Development of myelination and axon diameter for fast and precise action potential conductance.

Axons of globular bushy cells in the cochlear nucleus convey hyper-accurate signals to the superior olivary complex, the initial site of binaural processing via comparably thick axons and the calyx of the Held synapse. Bushy cell fibers involved in hyper-accurate binaural processing of low-frequency sounds are known to have an unusual internode length-to-axon caliber ratio (L/d) correlating with higher conduction velocity and superior temporal precision of action potentials. How the L/d-ratio develops and what determines this unusual myelination pattern is unclear. Here we describe a gradual developmental transition from very simple to complex, mature nodes of Ranvier on globular bushy cell axons during a 2-week period starting at postnatal day P6/7. The molecular composition of nodes matured successively along the axons from somata to synaptic terminals with morphologically and molecularly mature nodes appearing almost exclusively after hearing onset. Internodal distances are initially coherent with the canonical L/d-ratio of ~100. Several days after hearing onset, however, an over-proportional increase in axon caliber occurs in cells signaling low-frequency sounds which alters their L/d ratio to ~60. Hence, oligodendrocytes initially myelinating axons according to their transient axon caliber but a subsequent differential axon thickening after hearing onset results in the unusual myelination pattern.

An Active Sensing Paradigm for Studying Human Auditory Perception.

Our perception is based on active sensing, i.e., the relationship between self-motion and resulting changes to sensory inputs. Yet, traditional experimental paradigms are characterized by delayed reactions to a predetermined stimulus sequence. To increase the engagement of subjects and potentially provide richer behavioral responses, we developed Sensory Island Task for humans (SITh), a freely-moving search paradigm to study auditory perception. In SITh, subjects navigate an arena in search of an auditory target, relying solely on changes in the presented stimulus frequency, which is controlled by closed-loop position tracking. A "target frequency" was played when subjects entered a circular sub-area of the arena, the "island", while different frequencies were presented outside the island. Island locations were randomized across trials, making stimulus frequency the only informative cue for task completion. Two versions of SITh were studied: binary discrimination, and gradual change of the stimulus frequency. The latter version allowed determining frequency discrimination thresholds based on the subjects' report of the perceived island location (i.e., target frequency). Surprisingly, subjects exhibited similar thresholds as reported in traditional "stationary" forced-choice experiments after performing only 30 trials, highlighting the intuitive nature of SITh. Notably, subjects spontaneously employed a small variety of stereotypical search patterns, and their usage proportions varied between task versions. Moreover, frequency discrimination performance depended on the search pattern used. Overall, we demonstrate that the use of an ecologically driven paradigm is able to reproduce established findings while simultaneously providing rich behavioral data for the description of sensory ethology.

Temporal hyper-precision of brainstem neurons alters spatial sensitivity of binaural auditory processing with cochlear implants.

The ability to localize a sound source in complex environments is essential for communication and navigation. Spatial hearing relies predominantly on the comparison of differences in the arrival time of sound between the two ears, the interaural time differences (ITDs). Hearing impairments are highly detrimental to sound localization. While cochlear implants (CIs) have been successful in restoring many crucial hearing capabilities, sound localization via ITD detection with bilateral CIs remains poor. The underlying reasons are not well understood. Neuronally, ITD sensitivity is generated by coincidence detection between excitatory and inhibitory inputs from the two ears performed by specialized brainstem neurons. Due to the lack of electrophysiological brainstem recordings during CI stimulation, it is unclear to what extent the apparent deficits are caused by the binaural comparator neurons or arise already on the input level. Here, we use a bottom-up approach to compare response features between electric and acoustic stimulation in an animal model of CI hearing. Conducting extracellular single neuron recordings in gerbils, we find severe hyper-precision and moderate hyper-entrainment of both the excitatory and inhibitory brainstem inputs to the binaural comparator neurons during electrical pulse-train stimulation. This finding establishes conclusively that the binaural processing stage must cope with highly altered input statistics during CI stimulation. To estimate the consequences of these effects on ITD sensitivity, we used a computational model of the auditory brainstem. After tuning the model parameters to match its response properties to our physiological data during either stimulation type, the model predicted that ITD sensitivity to electrical pulses is maintained even for the hyper-precise inputs. However, the model exhibits severely altered spatial sensitivity during electrical stimulation compared to acoustic: while resolution of ITDs near midline was increased, more lateralized adjacent source locations became inseparable. These results directly resemble recent findings in rodent and human CI listeners. Notably, decreasing the phase-locking precision of inputs during electrical stimulation recovered a wider range of separable ITDs. Together, our findings suggest that a central problem underlying the diminished ITD sensitivity in CI users might be the temporal hyper-precision of inputs to the binaural comparator stage induced by electrical stimulation.

