Enhanced modulation of cell-type specific neuronal responses in mouse dorsal auditory field during locomotion.

As we move through the environment we experience constantly changing sensory input that must be merged with our ongoing motor behaviors - creating dynamic interactions between our sensory and motor systems. Active behaviors such as locomotion generally increase the sensory-evoked neuronal activity in visual and somatosensory cortices, but evidence suggests that locomotion largely suppresses neuronal responses in the auditory cortex. However, whether this effect is ubiquitous across different anatomical regions of the auditory cortex is largely unknown. In mice, auditory association fields such as the dorsal auditory cortex (AuD), have been shown to have different physiological response properties, protein expression patterns, and cortical as well as subcortical connections, in comparison to primary auditory regions (A1) - suggesting there may be important functional differences. Here we examined locomotion-related modulation of neuronal activity in cortical layers ⅔ of AuD and A1 using two-photon Ca2+ imaging in head-fixed behaving mice that are able to freely run on a spherical treadmill. We determined the proportion of neurons in these two auditory regions that show enhanced and suppressed sensory-evoked responses during locomotion and quantified the depth of modulation. We found that A1 shows more suppression and AuD more enhanced responses during locomotion periods. We further revealed differences in the circuitry between these auditory regions and motor cortex, and found that AuD is more highly connected to motor cortical regions. Finally, we compared the cell-type specific locomotion-evoked modulation of responses in AuD and found that, while subpopulations of PV-expressing interneurons showed heterogeneous responses, the population in general was largely suppressed during locomotion, while excitatory population responses were generally enhanced in AuD. Therefore, neurons in primary and dorsal auditory fields have distinct response properties, with dorsal regions exhibiting enhanced activity in response to movement. This functional distinction may be important for auditory processing during navigation and acoustically guided behavior.

Auditory Corticothalamic Neurons Are Recruited by Motor Preparatory Inputs.

Corticothalamic (CT) neurons comprise the largest component of the descending sensory corticofugal pathway, but their contributions to brain function and behavior remain an unsolved mystery. To address the hypothesis that layer 6 (L6) CTs may be activated by extra-sensory inputs prior to anticipated sounds, we performed optogenetically targeted single-unit recordings and two-photon imaging of Ntsr1-Cre+ L6 CT neurons in the primary auditory cortex (A1) while mice were engaged in an active listening task. We found that L6 CTs and other L6 units began spiking hundreds of milliseconds prior to orofacial movements linked to sound presentation and reward, but not to other movements such as locomotion, which were not linked to an explicit behavioral task. Rabies tracing of monosynaptic inputs to A1 L6 CT neurons revealed a narrow strip of cholinergic and non-cholinergic projection neurons in the external globus pallidus, suggesting a potential source of motor-related input. These findings identify new pathways and local circuits for motor modulation of sound processing and suggest a new role for CT neurons in active sensing.

Cortical State Fluctuations during Sensory Decision Making.

In many behavioral tasks, cortex enters a desynchronized state where low-frequency fluctuations in population activity are suppressed. The precise behavioral correlates of desynchronization and its global organization are unclear. One hypothesis holds that desynchronization enhances stimulus coding in the relevant sensory cortex. Another hypothesis holds that desynchronization reflects global arousal, such as task engagement. Here, we trained mice on tasks where task engagement could be distinguished from sensory accuracy. Using widefield calcium imaging, we found that performance-related desynchronization was global and correlated better with engagement than with accuracy. Consistent with this link between desynchronization and engagement, rewards had a long-lasting desynchronizing effect. To determine whether engagement-related state changes depended on the relevant sensory modality, we trained mice on visual and auditory tasks and found that in both cases desynchronization was global, including regions such as somatomotor cortex. We conclude that variations in low-frequency fluctuations are predominately global and related to task engagement.

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.

The effect of NMDA-R antagonist, MK-801, on neuronal mismatch along the rat auditory thalamocortical pathway.

