J. Gerard G. Borst

Individuals with tinnitus hear sounds that are not present in the external environment. Whereas hearing difficulties at frequencies near those matching the tinnitus pitch are a common complaint for individuals with tinnitus, it is unclear to what extent the internal tinnitus sounds interfere with the detection of external sounds. We therefore studied whether pure-tone detection at the estimated frequency corresponding to the tinnitus pitch (f _tp ) was affected by confusion with the tinnitus percept. Signs of confusion would be a high false alarm rate or a shallower slope of the psychometric function for tone detection at f _tp . We selected participants with symmetric, tonal tinnitus, who were able to estimate its pitch consistently (n = 18). Another 18 participants matched for high-frequency hearing loss, age, and sex, but without tinnitus, served as the control group. For both groups, we measured the psychometric function for detecting long-duration tones, maximizing the likelihood for confusion with an external sound. We observed that false alarm rates for tinnitus participants were not higher for test tones at f _tp , nor were they higher than for the control group without tinnitus. Similar results were obtained for the slopes of the psychometric functions. Apparently, individuals with tinnitus are well able to discriminate between their own tinnitus and comparable external sounds. Our results indicate that (tonal) tinnitus does not interfere with the detection of soft sounds at the tinnitus pitch-matched frequency.

Having two ears enables us to localize sound sources by exploiting interaural time differences (ITDs) in sound arrival. Principal neurons of the medial superior olive (MSO) are sensitive to ITD, and each MSO neuron responds optimally to a best ITD (bITD). In many cells, especially those tuned to low sound frequencies, these bITDs correspond to ITDs for which the contralateral ear leads, and are often larger than the ecologically relevant range, defined by the ratio of the interaural distance and the speed of sound. Using in vivo recordings in gerbils, we found that shortly after hearing onset the bITDs were even more contralaterally leading than found in adult gerbils, and travel latencies for contralateral sound-evoked activity clearly exceeded those for ipsilateral sounds. During the following weeks, both these latencies and their interaural difference decreased. A computational model indicated that spike timing-dependent plasticity can underlie this fine-tuning. Our results suggest that MSO neurons start out with a strong predisposition toward contralateral sounds due to their longer neural travel latencies, but that, especially in high-frequency neurons, this predisposition is subsequently mitigated by differential developmental fine-tuning of the travel latencies.

The amplitude of natural sounds, including speech and animal vocalizations, often shows characteristic modulations. We examined the relationship between neuronal responses in the mouse inferior colliculus and the behavioral detection of amplitude modulation (AM) in sound and modeled how the former can give rise to the latter. Our model suggests that behavioral detection can be well explained by the activity of a subset of neurons showing the largest firing rate changes in response to AM.

The medial superior olive (MSO) is a binaural nucleus that is specialized in detecting the relative arrival times of sounds at both ears. Excitatory inputs to its neurons originating from either ear are segregated to different dendrites. To study the integration of synaptic inputs both within and between dendrites, we made juxtacellular and whole-cell recordings from the MSO in anesthetized female gerbils, while presenting a “double zwuis” stimulus, in which each ear received its own set of tones, which were chosen in a way that all second-order distortion products (DP2s) could be uniquely identified. MSO neurons phase-locked to multiple tones within the multitone stimulus, and vector strength, a measure for spike phase-locking, generally depended linearly on the size of the average subthreshold response to a tone. Subthreshold responses to tones in one ear depended little on the presence of sound in the other ear, suggesting that inputs from different ears sum linearly without a substantial role for somatic inhibition. The “double zwuis” stimulus also evoked response components in the MSO neuron that were phase-locked to DP2s. Bidendritic subthreshold DP2s were quite rare compared with bidendritic suprathreshold DP2s. We observed that in a small subset of cells, the ability to trigger spikes differed substantially between both ears, which might be explained by a dendritic axonal origin. Some neurons that were driven monaurally by only one of the two ears nevertheless showed decent binaural tuning. We conclude that MSO neurons are remarkably good in finding binaural coincidences even among uncorrelated inputs.SIGNIFICANCE STATEMENTNeurons in the medial superior olive are essential for precisely localizing low-frequency sounds in the horizontal plane. From their soma, only two dendrites emerge, which are innervated by inputs originating from different ears. Using a new sound stimulus, we studied the integration of inputs both within and between these dendrites in unprecedented detail. We found evidence that inputs from different dendrites add linearly at the soma, but that small increases in somatic potentials could lead to large increases in the probability of generating a spike. This basic scheme allowed the MSO neurons to detect the relative arrival time of inputs at both dendrites remarkably efficient, although the relative size of these inputs could differ considerably.