Ketamine-xylazine anesthesia depth affects auditory neuronal responses in the lateral superior olive complex of the gerbil.

Studies of in vivo neuronal responses to auditory inputs in the superior olive complex (SOC) are usually done under anesthesia. However, little attention has been paid to the effect of anesthesia itself on response properties. Here, we assessed the effect of anesthesia depth under ketamine-xylazine anesthetics on auditory evoked response properties of lateral SOC neurons. Anesthesia depth was tracked by monitoring EEG spectral peak frequencies. An increase in anesthesia depth led to a decrease of spontaneous discharge activities and an elevated response threshold. The temporal responses to suprathreshold tones were also affected, with adapted responses reduced but peak responses unaffected. Deepening the anesthesia depth also increased first spike latency. However, spike jitter was not affected. Auditory brainstem responses to clicks confirmed that ketamine-xylazine anesthesia depth affects auditory neuronal activities and the effect on spike rate and spike timing persists through the auditory pathway. We concluded from those observations that ketamine-xylazine affects lateral SOC response properties depending on the anesthesia depth.NEW & NOTEWORTHY We studied how the depth of ketamine-xylazine anesthesia altered response properties of lateral superior olive complex neurons, and auditory brainstem evoked responses. Our results provide direct evidence that anesthesia depth affects auditory neuronal responses and reinforce the notion that both the anesthetics and the anesthesia depth should be considered when interpreting/comparing in vivo neuronal recordings.

Source identity shapes spatial preference in primary auditory cortex during active navigation.

Information about the position of sensory objects and identifying their concurrent behavioral relevance is vital to navigate the environment. In the auditory system, spatial information is computed in the brain based on the position of the sound source relative to the observer and thus assumed to be egocentric throughout the auditory pathway. This assumption is largely based on studies conducted in either anesthetized or head-fixed and passively listening animals, thus lacking self-motion and selective listening. Yet these factors are fundamental components of natural sensing1 that may crucially impact the nature of spatial coding and sensory object representation.2 How individual objects are neuronally represented during unrestricted self-motion and active sensing remains mostly unexplored. Here, we trained gerbils on a behavioral foraging paradigm that required localization and identification of sound sources during free navigation. Chronic tetrode recordings in primary auditory cortex during task performance revealed previously unreported sensory object representations. Strikingly, the egocentric angle preference of the majority of spatially sensitive neurons changed significantly depending on the task-specific identity (outcome association) of the sound source. Spatial tuning also exhibited large temporal complexity. Moreover, we encountered egocentrically untuned neurons whose response magnitude differed between source identities. Using a neural network decoder, we show that, together, these neuronal response ensembles provide spatiotemporally co-existent information about both the egocentric location and the identity of individual sensory objects during self-motion, revealing a novel cortical computation principle for naturalistic sensing.

Endogenous Cholinergic Signaling Modulates Sound-Evoked Responses of the Medial Nucleus of the Trapezoid Body.

The medial nucleus of trapezoid body (MNTB) is a major source of inhibition in auditory brainstem circuitry. The MNTB projects well-timed inhibitory output to principal sound-localization nuclei in the superior olive (SOC) as well as other computationally important centers. Acoustic information is conveyed to MNTB neurons through a single calyx of Held excitatory synapse arising from the cochlear nucleus. The encoding efficacy of this large synapse depends on its activity rate, which is primarily determined by sound intensity and stimulus frequency. However, MNTB activity rate is additionally influenced by inhibition and possibly neuromodulatory inputs, albeit their functional role is unclear. Happe and Morley (2004) discovered prominent expression of α7 nAChRs in rat SOC, suggesting possible engagement of ACh-mediated modulation of neural activity in the MNTB. However, the existence and nature of this putative modulation have never been physiologically demonstrated. We probed nicotinic cholinergic influences on acoustic responses of MNTB neurons from adult gerbils (Meriones unguiculatus) of either sex. We recorded tone-evoked MNTB single-neuron activity in vivo using extracellular single-unit recording. Piggyback multibarrel electrodes enabled pharmacological manipulation of nAChRs by reversibly applying antagonists to two receptor types, α7 and α4ß2. We observed that tone-evoked responses are dependent on ACh modulation by both nAChR subtypes. Spontaneous activity was not affected by antagonist application. Functionally, we demonstrate that ACh contributes to sustaining high discharge rates and enhances signal encoding efficacy. Additionally, we report anatomic evidence revealing novel cholinergic projections to MNTB arising from pontine and superior olivary nuclei.SIGNIFICANCE STATEMENT This study is the first to physiologically probe how acetylcholine, a pervasive neuromodulator in the brain, influences the encoding of acoustic information by the medial nucleus of trapezoid body, the most prominent source of inhibition in brainstem sound-localization circuitry. We demonstrate that this cholinergic input enhances neural discrimination of tones from noise stimuli, which may contribute to processing important acoustic signals, such as speech. Additionally, we describe novel anatomic projections providing cholinergic input to the MNTB. Together, these findings shed new light on the contribution of neuromodulation to fundamental computational processes in auditory brainstem circuitry and to a more holistic understanding of modulatory influences in sensory processing.

