Differences in auditory temporal processing in the left and right auditory cortices of the rat.

In the present study, we examined hemispheric differences in the representation and processing of temporally structured auditory stimuli. Neuronal responses evoked by sinusoidally frequency modulated (FM) tones, frequency sweeps, amplitude modulated (AM) tones and noise, click trains with constant inter-click intervals and natural vocalizations were recorded from the left (LAC) and right (RAC) auditory cortices in adult (4-6 months old) anaesthetized F344 rats. Using vector strength, modulation-transfer functions, van Rossum distances, or direction-selectivity index, representation and processing of structured auditory stimuli were compared in the LAC and the RAC. The RAC generally tended to exhibit a higher ability to synchronize with the stimulus, a higher reproducibility of responses, and a higher proportion of direction-selective units. The LAC, on the other hand, mostly had higher relative response magnitudes in the modulation transfer functions. Importantly, the hemispheric differences were dependent on the type of the stimulus and there was also a significant inter-individual variability. Our findings indicate that neural coding in the RAC is based more on timing of action potentials (temporal code), while the LAC uses more the response magnitudes (rate code). It is thus necessary to distinguish between the type of the neural code and the stimulus feature it encodes and reconsider the simple opinion about dominance of the LAC for temporal processing, as it may not hold in general for all types of temporally structured stimuli.

ISL1 is necessary for auditory neuron development and contributes toward tonotopic organization.

A cardinal feature of the auditory pathway is frequency selectivity, represented in a tonotopic map from the cochlea to the cortex. The molecular determinants of the auditory frequency map are unknown. Here, we discovered that the transcription factor ISL1 regulates the molecular and cellular features of auditory neurons, including the formation of the spiral ganglion and peripheral and central processes that shape the tonotopic representation of the auditory map. We selectively knocked out Isl1 in auditory neurons using Neurod1Cre strategies. In the absence of Isl1, spiral ganglion neurons migrate into the central cochlea and beyond, and the cochlear wiring is profoundly reduced and disrupted. The central axons of Isl1 mutants lose their topographic projections and segregation at the cochlear nucleus. Transcriptome analysis of spiral ganglion neurons shows that Isl1 regulates neurogenesis, axonogenesis, migration, neurotransmission-related machinery, and synaptic communication patterns. We show that peripheral disorganization in the cochlea affects the physiological properties of hearing in the midbrain and auditory behavior. Surprisingly, auditory processing features are preserved despite the significant hearing impairment, revealing central auditory pathway resilience and plasticity in Isl1 mutant mice. Mutant mice have a reduced acoustic startle reflex, altered prepulse inhibition, and characteristics of compensatory neural hyperactivity centrally. Our findings show that ISL1 is one of the obligatory factors required to sculpt auditory structural and functional tonotopic maps. Still, upon Isl1 deletion, the ensuing central plasticity of the auditory pathway does not suffice to overcome developmentally induced peripheral dysfunction of the cochlea.

The influence of developmental noise exposure on the temporal processing of acoustical signals in the auditory cortex of rats.

Previous experiments have acknowledged that inappropriate or missing auditory inputs during the critical period of development cause permanent changes of the structure and function of the auditory system (Bures et al., 2017). We explore in this study how developmental noise exposure influences the coding of temporally structured stimuli in the neurons of the primary auditory cortex (AC) in Long Evans rats. The animals were exposed on postnatal day 14 (P14) for 12 minutes to a loud (125 dB SPL) broad-band noise. The responses to an amplitude-modulated (AM) noise, frequency-modulated (FM) tones, and click trains, were recorded from the right AC of rats of two age groups: young-adult (ca. 6 months old) and adult (ca. 2 years old), both in the exposed animals and in control unexposed rats. The neonatal exposure resulted in a higher synchronization ability (phase-locking) of the AC neurons for all three stimuli; furthermore, the similarity of neuronal response patterns to repetitive stimulation was higher in the exposed rats. On the other hand, the exposed animals showed a steeper decline of modulation-transfer functions towards higher modulation frequencies/repetition rates. Differences between the two age groups were also apparent; in general, aging had qualitatively the same effect as the developmental exposure. The current results demonstrate that brief noise exposure during the maturation of the auditory system influences both the temporal and the rate coding of periodically modulated sounds in the AC of rats; the changes are permanent and observable up to late adulthood.

Acoustically Enriched Environment during the Critical Period of Postnatal Development Positively Modulates Gap Detection and Frequency Discrimination Abilities in Adult Rats.