Amplitude modulation (AM) is a common feature of natural sounds, including speech and animal vocalizations. Here, we used operant conditioning and in vivo electrophysiology to determine the AM detection threshold of mice as well as its underlying neuronal encoding. Mice were trained in a Go-NoGo task to detect the transition to AM within a noise stimulus designed to prevent the use of spectral side-bands or a change in intensity as alternative cues. Our results indicate that mice, in comparison with other species, detect high modulation frequencies up to 512 Hz well, but show much poorer performance at low frequencies. Our in vivo multielectrode recordings in the inferior colliculus (IC) of both anesthetized and awake mice revealed a few single units with remarkable phase-locking ability to 512 Hz modulation, but not sufficient to explain the good behavioral detection at that frequency. Using a model of the population response that combined dimensionality reduction with threshold detection, we reproduced the general band-pass characteristics of behavioral detection based on a subset of neurons showing the largest firing rate change (both increase and decrease) in response to AM, suggesting that these neurons are instrumental in the behavioral detection of AM stimuli by the mice. New and Noteworthy: The amplitude of natural sounds, including speech and animal vocalizations, often shows characteristic modulations. We examined the relationship between neuronal responses in the mouse inferior colliculus and the behavioral detection of amplitude modulation in sound, and modelled how the former can give rise to the latter. Our model suggests that behavioral detection can be well explained by the activity of a subset of neurons showing the largest firing rate changes in response to AM.

At synapses, the pre- and postsynaptic cells get so close that currents entering the cleft do not flow exclusively along its conductance,g_cl. A prominent example is found in the calyx of Held synapse in the medial nucleus of the trapezoid body (MNTB), where the presynaptic action potential can be recorded in the postsynaptic cell in the form of a prespike. Here, we developed a theoretical framework for ephaptic coupling via the synaptic cleft, and we tested its predictions using the MNTB prespike recorded in voltage-clamp. The shape of the prespike is predicted to resemble either the first or the second derivative of the inverted presynaptic action potential if cleft currents dissipate either mostly capacitively or resistively, respectively. We found that the resistive dissipation scenario provided a better description of the prespike shape. Its size is predicted to scale with the fourth power of the radius of the synapse, explaining why intracellularly recorded prespikes are uncommon in the central nervous system. We show that presynaptic calcium currents also contribute to the prespike shape. This calcium prespike resembled the first derivative of the inverted calcium current, again as predicted by the resistive dissipation scenario. Using this calcium prespike, we obtained an estimate forg_clof ~1 μS. We demonstrate that, for a circular synapse geometry, such as in conventional boutons or the immature calyx of Held,g_clis scale-invariant and only defined by extracellular resistivity, which was ~75 Ωcm, and by cleft height. During development the calyx of Held develops fenestrations. We show that these fenestrations effectively minimize the cleft potentials generated by the adult action potential, which might otherwise interfere with calcium channel opening. We thus provide a quantitative account of the dissipation of currents by the synaptic cleft, which can be readily extrapolated to conventional, bouton-like synapses.

