Amanda M. Lauer

The medial olivocochlear system attenuates the developmental impact of early noise exposure.

The early onset of peripheral deafness profoundly alters the functional maturation of the central auditory system. A prolonged exposure to an artificial acoustic environment has a similar disruptive influence. These observations establish the importance of normal patterns of sound-driven activity during the initial stages of auditory development. The present study was designed to address the role of cochlear gain control during these activity-dependent developmental processes. It was hypothesized that the regulation of auditory nerve activity by the medial olivocochlear system (MOCS) would preserve normal development when the immature auditory system was challenged by continuous background noise. To test this hypothesis, knock-out mice lacking MOCS feedback were reared in noisy or quiet environments and then evaluated with behavioral paradigms for auditory processing deficits. Relative to wild-type controls, noise-reared knock-out mice showed a decreased ability to process rapid acoustic events. Additional anatomical and physiological assessments linked these perceptual deficits to synaptic defects in the auditory brainstem that shared important features with human auditory neuropathy. Our findings offer a new perspective on the potentially damaging effects of environmental noise and how these risks are ameliorated by the protective role of MOCS feedback.

Efferent synapses return to inner hair cells in the aging cochlea

Efferent innervation of the cochlea undergoes extensive modification early in development, but it is unclear if efferent synapses are modified by age, hearing loss, or both. Structural alterations in the cochlea affecting information transfer from the auditory periphery to the brain may contribute to age-related hearing deficits. We investigated changes to efferent innervation in the vicinity of inner hair cells (IHCs) in young and old C57BL/6 mice using transmission electron microscopy to reveal increased efferent innervation of IHCs in older animals. Efferent contacts on IHCs contained focal presynaptic accumulations of small vesicles. Synaptic vesicle size and shape were heterogeneous. Postsynaptic cisterns were occasionally observed. Increased IHC efferent innervation was associated with a smaller number of afferent synapses per IHC, increased outer hair cell loss, and elevated auditory brainstem response thresholds. Efferent axons also formed synapses on afferent dendrites but with a reduced prevalence in older animals. Age-related reduction of afferent activity may engage signaling pathways that support the return to an immature state of efferent innervation of the cochlea.

Analysis of environmental sound levels in modern rodent housing rooms.

Noise in animal housing facilities is an environmental variable that can affect hearing, behavior and physiology in mice. The authors measured sound levels in two rodent housing rooms (room 1 and room 2) during several 24-h periods. Room 1, which was subject to heavy personnel traffic, contained ventilated racks and static cages that housed large numbers of mice. Room 2 was accessed by only a few staff members, contained static cages only and housed fewer mice. In both rooms, background sound levels were usually about 80 dB, and transient noises caused sound levels to temporarily rise 30–40 dB above the baseline level; such peaks occurred frequently during work hours (8:30 AM to 4:30 PM) and infrequently during non-work hours. Noise peaks during work hours in room 1 occurred about two times as often as in room 2 (P = 0.01). Use of changing stations located in the rooms caused background noise to increase by about 10 dB. Loud noise and noise variability were attributed mainly to personnel activity. Attempts to reduce noise should concentrate on controlling sounds produced by in-room activities and experimenter traffic; this may reduce the variability of research outcomes and improve animal welfare.

GluA4 is indispensable for driving fast neurotransmission across a high‐fidelity central synapse

Non‐technical summary  Localization of sound sources in the azimuth, which makes use of interaural differences in timing and/or intensity of acoustic signals, is of vital importance for most mammals. Using the small differences in time of arrival and/or intensity at the two ears requires that propagation of electric pulses in the auditory system be temporally precise. In this study, we found that elimination of GluA4, a protein particularly abundant in auditory cells, significantly impairs their ability to faithfully transmit electric signals, leading to profound deficits in auditory responses to sound stimuli in mice. Therefore, we conclude that GluA4 is indispensable for enabling information flow with high fidelity in the auditory circuitry. Our work has identified GluA4 as a potential molecular candidate involved in human hearing deficits and disorders.

