Bidirectional remodeling of the central auditory system caused by unilateral auditory deprivation.

Unilateral auditory deprivation (UAD) results in cross-modal reorganization of the auditory cortex (AC), which can impair auditory and cognitive functions and diminish the recovery effect of cochlear implantation. Moreover, the subcortical areas provide extensive ascending projections to the AC. To date, a thorough systematic study of subcortical auditory neural plasticity has not been undertaken. Therefore, this review aims to summarize the current evidence on the bidirectional remodeling of the central auditory system caused by UAD, particularly the changes in subcortical neural plasticity. Lateral changes occur in the cochlear nucleus, lateral superior olive, medial nucleus of the trapezoid body, inferior colliculus, and AC of individuals with UAD. Moreover, asymmetric neural activity becomes less prominent in the higher auditory nuclei, which may be due to cross-projection regulation of the bilateral pathway. As a result, subcortical auditory neural plasticity caused by UAD may contribute to the outcomes of cochlear implantation in patients with single-sided deafness (SSD), and the development of intervention strategies for patients with SSD is crucial. Considering that previous studies have focused predominantly on the neural plasticity of the AC, we believe that bidirectional remodeling of subcortical areas after UAD is also crucial for investigating the mechanisms of interventions.

Reduced white matter maturation in the central auditory system of children living with HIV.

Introduction: School-aged children experience crucial developmental changes in white matter (WM) in adolescence. The human immunodeficiency virus (HIV) affects neurodevelopment. Children living with perinatally acquired HIV (CPHIVs) demonstrate hearing and neurocognitive impairments when compared to their uninfected peers (CHUUs), but investigations into the central auditory system (CAS) WM integrity are lacking. The integration of the CAS and other brain areas is facilitated by WM fibers whose integrity may be affected in the presence of HIV, contributing to neurocognitive impairments. Methods: We used diffusion tensor imaging (DTI) tractography to map the microstructural integrity of WM between CAS regions, including the lateral lemniscus and acoustic radiation, as well as between CAS regions and non-auditory regions of 11-year-old CPHIVs. We further employed a DTI-based graph theoretical framework to investigate the nodal strength and efficiency of the CAS and other brain regions in the structural brain network of the same population. Finally, we investigated associations between WM microstructural integrity outcomes and neurocognitive outcomes related to auditory and language processing. We hypothesized that compared to the CHUU group, the CPHIV group would have lower microstructural in the CAS and related regions. Results: Our analyses showed higher mean diffusivity (MD), a marker of axonal maturation, in the lateral lemniscus and acoustic radiations, as well as WM between the CAS and non-auditory regions predominantly in frontotemporal areas. Most affected WM connections also showed higher axial and radial diffusivity (AD and RD, respectively). There were no differences in the nodal properties of the CAS regions between groups. The MD of frontotemporal and subcortical WM-connected CAS regions, including the inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and internal capsule showed negative associations with sequential processing in the CPHIV group but not in the CHUU group. Discussion: The current results point to reduced axonal maturation in WM, marked by higher MD, AD, and RD, within and from the CAS. Furthermore, alterations in WM integrity were associated with sequential processing, a neurocognitive marker of auditory working memory. Our results provide insights into the microstructural integrity of the CAS and related WM in the presence of HIV and link these alterations to auditory working memory.

Cochlear synaptopathy impairs suprathreshold tone-in-noise coding in the cochlear nucleus.

