Adult-Onset Hearing Impairment Induces Layer-Specific Cortical Reorganization: Evidence of Crossmodal Plasticity and Central Gain Enhancement.

Adult-onset hearing impairment can lead to hyperactivity in the auditory pathway (i.e., central gain enhancement) as well as increased cortical responsiveness to nonauditory stimuli (i.e., crossmodal plasticity). However, it remained unclear to what extent hearing loss-induced hyperactivity is relayed beyond the auditory cortex, and thus, whether central gain enhancement competes or coexists with crossmodal plasticity throughout the distinct layers of the audiovisual cortex. To that end, we investigated the effects of partial hearing loss on laminar processing in the auditory, visual and audiovisual cortices of adult rats using extracellular electrophysiological recordings performed 2 weeks after loud noise exposure. Current-source density analyses revealed that central gain enhancement was not relayed to the audiovisual cortex (V2L), and was instead restricted to the granular layer of the higher order auditory area, AuD. In contrast, crossmodal plasticity was evident across multiple cortical layers within V2L, and also manifested in AuD. Surprisingly, despite this coexistence of central gain enhancement and crossmodal plasticity, noise exposure did not disrupt the responsiveness of these neighboring cortical regions to combined audiovisual stimuli. Overall, we have shown for the first time that adult-onset hearing impairment causes a complex assortment of intramodal and crossmodal changes across the layers of higher order sensory cortices.

Activation of mGluR2/3 receptors in the ventro-rostral prefrontal cortex reverses sensorimotor gating deficits induced by systemic NMDA receptor antagonists.

Prepulse inhibition (PPI) of acoustic startle is an operational measure of sensorimotor gating, which is disrupted in schizophrenia. NMDA receptor (NMDAR) antagonist induced PPI disruption has become an important pharmacological model for schizophrenia; however, knowledge of the underlying mechanism remains incomplete. This study examines the role of NMDAR in the caudal pontine reticular nucleus (PnC) and the medial prefrontal cortex (mPFC) in NMDARs antagonist induced PPI deficits, as well as the NMDA receptor subtypes involved. We administered the NMDA antagonist MK-801 locally into the caudal pontine reticular formation (PnC), where the PPI mediating pathway converges with the primary startle pathway, and into the mPFC prior to behavioural testing. PnC microinjections had no effect on startle and PPI, whereas injections into the ventro-rostral part, but not into the dorso-caudal part of the mPFC, disrupted PPI. These effects could be mimicked by local injection of the NR2B subunit specific antagonist ifenprodil, whereas co-application of MK-801 and the mGluR2/3 agonist LY354740 had no effect on PPI. Moreover, PPI disruptions by systemically administered MK-801 could be reversed by local injections of LY354740 into the ventro-rostral mPFC, but not into the dorso-caudal mPFC. Our results indicate that NR2B subunit containing NMDARs in a specific subregion of the mPFC play a major role in PPI disruptions by systemic NMDAR antagonism. Our results further support the hypothesis that glutamate hyper-function in the mPFC is a main mechanism involved in sensory gating deficits induced by systemic MK-801, supporting the notion that this is an important mechanism in schizophrenia pathology.

Using an appetitive operant conditioning paradigm to screen rats for tinnitus induced by intense sound exposure: Experimental considerations and interpretation.

