Auditory Brainstem Neurons Research Articles

Metabolic response of auditory brainstem neurons to their broad physiological activity range.

Neurons exhibit a high energetic need, and the question arises as how they metabolically adapt to changing activity states. This is relevant for interpreting functional neuroimaging in different brain areas. Particularly, neurons with a broad firing range might exhibit metabolic adaptations. Therefore, we studied MNTB (medial nucleus of the trapezoid body) principal neurons, which generate action potentials (APs) at frequencies up to several hundred hertz. We performed the experiments in acute brainstem slices of the Mongolian gerbil (Meriones unguiculatus) at 22.5-24.5°C. Upon electrical stimulation of afferent MNTB fibres with 400 stimuli at varying frequencies, we monitored autofluorescence levels of NAD(P)H and FAD and determined the extremum amplitudes of their biphasic response. Additionally, we compared these data with alterations in O2 concentrations measured with an electrochemical sensor. These O2 changes are prominent since MNTB neurons rely on oxidative phosphorylation as shown by our pharmacological experiments. We calculated the O2 consumption rate as change in O2 concentration divided by stimulus durations, because these periods varied inversely with stimulus frequency as a result of the constant number of 400 stimuli applied. The O2 consumption rate increased with stimulation frequency up to a constant value at 600 Hz; that is, energy demand depends on temporal characteristics of activity despite the same number of stimuli. The rates showed no correlation with peak amplitudes of NAD(P)H or FAD, whilst the values of the two molecules were linearly correlated. This points at the complexity of analysing autofluorescence imaging for quantitative metabolic studies, because these values report only relative net changes of many superimposed oxidative and reductive processes. Monitoring O2 concentration rates is, thus, an important tool to improve the interpretation of NAD(P)H/FAD autofluorescence data, as they do not under all conditions and in all systems appropriately reflect the metabolic activity or energy demand.

Serine 937 phosphorylation enhances KCC2 activity and strengthens synaptic inhibition

The potassium chloride cotransporter KCC2 is crucial for Cl- extrusion from mature neurons and thus key to hyperpolarizing inhibition. Auditory brainstem circuits contain well-understood inhibitory projections and provide a potent model to study the regulation of synaptic inhibition. Two peculiarities of the auditory brainstem are (i) posttranslational activation of KCC2 during development and (ii) extremely negative reversal potentials in specific circuits. To investigate the role of the potent phospho-site serine 937 therein, we generated a KCC2 Thr934Ala/Ser937Asp double mutation, in which Ser937 is replaced by aspartate mimicking the phosphorylated state, and the neighbouring Thr934 arrested in the dephosphorylated state. This double mutant showed a twofold increased transport activity in HEK293 cells, raising the hypothesis that auditory brainstem neurons show lower [Cl−]i. and increased glycinergic inhibition. This was tested in a mouse model carrying the same KCC2 Thr934Ala/Ser937Asp mutation by the use of the CRISPR/Cas9 technology. Homozygous KCC2 Thr934Ala/Ser937Asp mice showed an earlier developmental onset of hyperpolarisation in the auditory brainstem. Mature neurons displayed stronger glycinergic inhibition due to hyperpolarized ECl−. These data demonstrate that phospho-regulation of KCC2 Ser937 is a potent way to interfere with the excitation-inhibition balance in neural circuits.

An inhibitory glycinergic projection from the cochlear nucleus to the lateral superior olive.

Auditory brainstem neurons in the lateral superior olive (LSO) receive excitatory input from the ipsilateral cochlear nucleus (CN) and inhibitory transmission from the contralateral CN via the medial nucleus of the trapezoid body (MNTB). This circuit enables sound localization using interaural level differences. Early studies have observed an additional inhibitory input originating from the ipsilateral side. However, many of its details, such as its origin, remained elusive. Employing electrical and optical stimulation of afferents in acute mouse brainstem slices and anatomical tracing, we here describe a glycinergic projection to LSO principal neurons that originates from the ipsilateral CN. This inhibitory synaptic input likely mediates inhibitory sidebands of LSO neurons in response to acoustic stimulation.