Throughout life, sensory systems adapt to the sensory environment to provide optimal responses to relevant tasks. In the case of a developing system, sensory inputs induce changes that are permanent and detectable up to adulthood. Previously, we have shown that rearing rat pups in a complex acoustic environment (spectrally and temporally modulated sound) from postnatal day 14 (P14) to P28 permanently improves the response characteristics of neurons in the inferior colliculus and auditory cortex, influencing tonotopical arrangement, response thresholds and strength, and frequency selectivity, along with stochasticity and the reproducibility of neuronal spiking patterns. In this study, we used a set of behavioral tests based on a recording of the acoustic startle response (ASR) and its prepulse inhibition (PPI), with the aim to extend the evidence of the persistent beneficial effects of the developmental acoustical enrichment. The enriched animals were generally not more sensitive to startling sounds, and also, their PPI of ASR, induced by noise or pure tone pulses, was comparable to the controls. They did, however, exhibit a more pronounced PPI when the prepulse stimulus was represented either by a change in the frequency of a background tone or by a silent gap in background noise. The differences in the PPI of ASR between the enriched and control animals were significant at lower (55 dB SPL), but not at higher (65-75 dB SPL), intensities of background sound. Thus, rearing pups in the acoustically enriched environment led to an improvement of the frequency resolution and gap detection ability under more difficult testing conditions, i.e., with a worsened stimulus clarity. We confirmed, using behavioral tests, that an acoustically enriched environment during the critical period of development influences the frequency and temporal processing in the auditory system, and these changes persist until adulthood.

Age-related changes in the temporal processing of acoustical signals in the auditory cortex of rats.

Age-related hearing loss is manifested primarily by a decreased sensitivity to faint sounds, that is, by elevation of the hearing thresholds. Nevertheless, aging also affects the ability of the auditory system to process temporal parameters of the sound stimulus. To explore the precision and reliability of auditory temporal processing during aging, responses to several types of sound stimuli were recorded from neurons of the auditory cortex (AC) of young and aged anaesthetized Fischer 344 rats. In response to broad-band noise bursts, the aged rats exhibited larger response magnitudes, a higher proportion of monotonic units, and also a larger variability of response magnitudes, suggesting a lower stability of the rate code. Of primary interest were the responses to temporally structured stimuli (amplitude-modulated (AM) noise, frequency-modulated (FM) tones, and click trains) recorded separately in the right and left AC. Significant differences of temporal processing were already found between the neuronal responses in the left and right AC in the young animals: for the click trains, the left hemisphere exhibited a greater responsiveness to higher repetition rates, lower vector strength values, and a lower similarity of responses. The two hemispheres were also affected differently by aging. In the right hemisphere, neurons in the aged animals displayed worse synchronization with the AM noise and clicks, but better synchronization with the FM tone. In the left hemisphere, neuronal synchronization with the stimulus modulation improved at a higher age for all three stimuli. The results show that the ability of the aging auditory system to process temporal parameters of the stimulus strongly depends on the stimulus type and on laterality. Furthermore, the commonly reported age-related decline in the temporal processing ability cannot be regarded as general as, at least at the neuronal level in the AC, objective measures of the temporal representation often exhibit age-related improvement instead of deterioration.

Neurod1 Is Essential for the Primary Tonotopic Organization and Related Auditory Information Processing in the Midbrain.

Hearing depends on extracting frequency, intensity, and temporal properties from sound to generate an auditory map for acoustical signal processing. How physiology intersects with molecular specification to fine tune the developing properties of the auditory system that enable these aspects remains unclear. We made a novel conditional deletion model that eliminates the transcription factor NEUROD1 exclusively in the ear. These mice (both sexes) develop a truncated frequency range with no neuroanatomically recognizable mapping of spiral ganglion neurons onto distinct locations in the cochlea nor a cochleotopic map presenting topographically discrete projections to the cochlear nuclei. The disorganized primary cochleotopic map alters tuning properties of the inferior colliculus units, which display abnormal frequency, intensity, and temporal sound coding. At the behavioral level, animals show alterations in the acoustic startle response, consistent with altered neuroanatomical and physiological properties. We demonstrate that absence of the primary afferent topology during embryonic development leads to dysfunctional tonotopy of the auditory system. Such effects have never been investigated in other sensory systems because of the lack of comparable single gene mutation models.SIGNIFICANCE STATEMENT All sensory systems form a topographical map of neuronal projections from peripheral sensory organs to the brain. Neuronal projections in the auditory pathway are cochleotopically organized, providing a tonotopic map of sound frequencies. Primary sensory maps typically arise by molecular cues, requiring physiological refinements. Past work has demonstrated physiologic plasticity in many senses without ever molecularly undoing the specific mapping of an entire primary sensory projection. We genetically manipulated primary auditory neurons to generate a scrambled cochleotopic projection. Eliminating tonotopic representation to auditory nuclei demonstrates the inability of physiological processes to restore a tonotopic presentation of sound in the midbrain. Our data provide the first insights into the limits of physiology-mediated brainstem plasticity during the development of the auditory system.

Acoustical Enrichment during Early Development Improves Response Reliability in the Adult Auditory Cortex of the Rat.