Sensory Island Task (SIT): A New Behavioral Paradigm to Study Sensory Perception and Neural Processing in Freely Moving Animals.

A central function of sensory systems is the gathering of information about dynamic interactions with the environment during self-motion. To determine whether modulation of a sensory cue was externally caused or a result of self-motion is fundamental to perceptual invariance and requires the continuous update of sensory processing about recent movements. This process is highly context-dependent and crucial for perceptual performances such as decision-making and sensory object formation. Yet despite its fundamental ecological role, voluntary self-motion is rarely incorporated in perceptual or neurophysiological investigations of sensory processing in animals. Here, we present the Sensory Island Task (SIT), a new freely moving search paradigm to study sensory processing and perception. In SIT, animals explore an open-field arena to find a sensory target relying solely on changes in the presented stimulus, which is controlled by closed-loop position tracking in real-time. Within a few sessions, animals are trained via positive reinforcement to search for a particular area in the arena ("target island"), which triggers the presentation of the target stimulus. The location of the target island is randomized across trials, making the modulated stimulus feature the only informative cue for task completion. Animals report detection of the target stimulus by remaining within the island for a defined time ("sit-time"). Multiple "non-target" islands can be incorporated to test psychometric discrimination and identification performance. We exemplify the suitability of SIT for rodents (Mongolian gerbil, Meriones unguiculatus) and small primates (mouse lemur, Microcebus murinus) and for studying various sensory perceptual performances (auditory frequency discrimination, sound source localization, visual orientation discrimination). Furthermore, we show that pairing SIT with chronic electrophysiological recordings allows revealing neuronal signatures of sensory processing under ecologically relevant conditions during goal-oriented behavior. In conclusion, SIT represents a flexible and easily implementable behavioral paradigm for mammals that combines self-motion and natural exploratory behavior to study sensory sensitivity and decision-making and their underlying neuronal processing.

Cooperative population coding facilitates efficient sound-source separability by adaptation to input statistics.

Our sensory environment changes constantly. Accordingly, neural systems continually adapt to the concurrent stimulus statistics to remain sensitive over a wide range of conditions. Such dynamic range adaptation (DRA) is assumed to increase both the effectiveness of the neuronal code and perceptual sensitivity. However, direct demonstrations of DRA-based efficient neuronal processing that also produces perceptual benefits are lacking. Here, we investigated the impact of DRA on spatial coding in the rodent brain and the perception of human listeners. Complex spatial stimulation with dynamically changing source locations elicited prominent DRA already on the initial spatial processing stage, the Lateral Superior Olive (LSO) of gerbils. Surprisingly, on the level of individual neurons, DRA diminished spatial tuning because of large response variability across trials. However, when considering single-trial population averages of multiple neurons, DRA enhanced the coding efficiency specifically for the concurrently most probable source locations. Intrinsic LSO population imaging of energy consumption combined with pharmacology revealed that a slow-acting LSO gain-control mechanism distributes activity across a group of neurons during DRA, thereby enhancing population coding efficiency. Strikingly, such "efficient cooperative coding" also improved neuronal source separability specifically for the locations that were most likely to occur. These location-specific enhancements in neuronal coding were paralleled by human listeners exhibiting a selective improvement in spatial resolution. We conclude that, contrary to canonical models of sensory encoding, the primary motive of early spatial processing is efficiency optimization of neural populations for enhanced source separability in the concurrent environment.

Precisely timed inhibition facilitates action potential firing for spatial coding in the auditory brainstem.