Efficient sensory processing requires that the brain maximize its response to unexpected stimuli, while suppressing responsivity to expected events. Mismatch negativity (MMN) is an auditory event-related potential that occurs when a regular pattern is interrupted by an event that violates the expected properties of the pattern. According to the predictive coding framework there are two mechanisms underlying the MMN: repetition suppression and prediction error. MMN has been found to be reduced in individuals with schizophrenia, an effect believed to be underpinned by glutamate N-methyl-D-aspartate receptor (NMDA-R) dysfunction. In the current study, we aimed to test how the NMDA-R antagonist, MK-801 in the anaesthetized rat, affected repetition suppression and prediction error processes along the auditory thalamocortical pathway. We found that low-dose systemic administration of MK-801 differentially affect thalamocortical responses, namely, increasing thalamic repetition suppression and cortical prediction error. Results demonstrate an enhancement of neuronal mismatch, also confirmed by large scale-responses. Furthermore, MK-801 produces faster and stronger dynamics of adaptation along the thalamocortical hierarchy. Clearly more research is required to understand how NMDA-R antagonism and dosage affects processes contributing to MMN. Nonetheless, because a low dose of an NMDA-R antagonist increased neuronal mismatch, the outcome has implications for schizophrenia treatment.

Thalamic gating contributes to forward suppression in the auditory cortex.

The neural mechanisms underlying forward suppression in the auditory cortex remain a puzzle. Little attention is paid to thalamic contribution despite the important fact that the thalamus gates upstreaming information to the auditory cortex. This study compared the time courses of forward suppression in the auditory thalamus, thalamocortical inputs and cortex using the two-tone stimulus paradigm. The preceding and succeeding tones were 20-ms long. Their frequency and amplitude were set at the characteristic frequency and 20 dB above the minimum threshold of given neurons, respectively. In the ventral division of the medial geniculate body of the thalamus, we found that the duration of complete forward suppression was about 75 ms and the duration of partial suppression was from 75 ms to about 300 ms after the onset of the preceding tone. We also found that during the partial suppression period, the responses to the succeeding tone were further suppressed in the primary auditory cortex. The forward suppression of thalamocortical field excitatory postsynaptic potentials was between those of thalamic and cortical neurons but much closer to that of thalamic ones. Our results indicate that early suppression in the cortex could result from complete suppression in the thalamus whereas later suppression may involve thalamocortical and intracortical circuitry. This suggests that the complete suppression that occurs in the thalamus provides the cortex with a "silence" window that could potentially benefit cortical processing and/or perception of the information carried by the preceding sound.

Postnatal exposure to an acoustically enriched environment alters the morphology of neurons in the adult rat auditory system.

The structure of neurons in the central auditory system is vulnerable to various kinds of acoustic exposures during the critical postnatal developmental period. Here we explored long-term effects of exposure to an acoustically enriched environment (AEE) during the third and fourth weeks of the postnatal period in rat pups. AEE consisted of a spectrally and temporally modulated sound of moderate intensity, reinforced by a behavioral paradigm. At the age of 3-6 months, a Golgi-Cox staining was used to evaluate the morphology of neurons in the inferior colliculus (IC), the medial geniculate body (MGB), and the auditory cortex (AC). Compared to controls, rats exposed to AEE showed an increased mean dendritic length and volume and the soma surface in the external cortex and the central nucleus of the IC. The spine density increased in both the ventral and dorsal divisions of the MGB. In the AC, the total length and volume of the basal dendritic segments of pyramidal neurons and the number and density of spines on these dendrites increased significantly. No differences were found on apical dendrites. We also found an elevated number of spines and spine density in non-pyramidal neurons. These results show that exposure to AEE during the critical developmental period can induce permanent changes in the structure of neurons in the central auditory system. These changes represent morphological correlates of the functional plasticity, such as an improvement in frequency tuning and synchronization with temporal parameters of acoustical stimuli.

Noise-Sensitive But More Precise Subcortical Representations Coexist with Robust Cortical Encoding of Natural Vocalizations.

