Biology subjects

Lauer, A. M.

Publications and source records attributed to Lauer, A. M..

7 recordsLinked to original sources

bioRxiv2025

Ultrastructural changes at auditory nerve synapses following moderate noise exposure

Moderate noise exposure is a common experience, yet its impact on central auditory synapses remains poorly understood. We study this issue at the first synapses in the central auditory pathway formed by auditory nerve afferents onto bushy cells in the cochlear nucleus, called endbulbs of Held. Non-traumatic noise exposure alters endbulb properties, decreasing the probability of vesicle release and enlarging the pool of releasable vesicles as assessed using electrophysiological methods and immunolabelling. These changes appear homeostatic, to maintain synaptic efficacy during periods of high activity. To identify structural changes underlying the larger vesicle pool, we used serial blockface electron microscopy of endbulbs from control and noise-exposed mice to quantitatively assess synaptic morphology. We observed no differences in the juxtapositional area between endbulbs and bushy cells, nor in the number or density of active zones and postsynaptic densities. Images of endbulb terminals were significantly darker after noise exposure, indicating an increase in the density of synaptic vesicles. These results suggest that moderate noise exposure induces an activity-dependent increase in presynaptic vesicle numbers, consistent with the observed physiological changes in neurotransmitter release. This work sets the stage for high-resolution studies to quantify docked and reserve vesicles. Significance statementNoise exposure is a fact of everyday life, and it is important to understand how noise affects function in the auditory pathway in the brain to understand the full consequences of noise exposure. Electrophysiological experiments indicate that noise triggers a homeostatic increase in the releasable pool of vesicles at auditory nerve synapses. We examined the cellular basis for this change using serial blockface electron microscopy of auditory nerve synapses with and without noise exposure. We reconstructed a number of bushy cells and their presynaptic auditory nerve terminals. After noise exposure, there was no significant increase in the area of synaptic contact or the number or density of synaptic release sites. There was an increase in the number of vesicles near release sites, which may account for the physiological changes. These results emphasize the importance of detailed anatomical studies to study the effects of noise exposure and thus determine the best mechanistic approach for therapies and treatments of noise-induced hearing loss.

neuroscience↗

bioRxiv2025

Tonotopically distinct OFF responses arise in the mouse auditory midbrain following sideband suppression

The parsing of sensory information into discrete topographic domains is a fundamental principle of sensory processing. In the auditory cortex, these domains evolve during a stimulus, with the onset and offset of tones evoking distinct spatial patterns of neural activity. However, it is not known where in the auditory system this spatial segregation occurs or how these dynamics are affected by hearing loss. Using widefield single photon neuronal Ca2+ imaging in the inferior colliculus (IC) of awake mice, we found that pure tone stimuli elicited both spatially constrained neural activity within isofrequency bands and simultaneous sideband suppression. At cessation of the stimulus, offset responses emerged within the region of sideband suppression, demonstrating that simple stimuli elicit spatiotemporally distinct neural activity patterns to represent the presence of sound and sound termination. Because sound frequency is spatially encoded in the IC, this spatial shift creates a tonotopically distinct offset (tdOFF) response relative to sound onset. Two-photon Ca2+ imaging confirmed that tdOFF neuron activity in the sideband region was suppressed during sound and elevated above baseline after stimulus termination, raising the possibility that rebound excitation could contribute to this post-stimulus activation. Loud noise exposure - a common model of hearing loss - abolished both sideband suppression and tdOFF responses. These results show that hearing loss profoundly reshapes the spatiotemporal pattern of sound processing by altering sideband activity. This preferential loss of sideband suppression and tdOFF activation after sound-induced injury in the auditory midbrain may contribute to hyperacusis and tinnitus by promoting neuronal hyperactivity. Key PointsO_LISensory systems encode different features of stimuli by activating distinct neural networks. C_LIO_LISound onsets and offsets elicit distinct neural patterns in the auditory cortex, although it is unclear where this separation originates or how it may change with hearing loss. C_LIO_LIUsing in vivo widefield Ca2+ imaging in awake mice, we find that pure tone stimuli evoke spatiotemporally distinct on-and off patterns of neural activity in the auditory midbrain. C_LIO_LINeurons active during stimulus offset were suppressed by sound in sideband regions, raising the possibility that rebound excitation contributes to this post-stimulus activation. C_LIO_LIBoth sideband suppression and off responses were preferentially abolished following noise-induced hearing loss, raising the possibility that these changes may contribute to hearing loss-related syndromes such as tinnitus and hyperacusis. C_LI

neuroscience↗

bioRxiv2025

Increased vulnerability to noise exposure of low spontaneous rate type 1C spiral ganglion neuron synapses with inner hair cells (Pre-Print)

