Rei Yamada

Tonotopic Specialization of Auditory Coincidence Detection in Nucleus Laminaris of the Chick

The interaural time difference (ITD) is a cue for localizing a sound source along the horizontal plane and is first determined in the nucleus laminaris (NL) in birds. Neurons in NL are tonotopically organized, such that ITDs are processed separately at each characteristic frequency (CF). Here, we investigated the excitability and coincidence detection of neurons along the tonotopic axis in NL, using a chick brainstem slice preparation. Systematic changes with CF were observed in morphological and electrophysiological properties of NL neurons. These properties included the length of dendrites, the input capacitance, the conductance of hyperpolarization-activated current, and the EPSC time course. In contrast to these gradients, the conductance of low-threshold K+ current and the expression of Kv1.2 channel protein were maximal in the central (middle-CF) region of NL. As a result, the middle-CF neuron had the smallest input resistance and membrane time constant, and consequently the fastest EPSP, and exhibited the most accurate coincidence detection. The specialization of middle-CF neurons as coincidence detectors may account for the high resolution of sound-source localization in the middle-frequency range observed in avians.

Sound-Intensity-Dependent Compensation for the Small Interaural Time Difference Cue for Sound Source Localization

Interaural time difference (ITD) is a major cue for sound source localization. However, animals with small heads experience small ITDs, making ITD detection difficult, particularly for low-frequency sound. Here, we describe a sound-intensity-dependent mechanism for compensating for the small ITD cues in the coincidence detector neurons in the nucleus laminaris (NL) of the chicken aged from 3 to 29 d after hatching. The hypothesized compensation mechanisms were confirmed by simulation. In vivo single-unit recordings revealed an improved contrast of ITD tuning in low-best-frequency (<1 kHz) NL neurons by suppressing the firing activity at the worst ITD, whereas the firing rate was increased with increasing sound intensity at the best ITD. In contrast, level-dependent suppression was so weak in the middle- and high-best-frequency (≥1 kHz) NL neurons that loud sounds led to increases in firing rate at both the best and the worst ITDs. The suppression of firing activity at the worst ITD in the low-best-frequency neurons required the activation of the superior olivary nucleus (SON) and was eliminated by electrolytic lesions of the SON. The frequency-dependent suppression reflected the dense projection from the SON to the low-frequency region of NL. Thus, the small ITD cues available in low-frequency sounds were partly compensated for by a sound-intensity-dependent inhibition from the SON.

Hyperpolarization-Activated Cyclic Nucleotide-Gated Cation Channels Regulate Auditory Coincidence Detection in Nucleus Laminaris of the Chick

Coincidence detection of bilateral acoustic signals in nucleus laminaris (NL) is the first step in azimuthal sound source localization in birds. Here, we demonstrate graded expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels along the tonotopic axis of NL and its role in the regulation of coincidence detection. Expression of HCN1 and HCN2, but not HCN3 or HCN4, was detected in NL. Based on measurement of both subtype mRNA and protein, HCN1 varied along the tonotopic axis and was minimal in high-characteristic frequency (CF) neurons. In contrast, HCN2 was evenly distributed. The resting conductance was larger and the steady-state activation curve of Ih was more positive in neurons of middle to low CF than those of high CF, consistent with the predominance of HCN1 channels in these neurons. Application of 8-Br-cAMP or noradrenaline generated a depolarizing shift of the Ih voltage activation curve. This shift was larger in neurons of high CF than in those of middle CF. The shift in the activation voltage of Ih depolarized the resting membrane, accelerated the EPSP time course, and significantly improved the coincidence detection in neurons of high CF, suggesting that Ih may improve the localization of sound sources.

Redistribution of Kv1 and Kv7 enhances neuronal excitability during structural axon initial segment plasticity

Structural plasticity of the axon initial segment (AIS), the trigger zone of neurons, is a powerful means for regulating neuronal activity. Here, we show that AIS plasticity is not limited to structural changes; it also occurs as changes in ion-channel expression, which substantially augments the efficacy of regulation. In the avian cochlear nucleus, depriving afferent inputs by removing cochlea elongated the AIS, and simultaneously switched the dominant Kv channels at the AIS from Kv1.1 to Kv7.2. Due to the slow activation kinetics of Kv7.2, the redistribution of the Kv channels reduced the shunting conductance at the elongated AIS during the initiation of action potentials and effectively enhanced the excitability of the deprived neurons. The results indicate that the functional plasticity of the AIS works cooperatively with the structural plasticity and compensates for the loss of afferent inputs to maintain the homeostasis of auditory circuits after hearing loss by cochlea removal.