Humans and animals maintain accurate sound discrimination in the presence of loud sources of background noise. It is commonly assumed that this ability relies on the robustness of auditory cortex responses. However, only a few attempts have been made to characterize neural discrimination of communication sounds masked by noise at each stage of the auditory system and to quantify the noise effects on the neuronal discrimination in terms of alterations in amplitude modulations. Here, we measured neural discrimination between communication sounds masked by a vocalization-shaped stationary noise from multiunit responses recorded in the cochlear nucleus, inferior colliculus, auditory thalamus, and primary and secondary auditory cortex at several signal-to-noise ratios (SNRs) in anesthetized male or female guinea pigs. Masking noise decreased sound discrimination of neuronal populations in each auditory structure, but collicular and thalamic populations showed better performance than cortical populations at each SNR. In contrast, in each auditory structure, discrimination by neuronal populations was slightly decreased when tone-vocoded vocalizations were tested. These results shed new light on the specific contributions of subcortical structures to robust sound encoding, and suggest that the distortion of slow amplitude modulation cues conveyed by communication sounds is one of the factors constraining the neuronal discrimination in subcortical and cortical levels.SIGNIFICANCE STATEMENT Dissecting how auditory neurons discriminate communication sounds in noise is a major goal in auditory neuroscience. Robust sound coding in noise is often viewed as a specific property of cortical networks, although this remains to be demonstrated. Here, we tested the discrimination performance of neuronal populations at five levels of the auditory system in response to conspecific vocalizations masked by noise. In each acoustic condition, subcortical neurons better discriminated target vocalizations than cortical ones and in each structure, the reduction in discrimination performance was related to the reduction in slow amplitude modulation cues.

A Cortico-Collicular Amplification Mechanism for Gap Detection.

Auditory cortex (AC) is necessary for the detection of brief gaps in ongoing sounds, but not for the detection of longer gaps or other stimuli such as tones or noise. It remains unclear why this is so, and what is special about brief gaps in particular. Here, we used both optogenetic suppression and conventional lesions to show that the cortical dependence of brief gap detection hinges specifically on gap termination. We then identified a cortico-collicular gap detection circuit that amplifies cortical gap termination responses before projecting to inferior colliculus (IC) to impact behavior. We found that gaps evoked off-responses and on-responses in cortical neurons, which temporally overlapped for brief gaps, but not long gaps. This overlap specifically enhanced cortical responses to brief gaps, whereas IC neurons preferred longer gaps. Optogenetic suppression of AC reduced collicular responses specifically to brief gaps, indicating that under normal conditions, the enhanced cortical representation of brief gaps amplifies collicular gap responses. Together these mechanisms explain how and why AC contributes to the behavioral detection of brief gaps, which are critical cues for speech perception, perceptual grouping, and auditory scene analysis.

Differential cortical and subcortical projection targets of subfields in the core region of mouse auditory cortex.

The core region of the rodent auditory cortex has two areas: the primary auditory area (A1) and the anterior auditory field (AAF). However, the functional difference between these areas is unclear. To elucidate this issue, here we studied the projections from A1 and AAF in mice using adeno-associated virus (AAV) vectors expressing either a green fluorescent protein or a red fluorescent protein. After mapping A1 and AAF using optical imaging, we injected a distinct AAV vector into each of the two fields at a frequency-matched high-frequency location. We found that A1 and AAF projected commonly to virtually all target areas examined, but each field had its own preference for projection targets. Frontal and parietal regions were the major cortical targets: in the frontal cortex, A1 and AAF showed dominant projections to the anterior cingulate cortex Cg1 and the secondary motor cortex (M2), respectively; in the parietal cortex, A1 and AAF exhibited dense projections to the medial secondary visual cortex and the posterior parietal cortex (PPC), respectively. Although M2 and PPC received considerable input from A1 as well, A1 innervated the medial part whereas AAF innervated the lateral part of these cortical regions. A1 also projected to the orbitofrontal cortex, while AAF also projected to the primary somatosensory cortex and insular auditory cortex. As for subcortical projections, A1 and AAF projected to a common ventromedial region in the caudal striatum with a comparable strength; they also both projected to the medial geniculate body and the inferior colliculus, innervating common and distinct divisions of the nuclei. A1 also projected to visual subcortical structures, such as the superior colliculus and the lateral posterior nucleus of the thalamus, where fibres from AAF were sparse. Our results demonstrate the preference of A1 and AAF for cortical and subcortical targets, and for divisions in individual target. The preference of A1 and AAF for sensory-related structures suggest a role for A1 in providing auditory information for audio-visual association at both the cortical and subcortical level, and a distinct role of AAF in providing auditory information for association with somatomotor information in the cortex.

Inhibitory mechanisms shaping delay-tuned combination-sensitivity in the auditory cortex and thalamus of the mustached bat.