The inner hair cells (IHCs) in the inner ear form synapses with auditory nerve fibers (ANFs) that send sound signals to the brain. ANFs have been grouped by their level of spontaneous firing rates (SRs) into high-, medium-, and low-SR ANFs. Based on their molecular profiles evaluated by RNAseq experiments, ANFs have been divided into three groups (1A, 1B, and 1C) that likely correspond to high-, medium-, and low-SR ANFs, respectively. In guinea pigs, the synapses between IHCs and low-SR ANFs have been shown to be more vulnerable to noise exposure compared to other ANF subtypes, but not in a study performed in CBA/CaJ mice, questioning if these results can be generalized. Here, an LYPD1 reporter mouse model on a C57Bl/6J background with specifically labeled group 1C, low-SR ANFs was used to examine whether LYPD1 positive ANF synapses are more vulnerable to noise exposure. Six-week-old mice were exposed to an 8-16 kHz octave band noise presented at 100 dBA for 2 hours. One week later, cochlear tissue was harvested to quantify ANF synapses and compare the percentage of LYPD1 positive ANF synapses in noise-exposed and unexposed animals. Auditory brainstem response measurements were performed to assess hearing function after noise exposure. The number of all ANF synapses and the percentage of LYPD1-positive ANF synapses were reduced following noise exposure, concurrent with increased ABR thresholds and decreased ABR wave 1 amplitudes. The reduction in the percentage of LYPD1-positive ANF synapses specifically indicates greater vulnerability of LYPD1 positive ANF synapses to noise exposure compared to other ANFs in C57Bl/6J mice.

neuroscience↗

bioRxiv2025

Revealing hidden knowledge in amnestic mice

Alzheimers disease (AD) is a form of dementia in which memory and cognitive decline is thought to arise from underlying neurodegeneration. These cognitive impairments, however, are transient when they first appear and can fluctuate across disease progression. Here, we investigate the neural mechanisms underlying fluctuations of performance in amnestic mice. We trained APP/PS1+ mice on an auditory go/no-go task that dissociated learning of task contingencies (knowledge) from its more variable expression under reinforcement (performance). APP/PS1+ exhibited significant performance deficits compared to control mice. Using large-scale two-photon imaging of 6,216 excitatory neurons in 8 mice, we found that auditory cortical networks were more suppressed, less selective to the sensory cues, and exhibited aberrant higher-order encoding of reward prediction compared to control mice. A small sub-population of neurons, however, displayed the opposite phenotype, reflecting a potential compensatory mechanism. Volumetric analysis demonstrated that deficits were concentrated near A{beta} plaques. Strikingly, we found that these cortical deficits were reversed almost instantaneously on probe (non-reinforced) trials when APP/PS1+ performed as well as control mice, providing neural evidence for intact stimulus-action knowledge despite variable ongoing performance. A biologically-plausible reinforcement learning model recapitulated these results and showed that synaptic weights from sensory-to-decision neurons were preserved (i.e. intact stimulus-action knowledge) despite poor performance that was due to inadequate contextual scaling (i.e. impaired performance). Our results suggest that the amnestic phenotype is transient, contextual, and endogenously reversible, with the underlying neural circuits retaining the underlying stimulus-action associations. Thus, memory deficits commonly observed in amnestic mouse models, and potentially at early stages of dementia in humans, relate more to contextual drivers of performance rather than degeneration of the underlying memory traces.

neuroscience↗

bioRxiv2025

Early Noise Exposure and Changes in Medial Olivocochlear Strength Alters Auditory Pathway Development

