Auditory Neurophysiology publications

Atoh1 is a basic helix–loop–helix transcription factor necessary for the specification of inner ear hair cells and central auditory system neurons derived from the rhombic lip. We used the Cre–loxP system and two Cre -driver lines ( Egr2 Cre and Hoxb1 Cre ) to delete Atoh1 from different regions of the cochlear nucleus (CN) and accessory auditory nuclei (AAN). Adult Atoh1 -conditional knock-out mice ( Atoh1 CKO ) are behaviorally deaf, have diminished auditory brainstem evoked responses, and have disrupted CN and AAN morphology and connectivity. In addition, Egr2; Atoh1 CKO mice lose spiral ganglion neurons in the cochlea and AAN neurons during the first 3 d of life, revealing a novel critical period in the development of these neurons. These new mouse models of predominantly central deafness illuminate the importance of the CN for support of a subset of peripheral and central auditory neurons.

The barn owl's midbrain and forebrain contain neurons tuned to sound direction. The spatial receptive fields of these neurons result from sensitivity to combinations of interaural time (ITD) and level (ILD) differences over a broad frequency range. While a map of auditory space has been described in the midbrain, no similar topographic representation has been found in the forebrain. The first nuclei that belong exclusively to the forebrain and midbrain pathways are the thalamic nucleus ovoidalis (Ov) and the external nucleus of the inferior colliculus (ICx), respectively. The midbrain projects to the auditory thalamus before sharp spatial receptive fields emerge; although Ov and ICx receive projections from the same midbrain nuclei, they are not directly connected. We compared the spatial tuning in Ov and ICx. Thalamic neurons respond to a broader frequency range and their ITD and ILD tuning varied more across frequency. However, neurons in Ov showed spatial receptive fields as selective as neurons in ICx. Thalamic spatial receptive fields were tuned to frontal and contralateral space and correlated with their tuning to ITD and ILD. Our results indicate that spatial tuning emerges in both pathways by similar combination selectivity to ITD and ILD. However, the midbrain and the thalamus do not appear to repeat exactly the same processing, as indicated by the difference in frequency range and the broader tuning to binaural cues. The differences observed at the initial stages of these sound-localization pathways may reflect diverse functions and coding schemes of midbrain and forebrain.

Responses of neural units in two areas of the medial auditory belt (middle medial area [MM] and rostral medial area [RM]) were tested with tones, noise bursts, monkey calls (MC), and environmental sounds (ES) in microelectrode recordings from two alert rhesus monkeys. For comparison, recordings were also performed from two core areas (primary auditory area [A1] and rostral area [R]) of the auditory cortex. All four fields showed cochleotopic organization, with best (center) frequency [BF(c)] gradients running in opposite directions in A1 and MM than in R and RM. The medial belt was characterized by a stronger preference for band-pass noise than for pure tones found medially to the core areas. Response latencies were shorter for the two more posterior (middle) areas MM and A1 than for the two rostral areas R and RM, reaching values as low as 6 ms for high BF(c) in MM and A1, and strongly depended on BF(c). The medial belt areas exhibited a higher selectivity to all stimuli, in particular to noise bursts, than the core areas. An increased selectivity to tones and noise bursts was also found in the anterior fields; the opposite was true for highly temporally modulated ES. Analysis of the structure of neural responses revealed that neurons were driven by low-level acoustic features in all fields. Thus medial belt areas RM and MM have to be considered early stages of auditory cortical processing. The anteroposterior difference in temporal processing indices suggests that R and RM may belong to a different hierarchical level or a different computational network than A1 and MM.

In the pallid bat auditory cortex and inferior colliculus (IC), the majority of neurons tuned in the echolocation range is selective for the direction and rate of frequency-modulated (FM) sweeps used in echolocation. Such selectivity is shaped mainly by spectrotemporal asymmetries in sideband inhibition. An early-arriving, low-frequency inhibition (LFI) shapes direction selectivity. A delayed, high-frequency inhibition (HFI) shapes rate selectivity for downward sweeps. Using iontophoretic blockade of GABAa receptors, we show that cortical FM sweep selectivity is at least partially shaped locally. GABAa receptor antagonists, bicuculline or gabazine, reduced or eliminated direction and rate selectivity in ∼50% of neurons. Intracortical GABA shapes FM sweep selectivity by either creating the underlying sideband inhibition or by advancing the arrival time of inhibition relative to excitation. Given that FM sweep selectivity and asymmetries in sideband inhibition are already present in the IC, these data suggest a refinement or recreation of similar response properties at the cortical level.

