Ventral Cochlear Nucleus Research Articles

Modulation of the excitability of stellate neurons in the ventral cochlear nucleus of mice by TRPM2 channels

Oxidative stress-induced Ca2+ permeable transient receptor potential melastatin 2 (TRPM2) channels are expressed at high levels in the brain, appear to link neuronal excitability to cellular metabolism, and are involved in the pathogenesis of neurodegenerative disorders. We aimed to study the electrophysiological properties of TRPM2 channels in stellate cells of the mouse ventral cochlear nucleus (VCN) using molecular, immunohistochemical and electrophysiological approaches.In the present study, the real time PCR analysis revealed the presence of the TRPM2 mRNA in the mouse VCN tissue. Cell bodies of stellate cells were moderately labeled with TRPM2 antibodies using immunohistochemical staining.Stellate cells were sensitive to intracellular ADP-ribose (ADPR), a TRPM2 agonist. Upon the application of ADPR, the resting membrane potential of the stellate cells was significantly depolarized, shifting from −61.2 ± 0.9 mV to −57.0 ± 0.8 mV (P < 0.001; n = 21), and the firing rate significantly increased (P < 0.001, n = 6). When the pipette solution contained ADPR (300 μM) and the TRPM2 antagonists flufenamic acid (FFA) (100 μM), N-(p-amylcinnamoyl) anthranilic acid (ACA) (50 μM) and 8-bromo-cADP-Ribose (8-Br-cADPR) (50 μM), the membrane potential shifted in a hyperpolarizing direction. ADPR did not significantly change the resting membrane potential and action potential firing rate of stellate cells from TRPM2−/− mice.In conclusion, the results obtained using these molecular, immunohistochemical and electrophysiological approaches reveal the expression of functional TRPM2 channels in stellate neurons of the mouse VCN. TRPM2 might exert a significant modulatory effect on setting the level of resting excitability.

Information Processing by Onset Neurons in the Cat Auditory Brainstem.

Octopus cells in the ventral cochlear nucleus (VCN) have been difficult to study because of the very features that distinguish them from other VCN neurons. We performed in vivo recordings in cats on well-isolated units, some of which were intracellularly labeled and histologically reconstructed. We found that responses to low-frequency tones with frequencies < 1kHz reveal higher levels of neural synchrony and entrainment to the stimulus than the auditory nerve. In responses to higher frequency tones, the neural discharges occur mostly near the stimulus onset. These neurons also respond in a unique way to 100% amplitude-modulated (AM) tones with discharges exhibiting a bandpass tuning. Responses to frequency-modulated sounds (FM) are unusual: Octopus cells react more vigorously during the ascending than the descending parts of the FM stimulus. We examined responses of neurons in the ventral nucleus of the lateral lemniscus (VNLL) whose discharges to tones and AM sounds are similar to octopus cells. Repeated stimulation with short tone pips of VCN and VNLL onset neurons evokes trains of action potentials with gradual shifts toward later times in their first spike latency. This behavior parallels short-term post-synaptic depression observed by other authors in in vitro VCN recordings of octopus cells. VCN and VNLL onset units in cats respond to frozen noise stimuli with gaps as narrow as 1ms with a robust discharge near the stimulus onset following the gap. This finding suggests that VCN and VNLL onset cells play a role in gap detection, which is of great importance to speech perception.

Transient Conductive Hearing Loss Regulates Cross-Modal VGLUT Expression in the Cochlear Nucleus of C57BL/6 Mice.

