Efferent feedback controls bilateral auditory spontaneous activity.

In the developing auditory system, spontaneous activity generated in the cochleae propagates into the central nervous system to promote circuit formation. The effects of peripheral firing patterns on spontaneous activity in the central auditory system are not well understood. Here, we describe wide-spread bilateral coupling of spontaneous activity that coincides with the period of transient efferent modulation of inner hair cells from the brainstem medial olivocochlear system. Knocking out α9/α10 nicotinic acetylcholine receptors, a requisite part of the efferent pathway, profoundly reduces bilateral correlations. Pharmacological and chemogenetic experiments confirm that the efferent system is necessary for normal bilateral coupling. Moreover, auditory sensitivity at hearing onset is reduced in the absence of pre-hearing efferent modulation. Together, these results demonstrate how afferent and efferent pathways collectively shape spontaneous activity patterns and reveal the important role of efferents in coordinating bilateral spontaneous activity and the emergence of functional responses during the prehearing period.

Spike Train Coactivity Encodes Learned Natural Stimulus Invariances in Songbird Auditory Cortex.

The capacity for sensory systems to encode relevant information that is invariant to many stimulus changes is central to normal, real-world, cognitive function. This invariance is thought to be reflected in the complex spatiotemporal activity patterns of neural populations, but our understanding of population-level representational invariance remains coarse. Applied topology is a promising tool to discover invariant structure in large datasets. Here, we use topological techniques to characterize and compare the spatiotemporal pattern of coactive spiking within populations of simultaneously recorded neurons in the secondary auditory region caudal medial neostriatum of European starlings (Sturnus vulgaris). We show that the pattern of population spike train coactivity carries stimulus-specific structure that is not reducible to that of individual neurons. We then introduce a topology-based similarity measure for population coactivity that is sensitive to invariant stimulus structure and show that this measure captures invariant neural representations tied to the learned relationships between natural vocalizations. This demonstrates one mechanism whereby emergent stimulus properties can be encoded in population activity, and shows the potential of applied topology for understanding invariant representations in neural populations.SIGNIFICANCE STATEMENT Information in neural populations is carried by the temporal patterns of spikes. We applied novel mathematical tools from the field of algebraic topology to quantify the structure of these temporal patterns. We found that, in a secondary auditory region of a songbird, these patterns reflected invariant information about a learned stimulus relationship. These results demonstrate that topology provides a novel approach for characterizing neural responses that is sensitive to invariant relationships that are critical for the perception of natural stimuli.

Circuit Mechanisms Underlying the Segregation and Integration of Parallel Processing Streams in the Inferior Colliculus.

The lateral cortex of the inferior colliculus (LCIC) forms a nexus between diverse multisensory, motor, and neuromodulatory streams. Like other integration hubs, it contains repeated neurochemical motifs with distinct inputs: GABA-rich modules are innervated by somatosensory structures, while auditory inputs to the LCIC target the surrounding extramodular matrix. To investigate potential mechanisms of convergence between these input streams, we used laser photostimulation circuit mapping to interrogate local LCIC circuits in adult mice of both sexes and found that input patterns are highly dependent on cell type (GABAergic/non-GABAergic) and location (module/matrix). At the circuit level, these inputs yield a directional flow of local information, primarily from the matrix to the modules. Further, the two compartments were found to project to distinct targets in the midbrain and thalamus. These data show that, while connectional modularity in the LCIC gives rise to segregated input-output channels, local circuits provide the architecture for integration between these two streams.SIGNIFICANCE STATEMENT Modularity is a widespread motif across the brain involving the segregation of structures into discrete subregions based on dichotomies in neurochemical expression or connectivity. The inferior colliculus is one such modular structure, containing auditory-recipient matrix regions and GABA-rich modules that are innervated by somatosensory inputs. While modularity suggests segregation of processing streams, here we show that local circuits in the inferior colliculus connect the module and matrix regions, providing an avenue for integration of information across compartments.

Serotonergic innervation of the auditory midbrain: dorsal raphe subregions differentially project to the auditory midbrain in male and female mice.