In an effort to help elucidate the neural mechanisms underlying tinnitus in humans, researchers have often relied on animal models; a preclinical approach which ultimately required that behavioral paradigms be designed to reliably screen animals for tinnitus. Previously, we developed a two-alternative forced-choice (2AFC) paradigm for rats that allowed for the simultaneous recording of neural activity at the very moments when they were reporting the presence/absence of tinnitus. Because we first validated our paradigm in rats experiencing transient tinnitus following a high-dose of sodium salicylate, the present study now sought to evaluate its utility to screen for tinnitus caused by intense sound exposure; a common tinnitus-inducer in humans. More specifically, through a series of experimental protocols, we aimed to (1) conduct sham experiments to ensure that the paradigm was able to correctly classify control rats as not having tinnitus, (2) confirm the time course over which the behavioral testing could reliably be performed post-exposure to assess chronic tinnitus, and (3) determine if the paradigm was sensitive to the variable outcomes often observed after intense sound exposure (e.g., hearing loss with our without tinnitus). Ultimately, in accordance with our predictions, the 2AFC paradigm was indeed resistant to false-positive screening of rats for intense sound-induced tinnitus, and it was able to reveal variable tinnitus and hearing loss profiles in individual rats following intense sound exposure. Taken together, the present study documents the utility of our appetitive operant conditioning paradigm to assess acute and chronic sound-induced tinnitus in rats. Finally, based on our findings, we discuss important experimental considerations that will help ensure that our paradigm is able to provide a suitable platform for future investigations into the neural basis of tinnitus.

The calyx of Held develops adult-like dynamics and reliability by hearing onset in the mouse in vivo.

The development of the auditory system has received increasing attention since the mechanisms of patterned, spontaneous activity in prehearing mammals were discovered. This early activity originates in the cochlea and is assumed to be of importance for the establishment and refinement of synaptic connections in the auditory system. In the present study we investigate synaptic transmission and its interplay with spontaneous discharges in the developing auditory system. We used the calyx of Held as a model system, where this question can be investigated in vivo over a broad range of ages [postnatal day 8 (P8)-P28]. To precisely quantify the timing and reliability of synaptic transmission, we developed a novel fitting approach which decomposes the extracellularly recorded signal into its presynaptic and postsynaptic components. In prehearing mice, we found signal transmission to be unreliable, with high variability in the transmission delay and in the amplitude of postsynaptic components. These timing and amplitude changes were strongly correlated with the preceding activity. Around hearing onset (P12-P14), the properties of signal transmission converged to the adult-like state which was characterized by high transmission reliability as well as high consistency in timing and amplitude. Although activity-dependent depression was still found in action potentials, EPSP depression no longer played a prominent role. In conclusion, the maturation of synaptic transmission at the calyx of Held seems to be precisely timed to achieve its adult potential by the time acoustically evoked signal processing commences.

Connected Hearing Devices and Audiologists: The User-Centered Development of Digital Service Innovations.

Today, medical technology manufacturers enter the service market through the development of digital service innovations. In the field of audiology, these developments increasingly shift the service capacities from audiologists to manufacturers and technical systems. However, the technology-driven developments of manufacturers lack acceptance of hearing device users and undermine the important role of audiologists within the service provision. By following a user-centered design approach in order to deal with the technological and social challenges of disruptive services, we aim to develop service innovations on an integrated service platform in the field of tele-audiology. To ensure the acceptance of technology-driven service innovations among hearing device users and audiologists, we systematically integrated these actors in a participatory innovation process. With qualitative and quantitative data we identified several requirements and preferences for different service innovations in the field of tele-audiology. According to the preferences of the different actors, we proposed a service platform approach based on a connected hearing device in three pillars of application: 1) one-to-one (1:1) service innovations based on a remote fitting concept directly improve the availability of services offered by audiologists without being physically present. Based on this, 2) one-to-many (1:N) service innovations allow the use of the connected hearing device as an indirect data source for training a machine learning algorithm that empowers users through the automation of service processes. A centralized server system collects the data and performs the training of this algorithm. The optimized algorithm is provided to the connected hearing devices to perform automatic acoustic scene classification. This in turn allows optimization of the hearing devices within each acoustic scene. After the user-centered development of the different service innovations which are designed to converge on an integrated service platform, we experimentally evaluated the functionality and applicability of the system as well as the associated role models between the technical system, the hearing device users and audiologists. As a future outlook, we show potentials to use the connected hearing device for 3) cross-industry (N:M) service innovations in contexts outside the healthcare domain and give practical implications for the market launch of successful service innovations in the field of tele-audiology.

