Synchronization of inspiratory burst onset along the ventral respiratory column in the neonate mouse is mediated by electrotonic coupling.

Breathing is a singularly robust behavior, yet this motor pattern is continuously modulated at slow and fast timescales to maintain blood-gas homeostasis, while intercalating orofacial behaviors. This functional multiplexing goes beyond the rhythmogenic function that is typically ascribed to medullary respiration-modulated networks and may explain lack of progress in identifying the mechanism and constituents of the respiratory rhythm generator. By recording optically along the ventral respiratory column in medulla, we found convergent evidence that rhythmogenic function is distributed over a dispersed and heterogeneous network that is synchronized by electrotonic coupling across a neuronal syncytium. First, high-speed recordings revealed that inspiratory onset occurred synchronously along the column and did not emanate from a rhythmogenic core. Second, following synaptic isolation, synchronized stationary rhythmic activity was detected along the column. This activity was attenuated following gap junction blockade and was silenced by tetrodotoxin. The layering of syncytial and synaptic coupling complicates identification of rhythmogenic mechanism, while enabling functional multiplexing.

Temporal Alterations to Central Auditory Processing without Synaptopathy after Lifetime Exposure to Environmental Noise.

People are increasingly exposed to environmental noise through the cumulation of occupational and recreational activities, which is considered harmless to the auditory system, if the sound intensity remains <80 dB. However, recent evidence of noise-induced peripheral synaptic damage and central reorganizations in the auditory cortex, despite normal audiometry results, has cast doubt on the innocuousness of lifetime exposure to environmental noise. We addressed this issue by exposing adult rats to realistic and nontraumatic environmental noise, within the daily permissible noise exposure limit for humans (80 dB sound pressure level, 8 h/day) for between 3 and 18 months. We found that temporary hearing loss could be detected after 6 months of daily exposure, without leading to permanent hearing loss or to missing synaptic ribbons in cochlear hair cells. The degraded temporal representation of sounds in the auditory cortex after 18 months of exposure was very different from the effects observed after only 3 months of exposure, suggesting that modifications to the neural code continue throughout a lifetime of exposure to noise.

GABAA receptors contribute more to rate than temporal coding in the IC of awake mice.

Speech is our most important form of communication, yet we have a poor understanding of how communication sounds are processed by the brain. Mice make great model organisms to study neural processing of communication sounds because of their rich repertoire of social vocalizations and because they have brain structures analogous to humans, such as the auditory midbrain nucleus inferior colliculus (IC). Although the combined roles of GABAergic and glycinergic inhibition on vocalization selectivity in the IC have been studied to a limited degree, the discrete contributions of GABAergic inhibition have only rarely been examined. In this study, we examined how GABAergic inhibition contributes to shaping responses to pure tones as well as selectivity to complex sounds in the IC of awake mice. In our set of long-latency neurons, we found that GABAergic inhibition extends the evoked firing rate range of IC neurons by lowering the baseline firing rate but maintaining the highest probability of firing rate. GABAergic inhibition also prevented IC neurons from bursting in a spontaneous state. Finally, we found that although GABAergic inhibition shaped the spectrotemporal response to vocalizations in a nonlinear fashion, it did not affect the neural code needed to discriminate vocalizations, based either on spiking patterns or on firing rate. Overall, our results emphasize that even if GABAergic inhibition generally decreases the firing rate, it does so while maintaining or extending the abilities of neurons in the IC to code the wide variety of sounds that mammals are exposed to in their daily lives.NEW & NOTEWORTHY GABAergic inhibition adds nonlinearity to neuronal response curves. This increases the neuronal range of evoked firing rate by reducing baseline firing. GABAergic inhibition prevents bursting responses from neurons in a spontaneous state, reducing noise in the temporal coding of the neuron. This could result in improved signal transmission to the cortex.

Is the din really harmless? Long-term effects of non-traumatic noise on the adult auditory system.

People are increasingly being exposed to environmental noise from traffic, media and other sources that falls within and outside legal limits. Although such environmental noise is known to cause stress in the auditory system, it is still generally considered to be harmless. This complacency may be misplaced: even in the absence of cochlear damage, new findings suggest that environmental noise may progressively degrade hearing through alterations in the way sound is represented in the adult auditory cortex.

Temporal information in tones, broadband noise, and natural vocalizations is conveyed by differential spiking responses in the superior paraolivary nucleus.

