Neural circuit repair by low-intensity magnetic stimulation requires cellular magnetoreceptors and specific stimulation patterns.

Although electromagnetic brain stimulation is a promising treatment in neurology and psychiatry, clinical outcomes are variable, and underlying mechanisms are ill-defined, which impedes the development of new effective stimulation protocols. Here, we show, in vivo and ex vivo, that repetitive transcranial magnetic stimulation at low-intensity (LI-rTMS) induces axon outgrowth and synaptogenesis to repair a neural circuit. This repair depends on stimulation pattern, with complex biomimetic patterns being particularly effective, and the presence of cryptochrome, a putative magnetoreceptor. Only repair-promoting LI-rTMS patterns up-regulated genes involved in neuronal repair; almost 40% of were cryptochrome targets. Our data open a new framework to understand the mechanisms underlying structural neuroplasticity induced by electromagnetic stimulation. Rather than neuronal activation by induced electric currents, we propose that weak magnetic fields act through cryptochrome to activate cellular signaling cascades. This information opens new routes to optimize electromagnetic stimulation and develop effective treatments for different neurological diseases.

Increased medial olivocochlear reflex strength in normal-hearing, noise-exposed humans.

Research suggests that college-aged adults are vulnerable to tinnitus and hearing loss due to exposure to traumatic levels of noise on a regular basis. Recent human studies have associated exposure to high noise exposure background (NEB, i.e., routine noise exposure) with the reduced cochlear output and impaired speech processing ability in subjects with clinically normal hearing sensitivity. While the relationship between NEB and the functions of the auditory afferent neurons are studied in the literature, little is known about the effects of NEB on functioning of the auditory efferent system. The objective of the present study was to investigate the relationship between medial olivocochlear reflex (MOCR) strength and NEB in subjects with clinically normal hearing sensitivity. It was hypothesized that subjects with high NEB would exhibit reduced afferent input to the MOCR circuit which would subsequently lead to reduced strength of the MOCR. In normal-hearing listeners, the study examined (1) the association between NEB and baseline click-evoked otoacoustic emissions (CEOAEs) and (2) the association between NEB and MOCR strength. The MOCR was measured using CEOAEs evoked by 60 dB pSPL linear clicks in a contralateral acoustic stimulation (CAS)-off and CAS-on (a broadband noise at 60 dB SPL) condition. Participants with at least 6 dB signal-to-noise ratio (SNR) in the CAS-off and CAS-on conditions were included for analysis. A normalized CEOAE inhibition index was calculated to express MOCR strength in a percentage value. NEB was estimated using a validated questionnaire. The results showed that NEB was not associated with the baseline CEOAE amplitude (r = -0.112, p = 0.586). Contrary to the hypothesis, MOCR strength was positively correlated with NEB (r = 0.557, p = 0.003). NEB remained a significant predictor of MOCR strength (ß = 2.98, t(19) = 3.474, p = 0.003) after the unstandardized coefficient was adjusted to control for effects of smoking, sound level tolerance (SLT) and tinnitus. These data provide evidence that MOCR strength is associated with NEB. The functional significance of increased MOCR strength is discussed.

BrainFrame: a node-level heterogeneous accelerator platform for neuron simulations.

OBJECTIVE: The advent of high-performance computing (HPC) in recent years has led to its increasing use in brain studies through computational models. The scale and complexity of such models are constantly increasing, leading to challenging computational requirements. Even though modern HPC platforms can often deal with such challenges, the vast diversity of the modeling field does not permit for a homogeneous acceleration platform to effectively address the complete array of modeling requirements. APPROACH: In this paper we propose and build BrainFrame, a heterogeneous acceleration platform that incorporates three distinct acceleration technologies, an Intel Xeon-Phi CPU, a NVidia GP-GPU and a Maxeler Dataflow Engine. The PyNN software framework is also integrated into the platform. As a challenging proof of concept, we analyze the performance of BrainFrame on different experiment instances of a state-of-the-art neuron model, representing the inferior-olivary nucleus using a biophysically-meaningful, extended Hodgkin-Huxley representation. The model instances take into account not only the neuronal-network dimensions but also different network-connectivity densities, which can drastically affect the workload's performance characteristics. MAIN RESULTS: The combined use of different HPC technologies demonstrates that BrainFrame is better able to cope with the modeling diversity encountered in realistic experiments while at the same time running on significantly lower energy budgets. Our performance analysis clearly shows that the model directly affects performance and all three technologies are required to cope with all the model use cases. SIGNIFICANCE: The BrainFrame framework is designed to transparently configure and select the appropriate back-end accelerator technology for use per simulation run. The PyNN integration provides a familiar bridge to the vast number of models already available. Additionally, it gives a clear roadmap for extending the platform support beyond the proof of concept, with improved usability and directly useful features to the computational-neuroscience community, paving the way for wider adoption.

