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

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

Role of ROCK2 in CD4+ cells in allergic airways responses in mice.

BACKGROUND: Rho kinases (ROCKs) contribute to allergic airways disease. ROCKs also play a role in lymphocyte proliferation and migration. OBJECTIVE: To determine the role of ROCK2 acting within CD4+ cells in allergic airways responses. METHODS: ROCK2-haploinsufficient (ROCK2+/- ) and wild-type mice were sensitized with ovalbumin (OVA). ROCK2+/- mice then received either CD4+ cells from ROCK2-sufficient OVA TCR transgenic (OT-II) mice or saline i.v. 48 h before challenge with aerosolized OVA. Wild-type mice received saline before challenge. Allergic airways responses were measured 48 h after the last challenge. Allergic airways responses were also assessed in mice lacking ROCK2 only in CD4+ cells (ROCK2CD4Cre mice) vs. control (CD4-Cre and ROCK2flox/flox ) mice. RESULTS: OVA-induced increases in bronchoalveolar lavage lymphocytes, eosinophils, IL-13, IL-5, and eotaxin were reduced in ROCK2+/- vs. wild-type mice, as were airway hyperresponsiveness and mucous hypersecretion. In ROCK2+/- mice, adoptive transfer with CD4+ cells from OT-II mice restored effects of OVA on lymphocytes, eosinophils, IL-13, IL-5, and mucous hypersecretion to wild-type levels, whereas eotaxin and airway hyperresponsiveness were not affected. ROCK2 inhibitors reduced IL-13-induced release of eotaxin from airway smooth muscle (ASM), similar to effects of these inhibitors on ASM contractility. Despite the ability of adoptive transfer to restore allergic airways inflammation in ROCK2-insufficient mice, allergic inflammation was not different in ROCK2CD4Cre vs. control mice. CONCLUSION: ROCK2 contributes to allergic airways responses likely via effects within ASM cells and within non-lymphocyte cells involved in lymphocyte activation and migration into the airways.

Altered vesicular glutamate transporter distributions in the mouse cochlear nucleus following cochlear insult.

Vesicular glutamate transporters 1 and 2 (VGLUT1 and VGLUT2) have distinct distributions in the cochlear nucleus that correspond to sources of the labeled terminals. VGLUT1 is mainly associated with terminals of auditory nerve fibers, whereas VGLUT2 is mainly associated with glutamatergic terminals deriving from other sources that project to the cochlear nucleus (CN), including somatosensory and vestibular terminals. Previous studies in guinea pig have shown that cochlear damage results in a decrease of VGLUT1-labeled puncta and an increase in VGLUT2-labeled puncta. This indicates cross-modal compensation that is of potential importance in somatic tinnitus. To examine whether this effect is consistent across species and to provide a background for future studies, using transgenesis, the current study examines VGLUT expression profiles upon cochlear insult by intracochlear kanamycin injections in the mouse. Intracochlear kanamycin injections abolished ipsilateral ABR responses in all animals and reduced ipsilateral spiral ganglion neuron densities in animals that were sacrificed after four weeks, but not in animals that were sacrificed after three weeks. In all unilaterally deafened animals, VGLUT1 density was decreased in CN regions that receive auditory nerve fiber terminals, i.e., in the deep layer of the dorsal cochlear nucleus (DCN), in the interstitial region where the auditory nerve enters the CN, and in the magnocellular region of the antero- and posteroventral CN. In contrast, density of VGLUT2 expression was upregulated in the fusiform cell layer of the DCN and in the granule cell lamina, which are known to receive somatosensory and vestibular terminals. These results show that a cochlear insult induces cross-modal compensation in the cochlear nucleus of the mouse, confirming previous findings in guinea pig, and that these changes are not dependent on the occurrence of spiral ganglion neuron degeneration.

Plasticity of somatosensory inputs to the cochlear nucleus--implications for tinnitus.