Presynaptic and postsynaptic origin of multicomponent extracellular waveforms at the endbulb of Held-spherical bushy cell synapse.

Extracellular signals from the endbulb of Held-spherical bushy cell (SBC) synapse exhibit up to three component waves ('P', 'A' and 'B'). Signals lacking the third component (B) are frequently observed but as the origin of each of the components is uncertain, interpretation of this lack of B has been controversial: is it a failure to release transmitter or a failure to generate or propagate an action potential? Our aim was to determine the origin of each component. We combined single- and multiunit in vitro methods in Mongolian gerbils and Wistar rats and used pharmacological tools to modulate glutamate receptors or voltage-gated sodium channels. Simultaneous extra- and intracellular recordings from single SBCs demonstrated a presynaptic origin of the P-component, consistent with data obtained with multielectrode array recordings of local field potentials. The later components (A and B) correspond to the excitatory postsynaptic potential (EPSP) and action potential of the SBC, respectively. These results allow a clear interpretation of in vivo extracellular signals. We conclude that action potential failures occurring at the endbulb-SBC synaptic junction largely reflect failures of the EPSP to trigger an action potential and not failures of synaptic transmission. The data provide the basis for future investigation of convergence of excitatory and inhibitory inputs in modulating transmission at a fully functional neuronal system using physiological stimulation.

Crossmodal plasticity in auditory, visual and multisensory cortical areas following noise-induced hearing loss in adulthood.

Complete or partial hearing loss results in an increased responsiveness of neurons in the core auditory cortex of numerous species to visual and/or tactile stimuli (i.e., crossmodal plasticity). At present, however, it remains uncertain how adult-onset partial hearing loss affects higher-order cortical areas that normally integrate audiovisual information. To that end, extracellular electrophysiological recordings were performed under anesthesia in noise-exposed rats two weeks post-exposure (0.8-20 kHz at 120 dB SPL for 2 h) and age-matched controls to characterize the nature and extent of crossmodal plasticity in the dorsal auditory cortex (AuD), an area outside of the auditory core, as well as in the neighboring lateral extrastriate visual cortex (V2L), an area known to contribute to audiovisual processing. Computer-generated auditory (noise burst), visual (light flash) and combined audiovisual stimuli were delivered, and the associated spiking activity was used to determine the response profile of each neuron sampled (i.e., unisensory, subthreshold multisensory or bimodal). In both the AuD cortex and the multisensory zone of the V2L cortex, the maximum firing rates were unchanged following noise exposure, and there was a relative increase in the proportion of neurons responsive to visual stimuli, with a concomitant decrease in the number of neurons that were solely responsive to auditory stimuli despite adjusting the sound intensity to account for each rat's hearing threshold. These neighboring cortical areas differed, however, in how noise-induced hearing loss affected audiovisual processing; the total proportion of multisensory neurons significantly decreased in the V2L cortex (control 38.8 ± 3.3% vs. noise-exposed 27.1 ± 3.4%), and dramatically increased in the AuD cortex (control 23.9 ± 3.3% vs. noise-exposed 49.8 ± 6.1%). Thus, following noise exposure, the cortical area showing the greatest relative degree of multisensory convergence transitioned ventrally, away from the audiovisual area, V2L, toward the predominantly auditory area, AuD. Overall, the collective findings of the present study support the suggestion that crossmodal plasticity induced by adult-onset hearing impairment manifests in higher-order cortical areas as a transition in the functional border of the audiovisual cortex.

Audiovisual Temporal Processing and Synchrony Perception in the Rat.

