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Sample records for auditory signals requires

  1. Auditory induction of discrete tones in signal detection tasks

    NASA Astrophysics Data System (ADS)

    Bennett, K. B.; Parasuraman, R.; Howard, J. H., Jr.; Otoole, A. J.

    1983-10-01

    Auditory induction is the apparent continuation of a fainter sound when alternated rapidly with a more intense interrupting sound. In the present study induction of discrete (non-alternating) tones by contextual tones was examined in three experiments using signal detection methods. Listeners were asked to detect pure tone signals of constant, rising, or falling frequency embedded in noise bursts. The noise bursts were preceded and followed by contextual tones that were designed to produce a constant or changing frequency context. Results indicated that auditory induction is a general factor influencing auditory perception and can be demonstrated either for discrete as well as continuous presentation of sounds. While induction of missing sounds can be beneficial, especially in speech perception, auditory induction can also impair perceptual performance, particularly in monitoring nonspeech sounds for faint signals. Finally, auditory-induction effects can be distinguished from peripheral-masking effects, and although a relation between auditory induction and central masking cannot be ruled out, induction and masking appear to be separate, independent factors, one largely central, and other largely peripheral in nature.

  2. Motor-related signals in the auditory system for listening and learning.

    PubMed

    Schneider, David M; Mooney, Richard

    2015-08-01

    In the auditory system, corollary discharge signals are theorized to facilitate normal hearing and the learning of acoustic behaviors, including speech and music. Despite clear evidence of corollary discharge signals in the auditory cortex and their presumed importance for hearing and auditory-guided motor learning, the circuitry and function of corollary discharge signals in the auditory cortex are not well described. In this review, we focus on recent developments in the mouse and songbird that provide insights into the circuitry that transmits corollary discharge signals to the auditory system and the function of these signals in the context of hearing and vocal learning.

  3. Hearing conspecific vocal signals alters peripheral auditory sensitivity

    PubMed Central

    Gall, Megan D.; Wilczynski, Walter

    2015-01-01

    We investigated whether hearing advertisement calls over several nights, as happens in natural frog choruses, modified the responses of the peripheral auditory system in the green treefrog, Hyla cinerea. Using auditory evoked potentials (AEP), we found that exposure to 10 nights of a simulated male chorus lowered auditory thresholds in males and females, while exposure to random tones had no effect in males, but did result in lower thresholds in females. The threshold change was larger at the lower frequencies stimulating the amphibian papilla than at higher frequencies stimulating the basilar papilla. Suprathreshold responses to tonal stimuli were assessed for two peaks in the AEP recordings. For the peak P1 (assessed for 0.8–1.25 kHz), peak amplitude increased following chorus exposure. For peak P2 (assessed for 2–4 kHz), peak amplitude decreased at frequencies between 2.5 and 4.0 kHz, but remained unaltered at 2.0 kHz. Our results show for the first time, to our knowledge, that hearing dynamic social stimuli, like frog choruses, can alter the responses of the auditory periphery in a way that could enhance the detection of and response to conspecific acoustic communication signals. PMID:25972471

  4. Auditory Signal Processing in Communication: Perception and Performance of Vocal Sounds

    PubMed Central

    Prather, Jonathan F.

    2013-01-01

    Learning and maintaining the sounds we use in vocal communication require accurate perception of the sounds we hear performed by others and feedback-dependent imitation of those sounds to produce our own vocalizations. Understanding how the central nervous system integrates auditory and vocal-motor information to enable communication is a fundamental goal of systems neuroscience, and insights into the mechanisms of those processes will profoundly enhance clinical therapies for communication disorders. Gaining the high-resolution insight necessary to define the circuits and cellular mechanisms underlying human vocal communication is presently impractical. Songbirds are the best animal model of human speech, and this review highlights recent insights into the neural basis of auditory perception and feedback-dependent imitation in those animals. Neural correlates of song perception are present in auditory areas, and those correlates are preserved in the auditory responses of downstream neurons that are also active when the bird sings. Initial tests indicate that singing-related activity in those downstream neurons is associated with vocal-motor performance as opposed to the bird simply hearing itself sing. Therefore, action potentials related to auditory perception and action potentials related to vocal performance are co-localized in individual neurons. Conceptual models of song learning involve comparison of vocal commands and the associated auditory feedback to compute an error signal that is used to guide refinement of subsequent song performances, yet the sites of that comparison remain unknown. Convergence of sensory and motor activity onto individual neurons points to a possible mechanism through which auditory and vocal-motor signals may be linked to enable learning and maintenance of the sounds used in vocal communication. PMID:23827717

  5. Signal type and signal-to-noise ratio interact to affect cortical auditory evoked potentials.

    PubMed

    Billings, Curtis J; Grush, Leslie D

    2016-08-01

    Use of speech signals and background noise is emerging in cortical auditory evoked potential (CAEP) studies; however, the interaction between signal type and noise level remains unclear. Two experiments determined the interaction between signal type and signal-to-noise ratio (SNR) on CAEPs. Three signals (syllable /ba/, 1000-Hz tone, and the /ba/ envelope with 1000-Hz fine structure) with varying SNRs were used in two experiments, demonstrating signal-by-SNR interactions due to both envelope and spectral characteristics. When using real-world stimuli such as speech to evoke CAEPs, temporal and spectral complexity leads to differences with traditional tonal stimuli, especially when presented in background noise. PMID:27586784

  6. Temporally selective processing of communication signals by auditory midbrain neurons

    PubMed Central

    Christensen-Dalsgaard, Jakob; Kelley, Darcy B.

    2011-01-01

    Perception of the temporal structure of acoustic signals contributes critically to vocal signaling. In the aquatic clawed frog Xenopus laevis, calls differ primarily in the temporal parameter of click rate, which conveys sexual identity and reproductive state. We show here that an ensemble of auditory neurons in the laminar nucleus of the torus semicircularis (TS) of X. laevis specializes in encoding vocalization click rates. We recorded single TS units while pure tones, natural calls, and synthetic clicks were presented directly to the tympanum via a vibration-stimulation probe. Synthesized click rates ranged from 4 to 50 Hz, the rate at which the clicks begin to overlap. Frequency selectivity and temporal processing were characterized using response-intensity curves, temporal-discharge patterns, and autocorrelations of reduplicated responses to click trains. Characteristic frequencies ranged from 140 to 3,250 Hz, with minimum thresholds of −90 dB re 1 mm/s at 500 Hz and −76 dB at 1,100 Hz near the dominant frequency of female clicks. Unlike units in the auditory nerve and dorsal medullary nucleus, most toral units respond selectively to the behaviorally relevant temporal feature of the rate of clicks in calls. The majority of neurons (85%) were selective for click rates, and this selectivity remained unchanged over sound levels 10 to 20 dB above threshold. Selective neurons give phasic, tonic, or adapting responses to tone bursts and click trains. Some algorithms that could compute temporally selective receptive fields are described. PMID:21289132

  7. A hardware model of the auditory periphery to transduce acoustic signals into neural activity

    PubMed Central

    Tateno, Takashi; Nishikawa, Jun; Tsuchioka, Nobuyoshi; Shintaku, Hirofumi; Kawano, Satoyuki

    2013-01-01

    To improve the performance of cochlear implants, we have integrated a microdevice into a model of the auditory periphery with the goal of creating a microprocessor. We constructed an artificial peripheral auditory system using a hybrid model in which polyvinylidene difluoride was used as a piezoelectric sensor to convert mechanical stimuli into electric signals. To produce frequency selectivity, the slit on a stainless steel base plate was designed such that the local resonance frequency of the membrane over the slit reflected the transfer function. In the acoustic sensor, electric signals were generated based on the piezoelectric effect from local stress in the membrane. The electrodes on the resonating plate produced relatively large electric output signals. The signals were fed into a computer model that mimicked some functions of inner hair cells, inner hair cell–auditory nerve synapses, and auditory nerve fibers. In general, the responses of the model to pure-tone burst and complex stimuli accurately represented the discharge rates of high-spontaneous-rate auditory nerve fibers across a range of frequencies greater than 1 kHz and middle to high sound pressure levels. Thus, the model provides a tool to understand information processing in the peripheral auditory system and a basic design for connecting artificial acoustic sensors to the peripheral auditory nervous system. Finally, we discuss the need for stimulus control with an appropriate model of the auditory periphery based on auditory brainstem responses that were electrically evoked by different temporal pulse patterns with the same pulse number. PMID:24324432

  8. A hardware model of the auditory periphery to transduce acoustic signals into neural activity.

    PubMed

    Tateno, Takashi; Nishikawa, Jun; Tsuchioka, Nobuyoshi; Shintaku, Hirofumi; Kawano, Satoyuki

    2013-01-01

    To improve the performance of cochlear implants, we have integrated a microdevice into a model of the auditory periphery with the goal of creating a microprocessor. We constructed an artificial peripheral auditory system using a hybrid model in which polyvinylidene difluoride was used as a piezoelectric sensor to convert mechanical stimuli into electric signals. To produce frequency selectivity, the slit on a stainless steel base plate was designed such that the local resonance frequency of the membrane over the slit reflected the transfer function. In the acoustic sensor, electric signals were generated based on the piezoelectric effect from local stress in the membrane. The electrodes on the resonating plate produced relatively large electric output signals. The signals were fed into a computer model that mimicked some functions of inner hair cells, inner hair cell-auditory nerve synapses, and auditory nerve fibers. In general, the responses of the model to pure-tone burst and complex stimuli accurately represented the discharge rates of high-spontaneous-rate auditory nerve fibers across a range of frequencies greater than 1 kHz and middle to high sound pressure levels. Thus, the model provides a tool to understand information processing in the peripheral auditory system and a basic design for connecting artificial acoustic sensors to the peripheral auditory nervous system. Finally, we discuss the need for stimulus control with an appropriate model of the auditory periphery based on auditory brainstem responses that were electrically evoked by different temporal pulse patterns with the same pulse number. PMID:24324432

  9. Auditory Evaluation of Sound Signals Radiated by a Vibrating Surface

    NASA Astrophysics Data System (ADS)

    MEUNIER, S.; HABAULT, D.; CANÉVET, G.

    2001-11-01

    This paper presents a combination of vibroacoustic and psychoacoustic studies of sounds radiated by a vibrating structure. The calculated sound field is the sound pressure radiated by a baffled thin-plate structure immersed in a fluid, on the surface of which the acceleration is given. Various configurations are selected for the time and space functions of the acceleration variable, each configuration leading to a particular acoustic signal (a low-frequency tone complex in our case). These signals are then transformed into sound files, which are used as test signals in psychoacoustic experiments for assessing their perceptual attributes and quality. Two experiments were run. In the first one, the unpleasantness of a series of signals at different levels was measured by direct estimation and compared with their calculated loudness and sharpness using Zwicker's model. The same measurements were repeated with the signals set to the same maximum amplitude. In the second experiment, the pleasantness of another series of sounds at equal loudness was measured, as well as dissimilarity and preference on pairs of these sounds. An MDS analysis was run to extract auditory attributes that could account for the perceived differences between sounds and correlate with the estimated pleasantness. The results from the first experiment show that pleasantness is always highly (and negatively) correlated with loudness. The same holds for sharpness, when sounds are played at the same maximum amplitude. The second experiment shows that the perceptual attributes revealed by the MDS analysis are related to pitch and timbre, the latter being highly correlated with pleasantness. Overall, this study confirms the interest of extending vibroacoustic studies to a more complete “psychomechanical” investigation of the whole process of sound generation. It is suggested that such investigations may apply to product sound quality and to active or passive noise control, by providing

  10. Effects of age, signal level, and signal rate on the auditory middle latency response.

    PubMed

    Tucker, D A; Ruth, R A

    1996-04-01

    The effects of age, signal rate, and signal level on the maturing auditory middle latency response (AMLR) were evaluated in 50 normal-hearing subjects ranging in age from 2 days to 35 years. Ipsilateral and contralateral AMLR waveforms were recorded in newborns (n = 10), children (n = 10), preteens (n = 10), teens (n = 10), and adults (n = 10). The AMLR Pa waveform was obtained in 70 to 100 percent of all subjects. The variables of age, signal level, and site of recording significantly affected Pa peak amplitude and absolute latency. However, stimulus rate did not significantly affect the response.

  11. Effects of age, signal level, and signal rate on the auditory middle latency response.

    PubMed

    Tucker, D A; Ruth, R A

    1996-04-01

    The effects of age, signal rate, and signal level on the maturing auditory middle latency response (AMLR) were evaluated in 50 normal-hearing subjects ranging in age from 2 days to 35 years. Ipsilateral and contralateral AMLR waveforms were recorded in newborns (n = 10), children (n = 10), preteens (n = 10), teens (n = 10), and adults (n = 10). The AMLR Pa waveform was obtained in 70 to 100 percent of all subjects. The variables of age, signal level, and site of recording significantly affected Pa peak amplitude and absolute latency. However, stimulus rate did not significantly affect the response. PMID:8652873

  12. Sound Sequence Discrimination Learning Motivated by Reward Requires Dopaminergic D2 Receptor Activation in the Rat Auditory Cortex

    ERIC Educational Resources Information Center

    Kudoh, Masaharu; Shibuki, Katsuei

    2006-01-01

    We have previously reported that sound sequence discrimination learning requires cholinergic inputs to the auditory cortex (AC) in rats. In that study, reward was used for motivating discrimination behavior in rats. Therefore, dopaminergic inputs mediating reward signals may have an important role in the learning. We tested the possibility in the…

  13. A new class of auditory warning signals for complex systems: auditory icons.

    PubMed

    Belz, S M; Robinson, G S; Casali, J G

    1999-12-01

    This simulator-based study examined conventional auditory warnings (tonal, nonverbal sounds) and auditory icons (representational, nonverbal sounds), alone and in combination with a dash-mounted visual display, to present information about impending collision situations to commercial motor vehicle operators. Brake response times were measured for impending front-to-rear collision scenarios under 6 display configurations, 2 vehicle speeds, and 2 levels of headway. Accident occurrence was measured for impending side collision scenarios under 2 vehicle speeds, 2 levels of visual workload, 2 auditory displays, absence/presence of mirrors, and absence/presence of a dash-mounted iconic visual display. For both front-to-rear and side collision scenarios, auditory icons elicited significantly improved driver performance over conventional auditory warnings. Driver performance improved when collision warning information was presented through multiple modalities. Brake response times were significantly faster for impending front-to-rear collision scenarios using the longer headway condition. The presence of mirrors significantly reduced the number of accidents for impending side collision scenarios. Subjective preference data indicated that participants preferred multimodal displays over single-modality displays. Actual or potential applications for this research include auditory displays and warnings, information presentation, and the development of alternative user interfaces.