Evaluation of the limiting acuity of coincidence detection in nucleus laminaris of the chicken

The localization of sounds requires the detection of very brief inter‐aural time differences (ITDs). In birds, ITDs are first encoded in neurons of the nucleus laminaris (NL) through the precise coincidence of binaural synaptic inputs. We examined the effects of temperature on acuity of coincidence detection in chick NL, by utilizing whole‐cell and cell‐attached recording techniques in brain slices while applying electrical stimuli bilaterally to axonal projections from the nucleus magnocellularis to NL. The precision of coincidence detection was measured as a time window, corresponding to the time interval that gave the half‐maximum spiking probability. Acuity improved with the elevation of recording temperature, and at 40°C, the avian body temperature, the time window was 0.38 ms. Although all synaptic events were briefer at higher temperature, the duration of EPSPs were equivalent to or faster than that of EPSCs at 40°C. Activation of low‐threshold K+ currents by a slight membrane depolarization during an EPSP was responsible for this EPSP acceleration. EPSPs were prolonged following inhibition of low‐threshold K+ currents by dendrotoxin (40 nm) or hyperpolarization‐activated cation currents by Cs+ (3 mm). The EPSP time course had a strong positive correlation with the sharpness of coincidence detection. The limiting value of the time window (0.16 ms), calculated from the estimated EPSP time course, was narrow enough to explain the acuity of ITD detection at NL in vivo.

Structural and Functional Plasticity at the Axon Initial Segment

The axon initial segment (AIS) is positioned between the axonal and somato-dendritic compartments and plays a pivotal role in triggering action potentials (APs) and determining neuronal output. It is now widely accepted that structural properties of the AIS, such as length and/or location relative to the soma, change in an activity-dependent manner. This structural plasticity of the AIS is known to be crucial for homeostatic control of neuronal excitability. However, it is obvious that the impact of the AIS on neuronal excitability is critically dependent on the biophysical properties of the AIS, which are primarily determined by the composition and characteristics of ion channels in this domain. Moreover, these properties can be altered via phosphorylation and/or redistribution of the channels. Recently, studies in auditory neurons showed that alterations in the composition of voltage-gated K+ (Kv) channels at the AIS coincide with elongation of the AIS, thereby enhancing the neuronal excitability, suggesting that the interaction between structural and functional plasticities of the AIS is important in the control of neuronal excitability. In this review, we will summarize the current knowledge regarding structural and functional alterations of the AIS and discuss how they interact and contribute to regulating the neuronal output.

Plasticity of the Axonal Trigger Zone

The axon initial segment (AIS) is a specialized axonal compartment that is involved in conversion of synaptic potentials into action potentials. Recent studies revealed that structural properties of the AIS, such as length and position relative to the soma, are differentiated in a cell-specific manner and shape signal processing of individual neurons. Moreover, these structural properties are not fixed but vary in response to prolonged changes of neuronal activity, which readjusts action potential threshold and compensates for the changes of activity, indicating that this structural plasticity of the AIS works as a homeostatic mechanism and contributes to maintain neuronal activity. Neuronal activity plays a crucial role in formation, maintenance, and refinement of neural circuits as well as in pathogenesis and/or pathophysiology of diseases. Thus, this plasticity should be a key to understand physiology and pathology of the brain.