Active integration of glutamatergic input to the inferior olive generates bidirectional postsynaptic potentials.

KEY POINTS: We establish experimental preparations for optogenetic investigation of glutamatergic input to the inferior olive. Neurones in the principal olivary nucleus receive monosynaptic extra-somatic glutamatergic input from the neocortex. Glutamatergic inputs to neurones in the inferior olive generate bidirectional postsynaptic potentials (PSPs), with a fast excitatory component followed by a slower inhibitory component. Small conductance calcium-activated potassium (SK) channels are required for the slow inhibitory component of glutamatergic PSPs and oppose temporal summation of inputs at intervals ≤ 20 ms. Active integration of synaptic input within the inferior olive may play a central role in control of olivo-cerebellar climbing fibre signals. ABSTRACT: The inferior olive plays a critical role in motor coordination and learning by integrating diverse afferent signals to generate climbing fibre inputs to the cerebellar cortex. While it is well established that climbing fibre signals are important for motor coordination, the mechanisms by which neurones in the inferior olive integrate synaptic inputs and the roles of particular ion channels are unclear. Here, we test the hypothesis that neurones in the inferior olive actively integrate glutamatergic synaptic inputs. We demonstrate that optogenetically activated long-range synaptic inputs to the inferior olive, including projections from the motor cortex, generate rapid excitatory potentials followed by slower inhibitory potentials. Synaptic projections from the motor cortex preferentially target the principal olivary nucleus. We show that inhibitory and excitatory components of the bidirectional synaptic potentials are dependent upon AMPA (GluA) receptors, are GABAA independent, and originate from the same presynaptic axons. Consistent with models that predict active integration of synaptic inputs by inferior olive neurones, we find that the inhibitory component is reduced by blocking large conductance calcium-activated potassium channels with iberiotoxin, and is abolished by blocking small conductance calcium-activated potassium channels with apamin. Summation of excitatory components of synaptic responses to inputs at intervals ≤ 20 ms is increased by apamin, suggesting a role for the inhibitory component of glutamatergic responses in temporal integration. Our results indicate that neurones in the inferior olive implement novel rules for synaptic integration and suggest new principles for the contribution of inferior olive neurones to coordinated motor behaviours.

Maturation of glutamatergic transmission in the vestibulo-olivary pathway impacts on the registration of head rotational signals in the brainstem of rats.

The recognition of head orientation in the adult involves multi-level integration of inputs within the central vestibular circuitry. How the different inputs are recruited during postnatal development remains unclear. We hypothesize that glutamatergic transmission at the vestibular nucleus contributes to developmental registration of head orientations along the vestibulo-olivary pathway. To investigate the maturation profile by which head rotational signals are registered in the brainstem, we used sinusoidal rotations on the orthogonal planes of the three pairs of semicircular canals. Fos expression was used as readout of neurons responsive to the rotational stimulus. Neurons in the vestibular nucleus and prepositus hypoglossal nucleus responded to all rotations as early as P4 and reached adult numbers by P21. In the reticular formation and inferior olive, neurons also responded to horizontal rotations as early as P4 but to vertical rotations not until P21 and P25, respectively. Neuronal subpopulations that distinguish between rotations activating the orthogonally oriented vertical canals were identifiable in the medial and spinal vestibular nuclei by P14 and in the inferior olivary subnuclei IOß and IOK by P25. Neonatal perturbation of glutamate transmission in the vestibular nucleus was sufficient to derange formation of this distribution in the inferior olive. This is the first demonstration that developmental refinement of glutamatergic synapses in the central vestibular circuitry is essential for developmental registration of head rotational signals in the brainstem.