Use of reverse noise to measure ongoing delay.

Counts of spike coincidences provide a powerful means to compare responses to different stimuli or of different neurons, particularly regarding temporal factors. A drawback is that these methods do not provide an absolute measure of latency, i.e., the temporal interval between stimulus features and response. It is desirable to have such a measure within the analysis framework of coincidence counting. Single neuron responses were obtained, from 130 fibers in several tracts (auditory nerve, trapezoid body, lateral lemniscus), to a broadband noise and its polarity-inverted version. The spike trains in response to these stimuli are the "forward noise" responses. The same stimuli were also played time-reversed. The resulting spike trains were then again time-reversed: These are the "reverse-noise" responses. The forward and reverse responses were then analyzed with the coincidence count methods we have introduced earlier. Correlograms between forward- and reverse-noise responses show maxima at values consistent with latencies measured with other methods; the pattern of latencies with characteristic frequency, sound pressure level, and recording location was also consistent. At low characteristic frequencies, correlograms were well-predicted by reverse-correlation functions. We conclude that reverse noise provides an easy and reliable means to estimate latency of auditory nerve and brainstem neurons.

Development of electrophysiological properties of fusiform neurons from the dorsal cochlear nucleus of mice before and after hearing onset.

The dorsal cochlear nucleus (DCN) in the auditory brainstem integrates auditory and somatosensory information. Mature DCN fusiform neurons fall into two qualitatively distinct types: quiet, with no spontaneous regular action potential firing, or active, with regular spontaneous action potential firing. However, how these firing states and other electrophysiological properties of fusiform neurons develop during early postnatal days to adulthood is not known. Thus, we recorded fusiform neurons from mice from P4 to P21 and analyzed their electrophysiological properties. In the prehearing phase (P4-P13), we found that most fusiform neurons are quiet, with active neurons emerging after hearing onset at P14. Subthreshold properties underwent significant changes before hearing onset, whereas changes to the action potential waveform occurred mainly after P14, with the depolarization and repolarization phases becoming markedly faster and half-width significantly decreased. The activity threshold in posthearing neurons was more negative than in prehearing cells. Persistent sodium current (INaP) was increased after P14, coinciding with the emergence of spontaneous firing. Thus, we suggest that posthearing expression of INaP leads to hyperpolarization of the activity threshold and the active state of the fusiform neuron. At the same time, other changes refine the passive membrane properties and increase the speed of action potential firing of fusiform neurons.NEW & NOTEWORTHY Auditory brainstem neurons express unique electrophysiological properties adapted for their complex physiological functions that develop before hearing onset. Fusiform neurons of the DCN present two firing states, quiet and active, but the origin of these states is not known. Here, we showed that the quiet and active states develop after hearing onset at P14, along with changes in action potentials, suggesting an influence of auditory input on the refining of fusiform neuron's excitability.

Structure and dynamics that specialize neurons for high-frequency coincidence detection in the barn owl nucleus laminaris.

A principal cue for sound source localization is the difference in arrival times of sounds at an animal's two ears (interaural time difference, ITD). Neurons that process ITDs are specialized to compare the timing of inputs with submillisecond precision. In the barn owl, ITD processing begins in the nucleus laminaris (NL) region of the auditory brain stem. Remarkably, NL neurons are sensitive to ITDs in high-frequency sounds (kilohertz-range). This contrasts with ITD-based sound localization in analogous regions in mammals where ITD sensitivity is typically restricted to lower-frequency sounds. Guided by previous experiments and modeling studies of tone-evoked responses of NL neurons, we propose NL neurons achieve high-frequency ITD sensitivity if they respond selectively to the small-amplitude, high-frequency oscillations in their inputs, and remain relatively non-responsive to mean input level. We use a biophysically based model to study the effects of soma-axon coupling on dynamics and function in NL neurons. First, we show that electrical separation of the soma from the axon region in the neuron enhances high-frequency ITD sensitivity. This soma-axon coupling configuration promotes linear subthreshold dynamics and rapid spike initiation, making the model more responsive to input oscillations, rather than mean input level. Second, we provide new evidence for the essential role of phasic dynamics for high-frequency neural coincidence detection. Transforming our model to the phasic firing mode further tunes the model to respond selectively to the oscillating inputs that carry ITD information. Similar structural and dynamical mechanisms specialize mammalian auditory brain stem neurons for ITD sensitivity, and thus, our work identifies common principles of ITD processing and neural coincidence detection across species and for sounds at widely different frequencies.