  14. Neural interactions in unilateral colliculus and between bilateral colliculi modulate auditory signal processing.

    PubMed

    Mei, Hui-Xian; Cheng, Liang; Chen, Qi-Cai

    2013-01-01

    In the auditory pathway, the inferior colliculus (IC) is a major center for temporal and spectral integration of auditory information. There are widespread neural interactions in unilateral (one) IC and between bilateral (two) ICs that could modulate auditory signal processing such as the amplitude and frequency selectivity of IC neurons. These neural interactions are either inhibitory or excitatory, and are mostly mediated by γ-aminobutyric acid (GABA) and glutamate, respectively. However, the majority of interactions are inhibitory while excitatory interactions are in the minority. Such unbalanced properties between excitatory and inhibitory projections have an important role in the formation of unilateral auditory dominance and sound location, and the neural interaction in one IC and between two ICs provide an adjustable and plastic modulation pattern for auditory signal processing.

  15. Neural interactions in unilateral colliculus and between bilateral colliculi modulate auditory signal processing

    PubMed Central

    Mei, Hui-Xian; Cheng, Liang; Chen, Qi-Cai

    2013-01-01

    In the auditory pathway, the inferior colliculus (IC) is a major center for temporal and spectral integration of auditory information. There are widespread neural interactions in unilateral (one) IC and between bilateral (two) ICs that could modulate auditory signal processing such as the amplitude and frequency selectivity of IC neurons. These neural interactions are either inhibitory or excitatory, and are mostly mediated by γ-aminobutyric acid (GABA) and glutamate, respectively. However, the majority of interactions are inhibitory while excitatory interactions are in the minority. Such unbalanced properties between excitatory and inhibitory projections have an important role in the formation of unilateral auditory dominance and sound location, and the neural interaction in one IC and between two ICs provide an adjustable and plastic modulation pattern for auditory signal processing. PMID:23626523

  16. Auditory Cortex Is Required for Fear Potentiation of Gap Detection

    PubMed Central

    Weible, Aldis P.; Liu, Christine; Niell, Cristopher M.

    2014-01-01

    Auditory cortex is necessary for the perceptual detection of brief gaps in noise, but is not necessary for many other auditory tasks such as frequency discrimination, prepulse inhibition of startle responses, or fear conditioning with pure tones. It remains unclear why auditory cortex should be necessary for some auditory tasks but not others. One possibility is that auditory cortex is causally involved in gap detection and other forms of temporal processing in order to associate meaning with temporally structured sounds. This predicts that auditory cortex should be necessary for associating meaning with gaps. To test this prediction, we developed a fear conditioning paradigm for mice based on gap detection. We found that pairing a 10 or 100 ms gap with an aversive stimulus caused a robust enhancement of gap detection measured 6 h later, which we refer to as fear potentiation of gap detection. Optogenetic suppression of auditory cortex during pairing abolished this fear potentiation, indicating that auditory cortex is critically involved in associating temporally structured sounds with emotionally salient events. PMID:25392510

  17. The effect of auditory verbal imagery on signal detection in hallucination-prone individuals

    PubMed Central

    Moseley, Peter; Smailes, David; Ellison, Amanda; Fernyhough, Charles

    2016-01-01

    Cognitive models have suggested that auditory hallucinations occur when internal mental events, such as inner speech or auditory verbal imagery (AVI), are misattributed to an external source. This has been supported by numerous studies indicating that individuals who experience hallucinations tend to perform in a biased manner on tasks that require them to distinguish self-generated from non-self-generated perceptions. However, these tasks have typically been of limited relevance to inner speech models of hallucinations, because they have not manipulated the AVI that participants used during the task. Here, a new paradigm was employed to investigate the interaction between imagery and perception, in which a healthy, non-clinical sample of participants were instructed to use AVI whilst completing an auditory signal detection task. It was hypothesized that AVI-usage would cause participants to perform in a biased manner, therefore falsely detecting more voices in bursts of noise. In Experiment 1, when cued to generate AVI, highly hallucination-prone participants showed a lower response bias than when performing a standard signal detection task, being more willing to report the presence of a voice in the noise. Participants not prone to hallucinations performed no differently between the two conditions. In Experiment 2, participants were not specifically instructed to use AVI, but retrospectively reported how often they engaged in AVI during the task. Highly hallucination-prone participants who retrospectively reported using imagery showed a lower response bias than did participants with lower proneness who also reported using AVI. Results are discussed in relation to prominent inner speech models of hallucinations. PMID:26435050

  18. Requirements for signaling channel authentication

    SciTech Connect

    Tarman, T.D.

    1995-12-11

    This contribution addresses requirements for ATM signaling channel authentication. Signaling channel authentication is an ATM security service that binds an ATM signaling message to its source. By creating this binding, the message recipient, and even a third party, can confidently verify that the message originated from its claimed source. This provides a useful mechanism to mitigate a number of threats. For example, a denial of service attack which attempts to tear-down an active connection by surreptitiously injecting RELEASE or DROP PARTY messages could be easily thwarted when authenticity assurances are in place for the signaling channel. Signaling channel authentication could also be used to provide the required auditing information for accurate billing which is impervious to repudiation. Finally, depending on the signaling channel authentication mechanism, end-to-end integrity of the message (or at least part of it) can be provided. None of these capabilities exist in the current specifications.

  19. A topographic instructive signal guides the adjustment of the auditory space map in the optic tectum.

    PubMed

    Hyde, P S; Knudsen, E I

    2001-11-01

    Maps of auditory space in the midbrain of the barn owl (Tyto alba) are calibrated by visual experience. When owls are raised wearing prismatic spectacles that displace the visual field in azimuth, the auditory receptive fields of neurons in the optic tectum shift to compensate for the optical displacement of the visual field. This shift results primarily from a shift in the tuning of tectal neurons for interaural time difference. The visually based instructive signal that guides this plasticity could be based on a topographic, point-by-point comparison between auditory and visual space maps or on a foveation-dependent visual assessment of the accuracy of auditory orienting responses. To distinguish between these two possibilities, we subjected owls to optical conditions that differed in the center of gaze and the visual periphery. A topographic signal would cause the portions of the space map representing the central and peripheral regions of visual space to adjust differently, according to the optical conditions that exist in each region. In contrast, a foveation-based signal would cause both portions of the map to adjust similarly, according to the optical conditions that exist at the center of gaze. In six of seven experiments, adaptive changes were as predicted by a topographic instructive signal. Although the results do not rule out the possible contribution of a foveation-based signal, they demonstrate that a topographic instructive signal is, indeed, involved in the calibration of the auditory space map in the barn owl optic tectum. PMID:11606646

  20. Auditory warnings, signal-referent relations, and natural indicators: re-thinking theory and application.

    PubMed

    Petocz, Agnes; Keller, Peter E; Stevens, Catherine J

    2008-06-01

    In auditory warning design the idea of the strength of the association between sound and referent has been pivotal. Research has proceeded via constructing classification systems of signal-referent associations and then testing predictions about ease of learning of different levels of signal-referent relation strength across and within different types of auditory signal (viz., speech, abstract sounds, and auditory icons). However, progress is hampered by terminological confusions and by neglect of the cognitive contribution (viz., learning) of the person or user. Drawing upon semiotics and cognitive psychology, the authors highlight the indexical (as opposed to iconic) nature of so-called auditory icons, and the authors identify the cogniser as an indispensable element in the tripartite nature of signification. Classifications that neglect this third element, defining signal-referent relation strength only dyadically, yield results confounded by learning; classifications that correctly include the triadic relation yield research predictions that are redundant. These limitations of the standard method of constructing and testing classification systems suggest that auditory warning design must take the cognitive contribution of the user into account at an earlier stage in the design process.

  1. Disproportionate tonotopic representation for processing CF-FM sonar signals in the mustache bat auditory cortex.

    PubMed

    Suga, N; Jen, P H

    1976-10-29

    The extent of cortical representation of the peripheral sensory field depends on its importance for species behavior. The orientation sound of the mustache bat (Pteronotus parnellii rubiginosus) invariably consists of long constant-frequency and short frequency-modulated components and is indispensable for its survival. A disproportionately large part of the auditory cortex of this bat is occupied by neurons processing the predominant components in the orientation signal and Doppler-shifted echoes. This disproportionate cortical representation related to features of biologically significant signals is comparable to that in the somatosensory and visual systems in many mammals, but it has not previously been observed in the auditory system.

  2. The influence of signal type on the internal auditory representation of a room

    NASA Astrophysics Data System (ADS)

    Teret, Elizabeth

    Currently, architectural acousticians make no real distinction between a room impulse response and the auditory system's internal representation of a room. With this lack of a good model for the auditory representation of a room, it is indirectly assumed that our internal representation of a room is independent of the sound source needed to make the room characteristics audible. The extent to which this assumption holds true is examined with perceptual tests. Listeners are presented with various pairs of signals (music, speech, and noise) convolved with synthesized impulse responses of different reverberation times. They are asked to adjust the reverberation of one of the signals to match the other. Analysis of the data show that the source signal significantly influences perceived reverberance. Listeners are less accurate when matching reverberation times of varied signals than they are with identical signals. Additional testing shows that perception of reverberation can be linked to the existence of transients in the signal.

  3. Modulation of Auditory Signal-to-Noise Ratios by Efferent Stimulation

    PubMed Central

    Tomchik, Seth M.; Lu, Zhongmin

    2006-01-01

    One of the primary challenges that sensory systems face is extracting relevant information from background noise. In the auditory system, the ear receives efferent feedback, which may help it extract signals from noise. Here we directly test the hypothesis that efferent activity increases the signal-to-noise ratio (SNR) of the ear, using the relatively simple teleost ear. Tone-evoked saccular potentials were recorded before and after efferent stimulation, and the SNR of the responses was calculated. In quiet conditions, efferent stimulation suppressed saccular responses to a tone, reducing the SNR. However, when masking noise was added, efferent stimulation increased the SNR of the saccular responses within a range of stimulus combinations. These data demonstrate that auditory efferent feedback can increase SNR in conditions where a signal is masked by noise, thereby enhancing the encoding of signals in noise. Efferent feedback thus performs a fundamental signal processing function, helping the animal to hear sounds in difficult listening conditions. PMID:16554519

  4. Auditory and tactile signals combine to influence vision during binocular rivalry.

    PubMed

    Lunghi, Claudia; Morrone, Maria Concetta; Alais, David

    2014-01-15

    Resolution of perceptual ambiguity is one function of cross-modal interactions. Here we investigate whether auditory and tactile stimuli can influence binocular rivalry generated by interocular temporal conflict in human subjects. Using dichoptic visual stimuli modulating at different temporal frequencies, we added modulating sounds or vibrations congruent with one or the other visual temporal frequency. Auditory and tactile stimulation both interacted with binocular rivalry by promoting dominance of the congruent visual stimulus. This effect depended on the cross-modal modulation strength and was absent when modulation depth declined to 33%. However, when auditory and tactile stimuli that were too weak on their own to bias binocular rivalry were combined, their influence over vision was very strong, suggesting the auditory and tactile temporal signals combined to influence vision. Similarly, interleaving discrete pulses of auditory and tactile stimuli also promoted dominance of the visual stimulus congruent with the supramodal frequency. When auditory and tactile stimuli were presented at maximum strength, but in antiphase, they had no influence over vision for low temporal frequencies, a null effect again suggesting audio-tactile combination. We also found that the cross-modal interaction was frequency-sensitive at low temporal frequencies, when information about temporal phase alignment can be perceptually tracked. These results show that auditory and tactile temporal processing is functionally linked, suggesting a common neural substrate for the two sensory modalities and that at low temporal frequencies visual activity can be synchronized by a congruent cross-modal signal in a frequency-selective way, suggesting the existence of a supramodal temporal binding mechanism. PMID:24431437

  5. A psychophysiological evaluation of the perceived urgency of auditory warning signals

    NASA Technical Reports Server (NTRS)

    Burt, J. L.; Bartolome, D. S.; Burdette, D. W.; Comstock, J. R. Jr

    1995-01-01

    One significant concern that pilots have about cockpit auditory warnings is that the signals presently used lack a sense of priority. The relationship between auditory warning sound parameters and perceived urgency is, therefore, an important topic of enquiry in aviation psychology. The present investigation examined the relationship among subjective assessments of urgency, reaction time, and brainwave activity with three auditory warning signals. Subjects performed a tracking task involving automated and manual conditions, and were presented with auditory warnings having various levels of perceived and situational urgency. Subjective assessments revealed that subjects were able to rank warnings on an urgency scale, but rankings were altered after warnings were mapped to a situational urgency scale. Reaction times differed between automated and manual tracking task conditions, and physiological data showed attentional differences in response to perceived and situational warning urgency levels. This study shows that the use of physiological measures sensitive to attention and arousal, in conjunction with behavioural and subjective measures, may lead to the design of auditory warnings that produce a sense of urgency in an operator that matches the urgency of the situation.

  6. Bilateral collicular interaction: modulation of auditory signal processing in frequency domain.

    PubMed

    Cheng, L; Mei, H-X; Tang, J; Fu, Z-Y; Jen, P H-S; Chen, Q-C

    2013-04-01

    In the ascending auditory pathway, the inferior colliculus (IC) receives and integrates excitatory and inhibitory inputs from a variety of lower auditory nuclei, intrinsic projections within the IC, contralateral IC through the commissure of the IC and the auditory cortex. All these connections make the IC a major center for subcortical temporal and spectral integration of auditory information. In this study, we examine bilateral collicular interaction in the modulation of frequency-domain signal processing of mice using electrophysiological recording and focal electrical stimulation. Focal electrical stimulation of neurons in one IC produces widespread inhibition and focused facilitation of responses of neurons in the other IC. This bilateral collicular interaction decreases the response magnitude and lengthens the response latency of inhibited IC neurons but produces an opposite effect on the response of facilitated IC neurons. In the frequency domain, the focal electrical stimulation of one IC sharpens or expands the frequency tuning curves (FTCs) of neurons in the other IC to improve frequency sensitivity and the frequency response range. The focal electrical stimulation also produces a shift in the best frequency (BF) of modulated IC (ICMdu) neurons toward that of electrically stimulated IC (ICES) neurons. The degree of bilateral collicular interaction is dependent upon the difference in the BF between the ICES neurons and ICMdu neurons. These data suggest that bilateral collicular interaction is a part of dynamic acoustic signal processing that adjusts and improves signal processing as well as reorganizes collicular representation of signal parameters according to the acoustic experience.

  7. Detectability of auditory signals presented without defined observation intervals

    NASA Technical Reports Server (NTRS)

    Watson, C. S.; Nichols, T. L.

