that offset responses are more facilitatory than sound responses, even in neurons where sound responses depress. In contrast to sound onset responses, offset responses are absent in many cells, are relatively homogenous, and show no cell-type specific differences in history dependence. Offset responses thus show unique response dynamics, suggesting their unique functions.

Transplanted Cells Are Essential for the Induction But Not the Expression of Cortical Plasticity.

Transplantation of even a small number of embryonic inhibitory neurons from the medial ganglionic eminence (MGE) into postnatal visual cortex makes it lose responsiveness to an eye deprived of vision when the transplanted neurons reach the age of the normal critical period of activity-dependent ocular dominance (OD) plasticity. The transplant might induce OD plasticity in the host circuitry or might instead construct a parallel circuit of its own to suppress cortical responses to the deprived eye. We transplanted MGE neurons expressing either archaerhodopsin or channelrhodopsin into the visual cortex of both male and female mice, closed one eyelid for 4-5 d, and, as expected, observed transplant-induced OD plasticity. This plasticity was evident even when the activity of the transplanted cells was suppressed or enhanced optogenetically, demonstrating that the plasticity was produced by changes in the host visual cortex.SIGNIFICANCE STATEMENT Interneuron transplantation into mouse V1 creates a window of heightened plasticity that is quantitatively and qualitatively similar to the normal critical period; that is, short-term occlusion of either eye markedly changes ocular dominance (OD). The underlying mechanism of this process is not known. Transplanted interneurons might either form a separate circuit to maintain the OD shift or might instead trigger changes in the host circuity. We designed experiments to distinguish the two hypotheses. Our findings suggest that while inhibition produced by the transplanted cells triggers this form of plasticity, the host circuity is entirely responsible for maintaining the OD shift.

Vesicular GABA Transporter Is Necessary for Transplant-Induced Critical Period Plasticity in Mouse Visual Cortex.

The maturation of GABAergic inhibitory circuits is necessary for the onset of the critical period for ocular dominance plasticity (ODP) in the postnatal visual cortex (Hensch, 2005; Espinosa and Stryker, 2012). When it is deficient, the critical period does not start. When inhibitory maturation or signaling is precocious, it induces a precocious critical period. Heterochronic transplantation of GABAergic interneuron precursors derived from the medial ganglionic eminence (MGE) can induce a second period of functional plasticity in the visual cortex (Southwell et al., 2010). Although the timing of MGE transplantation-induced plasticity is dictated by the maturation of the transplanted cells, its mechanisms remain largely unknown. Here, we sought to test the effect of blocking vesicular GABA loading and subsequent release by transplanted interneurons on the ability to migrate, integrate, and induce plasticity in the host circuitry. We show that MGE cells taken from male and female donors that lack vesicular GABA transporter (Vgat) expression disperse and differentiate into somatostatin- and parvalbumin-expressing interneurons upon heterochronic transplantation in the postnatal mouse cortex. Although transplanted Vgat mutant interneurons come to express mature interneuron markers and display electrophysiological properties similar to those of control cells, their morphology is significantly more complex. Significantly, Vgat mutant MGE transplants fail to induce ODP, demonstrating the pivotal role of vesicular GABAergic transmission for MGE transplantation-induced plasticity in the postnatal mouse visual cortex.SIGNIFICANCE STATEMENT Embryonic inhibitory neurons thrive when transplanted into postnatal brains, migrating and differentiating in the host as they would have done if left in the donor. Once integrated into the host, these new neurons can have profound effects. For example, in the visual cortex, such neurons induce a second critical period of activity-dependent plasticity when they reach the appropriate stage of development. The cellular mechanism by which these transplanted GABAergic interneurons induce plasticity is unknown. Here, we show that transplanted interneurons that are unable to fill synaptic vesicles with GABA migrate and integrate into the host circuit, but they do not induce a second period of plasticity. These data suggest a role for the vesicular GABA transporter in transplantation-mediated plasticity.

Visual Information Present in Infragranular Layers of Mouse Auditory Cortex.