In the auditory inferior colliculus (IC), serotonin reflects features of context including the valence of social interactions, stressful events, and prior social experience. However, within the dorsal raphe nucleus (DRN; B6 + B7), the source of serotonergic projections to the IC has not been resolved at the level of DRN subregions. Additionally, few studies have investigated which DRN subregions are engaged during naturalistic, sensory-driven social behaviors. We employ traditional, retrograde tract-tracing approaches to comprehensively map the topographic extent of DRN-IC projection neurons in male and female mice. We combine this approach with immediate early gene (cFos) mapping in order to describe the functional properties of DRN subregions during contexts in which serotonin fluctuates within the IC. These approaches provide novel evidence that the dorsal (DRd) and lateral (DRl) B7 subregions are primarily responsible for serotonergic innervation of the IC; further, we show that this projection is larger in male than in female mice. Additionally, DRd and the ventral B7 (DRv) contained more transcriptionally active serotonergic neurons irrespective of behavioral context. Male mice had more active serotonergic neurons in DRd and DRv than females following sociosexual encounters. However, serotonergic activity was correlated with the expression of female but not male social behaviors. The topographic organization of the DRN-IC projection provides the anatomical framework to test a mechanism underlying context-dependent auditory processing. We further highlight the importance of including sex as a biological variable when describing the functional topography of DRN.

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.

Spectral cues are necessary to encode azimuthal auditory space in the mouse superior colliculus.

Sound localization plays a critical role in animal survival. Three cues can be used to compute sound direction: interaural timing differences (ITDs), interaural level differences (ILDs) and the direction-dependent spectral filtering by the head and pinnae (spectral cues). Little is known about how spectral cues contribute to the neural encoding of auditory space. Here we report on auditory space encoding in the mouse superior colliculus (SC). We show that the mouse SC contains neurons with spatially-restricted receptive fields (RFs) that form an azimuthal topographic map. We found that frontal RFs require spectral cues and lateral RFs require ILDs. The neurons with frontal RFs have frequency tunings that match the spectral structure of the specific head and pinna filter for sound coming from the front. These results demonstrate that patterned spectral cues in combination with ILDs give rise to the topographic map of azimuthal auditory space.

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.

Shaping of discrete auditory inputs to extramodular zones of the lateral cortex of the inferior colliculus.

The multimodal lateral cortex of the inferior colliculus (LCIC) exhibits a modular-extramodular micro-organization that is evident early in development. In addition to a set of neurochemical markers that reliably highlight its modular-extramodular organization (e.g. modules: GAD67-positive, extramodular zones: calretinin-positive, CR), mature projection patterns suggest that major LCIC afferents recognize and adhere to such a framework. In adult mice, distinct afferent projections appear segregated, with somatosensory inputs targeting LCIC modules and auditory inputs surrounding extramodular fields. Currently lacking is an understanding regarding the development and shaping of multimodal LCIC afferents with respect to its emerging modular-extramodular microarchitecture. Combining living slice tract-tracing and immunocytochemical approaches in GAD67-GFP knock-in mice, the present study characterizes the critical period of projection shaping for LCIC auditory afferents arising from its neighboring central nucleus (CNIC). Both crossed and uncrossed projection patterns exhibit LCIC extramodular mapping characteristics that emerge from initially diffuse distributions. Projection mismatch with GAD-defined modules and alignment with encompassing extramodular zones becomes increasingly clear over the early postnatal period (birth to postnatal day 12). CNIC inputs terminate almost exclusively in extramodular zones that express CR. These findings suggest multimodal LCIC inputs may initially be sparse and intermingle, prior to segregation into distinct processing streams. Future experiments are needed to determine the likely complex interactions and mechanisms (e.g. activity-dependent and independent) responsible for shaping early modality-specific LCIC circuits.

Multiple Nonauditory Cortical Regions Innervate the Auditory Midbrain.