Delay-tuned auditory neurons of the mustached bat show facilitative responses to a combination of signal elements of a biosonar pulse-echo pair with a specific echo delay. The subcollicular nuclei produce latency-constant phasic on-responding neurons, and the inferior colliculus produces delay-tuned combination-sensitive neurons, designated "FM-FM" neurons. The combination-sensitivity is a facilitated response to the coincidence of the excitatory rebound following glycinergic inhibition to the pulse (1st harmonic) and the short-latency response to the echo (2nd-4th harmonics). The facilitative response of thalamic FM-FM neurons is mediated by glutamate receptors (NMDA and non-NMDA receptors). Different from collicular FM-FM neurons, thalamic ones respond more selectively to pulse-echo pairs than individual signal elements. A number of differences in response properties between collicular and thalamic or cortical FM-FM neurons have been reported. However, differences between thalamic and cortical FM-FM neurons have remained to be studied. Here, we report that GABAergic inhibition controls the duration of burst of spikes of facilitative responses of thalamic FM-FM neurons and sharpens the delay tuning of cortical ones. That is, intra-cortical inhibition sharpens the delay tuning of cortical FM-FM neurons that is potentially broad because of divergent/convergent thalamo-cortical projections. Compared with thalamic neurons, cortical ones tend to show sharper delay tuning, longer response duration, and larger facilitation index. However, those differences are statistically insignificant.

Thalamocortical and Intracortical Inputs Differentiate Layer-Specific Mouse Auditory Corticocollicular Neurons.

Long-range descending projections from the auditory cortex play key roles in shaping response properties in the inferior colliculus. The auditory corticocollicular projection is massive and heterogeneous, with axons emanating from cortical layers 5 and 6, and plays a key role in directing plastic changes in the inferior colliculus. However, little is known about the cortical and thalamic networks within which corticocollicular neurons are embedded. Here, laser scanning photostimulation glutamate uncaging and photoactivation of channelrhodopsin-2 were used to probe the local and long-range network differences between preidentified layer 5 and layer 6 auditory corticocollicular neurons from male and female mice in vitro Layer 5 corticocollicular neurons were found to vertically integrate supragranular excitatory and inhibitory input to a substantially greater degree than their layer 6 counterparts. In addition, all layer 5 corticocollicular neurons received direct and large thalamic inputs from channelrhodopsin-2-labeled thalamocortical fibers, whereas such inputs were less common in layer 6 corticocollicular neurons. Finally, a new low-calcium/synaptic blockade approach to separate direct from indirect inputs using laser photostimulation was validated. These data demonstrate that layer 5 and 6 corticocollicular neurons receive distinct sets of cortical and thalamic inputs, supporting the hypothesis that they have divergent roles in modulating the inferior colliculus. Furthermore, the direct connection between the auditory thalamus and layer 5 corticocollicular neurons reveals a novel and rapid link connecting ascending and descending pathways.SIGNIFICANCE STATEMENT Descending projections from the cortex play a critical role in shaping the response properties of sensory neurons. The projection from the auditory cortex to the inferior colliculus is a massive, yet poorly understood, pathway emanating from two distinct cortical layers. Here we show, using a range of optical techniques, that mouse auditory corticocollicular neurons from different layers are embedded into different cortical and thalamic networks. Specifically, we observed that layer 5 corticocollicular neurons integrate information across cortical lamina and receive direct thalamic input. The latter connection provides a hyperdirect link between acoustic sensation and descending control, thus demonstrating a novel mechanism for rapid "online" modulation of sensory perception.

Selective Strengthening of Intracortical Excitatory Input Leads to Receptive Field Refinement during Auditory Cortical Development.