This chapter reviews evidence for functional connections of the somatosensory and auditory systems at the very lowest levels of the nervous system. Neural inputs from the dosal root and trigeminal ganglia, as well as their brain stem nuclei, cuneate, gracillis and trigeminal, terminate in the cochlear nuclei. Terminations are primarily in the shell regions surrounding the cochlear nuclei but some terminals are found in the magnocellular regions of cochlear nucleus. The effects of stimulating these inputs on multisensory integration are shown as short and long-term, both suppressive and enhancing. Evidence that these projections are glutamatergic and are altered after cochlear damage is provided in the light of probable influences on the modulation and generation of tinnitus.

Role of Rho kinase isoforms in murine allergic airway responses.

Inhibition of Rho-associated coiled-coil forming kinases (ROCKs) reduces allergic airway responses in mice. The purpose of this study was to determine the roles of the two ROCK isoforms, ROCK1 and ROCK2, in these responses. Wildtype (WT) mice and heterozygous ROCK1 and ROCK2 knockout mice (ROCK1(+/-) and ROCK2(+/-), respectively) were sensitised and challenged with ovalbumin. ROCK expression and activation were assessed by western blotting. Airway responsiveness was measured by forced oscillation. Bronchoalveolar lavage was performed and the lungs were fixed for histological assessment. Compared with WT mice, ROCK1 and ROCK2 expression were 50% lower in lungs of ROCK1(+/-) and ROCK2(+/-) mice, respectively, without changes in the other isoform. In WT lungs, ROCK activation increased after ovalbumin challenge and was sustained for several hours. This activation was reduced in ROCK1(+/-) and ROCK2(+/-) lungs. Airway responsiveness was comparable in WT, ROCK1(+/-), and ROCK2(+/-) mice challenged with PBS. Ovalbumin challenge caused airway hyperresponsiveness in WT, but not ROCK1(+/-) or ROCK2(+/-) mice. Lavage eosinophils and goblet cell hyperplasia were significantly reduced in ovalbumin-challenged ROCK1(+/-) and ROCK2(+/-) versus WT mice. Ovalbumin-induced changes in lavage interleukin-13, interleukin-5 and lymphocytes were also reduced in ROCK1(+/-) mice. In conclusion, both ROCK1 and ROCK2 are important in regulating allergic airway responses.

Cuneate and spinal trigeminal nucleus projections to the cochlear nucleus are differentially associated with vesicular glutamate transporter-2.

There are distinct distributions and associations with vesicular glutamate transporters (VGLUTs) for auditory nerve and specific somatosensory projections in the cochlear nucleus (CN). Auditory nerve fibers project primarily to the magnocellular areas of the ventral cochlear nucleus and deepest layer of the dorsal cochlear nucleus and predominantly colabel with VGLUT1; whereas the spinal trigeminal nucleus (Sp5) projections terminate primarily in the granule cell domains (GCD) of CN and predominantly colabel with VGLUT2. Here, we demonstrate that the terminals of another somatosensory pathway, originating in the cuneate nucleus (Cu), also colabel with VGLUT2. Cu projections in cochlear nucleus exhibited a bilateral distribution pattern with ipsilateral dominance, with 30% of these classified as putative mossy fibers (MFs) and 70% as small boutons (SBs). Cu anterograde endings had a more prominent distribution in the GCD than Sp5, with a higher percentage of MF terminals throughout the CN and higher MF/SB ratio in GCD. 56% of Cu endings and only 25% of Sp5 endings colabeled with VGLUT2. In both cases these were mostly MFs with only 43% of Cu SBs and 18% of Sp5 SBs colabeled with VGLUT2. The few Cu and Sp5 terminals that colabeled with VGLUT1 (11% vs. 1%), were evenly distributed between MFs and SBs. The high number of VGLUT2-positive Cu MFs predominantly located in the GCD, may reflect a faster-acting pathway that activates primarily dorsal cochlear nucleus cells via granule cell axons. In contrast, the higher percentage of Sp5-labeled SB terminals and a greater number of projections outside the GCD suggest a slower-acting pathway that activates both dorsal and ventral cochlear nucleus principal cells. Both projections, with their associations to VGLUT2 likely play a role in the enhancement of VGLUT2 after unilateral deafness [Zeng C, Nannapaneni N, Zhou J, Hughes LF, Shore S (2009) J Neurosci 29:4210-4217] that may be associated with tinnitus.