Modulation of potassium conductances optimizes fidelity of auditory information.

Potassium channels in auditory neurons are rapidly modified by changes in the auditory environment. In response to elevated auditory stimulation, short-term mechanisms such as protein phosphorylation and longer-term mechanisms such as accelerated channel synthesis increase the amplitude of currents that promote high-frequency firing. It has been suggested that this allows neurons to fire at high rates in response to high sound levels. We have carried out simple simulations of the response to postsynaptic neurons to patterns of neurotransmitter release triggered by auditory stimuli. These demonstrate that the amplitudes of potassium currents required for optimal encoding of a low-amplitude auditory signal differ from those for louder sounds. Specifically, the cross-correlation of the output of a neuron with an auditory stimulus is improved by increasing potassium currents as sound amplitude increases. Temporal fidelity for low-frequency stimuli is improved by increasing potassium currents that activate at negative potentials, while that for high-frequency stimuli requires increases in currents that activate at positive membrane potentials. These effects are independent of the firing rate. Moreover, levels of potassium currents that maximize the fidelity of the output of an ensemble of neurons differ from those that maximize fidelity for a single neuron. This suggests that the modulatory mechanisms must coordinate channel activity in groups of neurons or an entire nucleus. The simulations provide an explanation for the modulation of the intrinsic excitability of auditory brainstem neurons by changes in environmental sound levels, and the results may extend to information processing in other neural systems.

Modulation of potassium channels preserves temporal fidelity in auditory network models.

Potassium channels in auditory neurons are rapidly modified by changes in the auditory environment. In response to elevated auditory stimulation, short-term mechanisms such as protein phosphorylation and long-term mechanisms linked to channel synthesis increase the activity of channels that promote high frequency firing. We have now used simple simulations of cochlear hair cells and postsynaptic neurons to demonstrate that the amplitudes of potassium currents in neurons required for optimal encoding of a low-level auditory signal differs substantially from that for louder sounds. Specifically, the cross correlation of the output of a neuron with an auditory stimulus is increased by increasing potassium currents as sound amplitude increases. Although it has been suggested that channel modulation allows neurons to fire at high rates in response to high sound levels, we found that the cross correlation is entirely independent of firing rate and that combinations of currents that maximize firing to a stimulus provide very poor temporal fidelity. We also found that levels of potassium currents that maximize the temporal fidelity of the output of an ensemble of thirty neurons differ from those that maximize temporal fidelity for a single neuron. This suggests that, to maximize preservation of temporal information, modulatory mechanisms must coordinate channel activity in groups of neurons receiving similar synaptic inputs. The simulations provide an explanation for the modulation of the intrinsic excitability of auditory brainstem neurons by changes in environmental sound levels, and the results may extend to information processing in other neural systems.

Low Intensity Noise Exposure Enhanced Auditory Loudness and Temporal Processing by Increasing Excitability of DCN.