Age related changes to the dynamics of contralateral DPOAE suppression in human subjects.

BACKGROUND: The two ears are linked with a neural pathway such that stimulation of one ear has a modulating effect on the contralateral cochlea. This is mediated by cochlear afferent neurons connecting with olivo-cochlear efferents. The monitoring of this pathway is easily achieved by measuring contralateral suppression of otoacoustic emissions, and there is some clinical value in the ability to assess the integrity of this pathway. An important step in an evaluation of clinical utility is to assess any age-related changes. Accordingly, in the present study we measure the dynamics of contralateral DPOAE suppression in a population of normal hearing subjects of different ages. METHODS: Using a real-time DPOAE recording method we assessed contralateral DPOAE suppression in 95 ears from 51 subjects (age range 2-52 years). DPOAE (2f1-f2; f2 = 4.4 kHz; f2/f1 = 1.22) input-output functions were measured. In response to contralateral broadband noise, dynamic aspects of DPOAE suppression were measured, specifically suppression onset latency and time constants. RESULTS: An age-related reduction in DPOAE amplitudes was observed. Both the detectability and the degree of contralateral DPOAE suppression were decreased in older age groups. We find an age-related increase in the latency of onset of DPOAE suppression to contralateral stimulation, but no significant change in suppression time-constants. CONCLUSION: Olivo-cochlear function as revealed by contralateral suppression of DPOAEs shows some important age-related changes. In addition to reduced emissions (outer haircell suppression) we find an increased latency that may reflect deterioration in auditory brainstem function. Regarding clinical utility, it is possible that the changes observed may reflect an aspect of age-related hearing loss that has not been previously considered.

Protection from noise-induced hearing loss by Kv2.2 potassium currents in the central medial olivocochlear system.

The central auditory brainstem provides an efferent projection known as the medial olivocochlear (MOC) system, which regulates the cochlear amplifier and mediates protection on exposure to loud sound. It arises from neurons of the ventral nucleus of the trapezoid body (VNTB), so control of neuronal excitability in this pathway has profound effects on hearing. The VNTB and the medial nucleus of the trapezoid body are the only sites of expression for the Kv2.2 voltage-gated potassium channel in the auditory brainstem, consistent with a specialized function of these channels. In the absence of unambiguous antagonists, we used recombinant and transgenic methods to examine how Kv2.2 contributes to MOC efferent function. Viral gene transfer of dominant-negative Kv2.2 in wild-type mice suppressed outward K(+) currents, increasing action potential (AP) half-width and reducing repetitive firing. Similarly, VNTB neurons from Kv2.2 knock-out mice (Kv2.2KO) also showed increased AP duration. Control experiments established that Kv2.2 was not expressed in the cochlea, so any changes in auditory function in the Kv2.2KO mouse must be of central origin. Further, in vivo recordings of auditory brainstem responses revealed that these Kv2.2KO mice were more susceptible to noise-induced hearing loss. We conclude that Kv2.2 regulates neuronal excitability in these brainstem nuclei by maintaining short APs and enhancing high-frequency firing. This safeguards efferent MOC firing during high-intensity sounds and is crucial in the mediation of protection after auditory overexposure.

Effects of climbing fiber driven inhibition on Purkinje neuron spiking.

Climbing fiber (CF) input to the cerebellum is thought to instruct associative motor memory formation through its effects on multiple sites within the cerebellar circuit. We used adeno-associated viral delivery of channelrhodopsin-2 (ChR2) to inferior olivary neurons to selectively express ChR2 in CFs, achieving nearly complete transfection of CFs in the caudal cerebellar lobules of rats. As expected, optical stimulation of ChR2-expressing CFs generates complex spike responses in individual Purkinje neurons (PNs); in addition we found that such stimulation recruits a network of inhibitory interneurons in the molecular layer. This CF-driven disynaptic inhibition prolongs the postcomplex spike pause observed when spontaneously firing PNs receive direct CF input; such inhibition also elicits pauses in spontaneously firing PNs not receiving direct CF input. Baseline firing rates of PNs are strongly suppressed by low-frequency (2 Hz) stimulation of CFs, and this suppression is partly relieved by blocking synaptic inhibition. We conclude that CF-driven, disynaptic inhibition has a major influence on PN excitability and contributes to the widely observed negative correlation between complex and simple spike rates. Because they receive input from many CFs, molecular layer interneurons are well positioned to detect the spatiotemporal patterns of CF activity believed to encode error signals. Together, our findings suggest that such inhibition may bind together groups of Purkinje neurons to provide instructive signals to downstream sites in the cerebellar circuit.