The cerebral cortex is a major hub for the convergence and integration of signals from across the sensory modalities; sensory cortices, including primary regions, are no exception. Here we show that visual stimuli influence neural firing in the auditory cortex of awake male and female mice, using multisite probes to sample single units across multiple cortical layers. We demonstrate that visual stimuli influence firing in both primary and secondary auditory cortex. We then determine the laminar location of recording sites through electrode track tracing with fluorescent dye and optogenetic identification using layer-specific markers. Spiking responses to visual stimulation occur deep in auditory cortex and are particularly prominent in layer 6. Visual modulation of firing rate occurs more frequently at areas with secondary-like auditory responses than those with primary-like responses. Auditory cortical responses to drifting visual gratings are not orientation-tuned, unlike visual cortex responses. The deepest cortical layers thus appear to be an important locus for cross-modal integration in auditory cortex.SIGNIFICANCE STATEMENT The deepest layers of the auditory cortex are often considered its most enigmatic, possessing a wide range of cell morphologies and atypical sensory responses. Here we show that, in mouse auditory cortex, these layers represent a locus of cross-modal convergence, containing many units responsive to visual stimuli. Our results suggest that this visual signal conveys the presence and timing of a stimulus rather than specifics about that stimulus, such as its orientation. These results shed light on both how and what types of cross-modal information is integrated at the earliest stages of sensory cortical processing.

Secretagogin is Expressed by Developing Neocortical GABAergic Neurons in Humans but not Mice and Increases Neurite Arbor Size and Complexity.

The neocortex of primates, including humans, contains more abundant and diverse inhibitory neurons compared with rodents, but the molecular foundations of these observations are unknown. Through integrative gene coexpression analysis, we determined a consensus transcriptional profile of GABAergic neurons in mid-gestation human neocortex. By comparing this profile to genes expressed in GABAergic neurons purified from neonatal mouse neocortex, we identified conserved and distinct aspects of gene expression in these cells between the species. We show here that the calcium-binding protein secretagogin (SCGN) is robustly expressed by neocortical GABAergic neurons derived from caudal ganglionic eminences (CGE) and lateral ganglionic eminences during human but not mouse brain development. Through electrophysiological and morphometric analyses, we examined the effects of SCGN expression on GABAergic neuron function and form. Forced expression of SCGN in CGE-derived mouse GABAergic neurons significantly increased total neurite length and arbor complexity following transplantation into mouse neocortex, revealing a molecular pathway that contributes to morphological differences in these cells between rodents and primates.

Amplitude modulation coding in awake mice and squirrel monkeys.

Both mice and primates are used to model the human auditory system. The primate order possesses unique cortical specializations that govern auditory processing. Given the power of molecular and genetic tools available in the mouse model, it is essential to understand the similarities and differences in auditory cortical processing between mice and primates. To address this issue, we directly compared temporal encoding properties of neurons in the auditory cortex of awake mice and awake squirrel monkeys (SQMs). Stimuli were drawn from a sinusoidal amplitude modulation (SAM) paradigm, which has been used previously both to characterize temporal precision and to model the envelopes of natural sounds. Neural responses were analyzed with linear template-based decoders. In both species, spike timing information supported better modulation frequency discrimination than rate information, and multiunit responses generally supported more accurate discrimination than single-unit responses from the same site. However, cortical responses in SQMs supported better discrimination overall, reflecting superior temporal precision and greater rate modulation relative to the spontaneous baseline and suggesting that spiking activity in mouse cortex was less strictly regimented by incoming acoustic information. The quantitative differences we observed between SQM and mouse cortex support the idea that SQMs offer advantages for modeling precise responses to fast envelope dynamics relevant to human auditory processing. Nevertheless, our results indicate that cortical temporal processing is qualitatively similar in mice and SQMs and thus recommend the mouse model for mechanistic questions, such as development and circuit function, where its substantial methodological advantages can be exploited. NEW & NOTEWORTHY To understand the advantages of different model organisms, it is necessary to directly compare sensory responses across species. Contrasting temporal processing in auditory cortex of awake squirrel monkeys and mice, with parametrically matched amplitude-modulated tone stimuli, reveals a similar role of timing information in stimulus encoding. However, disparities in response precision and strength suggest that anatomical and biophysical differences between squirrel monkeys and mice produce quantitative but not qualitative differences in processing strategy.

Diverse effects of stimulus history in waking mouse auditory cortex.