    1976-01-01

    Ability to detect tones in noise was measured without defined observation intervals. Latency density functions were estimated for the first response following a signal and, separately, for the first response following randomly distributed instances of background noise. Detection performance was measured by the maximum separation between the cumulative latency density functions for signal-plus-noise and for noise alone. Values of the index of detectability, estimated by this procedure, were approximately those obtained with a 2-dB weaker signal and defined observation intervals. Simulation of defined- and non-defined-interval tasks with an energy detector showed that this device performs very similarly to the human listener in both cases.

  8. Neuroestrogen signaling in the songbird auditory cortex propagates into a sensorimotor network via an 'interface' nucleus.

    PubMed

    Pawlisch, B A; Remage-Healey, L

    2015-01-22

    Neuromodulators rapidly alter activity of neural circuits and can therefore shape higher order functions, such as sensorimotor integration. Increasing evidence suggests that brain-derived estrogens, such as 17-β-estradiol, can act rapidly to modulate sensory processing. However, less is known about how rapid estrogen signaling can impact downstream circuits. Past studies have demonstrated that estradiol levels increase within the songbird auditory cortex (the caudomedial nidopallium, NCM) during social interactions. Local estradiol signaling enhances the auditory-evoked firing rate of neurons in NCM to a variety of stimuli, while also enhancing the selectivity of auditory-evoked responses of neurons in a downstream sensorimotor brain region, HVC (proper name). Since these two brain regions are not directly connected, we employed dual extracellular recordings in HVC and the upstream nucleus interfacialis of the nidopallium (NIf) during manipulations of estradiol within NCM to better understand the pathway by which estradiol signaling propagates to downstream circuits. NIf has direct input into HVC, passing auditory information into the vocal motor output pathway, and is a possible source of the neural selectivity within HVC. Here, during acute estradiol administration in NCM, NIf neurons showed increases in baseline firing rates and auditory-evoked firing rates to all stimuli. Furthermore, when estradiol synthesis was blocked in NCM, we observed simultaneous decreases in the selectivity of NIf and HVC neurons. These effects were not due to direct estradiol actions because NIf has little to no capability for local estrogen synthesis or estrogen receptors, and these effects were specific to NIf because other neurons immediately surrounding NIf did not show these changes. Our results demonstrate that transsynaptic, rapid fluctuations in neuroestrogens are transmitted into NIf and subsequently HVC, both regions important for sensorimotor integration. Overall, these

  9. Comparison of Gain-Like Properties of Eye Position Signals in Inferior Colliculus Versus Auditory Cortex of Primates

    PubMed Central

    Maier, Joost X.; Groh, Jennifer M.

    2010-01-01

    We evaluated to what extent the influence of eye position in the auditory pathway of primates can be described as a gain field. We compared single unit activity in the inferior colliculus (IC), core auditory cortex (A1) and the caudomedial belt (CM) region of auditory cortex (AC) in primates, and found stronger evidence for gain field-like interactions in the IC than in AC. In the IC, eye position signals showed both multiplicative and additive interactions with auditory responses, whereas in AC the effects were not as well predicted by a gain field model. PMID:20838470

  10. Piglets Learn to Use Combined Human-Given Visual and Auditory Signals to Find a Hidden Reward in an Object Choice Task

    PubMed Central

    Bensoussan, Sandy; Cornil, Maude; Meunier-Salaün, Marie-Christine; Tallet, Céline

    2016-01-01

    Although animals rarely use only one sense to communicate, few studies have investigated the use of combinations of different signals between animals and humans. This study assessed for the first time the spontaneous reactions of piglets to human pointing gestures and voice in an object-choice task with a reward. Piglets (Sus scrofa domestica) mainly use auditory signals–individually or in combination with other signals—to communicate with their conspecifics. Their wide hearing range (42 Hz to 40.5 kHz) fits the range of human vocalisations (40 Hz to 1.5 kHz), which may induce sensitivity to the human voice. However, only their ability to use visual signals from humans, especially pointing gestures, has been assessed to date. The current study investigated the effects of signal type (visual, auditory and combined visual and auditory) and piglet experience on the piglets’ ability to locate a hidden food reward over successive tests. Piglets did not find the hidden reward at first presentation, regardless of the signal type given. However, they subsequently learned to use a combination of auditory and visual signals (human voice and static or dynamic pointing gestures) to successfully locate the reward in later tests. This learning process may result either from repeated presentations of the combination of static gestures and auditory signals over successive tests, or from transitioning from static to dynamic pointing gestures, again over successive tests. Furthermore, piglets increased their chance of locating the reward either if they did not go straight to a bowl after entering the test area or if they stared at the experimenter before visiting it. Piglets were not able to use the voice direction alone, indicating that a combination of signals (pointing and voice direction) is necessary. Improving our communication with animals requires adapting to their individual sensitivity to human-given signals. PMID:27792731

  11. Specialized postsynaptic morphology enhances neurotransmitter dilution and high-frequency signaling at an auditory synapse.

    PubMed

    Graydon, Cole W; Cho, Soyoun; Diamond, Jeffrey S; Kachar, Bechara; von Gersdorff, Henrique; Grimes, William N

    2014-06-11

    Sensory processing in the auditory system requires that synapses, neurons, and circuits encode information with particularly high temporal and spectral precision. In the amphibian papillia, sound frequencies up to 1 kHz are encoded along a tonotopic array of hair cells and transmitted to afferent fibers via fast, repetitive synaptic transmission, thereby promoting phase locking between the presynaptic and postsynaptic cells. Here, we have combined serial section electron microscopy, paired electrophysiological recordings, and Monte Carlo diffusion simulations to examine novel mechanisms that facilitate fast synaptic transmission in the inner ear of frogs (Rana catesbeiana and Rana pipiens). Three-dimensional anatomical reconstructions reveal specialized spine-like contacts between individual afferent fibers and hair cells that are surrounded by large, open regions of extracellular space. Morphologically realistic diffusion simulations suggest that these local enlargements in extracellular space speed transmitter clearance and reduce spillover between neighboring synapses, thereby minimizing postsynaptic receptor desensitization and improving sensitivity during prolonged signal transmission. Additionally, evoked EPSCs in afferent fibers are unaffected by glutamate transporter blockade, suggesting that transmitter diffusion and dilution, and not uptake, play a primary role in speeding neurotransmission and ensuring fidelity at these synapses.

  12. Vocalization–whisking coordination and multisensory integration of social signals in rat auditory cortex

    PubMed Central

    Rao, Rajnish P; Mielke, Falk; Bobrov, Evgeny; Brecht, Michael

    2014-01-01

    Social interactions involve multi-modal signaling. Here, we study interacting rats to investigate audio-haptic coordination and multisensory integration in the auditory cortex. We find that facial touch is associated with an increased rate of ultrasonic vocalizations, which are emitted at the whisking rate (∼8 Hz) and preferentially initiated in the retraction phase of whisking. In a small subset of auditory cortex regular-spiking neurons, we observed excitatory and heterogeneous responses to ultrasonic vocalizations. Most fast-spiking neurons showed a stronger response to calls. Interestingly, facial touch-induced inhibition in the primary auditory cortex and off-responses after termination of touch were twofold stronger than responses to vocalizations. Further, touch modulated the responsiveness of auditory cortex neurons to ultrasonic vocalizations. In summary, facial touch during social interactions involves precisely orchestrated calling-whisking patterns. While ultrasonic vocalizations elicited a rather weak population response from the regular spikers, the modulation of neuronal responses by facial touch was remarkably strong. DOI: http://dx.doi.org/10.7554/eLife.03185.001 PMID:25485525

  13. Processing speech signal using auditory-like filterbank provides least uncertainty about articulatory gestures

    PubMed Central

    Ghosh, Prasanta Kumar; Goldstein, Louis M.; Narayanan, Shrikanth S.

    2011-01-01

    Understanding how the human speech production system is related to the human auditory system has been a perennial subject of inquiry. To investigate the production–perception link, in this paper, a computational analysis has been performed using the articulatory movement data obtained during speech production with concurrently recorded acoustic speech signals from multiple subjects in three different languages: English, Cantonese, and Georgian. The form of articulatory gestures during speech production varies across languages, and this variation is considered to be reflected in the articulatory position and kinematics. The auditory processing of the acoustic speech signal is modeled by a parametric representation of the cochlear filterbank which allows for realizing various candidate filterbank structures by changing the parameter value. Using mathematical communication theory, it is found that the uncertainty about the articulatory gestures in each language is maximally reduced when the acoustic speech signal is represented using the output of a filterbank similar to the empirically established cochlear filterbank in the human auditory system. Possible interpretations of this finding are discussed. PMID:21682422

  14. AUX: a scripting language for auditory signal processing and software packages for psychoacoustic experiments and education.

    PubMed

    Kwon, Bomjun J

    2012-06-01

    This article introduces AUX (AUditory syntaX), a scripting syntax specifically designed to describe auditory signals and processing, to the members of the behavioral research community. The syntax is based on descriptive function names and intuitive operators suitable for researchers and students without substantial training in programming, who wish to generate and examine sound signals using a written script. In this article, the essence of AUX is discussed and practical examples of AUX scripts specifying various signals are illustrated. Additionally, two accompanying Windows-based programs and development libraries are described. AUX Viewer is a program that generates, visualizes, and plays sounds specified in AUX. AUX Viewer can also be used for class demonstrations or presentations. Another program, Psycon, allows a wide range of sound signals to be used as stimuli in common psychophysical testing paradigms, such as the adaptive procedure, the method of constant stimuli, and the method of adjustment. AUX Library is also provided, so that researchers can develop their own programs utilizing AUX. The philosophical basis of AUX is to separate signal generation from the user interface needed for experiments. AUX scripts are portable and reusable; they can be shared by other researchers, regardless of differences in actual AUX-based programs, and reused for future experiments. In short, the use of AUX can be potentially beneficial to all members of the research community-both those with programming backgrounds and those without.

  15. Valid cues for auditory or somatosensory targets affect their perception: a signal detection approach.

    PubMed

    Van Hulle, Lore; Van Damme, Stefaan; Crombez, Geert

    2013-01-01

    We investigated the effects of focusing attention towards auditory or somatosensory stimuli on perceptual sensitivity and response bias using a signal detection task. Participants (N = 44) performed an unspeeded detection task in which weak (individually calibrated) somatosensory or auditory stimuli were delivered. The focus of attention was manipulated by the presentation of a visual cue at the start of each trial. The visual cue consisted of the word "warmth" or the word "tone". This word cue was predictive of the corresponding target on two-thirds of the trials. As hypothesised, the results showed that cueing attention to a specific sensory modality resulted in a higher perceptual sensitivity for validly cued targets than for invalidly cued targets, as well as in a more liberal response criterion for reporting stimuli in the valid modality than in the invalid modality. The value of this experimental paradigm for investigating excessive attentional focus or hypervigilance in various non-clinical and clinical populations is discussed.

  16. Effects of Signal-to-Noise Ratio on Auditory Cortical Frequency Processing

    PubMed Central

    Teschner, Magnus J.; Seybold, Bryan A.; Malone, Brian J.; Hüning, Jana

    2016-01-01

    The neural mechanisms that support the robust processing of acoustic signals in the presence of background noise in the auditory system remain largely unresolved. Psychophysical experiments have shown that signal detection is influenced by the signal-to-noise ratio (SNR) and the overall stimulus level, but this relationship has not been fully characterized. We evaluated the neural representation of frequency in rat primary auditory cortex by constructing tonal frequency response areas (FRAs) in primary auditory cortex for different SNRs, tone levels, and noise levels. We show that response strength and selectivity for frequency and sound level depend on interactions between SNRs and tone levels. At low SNRs, jointly increasing the tone and noise levels reduced firing rates and narrowed FRA bandwidths; at higher SNRs, however, increasing the tone and noise levels increased firing rates and expanded bandwidths, as is usually seen for FRAs obtained without background noise. These changes in frequency and intensity tuning decreased tone level and tone frequency discriminability at low SNRs. By contrast, neither response onset latencies nor noise-driven steady-state firing rates meaningfully interacted with SNRs or overall sound levels. Speech detection performance in humans was also shown to depend on the interaction between overall sound level and SNR. Together, these results indicate that signal processing difficulties imposed by high noise levels are quite general and suggest that the neurophysiological changes we see for simple sounds generalize to more complex stimuli. SIGNIFICANCE STATEMENT Effective processing of sounds in background noise is an important feature of the mammalian auditory system and a necessary feature for successful hearing in many listening conditions. Even mild hearing loss strongly affects this ability in humans, seriously degrading the ability to communicate. The mechanisms involved in achieving high performance in background noise are not

  17. What you see isn't always what you get: Auditory word signals trump consciously perceived words in lexical access.

    PubMed

    Ostrand, Rachel; Blumstein, Sheila E; Ferreira, Victor S; Morgan, James L

    2016-06-01

    Human speech perception often includes both an auditory and visual component. A conflict in these signals can result in the McGurk illusion, in which the listener perceives a fusion of the two streams, implying that information from both has been integrated. We report two experiments investigating whether auditory-visual integration of speech occurs before or after lexical access, and whether the visual signal influences lexical access at all. Subjects were presented with McGurk or Congruent primes and performed a lexical decision task on related or unrelated targets. Although subjects perceived the McGurk illusion, McGurk and Congruent primes with matching real-word auditory signals equivalently primed targets that were semantically related to the auditory signal, but not targets related to the McGurk percept. We conclude that the time course of auditory-visual integration is dependent on the lexicality of the auditory and visual input signals, and that listeners can lexically access one word and yet consciously perceive another.

