Inferior Colliculus Research Articles

Auditory-limbic-cerebellum interactions and cognitive impairments in noise-induced hearing loss.

This study aimed to explore the neural substrate of hearing loss-related central nervous system in rats and its correlation with cognition. We identified the neural mechanism for these debilitating abnormalities by inducing a bilateral hearing loss animal model using intense broadband noise (122 dB of broadband noise for 2h) and used the Morris water maze test to characterize the behavioral changes at 6months post-noise exposure. Functional magnetic resonance imaging (fMRI) was conducted to clarify disrupted functional network using bilateral auditory cortex (ACx) as a seed. Structural diffusion tensor imaging (DTI) was applied to illustrate characteristics of fibers in ACx and hippocampus. Pearson correlation was computed behavioral tests and other features. A deficit in spatial learning/memory, body weight, and negative correlation between them was observed. Functional connectivity revealed weakened coupling within the ACx and inferior colliculus, lateral lemniscus, the primary motor cortex, the olfactory tubercle, hippocampus, and the paraflocculus lobe of the cerebellum. The fiber number and mean length of ACx and different hippocampal subregions were also damaged in hearing loss rats. A new model of auditory-limbic-cerebellum interactions accounting for noise-induced hearing loss and cognitive impairments is proposed.

Neurotransmitter phenotype and axonal projection patterns of VIP-expressing neurons in the inferior colliculus

Neurons in the inferior colliculus (IC), the midbrain hub of the central auditory pathway, send ascending and descending projections to other auditory brain regions, as well as projections to other sensory and non-sensory brain regions. However, the axonal projection patterns of individual classes of IC neurons remain largely unknown. Vasoactive intestinal polypeptide (VIP) is a neuropeptide expressed by subsets of neurons in many brain regions. We recently identified a class of IC stellate neurons that we called VIP neurons because they are labeled by tdTomato (tdT) expression in VIP-IRES-Cre x Ai14 mice. Here, using fluorescence in situ hybridization, we found that tdT+ neurons in VIP-IRES-Cre x Ai14 mice express Vglut2, a marker of glutamatergic neurons, and VIP, suggesting that VIP neurons use both glutamatergic and VIPergic signaling to influence their postsynaptic targets. Next, using viral transfections with a Cre-dependent eGFP construct, we labeled the axonal projections of VIP neurons. As a group, VIP neurons project intrinsically, within the ipsilateral and contralateral IC, and extrinsically to all the major targets of the IC. Within the auditory system, VIP neurons sent axons and formed axonal boutons in higher centers, including the medial geniculate nucleus and the nucleus of the brachium of the IC. Less dense projections terminated in lower centers, including the nuclei of the lateral lemniscus, superior olivary complex, and dorsal cochlear nucleus. VIP neurons also project to several non-auditory brain regions, including the superior colliculus, periaqueductal gray, and cuneiform nucleus. The diversity of VIP projections compared to the homogeneity of VIP neuron intrinsic properties suggests that VIP neurons play a conserved role at the microcircuit level, likely involving neuromodulation through glutamatergic and VIPergic signaling, but support diverse functions at the systems level through their participation in different projection pathways.

Thioredoxin deficiency increases oxidative stress and causes bilateral symmetrical degeneration in rat midbrain

Thioredoxin, encoded by Txn1, acts as a critical antioxidant in the defense against oxidative stress by regulating the dithiol/disulfide balance of interacting proteins. The role of thioredoxin in the central nervous system (CNS) is largely unknown. A phenotype-driven study of N-ethyl-N-nitrosourea-mutated rats with wild-running seizures revealed the importance of Txn1 mutations in CNS degeneration. Genetic mapping identified Txn1-F54L in the epileptic rats. The insulin-reducing activity of Txn1-F54L was approximately one-third of that of the wild-type (WT). Bilateral symmetrical vacuolar degeneration in the midbrain, mainly in the thalamus and the inferior colliculus, was observed in the Txn1-F54L rats. The lesions displayed neuronal and oligodendrocytic cell death. Neurons in Txn1-F54L rats showed morphological changes in the mitochondria. Vacuolar degeneration peaked at five weeks of age, and spontaneous repair began at seven weeks. The TUNEL assay showed that fibroblasts derived from homozygotes were susceptible to cell death under oxidative stress. In five-week-old WT rats, energy metabolism in the thalamus was significantly higher than that in the cerebral cortex. In conclusion, in juvenile rats, Txn1 seems to play an essential role in reducing oxidative stress in the midbrains with high energy metabolism.