Communication sounds across all mammals consist of multiple frequencies repeated in sequence. The onset and offset of vocalizations are potentially important cues for recognizing distinct units, such as phonemes and syllables, which are needed to perceive meaningful communication. The superior paraolivary nucleus (SPON) in the auditory brainstem has been implicated in the processing of rhythmic sounds. Here, we compared how best frequency tones (BFTs), broadband noise (BBN), and natural mouse calls elicit onset and offset spiking in the mouse SPON. The results demonstrate that onset spiking typically occurs in response to BBN, but not BFT stimulation, while spiking at the sound offset occurs for both stimulus types. This effect of stimulus bandwidth on spiking is consistent with two of the established inputs to the SPON from the octopus cells (onset spiking) and medial nucleus of the trapezoid body (offset spiking). Natural mouse calls elicit two main spiking peaks. The first spiking peak, which is weak or absent with BFT stimulation, occurs most consistently during the call envelope, while the second spiking peak occurs at the call offset. This suggests that the combined spiking activity in the SPON elicited by vocalizations reflects the entire envelope, that is, the coarse amplitude waveform. Since the output from the SPON is purely inhibitory, it is speculated that, at the level of the inferior colliculus, the broadly tuned first peak may improve the signal-to-noise ratio of the subsequent, more call frequency-specific peak. Thus, the SPON may provide a dual inhibition mechanism for tracking phonetic boundaries in social-vocal communication.

Segmented linear modeling of CHO fed-batch culture and its application to large scale production.

We describe a systematic approach to model CHO metabolism during biopharmaceutical production across a wide range of cell culture conditions. To this end, we applied the metabolic steady state concept. We analyzed and modeled the production rates of metabolites as a function of the specific growth rate. First, the total number of metabolic steady state phases and the location of the breakpoints were determined by recursive partitioning. For this, the smoothed derivative of the metabolic rates with respect to the growth rate were used followed by hierarchical clustering of the obtained partition. We then applied a piecewise regression to the metabolic rates with the previously determined number of phases. This allowed identifying the growth rates at which the cells underwent a metabolic shift. The resulting model with piecewise linear relationships between metabolic rates and the growth rate did well describe cellular metabolism in the fed-batch cultures. Using the model structure and parameter values from a small-scale cell culture (2 L) training dataset, it was possible to predict metabolic rates of new fed-batch cultures just using the experimental specific growth rates. Such prediction was successful both at the laboratory scale with 2 L bioreactors but also at the production scale of 2000 L. This type of modeling provides a flexible framework to set a solid foundation for metabolic flux analysis and mechanistic type of modeling. Biotechnol. Bioeng. 2017;114: 785-797. © 2016 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc.

A new and fast characterization of multiple encoding properties of auditory neurons.

The functional properties of auditory cortex neurons are most often investigated separately, through spectrotemporal receptive fields (STRFs) for the frequency tuning and the use of frequency sweeps sounds for selectivity to velocity and direction. In fact, auditory neurons are sensitive to a multidimensional space of acoustic parameters where spectral, temporal and spatial dimensions interact. We designed a multi-parameter stimulus, the random double sweep (RDS), composed of two uncorrelated random sweeps, which gives an easy, fast and simultaneous access to frequency tuning as well as frequency modulation sweep direction and velocity selectivity, frequency interactions and temporal properties of neurons. Reverse correlation techniques applied to recordings from the primary auditory cortex of guinea pigs and rats in response to RDS stimulation revealed the variety of temporal dynamics of acoustic patterns evoking an enhanced or suppressed firing rate. Group results on these two species revealed less frequent suppression areas in frequency tuning STRFs, the absence of downward sweep selectivity, and lower phase locking abilities in the auditory cortex of rats compared to guinea pigs.

Cortical inhibition reduces information redundancy at presentation of communication sounds in the primary auditory cortex.