Extensive research on humans has improved our understanding of how the brain integrates information from our different senses, and has begun to uncover the brain regions and large-scale neural activity that contributes to an observer's ability to perceive the relative timing of auditory and visual stimuli. In the present study, we developed the first behavioral tasks to assess the perception of audiovisual temporal synchrony in rats. Modeled after the parameters used in human studies, separate groups of rats were trained to perform: (1) a simultaneity judgment task in which they reported whether audiovisual stimuli at various stimulus onset asynchronies (SOAs) were presented simultaneously or not; and (2) a temporal order judgment task in which they reported whether they perceived the auditory or visual stimulus to have been presented first. Furthermore, using in vivo electrophysiological recordings in the lateral extrastriate visual (V2L) cortex of anesthetized rats, we performed the first investigation of how neurons in the rat multisensory cortex integrate audiovisual stimuli presented at different SOAs. As predicted, rats (n = 7) trained to perform the simultaneity judgment task could accurately (~80%) identify synchronous vs. asynchronous (200 ms SOA) trials. Moreover, the rats judged trials at 10 ms SOA to be synchronous, whereas the majority (~70%) of trials at 100 ms SOA were perceived to be asynchronous. During the temporal order judgment task, rats (n = 7) perceived the synchronous audiovisual stimuli to be "visual first" for ~52% of the trials, and calculation of the smallest timing interval between the auditory and visual stimuli that could be detected in each rat (i.e., the just noticeable difference (JND)) ranged from 77 ms to 122 ms. Neurons in the rat V2L cortex were sensitive to the timing of audiovisual stimuli, such that spiking activity was greatest during trials when the visual stimulus preceded the auditory by 20-40 ms. Ultimately, given that our behavioral and electrophysiological results were consistent with studies conducted on human participants and previous recordings made in multisensory brain regions of different species, we suggest that the rat represents an effective model for studying audiovisual temporal synchrony at both the neuronal and perceptual level.

Mice with deficient BK channel function show impaired prepulse inhibition and spatial learning, but normal working and spatial reference memory.

Genetic variations in the large-conductance, voltage- and calcium activated potassium channels (BK channels) have been recently implicated in mental retardation, autism and schizophrenia which all come along with severe cognitive impairments. In the present study we investigate the effects of functional BK channel deletion on cognition using a genetic mouse model with a knock-out of the gene for the pore forming α-subunit of the channel. We tested the F1 generation of a hybrid SV129/C57BL6 mouse line in which the slo1 gene was deleted in both parent strains. We first evaluated hearing and motor function to establish the suitability of this model for cognitive testing. Auditory brain stem responses to click stimuli showed no threshold differences between knockout mice and their wild-type littermates. Despite of muscular tremor, reduced grip force, and impaired gait, knockout mice exhibited normal locomotion. These findings allowed for testing of sensorimotor gating using the acoustic startle reflex, as well as of working memory, spatial learning and memory in the Y-maze and the Morris water maze, respectively. Prepulse inhibition on the first day of testing was normal, but the knockout mice did not improve over the days of testing as their wild-type littermates did. Spontaneous alternation in the y-maze was normal as well, suggesting that the BK channel knock-out does not impair working memory. In the Morris water maze knock-out mice showed significantly slower acquisition of the task, but normal memory once the task was learned. Thus, we propose a crucial role of the BK channels in learning, but not in memory storage or recollection.

Habituation of reflexive and motivated behavior in mice with deficient BK channel function.

Habituation is considered the most basic form of learning. It describes the decrease of a behavioral response to a repeated non-threatening sensory stimulus and therefore provides an important sensory filtering mechanism. While some neuronal pathways mediating habituation are well described, underlying cellular/molecular mechanisms are not yet fully understood. In general, there is an agreement that short-term and long-term habituation are based on different mechanisms. Historically, a distinction has also been made between habituation of motivated versus reflexive behavior. In recent studies in invertebrates the large conductance voltage- and calcium-activated potassium (BK) channel has been implicated to be a key player in habituation by regulating synaptic transmission. Here, we tested mice deficient for the pore forming α-subunit of the BK channel for short-term and long-term habituation of the acoustic startle reflex (reflexive behavior) and of the exploratory locomotor behavior in the open field box (motivated behavior). Short-term habituation of startle was completely abolished in the BK knock-out mice, whereas neither long-term habituation of startle nor habituation of motivated behavior was affected by the BK deficiency. Our results support a highly preserved mechanism for short-term habituation of startle across species that is distinct from long-term habituation mechanisms. It also supports the notion that there are different mechanisms underlying habituation of motivated behavior versus reflexive behavior.