In the primary auditory cortex (A1) of rats, refinement of excitatory input to layer (L)4 neurons contributes to the sharpening of their frequency selectivity during postnatal development. L4 neurons receive both feedforward thalamocortical and recurrent intracortical inputs, but how potential developmental changes of each component can account for the sharpening of excitatory input tuning remains unclear. By combining in vivo whole-cell recording and pharmacological silencing of cortical spiking in young rats of both sexes, we examined developmental changes at three hierarchical stages: output of auditory thalamic neurons, thalamocortical input and recurrent excitatory input to an A1 L4 neuron. In the thalamus, the tonotopic map matured with an expanded range of frequency representations, while the frequency tuning of output responses was unchanged. On the other hand, the tuning shape of both thalamocortical and intracortical excitatory inputs to a L4 neuron became sharpened. In particular, the intracortical input became better tuned than thalamocortical excitation. Moreover, the weight of intracortical excitation around the optimal frequency was selectively strengthened, resulting in a dominant role of intracortical excitation in defining the total excitatory input tuning. Our modeling work further demonstrates that the frequency-selective strengthening of local recurrent excitatory connections plays a major role in the refinement of excitatory input tuning of L4 neurons.SIGNIFICANCE STATEMENT During postnatal development, sensory cortex undergoes functional refinement, through which the size of sensory receptive field is reduced. In the rat primary auditory cortex, such refinement in layer (L)4 is mainly attributed to improved selectivity of excitatory input a L4 neuron receives. In this study, we further examined three stages along the hierarchical neural pathway where excitatory input refinement might occur. We found that developmental refinement takes place at both thalamocortical and intracortical circuit levels, but not at the thalamic output level. Together with modeling results, we revealed that the optimal-frequency-selective strengthening of intracortical excitation plays a dominant role in the refinement of excitatory input tuning.

Direct Relay Pathways from Lemniscal Auditory Thalamus to Secondary Auditory Field in Mice.

Tonotopy is an essential functional organization in the mammalian auditory cortex, and its source in the primary auditory cortex (A1) is the incoming frequency-related topographical projections from the ventral division of the medial geniculate body (MGv). However, circuits that relay this functional organization to higher-order regions such as the secondary auditory field (A2) have yet to be identified. Here, we discovered a new pathway that projects directly from MGv to A2 in mice. Tonotopy was established in A2 even when primary fields including A1 were removed, which indicates that tonotopy in A2 can be established solely by thalamic input. Moreover, the structural nature of differing thalamocortical connections was consistent with the functional organization of the target regions in the auditory cortex. Retrograde tracing revealed that the region of MGv input to a local area in A2 was broader than the region of MGv input to A1. Consistent with this anatomy, two-photon calcium imaging revealed that neuronal responses in the thalamocortical recipient layer of A2 showed wider bandwidth and greater heterogeneity of the best frequency distribution than those of A1. The current study demonstrates a new thalamocortical pathway that relays frequency information to A2 on the basis of the MGv compartmentalization.

A characterization of laminar architecture in mouse primary auditory cortex.

Laminar architecture of primary auditory cortex (A1) has long been investigated by traditional histochemical techniques such as Nissl staining, retrograde and anterograde tracings. Uncertainty still remains, however, about laminar boundaries in mice. Here we investigated the cortical lamina structure by combining neuronal tracing and immunofluorochemistry for laminar specific markers. Most retrogradely labeled corticothalamic neurons expressed Forkhead box protein P2 (Foxp2) and distributed within the laminar band of Foxp2-expressing cells, identifying layer 6. Cut-like homeobox 1 (Cux1) expression in layer 2-4 neurons divided the upper layers into low expression layers 2/3 and high expression layers 3/4, which overlapped with the dense terminals of vesicular glutamate transporter 2 (vGluT2) and anterogradely labeled lemniscal thalamocortical axons. In layer 5, between Cux1-expressing layers 2-4 and Foxp2-defined layer 6, retrogradely labeled corticocollicular projection neurons mostly expressed COUP-TF interacting protein 2 (Ctip2). Ctip2-expressing neurons formed a laminar band in the middle of layer 5 distant from layer 6, creating a laminar gap between the two laminas. This gap contained a high population of commissural neurons projecting to contralateral A1 compared to other layers and received vGluT2-immunopositive, presumptive thalamocortical axon collateral inputs. Our study shows that layer 5 is much wider than layer 6, and layer 5 can be divided into at least three sublayers. The thalamorecipient layers 3/4 may be separated from layers 2/3 using Cux1 and can be also divided into layer 4 and layer 3 based on the neuronal soma size. These data provide a new insight for the laminar structure of mouse A1.

ON-OFF receptive fields in auditory cortex diverge during development and contribute to directional sweep selectivity.