  18. Bilateral Collicular Interaction: Modulation of Auditory Signal Processing in Amplitude Domain

    PubMed Central

    Fu, Zi-Ying; Wang, Xin; Jen, Philip H.-S.; Chen, Qi-Cai

    2012-01-01

    In the ascending auditory pathway, the inferior colliculus (IC) receives and integrates excitatory and inhibitory inputs from many lower auditory nuclei, intrinsic projections within the IC, contralateral IC through the commissure of the IC and from the auditory cortex. All these connections make the IC a major center for subcortical temporal and spectral integration of auditory information. In this study, we examine bilateral collicular interaction in modulating amplitude-domain signal processing using electrophysiological recording, acoustic and focal electrical stimulation. Focal electrical stimulation of one (ipsilateral) IC produces widespread inhibition (61.6%) and focused facilitation (9.1%) of responses of neurons in the other (contralateral) IC, while 29.3% of the neurons were not affected. Bilateral collicular interaction produces a decrease in the response magnitude and an increase in the response latency of inhibited IC neurons but produces opposite effects on the response of facilitated IC neurons. These two groups of neurons are not separately located and are tonotopically organized within the IC. The modulation effect is most effective at low sound level and is dependent upon the interval between the acoustic and electric stimuli. The focal electrical stimulation of the ipsilateral IC compresses or expands the rate-level functions of contralateral IC neurons. The focal electrical stimulation also produces a shift in the minimum threshold and dynamic range of contralateral IC neurons for as long as 150 minutes. The degree of bilateral collicular interaction is dependent upon the difference in the best frequency between the electrically stimulated IC neurons and modulated IC neurons. These data suggest that bilateral collicular interaction mainly changes the ratio between excitation and inhibition during signal processing so as to sharpen the amplitude sensitivity of IC neurons. Bilateral interaction may be also involved in acoustic

  19. Brain-Generated Estradiol Drives Long-Term Optimization of Auditory Coding to Enhance the Discrimination of Communication Signals

    PubMed Central

    Tremere, Liisa A.; Pinaud, Raphael

    2011-01-01

    Auditory processing and hearing-related pathologies are heavily influenced by steroid hormones in a variety of vertebrate species including humans. The hormone estradiol has been recently shown to directly modulate the gain of central auditory neurons, in real-time, by controlling the strength of inhibitory transmission via a non-genomic mechanism. The functional relevance of this modulation, however, remains unknown. Here we show that estradiol generated in the songbird homologue of the mammalian auditory association cortex, rapidly enhances the effectiveness of the neural coding of complex, learned acoustic signals in awake zebra finches. Specifically, estradiol increases mutual information rates, coding efficiency and the neural discrimination of songs. These effects are mediated by estradiol’s modulation of both rate and temporal coding of auditory signals. Interference with the local action or production of estradiol in the auditory forebrain of freely-behaving animals disrupts behavioral responses to songs, but not to other behaviorally-relevant communication signals. Our findings directly show that estradiol is a key regulator of auditory function in the adult vertebrate brain. PMID:21368039

  20. The effects of spectral and temporal parameters on perceived confirmation of an auditory non-speech signal.

    PubMed

    Bodendörfer, Xaver; Kortekaas, Reinier; Weingarten, Markus; Schlittmeier, Sabine

    2015-08-01

    In human-machine interactions, the confirmation of an action or input is a very important information for users. A paired comparison experiment explored the effects of four acoustic parameters on the perceived confirmation of auditory non-speech signals. Reducing the frequency-ratio and the pulse-to-pulse time between two successive pulses increased perceived confirmation. The effects of the parameters frequency and number of pulses were not clear-cut. The results provide information for designing auditory confirmation signals. It is shown that findings about the effects of certain parameters on the perceived urgency of warning signals cannot be easily inverted to perceived confirmation. PMID:26328737

  1. The Role of Amygdala Nuclei in the Expression of Auditory Signaled Two-Way Active Avoidance in Rats

    ERIC Educational Resources Information Center

    Choi, June-Seek; Cain, Christopher K.; LeDoux, Joseph E.

    2010-01-01

    Using a two-way signaled active avoidance (2-AA) learning procedure, where rats were trained in a shuttle box to avoid a footshock signaled by an auditory stimulus, we tested the contributions of the lateral (LA), basal (B), and central (CE) nuclei of the amygdala to the expression of instrumental active avoidance conditioned responses (CRs).…

  2. Decision-related cortical potentials during an auditory signal detection task with cued observation intervals

    NASA Technical Reports Server (NTRS)

    Squires, K. C.; Squires, N. K.; Hillyard, S. A.

    1975-01-01

    Cortical-evoked potentials were recorded from human subjects performing an auditory detection task with confidence rating responses. Unlike earlier studies that used similar procedures, the observation interval during which the auditory signal could occur was clearly marked by a visual cue light. By precisely defining the observation interval and, hence, synchronizing all perceptual decisions to the evoked potential averaging epoch, it was possible to demonstrate that high-confidence false alarms are accompanied by late-positive P3 components equivalent to those for equally confident hits. Moreover the hit and false alarm evoked potentials were found to covary similarly with variations in confidence rating and to have similar amplitude distributions over the scalp. In a second experiment, it was demonstrated that correct rejections can be associated with a P3 component larger than that for hits. Thus it was possible to show, within the signal detection paradigm, how the two major factors of decision confidence and expectancy are reflected in the P3 component of the cortical-evoked potential.

  3. Vertex potentials evoked during auditory signal detection - Relation to decision criteria

    NASA Technical Reports Server (NTRS)

    Squires, K. C.; Hillyard, S. A.; Lindsay, P. H.

    1973-01-01

    Vertex potentials were recorded from eight subjects performing in an auditory threshold detection task with rating scale responses. The amplitudes and latencies of both the N1 and the late positive (P3) components were found to vary systematically with the criterion level of the decision. These changes in the waveshape of the N1 component were comparable to those produced by varying the signal intensity in a passive condition, but the late positive component in the active task was not similarly related to the passively evoked P2 component. It was suggested that the N1 and P3 components represent distinctive aspects of the decision process, with N1 signifying the quantity of signal information received and P3 reflecting the certainty of the decision based upon that information.

  4. Recurrence of task set-related MEG signal patterns during auditory working memory.

    PubMed

    Peters, Benjamin; Bledowski, Christoph; Rieder, Maria; Kaiser, Jochen

    2016-06-01

    Processing of auditory spatial and non-spatial information in working memory has been shown to rely on separate cortical systems. While previous studies have demonstrated differences in spatial versus non-spatial processing from the encoding of to-be-remembered stimuli onwards, here we investigated whether such differences would be detectable already prior to presentation of the sample stimulus. We analyzed broad-band magnetoencephalography data from 15 healthy adults during an auditory working memory paradigm starting with a visual cue indicating the task-relevant stimulus feature for a given trial (lateralization or pitch) and a subsequent 1.5-s pre-encoding phase. This was followed by a sample sound (0.2s), the delay phase (0.8s) and a test stimulus (0.2s) after which participants made a match/non-match decision. Linear discriminant functions were trained to decode task-specific signal patterns throughout the task, and temporal generalization was used to assess whether the neural codes discriminating between the tasks during the pre-encoding phase would recur during later task periods. The spatial versus non-spatial tasks could indeed be discriminated after the onset of the cue onwards, and decoders trained during the pre-encoding phase successfully discriminated the tasks during both sample stimulus encoding and during the delay phase. This demonstrates that task-specific neural codes are established already before the memorandum is presented and that the same patterns are reestablished during stimulus encoding and maintenance. This article is part of a Special Issue entitled SI: Auditory working memory. PMID:26683086

  5. Canonical Notch signaling plays an instructive role in auditory supporting cell development

    PubMed Central

    Campbell, Dean P.; Chrysostomou, Elena; Doetzlhofer, Angelika

    2016-01-01

    The auditory sensory epithelium, composed of mechano-sensory hair cells (HCs) and highly specialized glial-like supporting cells (SCs), is critical for our ability to detect sound. SCs provide structural and functional support to HCs and play an essential role in cochlear development, homeostasis and repair. Despite their importance, however, surprisingly little is known about the molecular mechanisms guiding SC differentiation. Here, we provide evidence that in addition to its well-characterized inhibitory function, canonical Notch signaling plays a positive, instructive role in the differentiation of SCs. Using γ-secretase inhibitor DAPT to acutely block canonical Notch signaling, we identified a cohort of Notch-regulated SC-specific genes, with diverse functions in cell signaling, cell differentiation, neuronal innervation and synaptogenesis. We validated the newly identified Notch-regulated genes in vivo using genetic gain (Emx2Cre/+; Rosa26N1ICD/+) and loss-of-function approaches (Emx2Cre/+; Rosa26DnMAML1/+). Furthermore, we demonstrate that Notch over-activation in the differentiating murine cochlea (Emx2Cre/+; Rosa26N1ICD/+) actively promotes a SC-specific gene expression program. Finally, we show that outer SCs –so called Deiters’ cells are selectively lost by prolonged reduction (Emx2Cre/+; Rosa26DnMAML1/+/+) or abolishment of canonical Notch signaling (Fgfr3-iCreER; Rbpj−/Δ), indicating a critical role for Notch signaling in Deiters’ cell development. PMID:26786414

  6. 78 FR 36738 - Signal System Reporting Requirements

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-19

    ... Federal Railroad Administration 49 CFR Part 233 RIN 2130-AC44 Signal System Reporting Requirements AGENCY: Federal Railroad Administration (FRA), Department of Transportation (DOT). ACTION: Notice of proposed... Regulatory Action A. Elimination of the Signal System Five- ear Report On May 14, 2012, President...

  7. Calcium Signaling Is Required for Erythroid Enucleation.

    PubMed

    Wölwer, Christina B; Pase, Luke B; Russell, Sarah M; Humbert, Patrick O

    2016-01-01

    Although erythroid enucleation, the property of erythroblasts to expel their nucleus, has been known for 7ore than a century, surprisingly little is known regarding the molecular mechanisms governing this unique developmental process. Here we show that similar to cytokinesis, nuclear extrusion requires intracellular calcium signaling and signal transduction through the calmodulin (CaM) pathway. However, in contrast to cytokinesis we found that orthochromatic erythroblasts require uptake of extracellular calcium to enucleate. Together these functional studies highlight a critical role for calcium signaling in the regulation of erythroid enucleation.

  8. Calcium Signaling Is Required for Erythroid Enucleation

    PubMed Central

    Russell, Sarah M.; Humbert, Patrick O.

    2016-01-01

    Although erythroid enucleation, the property of erythroblasts to expel their nucleus, has been known for 7ore than a century, surprisingly little is known regarding the molecular mechanisms governing this unique developmental process. Here we show that similar to cytokinesis, nuclear extrusion requires intracellular calcium signaling and signal transduction through the calmodulin (CaM) pathway. However, in contrast to cytokinesis we found that orthochromatic erythroblasts require uptake of extracellular calcium to enucleate. Together these functional studies highlight a critical role for calcium signaling in the regulation of erythroid enucleation. PMID:26731108

  9. Influence of Different Envelope Maskers on Signal Recognition and Neuronal Representation in the Auditory System of a Grasshopper

    PubMed Central

    Neuhofer, Daniela; Ronacher, Bernhard

    2012-01-01

    Background Animals that communicate by sound face the problem that the signals arriving at the receiver often are degraded and masked by noise. Frequency filters in the receiver's auditory system may improve the signal-to-noise ratio (SNR) by excluding parts of the spectrum which are not occupied by the species-specific signals. This solution, however, is hardly amenable to species that produce broad band signals or have ears with broad frequency tuning. In mammals auditory filters exist that work in the temporal domain of amplitude modulations (AM). Do insects also use this type of filtering? Principal Findings Combining behavioural and neurophysiological experiments we investigated whether AM filters may improve the recognition of masked communication signals in grasshoppers. The AM pattern of the sound, its envelope, is crucial for signal recognition in these animals. We degraded the species-specific song by adding random fluctuations to its envelope. Six noise bands were used that differed in their overlap with the spectral content of the song envelope. If AM filters contribute to reduced masking, signal recognition should depend on the degree of overlap between the song envelope spectrum and the noise spectra. Contrary to this prediction, the resistance against signal degradation was the same for five of six masker bands. Most remarkably, the band with the strongest frequency overlap to the natural song envelope (0–100 Hz) impaired acceptance of degraded signals the least. To assess the noise filter capacities of single auditory neurons, the changes of spike trains as a function of the masking level were assessed. Increasing levels of signal degradation in different frequency bands led to similar changes in the spike trains in most neurones. Conclusions There is no indication that auditory neurones of grasshoppers are specialized to improve the SNR with respect to the pattern of amplitude modulations. PMID:22479619

  10. Subthreshold membrane responses underlying sparse spiking to natural vocal signals in auditory cortex

    PubMed Central

    Perks, Krista Eva; Gentner, Timothy Q.

    2015-01-01

    Natural acoustic communication signals, such as speech, are typically high-dimensional with a wide range of co-varying spectro-temporal features at multiple timescales. The synaptic and network mechanisms for encoding these complex signals are largely unknown. We are investigating these mechanisms in high-level sensory regions of the songbird auditory forebrain, where single neurons show sparse, object-selective spiking responses to conspecific songs. Using whole-cell in-vivo patch clamp techniques in the caudal mesopallium and the caudal nidopallium of starlings, we examine song-driven subthreshold and spiking activity. We find that both the subthreshold and the spiking activity are reliable (i.e., the same song drives a similar response each time it is presented) and specific (i.e. responses to different songs are distinct). Surprisingly, however, the reliability and specificity of the sub-threshold response was uniformly high regardless of when the cell spiked, even for song stimuli that drove no spikes. We conclude that despite a selective and sparse spiking response, high-level auditory cortical neurons are under continuous, non-selective, stimulus-specific synaptic control. To investigate the role of local network inhibition in this synaptic control, we then recorded extracellularly while pharmacologically blocking local GABA-ergic transmission. This manipulation modulated the strength and the reliability of stimulus-driven spiking, consistent with a role for local inhibition in regulating the reliability of network activity and the stimulus specificity of the subthreshold response in single cells. We discuss these results in the context of underlying computations that could generate sparse, stimulus-selective spiking responses, and models for hierarchical pooling. PMID:25728189

  11. Habitat-related differences in auditory processing of complex tones and vocal signal properties in four songbirds.

    PubMed

    Lucas, Jeffrey R; Vélez, Alejandro; Henry, Kenneth S

    2015-04-01

    We examined temporal processing of harmonic tone complexes in two woodland species (tufted titmice and white-breasted nuthatches) and two open-habitat species (house sparrows and white-crowned sparrows). Envelope and fine-structure processing were quantified using the envelope following response (EFR) and frequency following response (FFR). We predicted stronger EFRs in the open-habitat species based on broader auditory filters and greater amplitude modulation of vocal signals in this group. We predicted stronger FFRs in woodland species based on narrower auditory filters. As predicted, EFR amplitude was generally greatest in the open habitat species. FFR amplitude, in contrast, was greatest in white-crowned sparrows with no clear difference between habitats. This result cannot be fully explained by species differences in audiogram shape and might instead reflect greater acoustic complexity of songs in the white-crowned sparrow. Finally, we observed stronger FFRs in woodland species when tones were broadcast with the next higher harmonic in the complex. Thus, species such as nuthatches that have songs with strong harmonics may process these sounds using enhanced spectral processing instead of enhanced amplitude-envelope processing. The results suggest coevolution between signal design and temporal processing of complex signals and underscore the need to study auditory processing with a diversity of signals.