In all sensory modalities, intracortical inhibition shapes the functional properties of cortical neurons but also influences the responses to natural stimuli. Studies performed in various species have revealed that auditory cortex neurons respond to conspecific vocalizations by temporal spike patterns displaying a high trial-to-trial reliability, which might result from precise timing between excitation and inhibition. Studying the guinea pig auditory cortex, we show that partial blockage of GABAA receptors by gabazine (GBZ) application (10 µm, a concentration that promotes expansion of cortical receptive fields) increased the evoked firing rate and the spike-timing reliability during presentation of communication sounds (conspecific and heterospecific vocalizations), whereas GABAB receptor antagonists [10 µm saclofen; 10-50 µm CGP55845 (p-3-aminopropyl-p-diethoxymethyl phosphoric acid)] had nonsignificant effects. Computing mutual information (MI) from the responses to vocalizations using either the evoked firing rate or the temporal spike patterns revealed that GBZ application increased the MI derived from the activity of single cortical site but did not change the MI derived from population activity. In addition, quantification of information redundancy showed that GBZ significantly increased redundancy at the population level. This result suggests that a potential role of intracortical inhibition is to reduce information redundancy during the processing of natural stimuli.

The preBötzinger complex as a hub for network activity along the ventral respiratory column in the neonate rat.

In vertebrates, respiratory control is ascribed to heterogeneous respiration-modulated neurons along the Ventral Respiratory Column (VRC) in medulla, which includes the preBötzinger Complex (preBötC), the putative respiratory rhythm generator. Here, the functional anatomy of the VRC was characterized via optical recordings in the sagittaly sectioned neonate rat hindbrain, at sampling rates permitting coupling estimation between neuron pairs, so that each neuron was described using unitary, neuron-system, and coupling attributes. Structured coupling relations in local networks, significantly oriented coupling in the peri-inspiratory interval detected in pooled data, and significant correlations between firing rate and expiratory duration in subsets of neurons revealed network regulation at multiple timescales. Spatially averaged neuronal attributes, including coupling vectors, revealed a sharp boundary at the rostral margin of the preBötC, as well as other functional anatomical features congruent with identified structures, including the parafacial respiratory group and the nucleus ambiguus. Cluster analysis of attributes identified two spatially compact, homogenous groups: the first overlapped with the preBötC, and was characterized by strong respiratory modulation and dense bidirectional coupling with itself and other groups, consistent with a central role for the preBötC in respiratory control; the second lay between preBötC and the facial nucleus, and was characterized by weak respiratory modulation and weak coupling with other respiratory neurons, which is congruent with cardiovascular regulatory networks that are found in this region. Other groups identified using cluster analysis suggested that networks along VRC regulated expiratory duration, and the transition to and from inspiration, but these groups were heterogeneous and anatomically dispersed. Thus, by recording local networks in parallel, this study found evidence for respiratory regulation at multiple timescales along the VRC, as well as a role for the preBötC in the integration of functionally disparate respiratory neurons.

Component analysis reveals sharp tuning of the local field potential in the guinea pig auditory cortex.

Local field potentials (LFPs) recorded in the auditory cortex of mammals are known to reveal weakly selective and often multimodal spectrotemporal receptive fields in contrast to spiking activity. This may in part reflect the wider "listening sphere" of LFPs relative to spikes due to the greater current spread at low than high frequencies. We recorded LFPs and spikes from auditory cortex of guinea pigs using 16-channel electrode arrays. LFPs were processed by a component analysis technique that produces optimally tuned linear combinations of electrode signals. Linear combinations of LFPs were found to have sharply tuned responses, closer to spike-related tuning. The existence of a sharply tuned component implies that a cortical neuron (or group of neurons) capable of forming a linear combination of its inputs has access to that information. Linear combinations of signals from electrode arrays reveal information latent in the subspace spanned by multichannel LFP recordings and are justified by the fact that the observations themselves are linear combinations of neural sources.

Detecting Central Auditory Processing Disorders in Awake Mice.

Mice are increasingly used as models of human-acquired neurological or neurodevelopmental conditions, such as autism, schizophrenia, and Alzheimer's disease. All these conditions involve central auditory processing disorders, which have been little investigated despite their potential for providing interesting insights into the mechanisms behind such disorders. Alterations of the auditory steady-state response to 40 Hz click trains are associated with an imbalance between neuronal excitation and inhibition, a mechanism thought to be common to many neurological disorders. Here, we demonstrate the value of presenting click trains at various rates to mice with chronically implanted pins above the inferior colliculus and the auditory cortex for obtaining easy, reliable, and long-lasting access to subcortical and cortical complex auditory processing in awake mice. Using this protocol on a mutant mouse model of autism with a defect of the Shank3 gene, we show that the neural response is impaired at high click rates (above 60 Hz) and that this impairment is visible subcortically-two results that cannot be obtained with classical protocols for cortical EEG recordings in response to stimulation at 40 Hz. These results demonstrate the value and necessity of a more complete investigation of central auditory processing disorders in mouse models of neurological or neurodevelopmental disorders.