Our perceptual experience of sound depends on the integration of multiple sensory and cognitive domains, however the networks subserving this integration are unclear. Connections linking different cortical domains have been described, but we do not know the extent to which connections also exist between multiple cortical domains and subcortical structures. Retrograde tracing in adult male rats (Rattus norvegicus) revealed that the inferior colliculus, the auditory midbrain, receives dense descending projections not only, as previously established, from the auditory cortex, but also from the visual, somatosensory, motor, and prefrontal cortices. While all these descending connections are bilateral, those from sensory areas show a more pronounced ipsilateral dominance than those from motor and prefrontal cortices. Injections of anterograde tracers into the cortical areas identified by retrograde tracing confirmed those findings and revealed cortical fibers terminating in all three subdivisions of the inferior colliculus. Immunolabeling showed that cortical terminals target both GABAergic inhibitory, and putative glutamatergic excitatory neurons. These findings demonstrate that auditory perception and behavior are served by a network that includes extensive descending connections to the midbrain from sensory, behavioral, and executive cortices.SIGNIFICANCE STATEMENT Making sense of what we hear depends not only on the analysis of sound, but also on information from other senses together with the brain's predictions about the properties and significance of the sound. Previous work suggested that this interplay between the senses and the predictions from higher cognitive centers occurs within the cerebral cortex. By tracing neural connections in rat, we show that the inferior colliculus, the subcortical, midbrain center for hearing, receives extensive connections from areas of the cerebral cortex concerned with vision, touch, movement, and cognitive function, in addition to areas representing hearing. These findings demonstrate that wide-ranging cortical feedback operates at an earlier stage of the hearing pathway than previously recognized.

Effects of developmental noise exposure on inhibitory cell densities and perineuronal nets in A1 and AAF of mice.

Within the auditory cortex, there are two primary-like regions considered to be 'core' cortical fields, the primary auditory cortex (A1) and the anterior auditory field (AAF). Both fields have sharp frequency tuning, tonotopic organization, and inputs from the ventral division of the medial geniculate body of the thalamus. AAF seems to be more specialized for faster spectrotemporal processing than A1, but the underlying mechanisms are unclear. A1 has been studied extensively in developmental plasticity, but how AAF changes with developmental experience is less clear. To address potential cellular correlates of processing differences between the two fields, we used immunohistochemistry to quantify the density of GABA, parvalbumin (PV), and somatostatin (SOM) cells in A1 and AAF of mice. We also compared the density of perineuronal nets (PNN) between A1 and AAF. PNNs are a specialized assembly of extracellular matrix involved in network maturation and plasticity. Finally, we compared the effects of developmental noise exposure on inhibitory and PNN cell density in these two core regions. In adult mice, there were more PV cells and PNNs surrounding cell bodies in AAF than in A1. Moderate level noise exposure during early development leads to 1) increased GABA and SOM cell density in both A1 and AAF, and 2) decreased PNN cell density in A1, but not AAF. Inhibitory cells without PNN appear to be more susceptible to changes following developmental noise exposure in both fields. Deep layers (5/6) are more susceptible to change in PNN density compared to superficial layers (1-4) of A1. Results are consistent with altered cortical gain control models and impaired maturation of cortex in response to noisy environments, and suggest that PNNs may be more prone to modification in A1 than AAF.

Characterization of the human central nucleus of the inferior colliculus.

The inferior colliculus (IC) is a major relay station for both ascending and descending auditory pathways. The IC is divided into three major regions, the external cortex (ECIC), the dorsal cortex (DCIC) and the central nucleus of the inferior colliculus (CNIC). While the ECIC and DCIC receive many non-auditory inputs, the CNIC receives predominantly auditory input ascending within the lateral lemniscus and descending input from the cerebral cortex. Recent work in animal models emphasizes the complexity of the CNIC and provides evidence for multiple ascending informational streams reaching this nucleus. Despite an abundance of research on the CNIC in laboratory animals, the microscopic anatomy and neurochemistry of the human CNIC is poorly understood. Herein, we utilize a combination of gross morphology, myelin staining, Nissl staining, histochemistry, immunohistochemistry and immunofluorescence to characterize the human CNIC. Our results indicate that the human CNIC occupies a volume of approximately 22.4 mm3 and includes over 420,000 neurons. The human CNIC is dominated by round/oval neurons arranged with their long axis parallel to fibrodendritic lamina. Additionally, the vast majority of CNIC neurons are associated with a perineuronal net, there is an abundance of tyrosine hydroxylase immunoreactive axons and puncta and neurons immunoreactive for glutamic acid decarboxylase. These results are largely consistent with observations in laboratory animals.