O papel do sistema olivococlear medial em crianças portadoras de TDAH / Role of the medial olivocochlear system among children with ADHD

Crianças portadoras de Transtorno do Déficit de Atenção/Hiperatividade (TDAH) apresentam como um de seus principais sintomas a dificuldade de atenção. Na audição, a Atenção Seletiva que se caracteriza por ser a capacidade de compreender a fala em ambientes ruidosos, pode ser avaliada de várias formas, salientando-se o funcionamento do Sistema Eferente Olivococlear Medial. Este sistema pode ser avaliado pelo exame de emissões otoacústicas (EOA). OBJETIVO: Este trabalho teve por objetivo verificar a ocorrência do efeito de supressão de EOA, caracterizado pela diminuição da amplitude de resposta das emissões otoacústicas evocadas por estímulo transiente (EOAT) em resposta a apresentação de ruído contralateral, em crianças com TDAH (grupo estudo) e normais (grupo controle). Forma de Estudo: Estudo caso-controle. MATERIAL E MÉTODO: Foi realizado um estudo com 20 crianças alocadas em dois grupos de 10 crianças, pareadas por sexo e idade. Foi realizado o exame de EOAET sem e com ruído em ambos os grupos. RESULTADOS: Não houve diferença nas respostas das EOAET sem e com ruído, entre os grupos estudados. CONCLUSÕES: Pôde-se concluir que não há diferenças no funcionamento do Sistema Eferente Olivococlear Medial nas crianças com transtorno do déficit de atenção/hiperatividade em relação às crianças normais.

Attention deficit hyperactivity disorder (ADHD) patients show, as one of the main symptoms, an attentional impairment. Selective attention in the hearing process is the ability to understand speech in a noisy environment, which can be evaluated by several methods. One of the main approaches is the functioning of the Medial Olivocochlear Efferent System, which can be accessed by Transient-Evoked Otoacoustic Emissions (TOAE). OBJECTIVE:This study aimed at evaluating the suppression effect of contralateral noise on TOAE in ADHD (study group) and normal subjects (control group). Study Design: Case-control study. MATERIAL AND METHODS: A study with 20 children distributed in two, age- and gender-matched groups. RESULTS: No differences were found in TOAE responses between the two groups, with and without noise. CONCLUSIONS: We conclude that there were no functional differences in the Medial Olivocochlear Efferent System in the two groups analyzed.

Preliminary observations on the vasomotor responses to electrical stimulation of the ventrolateral surface of the human medulla.