It is well known that auditory experience during early development shapes response properties of auditory cortex (AC) neurons, influencing, for example, tonotopical arrangement, response thresholds and strength, or frequency selectivity. Here, we show that rearing rat pups in a complex acoustically enriched environment leads to an increased reliability of responses of AC neurons, affecting both the rate and the temporal codes. For a repetitive stimulus, the neurons exhibit a lower spike count variance, indicating a more stable rate coding. At the level of individual spikes, the discharge patterns of individual neurons show a higher degree of similarity across stimulus repetitions. Furthermore, the neurons follow more precisely the temporal course of the stimulus, as manifested by improved phase-locking to temporally modulated sounds. The changes are persistent and present up to adulthood. The results document that besides basic alterations of receptive fields presented in our previous study, the acoustic environment during the critical period of postnatal development also leads to a decreased stochasticity and a higher reproducibility of neuronal spiking patterns.

The Effect of Complex Acoustic Environment during Early Development on the Responses of Auditory Cortex Neurons in Rats.

Acoustical environment plays an important role during the maturation of the auditory system. It has been shown that the sensory inputs to the developing centres influence the development of the structure of projections, neuronal responsiveness, excitatory-inhibitory balance, or tonotopical arrangement, throughout the auditory pathway. Our previous study (Bures et al., 2014) showed that rats reared in a complex acoustic environment (spectrally and temporally modulated sound reinforced by an active behavioural paradigm with a positive feedback) exhibit permanently improved response characteristics of the inferior colliculus (IC) neurons. Extending these results, the current work provides evidence that the changes occur also at the level of auditory cortex (AC). In particular, the enriched animals have lower excitatory thresholds, sharper frequency selectivity, and a lower proportion of non-monotonic rate-intensity functions. In contrast to the changes observed in the IC, the cortical neurons of enriched animals have lower response magnitudes. In addition, the enrichment changed the AC responsiveness to frequency-modulated and also to a lesser extent, amplitude-modulated stimuli. Significantly, the alterations span the entire hearing range and may be regarded as general and not directly linked to the characteristics of the acoustical stimulation. Furthermore, these developmentally induced changes are permanent and detectable in adulthood. The findings indicate that an acoustically enriched environment during the critical period of postnatal development influences basic properties of neuronal receptive fields in the AC, which may have implications for the ability to detect and discriminate sounds.

Cooling of the auditory cortex modifies neuronal activity in the inferior colliculus in rats.

There are powerful pathways descending from the auditory cortex (AC) to the inferior colliculus (IC), yet their function is not fully understood. The aim of this study is to examine the effects of a reversible cortical inactivation, achieved by cooling of the AC, on the responses of neurons in the rat IC. Extracellular single-unit or multi-unit activity was recorded in the IC of anaesthetized rats with a 16-channel multielectrode probe introduced along the IC dorso-ventral axis through the dorsal cortex (DCIC) to the central nucleus of the IC (CIC). Cooling of the AC produced an increase in spontaneous activity and magnitude of the sound-evoked response in 47% of the IC neurons. Maximal changes in the neuronal activity were observed in the DCIC and the central part of the CIC. The final segments of the sustained responses to 60 ms stimuli and the off responses were more affected than the onset segments. Inactivation of the AC resulted in a suppression of the post-excitatory inhibition and neuronal adaptation, which was reflected in a pronounced enhancement of synchronized responses to a series of fast repeated clicks. The response parameters recovered, at least partly, to the pre-cooling levels 1 h after the cooling cessation. The frequency tuning properties of the IC neurons did not show any significant changes during the cooling period. The results demonstrate that AC cooling inactivates excitatory corticofugal pathways and results in a less activated intrinsic inhibitory network in the IC.

Differential distribution of glycine receptor subtypes at the rat calyx of Held synapse.

The properties of glycine receptors (GlyRs) depend upon their subunit composition. While the prevalent adult forms of GlyRs are heteromers, previous reports suggested functional α homomeric receptors in mature nervous tissues. Here we show two functionally different GlyRs populations in the rat medial nucleus of trapezoid body (MNTB). Postsynaptic receptors formed α1/ß-containing clusters on somatodendritic domains of MNTB principal neurons, colocalizing with glycinergic nerve endings to mediate fast, phasic IPSCs. In contrast, presynaptic receptors on glutamatergic calyx of Held terminals were composed of dispersed, homomeric α1 receptors. Interestingly, the parent cell bodies of the calyces of Held, the globular bushy cells of the cochlear nucleus, expressed somatodendritic receptors (α1/ß heteromers) and showed similar clustering and pharmacological profile as GlyRs on MNTB principal cells. These results suggest that specific targeting of GlyR ß-subunit produces segregation of GlyR subtypes involved in two different mechanisms of modulation of synaptic strength.