Neurons in the auditory cortex exhibit distinct frequency tuning to the onset and offset of sounds, but the cause and significance of ON and OFF receptive field (RF) organisation are not understood. Here we demonstrate that distinct ON and OFF frequency tuning is largely absent in immature mouse auditory cortex and is thus a consequence of cortical development. Simulations using a novel implementation of a standard Hebbian plasticity model show that the natural alternation of sound onset and offset is sufficient for the formation of non-overlapping adjacent ON and OFF RFs in cortical neurons. Our model predicts that ON/OFF RF arrangement contributes towards direction selectivity to frequency-modulated tone sweeps, which we confirm by neuronal recordings. These data reveal that a simple and universally accepted learning rule can explain the organisation of ON and OFF RFs and direction selectivity in the developing auditory cortex.

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.

A Role for Auditory Corticothalamic Feedback in the Perception of Complex Sounds.

Feedback signals from the primary auditory cortex (A1) can shape the receptive field properties of neurons in the ventral division of the medial geniculate body (MGBv). However, the behavioral significance of corticothalamic modulation is unknown. The aim of this study was to elucidate the role of this descending pathway in the perception of complex sounds. We tested the ability of adult female ferrets to detect the presence of a mistuned harmonic in a complex tone using a positive conditioned go/no-go behavioral paradigm before and after the input from layer VI in A1 to MGBv was bilaterally and selectively eliminated using chromophore-targeted laser photolysis. MGBv neurons were identified by their short latencies and sharp tuning curves. They responded robustly to harmonic complex tones and exhibited an increase in firing rate and temporal pattern changes when one frequency component in the complex tone was mistuned. Injections of fluorescent microbeads conjugated with a light-sensitive chromophore were made in MGBv, and, following retrograde transport to the cortical cell bodies, apoptosis was induced by infrared laser illumination of A1. This resulted in a selective loss of ∼60% of layer VI A1-MGBv neurons. After the lesion, mistuning detection was impaired, as indicated by decreased d' values, a shift of the psychometric curves toward higher mistuning values, and increased thresholds, whereas discrimination performance was unaffected when level cues were also available. Our results suggest that A1-MGBv corticothalamic feedback contributes to the detection of harmonicity, one of the most important grouping cues in the perception of complex sounds.SIGNIFICANCE STATEMENT Perception of a complex auditory scene is based on the ability of the brain to group those sound components that belong to the same source and to segregate them from those belonging to different sources. Because two people talking simultaneously may differ in their voice pitch, perceiving the harmonic structure of sounds is very important for auditory scene analysis. Here we demonstrate mistuning sensitivity in the thalamus and that feedback from the primary auditory cortex is required for the normal ability of ferrets to detect a mistuned harmonic within a complex sound. These results provide novel insight into the function of descending sensory pathways in the brain and suggest that this corticothalamic circuit plays an important role in scene analysis.

A Corticothalamic Circuit for Dynamic Switching between Feature Detection and Discrimination.

Sensory processing must be sensitive enough to encode faint signals near the noise floor but selective enough to differentiate between similar stimuli. Here we describe a layer 6 corticothalamic (L6 CT) circuit in the mouse auditory forebrain that alternately biases sound processing toward hypersensitivity and improved behavioral sound detection or dampened excitability and enhanced sound discrimination. Optogenetic activation of L6 CT neurons could increase or decrease the gain and tuning precision in the thalamus and all layers of the cortical column, depending on the timing between L6 CT activation and sensory stimulation. The direction of neural and perceptual modulation - enhanced detection at the expense of discrimination or vice versa - arose from the interaction of L6 CT neurons and subnetworks of fast-spiking inhibitory neurons that reset the phase of low-frequency cortical rhythms. These findings suggest that L6 CT neurons contribute to the resolution of the competing demands of detection and discrimination.

Distinct Translaminar Glutamatergic Circuits to GABAergic Interneurons in the Neonatal Auditory Cortex.

GABAergic activity is important in neocortical development and plasticity. Because the maturation of GABAergic interneurons is regulated by neural activity, the source of excitatory inputs to GABAergic interneurons plays a key role in development. We show, by laser-scanning photostimulation, that layer 4 and layer 5 GABAergic interneurons in the auditory cortex in neonatal mice (