OBJECT: Pulsatile arterial compression (AC) of the ventrolateral medulla (VLM) is hypothesized to produce the hypertension in a subset of patients with essential hypertension. In animals, a network of subpial neuronal aggregates in the VLM has been shown to control cardiovascular functions. Although histochemically similar, neurons have been identified in the retro-olivary sulcus (ROS) of the human VLM, but their function is unclear. METHODS: The authors recorded cardiovascular responses to electrical stimulation at various locations along the VLM surface, including the ROS, in patients who were undergoing posterior fossa surgery for trigeminal neuralgia. This vasomotor mapping of the medullary surface was performed using a bipolar electrode, with stimulation parameters ranging from 5- to 30-second trains (20-100 Hz), constant current (1.5-5 mA), and 0.1-msec pulse durations. Heart rate (HR) and blood pressure (BP) were recorded continuously from baseline (10 seconds before the stimulus) up to 1 minute poststimulus. In 6 patients, 17 stimulation responses in BP and HR were recorded. RESULTS: The frequency threshold for any cardiovascular response was 20 Hz; the stimulation intensity threshold ranged from 1.5 to 3 mA. In the first patient, all stimulation responses were significantly different from sham recordings (which consisted of electrodes placed without stimulations). Repeated stimulations in the lower ROS produced similar responses in 3 other patients. Two additional patients had similar responses to single stimulations in the lower ROS. Olive stimulation produced no response (control). Hypotensive and/or bradycardic responses were consistently followed by a reflex hypertensive response. Slight right/left differences were noted. No patient suffered short- or long-term effects from this stimulation. CONCLUSIONS: This stimulation technique for vasomotor mapping of the human VLM was safe and reproducible. Neuronal aggregates near the surface of the human ROS may be important in cardiovascular regulation. This method of vasomotor mapping with measures of responses in sympathetic tone (microneurography) should yield additional data for understanding the neuronal network that controls cardiovascular functions in the human VLM. Further studies in which a concentric bipolar electrode is used to generate this type of vasomotor map should also increase understanding of the pathophysiological mechanisms of neurogenically mediated hypertension, and assist in the design of studies to prove the hypothesis that it is caused by pulsatile AC of the VLM.

Alteration in auditory function during the ovarian cycle.

This study investigates whether physiological variations in ovarian hormones during the ovarian cycle (OC) are associated with changes in auditory function. Sixteen women with normal hearing underwent auditory tests and simultaneous measurements of the hormone levels four times during OC. The auditory tests included recording of otoacoustic emissions (OAEs), the medial olivocochlear (MOC) suppression and auditory brainstem responses (ABRs). The OC was defined by oestradiol and progesterone serum levels and menstrual cycle dating. A significant spontaneous OAE frequency shift [F(3,114.6)=15.8, p<0.001], with the greatest shift in the late follicular phase (highest oestrogen levels), was observed. Transient evoked OAE levels showed a consistent tendency in an increase in all frequency bands in the late follicular/early luteal stage and a decrease in the late follicular stage; TEOAE inter-session comparison indicated very small statistical differences. The MOC suppression changed significantly during OC [F(3,33.8)=3.2, p=0.036], with significant inter-session difference, lower in session 2 than in session 1 (p=0.019) and lower in session 4 than in session 1 (p=0.007). The ABR wave V absolute latency changed significantly during OC [F(3,33)=3.3, p=0.03], longer in the late follicular phase. There was also a significant positive correlation of TEOAEs and ABR (wave V latency and III-V interval) and significant negative correlation of MOC suppression with oestradiol levels in the follicular phase. The results of this study reflect very small changes in auditory function during OC, and they are suggestive of an increased hearing sensitivity around the time of ovulation.

Cochlear efferent innervation and function.

PURPOSE OF REVIEW: This review covers topics relevant to olivocochlear-efferent anatomy and function for which there are new findings in papers from 2009 to early 2010. RECENT FINDINGS: Work within the review period has increased our understanding of medial olivocochlear (MOC) mechanisms in outer hair cells, MOC-reflex tuning, MOC effects on distortion product otoacoustic emissions, the time course of MOC effects, MOC effects in psychophysical tests and on understanding speech, MOC effects in attention and learning, and lateral efferent function in binaural hearing. In addition, there are new insights into efferent molecular mechanisms and their effect on cochlear development. SUMMARY: Techniques for measuring efferent effects using otoacoustic emissions are now well developed and have promise in clinical applications ranging from predicting which patients are susceptible to acoustic trauma to characterizing relationships between efferent activation and learning disabilities. To realize this promise, studies are needed in which these techniques are applied with high standards.

[Projecting from the superior olivary complex to the inner ear in the cat: a retrograde fluorescent labelling study].