Multidimensional characterization and differentiation of neurons in the anteroventral cochlear nucleus.

Multiple parallel auditory pathways ascend from the cochlear nucleus. It is generally accepted that the origin of these pathways are distinct groups of neurons differing in their anatomical and physiological properties. In extracellular in vivo recordings these neurons are typically classified on the basis of their peri-stimulus time histogram. In the present study we reconsider the question of classification of neurons in the anteroventral cochlear nucleus (AVCN) by taking a wider range of response properties into account. The study aims at a better understanding of the AVCN's functional organization and its significance as the source of different ascending auditory pathways. The analyses were based on 223 neurons recorded in the AVCN of the Mongolian gerbil. The range of analysed parameters encompassed spontaneous activity, frequency coding, sound level coding, as well as temporal coding. In order to categorize the unit sample without any presumptions as to the relevance of certain response parameters, hierarchical cluster analysis and additional principal component analysis were employed which both allow a classification on the basis of a multitude of parameters simultaneously. Even with the presently considered wider range of parameters, high number of neurons and more advanced analytical methods, no clear boundaries emerged which would separate the neurons based on their physiology. At the current resolution of the analysis, we therefore conclude that the AVCN units more likely constitute a multi-dimensional continuum with different physiological characteristics manifested at different poles. However, more complex stimuli could be useful to uncover physiological differences in future studies.

Levodopa and Parkinson disease--electrophysiological perspectives in animal models.

Chronic administration of levodopa, while producing an "awakening" in patients with Parkinson disease (PD), causes disabling side effects such as motor fluctuations and dyskinesia. Indeed the most common reason for deep brain stimulation (DBS) in patients with PD is for treating these complications. However, our understanding of the complexities of these complications is still in the early days. Animal models (primate and rodent) have been exceedingly helpful in elucidating some of the mechanisms. More work needs to be done. In the paper by Gilmour et al. (2011) the authors have investigated the neuronal firing properties and local field potentials of two basal ganglia structures, in response to chronic treatment, to tackle this very question. This commentary attempts to place the work in the context of PD animal models, electrophysiology and where we need to go.

Reliability of synaptic transmission at the synapses of Held in vivo under acoustic stimulation.

BACKGROUND: The giant synapses of Held play an important role in high-fidelity auditory processing and provide a model system for synaptic transmission at central synapses. Whether transmission of action potentials can fail at these synapses has been investigated in recent studies. At the endbulbs of Held in the anteroventral cochlear nucleus (AVCN) a consistent picture emerged, whereas at the calyx of Held in the medial nucleus of the trapezoid body (MNTB) results on the reliability of transmission remain inconsistent. In vivo this discrepancy could be due to the difficulty in identifying failures of transmission. METHODS/FINDINGS: We introduce a novel method for detecting unreliable transmission in vivo. Based on the temporal relationship between a cells' waveform and other potentials in the recordings, a statistical test is developed that provides a balanced decision between the presence and the absence of failures. Its performance is quantified using simulated voltage recordings and found to exhibit a high level of accuracy. The method was applied to extracellular recordings from the synapses of Held in vivo. At the calyces of Held failures of transmission were found only rarely. By contrast, at the endbulbs of Held in the AVCN failures were found under spontaneous, excited, and suppressed conditions. In accordance with previous studies, failures occurred most abundantly in the suppressed condition, suggesting a role for inhibition. CONCLUSIONS/SIGNIFICANCE: Under the investigated activity conditions/anesthesia, transmission seems to remain largely unimpeded in the MNTB, whereas in the AVCN the occurrence of failures is related to inhibition and could be the basis/result of computational mechanisms for temporal processing. More generally, our approach provides a formal tool for studying the reliability of transmission with high statistical accuracy under typical in vivo recording conditions.