Cross-modal interactions of auditory and somatic inputs in the brainstem and midbrain and their imbalance in tinnitus and deafness.

PURPOSE: This review outlines the anatomical and functional bases of somatosensory influences on auditory processing in the normal brainstem and midbrain. It then explores how interactions between the auditory and somatosensory system are modified through deafness, and their impact on tinnitus is discussed. METHOD: Literature review, tract tracing, immunohistochemistry, and in vivo electrophysiological recordings were used. RESULTS: Somatosensory input originates in the dorsal root ganglia and trigeminal ganglia, and is transmitted directly and indirectly through 2nd-order nuclei to the ventral cochlear nucleus, dorsal cochlear nucleus (DCN), and inferior colliculus. The glutamatergic somatosensory afferents can be segregated from auditory nerve inputs by the type of vesicular glutamate transporters present in their terminals. Electrical stimulation of the somatosensory input results in a complex combination of excitation and inhibition, and alters the rate and timing of responses to acoustic stimulation. Deafness increases the spontaneous rates of those neurons that receive excitatory somatosensory input and results in a greater sensitivity of DCN neurons to trigeminal stimulation. CONCLUSIONS: Auditory-somatosensory bimodal integration is already present in 1st-order auditory nuclei. The balance of excitation and inhibition elicited by somatosensory input is altered following deafness. The increase in somatosensory influence on auditory neurons when their auditory input is diminished could be due to cross-modal reinnervation or increased synaptic strength, and may contribute to mechanisms underlying somatic tinnitus.

Dorsal cochlear nucleus responses to somatosensory stimulation are enhanced after noise-induced hearing loss.

Multisensory neurons in the dorsal cochlear nucleus (DCN) achieve their bimodal response properties [Shore (2005) Eur. J. Neurosci., 21, 3334-3348] by integrating auditory input via VIIIth nerve fibers with somatosensory input via the axons of cochlear nucleus granule cells [Shore et al. (2000) J. Comp. Neurol., 419, 271-285; Zhou & Shore (2004)J. Neurosci. Res., 78, 901-907]. A unique feature of multisensory neurons is their propensity for receiving cross-modal compensation following sensory deprivation. Thus, we investigated the possibility that reduction of VIIIth nerve input to the cochlear nucleus results in trigeminal system compensation for the loss of auditory inputs. Responses of DCN neurons to trigeminal and bimodal (trigeminal plus acoustic) stimulation were compared in normal and noise-damaged guinea pigs. The guinea pigs with noise-induced hearing loss had significantly lower thresholds, shorter latencies and durations, and increased amplitudes of response to trigeminal stimulation than normal animals. Noise-damaged animals also showed a greater proportion of inhibitory and a smaller proportion of excitatory responses compared with normal. The number of cells exhibiting bimodal integration, as well as the degree of integration, was enhanced after noise damage. In accordance with the greater proportion of inhibitory responses, bimodal integration was entirely suppressive in the noise-damaged animals with no indication of the bimodal enhancement observed in a sub-set of normal DCN neurons. These results suggest that projections from the trigeminal system to the cochlear nucleus are increased and/or redistributed after hearing loss. Furthermore, the finding that only neurons activated by trigeminal stimulation showed increased spontaneous rates after cochlear damage suggests that somatosensory neurons may play a role in the pathogenesis of tinnitus.

Simulation of special bubble detectors for PICASSO.

The PICASSO project is a cold dark matter (CDM) search experiment relying on the superheated droplet technique. The detectors use superheated freon liquid droplets (active material) dispersed and trapped in a polymerised gel. This detection technique is based on the phase transition of superheated droplets at about room temperature and ambient pressure. The phase transition is induced by nuclear recoils when an atomic nucleus in the droplets interacts with incoming subatomic particles. This includes CDM particles candidate as the neutralino (a yet-to-discover particle predicted in extensions of the standard model of particle physics). Simulations performed to understand the detector response to neutrons and alpha particles are presented along with corresponding data obtained at the Montreal Laboratory.

