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We reconstructed the intrinsic axons of 32 neurons in the guinea pig inferior colliculus (IC) following juxtacellular labeling. Biocytin was injected into cells in vivo, after first analyzing physiological response properties. Based on axonal morphology there were two classes of neuron: (1) laminar cells (14/32, 44%) with an intrinsic axon and flattened dendrites confined to a single fibrodendritic lamina and (2) translaminar cells (18/32, 56%) with axons that terminated in two or more laminae in the central nucleus (ICc) or the surrounding cortex. There was also one small, low-frequency cell with bushy-like dendrites that was very sensitive to interaural timing differences. The translaminar cells were subdivided into three groups of cells with: (a) stellate dendrites that crossed at least two laminae (8/32, 25%); (b) flattened dendrites confined to one lamina and that had mainly en passant axonal swellings (7/32, 22%) and (c) short, flattened dendrites and axons with distinctive clusters of large terminal boutons in the ICc (3/32, 9%). These terminal clusters were similar to those of cortical basket cells. The 14 laminar cells all had sustained responses apart from one offset response. Almost half the non-basket type translaminar cells (7/15) had onset responses while the others had sustained responses. The basket cells were the only ones to have short-latency (7–9 ms), chopper responses and this distinctive temporal response should allow them to be studied in more detail in future. This is the first description of basket cells in the auditory brainstem, but more work is required to confirm their neurotransmitter and precise post-synaptic targets.

AP-2 is a family of transcription factors involved in many aspects of development, cell differentiation, and regulation of cell growth and death. AP-2δ is a member of this group and specific gene expression patterns are required in the adult mouse brain for the development of parts of the inferior colliculus (IC), as well as the cortex, dorsal thalamus, and superior colliculus. The midbrain is one of the central areas in the brain where multimodal integration, i.e., integration of information from different senses, occurs. Previous data showed that AP-2δ-deficient mice are viable but due to increased apoptosis at the end of embryogenesis, lack part of the posterior midbrain. Despite the absence of the IC in AP-2δ-deficient mice, these animals retain at least some higher auditory functions. Neuronal responses to tones in the neocortex suggest an alternative auditory pathway that bypasses the IC. While sufficient data are available in mammals, little is known about AP-2δ in chickens, an avian model for the localization of sounds and the development of auditory circuits in the brain. Here, we identified and localized AP-2δ expression in the chicken midbrain during embryogenesis. Our data confirmed the presence of AP-2δ in the inferior colliculus and optic tectum (TeO), specifically in shepherd’s crook neurons, which are an essential component of the midbrain isthmic network and involved in multimodal integration. AP-2δ expression in the chicken midbrain may be related to the integration of both auditory and visual afferents in these neurons. In the future, these insights may allow for a more detailed study of circuitry and computational rules of auditory and multimodal networks.

Post-mortem neuropathological andin vivoneuroimaging methods have demonstrated the vulnerability of the inferior colliculus to the sequelae of thiamine deficiency as occurs in Wernicke-Korsakoff Syndrome (WKS). A rich literature in animal models ranging from mice to monkeys—including our neuroimaging studies in rats—has shown involvement of the inferior colliculi in the neural response to thiamine depletion, frequently accomplished with pyrithiamine, an inhibitor of thiamine metabolism. In uncomplicated alcoholism (i.e., absent diagnosable neurological concomitants), the literature citing involvement of the inferior colliculus is scarce, has nearly all been accomplished in preclinical models, and is predominately discussed in the context of ethanol withdrawal. Our recent work using novel, voxel-based analysis of structural Magnetic Resonance Imaging (MRI) has demonstrated significant, persistent shrinkage of the inferior colliculus using acute and chronic ethanol exposure paradigms in two strains of rats. We speculate that these consistent findings should be considered from the perspective of the inferior colliculi having a relatively high CNS metabolic rate. As such, they are especially vulnerable to hypoxic injury and may be provide a common anatomical link among a variety of disparate insults. An argument will be made that the inferior colliculi have functions, possibly related to auditory gating, necessary for awareness of the external environment. Multimodal imaging including diffusion methods to provide more accuratein vivovisualization and quantification of the inferior colliculi may clarify the roles of brain stem nuclei such as the inferior colliculi in alcoholism and other neuropathologies marked by altered metabolism.