The Cooperation of Sustained and Phasic Inhibitions Increases the Contrast of ITD-Tuning in Low-Frequency Neurons of the Chick Nucleus Laminaris

Neurons in the nucleus laminaris (NL) of birds detect the coincidence of binaural excitatory inputs from the nucleus magnocellularis (NM) on both sides and process the interaural time differences (ITDs) for sound localization. Sustained inhibition from the superior olivary nucleus is known to control the gain of coincidence detection, which allows the sensitivity of NL neurons to ITD tolerate strong-intensity sound. Here, we found a phasic inhibition in chicken brain slices that follows the ipsilateral NM inputs after a short time delay, sharpens coincidence detection, and may enhance ITD sensitivity in low-frequency NL neurons. GABA-positive small neurons are distributed in and near the NL. These neurons generate IPSCs in NL neurons when photoactivated by a caged glutamate compound, suggesting that these GABAergic neurons are interneurons that mediate phasic inhibition. These IPSCs have fast decay kinetics that is attributable to the α1-subunit of the GABAA receptor, the expression of which dominates in the low-frequency region of the NL. Model simulations demonstrate that phasic IPSCs narrow the time window of coincidence detection and increase the contrast of ITD-tuning during low-level, low-frequency excitatory input. Furthermore, cooperation of the phasic and sustained inhibitions effectively increases the contrast of ITD-tuning over a wide range of excitatory input levels. We propose that the complementary interaction between phasic and sustained inhibitions is the neural mechanism that regulates ITD sensitivity for low-frequency sound in the NL.

Activation of metabotropic glutamate receptors improves the accuracy of coincidence detection by presynaptic mechanisms in the nucleus laminaris of the chick

•  Interaural time difference (ITD) is a major cue for sound source localization and is processed by detecting a coincidence of bilateral excitatory postsynaptic potentials (EPSPs) in the nucleus laminaris (NL) in birds. •  The sharpness of coincidence detection (CD) depends on the speed and size of EPSPs. We found here a regulatory mechanism of EPSP size through the presynaptic mGluR activity. •  The activation of mGluRs reduced the transmitter release and extent of excitatory postsynaptic current depression during tetanic stimulation, but improved the CD. Furthermore, the activity of mGluRs and their expression were graded along the tonotopic axis and were stronger toward the low frequency neurons of NL. •  We proposed an idea that the presynaptic mGluRs may operate as a self‐regulatory mechanism to optimize the size of EPSP and have roles in sharpening the CD. This regulatory mechanism may underlie the sound source localization particularly during a long‐lasting sound in the NL.

Tonotopic variation of the T-type Ca2+ current in avian auditory coincidence detector neurons

Neurons in avian nucleus laminaris (NL) are binaural coincidence detectors for sound localization and are characterized by striking structural variations in dendrites and axon initial segment (AIS) according to their acoustic tuning [characteristic frequency (CF)]. T-type Ca2+ (CaT) channels regulate synaptic integration and firing behavior at these neuronal structures. However, whether or how CaT channels contribute to the signal processing in NL neurons is not known. In this study, we addressed this issue with whole-cell recording and two-photon Ca2+ imaging in brain slices of posthatch chicks of both sexes. We found that the CaT current was prominent in low-CF neurons, whereas it was almost absent in higher-CF neurons. In addition, a large Ca2+ transient occurred at the dendrites and the AIS of low-CF neurons, indicating a localization of CaT channels at these structures in the neurons. Because low-CF neurons have long dendrites, dendritic CaT channels may compensate for the attenuation of EPSPs at dendrites. Furthermore, the short distance of AIS from the soma may accelerate activation of axonal CaT current in the neurons and help EPSPs reach spike threshold. Indeed, the CaT current was activated by EPSPs and augmented the synaptic response and spike generation of the neurons. Notably, the CaT current was inactivated during repetitive inputs, and these augmenting effects predominated at the initial phase of synaptic activity. These results suggested that dendritic and axonal CaT channels increase the sensitivity to sound at its onset, which may expand the dynamic range for binaural computation in low-CF NL neurons. SIGNIFICANCE STATEMENT Neurons in nucleus laminaris are binaural coincidence detectors for sound localization. We report that T-type Ca2+ (CaT) current was prominent at dendrites and the axonal trigger zone in neurons tuned to low-frequency sound. Because these neurons have long dendrites and a closer trigger zone compared with those tuned to higher-frequency sound, the CaT current augmented EPSPs at dendrites and accelerated spike triggers in the neurons, implying a strategic arrangement of the current within the nucleus. This effect was limited to the onset of repetitive inputs due to progressive inactivation of CaT current. The results suggested that the CaT current increases the sensitivity to sound at its onset, which may expand the dynamic range for binaural computation of low-frequency sound.