Hearing impairment without threshold elevations can occur when there is damage to high-threshold auditory nerve fibre synapses with cochlear inner hair cells. Instead, cochlear synaptopathy produces suprathreshold deficits, especially in older patients, which affect conversational speech. Given that listening in noise at suprathreshold levels presents significant challenges to the ageing population, we examined the effects of synaptopathy on tone-in-noise coding on the central recipients of auditory nerve fibres, i.e. the cochlear nucleus neurons. To induce synaptopathy, guinea pigs received a unilateral sound overexposure to the left ears. A separate group received sham exposures. At 4 weeks post-exposure, thresholds had recovered but reduced auditory brainstem response wave 1 amplitudes and auditory nerve synapse loss remained on the left side. Single-unit responses were recorded from several cell types in the ventral cochlear nucleus to pure-tone and noise stimuli. Receptive fields and rate-level functions in the presence of continuous broadband noise were examined. The synaptopathy-inducing noise exposure did not affect mean unit tone-in-noise thresholds, nor the tone-in-noise thresholds in each animal, demonstrating equivalent tone-in-noise detection thresholds to sham animals. However, synaptopathy reduced single-unit responses to suprathreshold tones in the presence of background noise, particularly in the cochlear nucleus small cells. These data demonstrate that suprathreshold tone-in-noise deficits following cochlear synaptopathy are evident in the first neural station of the auditory brain, the cochlear nucleus neurons, and provide a potential target for assessment and treatment of listening-in-noise deficits in humans. KEY POINTS: Recording from multiple central auditory neurons can determine tone-in-noise deficits in animals with quantified cochlear synapse damage. Using this technique, we found that tone-in-noise thresholds are not altered by cochlear synaptopathy, whereas coding of suprathreshold tones-in-noise is disrupted. Suprathreshold deficits occur in small cells and primary-like neurons of the cochlear nucleus. These data provide important insights into the mechanisms underlying difficulties associated with hearing in noisy environments.

Effect of minocycline and its nano-formulation on central auditory system in blast-induced hearing loss rat model.

Blast injuries are common among the military service members and veterans. One of the devastating effects of blast wave induced TBI is either temporary or permanent hearing loss. Treating hearing loss using minocycline is restricted by optimal drug concentration, route of administration, and its half-life. Therefore, therapeutic approach using novel therapeutic delivery method is in great need. Among the different delivery methods, nanotechnology-based drug delivery is desirable, which can achieve longer systemic circulation, pass through some biological barriers and specifically targets desired sites. The current study aimed to examine therapeutic effect of minocycline and its nanoparticle formulation in moderate blast induced hearing loss rat model through central auditory system. The I.v. administered nanoparticle at reduced dose and frequency than regularly administered toxic dose. After moderate blast exposure, rats had hearing impairment as determined by ABR at 7- and 30-days post exposure. In chronic condition, free minocycline also showed the significant reduction in ABR threshold. In central auditory system, it is found in this study that minocycline nanoparticles ameliorate excitation in inferior colliculus; and astrocytes and microglia activation after the blast exposure is reduced by minocycline nanoparticles administration. The study demonstrated that in moderate blast induced hearing loss, minocycline and its nanoparticle formulation exhibited the optimal therapeutic effect on the recovery of the ABR impairment and a protective effect through central auditory system. In conclusion, targeted and non-targeted nanoparticle formulation have therapeutic effect on blast induced hearing loss.

Invoking the influence of emotion in central auditory processing to improve the treatment of speech impairments.

OBJECTIVES: To explore the benefits of invoking unconscious sentiment to improve the treatment of stuttering and misarticulation. METHODS: This cross-sectional study of 80 participants with speech issues (44 patients with misarticulation and 36 with stuttering) who underwent comprehensive speech and hearing evaluations to confirm and diagnose speech difficulties. Speech and language pathologists then calculated either the percentage of correctly pronounce sounds in misarticulation cases or stuttering severity index-4 scores in cases of stuttering following the use of therapeutic stimuli recorded with familiar and non-familiar voices of similar linguistic and phonetic complexity. Descriptive and inferential statistics were used to compare the data collected following the use of familiar and unfamiliar stimuli. RESULTS: The analysis showed that the number of dysfluencies in cases of stuttering were significantly fewer when employing familiar voices than unfamiliar voices (3% errors vs 12% errors; Z= -5.16 p<0.001). Additionally, the percentages of correct pronouncing of target sounds in cases of articulation disorders were prominently higher when using familiar voices compared with unfamiliar voices (88% PCC vs 66% PCC; Z= -5.65, p<0.001) CONCLUSION: This study confirms the utility of invoking emotion in improving speech therapy and maximizing therapeutic outcomes. This study also recommends engaging families and friends in providing speech services to the speech-impaired population to improve patient progress.

Noise Induced Hearing Loss and Tinnitus-New Research Developments and Remaining Gaps in Disease Assessment, Treatment, and Prevention.