In natural environments our auditory system is exposed to multiple and diverse signals of fluctuating amplitudes. Therefore, to detect, localize, and single out individual sounds the auditory system has to process and filter spectral and temporal information from both ears. It is known that the overall sound pressure level affects sensory signal transduction and therefore the temporal response pattern of auditory neurons. We hypothesize that the mammalian binaural system utilizes a dynamic mechanism to adjust the temporal filters in neuronal circuits to different overall sound pressure levels. Previous studies proposed an inhibitory mechanism generated by the reciprocally coupled dorsal nuclei of the lateral lemniscus (DNLL) as a temporal neuronal-network filter that suppresses rapid binaural fluctuations. Here we investigated the consequence of different sound levels on this filter during binaural processing. Our in vivo and in vitro electrophysiology in Mongolian gerbils shows that the integration of ascending excitation and contralateral inhibition defines the temporal properties of this inhibitory filter. The time course of this filter depends on the synaptic drive, which is modulated by the overall sound pressure level and N-methyl-D-aspartate receptor (NMDAR) signaling. In psychophysical experiments we tested the temporal perception of humans and show that detection and localization of two subsequent tones changes with the sound pressure level consistent with our physiological results. Together our data support the hypothesis that mammals dynamically adjust their time window for sound detection and localization within the binaural system in a sound level dependent manner.

Neurons at higher stages of sensory processing can partially compensate for a sudden drop in input from the periphery through a homeostatic plasticity process that increases the gain on weak afferent inputs. Even after a profound unilateral auditory neuropathy where > 95% of synapses between auditory nerve fibers and inner hair cells have been eliminated with ouabain, central gain can restore the cortical processing and perceptual detection of basic sounds delivered to the denervated ear. In this model of profound auditory neuropathy, cortical processing and perception recover despite the absence of an auditory brainstem response (ABR) or brainstem acoustic reflexes, and only a partial recovery of sound processing at the level of the inferior colliculus (IC), an auditory midbrain nucleus. In this study, we induced a profound cochlear neuropathy with ouabain and asked whether central gain enabled a compensatory plasticity in the auditory thalamus comparable to the full recovery of function previously observed in the auditory cortex (ACtx), the partial recovery observed in the IC, or something different entirely. Unilateral ouabain treatment in adult mice effectively eliminated the ABR, yet robust sound-evoked activity persisted in a minority of units recorded from the contralateral medial geniculate body (MGB) of awake mice. Sound-driven MGB units could decode moderate and high-intensity sounds with accuracies comparable to sham-treated control mice, but low-intensity classification was near chance. Pure tone receptive fields and synchronization to broadband pulse trains also persisted, albeit with significantly reduced quality and precision, respectively. MGB decoding of temporally modulated pulse trains and speech tokens were both greatly impaired in ouabain-treated mice. Taken together, the absence of an ABR belied a persistent auditory processing at the level of the MGB that was likely enabled through increased central gain. Compensatory plasticity at the level of the auditory thalamus was less robust overall than previous observations in auditory cortex or midbrain. Hierarchical differences in compensatory plasticity following sensorineural hearing loss may reflect differences in GABA circuit organization within the MGB, as compared to the ACtx or IC.

Receptive fields of sensory neurons are considered to be dynamic and depend on the stimulus history. In the auditory system, evidence of dynamic frequency-receptive fields has been found following stimulus-specific adaptation (SSA). However, the underlying mechanism and circuitry of SSA have not been fully elucidated. Here, we studied how frequency-receptive fields of neurons in rat inferior colliculus (IC) changed when exposed to a biased tone sequence. Pure tone with one specific frequency (adaptor) was presented markedly more often than others. The adapted tuning was compared with the original tuning measured with an unbiased sequence. We found inhomogeneous changes in frequency tuning in IC, exhibiting a center-surround pattern with respect to the neuron’s best frequency. Central adaptors elicited strong suppressive and repulsive changes while flank adaptors induced facilitative and attractive changes. Moreover, we proposed a two-layer model of the underlying network, which not only reproduced the adaptive changes in the receptive fields but also predicted novelty responses to oddball sequences. These results suggest that frequency-specific adaptation in auditory midbrain can be accounted for by an adapted frequency channel and its lateral spreading of adaptation, which shed light on the organization of the underlying circuitry.

Periodicities in sound waveforms are widespread, and shape important perceptual attributes of sound including rhythm and pitch. Previous studies have indicated that, in the inferior colliculus (IC), a key processing stage in the auditory midbrain, neurons tuned to different periodicities might be arranged along a periodotopic axis which runs approximately orthogonal to the tonotopic axis. Here we map out the topography of frequency and periodicity tuning in the IC of gerbils in unprecedented detail, using pure tones and different periodic sounds, including click trains, sinusoidally amplitude modulated (SAM) noise and iterated rippled noise. We found that while the tonotopic map exhibited a clear and highly reproducible gradient across all animals, periodotopic maps varied greatly across different types of periodic sound and from animal to animal. Furthermore, periodotopic gradients typically explained only about 10% of the variance in modulation tuning between recording sites. However, there was a strong local clustering of periodicity tuning at a spatial scale of ca. 0.5 mm, which also differed from animal to animal.