Sound stimulation is generally used for tinnitus and hyperacusis treatment. Recent studies found that long-term noise exposure can change synaptic and firing properties in the central auditory system, which will be detected by the acoustic startle reflex. However, the perceptual consequences of long-term low-intensity sound exposure are indistinct. This study will detect the effects of moderate-level noise exposure (83 dB SPL) on auditory loudness, and temporal processing was evaluated using CBA/CaJ mice. C-Fos staining was used to detect neural activity changes in the central auditory pathway. With two weeks of 83 dB SPL noise exposure (8 hours per day), no persistent threshold shift of the auditory brainstem response (ABR) was identified. On the other hand, noise exposure enhanced the acoustic startle response (ASR) and gap-induced prepulse inhibition significantly (gap-PPI). Low-level noise exposure, according to the findings, can alter temporal acuity. Noise exposure increased the number of c-Fos labeled neurons in the dorsal cochlear nucleus (DCN) and caudal pontine reticular nucleus (PnC) but not at a higher level in the central auditory nuclei. Our results suggested that noise stimulation can change acoustical temporal processing presumably by increasing the excitability of auditory brainstem neurons.

Absence of the Fragile X messenger ribonucleoprotein alters response patterns to sounds in the auditory midbrain.

Among the different autism spectrum disorders, Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. Sensory and especially auditory hypersensitivity is a key symptom in patients, which is well mimicked in the Fmr1 -/- mouse model. However, the physiological mechanisms underlying FXS’s acoustic hypersensitivity in particular remain poorly understood. Here, we categorized spike response patterns to pure tones of different frequencies and intensities from neurons in the inferior colliculus (IC), a central integrator in the ascending auditory pathway. Based on this categorization we analyzed differences in response patterns between IC neurons of wild-type (WT) and Fmr1 -/- mice. Our results report broadening of frequency tuning, an increased firing in response to monaural as well as binaural stimuli, an altered balance of excitation-inhibition, and reduced response latencies, all expected features of acoustic hypersensitivity. Furthermore, we noticed that all neuronal response types in Fmr1 -/- mice displayed enhanced offset-rebound activity outside their excitatory frequency response area. These results provide evidence that the loss of Fmr1 not only increases spike responses in IC neurons similar to auditory brainstem neurons, but also changes response patterns such as offset spiking. One can speculate this to be an underlying aspect of the receptive language problems associated with Fragile X syndrome.

A sound-driven cortical phase-locking change in the Fmr1 KO mouse requires Fmr1 deletion in a subpopulation of brainstem neurons

BackgroundSensory impairments commonly occur in patients with autism or intellectual disability. Fragile X syndrome (FXS) is one form of intellectual disability that is often comorbid with autism. In electroencephalographic (EEG) recordings obtained from humans with FXS, the ability of cortical regions to consistently synchronize, or “phase-lock”, to modulated auditory stimuli is reduced compared to that of typically developing individuals. At the same time, less time-locked, “non-phase-locked” power induced by sounds is higher. The same changes occur in the Fmr1 knockout (KO) mouse – an animal model of FXS. We determined if Fmr1 deletion in a subset of brainstem auditory neurons plays any role in these EEG changes in the mouse. MethodsWe reinstated FMRP expression in a subpopulation of brainstem auditory neurons in an otherwise Fmr1 KO control (conditional on; cON Fmr1) mouse and used EEG recordings to determine if reinstatement normalized, or “rescued”, the phase-locking phenotype observed in the cON Fmr1 mouse. In determining rescue, this also meant that Fmr1 deletion in the same neuron population was necessary for the phenotype to occur. ResultsWe find that Fmr1 reinstatement in a subset of brainstem neurons rescues certain aspects of the phase-locking phenotype but does not rescue the increase in non-phase-locked power. Unexpectedly, not all electrophysiological phenotypes observed in the Fmr1 KO were observed in the cON Fmr1 mouse used for the reinstatement experiments, and this was likely due to residual expression of FMRP in these Fmr1 KO controls. ConclusionsFmr1 deletion in brainstem neurons is necessary for certain aspects of the decreased phase-locking phenotype in the Fmr1 KO, but not necessary for the increase in non-phase-locked power induced by a sound. The most likely brainstem structure underlying these results is the inferior colliculus. We also demonstrate that low levels of FMRP can rescue some EEG phenotypes but not others. This latter finding provides a foundation for how symptoms in FXS individuals may vary due to FMRP levels and that reinstatement of low FMRP levels may be sufficient to alleviate particular symptoms.