Processing of auditory information in forebrain regions after hearing loss in adulthood: Behavioral and electrophysiological studies in a rat model.

Hearing loss was proposed as a factor affecting development of cognitive impairment in elderly. Deficits cannot be explained primarily by dysfunctional neuronal networks within the central auditory system. We here tested the impact of hearing loss in adult rats on motor, social, and cognitive function. Furthermore, potential changes in the neuronal activity in the medial prefrontal cortex (mPFC) and the inferior colliculus (IC) were evaluated. In adult male Sprague Dawley rats hearing loss was induced under general anesthesia with intracochlear injection of neomycin. Sham-operated and naive rats served as controls. Postsurgical acoustically evoked auditory brainstem response (ABR)-measurements verified hearing loss after intracochlear neomycin-injection, respectively, intact hearing in sham-operated and naive controls. In intervals of 8 weeks and up to 12 months after surgery rats were tested for locomotor activity (open field) and coordination (Rotarod), for social interaction and preference, and for learning and memory (4-arms baited 8-arms radial maze test). In a final setting, electrophysiological recordings were performed in the mPFC and the IC. Locomotor activity did not differ between deaf and control rats, whereas motor coordination on the Rotarod was disturbed in deaf rats (P < 0.05). Learning the concept of the radial maze test was initially disturbed in deaf rats (P < 0.05), whereas retesting every 8 weeks did not show long-term memory deficits. Social interaction and preference was also not affected by hearing loss. Final electrophysiological recordings in anesthetized rats revealed reduced firing rates, enhanced irregular firing, and reduced oscillatory theta band activity (4-8 Hz) in the mPFC of deaf rats as compared to controls (P < 0.05). In the IC, reduced oscillatory theta (4-8 Hz) and gamma (30-100 Hz) band activity was found in deaf rats (P < 0.05). Minor and transient behavioral deficits do not confirm direct impact of long-term hearing loss on cognitive function in rats. However, the altered neuronal activities in the mPFC and IC after hearing loss indicate effects on neuronal networks in and outside the central auditory system with potential consequences on cognitive function.

Volumetric analysis of the aging auditory pathway using high resolution magnetic resonance histology.

Numerous shown consequences of age-related hearing loss have been unveiled; however, the relationship of the cortical and subcortical structures of the auditory pathway with aging is not well known. Investigations into neural structure analysis remain sparse due to difficulties of doing so in animal models; however, recent technological advances have been able to achieve a resolution adequate to perform such studies even in the small mouse. We utilize 12 members of the BXD family of recombinant inbred mice and aged separate cohorts. Utilizing novel magnetic resonance histology imaging techniques, we imaged these mice and generated high spatial resolution three dimensional images which were then comprehensively labeled. We completed volumetric analysis of 12 separate regions of interest specific to the auditory pathway brainstem nuclei and cortical areas with focus on the effect of aging upon said structures. Our results showed significant interstrain variation in the age-related effect on structure volume supporting a genetic influence in this interaction. Through multivariable modeling, we observed heterogenous effects of aging between different structures. Six of the 12 regions of interests demonstrated a significant age-related effect. The auditory cortex and ventral cochlear nucleus were found to decrease in volume with age, while the medial division of the medial geniculate nucleus, lateral lemniscus and its nucleus, and the inferior colliculus increased in size with age. Additionally, no sex-based differences were noted, and we observed a negative relationship between auditory cortex volume and mouse weight. This study is one of the first to perform comprehensive magnetic resonance imaging and quantitative analysis in the mouse brain auditory pathway cytoarchitecture, offering both novel insights into the neuroanatomical basis of age-related changes in hearing as well as evidence toward a genetic influence in this interaction. High resonance magnetic resonance imaging provides a promising efficacious avenue in future mouse model hearing loss investigations.