Long-term noise exposure often results in noise induced hearing loss (NIHL). Tinnitus, the generation of phantom sounds, can also result from noise exposure, although understanding of its underlying mechanisms are limited. Recent studies, however, are shedding light on the neural processes involved in NIHL and tinnitus, leading to potential new and innovative treatments. This review focuses on the assessment of NIHL, available treatments, and development of new pharmacologic and non-pharmacologic treatments based on recent studies of central auditory plasticity and adaptive changes in hearing. We discuss the mechanisms and maladaptive plasticity of NIHL, neuronal aspects of tinnitus triggers, and mechanisms such as tinnitus-associated neural changes at the cochlear nucleus underlying the generation of tinnitus after noise-induced deafferentation. We include observations from recent studies, including our own studies on associated risks and emerging treatments for tinnitus. Increasing knowledge of neural plasticity and adaptive changes in the central auditory system suggest that NIHL is preventable and transient abnormalities may be reversable, although ongoing research in assessment and early detection of hearing difficulties is still urgently needed. Since no treatment can yet reverse noise-related damage completely, preventative strategies and increased awareness of hearing health are essential.

Postnatal exposure to an acoustically enriched environment alters the morphology of neurons in the adult rat auditory system.

The structure of neurons in the central auditory system is vulnerable to various kinds of acoustic exposures during the critical postnatal developmental period. Here we explored long-term effects of exposure to an acoustically enriched environment (AEE) during the third and fourth weeks of the postnatal period in rat pups. AEE consisted of a spectrally and temporally modulated sound of moderate intensity, reinforced by a behavioral paradigm. At the age of 3-6 months, a Golgi-Cox staining was used to evaluate the morphology of neurons in the inferior colliculus (IC), the medial geniculate body (MGB), and the auditory cortex (AC). Compared to controls, rats exposed to AEE showed an increased mean dendritic length and volume and the soma surface in the external cortex and the central nucleus of the IC. The spine density increased in both the ventral and dorsal divisions of the MGB. In the AC, the total length and volume of the basal dendritic segments of pyramidal neurons and the number and density of spines on these dendrites increased significantly. No differences were found on apical dendrites. We also found an elevated number of spines and spine density in non-pyramidal neurons. These results show that exposure to AEE during the critical developmental period can induce permanent changes in the structure of neurons in the central auditory system. These changes represent morphological correlates of the functional plasticity, such as an improvement in frequency tuning and synchronization with temporal parameters of acoustical stimuli.

Age-related Changes in Auditory Cortex Without Detectable Peripheral Alterations: A Multi-level Study in Sprague-Dawley Rats.

Aging is often considered to affect both the peripheral (i.e. the cochlea) and central (brainstem and thalamus-cortex) auditory systems. We investigated the effects of aging on the cochlea, brainstem and cortex of female Sprague-Dawley rats. The auditory nerve threshold remained stable between the ages of nine and 21 months, as did distortion product otoacoustic emissions and the number of ribbon synapses between inner hair cells and nerve fibers. The first clear signs of aging appeared in the brainstem, in which response amplitude decreased, with thresholds remaining stable until the age of 15 months, and increasing slightly thereafter. The responses of primary auditory cortex neurons revealed specific effects of aging: at 21 months, receptive fields were spectrally narrower and the temporal reliability of responses to communication sounds was lower. However, aging had a null or even positive effect on neuronal responses in the presence of background noise, responses to amplitude-modulated sounds, and responses in gap-detection protocols. Overall, inter-animal variability remained high relative to the variability across groups of different ages, for all parameters tested. Behavioral performance for the modulation depth of amplitude modulation noise was worse in 21-month old animals than in other animals. Age-related alterations of cortical and behavioral responses were thus observed in animals displaying no signs of aging at the peripheral level. These results suggest that intrinsic, central aging effects can affect the perception of acoustic stimuli independently of the effects of aging on peripheral receptors.

Acute Noise Exposure Is Associated With Intrinsic Apoptosis in Murine Central Auditory Pathway.