  12. Development of a Method to Compensate for Signal Quality Variations in Repeated Auditory Event-Related Potential Recordings

    PubMed Central

    Paukkunen, Antti K. O.; Leminen, Miika M.; Sepponen, Raimo

    2010-01-01

    Reliable measurements are mandatory in clinically relevant auditory event-related potential (AERP)-based tools and applications. The comparability of the results gets worse as a result of variations in the remaining measurement error. A potential method is studied that allows optimization of the length of the recording session according to the concurrent quality of the recorded data. In this way, the sufficiency of the trials can be better guaranteed, which enables control of the remaining measurement error. The suggested method is based on monitoring the signal-to-noise ratio (SNR) and remaining measurement error which are compared to predefined threshold values. The SNR test is well defined, but the criterion for the measurement error test still requires further empirical testing in practice. According to the results, the reproducibility of average AERPs in repeated experiments is improved in comparison to a case where the number of recorded trials is constant. The test-retest reliability is not significantly changed on average but the between-subject variation in the value is reduced by 33–35%. The optimization of the number of trials also prevents excessive recordings which might be of practical interest especially in the clinical context. The efficiency of the method may be further increased by implementing online tools that improve data consistency. PMID:20407635

  13. Effects of Signal Level and Background Noise on Spectral Representations in the Auditory Nerve of the Domestic Cat

    PubMed Central

    Ramachandran, Ramnarayan; May, Bradford J.

    2010-01-01

    Background noise poses a significant obstacle for auditory perception, especially among individuals with hearing loss. To better understand the physiological basis of this perceptual impediment, the present study evaluated the effects of background noise on the auditory nerve representation of head-related transfer functions (HRTFs). These complex spectral shapes describe the directional filtering effects of the head and torso. When a broadband sound passes through the outer ear en route to the tympanic membrane, the HRTF alters its spectrum in a manner that establishes the perceived location of the sound source. HRTF-shaped noise shares many of the acoustic features of human speech, while communicating biologically relevant localization cues that are generalized across mammalian species. Previous studies have used parametric manipulations of random spectral shapes to elucidate HRTF coding principles at various stages of the cat’s auditory system. This study extended that body of work by examining the effects of sound level and background noise on the quality of spectral coding in the auditory nerve. When fibers were classified by their spontaneous rates, the coding properties of the more numerous low-threshold, high-spontaneous rate fibers were found to degrade at high presentation levels and in low signal-to-noise ratios. Because cats are known to maintain accurate directional hearing under these challenging listening conditions, behavioral performance may be disproportionally based on the enhanced dynamic range of the less common high-threshold, low-spontaneous rate fibers. PMID:20824483

  14. Retrosplenial cortex is required for the retrieval of remote memory for auditory cues.

    PubMed

    Todd, Travis P; Mehlman, Max L; Keene, Christopher S; DeAngeli, Nicole E; Bucci, David J

    2016-06-01

    The restrosplenial cortex (RSC) has a well-established role in contextual and spatial learning and memory, consistent with its known connectivity with visuo-spatial association areas. In contrast, RSC appears to have little involvement with delay fear conditioning to an auditory cue. However, all previous studies have examined the contribution of the RSC to recently acquired auditory fear memories. Since neocortical regions have been implicated in the permanent storage of remote memories, we examined the contribution of the RSC to remotely acquired auditory fear memories. In Experiment 1, retrieval of a remotely acquired auditory fear memory was impaired when permanent lesions (either electrolytic or neurotoxic) were made several weeks after initial conditioning. In Experiment 2, using a chemogenetic approach, we observed impairments in the retrieval of remote memory for an auditory cue when the RSC was temporarily inactivated during testing. In Experiment 3, after injection of a retrograde tracer into the RSC, we observed labeled cells in primary and secondary auditory cortices, as well as the claustrum, indicating that the RSC receives direct projections from auditory regions. Overall our results indicate the RSC has a critical role in the retrieval of remotely acquired auditory fear memories, and we suggest this is related to the quality of the memory, with less precise memories being RSC dependent.

  15. Retrosplenial cortex is required for the retrieval of remote memory for auditory cues.

    PubMed

    Todd, Travis P; Mehlman, Max L; Keene, Christopher S; DeAngeli, Nicole E; Bucci, David J

    2016-06-01

    The restrosplenial cortex (RSC) has a well-established role in contextual and spatial learning and memory, consistent with its known connectivity with visuo-spatial association areas. In contrast, RSC appears to have little involvement with delay fear conditioning to an auditory cue. However, all previous studies have examined the contribution of the RSC to recently acquired auditory fear memories. Since neocortical regions have been implicated in the permanent storage of remote memories, we examined the contribution of the RSC to remotely acquired auditory fear memories. In Experiment 1, retrieval of a remotely acquired auditory fear memory was impaired when permanent lesions (either electrolytic or neurotoxic) were made several weeks after initial conditioning. In Experiment 2, using a chemogenetic approach, we observed impairments in the retrieval of remote memory for an auditory cue when the RSC was temporarily inactivated during testing. In Experiment 3, after injection of a retrograde tracer into the RSC, we observed labeled cells in primary and secondary auditory cortices, as well as the claustrum, indicating that the RSC receives direct projections from auditory regions. Overall our results indicate the RSC has a critical role in the retrieval of remotely acquired auditory fear memories, and we suggest this is related to the quality of the memory, with less precise memories being RSC dependent. PMID:27194795

  16. The dependence of behavioral auditory thresholds on the delay of echo-like signals in noctuid moths (lepidoptera, noctuidae).

    PubMed

    Lapshin, D N; Vorontsov, D D

    2009-03-01

    The auditory system of noctuoid moths capable to respond to ultrasounds has long been a model for anti-predator studies in neuroethology. Many moths avoid hunting bats by listening for their echolocation calls and taking evasive manoeuvres to escape predation. Besides these flight defences, certain tiger moths (Arctiidae) emit high-frequency clicks to jam the echolocator of an attacking bat. Another suggested function for ultrasonic audition in moths along with their capability to emit loud ultrasonic clicks was pulse echolocation. However, it seemed difficult to arrange sufficient temporal resolution in a simple invertebrate auditory system. Here we present an evidence of moth's capability to perceive an echo following its own click with a very short delay. The behavioral responses of moths to the acoustic pulses imitating echoes of their own clicks were investigated under conditions of tethered flight. It has been found that such echo-like stimulation evokes an increase in average emission rate of own acoustic signals in moths. Auditory thresholds were measured in two noctuid species (Enargia paleacea Esp. and Blepharita satura Schiff.) at stimulus delays 0.2, 0.3, 0.5 and 1 ms in relation to the respective moth clicks. Our findings reveal the ability of these moths to perceive echoes of their own signals, thus demonstrating potential possibility for use of pulse echolocation.

  17. Autoshaping in the rat: The effects of localizable visual and auditory signals for food

    PubMed Central

    Cleland, Gary G.; Davey, Graham C. L.

    1983-01-01

    Two experiments investigated autoshaping in rats to localizable visual and auditory conditioned stimuli predicting response-independent food. In Experiment 1 considerable conditioned-stimulus approach behavior was generated by a localizable visual conditioned stimulus that was situated approximately 35 cm from the food tray. Using the same apparatus in Experiment 2 we found that the conditioned-stimulus approach was generated only to a visual conditioned stimulus and not to a localizable auditory conditioned stimulus even though subjects (1) could discriminate presentations of the auditory conditioned stimulus, (2) had associated it with food, (3) could localize it, and (4) would approach the auditory stimulus if this behavior constituted an instrumental response to food. The predominant conditioned responses to the auditory stimuli were goal tracking (entering the food tray) and orienting towards the food-paired conditioned stimulus by head turning and rearing and turning. These results imply that rats do not invariably approach a localizable appetitive Pavlovian conditioned stimulus but that stimulus-approach responses depend on the nature and modality of the conditioned stimulus. PMID:16812336

  18. The contribution of auditory temporal processing to the separation of competing speech signals in listeners with normal hearing

    NASA Astrophysics Data System (ADS)

    Adam, Trudy J.; Pichora-Fuller, Kathy

    2002-05-01

    The hallmark of auditory function in aging adults is difficulty listening in a background of competing talkers, even when hearing sensitivity in quiet is good. Age-related physiological changes may contribute by introducing small timing errors (jitter) to the neural representation of sound, compromising the fidelity of the signal's fine temporal structure. This may preclude the association of spectral features to form an accurate percept of one complex stimulus, distinct from competing sounds. For simple voiced speech (vowels), the separation of two competing stimuli can be achieved on the basis of their respective harmonic (temporal) structures. Fundamental frequency (F0) differences in competing stimuli facilitate their segregation. This benefit was hypothesized to rely on the adequate temporal representation of the speech signal(s). Auditory aging was simulated via the desynchronization (~0.25-ms jitter) of the spectral bands of synthesized vowels. The perceptual benefit of F0 difference for the identification of concurrent vowel pairs was examined for intact and jittered vowels in young adults with normal hearing thresholds. Results suggest a role for reduced signal fidelity in the perceptual difficulties encountered in noisy everyday environments by aging listeners. [Work generously supported by the Michael Smith Foundation for Health Research.

  19. Verbal Recall of Auditory and Visual Signals by Normal and Deficient Reading Children.

    ERIC Educational Resources Information Center

    Levine, Maureen Julianne

    Verbal recall of bisensory memory tasks was compared among 48 9- to 12-year old boys in three groups: normal readers, primary deficit readers, and secondary deficit readers. Auditory and visual stimulus pairs composed of digits, which incorporated variations of intersensory and intrasensory conditions were administered to Ss through a Bell and…

  20. [The role of the ventral nucleus of the lateral lemniscus in sound signal processing and auditory ascending transmission].

    PubMed

    Liu, Hui-Hua; Luo, Feng; Wang, Xin

    2014-06-25

    The ventral nucleus of the lateral lemniscus (VNLL) is an important nucleus in the central auditory pathway which connects the lower brainstem and the midbrain inferior colliculus (IC). Previous studies have demonstrated that neurons in the VNLL could respond to sound signal parameters. Frequency tuning curves (FTCs) of VNLL neurons are generally wider than FTCs of IC neurons, suggesting that the VNLL does not enhance abilities of frequency discrimination and coding. Two types of rate-intensity functions (RIFs) are found in the VNLL: monotonic and non-monotonic RIFs. Intensity-tuning of VNLL neurons are affected by the temporal firing patterns during processing and encoding intensity. There are multiple temporal firing patterns in VNLL neurons. Onset pattern has a precise timing characteristic which is well suited to encode temporal features of stimuli, and also very important to animal behavior including bat's echolocation. The VNLL accepts inputs from lower nuclei, uploads glycine inhibitory outputs to IC, and modulates response characteristics generating and acoustic signal processing of IC neurons. Recent research suggests that fast inhibitory projection from the VNLL may delay the first spike latency of IC neurons, and the delayed inhibitory projection from the VNLL may mediate the temporal firing patterns of IC neurons. But how inhibitory inputs from the VNLL integrate in IC, and how inhibitory inputs from the VNLL enhance the ability of detecting sound signal of IC neurons are not very clear and need more direct evidence at the level of neurons. These questions will help further understand the role of upload during IC processes acoustic signal, which are our research target in the future. This article reviews the current literature regarding the roles of the VNLL in sound signal processing and the auditory ascending transmission, including advances in the relevant research in our laboratory.

  1. Representation of reward feedback in primate auditory cortex.

    PubMed

    Brosch, Michael; Selezneva, Elena; Scheich, Henning

    2011-01-01

    It is well established that auditory cortex is plastic on different time scales and that this plasticity is driven by the reinforcement that is used to motivate subjects to learn or to perform an auditory task. Motivated by these findings, we study in detail properties of neuronal firing in auditory cortex that is related to reward feedback. We recorded from the auditory cortex of two monkeys while they were performing an auditory categorization task. Monkeys listened to a sequence of tones and had to signal when the frequency of adjacent tones stepped in downward direction, irrespective of the tone frequency and step size. Correct identifications were rewarded with either a large or a small amount of water. The size of reward depended on the monkeys' performance in the previous trial: it was large after a correct trial and small after an incorrect trial. The rewards served to maintain task performance. During task performance we found three successive periods of neuronal firing in auditory cortex that reflected (1) the reward expectancy for each trial, (2) the reward-size received, and (3) the mismatch between the expected and delivered reward. These results, together with control experiments suggest that auditory cortex receives reward feedback that could be used to adapt auditory cortex to task requirements. Additionally, the results presented here extend previous observations of non-auditory roles of auditory cortex and shows that auditory cortex is even more cognitively influenced than lately recognized.

  2. Auditory, visual, and auditory-visual processing performance in typically developing children: modality independence versus dependence.

    PubMed

    Pillai, Roshni; Yathiraj, Asha

    2015-02-01

    The study was carried out to determine whether cross-modal interactions occur during processing of auditory and/or visual signals that require separation/closure, integration, and duration pattern perception in typically developing children. Thirty typically developing children were evaluated on three auditory processing tests (speech-in-noise test in Indian-English, dichotic-consonant vowel test, and duration pattern test) that tapped separation/closure, integration and duration pattern perception. The children were also evaluated on the visual and auditory-visual analogues of the auditory tests. Differences in modality were found in each of the processes that were tested. The performance when the auditory and visual modalities were tested simultaneously was significantly higher than the auditory or visual modality for tests that involved separation/closure and integration. In contrast, scores on the analogous auditory-visual duration pattern test were significantly higher than the auditory test but not the visual analogous test. Further, the scores of the auditory modality were significantly poorer than the visual modality for separation/closure and duration patterning but not for integration. Findings of the study indicate that performance on higher level processing varies depending on the modality that is assessed and supports the presence of cross-modality interactions.

  3. Retrosplenial Cortex Is Required for the Retrieval of Remote Memory for Auditory Cues

    ERIC Educational Resources Information Center

    Todd, Travis P.; Mehlman, Max L.; Keene, Christopher S.; DeAngeli, Nicole E.; Bucci, David J.

    2016-01-01

    The retrosplenial cortex (RSC) has a well-established role in contextual and spatial learning and memory, consistent with its known connectivity with visuo-spatial association areas. In contrast, RSC appears to have little involvement with delay fear conditioning to an auditory cue. However, all previous studies have examined the contribution of…

  4. Auditory object salience: human cortical processing of non-biological action sounds and their acoustic signal attributes

    PubMed Central

    Lewis, James W.; Talkington, William J.; Tallaksen, Katherine C.; Frum, Chris A.