Measuring ongoing delay with reverse noise

Counts of spike coincidences provide a powerful means to compare responses to different stimuli or of different neurons, particularly regarding temporal factors. A drawback is that these methods do not provide an absolute measure of latency, i.e., the temporal interval between stimulus and response. It is desirable to obtain such a measurement within the same analysis framework of coincidence counting. Single neuron responses were obtained from several fiber tracts (nerve, trapezoid body, lateral lemniscus) in two species to a broadband noise and its polarity-inverted version. The spike trains in response to these stimuli are the “forward noise” responses. The same stimuli were also played time-reversed. The resulting spike trains are then again time-reversed: these are the “reverse noise” responses. The forward and reverse responses were then analyzed with the coincidence count methods we have introduced earlier. Latency measurements derived from correlograms between forward and reverse noise responses show maxima at twice the latency value measured with other methods, as expected. Correlograms were often asymmetric but, at low-characteristic frequencies, were well-predicted by crosscorrelation of the reverse-correlation function and its reverse. We conclude that reverse noise provides an easy and reliable means to estimate latency of auditory nerve and brainstem neurons.

Non-Apoptotic Caspase Activity Preferentially Targets a Novel Consensus Sequence Associated With Cytoskeletal Proteins in the Developing Auditory Brainstem.

The auditory brainstem relies on precise circuitry to facilitate sound source localization. In the chick, the development of this specialized circuitry requires non-apoptotic activity of caspase-3, for which we previously identified several hundred proteolytic substrates. Here we tested whether the sequence of the caspase cleavage site differentially encodes proteolytic preference in apoptotic and non-apoptotic contexts. We constructed a consensus sequence for caspase activity in the non-apoptotic chick auditory brainstem comprising the four residues N-terminal to the cleavage site: IX(G/R)D↓ where X represents no significant enrichment and ↓ represents the cleavage site. We identified GO terms significantly enriched among caspase substrates containing motifs found in the above consensus sequence. (G/R)D↓ was associated with the term “Structural Constituent of Cytoskeleton” (SCoC), suggesting that SCoC proteins may be specifically targeted by caspase activity during non-apoptotic developmental processes. To ascertain whether this consensus sequence was specific to the non-apoptotic auditory brainstem at embryonic day (E) 10, we used protein mass spectrometry of brainstems harvested at a time when auditory brainstem neurons undergo apoptotic cell death (E13). The apoptotic motif VD was significantly enriched among E13 cleavage sites, indicating that motif preference at the P2 subsite had shifted toward the canonical caspase consensus sequence. Additionally, Monte Carlo simulations revealed that only the GD motif was associated with SCoC substrates in the apoptotic auditory brainstem, indicating that GD encodes specificity for SCoC proteins in both non-apoptotic and apoptotic contexts, despite not being preferred in the latter. Finally, to identify candidate human non-apoptotic consensus sequences, we used Monte Carlo analyses to determine motifs and motif pairs associated with SCoC caspase substrates in the Degrabase, a database of cleavage sites in human apoptotic cell lines. We found 11 motifs significantly associated with SCoC proteolysis, including IXXD and GD. We employed a stepwise method to select motif pairs that optimized SCoC specificity for a given coverage of SCoC cleavage events, yielding 11 motif pairs likely to be preferred in SCoC-directed human non-apoptotic caspase consensus sequences. GD + IXXD was among these motif pairs, suggesting a conservation of non-apoptotic consensus sites among vertebrates.

The Cl--channel TMEM16A is involved in the generation of cochlear Ca2+ waves and promotes the refinement of auditory brainstem networks in mice.