Choice-Selective Neurons in the Auditory Cortex and in Its Striatal Target Encode Reward Expectation.

Learned behavioral responses to sounds depend largely on the expected outcomes associated with each potential choice. Where and how the nervous system integrates expectations about reward with auditory sensory information to drive appropriate decisions is not fully understood. Using a two-alternative choice task in which the expected reward associated with each sound varied over time, we investigated potential sites along the corticostriatal pathway for the integration of sound signals, behavioral choice, and reward information in male mice. We found that auditory cortical neurons encode not only sound identity, but also the animal's choice and the expected size of reward. This influence of reward expectation on sound- and choice-related activity was further enhanced in the major striatal target of the auditory cortex: the posterior tail of the dorsal striatum. These results indicate that choice-specific information is integrated with reward signals throughout the corticostriatal pathway, potentially contributing to adaptation in sound-driven behavior.SIGNIFICANCE STATEMENT Learning and maintenance of sensory-motor associations require that neural circuits keep track of sensory stimuli, choices, and outcomes. It is not clear at what stages along the auditory sensorimotor pathway these signals are integrated to influence future behavior in response to sounds. Our results show that the activity of auditory cortical neurons and of their striatal targets encodes the animals' choices and expectation of reward, in addition to stimulus identity. These results challenge previous views of the influence of motor signals on auditory circuits and identifies potential loci for integration of task-related information necessary for updating auditory decisions in changing environments.

The ion channels and synapses responsible for the physiological diversity of mammalian lower brainstem auditory neurons.

The auditory part of the brainstem is composed of several nuclei specialized in the computation of the different spectral and temporal features of the sound before it reaches the higher auditory regions. There are a high diversity of neuronal types in these nuclei, many with remarkable electrophysiological and synaptic properties unique to these structures. This diversity reflects specializations necessary to process the different auditory signals in order to extract precisely the acoustic information necessary for the auditory perception by the animal. Low threshold Kv1 channels and HCN channels are expressed in neurons that use timing clues for auditory processing, like bushy and octopus cells, in order to restrict action potential firing and reduce input resistance and membrane time constant. Kv3 channels allow principal neurons of the MNTB and pyramidal DCN neurons to fire fast trains of action potentials. Calcium channels on cartwheel DCN neurons produce complex spikes characteristic of these neurons. Calyceal synapses compensate the low input resistance of bushy and principal neurons of the MNTB by releasing hundreds of glutamate vesicles resulting in large EPSCs acting in fast ionotropic glutamate receptors, in order to reduce temporal summation of synaptic potentials, allowing more precise correspondence of pre- and post-synaptic potentials, and phase-locking. Pre-synaptic calyceal sodium channels have fast recovery from inactivation allowing extremely fast trains of action potential firing, and persistent sodium channels produce spontaneous activity of fusiform neurons at rest, which expands the dynamic range of these neurons. The unique combinations of different ion channels, ionotropic receptors and synaptic structures create a unique functional diversity of neurons extremely adapted to their complex functions in the auditory processing.

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.

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.

Subtypes of GABAergic cells in the inferior colliculus.