A unique aspect of the auditory system is the inferior colliculus (IC). This large midbrain structure serves as an obligatory synaptic station in both the ascending and descending auditory pathways. It has no equivalent in other sensory systems and it meets several unique needs of the auditory system. Most important, of course, is unifying the representation of sound in the two ears, which allows sound localization and other spatial calculations such as demasking and the analysis of complex auditory scenes. In addition, the IC is a major target for non-auditory inputs to the auditory system, including connections from other sensory systems and from neuromodulatory systems like the locus coeruleus. The IC also distributes auditory information in cortico-cortical loops and in connections to the superior colliculus. There is much to be learned about the IC. The goal of this special topic is to bring together papers, both reviews and original research, on a wide range of aspects of the IC's organization and function. These include the internal and external connections of the IC, the molecular determinants of its response properties, and the nature of sound encoding in the IC. In this e-book, 31 contributions are organized into these three broad categories. The first 12 chapters address the morphological and functional organization of the IC. They include descriptions of the connections of the IC to other parts of the brain, both ascending and descending projections, as well as the organization of internal microcircuits within the IC itself. In most brainstem auditory centers, the neurons have a diverse array of morphological and molecular structure which correlates strongly with connectivity and functional role (inhibition vs. excitation for example). By contrast, it has been difficult to define such internal circuitry in the IC. The papers in this section describe a variety of approaches, anatomical, molecular, and physiological to this question and contribute to our emerging understanding of IC's internal and external organization. The next 6 chapters describe analyses of the molecular characteristics of IC neurons in relationship to function. These include papers on the role of ion channels in generating responses of IC neurons and on the effects of mutations, aging, and damage to the auditory system. Such insults change the expression of genes and produce a variety of functional consequences for the representation of sound. The final 13 chapters describe the encoding of sound in the IC, especially in its ascending pathways. These include analyses of responses to sound, convergence of auditory and other inputs in the IC, and analyses of emergent properties like stimulus-specific adaptation. The bat auditory system has long provided fertile ground for auditory research, because of the relatively well-defined computations needed for sonar processing. Almost half of the chapters on sound encoding deal with the bat IC, especially the role of inhibition in determining response selectivity, delay tuning, and duration tuning. The study of the IC is too large a topic to produce a satisfactory overall view in a collection of papers of the size of this one. However, these papers do represent the main trends in current research on the IC and make clear some of the most important outstanding problems. It is hoped that they will inspire and guide the next steps in working out this critical part of the auditory system.

Hierarchical processing of sensory information requires interaction at multiple levels along the peripheral to central pathway. Recent evidence suggests that interaction between driving and modulating components can shape both top down and bottom up processing of sensory information. Here we show that a component inherited from extrinsic sources combines with local components to code sound intensity. By applying high concentrations of divalent cations to neurons in the nucleus of the inferior colliculus in the auditory midbrain, we show that as sound intensity increases, the source of synaptic efficacy changes from inherited inputs to local circuits. In neurons with a wide dynamic range response to intensity, inherited inputs increase firing rates at low sound intensities but saturate at mid-to-high intensities. Local circuits activate at high sound intensities and widen dynamic range by continuously increasing their output gain with intensity. Inherited inputs are necessary and sufficient to evoke tuned responses, however local circuits change peak output. Push-pull driving inhibition and excitation create net excitatory drive to intensity-variant neurons and tune neurons to intensity. Our results reveal that dynamic range and tuning re-emerge in the auditory midbrain through local circuits that are themselves variable or tuned.

Hierarchical processing of sensory information occurs at multiple levels between the peripheral and central pathway. Different extents of convergence and divergence in top down and bottom up projections makes it difficult to separate the various components activated by a sensory input. In particular, hierarchical processing at sub-cortical levels is little understood. Here we have developed a method to isolate extrinsic inputs to the inferior colliculus (IC), a nucleus in the midbrain region of the auditory system, with extensive ascending and descending convergence. By applying a high concentration of divalent cations (HiDi) locally within the IC, we isolate a HiDi-sensitive from a HiDi-insensitive component of responses evoked by afferent input in brain slices and in vivo during a sound stimulus. Our results suggest that the HiDi sensitive component is a monosynaptic input to the IC, while the HiDi-insensitive component is a local polysynaptic circuit. Monosynaptic inputs have short latencies, rapid rise times and underlie first spike latencies. Local inputs have variable delays and evoke long-lasting excitation. In vivo, local circuits have variable onset times and temporal profiles. Our results suggest that high concentrations of divalent cations should prove to be a widely useful method of isolating extrinsic monosynaptic inputs from local circuits in vivo.