Before hearing onset (postnatal day 12 in mice), inner hair cells (IHCs) spontaneously fire action potentials, thereby driving pre-sensory activity in the ascending auditory pathway. The rate of IHC action potential bursts is modulated by inner supporting cells (ISCs) of Kölliker's organ through the activity of the Ca2+-activated Cl--channel TMEM16A (ANO1). Here, we show that conditional deletion of Ano1 (Tmem16a) in mice disrupts Ca2+ waves within Kölliker's organ, reduces the burst-firing activity and the frequency selectivity of auditory brainstem neurons in the medial nucleus of the trapezoid body (MNTB), and also impairs the functional refinement of MNTB projections to the lateral superior olive. These results reveal the importance of the activity of Kölliker's organ for the refinement of central auditory connectivity. In addition, our study suggests the involvement of TMEM16A in the propagation of Ca2+ waves, which may also apply to other tissues expressing TMEM16A.

Brain-Derived Neurotrophic Factor Is Involved in Activity-Dependent Tonotopic Refinement of MNTB Neurons.

In the mammalian brain, auditory brainstem nuclei are arranged topographically according to acoustic frequency responsiveness. During postnatal development, the axon initial segment (AIS) of principal neurons undergoes structural refinement depending on location along the tonotopic axis within the medial nucleus of the trapezoid body (MNTB). However, the molecular mechanisms underlying the structural refinement of the AIS along the tonotopic axis in the auditory brainstem have not been explored. We tested the hypothesis that brain-derived neurotrophic factor (BDNF) is a molecular mediator of the structural development of the MNTB in an activity-dependent manner. Using BDNF heterozygous mutant (BDNF+/–) mice, we examined the impact of global BDNF reduction on structural and functional development of MNTB neurons by assessing AIS structure and associated intrinsic neuronal properties. BDNF reduction inhibits the structural and functional differentiation of principal neurons along the tonotopic axis in the MNTB. Augmented sound input during the critical period of development has been shown to enhance the structural refinement of the AIS of MNTB neurons. However, in BDNF +/– mice, MNTB neurons did not show this activity-dependent structural modification of the AIS following repeated sound stimulation. In addition, BDNF+/– mice lacked a defined isofrequency band of neuronal activity following exposure to 16 kHz sound, suggesting degradation of tonotopy. Taken together, structural development and functional refinement of auditory brainstem neurons require physiological levels of BDNF to establish proper tonotopic gradients.

Characterization of Developmental Changes in Spontaneous Electrical Activity of Medial Superior Olivary Neurons Before Hearing Onset With a Combination of Injectable and Volatile Anesthesia.

In this work the impact of two widely used anesthetics on the electrical activity of auditory brainstem neurons was studied during postnatal development. Spontaneous electrical activity in neonate rats of either sex was analyzed through a ventral craniotomy in mechanically ventilated pups to carry out patch clamp and multi-electrode electrophysiology recordings in the medial region of the superior olivary complex (SOC) between birth (postnatal day 0, P0) and P12. Recordings were obtained in pups anesthetized with the injectable mix of ketamine/xylazine (K/X mix), with the volatile anesthetic isoflurane (ISO), or in pups anesthetized with K/X mix that were also exposed to ISO. The results of patch clamp recordings demonstrate for the first time that olivary and periolivary neurons in the medial region of the SOC fire bursts of action potentials. The results of multielectrode recordings suggest that the firing pattern of single units recorded in K/X mix is similar to that recorded in ISO anesthetized rat pups. Taken together, the results of this study provide a framework to use injectable and volatile anesthetics for future studies to obtain functional information on the activity of medial superior olivary neurons in vivo.

Structural Refinement of the Auditory Brainstem Neurons in Baboons During Perinatal Development.

Children born prematurely suffer from learning disabilities and exhibit reading, speech, and cognitive difficulties, which are associated with an auditory processing disorder. However, it is unknown whether gestational age at delivery and the unnatural auditory environment in neonatal intensive care units (NICU) collectively affect proper auditory development and neuronal circuitry in premature newborns. We morphologically characterized fetal development of the medial superior olivary nucleus (MSO), an area important for binaural hearing and sound localization, in the auditory brainstem of baboon neonates at different gestational ages. Axonal and synaptic structures and the tonotopic differentiation of ion channels in the MSO underwent profound refinements after hearing onset in the uterus. These developmental refinements of the MSO were significantly altered in preterm baboon neonates in the NICU. Thus, the maternal environment in uterus is critical for auditory nervous system development during the last trimester of pregnancy and critically affects the anatomic and functional formation of synapses and neural circuitry in the preterm newborn brain.