Auditory nerve fibers synapse onto the cochlear nucleus (CN) and are labeled using the vesicular glutamate transporter-1 (VGLUT-1), whereas non-auditory inputs are labeled using the VGLUT-2. However, the underlying regulatory mechanism of VGLUT expression in the CN remains unknown. We examined whether a sound level decrease, without primary neural damage, induces cellular and VGLUT expression change in the CN, and examined the potential for neural plasticity of the CN using unilateral conductive hearing loss models. We inserted earplugs in 8-week-old mice unilaterally for 4 weeks and subsequently removed them for another 4 weeks. Although the threshold of an auditory brainstem response significantly increased across all tested frequencies following earplug insertion, it completely recovered after earplug removal. Auditory deprivation had no significant impact on spiral ganglion and ventral CN (VCN) neurons’ survival. Conversely, although the cell size and VGLUT-1 expression in the VCN significantly decreased after earplug insertion, VGLUT-2 expression in the granule cell lamina significantly increased. These cell sizes decreased and the alterations in VGLUT-1 and -2 expression almost completely recovered at 1 month after earplug removal. Our results suggested that the cell size and VGLUT expression in the CN have a neuroplasticity capacity, which is regulated by increases and decreases in sound levels. Restoration of the sound levels might partly prevent cell size decrease and maintain VGLUT expression in the CN.

Morphological and molecular correlates of altered hearing sensitivity in the genetically audiogenic seizure-prone hamster GASH/Sal

Rodent models of audiogenic seizures, in which seizures are precipitated by an abnormal response of the brain to auditory stimuli, are crucial to investigate the neural bases underlying ictogenesis. Despite significant advances in understanding seizure generation in the inferior colliculus, namely the epileptogenic nucleus, little is known about the contribution of lower auditory stations to the seizure-prone network. Here, we examined the cochlea and cochlear nucleus of the genetic audiogenic seizure hamster from Salamanca (GASH/Sal), a model of reflex epilepsy that exhibits generalized tonic–clonic seizures in response to loud sound. GASH/Sal animals under seizure-free conditions were compared with matched control hamsters in a multi-technical approach that includes auditory brainstem responses (ABR) testing, histology, scanning electron microscopy analysis, immunohistochemistry, quantitative morphometry and gene expression analysis (RT-qPCR). The cochlear histopathology of the GASH/Sal showed preservation of the sensory hair cells, but a significant loss of spiral ganglion neurons and mild atrophy of the stria vascularis. At the electron microscopy level, the reticular lamina exhibited disarray of stereociliary tufts with blebs, loss or elongated stereocilia as well as non-parallel rows of outer hair cells due to protrusions of Deiters’ cells. At the molecular level, the abnormal gene expression patterns of prestin, cadherin 23, protocadherin 15, vesicular glutamate transporters 1 (Vglut1) and -2 (Vglut2) indicated that the hair-cell mechanotransduction and cochlear amplification were markedly altered. These were manifestations of a cochlear neuropathy that correlated to ABR waveform I alterations and elevated auditory thresholds. In the cochlear nucleus, the distribution of VGLUT2-immunolabeled puncta was differently affected in each subdivision, showing significant increases in magnocellular regions of the ventral cochlear nucleus and drastic reductions in the granule cell domain. This modified inputs lead to disruption of Vglut1 and Vglut2 gene expression in the cochlear nucleus. In sum, our study provides insight into the morphological and molecular traits associated with audiogenic seizure susceptibility in the GASH/Sal, suggesting an upward spread of abnormal glutamatergic transmission throughout the primary acoustic pathway to the epileptogenic region.

Loss of inner hair cell ribbon synapses and auditory nerve fiber regression in Cldn14 knockout mice