Three-dimensional electrode arrays have a variety of potential applications in the fields of both intracortical mapping as well as basic research studies designed to characterize and understand the physiology of the brain. While higher channels counts are desired in brain-machine interface applications, the ability to analyze synchronous data from multiple cortical locations, including various depths is pivotal to fully mapping the underlying neurophysiology of sensory cortices. Within this study, we present a proof of concept validation of a 3D probe technology consisting of 16 silicon shanks in a 4x4 grid arrangement with four electrode sites per shank. This 3D array has been implanted in a rat primary auditory cortex and electrophysiological data are presented showing the utility of electrode sites spanning multilateral cortical space as well as cortical depth.

Hearing relies on Ca 2+ influx-triggered exocytosis in cochlear inner hair cells (IHCs). Here we studied the role of the Ca 2+ channel subunit Ca V β 2 in hearing. Of the Ca V β 1–4 mRNAs, IHCs predominantly contained Ca V β 2 . Hearing was severely impaired in mice lacking Ca V β 2 in extracardiac tissues ( Ca V β 2 −/− ). This involved deficits in cochlear amplification and sound encoding. Otoacoustic emissions were reduced or absent in Ca V β 2 −/− mice, which showed strongly elevated auditory thresholds in single neuron recordings and auditory brainstem response measurements. Ca V β 2 −/− IHCs showed greatly reduced exocytosis (by 68%). This was mostly attributable to a decreased number of membrane-standing Ca V 1.3 channels. Confocal Ca 2+ imaging revealed presynaptic Ca 2+ microdomains albeit with much lower amplitudes, indicating synaptic clustering of fewer Ca V 1.3 channels. The coupling of the remaining Ca 2+ influx to IHC exocytosis appeared unaffected. Extracellular recordings of sound-evoked spiking in the cochlear nucleus and auditory nerve revealed reduced spike rates in the Ca V β 2 −/− mice. Still, sizable onset and adapted spike rates were found during suprathreshold stimulation in Ca V β 2 −/− mice. This indicated that residual synaptic sound encoding occurred, although the number of presynaptic Ca V 1.3 channels and exocytosis were reduced to one-third. The normal developmental upregulation, clustering, and gating of large-conductance Ca 2+ activated potassium channels in IHCs were impaired in the absence of Ca V β 2 . Moreover, we found the developmental efferent innervation to persist in Ca V β 2 -deficient IHCs. In summary, Ca V β 2 has an essential role in regulating the abundance and properties of Ca V 1.3 channels in IHCs and, thereby, is critical for IHC development and synaptic encoding of sound.

The responses of neocortical cells to sensory stimuli are variable and state dependent. It has been hypothesized that intrinsic cortical dynamics play an important role in trial-to-trial variability; the precise nature of this dependence, however, is poorly understood. We show here that in auditory cortex of urethane-anesthetized rats, population responses to click stimuli can be quantitatively predicted on a trial-by-trial basis by a simple dynamical system model estimated from spontaneous activity immediately preceding stimulus presentation. Changes in cortical state correspond consistently to changes in model dynamics, reflecting a nonlinear, self-exciting system in synchronized states and an approximately linear system in desynchronized states. We propose that the complex and state-dependent pattern of trial-to-trial variability can be explained by a simple principle: sensory responses are shaped by the same intrinsic dynamics that govern ongoing spontaneous activity.