Application of diffusion tensor imaging and functional alterations in evaluating brain alterations related to heatstroke in a rat model

ObjectivesTo assess the alterations in resting-state functions and neural structures in the brain of a heatstroke rat model and explore the underlying relationship. MethodsIn total, 17 male Sprague Dawley rats were randomly divided into a control group (CTRL, n = 7) and a heatstroke group (HS, n = 10). All rats underwent 7.0 T magnetic resonance imaging (MRI). T2-weighted imaging, resting-state functional MRI (rs-fMRI), and diffusion tensor imaging (DTI) were obtained. On day 25, the surviving HS group rats (the follow-up group, FU, n = 7) were scanned again. ResultsHeatstroke resulted in functional alterations and structural damage in the cerebellar molecular layer (CML), right perirhinal area (PA), pretectal region (PR), right dentate gyrus, and external cortex of the inferior colliculus (ECIC). Further functional changes occur in the right temporal associative cortex (TAC), left retrosplenial cortex (RC), and CML during convalescence. The fractional anisotropy values were significantly positively correlated with the amplitude of low-frequency fluctuation (ALFF) (HS–CML: r = 0.746, p = 0.034; right PR: r = 0.648, p = 0.049; FU–right PA: r = 0.817, p = 0.025)/regional homogeneity (ReHo) ratio (HS–CML: r = 0.833, p = 0.008; ECIC: r = 0.678, p = 0.045) and negatively correlated with the ALFF (FU–left RC: r = −0.818, p = 0.024; right TAC: r = −0.813, p = 0.049). ConclusionDTI and rs-fMRI allow meticulous monitoring of the progression of neurological and functional alterations in the brain after heatstroke.

Descending projections to the auditory midbrain: evolutionary considerations.

The mammalian inferior colliculus (IC) is massively innervated by multiple descending projection systems. In addition to a large projection from the auditory cortex (AC) primarily targeting the non-lemniscal portions of the IC, there are less well-characterized projections from non-auditory regions of the cortex, amygdala, posterior thalamus and the brachium of the IC. By comparison, the frog auditory midbrain, known as the torus semicircularis, is a large auditory integration center that also receives descending input, but primarily from the posterior thalamus and without a projection from a putative cortical homolog: the dorsal pallium. Although descending projections have been implicated in many types of behaviors, a unified understanding of their function has not yet emerged. Here, we take a comparative approach to understanding the various top-down modulators of the IC to gain insights into their functions. One key question that we identify is whether thalamotectal projections in mammals and amphibians are homologous and whether they interact with evolutionarily more newly derived projections from the cerebral cortex. We also consider the behavioral significance of these descending pathways, given anurans' ability to navigate complex acoustic landscapes without the benefit of a corticocollicular projection. Finally, we suggest experimental approaches to answer these questions.

Developmental spontaneous activity promotes formation of sensory domains, frequency tuning and proper gain in central auditory circuits.

Neurons that process sensory information exhibit bursts of electrical activity during development, providing early training to circuits that will later encode similar features of the external world. In the mammalian auditory system, this intrinsically generated activity emerges from the cochlea prior to hearing onset, but its role in maturation of auditory circuitry remains poorly understood. We show that selective suppression of cochlear supporting cell spontaneous activity disrupts patterned burst firing of central auditory neurons without affecting cell survival or acoustic thresholds. However, neurons in the inferior colliculus of these mice exhibit enhanced acoustic sensitivity and broader frequency tuning, resulting in wider isofrequency laminae. Despite this enhanced neural responsiveness, total tone-responsive regions in the auditory cortex are substantially smaller. Thus, disruption of pre-hearing cochlear activity causes profound changes in neural encoding of sound, with important implications for restoration of hearing in individuals who experience reduced activity during this critical developmental period.