Direct dark matter search using large-mass superheated droplet detectors in the PICASSO experiment.

The PICASSO experiment investigates the presence and nature of dark matter in the Universe. The experiment is based on the detection of acoustic signals generated in explosive phase transitions induced by dark matter particles. This technique is an alternative more traditional detection technique like scintillation and ionisation, which are largely employed for dark matter search. One of the main advantages of this technique, besides its sensitivity to very low nuclear recoil energies (few keV), is its excellent background suppression features. A pilot experiment consisting of six superheated droplet detectors (40 g of active mass) is presently taking data at the Sudbury Neutrino Observatory (SNO) at a depth of 2000 m. We discuss the operation, calibration and data acquisition of the experiment and also the ongoing work to increase the sensitivity and the active mass of the detectors.

Neoplastic transformation by the gep oncogene, Galpha12, involves signaling by STAT3.

Galpha(12), the alpha-subunit of G12, which has been referred to as the gep oncogene, stimulates mitogenic pathways in different cell types and readily induces neoplastic transformation of fibroblast cell lines. Recently, we have shown that the oncogenic pathway activated by Galpha(12) involves the receptor tyrosine kinase platelet derived growth factor receptor-alpha (PDGFRalpha) and JAK3. In the present study, we demonstrate that the GTPase-deficient activated mutant of Galpha(12) activates signal transducer and activator of transcription 3 (STAT3) via PDGFRalpha as well as JAK3. Here we show that Galpha(12) stimulates the phosphorylation of STAT3 at both Tyrosine-705 and Serine-727 residues. Studies to delineate the mechanism by which Galpha(12) stimulates STAT3 have indicated that the Tyrosine-705-phosphorylation of STAT3 involves the tyrosine kinases, Janus Kinase-3 as well as Src kinase, whereas the Serine-727 phosphorylation of STAT3 occurs via the receptor tyrosine kinase, PDGFRalpha and phosphatidylinositol 3-OH kinase pathway. Our results also indicate that the coexpression of the dominant negative, DNA binding mutant of STAT3 (STAT3DB) inhibits the foci formation as well as anchorage-independent growth of Galpha(12)QL-transfectants, thereby establishing the critical role of STAT3 in Galpha(12)QL-mediated neoplastic cell growth. The results presented here demonstrate, for the first time, the ability of Galpha(12) to recruit multiple receptor-, nonreceptor-, and Ser/Thr kinases to stimulate STAT3-signaling to promote neoplastic transformation.

Multisensory integration in the dorsal cochlear nucleus: unit responses to acoustic and trigeminal ganglion stimulation.

A necessary requirement for multisensory integration is the convergence of pathways from different senses. The dorsal cochlear nucleus (DCN) receives auditory input directly via the VIIIth nerve and somatosensory input indirectly from the Vth nerve via granule cells. Multisensory integration may occur in DCN cells that receive both trigeminal and auditory nerve input, such as the fusiform cell. We investigated trigeminal system influences on guinea pig DCN cells by stimulating the trigeminal ganglion while recording spontaneous and sound-driven activity from DCN neurons. A bipolar stimulating electrode was placed into the trigeminal ganglion of anesthetized guinea pigs using stereotaxic co-ordinates. Electrical stimuli were applied as bipolar pulses (100 micros per phase) with amplitudes ranging from 10 to 100 microA. Responses from DCN units were obtained using a 16-channel, four-shank electrode. Current pulses were presented alone or preceding 100- or 200-ms broadband noise (BBN) bursts. Thirty percent of DCN units showed either excitatory, inhibitory or excitatory-inhibitory responses to trigeminal ganglion stimulation. When paired with BBN stimulation, trigeminal stimulation suppressed or facilitated the firing rate in response to BBN in 78% of units, reflecting multisensory integration. Pulses preceding the acoustic stimuli by as much as 95 ms were able to alter responses to BBN. Bimodal suppression may play a role in attenuating body-generated sounds, such as vocalization or respiration, whereas bimodal enhancement may serve to direct attention in low signal-to-noise environments.