The integration of excitatory and inhibitory synaptic inputs is fundamental to neuronal processing. In the mammalian auditory brainstem, neurons compare excitatory and inhibitory inputs from the ipsilateral and contralateral ear, respectively, for sound localization. However, the temporal precision and functional roles of inhibition in this integration process are unclear. Here, we demonstrate by in vivo recordings from the lateral superior olive (LSO) that inhibition controls spiking with microsecond precision throughout high frequency click trains. Depending on the relative timing of excitation and inhibition, neuronal spike probability is either suppressed or-unexpectedly-facilitated. In vitro conductance-clamp LSO recordings establish that a reduction in the voltage threshold for spike initiation due to a prior hyperpolarization results in post-inhibitory facilitation of otherwise sub-threshold synaptic events. Thus, microsecond-precise differences in the arrival of inhibition relative to excitation can facilitate spiking in the LSO, thereby promoting spatial sensitivity during the processing of faint sounds.

Input timing for spatial processing is precisely tuned via constant synaptic delays and myelination patterns in the auditory brainstem.

Precise timing of synaptic inputs is a fundamental principle of neural circuit processing. The temporal precision of postsynaptic input integration is known to vary with the computational requirements of a circuit, yet how the timing of action potentials is tuned presynaptically to match these processing demands is not well understood. In particular, action potential timing is shaped by the axonal conduction velocity and the duration of synaptic transmission delays within a pathway. However, it is not known to what extent these factors are adapted to the functional constraints of the respective circuit. Here, we report the finding of activity-invariant synaptic transmission delays as a functional adaptation for input timing adjustment in a brainstem sound localization circuit. We compared axonal and synaptic properties of the same pathway between two species with dissimilar timing requirements (gerbil and mouse): In gerbils (like humans), neuronal processing of sound source location requires exceptionally high input precision in the range of microseconds, but not in mice. Activity-invariant synaptic transmission and conduction delays were present exclusively in fast conducting axons of gerbils that also exhibited unusual structural adaptations in axon myelination for increased conduction velocity. In contrast, synaptic transmission delays in mice varied depending on activity levels, and axonal myelination and conduction velocity exhibited no adaptations. Thus, the specializations in gerbils and their absence in mice suggest an optimization of axonal and synaptic properties to the specific demands of sound localization. These findings significantly advance our understanding of structural and functional adaptations for circuit processing.

Differences in synaptic and intrinsic properties result in topographic heterogeneity of temporal processing of neurons within the inferior colliculus.

The identification and characterization of organization principals is essential for the understanding of neural function of brain areas. The inferior colliculus (IC) represents a midbrain nexus involved in numerous aspects of auditory processing. Likewise, neurons throughout the IC are tuned to a diverse range of specific stimulus features. Yet beyond a topographic arrangement of the cochlea-inherited frequency tuning, the functional organization of the IC is not well understood. Particularly, a common principle that links the diverse tuning characteristics is unknown. Here we used in vitro patch clamp recordings combined with laser-uncaging, and in vivo single cell recordings to study the spatial and functional organization principles of the central IC. We identified a topographic bias of ascending synaptic input timing that is balanced between inhibition and excitation and co-varies with in vivo first-spike latency. This bias was paralleled post-synaptically by differences in biophysical membrane properties and firing patterns, with integrating neurons predominantly found in the dorso-medial part, and coincidence-detector neurons biased to the ventro-lateral IC. Importantly, these cellular and network features translated into distinct temporal processing capabilities irrespectively of the neurons' characteristic frequency. Our data therefore imply that heterogeneity of synaptic inputs, intrinsic properties and temporal processing are functional principles that underlie the spatial organization of the central IC.

Tuning of Ranvier node and internode properties in myelinated axons to adjust action potential timing.

Action potential timing is fundamental to information processing; however, its determinants are not fully understood. Here we report unexpected structural specializations in the Ranvier nodes and internodes of auditory brainstem axons involved in sound localization. Myelination properties deviated significantly from the traditionally assumed structure. Axons responding best to low-frequency sounds had a larger diameter than high-frequency axons but, surprisingly, shorter internodes. Simulations predicted that this geometry helps to adjust the conduction velocity and timing of action potentials within the circuit. Electrophysiological recordings in vitro and in vivo confirmed higher conduction velocities in low-frequency axons. Moreover, internode length decreased and Ranvier node diameter increased progressively along the distal axon segments, which simulations show was essential to ensure precisely timed depolarization of the giant calyx of Held presynaptic terminal. Thus, individual anatomical parameters of myelinated axons can be tuned to optimize pathways involved in temporal processing.