Morphological Characterization of Bushy Cells and Their Inputs in the Laboratory Mouse (Mus musculus) Anteroventral Cochlear Nucleus

Spherical and globular bushy cells of the AVCN receive huge auditory nerve endings specialized for high fidelity neural transmission in response to acoustic events. Recent studies in mice and other rodent species suggest that the distinction between bushy cell subtypes is not always straightforward. We conducted a systematic investigation of mouse bushy cells along the rostral-caudal axis in an effort to understand the morphological variation that gives rise to reported response properties in mice. We combined quantitative light and electron microscopy to investigate variations in cell morphology, immunostaining, and the distribution of primary and non-primary synaptic inputs along the rostral-caudal axis. Overall, large regional differences in bushy cell characteristics were not found; however, rostral bushy cells received a different complement of axosomatic input compared to caudal bushy cells. The percentage of primary auditory nerve terminals was larger in caudal AVCN, whereas non-primary excitatory and inhibitory inputs were more common in rostral AVCN. Other ultrastructural characteristics of primary auditory nerve inputs were similar across the rostral and caudal AVCN. Cross sectional area, postsynaptic density length and curvature, and mitochondrial volume fraction were similar for axosomatic auditory nerve terminals, although rostral auditory nerve terminals contained a greater concentration of synaptic vesicles near the postsynaptic densities. These data demonstrate regional differences in synaptic organization of inputs to mouse bushy cells rather than the morphological characteristic of the cells themselves.

Acoustic Basis of Directional Acuity in Laboratory Mice

The acoustic basis of auditory spatial acuity was investigated in CBA/129 mice by relating patterns of behavioral errors to directional features of the head-related transfer function (HRTF). Behavioral performance was assessed by training the mice to lick a water spout during sound presentations from a “safe” location and to suppress the response during presentations from “warning” locations. Minimum audible angles (MAAs) were determined by delivering the safe and warning sounds from different locations in the inter-aural horizontal and median vertical planes. HRTFs were measured at the same locations by implanting a miniature microphone and recording the gain of sound energy near the ear drum relative to free field. Mice produced an average MAA of 31° when sound sources were located in the horizontal plane. Acoustic measures indicated that binaural inter-aural level differences (ILDs) and monaural spectral features of the HRTF change systematically with horizontal location and therefore may have contributed to the accuracy of behavioral performance. Subsequent manipulations of the auditory stimuli and the directional properties of the ear produced errors that suggest the mice primarily relied on ILD cues when discriminating changes in azimuth. The MAA increased beyond 80° when the importance of ILD cues was minimized by testing in the median vertical plane. Although acoustic measures demonstrated a less robust effect of vertical location on spectral features of the HRTF, this poor performance provides further evidence for the insensitivity to spectral cues that was noted during behavioral testing in the horizontal plane.

The Pex1-G844D mouse: A model for mild human Zellweger spectrum disorder

Zellweger spectrum disorder (ZSD) is a disease continuum that results from inherited defects in PEX genes essential for normal peroxisome assembly. These autosomal recessive disorders impact brain development and also cause postnatal liver, adrenal, and kidney dysfunction, as well as loss of vision and hearing. The hypomorphic PEX1-G843D missense allele, observed in approximately 30% of ZSD patients, is associated with milder clinical and biochemical phenotypes, with some homozygous individuals surviving into early adulthood. Nonetheless, affected children with the PEX1-G843D allele have intellectual disability, failure to thrive, and significant sensory deficits. To enhance our ability to test candidate therapies that improve human PEX1-G843D function, we created the novel Pex1-G844D knock-in mouse model that represents the murine equivalent of the common human mutation. We show that Pex1-G844D homozygous mice recapitulate many classic features of mild ZSD cases, including growth retardation and fatty livers with cholestasis. In addition, electrophysiology, histology, and gene expression studies provide evidence that these animals develop a retinopathy similar to that observed in human patients, with evidence of cone photoreceptor cell death. Similar to skin fibroblasts obtained from ZSD patients with a PEX1-G843D allele, we demonstrate that murine cells homozygous for the Pex1-G844D allele respond to chaperone-like compounds, which normalizes peroxisomal β-oxidation. Thus, the Pex1-G844D mouse provides a powerful model system for testing candidate therapies that address the most common genetic cause of ZSD. In addition, this murine model will enhance studies focused on mechanisms of pathogenesis.