    2012-01-01

    Whether viewed or heard, an object in action can be segmented as a distinct salient event based on a number of different sensory cues. In the visual system, several low-level attributes of an image are processed along parallel hierarchies, involving intermediate stages wherein gross-level object form and/or motion features are extracted prior to stages that show greater specificity for different object categories (e.g., people, buildings, or tools). In the auditory system, though relying on a rather different set of low-level signal attributes, meaningful real-world acoustic events and “auditory objects” can also be readily distinguished from background scenes. However, the nature of the acoustic signal attributes or gross-level perceptual features that may be explicitly processed along intermediate cortical processing stages remain poorly understood. Examining mechanical and environmental action sounds, representing two distinct non-biological categories of action sources, we had participants assess the degree to which each sound was perceived as object-like versus scene-like. We re-analyzed data from two of our earlier functional magnetic resonance imaging (fMRI) task paradigms (Engel et al., 2009) and found that scene-like action sounds preferentially led to activation along several midline cortical structures, but with strong dependence on listening task demands. In contrast, bilateral foci along the superior temporal gyri (STG) showed parametrically increasing activation to action sounds rated as more “object-like,” independent of sound category or task demands. Moreover, these STG regions also showed parametric sensitivity to spectral structure variations (SSVs) of the action sounds—a quantitative measure of change in entropy of the acoustic signals over time—and the right STG additionally showed parametric sensitivity to measures of mean entropy and harmonic content of the environmental sounds. Analogous to the visual system, intermediate stages

  5. 29 CFR 1926.1419 - Signals-general requirements.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    .... Where a signal person(s) is in communication with more than one crane/derrick, a system must be used for... 29 Labor 8 2011-07-01 2011-07-01 false Signals-general requirements. 1926.1419 Section 1926.1419... Construction § 1926.1419 Signals—general requirements. (a) A signal person must be provided in each of...

  6. 49 CFR 236.205 - Signal control circuits; requirements.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Signal control circuits; requirements. 236.205... Block Signal Systems Standards § 236.205 Signal control circuits; requirements. The circuits shall be so... fouling point derail equipped with switch circuit controller is not in derailing position, (d) When...

  7. 49 CFR 236.205 - Signal control circuits; requirements.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Signal control circuits; requirements. 236.205... Block Signal Systems Standards § 236.205 Signal control circuits; requirements. The circuits shall be so... fouling point derail equipped with switch circuit controller is not in derailing position, (d) When...

  8. 49 CFR 236.205 - Signal control circuits; requirements.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Signal control circuits; requirements. 236.205... Block Signal Systems Standards § 236.205 Signal control circuits; requirements. The circuits shall be so... fouling point derail equipped with switch circuit controller is not in derailing position, (d) When...

  9. 49 CFR 236.14 - Spring switch signal protection; requirements.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Spring switch signal protection; requirements. 236... Rules and Instructions: All Systems General § 236.14 Spring switch signal protection; requirements. (a... track signaled for movements in only one direction through a spring switch in automatic block...

  10. 49 CFR 236.14 - Spring switch signal protection; requirements.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Spring switch signal protection; requirements. 236... Rules and Instructions: All Systems General § 236.14 Spring switch signal protection; requirements. (a... track signaled for movements in only one direction through a spring switch in automatic block...

  11. 49 CFR 236.14 - Spring switch signal protection; requirements.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Spring switch signal protection; requirements. 236... Rules and Instructions: All Systems General § 236.14 Spring switch signal protection; requirements. (a... track signaled for movements in only one direction through a spring switch in automatic block...

  12. 49 CFR 236.14 - Spring switch signal protection; requirements.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Spring switch signal protection; requirements. 236... Rules and Instructions: All Systems General § 236.14 Spring switch signal protection; requirements. (a... track signaled for movements in only one direction through a spring switch in automatic block...

  13. 49 CFR 236.205 - Signal control circuits; requirements.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Signal control circuits; requirements. 236.205... Block Signal Systems Standards § 236.205 Signal control circuits; requirements. The circuits shall be so... fouling point derail equipped with switch circuit controller is not in derailing position, (d) When...

  14. The autophagy pathway maintained signaling crosstalk with the Keap1-Nrf2 system through p62 in auditory cells under oxidative stress.

    PubMed

    Hayashi, Ken; Dan, Katsuaki; Goto, Fumiyuki; Tshuchihashi, Nana; Nomura, Yasuyuki; Fujioka, Masato; Kanzaki, Sho; Ogawa, Kaoru

    2015-02-01

    The main purposes of our study were to consider the effect of autophagy on auditory cells under oxidative stress, and the function of possible crosstalk among p62, Keap1 and Nrf2 in autophagy-deficient auditory cells. First, we described how cell death was induced in auditory cell line (HEI-OC1) exposed to H2O2. We found that the decision for the cell death of auditory cells under oxidative stress depends on the balance between autophagy and necrosis due to ATP depletion, and autophagy plays a cytoprotective function in oxidative stress-induced necrosis. Our data clearly suggested that autophagy was a cell survival mechanism in H2O2-induced cell death, based on the observation that suppression of autophagy by knockdown of Atg7 sensitized, whereas activation of autophagy by rapamycin protected against H2O2-induced cell death. Next, our results regarding the relationship among p62, Nrf2 and Keap1 by siRNA paradoxically showed that p62 creates a positive feedback loop in the Keap1/Nrf2 pathway. Autophagy impaired by Atg7 knockdown degrades Keap1 in a p62-dependent manner, whereas Nrf2 is activated. As a result, the cell death induced by H2O2 was promoted in auditory cells. Taken together, these results suggested that the autophagy pathway maintained signaling crosstalk with the Keap1-Nrf2 system through p62 in auditory cells under oxidative stress. PMID:25435427

  15. Habituation of Auditory Steady State Responses Evoked by Amplitude-Modulated Acoustic Signals in Rats

    PubMed Central

    Prado-Gutierrez, Pavel; Castro-Fariñas, Anisleidy; Morgado-Rodriguez, Lisbet; Velarde-Reyes, Ernesto; Martínez, Agustín D.; Martínez-Montes, Eduardo

    2015-01-01

    Generation of the auditory steady state responses (ASSR) is commonly explained by the linear combination of random background noise activity and the stationary response. Based on this model, the decrease of amplitude that occurs over the sequential averaging of epochs of the raw data has been exclusively linked to the cancelation of noise. Nevertheless, this behavior might also reflect the non-stationary response of the ASSR generators. We tested this hypothesis by characterizing the ASSR time course in rats with different auditory maturational stages. ASSR were evoked by 8-kHz tones of different supra-threshold intensities, modulated in amplitude at 115 Hz. Results show that the ASSR amplitude habituated to the sustained stimulation and that dishabituation occurred when deviant stimuli were presented. ASSR habituation increased as animals became adults, suggesting that the ability to filter acoustic stimuli with no-relevant temporal information increased with age. Results are discussed in terms of the current model of the ASSR generation and analysis procedures. They might have implications for audiometric tests designed to assess hearing in subjects who cannot provide reliable results in the psychophysical trials. PMID:26557360

  16. Auditory scene analysis by echolocation in bats.

    PubMed

    Moss, C F; Surlykke, A

    2001-10-01

    Echolocating bats transmit ultrasonic vocalizations and use information contained in the reflected sounds to analyze the auditory scene. Auditory scene analysis, a phenomenon that applies broadly to all hearing vertebrates, involves the grouping and segregation of sounds to perceptually organize information about auditory objects. The perceptual organization of sound is influenced by the spectral and temporal characteristics of acoustic signals. In the case of the echolocating bat, its active control over the timing, duration, intensity, and bandwidth of sonar transmissions directly impacts its perception of the auditory objects that comprise the scene. Here, data are presented from perceptual experiments, laboratory insect capture studies, and field recordings of sonar behavior of different bat species, to illustrate principles of importance to auditory scene analysis by echolocation in bats. In the perceptual experiments, FM bats (Eptesicus fuscus) learned to discriminate between systematic and random delay sequences in echo playback sets. The results of these experiments demonstrate that the FM bat can assemble information about echo delay changes over time, a requirement for the analysis of a dynamic auditory scene. Laboratory insect capture experiments examined the vocal production patterns of flying E. fuscus taking tethered insects in a large room. In each trial, the bats consistently produced echolocation signal groups with a relatively stable repetition rate (within 5%). Similar temporal patterning of sonar vocalizations was also observed in the field recordings from E. fuscus, thus suggesting the importance of temporal control of vocal production for perceptually guided behavior. It is hypothesized that a stable sonar signal production rate facilitates the perceptual organization of echoes arriving from objects at different directions and distances as the bat flies through a dynamic auditory scene. Field recordings of E. fuscus, Noctilio albiventris, N

  17. Selective attention and the auditory vertex potential. 2: Effects of signal intensity and masking noise

    NASA Technical Reports Server (NTRS)

    Schwent, V. L.; Hillyard, S. A.; Galambos, R.

    1975-01-01

    A randomized sequence of tone bursts was delivered to subjects at short inter-stimulus intervals with the tones originating from one of three spatially and frequency specific channels. The subject's task was to count the tones in one of the three channels at a time, ignoring the other two, and press a button after each tenth tone. In different conditions, tones were given at high and low intensities and with or without a background white noise to mask the tones. The N sub 1 component of the auditory vertex potential was found to be larger in response to attended channel tones in relation to unattended tones. This selective enhancement of N sub 1 was minimal for loud tones presented without noise and increased markedly for the lower tone intensity and in noise added conditions.

  18. Neural processing of auditory signals in the time domain: delay-tuned coincidence detectors in the mustached bat.

    PubMed

    Suga, Nobuo

    2015-06-01

    The central auditory system produces combination-sensitive neurons tuned to a specific combination of multiple signal elements. Some of these neurons act as coincidence detectors with delay lines for the extraction of spectro-temporal information from sounds. "Delay-tuned" neurons of mustached bats are tuned to a combination of up to four signal elements with a specific delay between them and form a delay map. They are produced in the inferior colliculus by the coincidence of the rebound response following glycinergic inhibition to the first harmonic of a biosonar pulse with the short-latency response to the 2nd-4th harmonics of its echo. Compared with collicular delay-tuned neurons, thalamic and cortical ones respond more to pulse-echo pairs than individual sounds. Cortical delay-tuned neurons are clustered in the three separate areas. They interact with each other through a circuit mediating positive feedback and lateral inhibition for adjustment and improvement of the delay tuning of cortical and subcortical neurons. The current article reviews the mechanisms for delay tuning and the response properties of collicular, thalamic and cortical delay-tuned neurons in relation to hierarchical signal processing. PMID:25752443

  19. Diet-Induced Obesity Exacerbates Auditory Degeneration via Hypoxia, Inflammation, and Apoptosis Signaling Pathways in CD/1 Mice

    PubMed Central

    Hwang, Juen-Haur; Hsu, Chuan-Jen; Yu, Wei-Hsuan; Liu, Tien-Chen; Yang, Wei-Shiung

    2013-01-01

    The aim of this study was to investigate the mechanisms of diet-induced obesity on hearing degeneration in CD/1 mice. Sixty 4-week-old male CD/1 mice were randomly and equally divided into 2 groups. For 16 weeks, the diet-induced obesity (DIO) group was fed a high fat diet and the control group was fed a standard diet of 13.43 % kcal fat. The morphometry, biochemistry, auditory brainstem response thresholds, omental fat, and histopathology of the cochlea were compared between the beginning and end of the study (4 vs. 20 weeks old). The results show that the body weight, fasting plasma triglyceride concentrations, and omental fat weight were higher in the DIO group than in the control group at the end of experiment. The auditory brainstem response thresholds at high frequencies were significantly elevated in the DIO group compared to those of the control group. Histology studies showed that, compared to the control group, the DIO group had blood vessels with smaller diameters and thicker walls in the stria vascularis at the middle and basal turns of the cochlea. The cell densities in the spiral ganglion and spiral ligament at the basal turn of the cochlea were significantly lower in the DIO group. Immunohistochemical staining showed that hypoxia-induced factor 1 (HIF-1), tumor necrosis factor alpha (TNF-α), nuclear factor kappa B (NF-κB), caspase 3, poly(ADP-ribose) polymerase-1, and apoptosis inducing factor were all significantly more dense in the spiral ganglion and spiral ligament at the basal turn of cochlea in the DIO group. Our results suggest that diet-induced obesity exacerbates hearing degeneration via increased hypoxia, inflammatory responses, and cell loss in the spiral ganglion and spiral ligament and is associated with the activation of both caspase-dependent and -independent apoptosis signaling pathways in CD/1 mice. PMID:23637762

  20. Acoustic duetting in Drosophila virilis relies on the integration of auditory and tactile signals

    PubMed Central

    LaRue, Kelly M; Clemens, Jan; Berman, Gordon J; Murthy, Mala

    2015-01-01

    Many animal species, including insects, are capable of acoustic duetting, a complex social behavior in which males and females tightly control the rate and timing of their courtship song syllables relative to each other. The mechanisms underlying duetting remain largely unknown across model systems. Most studies of duetting focus exclusively on acoustic interactions, but the use of multisensory cues should aid in coordinating behavior between individuals. To test this hypothesis, we develop Drosophila virilis as a new model for studies of duetting. By combining sensory manipulations, quantitative behavioral assays, and statistical modeling, we show that virilis females combine precisely timed auditory and tactile cues to drive song production and duetting. Tactile cues delivered to the abdomen and genitalia play the larger role in females, as even headless females continue to coordinate song production with courting males. These data, therefore, reveal a novel, non-acoustic, mechanism for acoustic duetting. Finally, our results indicate that female-duetting circuits are not sexually differentiated, as males can also produce ‘female-like’ duets in a context-dependent manner. DOI: http://dx.doi.org/10.7554/eLife.07277.001 PMID:26046297

  1. Synaptic Plasticity and NO-cGMP-PKG Signaling Coordinately Regulate ERK-Driven Gene Expression in the Lateral Amygdala and in the Auditory Thalamus Following Pavlovian Fear Conditioning

    ERIC Educational Resources Information Center

    Ota, Kristie T.; Monsey, Melissa S.; Wu, Melissa S.; Young, Grace J.; Schafe, Glenn E.

    2010-01-01

    We have recently hypothesized that NO-cGMP-PKG signaling in the lateral nucleus of the amygdala (LA) during auditory fear conditioning coordinately regulates ERK-driven transcriptional changes in both auditory thalamic (MGm/PIN) and LA neurons that serve to promote pre- and postsynaptic alterations at thalamo-LA synapses, respectively. In the…

  2. The acquisition of mechano‐electrical transducer current adaptation in auditory hair cells requires myosin VI

    PubMed Central

    Marcotti, Walter; Corns, Laura F.; Goodyear, Richard J.; Rzadzinska, Agnieszka K.; Avraham, Karen B.; Steel, Karen P.; Richardson, Guy P.