Predicting progressive hepatic fibrosis stage on subsequent liver biopsy in chronic hepatitis C virus infection.

Retrospective cross-sectional studies indicate that 20% with chronic hepatitis C virus (HCV) infection become cirrhotic within 20 years. Known risk factors for advanced hepatic fibrosis include age at time of infection, male sex, excess alcohol consumption and cytokine polymorphisms. Prospective study to assess and identify factors predictive of change in hepatic fibrosis stage in chronic HCV infection by interval protocol liver biopsy was performed. One hundred and five patients with paired liver biopsy specimens separated by a mean 41 months were recruited from a cohort of 823 HCV carriers. Five per cent developed worsening hepatic fibrosis by more than two stages. In 43% there was no change in fibrosis stage. Excessive alcohol intake currently (P = 0.037) or previously (P = 0.07) predicted progression. In contrast, always having a normal alanine transaminase (P = 0.038) and always being negative in serum for HCV RNA (P =0.067) predicted no progression. Three models were developed to predict outcome. Progressive fibrosis was predicted by baseline fibrosis (P = 0.018), steatosis (P = 0.02) and age (P = 0.017). The rate of progressive fibrosis was predicted by baseline fibrosis (P = 0.0002), steatosis (P =0.039) and lobular inflammation (P = 0.09). Fibrosis stage on the second biopsy was predicted by baseline fibrosis alone (P = 0.01). The rate of progression varies widely. Alcohol misuse is an important co-factor. Progressive fibrosis can be predicted at first liver biopsy, where baseline fibrosis is most critical, allowing targeted therapy for those with early disease and a significant risk of progression.

Src: regulation, role in human carcinogenesis and pharmacological inhibitors.

The cellular signaling machinery is a complex network of cross-talking proteins that enables dynamic communication between upstream causal factors and downstream effectors. Non-receptor tyrosine kinases, including Src, are the intermediates of signal transfer, controlling pathways as diverse as cell growth, death, differentiation, migration, and genome maintenance. When expressed as viral genes these proteins are potent carcinogens. Furthermore, analogous genetic alterations are observed, albeit not frequently, in human tumors. In a variety of tumors including those derived from the colon and breast, Src is either over expressed or constitutively active in a large percentage of patients. Increased expression or activity of Src correlates with the stage and metastatic potential of some neoplasia. The detailed knowledge of Src activation facilitates rational design of drugs that potentially interfere with either binding of ATP or substrate peptides. Several existing inhibitors are available as lead compounds for further development of Src inhibitors.

Umbilical venous IGF-1 concentration, neonatal bone mass, and body composition.

UNLABELLED: IGF-1 is a key growth factor during fetal life. Using DXA, we found that the concentration of IGF-1 in umbilical cord serum is strongly related to neonatal whole body bone mineral content, lean mass, and fat mass. However IGF-1 did not explain the relationships of maternal smoking, fat mass, and physical activity with neonatal bone mass. The study supports a direct role for circulating IGF-1 in growth of the fetal skeleton. INTRODUCTION: Evidence is accumulating that the risk of osteoporosis in later life may be determined in part by environmental influences during intrauterine and early postnatal life. We previously reported that maternal birthweight, smoking, fat stores, and physical activity during pregnancy predict neonatal bone mass. While the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis is an important determinant of postnatal skeletal growth, there are few data relating the concentration of growth factors in umbilical cord blood to bone mineral content (BMC) and other indices of body composition in the newborn infant. MATERIALS AND METHODS: We conducted a population-based study in a cohort of full-term, newborn infants whose mothers were characterized for lifestyle, body composition, and nutrition through their normal pregnancies. In a sample of 119 infants from the cohort, we related cord serum IGF-1 and insulin-like growth factor binding protein (IGFBP)-3 concentrations to neonatal body composition measured by DXA and evaluated the extent to which this cytokine mediates the previously reported effects of maternal diet and lifestyle on neonatal bone mass. RESULTS: There were strong positive associations between cord serum IGF-1 concentration and whole body BMC (r = 0.38, p < 0.001), whole body lean mass (r = 0.40, p < 0.001), and whole body fat mass (r = 0.50, p < 0.001) after adjusting for gestational age and sex. There was no association between cord serum IGF-1 and BMC adjusted for bone size. Neither cord serum IGF-1 nor IGFBP-3 explained the relationships that we previously reported between maternal influences and neonatal bone mass. CONCLUSIONS: Cord serum IGF-1 is more closely related to the size of the neonatal skeleton than to its degree of mineralization. Documented maternal determinants of neonatal bone mass seem to mediate their effects independently of variations in cord serum IGF-1 in healthy pregnancies.