The early onset of peripheral deafness significantly alters the proper development of the auditory system. Likewise, exposure to loud noise during early development produces a similar disruptive effect. Before hearing onset in altricial mammals, cochlear inner hair cells exhibit spontaneous electrical activity that drives auditory circuit development. This activity is modulated by medial olivocochlear (MOC) efferent feedback through 910 nicotinic cholinergic receptors in inner hair cells. In adults, these receptors are restricted to outer hair cells, where they mediate MOC feedback to regulate cochlear amplification. Although the MOC systems protective role to prevent noise-induced hearing loss in adulthood is well-established, its influence during early developmental stages-especially in response to exposure to loud noise-remains largely unexplored. In this study, we investigated the role of MOC feedback during early postnatal development using 9 knockout (KO) and 9 knock-in (KI) mice of either sex, which respectively lack or exhibit enhanced cholinergic activity. Our findings reveal that both increased and absent olivocochlear activity result in altered auditory sensitivity at the onset of hearing, along with long- range alterations in the number and morphology of ribbon synapses. Early noise exposure caused lasting auditory damage in both wild-type and 9KO mice, with deficits persisting into adulthood. In contrast, 9KI mice were protected from noise-induced damage, with no long-term effects on auditory function. These results highlight the increased susceptibility of the auditory system during early postnatal development. Moreover, they indicate that an enhanced MOC feedback shields the auditory system from noise damage during this period. SIGNIFICANCE STATEMENTEarly development represents a sensitive window for shaping auditory function. We show that the medial olivocochlear system is critical for establishing normal ribbon synapse density and size; key features for proper hearing onset. We also show that the developing auditory system is especially vulnerable to loud noise, with early exposure causing more severe and lasting effects than similar noise later in life. Notably, enhancing 910 nAChR receptor activity during this early stage offers protection against noise-induced damage, revealing a time-sensitive opportunity to safeguard auditory development.

neuroscience↗

bioRxiv2024

Resistance to age-related hearing loss in the echolocating big brown bat (Eptesicus fuscus)

Hearing mediates many behaviors critical for survival in echolocating bats, including foraging and navigation. Most mammals are susceptible to progressive age-related hearing loss; however, the evolution of biosonar, which requires the ability to hear low-intensity echoes from outgoing sonar signals, may have selected against the development of hearing deficits in echolocating bats. Although many echolocating bats exhibit exceptional longevity and rely on acoustic behaviors for survival to old age, relatively little is known about the aging bat auditory system. In this study, we used DNA methylation to estimate the ages of wild-caught big brown bats (Eptesicus fuscus) and measured hearing sensitivity in young and aging bats using auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs). We found no evidence for hearing deficits in aging bats, demonstrated by comparable thresholds and similar ABR wave and DPOAE amplitudes across age groups. We additionally found no significant histological evidence for cochlear aging, with similar hair cell counts, afferent, and efferent innervation patterns in young and aging bats. Here we demonstrate that big brown bats show minimal evidence for age-related loss of peripheral hearing sensitivity and therefore represent informative models for investigating mechanisms that may preserve hearing function over a long lifetime.

neuroscience↗

bioRxiv2024

Effects of age on responses of principal cells of the mouse anteroventral cochlear nucleus in quiet and noise

Older listeners often report difficulties understanding speech in noisy environments. It is important to identify where in the auditory pathway hearing-in-noise deficits arise to develop appropriate therapies. We tested how encoding of sounds is affected by masking noise at early stages of the auditory pathway by recording responses of principal cells in the anteroventral cochlear nucleus (AVCN) of aging CBA/CaJ and C57BL/6J mice in vivo. Previous work indicated that masking noise shifts the dynamic range of single auditory nerve fibers (ANFs), leading to elevated tone thresholds. We hypothesized that such threshold shifts could contribute to increased hearing-in-noise deficits with age if susceptibility to masking increased in AVCN units. We tested this by recording the responses of AVCN principal neurons to tones in the presence and absence of masking noise. Surprisingly, we found that masker-induced threshold shifts decreased with age in primary-like units and did not change in choppers. In addition, spontaneous activity decreased in primary-like and chopper units of old mice, with no change in dynamic range or tuning precision. In C57 mice, which undergo early onset hearing loss, units showed similar changes in threshold and spontaneous rate at younger ages, suggesting they were related to hearing loss and not simply aging. These findings suggest that sound information carried by AVCN principal cells remains largely unchanged with age. Therefore, hearing-in-noise deficits may result from other changes during aging, such as distorted across-channel input from the cochlea and changes in sound coding at later stages of the auditory pathway. Significance StatementMiddle age and older listeners commonly experience hearing deficits in the presence of background noise. Central auditory areas have been implicated in hearing-in-noise deficits, but it is not known where these deficits arise. We performed in vivo recordings in mice of different ages at the first stage of the auditory pathway in the brain, the cochlear nucleus, to examine how encoding of sounds is perturbed by masking noise. We found that the responses of individual neurons remain largely intact with age, including the processing of tones in masking noise, despite previously documented structural and physiological degeneration of their auditory nerve inputs. This suggests that problems hearing in masking noise result from changes at other stages of the auditory pathway.

neuroscience↗