We used acoustic clicks to study the impulse response of the neurophonic potential in the barn owl's nucleus laminaris. Clicks evoked a complex oscillatory neural response with a component that reflected the best frequency measured with tonal stimuli. The envelope of this component was obtained from the analytic signal created using the Hilbert transform. The time courses of the envelope and carrier waveforms were characterized by fitting them with filters. The envelope was better fitted with a Gaussian than with the envelope of a gamma-tone function. The carrier was better fitted with a frequency glide than with a constant instantaneous frequency. The change of the instantaneous frequency with time was better fitted with a linear fit than with a saturating nonlinearity. Frequency glides had not been observed in the bird's auditory system before. The glides were similar to those observed in the mammalian auditory nerve. Response amplitude, group delay, frequency, and phase depended in a systematic way on click level. In most cases, response amplitude decreased linearly as stimulus level decreased, while group delay, phase, and frequency increased linearly as level decreased. Thus the impulse response of the neurophonic potential in the nucleus laminaris of barn owls reflects many characteristics also observed in responses of the basilar membrane and auditory nerve in mammals.

For analyses of complex sounds, many neurons integrate information across different spectral elements via suppressive effects that are distant from the neurons' excitatory tuning. In the mustached bat, suppression evoked by sounds within the first sonar harmonic (23–30 kHz) or in the subsonar band (<23 kHz) alters responsiveness to the higher best frequencies of many neurons. This study examined features and mechanisms associated with low-frequency (LF) suppression among neurons of the lateral lemniscal nuclei (NLL). We obtained extracellular recordings from neurons in the intermediate and ventral nuclei of the lateral lemniscus, observing different forms of LF suppression related to the two above-cited frequency bands. To understand the mechanisms underlying this suppression in NLL neurons, we examined the roles of glycinergic and GABAergic input through local microiontophoretic application of strychnine, an antagonist to glycine receptors (GlyRs), or bicuculline, an antagonist to γ-aminobutyric acid type A receptors (GABA A Rs). With blockade of GABA A Rs, neurons showed an increase in firing rate to best frequency (BF) and/or LF tones but retained LF suppression of BF sounds. For neurons that displayed LF suppression tuned to 23–30 kHz, the suppression was eliminated or nearly eliminated by GlyR blockade. In contrast, GABA A R blockade did not eliminate nor had any consistent effect on suppression tuned to these frequencies. We conclude that LF suppression tuned in the 23- to 30-kHz range results from neuronal inhibition within the NLL via glycinergic inputs. For neurons displaying suppression tuned <23 kHz, neither GlyR nor GABAR blockade altered LF suppression. We conclude that such suppression originates at a lower auditory level, perhaps a result of cochlear mechanisms. These findings demonstrate that neuronal interactions within NLL create a particular form of LF suppression that contributes to the analysis of complex acoustic signals.

Experience-dependent plasticity in the central sensory systems depends on activation of both the sensory and neuromodulatory systems. Sensitization or nonspecific augmentation of central auditory neurons elicited by pseudo-conditioning with unpaired conditioning tonal (CS) and unconditioned electric leg (US) stimuli is quite different from tone-specific plasticity, called best frequency (BF) shifts, of the neurons elicited by auditory fear conditioning with paired CS and US. Therefore the neural circuits eliciting the nonspecific augmentation must be different from that eliciting the BF shifts. We first examined plastic changes in the response properties of collicular neurons of the big brown bat elicited by pseudo-conditioning and found that it elicited prominent nonspecific augmentation—an auditory response increase, a frequency-tuning broadening, and a threshold decreas—and that, in addition, it elicited a small short-lasting BF shift only when the CS frequency was 5 kHz lower than the BF of a recorded neuron. We examined the role of acetylcholine and the auditory and somatosensory cortices in these collicular changes. The development of the nonspecific augmentation was affected little by a muscarinic acetylcholine receptor antagonist applied to the inferior colliculus and by a GABA A receptor agonist applied to the auditory or somatosensory cortex. However, these drugs abolished the small short-lasting BF shift as they abolished the large long-lasting cortical and short-lasting collicular BF shifts elicited by the conditioning. These results indicate that, different from the BF shift, the nonspecific augmentation of the inferior colliculus depends on neither the cholinergic neuromodulator nor the auditory and somatosensory cortices.