OBJECTIVE: To investigate the distribution and projective feature of cat olivocochlear neurons. METHODS: Eleven adult cats were divided into two groups randomly. The experimental group of eight cats was injected of 1% cholera toxin B (CTB) to the left cochlea, while injected of 5% fluoro gold (FG) to the right cochlea. The control group of three cats was injected of saline to bilateral cochlea. After a survival time of 7 days, serial frozen sections were cut in the cat brainstem. All the sections were processed by immunofluorescent procedure for CTB and FG, and the labeled olivocochlear neurons were observed by fluorescent microscope. RESULTS: In the experimental group, the mean total of olivocochlear neurons labeled by CTB and FG was 3210 +/- 168, including lateral olivocochlear neurons (LOC, 2298 +/- 120) and medial olivocochlear neurons (MOC, 913 +/- 64). The labeled neurons were divided into three different types according to their feature of projection: neurons which only projected to the ipsilateral cochlea, neurons which only projected to the contralateral cochlea, and double-labeled neurons which projected both to the ipsilateral and contralateral cochlea, but the double-labeled neurons comprised 3.9% and 15.1% in the LOC and MOC system respectively. No labeled neurons were found in the control group. CONCLUSIONS: There are three types of neurons in the cat olivocochlear system. The neurons which projected to the bilateral cochlea may distribute both in the LOC and MOC system.

Miniature EPSCs in the lateral superior olive before hearing onset: regional and cell-type-specific differences and heterogeneous neuromodulatory effects of ATP.

Spontaneous activity occurs in the mammalian auditory system prior to hearing onset and is relevant for neuronal differentiation. Growing evidence indicates that miniature events, i.e., action potential-independent synaptic activity, also have some developmental relevance. An intriguing question is whether these events are purely stochastic or rather display specific characteristics. We addressed this question and studied miniature excitatory postsynaptic currents (mEPSCs) in morphologically defined neurons of the rat lateral superior olive (LSO) during early neonatal life. To do so, whole-cell recordings from neurons in acute slices were combined with Lucifer yellow fillings. mEPSCs were identified by their TTX insensitivity and their blockade by glutamate receptor antagonists. Altogether, 60% of the LSO neurons displayed mEPSCs, and their presence correlated with the cell location and morphology. Their percentage was highest in the medial limb (86%) and lowest in the lateral limb (14%). Seventy-seven percent of the neurons with mEPSCs were bipolar cells, whereas 77% of those without mEPSCs were multipolar cells. The neuromodulator ATP affected the frequency of mEPSCs in 61% of the LSO neurons in a heterogeneous manner: both frequency increases and decreases occurred. These data provide further evidence for the specificity of mEPSCs. Finally, we investigated whether missing cochlear input changes mEPSCs characteristics. Characterizing LSO neurons of Ca(V)1.3(-/-) mice, which lack cochlea-driven nerve activity, we observed higher mEPSC frequencies and peak amplitudes, indicative of a compensatory response to deprivation. Together, our results demonstrate specific, rather than stochastic, characteristics of mEPSCs in the neonatal LSO, in accordance with their potential developmental significance.

Differential expression of TrkB isoforms switches climbing fiber-Purkinje cell synaptogenesis to selective synapse elimination.

Correct neural function depends on precisely organized connectivity, which is refined from broader projections through synaptic/collateral elimination. In the rat, olivocerebellar topography is refined by regression of multiple climbing fiber (CF) innervation of Purkinje cells (PC) during the first two postnatal weeks. The molecules that initiate this regression are not fully understood. We assessed the role of cerebellar neurotrophins by examining tropomycin receptor kinase (Trk) receptor expression in the inferior olive and cerebellum between postnatal days (P)3-7, when CF-PC innervation changes from synapse formation to selective synapse elimination, and in a denervation-reinnervation model when synaptogenesis is delayed. Trks A, B, and C are expressed in olivary neurons; although TrkA was not transported to the cerebellum and TrkC was unchanged during innervation and reinnervation, suggesting that neither receptor is involved in CF-PC synaptogenesis. In contrast, both total and truncated TrkB (TrkB.T) increased in the olive and cerebellum from P4, whereas full-length and activated phosphorylated TrkB (phospho-TrkB) decreased from P4-5. This reveals less TrkB signaling at the onset of CF regression. This expression pattern was reproduced during CF-PC reinnervation: in the denervated hemicerebellum phospho-TrkB decreased as CF terminals degenerated, then increased in parallel with the delayed neosynaptogenesis as new CFs reinnervated the denervated hemicerebellum. In the absence of this signaling, CF reinnervation did not develop. Our data reveal that olivocerebellar TrkB activity parallels CF-PC synaptic formation and stabilization and is required for neosynaptogenesis. Furthermore, TrkB.T expression rises to reduce TrkB signaling and permit synapse elimination.