Noise that is capable of inducing the hearing loss (NIHL) has a strong impact on the inner ear structures and causes early and most obvious pathophysiological changes in the auditory periphery. Several studies indicated that intrinsic apoptotic cell death mechanisms are the key factors inducing cellular degeneration immediately after noise exposure and are maintained for days or even weeks. In addition, studies demonstrated several changes in the central auditory system following noise exposure, consistent with early apoptosis-related pathologies. To clarify the underlying mechanisms, the present study focused on the noise-induced gene and protein expression of the pro-apoptotic protease activating factor-1 (APAF1) and the anti-apoptotic B-cell lymphoma 2 related protein a1a (BCL2A1A) in the cochlear nucleus (CN), inferior colliculus (IC) and auditory cortex (AC) of the murine central auditory pathway. The expression of Bcl2a1a mRNA was upregulated immediately after trauma in all tissues investigated, whereas the protein levels were significantly reduced at least in the auditory brainstem. Conversely, acute noise has decreased the expression of Apaf1 gene along the auditory pathway. The changes in APAF1 protein level were not statistically significant. It is tempting to speculate that the acoustic overstimulation leads to mitochondrial dysfunction and induction of apoptosis by regulation of proapoptotic and antiapoptotic proteins. The inverse expression pattern on the mRNA level of both genes might reflect a protective response to decrease cellular damage. Our results indicate the immediate presence of intrinsic apoptosis following noise trauma. This, in turn, may significantly contribute to the development of central structural deficits. Auditory pathway-specific inhibition of intrinsic apoptosis could be a therapeutic approach for the treatment of acute (noise-induced) hearing loss to prevent irreversible neuronal injury in auditory brain structures and to avoid profound deficits in complex auditory processing.

The effect of obstructive sleep apnea syndrome on the central auditory system

Background/aim: Obstructive sleep apnea syndrome (OSAS) is a disease characterized by repeated hypoxia attacks during sleep. The effect of hypoxia on the central nervous system is a well-known entity. In this study we aimed to investigate the effect of OSAS on the central auditory system. Materials and methods: Twenty-one OSAS patients diagnosed by polysomnography (PSG) and 10 control subjects were included in the study. After a thorough otorhinolaryngology examination, all subjects underwent pure tone audiometry (250 to 8000 Hz frequency). The subjects with normal otoscopic examination and hearing threshold were included in the study. All participants underwent speech discrimination analyses and auditory time processing and sequencing tests, i.e. frequency pattern test (FPT) and duration pattern test (DPT). Results: Although hearing was normal in the OSAS patients, significant loss was observed in the speech discrimination rates compared to the control group (P < 0.05). Significant disruption was also detected in the FPT and SPT in the OSAS patients (P < 0.05). Conclusion: Repeated hypoxic episodes in OSAS resulted in statistically significant impairments in the central auditory pathways, even if the hearing threshold was within normal limits.

Cellular and Molecular Underpinnings of Neuronal Assembly in the Central Auditory System during Mouse Development.

During development, the organization of the auditory system into distinct functional subcircuits depends on the spatially and temporally ordered sequence of neuronal specification, differentiation, migration and connectivity. Regional patterning along the antero-posterior axis and neuronal subtype specification along the dorso-ventral axis intersect to determine proper neuronal fate and assembly of rhombomere-specific auditory subcircuits. By taking advantage of the increasing number of transgenic mouse lines, recent studies have expanded the knowledge of developmental mechanisms involved in the formation and refinement of the auditory system. Here, we summarize several findings dealing with the molecular and cellular mechanisms that underlie the assembly of central auditory subcircuits during mouse development, focusing primarily on the rhombomeric and dorso-ventral origin of auditory nuclei and their associated molecular genetic pathways.

Saturation of long-term potentiation in the dorsal cochlear nucleus and its pharmacological reversal in an experimental model of tinnitus.