A radiofrequency coil to facilitate task-based fMRI of awake marmosets

BackgroundThe small common marmoset (Callithrix jacchus) is an ideal nonhuman primate for awake fMRI in ultra-high field small animal MRI scanners. However, it can often be challenging in task-based fMRI experiments to provide a robust stimulus within the MRI environment while using hardware (an RF coil and restraint system) that is compatible with awake imaging. New methodHere we present an RF coil and restraint system that permits unimpeded access to an awake marmoset’s head subsequent to immobilization, thereby permitting the setup of peripheral devices and stimuli proximal to the head. ResultsAs an example application, an fMRI experiment probing whole-brain activation in response to marmoset vocalizations was conducted—this paradigm showed significant bilateral activation in the inferior colliculus, medial lateral geniculate nucleus, and auditory cortex. Comparison with existing method(s)The coil performance was evaluated and compared to a previously published restraint system with integrated RF coil. The image and temporal SNR were improved by up to 58 % and 27 %, respectively, in the peripheral cortex and by 30 % and 3 % in the centre of the brain. The restraint-system topology limited head motion to less than 100 µm of translation and 0.30° of rotation when measured over a 15-minute acquisition. ConclusionsThe proposed hardware solution provides a versatile approach to awake-marmoset imaging and, as demonstrated, can facilitate task-based fMRI.

Leveling up: a long-range olivary projection to the medial geniculate without collaterals to the central nucleus of the inferior colliculus in rats.

The medial nucleus of the trapezoid body (MNTB) is one of the monaural cell groups situated within the superior olivary complex (SOC), a constellation of brainstem nuclei with numerous roles in hearing. Principal MNTB neurons are glycinergic and express the calcium-binding protein, calbindin (CB). The MNTB receives its main glutamatergic, excitatory input from the contralateral cochlear nucleus via the calyx of Held and converts this into glycinergic inhibition directed toward nuclei in the SOC and the ventral and intermediate nuclei of the lateral lemniscus (VNLL and INLL). Through this inhibition, the MNTB plays essential roles in localization of sound sources and encoding spectral and temporal features of sound. In rats, very few MNTB neurons project to the inferior colliculus. However, our recent study of SOC projections to the auditory thalamus revealed a substantial number of retrogradely labeled MNTB neurons. This observation led us to examine whether the rat MNTB provides a long-range projection to the medial geniculate body (MGB). We examined this possible projection using retrograde and anterograde tract tracing and immunohistochemistry for CB and the glycine receptor. Our results demonstrate a significant projection to the MGB from the ipsilateral MNTB that does not involve a collateral projection to the inferior colliculus.

Targeted Inhibition of Upregulated Sodium-Calcium Exchanger in Rat Inferior Colliculus Suppresses Alcohol Withdrawal Seizures.

The inferior colliculus (IC) is critical in initiating acoustically evoked alcohol withdrawal-induced seizures (AWSs). Recently, we reported that systemic inhibition of Ca2+ entry via the reverse mode activity of the Na+/Ca2+ exchanger (NCXrev) suppressed AWSs, suggesting remodeling of NCX expression and function, at least in the IC, the site of AWS initiation. Here, we probe putative changes in protein expression in the IC of NCX isoforms, including NCX type 1 (NCX1), 2 (NCX2), and 3 (NCX3). We also evaluated the efficacy of targeted inhibition of NCX1rev and NCX3rev activity in the IC on the occurrence and severity of AWSs using SN-6 and KB-R943, respectively. We used our well-characterized alcohol intoxication/withdrawal model associated with enhanced AWS susceptibility. IC tissues from the alcohol-treated group were collected 3h (before the onset of AWS susceptibility), 24h (when AWS susceptibility is maximal), and 48h (when AWS susceptibility is resolved) following alcohol withdrawal; in comparison, IC tissues from the control-treated group were collected at 24h after the last gavage. Analysis shows that NCX1 protein levels were markedly higher 3 and 24h following alcohol withdrawal. However, NCX3 protein levels were only higher 3h following alcohol withdrawal. The analysis also reveals that bilateral microinjections of SN-6 (but not KB-R7943) within the IC markedly suppressed the occurrence and severity of AWSs. Together, these findings indicate that NCX1 is a novel molecular target that may play an essential role in the pathogenesis and pathophysiology of AWSs.

The lateral superior olive in the mouse: Two systems of projecting neurons.