Responses to auditory stimuli are often strongly influenced by recent stimulus history. For example, in a paradigm called forward suppression, brief sounds can suppress the perception of, and the neural responses to, a subsequent sound, with the magnitude of this suppression depending on both the spectral and temporal distances between the sounds. As a step towards understanding the mechanisms that generate these adaptive representations in awake animals, we quantitatively characterize responses to two-tone sequences in the auditory cortex of waking mice. We find that cortical responses in a forward suppression paradigm are more diverse in waking mice than previously appreciated, that these responses vary between cells with different firing characteristics and waveform shapes, but that the variability in these responses is not substantially related to cortical depth or columnar location. Moreover, responses to the first tone in the sequence are often not linearly related to the suppression of the second tone response, suggesting that spike-frequency adaptation of cortical cells is not a large contributor to forward suppression or its variability. Instead, we use a simple multilayered model to show that cell-to-cell differences in the balance of intracortical inhibition and excitation will naturally produce such a diversity of forward interactions. We propose that diverse inhibitory connectivity allows the cortex to encode spectro-temporally fluctuating stimuli in multiple parallel ways.NEW & NOTEWORTHY Behavioral and neural responses to auditory stimuli are profoundly influenced by recent sounds, yet how this occurs is not known. Here, the authors show in the auditory cortex of awake mice that the quality of history-dependent effects is diverse and related to cell type, response latency, firing rates, and receptive field bandwidth. In a cortical model, differences in excitatory-inhibitory balance can produce this diversity, providing the cortex with multiple ways of representing temporally complex information.

Development and long-term integration of MGE-lineage cortical interneurons in the heterochronic environment.

Interneuron precursors transplanted into visual cortex induce network plasticity during their heterochronic maturation. Such plasticity can have a significant impact on the function of the animal and is normally present only during a brief critical period in early postnatal development. Elucidating the synaptic and physiological properties of interneuron precursors as they mature is key to understanding how long-term circuit changes are induced by transplants. We studied the development of transplant-derived interneurons and compared it to endogenously developing interneurons (those that are born and develop in the same animal) at parallel developmental time points, using patch-clamp recordings in acute cortical slices. We found that transplant-derived interneurons develop into fast-spiking and non-fast-spiking neurons characteristic of the medial ganglionic eminence (MGE) lineage. Transplant-derived interneurons matured more rapidly than endogenously developing interneurons, as shown by more hyperpolarized membrane potentials, smaller input resistances, and narrower action potentials at a juvenile age. In addition, transplant-derived fast-spiking interneurons have more quickly saturating input-output relationships and lower maximal firing rates in adulthood, indicating a possible divergence in function. Transplant-derived interneurons both form inhibitory synapses onto host excitatory neurons and receive excitatory synapses from host pyramidal cells. Unitary connection properties are similar to those of host interneurons. These transplant-derived interneurons, however, were less densely functionally connected onto host pyramidal cells than were host interneurons and received fewer spontaneous excitatory inputs from host cells. These findings suggest that many physiological characteristics of interneurons are autonomously determined, while some factors impacting their circuit function may be influenced by the environment in which they develop.NEW & NOTEWORTHY Transplanting embryonic interneurons into older brains induces a period of plasticity in the recipient animal. We find that these interneurons develop typical fast-spiking and non-fast-spiking phenotypes by the end of adolescence. However, the input-output characteristics of transplant-derived neurons diverged from endogenously developing interneurons during adulthood, and they showed lower connection rates to local pyramidal cells at all time points. This suggests a unique and ongoing role of transplant-derived interneurons in host circuits, enabling interneuron transplant therapies.

Cell Type-Specific Control of Spike Timing by Gamma-Band Oscillatory Inhibition.