Projections from auditory cortex (AC) can alter the responses of cells in the inferior colliculus (IC) to sounds. Most IC cells show excitation and inhibition after stimulation of the AC. AC axons release glutamate and excite their targets, so inhibition is presumed to result from cortical activation of GABAergic IC cells that inhibit other IC cells via local projections. However, it is not known whether cortical axons contact GABAergic IC cells directly. We labeled corticocollicular axons by injecting fluorescent dextrans into the AC in guinea pigs. We visualized the tracer with diaminobenzidine and processed the tissue for electron microscopy. We identified presumptive GABAergic profiles with post-embedding anti-GABA immunogold histochemistry on ultrathin sections. We identified dextran-labeled cortical boutons in the IC and identified their postsynaptic targets according to morphology (e.g., spine, dendrite) and GABA-reactivity. Cortical synapses were observed in all IC subdivisions, but were comparatively rare in the central nucleus. Cortical boutons contain round vesicles and few mitochondria. They form asymmetric synapses with spines (most frequently), dendritic shafts and, least often, with cell bodies. Excitatory boutons in the IC can be classified as large, medium or small; most cortical boutons belong to the small excitatory class, while a minority (~14%) belong to the medium excitatory class. Approximately 4% of the cortical targets were GABA-positive; these included dendritic shafts, spines, and cell bodies. We conclude that the majority of cortical boutons contact non-GABAergic (i.e., excitatory) IC cells and a small proportion (4%) contact GABAergic cells. Given that most IC cells show inhibition (as well as excitation) after cortical stimulation, it is likely that the majority of cortically-driven inhibition in the IC results from cortical activation of a relatively small number of IC GABAergic cells that have extensive local axons.

Projections to the inferior colliculus from the lateral and medial superior olivary nuclei were studied in the gerbil (Meriones unguiculatus) with neuroanatomical tract-tracing methods. The terminal fields of projecting axons were labeled via anterograde transport of biotinylated dextran amine and were localized on series of horizontal sections through the inferior colliculus. In addition, to make the results easier to visualize in three dimensions and to facilitate comparisons among cases, the data were also reconstructed into the transverse plane. The results show that the terminal fields from the low frequency parts of the lateral and medial superior olivary nuclei are concentrated in a dorsal, lateral and rostral area that is referred to as the “pars lateralis” of the central nucleus by analogy with the cat. This region also receives substantial input from both the contralateral and ipsilateral cochlear nuclei (Cant and Benson, 2008) and presumably plays a major role in processing binaural, low frequency information. The basic pattern of organization in the gerbil inferior colliculus is similar to that of other rodents, although the low frequency part of the central nucleus in gerbils appears to be relatively greater than in the rat, consistent with differences in the audiograms of the two species.

Frequency modulations occur in many natural sounds, including vocalizations. The neuronal response to frequency modulated (FM) stimuli has been studied extensively in different brain areas, with an emphasis on the auditory cortex and the central nucleus of the inferior colliculus. Here, we measured the responses to FM sweeps in whole-cell recordings from neurons in the dorsal cortex of the mouse inferior colliculus. Both up- and downward logarithmic FM sweeps were presented at two different speeds to both the ipsi- and the contralateral ear. Based on the number of action potentials that were fired, between 10 and 24% of cells were selective for rate or direction of the FM sweeps. A somewhat lower percentage of cells, 6-21%, showed selectivity based on EPSP size. To study the mechanisms underlying the generation of FM selectivity, we compared FM responses with responses to simple tones in the same cells. We found that if pairs of neurons responded in a similar way to simple tones, they generally also responded in a similar way to FM sweeps. Further evidence that FM selectivity can be generated within the dorsal cortex was obtained by reconstructing FM sweeps from the response to simple tones using three different models. In about half of the direction selective neurons the selectivity was generated by spectrally asymmetric synaptic inhibition. In addition, evidence for direction selectivity based on the timing of excitatory responses was also obtained in some cells. No clear evidence for the local generation of rate selectivity was obtained. We conclude that FM direction selectivity can be generated within the dorsal cortex of the mouse inferior colliculus by multiple mechanisms.