The lateral superior olive (LSO) is a key structure in the central auditory system of mammals that exerts efferent control on cochlear sensitivity and is involved in the processing of binaural level differences for sound localization. Understanding how the LSO contributes to these processes requires knowledge about the resident cells and their connections with other auditory structures. We used standard histological stains and retrograde tracer injections into the inferior colliculus (IC) and cochlea in order to characterize two basic groups of neurons: (1) Principal and periolivary (PO) neurons have projections to the IC as part of the ascending auditory pathway; and (2) lateral olivocochlear (LOC) intrinsic and shell efferents have descending projections to the cochlea. Principal and intrinsic neurons are intermixed within the LSO, exhibit fusiform somata, and have disk-shaped dendritic arborizations. The principal neurons have bilateral, symmetric, and tonotopic projections to the IC. The intrinsic efferents have strictly ipsilateral projections, known to be tonotopic from previous publications. PO and shell neurons represent much smaller populations (&lt;10% of principal and intrinsic neurons, respectively), have multipolar somata, reside outside the LSO, and have non-topographic, bilateral projections. PO and shell neurons appear to have widespread projections to their targets that imply a more diffuse modulatory function. The somata and dendrites of principal and intrinsic neurons form a laminar matrix within the LSO and share quantifiably similar alignment to the tonotopic axis. Their restricted projections emphasize the importance of frequency in binaural processing and efferent control for auditory perception. This study addressed and expanded on previous findings of cell types, circuit laterality, and projection tonotopy in the LSO of the mouse.

Amyloid Pathology in the Central Auditory Pathway of 5XFAD Mice Appears First in Auditory Cortex.

Effective treatment of Alzheimer's disease (AD) will hinge on early detection. This has led to the search for early biomarkers that use non-invasive testing. One possible early biomarker is auditory temporal processing deficits, which reflect central auditory pathway dysfunction and precede cognitive and memory declines in AD. Gap detection is a measure of auditory temporal processing, is impaired in human AD, and is also impaired in the 5XFAD mouse model of AD. Gap detection deficits appear as early as postnatal day 60 in 5XFAD mice, months before cognitive deficits or cell death, supporting gap detection as an early biomarker. However, it remains unclear how gap detection deficits relate to the progression of amyloid pathology in the auditory system. To determine the progression of amyloid pathology throughout the central auditory system and across age in 5XFAD mice. We quantified intracellular and extracellular antibody labelling of Aβ42 in 6 regions of the central auditory system from p14 to p150. Pathology appeared first in primary auditory cortex (A1) as intracellular accumulation of Aβ42 in layer 5 pyramidal neurons by age p21. Extracellular plaques appeared later, by age p90, in A1, medial geniculate body, and inferior colliculus. Auditory brainstem structures showed minimal amyloid pathology. We also observed pathology in the caudal pontine reticular nucleus, a brainstem structure that is outside of the central auditory pathway but which is involved in the acoustic startle reflex. These results suggest that Aβ42 accumulation, but not plaques, may impair gap detection.

Comparison of two behavioral tests for tinnitus assessment in mice

Animal research focused on chronic tinnitus associated with noise-induced hearing loss can be expensive and time-consuming as a result of the behavioral training required. Although there exist a number of behavioral tests for tinnitus; there have been few formal direct comparisons of these tests. Here, we evaluated animals in two different tinnitus assessment methods. CBA/CaJ mice were trained in an operant conditioning, active avoidance (AA) test, and a reflexive, gap-induced pre-pulse inhibition of acoustic startle (GPIAS) test, or both. Tinnitus was induced in awake mice by unilateral continuous sound exposure using a 2-kHz- or octave-wide noise centered at 16 kHz and presented at 113- or 116-dB SPL. Tinnitus was assessed 8 weeks after sound overexposure. Most mice had evidence of tinnitus behavior in at least one of the two behaviors. Of the mice evaluated in AA, over half (55%) had tinnitus positive behavior. In GPIAS, fewer animals (13%) were positive than were identified using the AA test. Few mice were positive in both tests (10%), and only one was positive for tinnitus behavior at the same spectral frequency in both tests. When the association between tinnitus behavior and spontaneous activity recorded in the inferior colliculus was compared, animals with tinnitus behavior in AA exhibited increased spontaneous activity, while those positive in GPIAS did not. Thus, it appears that operant conditioning tests, like AA, maybe more reliable and accurate tests for tinnitus than reflexive tests.