A novel role for MNTB neuron dendrites in regulating action potential amplitude and cell excitability during repetitive firing.

Principal cells of the medial nucleus of the trapezoid body (MNTB) are simple round neurons that receive a large excitatory synapse (the calyx of Held) and many small inhibitory synapses on the soma. Strangely, these neurons also possess one or two short tufted dendrites, whose function is unknown. Here we assess the role of these MNTB cell dendrites using patch-clamp recordings, imaging and immunohistochemistry techniques. Using outside-out patches and immunohistochemistry, we demonstrate the presence of dendritic Na+ channels. Current-clamp recordings show that tetrodotoxin applied onto dendrites impairs action potential (AP) firing. Using Na+ imaging, we show that the dendrite may serve to maintain AP amplitudes during high-frequency firing, as Na+ clearance indendritic compartments is faster than axonal compartments. Prolonged high-frequency firing can diminish Na+ gradients in the axon while the dendritic gradient remains closer to resting conditions; therefore, the dendrite can provide additional inward current during prolonged firing. Using electron microscopy, we demonstrate that there are small excitatory synaptic boutons on dendrites. Multi-compartment MNTB cell simulations show that, with an active dendrite, dendritic excitatory postsynaptic currents (EPSCs) elicit delayed APs compared with calyceal EPSCs. Together with high- and low-threshold voltage-gated K+ currents, we suggest that the function of the MNTB dendrite is to improve high-fidelity firing, and our modelling results indicate that an active dendrite could contribute to a 'dual' firing mode for MNTB cells (an instantaneous response to calyceal inputs and a delayed response to non-calyceal dendritic excitatory postsynaptic potentials).

c-Fos expression in the mouse brainstem after unilateral labyrinthectomy.

CONCLUSION: The results indicated that the vestibular, prepositus hypoglossal, and inferior olive nuclei were activated after unilateral labyrinthectomy in mice like in other species. It is expected that the application of the present procedure to appropriate gene-deficient mice will elucidate the mechanism of the process of vestibular compensation. OBJECTIVE: Vestibular compensation is attributed to functional and structural reorganization of neural networks in the central vestibular system, but its precise mechanism is still not clear. c-Fos protein is used as a marker of neuronal activation, because of its very limited expression in the normal state and rapid appearance after external stimulation. Previous reports, investigating c-Fos expression after unilateral labyrinthectomy were made in rats and guinea pigs, but not in the mouse brainstem. MATERIALS AND METHODS: For future application to the gene knockout mouse, we examined c-Fos expression in the mouse after unilateral labyrinthectomy. RESULTS: Twenty-four hours after surgery, significantly increased c-Fos positive cells were observed in the bilateral medial vestibular nucleus (MVe), bilateral spinal vestibular nucleus (SpVe), contralateral prepositus hypoglossal nucleus (PrH), and contralateral inferior olive nucleus (IO).

Percepção auditiva em síndrome de Alport / Auditory perception in Alport's Syndrome

A síndrome de Alport é caracterizada por comprometimentos auditivos, renal, e visual. Objetivo deste estudo é caracterizar as EOAT e a atividade do SOEM (efeito de supressão) em indivíduos com Síndrome de Alport. MATERIAL E MÉTODO: Foram avaliados dez indivíduos com diagnóstico de síndrome de Alport. Foi realizado estudo prospectivo. Foi realizado registro das EOAT na ausência e na presença de estimulação acústica contralateral com a utilização do programa de computador ILO 92 - Otodynamics. RESULTADOS: As amplitudes de resposta das EOAT foram presentes para a resposta global (A) e por faixa de freqüência em 1000, 1500, 2000 e 3000 Hz, em 4 (40 por cento) dos indivíduos e ausentes em 6 (60 por cento) dos indivíduos com perda auditiva. Foram ausentes as respostas na freqüência de 4000 Hz, nas orelhas direita e esquerda. Esses achados são compatíveis com o nível de audição (em dBNA) avaliados. Os indivíduos com resposta global presente em EOAT apresentaram supressão dessa resposta na presença de ruído. CONCLUSÃO: Indivíduos com síndrome de Alport apresentam resultados de EOAT compatíveis com a perda auditiva. Ocorreu o efeito de supressão, sugerindo que a perda auditiva é predominantemente originada por uma disfunção coclear.