Many lines of theoretical and experimental investigation have suggested that gamma oscillations provide a temporal framework for cortical information processing, acting to either synchronize neuronal firing, restrict neuron's relative spike times, and/or provide a global reference signal to which neurons encode input strength. Each theory has been disputed and some believe that gamma is an epiphenomenon. We investigated the biophysical plausibility of these theories by performing in vitro whole-cell recordings from 6 cortical neuron subtypes and examining how gamma-band and slow fluctuations in injected input affect precision and phase of spike timing. We find that gamma is at least partially able to restrict the spike timing in all subtypes tested, but to varying degrees. Gamma exerts more precise control of spike timing in pyramidal neurons involved in cortico-cortical versus cortico-subcortical communication and in inhibitory neurons that target somatic versus dendritic compartments. We also find that relatively few subtypes are capable of phase-based information coding. Using simple neuron models and dynamic clamp, we determine which intrinsic differences lead to these variations in responsiveness and discuss both the flexibility and confounds of gamma-based spike-timing systems.

Contrast dependence and differential contributions from somatostatin- and parvalbumin-expressing neurons to spatial integration in mouse V1.

A characteristic feature in the primary visual cortex is that visual responses are suppressed as a stimulus extends beyond the classical receptive field. Here, we examined the role of inhibitory neurons expressing somatostatin (SOM⁺) or parvalbumin (PV⁺) on surround suppression and preferred receptive field size. We recorded multichannel extracellular activity in V1 of transgenic mice expressing channelrhodopsin in SOM⁺ neurons or PV⁺ neurons. Preferred size and surround suppression were measured using drifting square-wave gratings of varying radii and at two contrasts. Consistent with findings in primates, we found that the preferred size was larger for lower contrasts across all cortical depths, whereas the suppression index (SI) showed a trend to decrease with contrast. We then examined the effect of these metrics on units that were suppressed by photoactivation of either SOM⁺ or PV⁺ neurons. When activating SOM⁺ neurons, we found a significant increase in SI at cortical depths >400 µm, whereas activating PV⁺ neurons caused a trend toward lower SIs regardless of cortical depth. Conversely, activating PV⁺ neurons significantly increased preferred size across all cortical depths, similar to lowering contrast, whereas activating SOM⁺ neurons had no systematic effect on preferred size across all depths. These data suggest that SOM⁺ and PV⁺ neurons contribute differently to spatial integration. Our findings are compatible with the notion that SOM⁺ neurons mediate surround suppression, particularly in deeper cortex, whereas PV⁺ activation decreases the drive of the input to cortex and therefore resembles the effects on spatial integration of lowering contrast.

Sst- and Vip-Cre mouse lines without age-related hearing loss.

GABAergic interneurons, including somatostatin (SST) and vasoactive intestinal peptide (VIP) positive cells, play a crucial role in cortical circuit processing. Cre recombinase-mediated manipulation of these interneurons is facilitated by commercially available knock-in mouse strains such as Sst-IRES-Cre (Sst-Cre) and Vip-IRES-Cre (Vip-Cre). However, these strains are troublesome for hearing research because they are only available on the C57BL/6 genetic background, which suffer from early onset age-related hearing loss (AHL) due to a mutation of the Cdh23 gene. To overcome this limitation, we backcrossed Sst-Cre and Vip-Cre mice to CBA mice to create normal-hearing offspring with the desired Cre transgenes. We confirmed that in these "CBA Cre" lines, Cre drives appropriate expression of Cre-dependent genes, by crossing CBA Cre mice to Ai14 reporter mice. To assess the hearing capabilities of the CBA Cre mice, we measured auditory brainstem responses (ABRs) using clicks and tones. CBA Cre mice showed significantly lower ABR thresholds compared to C57 control mice at 3, 6, 9, and 12 months. In conclusion, our study successfully generated Sst-Cre and Vip-Cre mouse lines on the CBA background that will be valuable tools for investigating the roles of SST and VIP positive interneurons without the confounding effects of age-related hearing loss.

Metabolic cost as a unifying principle governing neuronal biophysics.

The brain contains an astonishing diversity of neurons, each expressing only one set of ion channels out of the billions of potential channel combinations. Simple organizing principles are required for us to make sense of this abundance of possibilities and wealth of related data. We suggest that energy minimization subject to functional constraints may be one such unifying principle. We compared the energy needed to produce action potentials singly and in trains for a wide range of channel densities and kinetic parameters and examined which combinations of parameters maximized spiking function while minimizing energetic cost. We confirmed these results for sodium channels using a dynamic current clamp in neocortical fast spiking interneurons. We find further evidence supporting this hypothesis in a wide range of other neurons from several species and conclude that the ion channels in these neurons minimize energy expenditure in their normal range of spiking.