The natural history of sound localization in mammals--a story of neuronal inhibition.

Our concepts of sound localization in the vertebrate brain are widely based on the general assumption that both the ability to detect air-borne sounds and the neuronal processing are homologous in archosaurs (present day crocodiles and birds) and mammals. Yet studies repeatedly report conflicting results on the neuronal circuits and mechanisms, in particular the role of inhibition, as well as the coding strategies between avian and mammalian model systems. Here we argue that mammalian and avian phylogeny of spatial hearing is characterized by a convergent evolution of hearing air-borne sounds rather than by homology. In particular, the different evolutionary origins of tympanic ears and the different availability of binaural cues in early mammals and archosaurs imposed distinct constraints on the respective binaural processing mechanisms. The role of synaptic inhibition in generating binaural spatial sensitivity in mammals is highlighted, as it reveals a unifying principle of mammalian circuit design for encoding sound position. Together, we combine evolutionary, anatomical and physiological arguments for making a clear distinction between mammalian processing mechanisms and coding strategies and those of archosaurs. We emphasize that a consideration of the convergent nature of neuronal mechanisms will significantly increase the explanatory power of studies of spatial processing in both mammals and birds.

Experience-dependent specialization of receptive field surround for selective coding of natural scenes.

At eye opening, neurons in primary visual cortex (V1) are selective for stimulus features, but circuits continue to refine in an experience-dependent manner for some weeks thereafter. How these changes contribute to the coding of visual features embedded in complex natural scenes remains unknown. Here we show that normal visual experience after eye opening is required for V1 neurons to develop a sensitivity for the statistical structure of natural stimuli extending beyond the boundaries of their receptive fields (RFs), which leads to improvements in coding efficiency for full-field natural scenes (increased selectivity and information rate). These improvements are mediated by an experience-dependent increase in the effectiveness of natural surround stimuli to hyperpolarize the membrane potential specifically during RF-stimulus epochs triggering action potentials. We suggest that neural circuits underlying surround modulation are shaped by the statistical structure of visual input, which leads to more selective coding of features in natural scenes.

Emphasis of spatial cues in the temporal fine structure during the rising segments of amplitude-modulated sounds II: single-neuron recordings.

Recently, with the use of an amplitude-modulated binaural beat (AMBB), in which sound amplitude and interaural-phase difference (IPD) were modulated with a fixed mutual relationship (Dietz et al. 2013b), we demonstrated that the human auditory system uses interaural timing differences in the temporal fine structure of modulated sounds only during the rising portion of each modulation cycle. However, the degree to which peripheral or central mechanisms contribute to the observed strong dominance of the rising slope remains to be determined. Here, by recording responses of single neurons in the medial superior olive (MSO) of anesthetized gerbils and in the inferior colliculus (IC) of anesthetized guinea pigs to AMBBs, we report a correlation between the position within the amplitude-modulation (AM) cycle generating the maximum response rate and the position at which the instantaneous IPD dominates the total neural response. The IPD during the rising segment dominates the total response in 78% of MSO neurons and 69% of IC neurons, with responses of the remaining neurons predominantly coding the IPD around the modulation maximum. The observed diversity of dominance regions within the AM cycle, especially in the IC, and its comparison with the human behavioral data suggest that only the subpopulation of neurons with rising slope dominance codes the sound-source location in complex listening conditions. A comparison of two models to account for the data suggests that emphasis on IPDs during the rising slope of the AM cycle depends on adaptation processes occurring before binaural interaction.

Adaptation in sound localization: from GABA(B) receptor-mediated synaptic modulation to perception.

Across all sensory modalities, the effect of context-dependent neural adaptation can be observed at every level, from receptors to perception. Nonetheless, it has long been assumed that the processing of interaural time differences, which is the primary cue for sound localization, is nonadaptive, as its outputs are mapped directly onto a hard-wired representation of space. Here we present evidence derived from in vitro and in vivo experiments in gerbils indicating that the coincidence-detector neurons in the medial superior olive modulate their sensitivity to interaural time differences through a rapid, GABA(B) receptor-mediated feedback mechanism. We show that this mechanism provides a gain control in the form of output normalization, which influences the neuronal population code of auditory space. Furthermore, psychophysical tests showed that the paradigm used to evoke neuronal GABA(B) receptor-mediated adaptation causes the perceptual shift in sound localization in humans that was expected on the basis of our physiological results in gerbils.