Transient Delivery of aKCNQ2/3-Specific Channel Activator 1 Week After Noise Trauma Mitigates Noise-Induced Tinnitus.

Exposure to loud noise can cause hearing loss and tinnitus in mice and humans. In mice, one major underlying mechanism of noise-induced tinnitus is hyperactivity of auditory brainstem neurons, due at least in part, to decreased Kv7.2/3 (KCNQ2/3) potassium channel activity. In our previous studies, we used a reflex-based mouse model of tinnitus and showed that administration of a non-specific KCNQ channel activator, immediately after noise trauma, prevented the development of noise-induced tinnitus, assessed 1week after trauma. Subsequently, we developed RL-81, a very potent and highly specific activator of KCNQ2/3 channels. Here, to test the timing window within which RL-81 prevents tinnitus in mice, we modified and employed an operant animal model of tinnitus, where mice are trained to move in response to sound but not move in silence. Mice with behavioral evidence of tinnitus are expected to move in silence. We validated this mouse model by testing the effect of salicylate, which is known to induce tinnitus. We found that transient administration of RL-81 1week after noise exposure did not affect hearing loss but reduced significantly the percentage of mice with behavioral evidence of tinnitus, assessed 2weeks after noise exposure. Our results indicate that RL-81 is a promising drug candidate for further development for the treatment of noise-induced tinnitus.

Modulation of Neuronal Potassium Channels During Auditory Processing.

The extraction and localization of an auditory stimulus of interest from among multiple other sounds, as in the ‘cocktail-party’ situation, requires neurons in auditory brainstem nuclei to encode the timing, frequency, and intensity of sounds with high fidelity, and to compare inputs coming from the two cochleae. Accurate localization of sounds requires certain neurons to fire at high rates with high temporal accuracy, a process that depends heavily on their intrinsic electrical properties. Studies have shown that the membrane properties of auditory brainstem neurons, particularly their potassium currents, are not fixed but are modulated in response to changes in the auditory environment. Here, we review work focusing on how such modulation of potassium channels is critical to shaping the firing pattern and accuracy of these neurons. We describe how insights into the role of specific channels have come from human gene mutations that impair localization of sounds in space. We also review how short-term and long-term modulation of these channels maximizes the extraction of auditory information, and how errors in the regulation of these channels contribute to deficits in decoding complex auditory information.

Phonophobia and brainstem excitability in migraine.

Phonophobia in migraineurs may be due to lower hearing threshold (HT) and higher brainstem neuronal excitability. We report the correlation of phonophobia in migraineurs with HT, brain stem auditory evoked potential (BAEP) findings, and auditory triggers. Sixty-one migraineurs and 101 controls were included for HT, of whom 59 migraineurs and 31 controls had BAEP studies. Clinical details, migraine triggers, and headache frequency were noted. Hearing threshold was measured, and amplitudes of waves I to V of BAEP studies were measured. Migraineurs had lower HT compared with controls (41.61±5.25 versus 45.39±6.26dB; p<0.001) especially in chronic migraine (40.24±4.81; p<0.001). Hearing threshold correlated with headache frequency (p<0.05) and auditory, visual, and tactile (p<0.05) triggers. Hearing threshold was lower during headache (p<0.001). Wave II, III, and IV amplitudes of BAEP were higher in migraineurs than the controls. Wave II (p<0.05) and III (p<0.05) amplitudes correlated with HT. Migraineurs have lower HT, especially in those having chronic migraine, ictal HT recording, and multiple sensory triggers. Higher amplitudes of BAEP waves in migraineurs and their relationship with the frequency of headache and HT suggest the sensitization of brainstem auditory neurons.