    2016-01-01

    Key points The transduction of sound into electrical signals occurs at the hair bundles atop sensory hair cells in the cochlea, by means of mechanosensitive ion channels, the mechano‐electrical transducer (MET) channels.The MET currents decline during steady stimuli; this is termed adaptation and ensures they always work within the most sensitive part of their operating range, responding best to rapidly changing (sound) stimuli.In this study we used a mouse model (Snell's waltzer) for hereditary deafness in humans that has a mutation in the gene encoding an unconventional myosin, myosin VI, which is present in the hair bundles.We found that in the absence of myosin VI the MET current fails to acquire its characteristic adaptation as the hair bundles develop.We propose that myosin VI supports the acquisition of adaptation by removing key molecules from the hair bundle that serve a temporary, developmental role. Abstract Mutations in Myo6, the gene encoding the (F‐actin) minus end‐directed unconventional myosin, myosin VI, cause hereditary deafness in mice (Snell's waltzer) and humans. In the sensory hair cells of the cochlea, myosin VI is expressed in the cell bodies and along the stereocilia that project from the cells’ apical surface. It is required for maintaining the structural integrity of the mechanosensitive hair bundles formed by the stereocilia. In this study we investigate whether myosin VI contributes to mechano‐electrical transduction. We report that Ca2+‐dependent adaptation of the mechano‐electrical transducer (MET) current, which serves to keep the transduction apparatus operating within its most sensitive range, is absent in outer and inner hair cells from homozygous Snell's waltzer mutant mice, which fail to express myosin VI. The operating range of the MET channels is also abnormal in the mutants, resulting in the absence of a resting MET current. We found that cadherin 23, a component of the hair bundle's transient lateral links

  3. 46 CFR 161.013-7 - Signal requirements.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ...: SPECIFICATIONS AND APPROVAL ELECTRICAL EQUIPMENT Electric Distress Light for Boats § 161.013-7 Signal requirements. (a) An electric light must have a flash characteristic of the International Morse Code for...

  4. A signal detection analysis of auditory-frequency discrimination in the rat.

    PubMed

    Talwar, S K; Gerstein, G L

    1999-03-01

    The frequency-discrimination behavior of rats in a simple go/no-go task was analyzed using the theory of signal detection. Discrimination acuity was studied and the receiver operating characteristic (ROC) was generated in subjects by varying the reinforcement schedule and signal probability. The detectability indices d', A', and sensitivity index (SI) and response-bias indices B" and responsivity index (RI) were used to describe behavior. A' gave the most suitable psychometric functions while RI best described response-bias behavior. Weber ratios were 6.25% +/- 0.23% at 5 kHz in three subjects. The best method to obtain the ROC was to vary the probability with which subjects were reinforced. The ROC in two subjects demonstrated classical forms; in another subject, the function was asymmetric to the extent that detectability was not independent of response bias. Subjects altered their decision criterion in reporting a signal from trial to trial depending on previous trial events. On any given trial, subjects made a decision in one of several "decision states." Variables that influenced decision states included previous reinforcement and timeouts. The data indicate that timeouts may not be a useful feature in go/no-go tasks. The identification of multiple-decision states within a single behavioral session is a convenient method to generate the ROC without expressly manipulating experimental conditions.

  5. Hwanggunchungyitang prevents cadmium-induced ototoxicity through suppression of the activation of caspase-9 and extracellular signal-related kinase in auditory HEI-OC1 cells.

    PubMed

    Kim, Su-Jin; Shin, Bong-Gi; Choi, In-Young; Kim, Dong-Hyun; Kim, Min-Cheol; Myung, Noh-Yil; Moon, Phil-Dong; Lee, Jeong-Han; An, Hyo-Jin; Kim, Na-Hyung; Lee, Joo-Young; So, Hong-Seob; Park, Rae-Kil; Jeong, Hyun-Ja; Um, Jae-Young; Kim, Hyung-Min; Hong, Seung-Heon

    2009-02-01

    Hwanggunchungyitang (HGCYT) is a newly designed herbal drug formula for the purpose of treating auditory diseases. A number of heavy metals have been associated with toxic effects to the peripheral or central auditory system. Cadmium (Cd(2+)) is a heavy metal and a potent carcinogen implicated in tumor development through occupational and environmental exposure. However, the auditory effect of Cd(2+) is not poorly understood. The purpose of the present study was to investigate whether HGCYT prevent the ototoxic effects induced by Cd(2+) in auditory cell line, HEI-OC1. HGCYT inhibited the cell death, reactive oxygen species generation (ROS), activation of caspase-9, and extracellular signal-related kinase (ERK) induced by Cd(2+). In addition, we observed that cochlear hair cells in middle turn were damaged by Cd(2+). However, HGCYT prevented the destruction of hair cell arrays of the rat primary organ of Corti explants in the presence of Cd(2+). These results support the notion that ROS are involved in Cd(2+) ototoxicity and suggest HGCYT therapeutic usefulness, against Cd(2+)-induced activation of caspase-9 and ERK. PMID:19182378

  6. Signal-to-noise ratio in the membrane potential of the owl's auditory coincidence detectors

    PubMed Central

    Funabiki, Kazuo; Kuokkanen, Paula T.; Kempter, Richard; Carr, Catherine E.

    2012-01-01

    Owls use interaural time differences (ITDs) to locate a sound source. They compute ITD in a specialized neural circuit that consists of axonal delay lines from the cochlear nucleus magnocellularis (NM) and coincidence detectors in the nucleus laminaris (NL). Recent physiological recordings have shown that tonal stimuli induce oscillatory membrane potentials in NL neurons (Funabiki K, Ashida G, Konishi M. J Neurosci 31: 15245–15256, 2011). The amplitude of these oscillations varies with ITD and is strongly correlated to the firing rate. The oscillation, termed the sound analog potential, has the same frequency as the stimulus tone and is presumed to originate from phase-locked synaptic inputs from NM fibers. To investigate how these oscillatory membrane potentials are generated, we applied recently developed signal-to-noise ratio (SNR) analysis techniques (Kuokkanen PT, Wagner H, Ashida G, Carr CE, Kempter R. J Neurophysiol 104: 2274–2290, 2010) to the intracellular waveforms obtained in vivo. Our theoretical prediction of the band-limited SNRs agreed with experimental data for mid- to high-frequency (>2 kHz) NL neurons. For low-frequency (≤2 kHz) NL neurons, however, measured SNRs were lower than theoretical predictions. These results suggest that the number of independent NM fibers converging onto each NL neuron and/or the population-averaged degree of phase-locking of the NM fibers could be significantly smaller in the low-frequency NL region than estimated for higher best-frequency NL. PMID:22933726

  7. 29 CFR 1926.1421 - Signals-voice signals-additional requirements.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 29 Labor 8 2014-07-01 2014-07-01 false Signals-voice signals-additional requirements. 1926.1421 Section 1926.1421 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) SAFETY AND HEALTH REGULATIONS FOR CONSTRUCTION Cranes...

  8. 29 CFR 1926.1421 - Signals-voice signals-additional requirements.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) SAFETY AND HEALTH REGULATIONS FOR CONSTRUCTION Cranes and Derricks in Construction § 1926.1421 Signals—voice signals—additional requirements. (a) Prior to beginning... agree on the voice signals that will be used. Once the voice signals are agreed upon, these workers...

  9. 29 CFR 1926.1421 - Signals-voice signals-additional requirements.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) SAFETY AND HEALTH REGULATIONS FOR CONSTRUCTION Cranes and Derricks in Construction § 1926.1421 Signals—voice signals—additional requirements. (a) Prior to beginning... agree on the voice signals that will be used. Once the voice signals are agreed upon, these workers...

  10. Responses of neurons in the auditory pathway of the barn owl to partially correlated binaural signals.

    PubMed

    Albeck, Y; Konishi, M

    1995-10-01

    VLVa and ICcC. 5. Almost all ramp neurons occurred in either ICx or ICcLS where neurons are more broadly tuned to frequency than those in the lower nuclei. The synthesis of this response type requires, however, not only the convergence of different frequency channels but also inhibition between different ITD channels. We modeled the ramp response as a three-step process. First, different spectral channels converge to create broad frequency tuning. The response to variation in BC will be linear (or parabolic) because it is a sum of linear (parabolic) responses. Second, the activity in some adjacent ITD channels is subtracted by lateral inhibition. Finally, the result is rectified using a high threshold to avoid negative activity. PMID:8989405

  11. Subcortical processing in auditory communication.

    PubMed

    Pannese, Alessia; Grandjean, Didier; Frühholz, Sascha

    2015-10-01

    The voice is a rich source of information, which the human brain has evolved to decode and interpret. Empirical observations have shown that the human auditory system is especially sensitive to the human voice, and that activity within the voice-sensitive regions of the primary and secondary auditory cortex is modulated by the emotional quality of the vocal signal, and may therefore subserve, with frontal regions, the cognitive ability to correctly identify the speaker's affective state. So far, the network involved in the processing of vocal affect has been mainly characterised at the cortical level. However, anatomical and functional evidence suggests that acoustic information relevant to the affective quality of the auditory signal might be processed prior to the auditory cortex. Here we review the animal and human literature on the main subcortical structures along the auditory pathway, and propose a model whereby the distinction between different types of vocal affect in auditory communication begins at very early stages of auditory processing, and relies on the analysis of individual acoustic features of the sound signal. We further suggest that this early feature-based decoding occurs at a subcortical level along the ascending auditory pathway, and provides a preliminary coarse (but fast) characterisation of the affective quality of the auditory signal before the more refined (but slower) cortical processing is completed.

  12. Subcortical processing in auditory communication.

    PubMed

    Pannese, Alessia; Grandjean, Didier; Frühholz, Sascha

    2015-10-01

    The voice is a rich source of information, which the human brain has evolved to decode and interpret. Empirical observations have shown that the human auditory system is especially sensitive to the human voice, and that activity within the voice-sensitive regions of the primary and secondary auditory cortex is modulated by the emotional quality of the vocal signal, and may therefore subserve, with frontal regions, the cognitive ability to correctly identify the speaker's affective state. So far, the network involved in the processing of vocal affect has been mainly characterised at the cortical level. However, anatomical and functional evidence suggests that acoustic information relevant to the affective quality of the auditory signal might be processed prior to the auditory cortex. Here we review the animal and human literature on the main subcortical structures along the auditory pathway, and propose a model whereby the distinction between different types of vocal affect in auditory communication begins at very early stages of auditory processing, and relies on the analysis of individual acoustic features of the sound signal. We further suggest that this early feature-based decoding occurs at a subcortical level along the ascending auditory pathway, and provides a preliminary coarse (but fast) characterisation of the affective quality of the auditory signal before the more refined (but slower) cortical processing is completed. PMID:26163900

  13. Hedgehog signalling in the mouse requires intraflagellar transport proteins.

    PubMed

    Huangfu, Danwei; Liu, Aimin; Rakeman, Andrew S; Murcia, Noel S; Niswander, Lee; Anderson, Kathryn V

    2003-11-01

    Intraflagellar transport (IFT) proteins were first identified as essential factors for the growth and maintenance of flagella in the single-celled alga Chlamydomonas reinhardtii. In a screen for embryonic patterning mutations induced by ethylnitrosourea, here we identify two mouse mutants, wimple (wim) and flexo (fxo), that lack ventral neural cell types and show other phenotypes characteristic of defects in Sonic hedgehog signalling. Both mutations disrupt IFT proteins: the wim mutation is an allele of the previously uncharacterized mouse homologue of IFT172; and fxo is a new hypomorphic allele of polaris, the mouse homologue of IFT88. Genetic analysis shows that Wim, Polaris and the IFT motor protein Kif3a are required for Hedgehog signalling at a step downstream of Patched1 (the Hedgehog receptor) and upstream of direct targets of Hedgehog signalling. Our data show that IFT machinery has an essential and vertebrate-specific role in Hedgehog signal transduction. PMID:14603322

  14. Potyviruses differ in their requirement for TOR signalling.

    PubMed

    Ouibrahim, Laurence; Rubio, Ana Giner; Moretti, André; Montané, Marie-Hélène; Menand, Benoît; Meyer, Christian; Robaglia, Christophe; Caranta, Carole

    2015-09-01

    Potyviruses are important plant pathogens that rely on many plant cellular processes for successful infection. TOR (target of rapamycin) signalling is a key eukaryotic energy-signalling pathway controlling many cellular processes such as translation and autophagy. The dependence of potyviruses on active TOR signalling was examined. Arabidopsis lines downregulated for TOR by RNAi were challenged with the potyviruses watermelon mosaic virus (WMV) and turnip mosaic virus (TuMV). WMV accumulation was found to be severely altered while TuMV accumulation was only slightly delayed. In another approach, using AZD-8055, an active site inhibitor of the TOR kinase, WMV infection was found to be strongly affected. Moreover, AZD-8055 application can cure WMV infection. In contrast, TuMV infection was not affected by AZD-8055. This suggests that potyviruses have different cellular requirements for active plant TOR signalling.

  15. The Temporal Requirements for Insulin Signaling During Development in Drosophila

    PubMed Central

    2005-01-01

    Recent studies have indicated that the insulin-signaling pathway controls body and organ size in Drosophila, and most metazoans, by signaling nutritional conditions to the growing organs. The temporal requirements for insulin signaling during development are, however, unknown. Using a temperature-sensitive insulin receptor (Inr) mutation in Drosophila, we show that the developmental requirements for Inr activity are organ specific and vary in time. Early in development, before larvae reach the “critical size” (the size at which they commit to metamorphosis and can complete development without further feeding), Inr activity influences total development time but not final body and organ size. After critical size, Inr activity no longer affects total development time but does influence final body and organ size. Final body size is affected by Inr activity from critical size until pupariation, whereas final organ size is sensitive to Inr activity from critical size until early pupal development. In addition, different organs show different sensitivities to changes in Inr activity for different periods of development, implicating the insulin pathway in the control of organ allometry. The reduction in Inr activity is accompanied by a two-fold increase in free-sugar levels, similar to the effect of reduced insulin signaling in mammals. Finally, we find that varying the magnitude of Inr activity has different effects on cell size and cell number in the fly wing, providing a potential linkage between the mode of action of insulin signaling and the distinct downstream controls of cell size and number. We present a model that incorporates the effects of the insulin-signaling pathway into the Drosophila life cycle. We hypothesize that the insulin-signaling pathway controls such diverse effects as total developmental time, total body size and organ size through its effects on the rate of cell growth, and proliferation in different organs. PMID:16086608

  16. Auditory agnosia.

    PubMed

    Slevc, L Robert; Shell, Alison R

    2015-01-01

    Auditory agnosia refers to impairments in sound perception and identification despite intact hearing, cognitive functioning, and language abilities (reading, writing, and speaking). Auditory agnosia can be general, affecting all types of sound perception, or can be (relatively) specific to a particular domain. Verbal auditory agnosia (also known as (pure) word deafness) refers to deficits specific to speech processing, environmental sound agnosia refers to difficulties confined to non-speech environmental sounds, and amusia refers to deficits confined to music. These deficits can be apperceptive, affecting basic perceptual processes, or associative, affecting the relation of a perceived auditory object to its meaning. This chapter discusses what is known about the behavioral symptoms and lesion correlates of these different types of auditory agnosia (focusing especially on verbal auditory agnosia), evidence for the role of a rapid temporal processing deficit in some aspects of auditory agnosia, and the few attempts to treat the perceptual deficits associated with auditory agnosia. A clear picture of auditory agnosia has been slow to emerge, hampered by the considerable heterogeneity in behavioral deficits, associated brain damage, and variable assessments across cases. Despite this lack of clarity, these striking deficits in complex sound processing continue to inform our understanding of auditory perception and cognition.