Differential effects of ozone on airway and tissue mechanics in obese mice.

Obesity is an important risk factor for asthma. We recently reported increased ozone (O(3))-induced hyperresponsiveness to methacholine in obese mice (Shore SA, Rivera-Sanchez YM, Schwartzman IN, and Johnston RA. J Appl Physiol 95: 938-945, 2003). The purpose of this study was to determine whether this increased hyperresponsiveness is the result of changes in the airways, the lung tissue, or both. To that end, we examined the effect of O(3) (2 parts/million for 3 h) on methacholine-induced changes in lung mechanics with the use of a forced oscillation technique in wild-type C57BL/6J mice and mice obese because of a genetic deficiency in leptin (ob/ob mice). In ob/ob mice, O(3) increased baseline values for all parameters measured in the study: airway resistance (Raw), lung tissue resistance (Rtis), lung tissue damping (G) and elastance (H), and lung hysteresivity (eta). In contrast, no effect of O(3) on baseline mechanics was observed in wild-type mice. O(3) exposure significantly increased Raw, Rtis, lung resistance (Rl), G, H, and eta responses to methacholine in both groups of mice. For G, Rtis, and Rl there was a significant effect of obesity on the response to O(3). Our results demonstrate that both airways and lung tissue contribute to the hyperresponsiveness that occurs after O(3) exposure in wild-type mice. Our results also demonstrate that changes in the lung tissue rather than the airways account for the amplification of O(3)-induced hyperresponsiveness observed in obese mice.

Review article: chemotherapy for pancreatic cancer.

Pancreatic cancer is a common, highly lethal disease that is rising in incidence. Chemotherapy based on 5-fluorouracil (5-FU) has been shown to prolong survival in advanced pancreatic cancer. Gemcitabine improves major symptoms and survival outcomes compared with bolus 5-FU. Many novel small molecules are being widely and actively researched. These compounds are based on classical mechanisms of action as well as biological therapies targeting novel cellular survival pathways, and include fluoropyrimidines, nucleoside cytidine analogues, platinum analogues, topoisomerase-inhibitors, antimicrotubule agents, proteasome inhibitors, vitamin D analogues, arachidonic acid pathway inhibitors, histone deacytylator inhibitors, farnesyltransferase inhibitors and epidermal growth factor receptor therapies. Adjuvant chemotherapy has also demonstrated the best survival outcomes following resection compared to other adjuvant or neo-adjuvant strategies such as radiation-based treatments. These benefits are superimposed on the dramatic increase in resectability rates and reduction in post-operative mortality achieved by centralisation of treatment in high-volume speciality centres. Newer 'small-molecule' drugs as well as the latest 'large-molecule' biological agents hold considerable promise for the future. Real advances are anticipated over the next five years but are dependent on large randomised controlled trials for success.

Spatial representation of corticofugal input in the inferior colliculus: a multicontact silicon probe approach.