MRI acoustic noise can harm experimental and companion animals

To assess possible damage to the hearing of experimental and companion animal subjects of magnetic resonance imaging (MRI) scans.

Activity-dependent, homeostatic regulation of neurotransmitter release from auditory nerve fibers

Significance Synapses with high probability of neurotransmitter release (Pr) depress during prolonged activity, which reduces the faithful transfer of information. Auditory nerve synapses onto bushy cells show particularly strong depression at physiologically relevant rates of activity, which raises the question of how bushy cells transmit information when sound levels are high for a prolonged period. After rearing mice in constant, nondamaging noise, auditory nerve synapses changed from high to low Pr, with a corresponding increase in the number of release sites, which increased spike fidelity during high activity. Neither quantal size nor average excitatory postsynaptic current changed. After returning to control conditions, Pr recovered to high. These changes seem to reflect a homeostatic response to enhance fidelity. Information processing in the brain requires reliable synaptic transmission. High reliability at specialized auditory nerve synapses in the cochlear nucleus results from many release sites (N), high probability of neurotransmitter release (Pr), and large quantal size (Q). However, high Pr also causes auditory nerve synapses to depress strongly when activated at normal rates for a prolonged period, which reduces fidelity. We studied how synapses are influenced by prolonged activity by exposing mice to constant, nondamaging noise and found that auditory nerve synapses changed to facilitating, reflecting low Pr. For mice returned to quiet, synapses recovered to normal depression, suggesting that these changes are a homeostatic response to activity. Two additional properties, Q and average excitatory postsynaptic current (EPSC) amplitude, were unaffected by noise rearing, suggesting that the number of release sites (N) must increase to compensate for decreased Pr. These changes in N and Pr were confirmed physiologically using the integration method. Furthermore, consistent with increased N, endbulbs in noise-reared animals had larger VGlut1-positive puncta, larger profiles in electron micrographs, and more release sites per profile. In current-clamp recordings, noise-reared BCs had greater spike fidelity even during high rates of synaptic activity. Thus, auditory nerve synapses regulate excitability through an activity-dependent, homeostatic mechanism, which could have major effects on all downstream processing. Our results also suggest that noise-exposed bushy cells would remain hyperexcitable for a period after returning to normal quiet conditions, which could have perceptual consequences.

Phase effects in masking by harmonic complexes in birds.

Masking by harmonic complexes depends on the frequency content of the masker and its phase spectrum. Harmonic complexes created with negative Schroeder phases (component phases decreasing with increasing frequency) produce more masking than those with positive Schroeder phases (increasing phase) in humans, but not in birds. The masking differences in humans have been attributed to interactions between the masker phase spectrum and the phase characteristic of the basilar membrane. In birds, the similarity in masking by positive and negative Schroeder maskers, and reduced masking by cosine-phase maskers (constant phase), suggests a phase characteristic that does not change much along the basilar papilla. To evaluate this possibility, the rate of phase change across masker bandwidth was varied by systematically altering the Schroeder algorithm. Humans and three species of birds detected tones added in phase to a single component of a harmonic complex. As observed in earlier studies, the minimum amount of masking in humans occurred for positive phase gradients. However, minimum masking in birds occurred for a shallow negative phase gradient. These results suggest a cochlear delay in birds that is reduced compared to that found in humans, probably related to the shorter avian basilar epithelia.