In the normal guinea pig, contralateral sound inhibits more than a third of ventral cochlear nucleus (VCN) neurons but excites <4% of these neurons. However, unilateral conductive hearing loss (CHL) and cochlear ablation (CA) result in a major enhancement of contralateral excitation. The response properties of the contralateral excitation produced by CHL and CA are similar, suggesting similar pathways are involved for both types of hearing loss. Here we used the neurotoxin melittin to test the hypothesis that this “compensatory” contralateral excitation is mediated either by direct glutamatergic CN-commissural projections or by cholinergic neurons of the olivocochlear bundle (OCB) that send collaterals to the VCN. Unit responses were recorded from the left VCN of anesthetized, unilaterally deafened guinea pigs (CHL via ossicular disruption, or CA via mechanical destruction). Neural responses were obtained with 16-channel electrodes to enable simultaneous data collection from a large number of single- and multiunits in response to ipsi- and contralateral tone burst and noise stimuli. Lesions of each pathway had differential effects on the contralateral excitation. We conclude that contralateral excitation has a fast and a slow component. The fast excitation is likely mediated by glutamatergic neurons located in medial regions of VCN that send their commissural axons to the other CN via the dorsal/intermediate acoustic striae. The slow component is likely mediated by the OCB collateral projections to the CN. Commissural neurons that leave the CN via the trapezoid body are an additional source of fast, contralateral excitation.

Frequency tuning of auditory cortical neurons is typically determined by integrating spikes over the entire duration of a tone stimulus. However, this approach may mask functionally significant variations in tuning over the time course of the response. To explore this possibility, frequency response functions (FRFs) based on population multiunit activity evoked by pure tones of 175 or 200 ms duration were examined within four time windows relative to stimulus onset corresponding to "on" (10-30 ms), "early sustained" (30-100 ms), "late sustained" (100-175 ms), and "off" (185-235 or 210-260 ms) portions of responses in primary auditory cortex (A1) of 5 awake macaques. FRFs of "on" and "early sustained" responses displayed a good concordance, with best frequencies (BFs) differing, on average, by less than 0.25 octaves. In contrast, FRFs of "on" and "late sustained" responses differed considerably, with a mean difference in BF of 0.68 octaves. At many sites, tuning of "off" responses was inversely related to that of "on" responses, with "off" FRFs displaying a trough at the BF of "on" responses. Inversely correlated "on" and "off" FRFs were more common at sites with a higher "on" BF, thus suggesting functional differences between sites with low and high "on" BF. These results indicate that frequency tuning of population responses in A1 may vary considerably over the course of the response to a tone, thus revealing a temporal dimension to the representation of sound spectrum in A1.

The purpose of this study was to determine the effect of signal level and signal-to-noise ratio (SNR) on the latency and amplitude of evoked cortical activity to further our understanding of how the human central auditory system encodes signals in noise. Cortical auditory evoked potentials (CAEPs) were recorded from 15 young normal-hearing adults in response to a 1000 Hz tone presented at two tone levels in quiet and while continuous background noise levels were varied in five equivalent SNR steps. These 12 conditions were used to determine the effects of signal level and SNR level on CAEP components P1, N1, P2, and N2. Based on prior signal-in-noise experiments conducted in animals, we hypothesized that SNR, would be a key contributor to human CAEP characteristics. As hypothesized, amplitude increased and latency decreased with increasing SNR; in addition, there was no main effect of tone level across the two signal levels tested (60 and 75 dB SPL). Morphology of the P1-N1-P2 complex was driven primarily by SNR, highlighting the importance of noise when recording CAEPs. Results are discussed in terms of the current interest in recording CAEPs in hearing aid users.

A common visual pathway in all amniotes is the tectofugal pathway connecting the optic tectum with the forebrain. The tectofugal pathway has been suggested to be involved in tasks such as orienting and attention, tasks that may benefit from integrating information across senses. Nevertheless, previous research has characterized the tectofugal pathway as strictly visual. Here we recorded from two stations along the tectofugal pathway of the barn owl: the thalamic nucleus rotundus (nRt) and the forebrain entopallium (E). We report that neurons in E and nRt respond to auditory stimuli as well as to visual stimuli. Visual tuning to the horizontal position of the stimulus and auditory tuning to the corresponding spatial cue (interaural time difference) were generally broad, covering a large portion of the contralateral space. Responses to spatiotemporally coinciding multisensory stimuli were mostly enhanced above the responses to the single modality stimuli, whereas spatially misaligned stimuli were not. Results from inactivation experiments suggest that the auditory responses in E are of tectal origin. These findings support the notion that the tectofugal pathway is involved in multisensory processing. In addition, the findings suggest that the ascending auditory information to the forebrain is not as bottlenecked through the auditory thalamus as previously thought.