The impact of early reflections on binaural cues.

Animals live in cluttered auditory environments, where sounds arrive at the two ears through several paths. Reflections make sound localization difficult, and it is thought that the auditory system deals with this issue by isolating the first wavefront and suppressing later signals. However, in many situations, reflections arrive too early to be suppressed, for example, reflections from the ground in small animals. This paper examines the implications of these early reflections on binaural cues to sound localization, using realistic models of reflecting surfaces and a spherical model of diffraction by the head. The fusion of direct and reflected signals at each ear results in interference patterns in binaural cues as a function of frequency. These cues are maximally modified at frequencies related to the delay between direct and reflected signals, and therefore to the spatial location of the sound source. Thus, natural binaural cues differ from anechoic cues. In particular, the range of interaural time differences is substantially larger than in anechoic environments. Reflections may potentially contribute binaural cues to distance and polar angle when the properties of the reflecting surface are known and stable, for example, for reflections on the ground.

Characterizing subcutaneous cortical auditory evoked potentials in mice.

Auditory Brainstem Responses (ABRs) are a reliably robust measure of auditory thresholds in the mammalian hearing system and can be used to determine deficits in the auditory periphery. However, because these measures are limited to the lower stages of the auditory pathway, they are insensitive to changes or deficits that occur in the thalamic and cortical regions. Cortical Auditory Evoked Potentials (CAEPs), as longer latency responses, capture information from these regions. However they are less frequently used as a diagnostic tool, particularly in rodent models, due to their inherent variability and subsequent difficult interpretation. The purpose of this study was to develop a consistent measure of subcutaneous CAEPs to auditory stimuli in mice and to determine their origin. To this end, we investigated the effect on the CAEPs recorded in response to different stimuli (noise, click, and tone (16 kHz) bursts), stimulus presentation rates (2/s, 6/s, 10/s) and electrode placements. Recordings were examined for robust CAEP components to determine the optimal experimental paradigm. We argue that CAEPs can measure robust and replicable cortical responses. Furthermore, by deactivating the auditory cortex with lidocaine we demonstrated that the contralateral cortex is the main contributor to the CAEP. Thus CAEP measurements could prove to be of value diagnostically in future for deficits in higher auditory areas.

Age-related changes in the guinea pig auditory cortex: relationship with brainstem changes and comparison with tone-induced hearing loss.

Elderly people often show degraded hearing performance and have difficulties in understanding speech, particularly in noisy environments. Although loss in peripheral hearing sensitivity is an important factor in explaining these low performances, central alterations also have an impact but their exact contributions remained unclear. In this study, we focus on the functional effects of aging on auditory cortex responses. Neuronal discharges and local field potentials were recorded in the auditory cortex of aged guinea pigs (> 3 years), and several parameters characterizing the processing of auditory information were quantified: the acoustic thresholds, response strength, latency and duration of the response, and breadth of tuning. Several of these parameters were also quantified from auditory brainstem responses collected from the same animals, and recordings obtained from a population of animals with trauma-induced hearing loss were also included in this study. The results showed that aging and acoustic trauma reduced the response strength at both brainstem and cortical levels, and increased the response latencies more at the cortical level than at the brainstem level. In addition to the brainstem hearing loss, aging induced a 'cortical hearing loss' as judged by additive changes in the threshold and frequency response seen in the cortex. It also increased the duration of neural responses and reduced the receptive field bandwidth, effects that were not found in traumatized animals. These effects substantiate the notion that presbycusis involves both peripheral hearing loss and biological aging in the central auditory system.

Directional coupling from the olfactory bulb to the hippocampus during a go/no-go odor discrimination task.

The hippocampus and olfactory regions are anatomically close, and both play a major role in memory formation. However, the way they interact during odor processing is still unclear. In both areas, strong oscillations of the local field potential (LFP) can be recorded, and are modulated by behavior. In particular, in the olfactory system, the beta rhythm (15-35 Hz) is associated with cognitive processing of an olfactory stimulus. Using LFP recordings in the olfactory bulb and dorsal and ventral hippocampus during performance of an olfactory go/no-go task in rats, we previously showed that beta oscillations are also present in the hippocampus, coherent with those in the olfactory bulb, during odor sampling. In this study, we provide further insight into information transfer in the olfacto-hippocampal network by using directional coherence (DCOH estimate), a method based on the temporal relation between two or more signals in the frequency domain. In the theta band (6-12 Hz), coherence between the olfactory bulb (OB) and the hippocampus (HPC) is weak and can be both in the feedback and feedforward directions. However, at this frequency, modulation of the coupling between the dorsal and ventral hippocampus is seen during stimulus expectation versus odor processing. In the beta frequency band (15-35 Hz), analysis showed a strong unidirectional coupling from the OB to dorsal and ventral HPC, indicating that, during odor processing, beta oscillations in the hippocampus are driven by the olfactory bulb.