Proper functioning of the auditory nerve is of critical importance for auditory rehabilitation by cochlear implants. Here we used the Cldn14−/− mouse to study in detail the effects of Claudin 14 loss on auditory synapses and the auditory nerve. Mutations in the tight junction protein Claudin 14 cause autosomal recessive non-syndromic hearing loss (DFNB29) in humans and mice, due to extensive degeneration of outer and inner hair cells. Here we show that massive inner hair cell loss in Cldn14−/− mice starts after the third postnatal week. Immunohistochemical analysis, using presynaptic Ribeye and postsynaptic GluR2 or PSD 95 as markers, revealed the degeneration of full ribbon synapses in inner hair cells from apical cochlear regions already at postnatal day 12 (P12). At P20, significant reduction in number of ribbon synapses has been observed for all cochlear regions and the loss of synaptic ribbons becomes even more prominent in residual inner hair cells from middle and apical cochlear regions at P45, which by then lost more than 40% of all ribbon synapses. In contrast to excessive noise exposure, loss of Claudin 14 does not cause an increase in “orphan” ribbons with no postsynaptic counterpart due to a reduction of postsynaptic structures. Hair cell loss in Cldn14−/− mice is associated with regression of peripheral auditory nerve processes, especially of outer radial fibers, which normally innervate the outer hair cells. The number of spiral ganglion neurons per area, however, was unchanged between the genotypes. Different effects were observed in the cochlear nucleus complex (CNC), the central projection area of the auditory nerve. While the dorsal cochlear nucleus (DCN) showed a significant 19.7% volume reduction, VGLUT-1 input was reduced by 34.4% in the ventral cochlear nucleus (VCN) but not in the DCN of Cldn14−/− mice. Taken together, massive inner hair cell loss starts after the third postnatal week in Cldn14−/− mice, but is preceded by the loss of ribbon synapses, which may be a first sign of an ongoing degeneration process in otherwise morphologically inconspicuously inner hair cells. In addition to the regression of peripheral nerve processes, reduced levels of VGLUT-1 in the VCN of Cldn14−/− mice suggests that Claudin 14 loss does not only cause hair cell loss but also affects peripheral and central connectivity of the auditory nerve.

Muscarinic modulation of M and h currents in gerbil spherical bushy cells.

Descending cholinergic fibers innervate the cochlear nucleus. Spherical bushy cells, principal neurons of the anterior part of the ventral cochlear nucleus, are depolarized by cholinergic agonists on two different time scales. A fast and transient response is mediated by alpha-7 homomeric nicotinic receptors while a slow and long-lasting response is mediated by muscarinic receptors. Spherical bushy cells were shown to express M3 receptors, but the receptor subtypes involved in the slow muscarinic response were not physiologically identified yet. Whole-cell patch clamp recordings combined with pharmacology and immunohistochemistry were performed to identify the muscarinic receptor subtypes and the effector currents involved. Spherical bushy cells also expressed both M1 and M2 receptors. The M1 signal was stronger and mainly somatic while the M2 signal was localized in the neuropil and on the soma of bushy cells. Physiologically, the M-current was observed for the gerbil spherical bushy cells and was inhibited by oxotremorine-M application. Surprisingly, long application of carbachol showed only a transient depolarization. Even though no muscarinic depolarization could be detected, the input resistance increased suggesting a decrease in the cell conductance that matched with the closure of M-channels. The hyperpolarization-activated currents were also affected by muscarinic activation and counteracted the effect of the inactivation of M-current on the membrane potential. We hypothesize that this double muscarinic action might allow adaptation of effects during long durations of cholinergic activation.

D-Stellate Neurons of the Ventral Cochlear Nucleus Decrease in Auditory Nerve-Evoked Activity during Age-Related Hearing Loss.

Age-related hearing loss (ARHL) is associated with weakened inhibition in the central auditory nervous system including the cochlear nucleus. One of the main inhibitory neurons of the cochlear nucleus is the D-stellate neuron, which provides extensive glycinergic inhibition within the local neural network. It remains unclear how physiological activities of D-stellate neurons change during ARHL and what are the underlying mechanisms. Using in vitro whole-cell patch clamp technique, we studied the intrinsic membrane properties of D-stellate neurons, the changes of their firing properties, and the underlying mechanisms in CBA/CaJ mice at the ages of 3–4 months (young), 17–19 months (middle age), and 27–33 months (aged). We found that the intrinsic membrane properties of D-stellate neurons were unchanged among these three age groups. However, these neurons showed decreased firing rate with age in response to sustained auditory nerve stimulation. Further investigation showed that auditory nerve-evoked excitatory postsynaptic currents (EPSCs) were significantly reduced in strength with age. These findings suggest that D-stellate neurons receive weakened synaptic inputs from the auditory nerve and decreased sound driven activity with age, which are expected to reduce the overall inhibition and enhance the central gain in the cochlear nucleus during ARHL.