Acoustic activation of the vestibular system has been well documented in humans and animal models. In the past decade, sound-evoked myogenic potentials in the sternocleidomastoid muscle (cVEMP) and the extraocular muscles (oVEMP) have been extensively studied, and their potentials as new tests for vestibular function have been widely recognized. However, the extent to which sound activates the otolith and canal pathways remains controversial. In the present study, we examined this issue in a recently developed nonhuman primate model of acoustic activation of the vestibular system, i.e., sound-evoked vestibulo-ocular reflexes (VOR) in behaving monkeys. To determine whether the canal and otolith VOR pathways are activated by sound, we analyzed abducens neurons' responses to clicks that were delivered into either ear. The main finding was that clicks evoked short-latency excitatory responses in abducens neurons on both sides. The latencies of the two responses, however, were different. The mean latency of the contralateral and ipsilateral abducens neurons was 2.44 +/- 0.4 and 1.65 +/- 0.28 ms, respectively. A further analysis of the excitatory latencies, in combination with the known canal and otolith VOR pathways, suggests that the excitatory responses of the contralateral abducens neurons were mediated by the contralateral disynaptic VOR pathways that connect the lateral canal to the contralateral abducens neurons, and the excitatory responses of the ipsilateral abducens neurons were mediated by the ipsilateral monosynaptic VOR pathways that connect the utricle to the ipsilateral abducens neurons. These results provide new insights into the understanding of the neural basis for sound-evoked vestibular responses, which is essential for developing new tests for both canal and otolith functions in humans.

Various clinical populations display atypical volume asymmetry of language structures and also the auditory M100 source. Although such atypical volume asymmetries have also been observed in autism, M100 source asymmetries have not yet been investigated. We examined M100 asymmetry in autism and its relationship with language functioning. Evoked neural activity to a 1 kHz tone was recorded using whole-cortex 151-channel magnetoencephalography in three groups of individuals. A single-dipole model identified the M100 generator in auditory cortex in each hemisphere. Healthy adults and control children displayed the expected right-sided M100 anteriority, whereas children with autism showed no such asymmetry. An association was found between language functioning and the degree of asymmetry across the two groups of children, suggesting a possible relationship between functional-structural asymmetry and language ability.

Neuroanatomical studies have revealed a vast network of corticocortical connections among the various fields that form cat auditory cortex. However, few studies have explored the functional communicative properties of these connections. The purpose of the present study was to examine the bidirectional processing contributions between the primary auditory cortex (A1) and the nonprimary anterior auditory field (AAF). Using acute recording techniques, multiunit neuronal activity was collected from the right hemisphere of nine mature cats. Cortical maps were generated, and the precise location of A1 and AAF was identified. Subsequently, the synaptic activity of A1 or AAF was suppressed with reversible thermal deactivation procedures while the neuronal response to tonal stimuli of the non-inactivated area (A1 or AAF) was measured. We examined response strength and latency, characteristic frequency, bandwidth, and neuronal threshold of A1 and AAF receptive fields before and during epochs of deactivation. Three major changes in A1 response properties were observed during AAF neuronal suppression: a decrease in response strength, an increase in neuronal thresholds, and a sharpening of receptive field bandwidths. In contrast, A1 deactivation did not produce any discernible changes in AAF neuronal responses. Collectively, these results suggest that the modulation of acoustic information between A1 and AAF in cat auditory cortex is dominated by a unidirectional AAF to A1 pathway.