The inferior colliculus occupies a central position in ascending and descending auditory pathways. A substantial proportion of its neurons are GABAergic, and these neurons contribute to intracollicular circuits as well as to extrinsic projections to numerous targets. A variety of types of evidence - morphology, physiology, molecular markers - indicate that the GABAergic cells can be divided into at least four subtypes that serve different functions. However, there has yet to emerge a unified scheme for distinguishing these subtypes. The present review discusses these criteria and, where possible, relates the different properties. In contrast to GABAergic cells in cerebral cortex, where subtypes are much more thoroughly characterized, those in the inferior colliculus contribute substantially to numerous long range extrinsic projections. At present, the best characterized subtype is a GABAergic cell with a large soma, dense perisomatic synaptic inputs and a large axon that provides rapid auditory input to the thalamus. This large GABAergic subtype projects to additional targets, and other subtypes also project to the thalamus. The eventual characterization of these subtypes can be expected to reveal multiple functions of these inhibitory cells and the many circuits to which they contribute.

Bilateral projections to the thalamus from individual neurons in the inferior colliculus.

The medial geniculate body (MG) receives a large input from the ipsilateral inferior colliculus (IC) and a smaller but substantial input from the contralateral IC. Both crossed and uncrossed inputs comprise a large percentage of glutamatergic cells and a smaller percentage of GABAergic cells. We used double labeling with fluorescent retrograde tracers to identify individual IC cells that project bilaterally to the MGs in adult guinea pigs. We also used immunohistochemistry for glutamic acid decarboxylase to distinguish GABAergic from glutamatergic cells that project bilaterally to the MG. We found cells in the IC that contained both retrograde tracers, indicating that they project bilaterally. Across cases, the bilaterally projecting cells constituted up to 37% of the cells that project to the ipsilateral MG and up to 73% of the cells that project to the contralateral MG. GABAergic cells averaged 20% of the bilaterally-projecting population. We conclude that a population of IC cells sends branching axonal projections to innervate the MG bilaterally. Most of the neurons in this population are glutamatergic, with a minority that are GABAergic. A mixed projection, with glutamatergic cells outnumbering GABAergic cells, originates from each of the major IC subdivisions (central nucleus, dorsal cortex, and lateral cortex). The bilaterally projecting cells are likely to serve functions different from the larger unilateral projections, perhaps synchronizing activity on the two sides of the auditory brain.

Conserved and divergent development of brainstem vestibular and auditory nuclei.

Vestibular function was established early in vertebrates and has remained, for the most part, unchanged. In contrast, each group of tetrapods underwent independent evolutionary processes to solve the problem of hearing on land, resulting in a remarkable mixture of conserved, divergent and convergent features that define extant auditory systems. The vestibuloacoustic nuclei of the hindbrain develop from a highly conserved ground plan and provide an ideal framework on which to address the participation of developmental processes to the evolution of neuronal circuits. We employed an electroporation strategy to unravel the contribution of two dorsoventral and four axial lineages to the development of the chick hindbrain vestibular and auditory nuclei. We compare the chick developmental map with recently established genetic fate-maps of the developing mouse hindbrain. Overall, we find considerable conservation of developmental origin for the vestibular nuclei. In contrast, a comparative analysis of the developmental origin of hindbrain auditory structures echoes the complex evolutionary history of the auditory system. In particular, we find that the developmental origin of the chick auditory interaural time difference circuit supports its emergence from an ancient vestibular network, unrelated to the analogous mammalian counterpart.

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.

Mechanotransduction is required for establishing and maintaining mature inner hair cells and regulating efferent innervation.

In the adult auditory organ, mechanoelectrical transducer (MET) channels are essential for transducing acoustic stimuli into electrical signals. In the absence of incoming sound, a fraction of the MET channels on top of the sensory hair cells are open, resulting in a sustained depolarizing current. By genetically manipulating the in vivo expression of molecular components of the MET apparatus, we show that during pre-hearing stages the MET current is essential for establishing the electrophysiological properties of mature inner hair cells (IHCs). If the MET current is abolished in adult IHCs, they revert into cells showing electrical and morphological features characteristic of pre-hearing IHCs, including the re-establishment of cholinergic efferent innervation. The MET current is thus critical for the maintenance of the functional properties of adult IHCs, implying a degree of plasticity in the mature auditory system in response to the absence of normal transduction of acoustic signals.