Maximum decoding abilities of temporal patterns and synchronized firings: application to auditory neurons responding to click trains and amplitude modulated white noise.

Simultaneous recordings of an increasing number of neurons have recently become available, but few methods have been proposed to handle this activity. Here, we extract and investigate all the possible temporal neural activity patterns based on synchronized firings of neurons recorded on multiple electrodes, or based on bursts of single-electrode activity in cat primary auditory cortex. We apply this to responses to periodic click trains or sinusoïdal amplitude modulated noise by obtaining for each pattern its temporal modulation transfer function. An algorithm that maximizes the mutual information between all patterns and stimuli subsequently leads to the identification of patterns that optimally decode modulation frequency (MF). We show that stimulus information contained in multi-electrode synchronized firing is not redundant with single-electrode firings and leads to improved efficiency of MF decoding. We also show that the combined use of firing rate and temporal codes leads to a better discrimination of the MF.

Spectrotemporal receptive fields in anesthetized cat primary auditory cortex are context dependent.

In order to investigate how the auditory scene is analyzed and perceived, auditory spectrotemporal receptive fields (STRFs) are generally used as a convenient way to describe how frequency and temporal sound information is encoded. However, using broadband sounds to estimate STRFs imperfectly reflects the way neurons process complex stimuli like conspecific vocalizations insofar as natural sounds often show limited bandwidth. Using recordings in the primary auditory cortex of anesthetized cats, we show that presentation of narrowband stimuli not including the best frequency of neurons provokes the appearance of residual peaks and increased firing rate at some specific spectral edges of stimuli compared with classical STRFs obtained from broadband stimuli. This result is the same for STRFs obtained from both spikes and local field potentials. Potential mechanisms likely involve release from inhibition. We thus emphasize some aspects of context dependency of STRFs, that is, how the balance of inhibitory and excitatory inputs is able to shape the neural response from the spectral content of stimuli.

Spectrally enhanced acoustic environment disrupts frequency representation in cat auditory cortex.

Sensory environments are known to shape nervous system organization. Here we show that passive long-term exposure to a spectrally enhanced acoustic environment (EAE) causes reorganization of the tonotopic map in juvenile cat auditory cortex without inducing any hearing loss. The EAE consisted of tone pips of 32 different frequencies (5-20 kHz), presented in random order at an average rate of 96 Hz. The EAE caused a strong reduction of the representation of EAE frequencies and an over-representation of frequencies neighboring those of the EAE. This is in sharp contrast with earlier developmental studies showing an enlargement of the cortical representation of EAEs consisting of a narrow frequency band. We observed fewer than normal appropriately tuned short-latency responses to EAE frequencies, together with more common long-latency responses tuned to EAE-neighboring frequencies.

Oscillations in the auditory system and their possible role.

GOURÉVITCH, B., C. Martin, O. Postal, J.J. Eggermont. Oscillations in the auditory system, their possible role. NEUROSCI BIOBEHAV REV XXX XXX-XXX, 2020. - Neural oscillations are thought to have various roles in brain processing such as, attention modulation, neuronal communication, motor coordination, memory consolidation, decision-making, or feature binding. The role of oscillations in the auditory system is less clear, especially due to the large discrepancy between human and animal studies. Here we describe many methodological issues that confound the results of oscillation studies in the auditory field. Moreover, we discuss the relationship between neural entrainment and oscillations that remains unclear. Finally, we aim to identify which kind of oscillations could be specific or salient to the auditory areas and their processing. We suggest that the role of oscillations might dramatically differ between the primary auditory cortex and the more associative auditory areas. Despite the moderate presence of intrinsic low frequency oscillations in the primary auditory cortex, rhythmic components in the input seem crucial for auditory processing. This allows the phase entrainment between the oscillatory phase and rhythmic input, which is an integral part of stimulus selection within the auditory system.