Small nuclei identification with a hemispherical brain PET

BackgroundTo confirm the performance of the first hemispherical positron emission tomography (PET) for the brain (Vrain) that we developed to visualise the small nuclei in the deep brain area, we compared 18F-fluorodeoxyglucose (FDG) brain images with whole-body PET images.MethodsTen healthy male volunteers (aged 22–45 years) underwent a representative clinical whole-body PET, followed by Vrain each for 10 min. These two scans were initiated 30 min and 45 min after FDG injection (4.1 ± 0.5 MBq/kg), respectively. First, we visually identified the small nuclei and then compared their standardised uptake values (SUVs) with the participants’ age. Next, the SUVs of each brain region, which were determined by applying a volume-of-interest template for anatomically normalised PET images, were compared between the brain images with the Vrain and those with the whole-body PET images.ResultsSmall nuclei, such as the inferior colliculus, red nucleus, and substantia nigra, were more clearly visualised in Vrain than in whole-body PET. The anterior nucleus and dorsomedial nucleus in the thalamus and raphe nucleus in the brainstem were identified in Vrain but not in whole-body PET. The SUVs of the inferior colliculus and dentate gyrus in the cerebellum positively correlated with age (Spearman’s correlation coefficient r = 0.811, p = 0.004; r = 0.738, p = 0.015, respectively). The SUVs of Vrain were slightly higher in the mesial temporal and medial parietal lobes than those in whole-body PET.ConclusionsThis was the first time that the raphe nuclei, anterior nuclei, and dorsomedial nuclei were successfully visualised using the first hemispherical brain PET.Trial registration Japan Registry of Clinical Trials, jRCTs032210086, Registered 13 May 2021, https://jrct.niph.go.jp/latest-detail/jRCTs032210086.

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.

Absence of the Fragile X messenger ribonucleoprotein alters response patterns to sounds in the auditory midbrain.

Among the different autism spectrum disorders, Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. Sensory and especially auditory hypersensitivity is a key symptom in patients, which is well mimicked in the Fmr1 -/- mouse model. However, the physiological mechanisms underlying FXS’s acoustic hypersensitivity in particular remain poorly understood. Here, we categorized spike response patterns to pure tones of different frequencies and intensities from neurons in the inferior colliculus (IC), a central integrator in the ascending auditory pathway. Based on this categorization we analyzed differences in response patterns between IC neurons of wild-type (WT) and Fmr1 -/- mice. Our results report broadening of frequency tuning, an increased firing in response to monaural as well as binaural stimuli, an altered balance of excitation-inhibition, and reduced response latencies, all expected features of acoustic hypersensitivity. Furthermore, we noticed that all neuronal response types in Fmr1 -/- mice displayed enhanced offset-rebound activity outside their excitatory frequency response area. These results provide evidence that the loss of Fmr1 not only increases spike responses in IC neurons similar to auditory brainstem neurons, but also changes response patterns such as offset spiking. One can speculate this to be an underlying aspect of the receptive language problems associated with Fragile X syndrome.

Small molecule modulation of the large-conductance calcium-activated potassium channel suppresses salicylate-induced tinnitus in mice

Tinnitus is the phantom perception of sound that has no external source. A neurological signature of tinnitus, and the frequently associated hyperacusis, is an imbalance between excitatory and inhibitory activity in the central auditory system (CAS), leading to dysregulated network excitability. The large conductance, calcium-activated potassium (BK) channel is a key player in pre- and post-synaptic excitability through its mediation of K+ currents. Changes in BK channel activity are associated with aberrant network activity in sensory regions of the CNS, raising the possibility that BK channel modulation could regulate activity associated with tinnitus and hyperacusis. To test whether BK channel openers are able to suppress biomarkers of drug-induced tinnitus and hyperacusis, the 1,3,4 oxadiazole BMS-191011 was given to young adult CBA mice that had been administered 250 mg/kg sodium salicylate (SS). Systemic treatment with BMS-191011 reduced behavioral manifestations of SS-induced tinnitus, but not hyperacusis, probed via the gap-in-noise startle response method. Systemic BMS-191011 treatment did not influence SS-induced increases in auditory brainstem response functions, but local application at the inferior colliculus did reverse SS-suppressed spontaneous activity, particularly in the frequency region of the tinnitus percept. Thus, action of BMS-191011 in the inferior colliculus may contribute to the reduction in behaviorally measured tinnitus. Together, these findings support the utility of BK channel openers in reducing central auditory processing changes associated with the formation of the tinnitus percept.