The inferior colliculus (IC) is a well-established target of descending projections from the auditory cortex (AC). However, our understanding of these pathways has been limited by an incomplete picture of their functional influence within the three-dimensional space of the IC. Our goal was to study the properties and spatial representation of corticofugal input in the IC of guinea pigs with a high degree of spatial resolution. We systematically mapped neural activity in the IC using two types of silicon substrate probes that allow for simultaneous recording at multiple neural sites. One probe provided a high resolution in the dorsal-ventral plane and the other provided spatial resolution in the medial-lateral plane. Electrical stimulation of the ipsilateral AC produced excitatory responses in the IC with thresholds usually below 5-10 microA. First spike latencies were predominantly in the 6-20 ms range, although latencies from 3-5 ms were also observed. Broadly distributed unimodal spike patterns with modal latencies greater than 30 ms were occasionally seen. The excitatory responses to cortical stimulation were mostly unimodal and occasionally bimodal with a wide range of spike distribution patterns and response durations. Excitation was often followed by suppression of spontaneous activity. Suppression of acoustic responses was observed even when there was little or no response to electrical stimulation, suggesting spatial-temporal integration. A few of the responding neurons showed purely inhibitory responses to electrical stimulation, suggesting that there are disynaptic routes of corticocollicular inhibition. Detailed spatial mapping revealed that the response patterns and their durations had a characteristic spatial distribution in the IC.

Effects of contralateral sound stimulation on unit activity of ventral cochlear nucleus neurons.

The cochlear nucleus (CN) commissural connection represents the first opportunity for convergence of binaural information in the auditory brainstem. All major neuron types in the ventral CN (VCN) are innervated by a diverse population of cells in the contralateral VCN. This study examined the effect of contralateral sound stimulation on the spontaneous rates (SRs) of neurons in the VCN. Unit activity was recorded with silicon-substrate multichannel probes which allowed recordings from up to 16 sites simultaneously. On average, 30% of units showed short-latency (often only 2 ms greater than the latencies of ipsilateral sound-evoked responses) inhibition of SR by wideband contralateral noise bursts. Fewer units (4.5%) were excited by contralateral noise at sound levels low enough to exclude excitation by acoustic crossover. Both regular and irregular units in the anterior VCN (AVCN) and posterior VCN (PVCN) were inhibited by contralateral sound. Decrements in SR followed a monotonic function with increases in contralateral sound level, except where responses could be attributed to acoustic crossover. Restricting the contralateral noise bandwidth resulted in a frequency-specific inhibition, dominated by frequencies at and below the ipsilateral BF of the unit, consistent with anatomical findings of the tonotopic organization of the CN commissural pathway. The latencies of these effects are compatible with mono, di and tri-synaptic connections reflecting CN commissural pathway effects.

Effects of trigeminal ganglion stimulation on unit activity of ventral cochlear nucleus neurons.

The trigeminal ganglion sends a projection to the granule and magnocellular regions of the ventral cochlear nucleus (VCN; [J Comp Neurol 419 (2000) 271]), as well as to the cochlea ([Neuroscience 79 (1997) 605; Neuroscience 84 (1998a) 559]). We investigated the effects of electrically stimulating the trigeminal ganglion on unit responses in the guinea-pig VCN. Responses consisted of one, two or more phases of excitation, sometimes followed by a longer inhibitory phase. The latencies to the first excitation peak ranged between 5 and 17 ms from the onset of stimulation. These responses were preceded by a slow wave potential evoked by the stimulation. Applying kainic acid, which eliminates VIIIth nerve responses, diminished the firing rates of VCN units to trigeminal stimulation, and increased their first spike latencies. Cochlear destruction had a similar effect. The responses in VCN evoked by trigeminal ganglion stimulation therefore appear to result from direct stimulation of the trigeminal ganglion-cochlear nucleus pathway, as well as modulation by the trigeminal ganglion-cochlear pathway. Alternatively, a reduction in spontaneous rate of VCN neurons by removal of VIIIth nerve input could explain the decreased response to trigeminal stimulation after cochlear manipulations. The modulation of firing rate in second order auditory neurons by first order somatosensory neurons could influence central auditory targets and may be involved in generating or modulating perceptions of phantom sounds which can be modified by manipulations of somatic regions of the head and neck ("somatic tinnitus").