Nitric oxide regulates the firing rate of neuronal subtypes in the guinea pig ventral cochlear nucleus.

The gaseous free radical, nitric oxide (NO) acts as a ubiquitous neuromodulator, contributing to synaptic plasticity in a complex way that can involve either long term potentiation or depression. It is produced by neuronal nitric oxide synthase (nNOS) which is presynaptically expressed and also located postsynaptically in the membrane and cytoplasm of a subpopulation of each major neuronal type in the ventral cochlear nucleus (VCN). We have used iontophoresis in vivo to study the effect of the NOS inhibitor L‐NAME (L‐NG‐Nitroarginine methyl ester) and the NO donors SIN‐1 (3‐Morpholinosydnonimine hydrochloride) and SNOG (S‐Nitrosoglutathione) on VCN units under urethane anaesthesia. Collectively, both donors produced increases and decreases in driven and spontaneous firing rates of some neurones. Inhibition of endogenous NO production with L‐NAME evoked a consistent increase in driven firing rates in 18% of units without much effect on spontaneous rate. This reduction of gain produced by endogenous NO was mirrored when studying the effect of L‐NAME on NMDA(N‐Methyl‐D‐aspartic acid)‐evoked excitation, with 30% of units showing enhanced NMDA‐evoked excitation during L‐NAME application (reduced NO levels). Approximately 25% of neurones contain nNOS and the NO produced can modulate the firing rate of the main principal cells: medium stellates (choppers), large stellates (onset responses) and bushy cells (primary‐like responses). The main endogenous role of NO seems to be to partly suppress driven firing rates associated with NMDA channel activity but there is scope for it to increase neural gain if there were a pathological increase in its production following hearing loss.

Hearing impairment and associated morphological changes in pituitary adenylate cyclase activating polypeptide (PACAP)-deficient mice

Pituitary adenylate cyclase activating polypeptide (PACAP) is a regulatory and cytoprotective neuropeptide, its deficiency implies accelerated aging in mice. It is present in the auditory system having antiapoptotic effects. Expression of Ca2+-binding proteins and its PAC1 receptor differs in the inner ear of PACAP-deficient (KO) and wild-type (WT) mice. Our aim was to elucidate the functional role of PACAP in the auditory system. Auditory brainstem response (ABR) tests found higher hearing thresholds in KO mice at click and low frequency burst stimuli. Hearing impairment at higher frequencies showed as reduced ABR wave amplitudes and latencies in KO animals. Increase in neuronal activity, demonstrated by c-Fos immunolabeling, was lower in KO mice after noise exposure in the ventral and dorsal cochlear nuclei. Noise induced neuronal activation was similar in further relay nuclei of the auditory pathway of WT and KO mice. Based on the similar inflammatory and angiogenic protein profile data from cochlear duct lysates, neither inflammation nor disturbed angiogenesis, as potential pathological components in sensorineural hearing losses, seem to be involved in the pathomechanism of the presented functional and morphological changes in PACAP KO mice. The hearing impairment is probably concomitant with the markedly accelerated aging processes in these animals.

Classification of neurons in the adult mouse cochlear nucleus: Linear discriminant analysis.