At synapses, the pre- and postsynaptic cell get so close that currents entering the cleft do not flow exclusively along its conductance, g _cl . A prominent example is found in the calyx of Held synapse in the medial nucleus of the trapezoid body (MNTB), where the presynaptic action potential can be recorded in the postsynaptic cell in the form of a prespike. Here, we developed a theoretical framework for ephaptic coupling via the synaptic cleft, and we tested its predictions using the MNTB prespike recorded in voltage-clamp. The shape of the prespike is predicted to resemble either the first or the second derivative of the inverted, presynaptic action potential if cleft currents dissipate either mostly capacitively or resistively, respectively. We found that the resistive dissipation scenario provided a better description of the prespike shape. Its size is predicted to scale with the fourth power of the radius of the synapse, explaining why intracellularly recorded prespikes are uncommon in the central nervous system. We show that presynaptic calcium currents also contribute to the prespike shape. This calcium prespike resembled the first derivative of the inverted calcium current, again as predicted by the resistive dissipation scenario. Using this calcium prespike, we obtained an estimate for g _cl of ~1 μS. We demonstrate that, for a circular synapse geometry, such as in conventional boutons or the immature calyx of Held, g _cl is scale-invariant and only defined by extracellular resistivity, which was ~75 Ωcm, and by cleft height. During development the calyx of Held develops fenestrations. We show that these fenestrations effectively minimize the cleft potentials generated by the adult action potential, which might otherwise interfere with calcium channel opening. We thus provide a quantitative account of the dissipation of currents by the synaptic cleft, which can be readily extrapolated to conventional, bouton-like synapses. Author Summary: At chemical synapses two neurons are separated by a cleft, which is very narrow. As a result, the concentration of released neurotransmitter can rapidly peak, which is essential for fast synaptic transmission. At the same time, the currents that flow across the membranes that face the synaptic cleft are also substantial, and a fraction of these currents will enter the other cell. We made an electronic model of the synaptic cleft, which indicated that if the shape and fraction of these currents are known, the electrical resistance of the synaptic cleft can be inferred. We tested several of the predictions of our model by comparing the membrane currents during a presynaptic action potential in a giant terminal, the calyx of Held, with the much smaller prespike evoked by these currents in the postsynaptic cell. We estimate the cleft resistance to be about 1 MΩ, which means that the changes in the cleft potential due to the membrane currents can become large enough to have an impact on voltage-dependent calcium channels controlling neurotransmitter release.

Key points During development the giant, auditory calyx of Held forms a one‐to‐one connection with a principal neuron of the medial nucleus of the trapezoid body. While anatomical studies described that most of the target cells are temporarily contacted by multiple calyces, multi‐calyceal innervation was only sporadically observed in in vivo recordings, suggesting a structure–function discrepancy. We correlated synaptic strength of inputs, identified in in vivo recordings, with post hoc labelling of the recorded neuron and synaptic terminals containing vesicular glutamate transporters (VGluT). During development only one input increased to the level of the calyx of Held synapse, and its strength correlated with the large VGluT cluster contacting the postsynaptic soma. As neither competing strong inputs nor multiple large VGluT clusters on a single cell were observed, our findings did not indicate a structure–function discrepancy. Abstract In adult rodents, a principal neuron in the medial nucleus of the trapezoid (MNTB) is generally contacted by a single, giant axosomatic terminal called the calyx of Held. How this one‐on‐one relation is established is still unknown, but anatomical evidence suggests that during development principal neurons are innervated by multiple calyces, which may indicate calyceal competition. However, in vivo electrophysiological recordings from principal neurons indicated that only a single strong synaptic connection forms per cell. To test whether a mismatch exists between synaptic strength and terminal size, we compared the strength of synaptic inputs with the morphology of the synaptic terminals. In vivo whole‐cell recordings of the MNTB neurons from newborn Wistar rats of either sex were made while stimulating their afferent axons, allowing us to identify multiple inputs. The strength of the strongest input increased to calyceal levels in a few days across cells, while the strength of the second strongest input was stable. The recorded cells were subsequently immunolabelled for vesicular glutamate transporters (VGluT) to reveal axosomatic terminals with structured‐illumination microscopy. Synaptic strength of the strongest input was correlated with the contact area of the largest VGluT cluster at the soma (r = 0.8), and no indication of a mismatch between structure and strength was observed. Together, our data agree with a developmental scheme in which one input strengthens and becomes the calyx of Held, but not with multi‐calyceal competition.