Animal models have demonstrated that tinnitus is a pathology of dysfunctional excitability in the central auditory system, in particular in the dorsal cochlear nucleus (DCN) of the brainstem. We used a murine model and studied whether acoustic over-exposure leading to hearing loss and tinnitus, affects long-term potentiation (LTP) at DCN multisensory synapses. Whole cell and field potential recordings were used to study the effects on release probability and synaptic plasticity, respectively in brainstem slices. Shifts in hearing threshold were quantified by auditory brainstem recordings, and gap-induced prepulse inhibition of the acoustic startle reflex was used as an index for tinnitus. An increased release probability that saturated LTP and thereby induced metaplasticity at DCN multisensory synapses, was observed 4-5days following acoustic over-exposure. Perfusion of an NMDA receptor antagonist or decreasing extracellular calcium concentration, decreased the release probability and restored LTP following acoustic over-exposure. In vivo administration of magnesium-threonate following acoustic over-exposure restored LTP at DCN multisensory synapses, and reduced gap detection deficits observed four months following acoustic over-exposure. These observations suggest that consequences of noise-induced metaplasticity could underlie the gap detection deficits that follow acoustic over-exposure, and that early therapeutic intervention could target metaplasticity and alleviate tinnitus.

Structural changes in the adult rat auditory system induced by brief postnatal noise exposure.

In previous studies (Grécová et al., Eur J Neurosci 29:1921-1930, 2009; Bures et al., Eur J Neurosci 32:155-164, 2010), we demonstrated that after an early postnatal short noise exposure (8 min 125 dB, day 14) changes in the frequency tuning curves as well as changes in the coding of sound intensity are present in the inferior colliculus (IC) of adult rats. In this study, we analyze on the basis of the Golgi-Cox method the morphology of neurons in the IC, the medial geniculate body (MGB) and the auditory cortex (AC) of 3-month-old Long-Evans rats exposed to identical noise at postnatal day 14 and compare the results to littermate controls. In rats exposed to noise as pups, the mean total length of the neuronal tree was found to be larger in the external cortex and the central nucleus of the IC and in the ventral division of the MGB. In addition, the numerical density of dendritic spines was decreased on the branches of neurons in the ventral division of the MGB in noise-exposed animals. In the AC, the mean total length of the apical dendritic segments of pyramidal neurons was significantly shorter in noise-exposed rats, however, only slight differences with respect to controls were observed in the length of basal dendrites of pyramidal cells as well as in the neuronal trees of AC non-pyramidal neurons. The numerical density of dendritic spines on the branches of pyramidal AC neurons was lower in exposed rats than in controls. These findings demonstrate that early postnatal short noise exposure can induce permanent changes in the development of neurons in the central auditory system, which apparently represent morphological correlates of functional plasticity.

Inner Hair Cell Loss Disrupts Hearing and Cochlear Function Leading to Sensory Deprivation and Enhanced Central Auditory Gain.

There are three times as many outer hair cells (OHC) as inner hair cells (IHC), yet IHC transmit virtually all acoustic information to the brain as they synapse with 90-95% of type I auditory nerve fibers. Here we review a comprehensive series of experiments aimed at determining how loss of the IHC/type I system affects hearing by selectively destroying these cells in chinchillas using the ototoxic anti-cancer agent carboplatin. Eliminating IHC/type I neurons has no effect on distortion product otoacoustic emission or the cochlear microphonic potential generated by OHC; however, it greatly reduces the summating potential produced by IHC and the compound action potential (CAP) generated by type I neurons. Remarkably, responses from remaining auditory nerve fibers maintain sharp tuning and low thresholds despite innervating regions of the cochlea with ~80% IHC loss. Moreover, chinchillas with large IHC lesions have surprisingly normal thresholds in quiet until IHC losses exceeded 80%, suggesting that only a few IHC are needed to detect sounds in quiet. However, behavioral thresholds in broadband noise are elevated significantly and tone-in-narrow band noise masking patterns exhibit greater remote masking. These results suggest the auditory system is able to compensate for considerable loss of IHC/type I neurons in quiet but not in difficult listening conditions. How does the auditory brain deal with the drastic loss of cochlear input? Recordings from the inferior colliculus found a relatively small decline in sound-evoked activity despite a large decrease in CAP amplitude after IHC lesion. Paradoxically, sound-evoked responses are generally larger than normal in the auditory cortex, indicative of increased central gain. This gain enhancement in the auditory cortex is associated with decreased GABA-mediated inhibition. These results suggest that when the neural output of the cochlea is reduced, the central auditory system compensates by turning up its gain so that weak signals once again become comfortably loud. While this gain enhancement is able to restore normal hearing under quiet conditions, it may not adequately compensate for peripheral dysfunction in more complex sound environments. In addition, excessive gain increases may convert recruitment into the debilitating condition known as hyperacusis.