The cochlear nucleus (CN) transforms the spike trains of spiral ganglion cells into a set of sensory representations that are essential for auditory discriminations and perception. These transformations require the coordinated activity of different classes of neurons that are embryologically derived from distinct sets of precursors. Decades of investigation have shown that the neurons of the CN are differentiated by their morphology, neurotransmitter receptors, ion channel expression and intrinsic excitability. In the present study we have used linear discriminant analysis (LDA) to perform an unbiased analysis of measures of the responses of CN neurons to current injections to objectively categorize cells on the basis of both morphology and physiology. Recordings were made from cells in brain slices from CBA/CaJ mice and a transgenic mouse line, NF107, crossed against the Ai32 line. For each cell, responses to current injections were analyzed for spike rate, spike shape, input resistance, resting membrane potential, membrane time constant, hyperpolarization-activated sag and time constant. Cells were filled with dye for morphological classification, and visually classified according to published accounts. The different morphological classes of cells were separated with the LDA. Ventral cochlear nucleus (VCN) bushy cells, planar multipolar (T-stellate) cells, and radiate multipolar (D-stellate) cells were in separate clusters and separate from all of the neurons from the dorsal cochlear nucleus (DCN). Within the DCN, the pyramidal cells and tuberculoventral cells were largely separated from a distinct cluster of cartwheel cells. principal axes, whereas VCN cells were in 3 clouds approximately orthogonal to this plane. VCN neurons from the two mouse strains overlapped but were slightly separated, indicating either a strain dependence or differences in slice preparation methods. We conclude that cochlear nucleus neurons can be objectively distinguished based on their intrinsic electrical properties, but such distinctions are still best aided by morphological identification.

Is there “hidden hearing loss” in patients with chronic rhinosinusitis?

Objective: This study was to investigate whether there is impairment of auditory function in chronic rhinosinusitis (CRS).Study sample: A total of 85 patients were allocated into either the CRS group (n = 65) or a simple deviated nasal septum group (n = 20). Both groups without other risk factors for sensorineural hearing loss exhibited normal thresholds at standard audiometric frequencies. Another group (n = 30) of healthy subjects without CRS or a deviated nasal septum were gender and age matched.Design: Analyse the results of audiology test including pure tone audiometry, an acoustic impedance test, distortion product otoacoustic emissions (DPOAE) and the auditory brainstem response (ABR) for each subject analyse the test results of for each object.Results: The group differences were statistically significant for each high-frequency pure tone (p < 0.05). The ABR showed a difference between groups in amplitude. The DPOAE pass rate of the CRS group was lower than that of the control group.Conclusions: This study showed a significant correlation between CRS and auditory impairment. CRS might impair cochlear functions by damaging inner ear hair cells and/or, outer hair cells (OHCs), consequently altering the activity of the entire auditory pathway originating in the ventral cochlear nucleus (VCN) to the inferior colliculus.

Large-Scale Networks for Auditory Sensory Gating in the Awake Mouse.

The amplitude of the brain response to a repeated auditory stimulus is diminished as compared to the response to the first tone (T1) for interstimulus intervals (ISI) lasting up to hundreds of milliseconds. This adaptation process, called auditory sensory gating (ASG), is altered in various psychiatric diseases including schizophrenia and is classically studied by focusing on early evoked cortical responses to the second tone (T2) using 500-ms ISI. However, mechanisms underlying ASG are still not well-understood. We investigated ASG in awake mice from the brainstem to cortex at variable ISIs (125–2000 ms) using high-density EEG and intracerebral recordings. While ASG decreases at longer ISIs, it is still present at durations (500–2000 ms) far beyond the time during which brain responses to T1 could still be detected. T1 induces a sequence of specific stable scalp EEG topographies that correspond to the successive activation of distinct neural networks lasting about 350 ms. These brain states remain unaltered if T2 is presented during this period, although T2 is processed by the brain, suggesting that ongoing networks of brain activity are active for longer than early evoked-potentials and are not overwritten by an upcoming new stimulus. Intracerebral recordings demonstrate that ASG is already present at the level of ventral cochlear nucleus (vCN) and inferior colliculus and is amplified across the hierarchy in bottom-up direction. This study uncovers the extended stability of sensory-evoked brain states and long duration of ASG, and sheds light on generators of ASG and possible interactions between bottom-up and top-down mechanisms.