Age-related ultrastructural changes in the lateral cortex of the inferior colliculus

Temporal precision, a key component of sound and speech processing in the inferior colliculus (IC), depends on a balance of inhibition and excitation, and this balance degrades during aging. The cause of disrupted excitatory-inhibitory balance in aging is unknown, however changes at the synapse are a likely candidate. We sought to determine whether synaptic changes occur in the lateral cortex of the IC (IClc), a multimodal nucleus that processes lemniscal, intrinsic, somatosensory, and descending auditory input. Using electron microscopic techniques across young, middle age and old Fisher Brown Norway rats, our results demonstrate minimal loss of synapses in middle age, but significant (∼28%) loss during old age. However, in middle age, targeting of GABAergic dendrites by GABAergic synapses is increased and the active zones of excitatory synapses (that predominantly target GABA-negative dendrites) are lengthened. These synaptic changes likely result in a net increase of excitation in the IClc during middle age. Thus, disruption of excitatory-inhibitory balance in the aging IClc may be due to synaptic changes that begin in middle age.

Downregulated miRNAs associated with auditory deafferentation and compensatory neural plastic changes following single-sided deafness in the inferior colliculi of rats

Background and aimsDeafferentation and compensatory neural plastic changes in the inferior colliculus (IC) have been suggested following single-sided deafness (SSD). We explored related miRNA changes in the IC of SSD rats using miRNA microarray analyses. MethodsEight-week-old rats were divided into control and SSD rats (n = 8 for each group). SSD rats underwent right-side cochlear ablation surgery, with the IC harvested two weeks post-surgery. miRNA microarray analysis was performed using GeneChip miRNA 4.0, microarray (Affymetrix Inc.). miRNAs whose expression levels differed between SSD and control rats with a fold-change ≥ 1.5 and P < 0.05 were examined using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Target genes of differentially expressed miRNAs were predicted using TargetScan software. The pathways related to predicted target genes were analyzed. mRNA levels of predicted target genes were estimated using qRT-PCR. ResultsThe expression of miR-15b-5p, miR-202-5p, and miR-212-3p was lower in the contralateral (left) IC of SSD rats than that of control rats. In SSD rats, miRNA expression levels in the contralateral IC were 0.45-, 0.25-, and 0.50-fold lower for miR-15b-5p, miR-202-5p, and miR-212-3p, respectively (P < 0.05). The expression of predicted target genes (Spred1, Rasa1, Lsm11, and Srsf1) was higher in the contralateral IC of SSD rats than in control rats. The targets were predicted to be related with cleavage of growing transcripts in the termination region, mitogen-activated protein kinase family signaling cascades, RAF/AMP kinase cascade, regulation of RAS by GTPase activating proteins (GAPs), and RNA polymerase II transcription termination. For ipsilateral ICs, miR-425-3p, miR-199a-5p, and miR-134-3p showed lower expressions in SSD rats than in control rats, which were 0.55-, 0.61-, and 0.69-fold lower, respectively (P < 0.05). The expression of predicted target genes (Atp2b2, Grin2b, Foxp1, Ztbt20, Zfp91, and Strn) was higher in the ipsilateral IC of SSD rats; the regulation of synaptic plasticity, cAMP signaling pathway, metal ion binding, and calcium ion transport can be associated with these target genes. ConclusionAdult rats with unilateral auditory deprivation showed miRNA changes in the IC. The contralateral IC showed decreased miRNA expression predicted to be related to MAPK and RAS signaling, whereas the ipsilateral IC revealed decreased miRNA expression predicted to be associated with synaptic plasticity and calcium ion transport.