Aging and Speech Understanding.

As people age, structural as well as neural degeneration occurs throughout the auditory system. Many older adults experience difficulty in understanding speech especially in adverse listening conditions although they can hear speech sounds. According to a report of the Committee on Hearing and Bioacoustics and Biomechanics of the National Research Council, peripheral, central-auditory, and cognitive systems have long been considered major factors affecting the understanding of speech. The present study aims to review 1) age-related changes in the peripheral, central-auditory, and cognitive systems, 2) the resulting decline in the understanding of speech, and 3) the clinical implication for audiologic rehabilitation of older adults. Once the factors affecting the understanding of speech in older adults are identified and the characteristics of age-related speech understanding difficulties are examined, clinical management could be developed for prevention and treatment. Future research about problems related to the understanding of speech in older adults will help to improve the quality of life in the elderly.

NADPH oxidase 2-dependent oxidative stress, mitochondrial damage and apoptosis in the ventral cochlear nucleus of D-galactose-induced aging rats.

Aging has been associated with oxidative stress and the accumulation of mitochondrial DNA (mtDNA) mutation. The previous study has established a mimetic rat model of aging using D-galactose (D-gal) and revealed that chronic injection of D-gal can increase NADPH oxidase (NOX)-dependent oxidative stress, mitochondrial damage and apoptosis in the peripheral auditory system. However, the effects of NOXs in the central auditory system (CAS) were still obscure. The current study was designed to investigate potential causative mechanisms of central presbycusis by using the D-gal-induced aging rats. We found that the levels of H2O2 and the expression of NADPH oxidase 2 (NOX2) and its corresponding subunits P22(phox), P47(phox) and P67(phox) were greatly increased in the ventral cochlear nucleus (VCN) of D-gal-treated rats as compared with controls. And, the levels of a typical biomarker of oxidative stress, 8-hydroxy-2-deoxyguanosine (8-OHdG), and the accumulation of mtDNA common deletion (CD) were also increased in the VCN of D-gal-treated rats as compared with controls. Moreover, the damage of mitochondrial ultrastructure, a decline in ATP levels, the loss of mitochondrial membrane potential (MMP), an increase in the amount of cytochrome c (cyt c) translocated to the cytoplasm and caspase-3 activation were observed in the VCN induced by D-gal. In addition, we also found that the terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end-labeling (TUNEL)-positive cells in the VCN were increased in D-gal-treated rats. Taken together, these findings suggest that NOX2-dependent oxidative stress may contribute to mitochondrial damage and activate a caspase-3-dependent apoptosis pathway in the CAS during aging. This study also provides new insights into the development of presbycusis.

Avances en corteza auditiva / Advances in auditory cortex

El sistema auditivo nos permite detectar e interpretar las señales acústicas del medio ambiente y así modificar nuestro comportamiento. En humanos la corteza auditiva se ubica en el giro temporal superior del lóbulo temporal. Esta corteza presenta una organización estructural y funcional característica, que se ha identificado en muchas especies de mamíferos. Las áreas de organización de la corteza auditiva son: (i) una región central denominada corteza auditiva primaria o core, que corresponde al primer nivel de procesamiento, cuyas características cito-arquitectónicas y funcionales principales son poseer una capa IV prominente y presentar una organización tonotópica especular. Además, (ii) una región circundante conocida como cinturón o belt, que corresponde a las cortezas secundarias que participan de la localización espacial y reconocimiento del sonido, como también en el procesamiento del habla. Por último, (iii) las áreas de asociación auditiva integran la información auditiva con la de otros sistemas sensoriales. En este artículo se revisan las bases neuroanatómicas y las propiedades funcionales de la corteza auditiva, las que constituyen pilares fundamentales para el desarrollo de métodos diagnósticos y terapéuticos del procesamiento auditivo central.