Morphological development of the human cochlear nucleus

Morphological studies in developing brain determine critical periods of proliferation, neurogenesis, gliogenesis, and apoptosis. During these periods both intrinsic and extrinsic pathological factors can hamper development. These time points are not available for the human cochlear nucleus (CN). We have used design-based stereology and determined that 18–22 weeks of gestation (WG) are critical in the development of the human CN. Twenty-three fetuses and seven postnatal brainstems were processed for cresyl violet (CV) staining and immunoexpression of NeuN (neurons), GFAP (astrocytes), Ki-67 (proliferation) and TUNEL (apoptosis) and 3-D reconstruction. The volume of CN, total number of neurons selected profiles and the volume of neurons and their nuclei were estimated. Data were grouped (G) into: G1:18-20 WG, G2: 21–24 WG, G3: 25–28 WG and G4 >29 WG. The dimensions of morphologically identified neurons were also measured. The CN primordium was first identifiable at 10WG. Definitive DCN (Dorsal cochlear nucleus) and VCN (ventral cochlear nucleus) were identifiable at 16 WG. There was a sudden growth spurt in total volume of CN, number of neurons and astrocytes from 18 WG. We also observed an increase in proliferation and apoptosis after 22 WG. The number of neurons identifiable by CV was significantly lower than that by NeuN-immunostaining till 25 WG (p = 0.020), after which, both methods were equivalent. Eight morphological types of neurons were identifiable by 26 WG and could be resolved into four clusters by volume and diameter. The CN changed orientation from small, flat and horizontal at 10–16 WG to larger and oblique from 18WG onwards. Prevention of exposure to noxious factors at 18–22 WG may be important in preventing congenital deafness.

Increased Gain in the Auditory Pathway, Alzheimer's Disease Continuum, and Air Pollution: Peripheral and Central Auditory System Dysfunction Evolves Across Pediatric and Adult Urbanites.

A major impediment in early diagnosis of Alzheimer's disease (AD) is the lack of robust non-invasive biomarkers of early brain dysfunction. Metropolitan Mexico City (MMC) children and young adults show hyperphosphorylated tau, amyloid-β, and α-synuclein within auditory and vestibular nuclei and marked dysmorphology in the ventral cochlear nucleus and superior olivary complex. Based on early involvement of auditory brainstem centers, we believe brainstem auditory evoked potentials can provide early AD biomarkers in MMC young residents. We measured brainstem auditory evoked potentials in MMC clinically healthy children (8.52±3.3 years) and adults (21.08±3.0 years, 42.48±8.5 years, and 71.2±6.4 years) compared to clean air controls (6.5±0.7 years) and used multivariate analysis adjusting for age, gender, and residency. MMC children had decreased latency to wave I, delays in waves III and V, and longer latencies for interwave intervals, consistent with delayed central conduction time of brainstem neural transmission. In sharp contrast, young adults have significantly shortened interwave intervals I-III and I-V. By the 5th decade, wave V and interval I-V were significantly shorter, while the elderly cohort had significant delay in mean latencies and interwave intervals. Compensatory plasticity, increased auditory gain, cochlear synaptopathy, neuroinflammation, and AD continuum likely play a role in the evolving distinct auditory pathology in megacity urbanites. Understanding auditory central and peripheral dysfunction in the AD continuum evolving and progressing in pediatric and young adult populations may shed light on the complex mechanisms of AD development and help identify strong noninvasive biomarkers. AD evolving from childhood in air pollution environments ought to be preventable.

Sensory deafferentation modulates and redistributes neurocan in the rat auditory brainstem.