This report examines temporal features of facilitation and suppression that underlie spectrally integrative responses to complex vocal signals. Auditory responses were recorded from 160 neurons in the inferior colliculus (IC) of awake mustached bats. Sixty-two neurons showed combination-sensitive facilitation: responses to best frequency (BF) signals were facilitated by well-timed signals at least an octave lower in frequency, in the range 16–31 kHz. Temporal features and strength of facilitation were generally unaffected by changes in duration of facilitating signals from 4 to 31 ms. Changes in stimulus rise time from 0.5 to 5.0 ms had little effect on facilitatory strength. These results suggest that low frequency facilitating inputs to high BF neurons have phasic-on temporal patterns and are responsive to stimulus rise times over the tested range. We also recorded from 98 neurons showing low-frequency (11–32 kHz) suppression of higher BF responses. Effects of changing duration were related to the frequency of suppressive signals. Signals <23 kHz usually evoked suppression sustained throughout signal duration. This and other features of such suppression are consistent with a cochlear origin that results in masking of responses to higher, near-BF signal frequencies. Signals in the 23- to 30-kHz range—frequencies in the first sonar harmonic—generally evoked phasic suppression of BF responses. This may result from neural inhibitory interactions within and below IC. In many neurons, we observed two or more forms of the spectral interactions described here. Thus IC neurons display temporally and spectrally complex responses to sound that result from multiple spectral interactions at different levels of the ascending auditory pathway.

Primary sensory cortices have been assumed to serve as stimulus analyzers while cognitive functions such as learning and memory have been allocated to "higher" cortical areas. However, the primary auditory cortex (A1) is now known to encode the acquired significance of sound as indicated by associatively-induced specific shifts of tuning to the frequencies of conditioned stimuli (CS) and gains in area of CS representations. Rewarding brain stimulation can be a very powerful motivator and brain reward systems have been implicated in addictive behavior. Therefore, it is possible that a cue for brain reward will gain cortical territory and perhaps thereby increase its control of subsequent behavior. To investigate the effect of brain reward on cortical organization, adult male rats (n=11) were first tested with varying amounts of stimulation of the ventral tegmental area (VTAstm) to generate sigmoidal psychometric functions of nose poke (NP) rates as a function of reward magnitude (duration). Next, we attempted to accomplish tone control of NPs by maintaining intertrial NPs using a low reward duration and presenting a 20s tone (2.0kHz, 70dB) which signaled an increase in reward to a high magnitude 10s after tone onset. Tone control was demonstrated by a significant increase in the rate of NPs during the first 10s of tone presentation, which anticipated the delivery of the high magnitude of reward. Tone control was achieved in seven of 11 subjects. This was accompanied by a highly specific and significant gain in representational area, specifically for the half-octave range centered on the CS frequency. However, this plasticity developed only in tone-controlled (TC) animals. The auditory cortex of non-tone-controlled subjects (n=4) did not differ from that of naïve controls (n=9) although their VTAstm was as rewarding as for the TC group. These findings reveal that auditory instrumental behavior can be controlled by rewarding VTAstm and that such control appears necessary for the highly specific recruitment of cortical cells to increase the representation of a sound that acquires behavioral importance.

Complexins (CPXs I-IV) presumably act as regulators of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex, but their function in the intact mammalian nervous system is not well established. Here, we explored the role of CPXs in the mouse auditory system. Hearing was impaired in CPX I knock-out mice but normal in knock-out mice for CPXs II, III, IV, and III/IV as measured by auditory brainstem responses. Complexins were not detectable in cochlear hair cells but CPX I was expressed in spiral ganglion neurons (SGNs) that give rise to the auditory nerve. Ca(2+)-dependent exocytosis of inner hair cells and sound encoding by SGNs were unaffected in CPX I knock-out mice. In the absence of CPX I, the resting release probability in the endbulb of Held synapses of the auditory nerve fibers with bushy cells in the cochlear nucleus was reduced. As predicted by computational modeling, bushy cells had decreased spike rates at sound onset as well as longer and more variable first spike latencies explaining the abnormal auditory brainstem responses. In addition, we found synaptic transmission to outlast the stimulus at many endbulb of Held synapses in vitro and in vivo, suggesting impaired synchronization of release to stimulus offset. Although sound encoding in the cochlea proceeds in the absence of complexins, CPX I is required for faithful processing of sound onset and offset in the cochlear nucleus.