The auditory system allows us to detect and interpret the acoustic signals of the environment and thus change our behavior. In humans, the auditory cortex is located in the superior temporal gyrus of the temporal lobe. This cortex has a characteristic structural organization and functionality that have been identified in many mammalian species. The auditory cortex has different organizational areas: (i) a core called "primary auditory cortex," which corresponds to the first level of processing, and its cyto-architectural and physiological main features are to present a prominent layer IV and to display a mirror-tonotopic organization. In addition, (ii) a surrounding region known as belt that corresponds to the secondary auditory cortices and participates in the location and recognition of sound, as well as in speech processing. Finally, (iii) auditory association areas that integrate auditory information with other sensory systems. In this article, the neuroanatomical bases and functional properties of auditory cortex processing are reviewed. These topics constitute the foundations for the development of diagnostic tools and therapeutic procedures of central auditory processing.

Age-dependent changes of calcium related activity in the central auditory pathway.

Age-related hearing loss (ARHL) represents one of the most common chronic health problems that faces an aging population. In the peripheral auditory system, aging is accompanied by functional loss or degeneration of sensory as well as non-sensory tissue. It has been recently described that besides the degeneration of cochlear structures, the central auditory system is also involved in ARHL. Although mechanisms of central presbycusis are not well understood, previous animal studies have reported some signs of central neurodegeneration in the lower auditory pathway. Moreover, changes in neurophysiology are indicated by alterations in synaptic transmission. In particular, neurotransmission and spontaneous neuronal activity appear to be affected in aging animals. Therefore, it was the aim of the present study to determine the neuronal activity within the central auditory pathway in aging mice over their whole lifespan compared to a control group (young adult animals, ~3months of age) using the non-invasive manganese-enhanced MRI technique. MRI signal strength showed a comparable pattern in most investigated auditory brain areas. An increase in activity was particularly pronounced in the middle-aged groups (13 or 18 months), with the largest effect in the dorsal and ventral cochlear nucleus. In higher auditory structures, namely the inferior colliculus, medial geniculate body and auditory cortex, the enhancement was much less expressed; while a decrease was detected in the superior olivary complex. Interestingly, calcium-dependent activity reduced to control levels in the oldest animals (22 months) in the cochlear nucleus and was significantly reduced in higher auditory structures. A similar finding was also found in the hippocampus. The observed changes might be related to central neuroplasticity (including hyperactivity) as well as neurodegenerative mechanisms and represent central nervous correlates of the age-related decline in auditory processing and perception.

Distribution of neuronal KCC2a and KCC2b isoforms in mouse CNS.

The neuronal K-Cl cotransporter KCC2 maintains the low intracellular chloride concentration required for the fast hyperpolarizing actions of inhibitory neurotransmitters in mature central nervous system (CNS). The KCC2 gene produces two isoforms, KCC2a and KCC2b, that differ in their N-termini. Increase of KCC2b in the cortex underlies the developmental shift in γ-aminobutyric acid (GABA)ergic responses, whereas the physiological role of KCC2a is still poorly characterized. The two KCC2 isoforms show equal distribution in mouse brainstem neurons at birth; however their postnatal expression patterns, and the subcellular localization of KCC2a, have not yet been described. Here, we compared the pattern of KCC2a and KCC2b expression in different regions of postnatal mouse CNS by immunohistochemistry by using isoform-specific antibodies. Tissue from KCC2a isoform-specific knockout mice was used as a negative control. KCC2b expression increased postnatally and was widely expressed in adult brain. KCC2a immunoreactivity was low or absent in most parts of the adult cortex, hippocampus, thalamus, and cerebellar cortex. Both isoforms were widely present in the developing and mature hypothalamus, a large part of the brainstem, and the spinal cord. A notable exception was the lack of KCC2a staining in the brainstem auditory system. At the subcellular level, the isoforms were only partially colocalized. In neuronal somas, KCC2b immunoreactivity was concentrated at the plasma membrane, whereas KCC2a signal was not. Moreover, although both isoforms were expressed in microtubule-associated protein (MAP)2-positive dendrites, they appeared in non-overlapping dendritic compartments. The results, together with those of previous studies, suggest that KCC2a and KCC2b have overlapping roles in neonatal neurons but presumably different roles in mature neurons.