The h-current controls cortical recurrent network activity through modulation of dendrosomatic communication.

A fundamental feature of the cerebral cortex is the ability to rapidly turn on and off maintained activity within ensembles of neurons through recurrent excitation balanced by inhibition. Here we demonstrate that reduction of the h-current, which is especially prominent in pyramidal cell dendrites, strongly increases the ability of local cortical networks to generate maintained recurrent activity. Reduction of the h-current resulted in hyperpolarization and increase in input resistance of both the somata and apical dendrites of layer 5 pyramidal cells, while strongly increasing the dendrosomatic transfer of low (<20 Hz) frequencies, causing an increased responsiveness to dynamic clamp-induced recurrent network-like activity injected into the dendrites and substantially increasing the duration of spontaneous Up states. We propose that modulation of the h-current may strongly control the ability of cortical networks to generate recurrent persistent activity and the formation and dissolution of neuronal ensembles.

The Clustered Gamma Protocadherin Pcdhγc4 Isoform Regulates Cortical Interneuron Programmed Cell Death in the Mouse Cortex.

Cortical function critically depends on inhibitory/excitatory balance. Cortical inhibitory interneurons (cINs) are born in the ventral forebrain and migrate into cortex, where their numbers are adjusted by programmed cell death. Previously, we showed that loss of clustered gamma protocadherins (Pcdhγ), but not of genes in the alpha or beta clusters, increased dramatically cIN BAX-dependent cell death in mice. Here we show that the sole deletion of the Pcdhγc4 isoform, but not of the other 21 isoforms in the Pcdhγ gene cluster, increased cIN cell death in mice during the normal period of programmed cell death. Viral expression of the Pcdhγc4 isoform rescued transplanted cINs lacking Pcdhγ from cell death. We conclude that Pcdhγ, specifically Pcdhγc4, plays a critical role in regulating the survival of cINs during their normal period of cell death. This demonstrates a novel specificity in the role of Pcdhγ isoforms in cortical development.

Modulation of intracortical synaptic potentials by presynaptic somatic membrane potential.

Traditionally, neuronal operations in the cerebral cortex have been viewed as occurring through the interaction of synaptic potentials in the dendrite and soma, followed by the initiation of an action potential, typically in the axon. Propagation of this action potential to the synaptic terminals is widely believed to be the only form of rapid communication of information between the soma and axonal synapses, and hence to postsynaptic neurons. Here we show that the voltage fluctuations associated with dendrosomatic synaptic activity propagate significant distances along the axon, and that modest changes in the somatic membrane potential of the presynaptic neuron modulate the amplitude and duration of axonal action potentials and, through a Ca2+-dependent mechanism, the average amplitude of the postsynaptic potential evoked by these spikes. These results indicate that synaptic activity in the dendrite and soma controls not only the pattern of action potentials generated, but also the amplitude of the synaptic potentials that these action potentials initiate in local cortical circuits, resulting in synaptic transmission that is a mixture of triggered and graded (analogue) signals.

Audiovisual task switching rapidly modulates sound encoding in mouse auditory cortex.

In everyday behavior, sensory systems are in constant competition for attentional resources, but the cellular and circuit-level mechanisms of modality-selective attention remain largely uninvestigated. We conducted translaminar recordings in mouse auditory cortex (AC) during an audiovisual (AV) attention shifting task. Attending to sound elements in an AV stream reduced both pre-stimulus and stimulus-evoked spiking activity, primarily in deep-layer neurons and neurons without spectrotemporal tuning. Despite reduced spiking, stimulus decoder accuracy was preserved, suggesting improved sound encoding efficiency. Similarly, task-irrelevant mapping stimuli during inter-trial intervals evoked fewer spikes without impairing stimulus encoding, indicating that attentional modulation generalized beyond training stimuli. Importantly, spiking reductions predicted trial-to-trial behavioral accuracy during auditory attention, but not visual attention. Together, these findings suggest auditory attention facilitates sound discrimination by filtering sound-irrelevant background activity in AC, and that the deepest cortical layers serve as a hub for integrating extramodal contextual information.