IntroductionCochlear ablation causing sensory deafferentation (SD) of the cochlear nucleus triggers complex re‐arrangements in the cellular and molecular communication networks of the adult mammalian central auditory system. Participation of the extracellular matrix (ECM) in these processes is not well understood.MethodsWe investigated consequences of unilateral SD for the expression and distribution of the chondroitin sulfate proteoglycans, neurocan (Ncan) and aggrecan (Agg), alongside various plasticity markers in the auditory brainstem of the adult rat using immunohistochemical techniques.ResultsIn the deafferented ventral cochlear nucleus (VCN), Ncan expression increased massively within 3 postoperative days (POD), but rapidly decreased thereafter. Agg showed a similar but less pronounced progression. Decrease in Ncan was spatially and temporally related to the re‐innervation of VCN documented by the emergence of growth‐associated protein Gap43 contained in nerve fibers and presynaptic boutons. Concurrently, astrocytes grew and expressed matrix metalloproteinase‐2 (MMP2), an enzyme known to emerge only under re‐innervation of VCN. MMP2 is capable of cleaving both Ncan and Agg when released. A transient modulation of the ECM in the central inferior colliculus on the side opposite to SD occurred by POD1. Modulations of glutamatergic synapses and Gap43 expression were detected, reflecting state changes of the surrounding tissue induced by transsynaptic effects of SD.ConclusionsThe ECM variously participates in adaptive responses to sudden deafness by SD on several levels along the central auditory pathway, with a striking spatial and temporal relationship of Ncan modulation to astrocytic activation and to synaptogenesis.

Npr2 null mutants show initial overshooting followed by reduction of spiral ganglion axon projections combined with near-normal cochleotopic projection.

Npr2 (natriuretic peptide receptor 2) affects bifurcation of neural crest or placode-derived afferents upon entering the brain stem/spinal cord, leading to a lack of either rostral or caudal branches. Previous work has shown that early embryonic growth of cochlear and vestibular afferents is equally affected in this mutant but later work on postnatal Npr2 point mutations suggested some additional effects on the topology of afferent projections and mild functional defects. Using multicolor lipophilic dye tracing, we show that absence of Npr2 has little to no effect on the initial patterning of inner ear afferents with respect to their dorsoventral cochleotopic-specific projections. However, in contrast to control animals, we found a variable degree of embryonic extension of auditory afferents beyond the boundaries of the anterior cochlear nucleus into the cerebellum that emanates only from apical spiral ganglion neurons. Such expansion has previously only been reported for Hox gene mutants and implies an unclear interaction of Hox codes with Npr2-mediated afferent projection patterning to define boundaries. Some vestibular ganglion neurons expand their projections to reach the cochlear apex and the cochlear nuclei, comparable to previous findings in Neurod1 mutant mice. Before birth, such expansions are reduced or lost leading to truncated projections to the anteroventral cochlear nucleus and expansion of low-frequency fibers of the apex to the posteroventral cochlear nucleus.

Nitric Oxide-Mediated Plasticity of Interconnections Between T-Stellate cells of the Ventral Cochlear Nucleus Generate Positive Feedback and Constitute a Central Gain Control in the Auditory System.

T-stellate cells in the ventral cochlear nucleus (VCN) form an ascending pathway that conveys spectral information from the cochlea to brainstem nuclei, the inferior colliculi, and the thalamus. The tonotopic array of T-stellate cells enhances the encoding of spectral peaks relative to their auditory nerve fiber inputs. The alignment of local collaterals and T-stellate cell dendrites within the isofrequency lamina suggests that the cells make connections within the isofrequency lamina in which they reside. Recordings from pairs of T-stellate cells in mice of both sexes revealed that firing in the presynaptic cell evoked responses in the postsynaptic cell when presynaptic firing was paired with depolarization of the postsynaptic cell. After such experimental coactivation, presynaptic firing evoked EPSCs of uniform amplitude whose frequency depended on the duration of depolarization and diminished over minutes. Nitric oxide (NO) donors evoked EPSCs in T-stellate cells but not in the other types of principal cells. Blockers of neuronal nitric oxide synthase (nNOS) and of NMDA receptors blocked potentiation, indicating that NO mediates potentiation. nNOS and its receptor, guanylate cyclase (NO-GC), are expressed in somata of T-stellate cells. Excitatory interconnections were bidirectional and polysynaptic, indicating that T-stellate cells connect in networks. Positive feedback provided by temporarily potentiated interconnections between T-stellate cells could enhance the gain of auditory nerve excitation in proportion to the excitation, generating a form of short-term central gain control that could account for the ability of T-stellate cells to enhance the encoding of spectral peaks.SIGNIFICANCE STATEMENT T-stellate cells are interconnected through synapses that have a previously undescribed form of temporary, nitric oxide-mediated plasticity. Coactivation of neighboring cells enhances the activation of an excitatory network that feeds back on itself by enhancing the probability of EPSCs. Although there remain gaps in our understanding of how the interconnections revealed in slices contribute to hearing, our findings have interesting implications. Positive feedback through a network of interconnections could account for how T-stellate cells are able to encode spectral peaks over a wider range of intensities than many of their auditory nerve inputs (Blackburn and Sachs, 1990; May et al., 1998). The magnitude of the gain may itself be plastic because neuronal nitric oxide synthase increases when animals have tinnitus (Coomber et al., 2015).