Mechanisms of sound localization in mammals.

The ability to determine the location of a sound source is fundamental to hearing. However, auditory space is not represented in any systematic manner on the basilar membrane of the cochlea, the sensory surface of the receptor organ for hearing. Understanding the means by which sensitivity to spatial cues is computed in central neurons can therefore contribute to our understanding of the basic nature of complex neural representations. We review recent evidence concerning the nature of the neural representation of auditory space in the mammalian brain and elaborate on recent advances in the understanding of mammalian subcortical processing of auditory spatial cues that challenge the "textbook" version of sound localization, in particular brain mechanisms contributing to binaural hearing.

Enhancement of ITD coding within the initial stages of the auditory pathway.

Sensory systems use a variety of strategies to increase the signal-to-noise ratio in their inputs at the receptor level. However, important cues for sound localization are not present at the individual ears but are computed after inputs from the two ears converge within the brain, and we hypothesized that additional strategies to enhance the representation of these cues might be employed in the initial stages after binaural convergence. Specifically, we investigated the transformation that takes place between the first two stages of the gerbil auditory pathway that are sensitive to differences in the arrival time of a sound at the two ears (interaural time differences; ITDs): the medial superior olive (MSO), where ITD tuning originates, and the dorsal nucleus of the lateral lemniscus (DNLL), to which the MSO sends direct projections. We use a combined experimental and computational approach to demonstrate that the coding of ITDs is dramatically enhanced between these two stages, with the mutual information in the responses of single neurons increasing by a factor of 2. We also show that this enhancement is related to an increase in dynamic range for neurons with high preferred frequencies and a decrease in variability for neurons with low preferred frequencies. These results suggest that a major role of the initial stages of the ITD pathway may be to enhance the representation created at the site of coincidence detection and illustrate the potential of this pathway as a model system for the study of strategies for enhancing sensory representations in the mammalian brain.

Interaural time difference processing in the mammalian medial superior olive: the role of glycinergic inhibition.

The dominant cue for localization of low-frequency sounds are microsecond differences in the time-of-arrival of sounds at the two ears [interaural time difference (ITD)]. In mammals, ITD sensitivity is established in the medial superior olive (MSO) by coincidence detection of excitatory inputs from both ears. Hence the relative delay of the binaural inputs is crucial for adjusting ITD sensitivity in MSO cells. How these delays are constructed is, however, still unknown. Specifically, the question of whether inhibitory inputs are involved in timing the net excitation in MSO cells, and if so how, is controversial. These inhibitory inputs derive from the nuclei of the trapezoid body, which have physiological and structural specializations for high-fidelity temporal transmission, raising the possibility that well timed inhibition is involved in tuning ITD sensitivity. Here, we present physiological and pharmacological data from in vivo extracellular MSO recordings in anesthetized gerbils. Reversible blockade of synaptic inhibition by iontophoretic application of the glycine antagonist strychnine increased firing rates and significantly shifted ITD sensitivity of MSO neurons. This indicates that glycinergic inhibition plays a major role in tuning the delays of binaural excitation. We also tonically applied glycine, which lowered firing rates but also shifted ITD sensitivity in a way analogous to strychnine. Hence tonic glycine application experimentally decoupled the effect of inhibition from the timing of its inputs. We conclude that, for proper ITD processing, not only is inhibition necessary, but it must also be precisely timed.

Retrograde GABA signaling adjusts sound localization by balancing excitation and inhibition in the brainstem.

Central processing of acoustic cues is critically dependent on the balance between excitation and inhibition. This balance is particularly important for auditory neurons in the lateral superior olive, because these compare excitatory inputs from one ear and inhibitory inputs from the other ear to compute sound source location. By applying GABA(B) receptor antagonists during sound stimulation in vivo, it was revealed that these neurons adjust their binaural sensitivity through GABA(B) receptors. Using an in vitro approach, we then demonstrate that these neurons release GABA during spiking activity. Consequently, GABA differentially regulates transmitter release from the excitatory and inhibitory terminals via feedback to presynaptic GABA(B) receptors. Modulation of the synaptic input strength, by putative retrograde release of neurotransmitter, may enable these auditory neurons to rapidly adjust the balance between excitation and inhibition, and thus their binaural sensitivity, which could play an important role as an adaptation to various listening situations.