Alport's Syndrome is characterized by the presence of renal, hearing and visual disorders. Objective: To characterize the TOAE and the MOES activity (suppression effect) in individuals with Alport's Syndrome. MATERIAL AND METHOD: This is a prospective study of a sample included ten individuals with a diagnosis of Alport's Syndrome. MOES recording was made in the presence and absence of contralateral stimulation (CLS) stimulation using the computer software ILO 92 - Otodynamics. RESULTS: TOAE was present in the global response (A) and in frequency ranges of 1000, 1500, 2000 and 3000 Hz in 4 individuals (40 percent), and absent in 6 individuals (60 percent) with hearing loss. We observed no responses at 4000 Hz in the right and left ears. Individuals that presented global responses to TOAE also suppressed that response when there was noise. CONCLUSION: The suppression effect also occurs with TOAE, suggesting that the hearing loss is predominantly the result of cochlear dysfunction.

Neuroprotective effect of mifepristone involves neuron depolarization.

In several regions of the developing nervous system, neurons undergo programmed cell death. In the rat cerebellum, Purkinje cell apoptosis is exacerbated when cerebellar slices are cultured during the first postnatal week. To understand the mechanism of this developmental apoptosis, we took advantage of its inhibition by the steroid analog mifepristone. This effect did not involve the classical steroid nuclear receptors. Microarray analysis revealed that mifepristone down-regulated mRNA levels of the Na+/K+-ATPase alpha3 subunit more than three times. Consistent with the down-regulation of the Na+/K+-ATPase, mifepristone caused Purkinje cell membrane depolarization. Depolarizing agents like ouabain (1 microM), tetraethylammonium (2 mM), and veratridine (2 microM) protected Purkinje cells from apoptosis. These results suggest a role of excitatory inputs in Purkinje cell survival during early postnatal development. Indeed, coculturing cerebellar slices with glutamatergic inferior olivary neuron preparations allowed rescue of Purkinje cells. These findings reveal a new neuroprotective mechanism of mifepristone and support a pivotal role for excitatory inputs in the survival of Purkinje neurons. Mifepristone may be a useful lead compound in the development of novel therapeutic approaches for maintaining the resting potential of neurons at values favorable for their survival under neuropathological conditions.

Zonal organization of the mouse flocculus: physiology, input, and output.

The zones of the flocculus have been mapped in many species with a noticeable exception, the mouse. Here, the functional map of the mouse was constructed via extracellular recordings followed by tracer injections of biotinylated-dextran-amine and immunohistochemistry for heat-shock protein-25. Zones were identified based on the Purkinje cell complex spike modulation occurring in response to optokinetic stimulation. In zones 1 and 3 Purkinje cells responded best to rotation about a horizontal axis oriented at 135 degrees ipsilateral azimuth, whereas in zones 2 and 4 they responded best to rotation about the vertical axis. The tracing experiments showed that Purkinje cells of zone 1 projected to the parvicellular part of lateral cerebellar nucleus and superior vestibular nucleus, while Purkinje cells of zone 3 projected to group Y and the superior vestibular nucleus. Purkinje cells of zones 2 and 4 projected to the magnocellular and parvicellular parts of the medial vestibular nucleus, while some also innervated the lateral vestibular nucleus or nucleus prepositus hypoglossi. The climbing fiber inputs to Purkinje cells in zones 1 and 3 were derived from neurons in the ventrolateral outgrowth of the contralateral inferior olive, whereas those in zones 2 and 4 were derived from the contralateral caudal dorsal cap. Purkinje cells in zones 1 and 2, but not in zones 3 and 4, were positively labeled for heat-shock protein-25. The present study illustrates that Purkinje cells in the murine flocculus are organized in discrete zones with specific functions, specific input - output relations, and a specific histochemical signature.