Biophysical Properties of ERG Channels in Octopus Neurons of Ventral Cochlear Nucleus

Biophysical Properties of ERG Channels in Octopus Neurons of Ventral Cochlear Nucleus

LAMP5 in presynaptic inhibitory terminals in the hindbrain and spinal cord: a role in startle response and auditory processing

Lysosome-associated membrane protein 5 (LAMP5) is a mammalian ortholog of the Caenorhabditis elegans protein, UNC-46, which functions as a sorting factor to localize the vesicular GABA transporter UNC-47 to synaptic vesicles. In the mouse forebrain, LAMP5 is expressed in a subpopulation of GABAergic neurons in the olfactory bulb and the striato-nigral system, where it is required for fine-tuning of GABAergic synaptic transmission. Here we focus on the prominent expression of LAMP5 in the brainstem and spinal cord and suggest a role for LAMP5 in these brain regions. LAMP5 was highly expressed in several brainstem nuclei involved with auditory processing including the cochlear nuclei, the superior olivary complex, nuclei of the lateral lemniscus and grey matter in the spinal cord. It was localized exclusively in inhibitory synaptic terminals, as has been reported in the forebrain. In the absence of LAMP5, localization of the vesicular inhibitory amino acid transporter (VIAAT) was unaltered in the lateral superior olive and the ventral cochlear nuclei, arguing against a conserved role for LAMP5 in trafficking VIAAT. Lamp5 knockout mice showed no overt behavioral abnormality but an increased startle response to auditory and tactile stimuli. In addition, LAMP5 deficiency led to a larger intensity-dependent increase of wave I, II and V peak amplitude of auditory brainstem response. Our results indicate that LAMP5 plays a pivotal role in sensorimotor processing in the brainstem and spinal cord.

Diameters of Perikarya in Different Regions of Rat Central Nervous System after Streptomycin and Kanamycin Intoxication

Introduction: Streptomycin and Kanamycin, an aminoglycosidic antibiotic, is known to destroy the ventral cochlear nuclei of brainstem in man. Ototoxicity is well known side effect of kanamycin, the effect on central nervous system in general and central auditory pathway in particular is still unclear. Subjects and Methods: Thirty albino rats were divided into three groups I, II and III of ten animals each. Group III was control. Group I and II received Streptomycin (30mg/Kg body weight) and kanamycin (400mg/kg body weight) intramuscular injections, daily for 3 weeks. Paraffin embedded sections of cerebellum, spinal cord, dorsal cochlear nucleus, inferior colliculus nucleus and auditory cortex were stained with haematoxylin and eosin stains and perikarya measured using slide and ocular micrometres. Results: Size of cerebellar Purkinje cells increased significantly in control rats for streptomycin and kanamycin intoxicated animals respectively. Ventral horn cells of spinal cord are affected highly significantly only by streptomycin. Vestibular nucleus also showed similar results i.e. neuronal body. Neurons of dorsal cochlear nucleus is affected significantly by both the drugs i.e. streptomycin and kanamycin. Conclusion: Streptomycin causes an increase in diameter of auditory cortical cells on other hand kanamycin led to highly significant decrement in size of cells of same region. Preferential affinity and differential effects were noticed. The latter throws some clues about mechanism of action.