  17. [Use of self-organizing neural networks (Kohonen maps) for classification of voice acoustic signals exemplified by the infant voice with and without time-delayed auditory feedback].

    PubMed

    Schönweiler, R; Kaese, S; Möller, S; Rinscheid, A; Ptok, M

    1996-04-01

    Subjective and auditory assessment of the voice is now more commonly being replaced by objective voice analysis. Because of the amount of data available from computer-aided voice analysis, subjective selection and interpretation of single data sets remain a matter of experience of the individual investigator. Since neuronal networks are widely used in telecommunication and speech recognition, we applied self-organizing Kohonen networks to classify voice patterns. In the phase of "learning," the Kohonen map is adapted to patterns of the primary signals obtained. If, in the phase of using the map, the input signal hits the field of the primary signals, it will resemble them closely. In this study, we recorded newborn and young infant cries using a DAT recorder and a high-quality microphone. The cries were elicited by wearing uncomfortable headphones ("cries of discomfort"). Spectrographic characteristics of the cries were classified by 20-step bark spectra and then applied to the neuronal networks. It was possible to recognize similarities of different cries of the same children and interindividual differences, as well as cries of children with profound hearing loss. In addition, delayed auditory feedback at 80 dB SL was presented to 27 children via headphone using a three-headed tape-recorder as a model for induced individual cry changes. However, it was not possible to classify short-term changes as in a delayed feedback procedure. Nevertheless, neuronal networks may be helpful as an additional tool in spectrographic voice analysis.

  18. Incorporating Auditory Models in Speech/Audio Applications

    NASA Astrophysics Data System (ADS)

    Krishnamoorthi, Harish

    2011-12-01

    Following the success in incorporating perceptual models in audio coding algorithms, their application in other speech/audio processing systems is expanding. In general, all perceptual speech/audio processing algorithms involve minimization of an objective function that directly/indirectly incorporates properties of human perception. This dissertation primarily investigates the problems associated with directly embedding an auditory model in the objective function formulation and proposes possible solutions to overcome high complexity issues for use in real-time speech/audio algorithms. Specific problems addressed in this dissertation include: 1) the development of approximate but computationally efficient auditory model implementations that are consistent with the principles of psychoacoustics, 2) the development of a mapping scheme that allows synthesizing a time/frequency domain representation from its equivalent auditory model output. The first problem is aimed at addressing the high computational complexity involved in solving perceptual objective functions that require repeated application of auditory model for evaluation of different candidate solutions. In this dissertation, a frequency pruning and a detector pruning algorithm is developed that efficiently implements the various auditory model stages. The performance of the pruned model is compared to that of the original auditory model for different types of test signals in the SQAM database. Experimental results indicate only a 4-7% relative error in loudness while attaining up to 80-90 % reduction in computational complexity. Similarly, a hybrid algorithm is developed specifically for use with sinusoidal signals and employs the proposed auditory pattern combining technique together with a look-up table to store representative auditory patterns. The second problem obtains an estimate of the auditory representation that minimizes a perceptual objective function and transforms the auditory pattern back to

  19. Development of the auditory system

    PubMed Central

    Litovsky, Ruth

    2015-01-01

    Auditory development involves changes in the peripheral and central nervous system along the auditory pathways, and these occur naturally, and in response to stimulation. Human development occurs along a trajectory that can last decades, and is studied using behavioral psychophysics, as well as physiologic measurements with neural imaging. The auditory system constructs a perceptual space that takes information from objects and groups, segregates sounds, and provides meaning and access to communication tools such as language. Auditory signals are processed in a series of analysis stages, from peripheral to central. Coding of information has been studied for features of sound, including frequency, intensity, loudness, and location, in quiet and in the presence of maskers. In the latter case, the ability of the auditory system to perform an analysis of the scene becomes highly relevant. While some basic abilities are well developed at birth, there is a clear prolonged maturation of auditory development well into the teenage years. Maturation involves auditory pathways. However, non-auditory changes (attention, memory, cognition) play an important role in auditory development. The ability of the auditory system to adapt in response to novel stimuli is a key feature of development throughout the nervous system, known as neural plasticity. PMID:25726262

  20. The relationship between verbal and nonverbal auditory signal processing in conduction aphasia: behavioral and anatomical evidence for common decoding mechanisms.

    PubMed

    Sidiropoulos, Kyriakos; de Bleser, Ria; Ablinger, Irene; Ackermann, Hermann

    2015-01-01

    The processing of nonverbal auditory stimuli has not yet been sufficiently investigated in patients with aphasia. On the basis of a duration discrimination task, we examined whether patients with left-sided cerebrovascular lesions were able to perceive time differences in the scale of approximately 150 ms. Further linguistic and memory-related tasks were used to characterize more exactly the relationships in the performances between auditory nonverbal task and selective linguistic or mnemonic disturbances. All examined conduction aphasics showed increased thresholds in the duration discrimination task. The low thresholds on this task were in a strong correlative relation to the reduced performances in repetition and working memory task. This was interpreted as an indication of a pronounced disturbance in integrating auditory verbal information into a long-term window (sampling disturbance) resulting in an additional load of working memory. In order to determine the lesion topography of patients with sampling disturbances, the anatomical and psychophysical data were correlated on the basis of a voxelwise statistical approach. It was found that tissue damage extending through the insula, the posterior superior temporal gyrus, and the supramarginal gyrus causes impairments in sequencing of time-sensitive information.

  1. Canonical wnt signaling is required for commissural axon guidance

    PubMed Central

    Avilés, Evelyn C.

    2015-01-01

    ABSTRACT Morphogens have been identified as guidance cues for postcrossing commissural axons in the spinal cord. Shh has a dual effect on postcrossing commissural axons: a direct repellent effect mediated by Hhip as a receptor, and an indirect effect by shaping a Wnt activity gradient. Wnts were shown to be attractants for postcrossing commissural axons in both chicken and mouse embryos. In mouse, the effects of Wnts on axon guidance were concluded to depend on the planar cell polarity (PCP) pathway. Canonical Wnt signaling was excluded based on the absence of axon guidance defects in mice lacking Lrp6 which is an obligatory coreceptor for Fzd in canonical Wnt signaling. In the loss‐of‐function studies reported here, we confirmed a role for the PCP pathway in postcrossing commissural axon guidance also in the chicken embryo. However, taking advantage of the precise temporal control of gene silencing provided by in ovo RNAi, we demonstrate that canonical Wnt signaling is also required for proper guidance of postcrossing commissural axons in the developing spinal cord. Thus, axon guidance does not seem to depend on any one of the classical Wnt signaling pathways but rather involve a network of Wnt receptors and downstream components. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 190–208, 2016 PMID:26014644

  2. Required signal-to-interference ratios for shortwave broadcasting

    NASA Astrophysics Data System (ADS)

    Lane, George

    1997-09-01

    The required signal-to-Interference (RSI) ratio for a specified grade of HF radio service is the hourly median wanted signal power at the input of the receiver needed relative to the sum of the hourly median unwanted signal power and the hourly median radio noise power in the RF bandwidth of the receiver, adjusted so that the hourly median ratio will not fall below the RSI ratio more than a certain percentage of the time due to minute-to-minute fading within the hour. Shortwave listeners are well aware of the deleterious effects of cochannel and adjacent channel interference. This type of interference is especially prevalent in the overcrowded international broadcast bands where it is manifested by cross talk and a beat note produced in the receiver by the carrier of the unwanted signal. Yet little agreement exists as to the magnitude of the amplitude-modulated, double sideband (AM-DSB) interfering signal that can be tolerated by the listener. Numerous protection ratios have been proposed in the literature, as well as by elements of the International Telecommunication Union. These values tend to range from 17 dB [International Frequency Registration Board, 1989] to as high as 50 dB for "good commercial quality," offset in carrier frequency of 500 Hz and 10 dB short-term fade protection [CCIR, 1970]. In this paper, several significant experiments are reviewed for the purpose of normalizing their findings to a common set of parameters. The parameters relate to articulation scoring, type of noise (if used), fading of wanted and unwanted signals, type of interference, listener skill, bandwidth of the receiver, carrier frequency offset, etc. From this compilation of normalized data, RSI values are recommended as they relate to the desired broadcast quality and the signal-to-noise ratio of the wanted signal. The RSI ratios are compatible for use in HF sky wave prediction programs that contain appropriate RF noise and interference combining subroutines. The recommended

  3. Axon Guidance in the Auditory System: Multiple Functions of Eph Receptors

    PubMed Central

    Cramer, Karina S.; Gabriele, Mark L.

    2014-01-01

    The neural pathways of the auditory system underlie our ability to detect sounds and to transform amplitude and frequency information into rich and meaningful perception. While it shares some organizational features with other sensory systems, the auditory system has some unique functions that impose special demands on precision in circuit assembly. In particular, the cochlear epithelium creates a frequency map rather than a space map, and specialized pathways extract information on interaural time and intensity differences to permit sound source localization. The assembly of auditory circuitry requires the coordinated function of multiple molecular cues. Eph receptors and their ephrin ligands constitute a large family of axon guidance molecules with developmentally regulated expression throughout the auditory system. Functional studies of Eph/ephrin signaling have revealed important roles at multiple levels of the auditory pathway, from the cochlea to the auditory cortex. These proteins provide graded cues used in establishing tonotopically ordered connections between auditory areas, as well as discrete cues that enable axons to form connections with appropriate postsynaptic partners within a target area. Throughout the auditory system, Eph proteins help to establish patterning in neural pathways during early development. This early targeting, which is further refined with neuronal activity, establishes the precision needed for auditory perception. PMID:25010398

  4. Wnt signaling is required for long-term memory formation

    PubMed Central

    Tan, Ying; Yu, Dinghui; Busto, Germain U.; Wilson, Curtis; Davis, Ronald L.

    2013-01-01

    SUMMARY Wnt signaling regulates synaptic plasticity and neurogenesis in the adult nervous system, suggesting a potential role in behavioral processes. Here, we probed the requirement for Wnt signaling during olfactory memory formation in Drosophila using an inducible RNA interference approach. Interfering with β-catenin expression in the adult mushroom body neurons specifically impaired long-term memory without altering short-term memory. The impairment was reversible, rescued with expression of a wild-type β-catenin transgene, and correlated with a disruption of a cellular long-term memory trace. Inhibition of wingless, a Wnt ligand, and arrow, a Wnt co-receptor, also impaired long-term memory. Wingless expression in wild type flies was transiently elevated in the brain after long-term memory conditioning. Thus, inhibiting three key components of the Wnt signaling pathway in the adult mushroom bodies impairs long-term memory, collectively indicating that this pathway mechanistically underlies this specific form of memory. PMID:24035392

  5. Requirement for Pangolin/dTCF in Drosophila Wingless signaling.

    PubMed

    Schweizer, Liang; Nellen, Denise; Basler, Konrad

    2003-05-13

    The Wingless (Wg) protein is a secreted glycoprotein involved in intercellular signaling. On activation of the Wg signaling pathway, Armadillo is stabilized, causing target genes to be activated by the transcription factor Pangolin (Pan). This study investigated the roles of Pan in the developing wing of Drosophila by clonal analysis. Three different aspects of wing development were examined: cell proliferation, wing margin specification, and wg self-refinement. Our results indicate that Pan function is critically required for all three of these processes. Consequently, lack of pan causes a severe reduction in the activity of the Wg target genes Distalless and vestigial within their normal domain of expression. Loss of pan function does not, however, lead to a derepression of these genes outside this domain. Thus, although Pan is positively required for the induction of Wg targets in the wing imaginal disk, it does not appear to play a default repressor function in the absence of Wg input. In contrast, lack of zygotic pan function causes a milder phenotype than that caused by the lack of wg function in the embryo. We show that this difference cannot be attributed to maternally provided pan product, indicating that a Pan repressor function usually prevents the expression of embryonic Wg targets. Together, our results suggest that for embryonic patterning the activator as well as repressor forms of Pan play important roles, while for wing development Pan operates primarily in the activator mode. PMID:12730381

  6. Requirement for Pangolin/dTCF in Drosophila Wingless signaling.

    PubMed

    Schweizer, Liang; Nellen, Denise; Basler, Konrad

    2003-05-13

    The Wingless (Wg) protein is a secreted glycoprotein involved in intercellular signaling. On activation of the Wg signaling pathway, Armadillo is stabilized, causing target genes to be activated by the transcription factor Pangolin (Pan). This study investigated the roles of Pan in the developing wing of Drosophila by clonal analysis. Three different aspects of wing development were examined: cell proliferation, wing margin specification, and wg self-refinement. Our results indicate that Pan function is critically required for all three of these processes. Consequently, lack of pan causes a severe reduction in the activity of the Wg target genes Distalless and vestigial within their normal domain of expression. Loss of pan function does not, however, lead to a derepression of these genes outside this domain. Thus, although Pan is positively required for the induction of Wg targets in the wing imaginal disk, it does not appear to play a default repressor function in the absence of Wg input. In contrast, lack of zygotic pan function causes a milder phenotype than that caused by the lack of wg function in the embryo. We show that this difference cannot be attributed to maternally provided pan product, indicating that a Pan repressor function usually prevents the expression of embryonic Wg targets. Together, our results suggest that for embryonic patterning the activator as well as repressor forms of Pan play important roles, while for wing development Pan operates primarily in the activator mode.

  7. An auditory feature detection circuit for sound pattern recognition

    PubMed Central

    Schöneich, Stefan; Kostarakos, Konstantinos; Hedwig, Berthold

    2015-01-01

    From human language to birdsong and the chirps of insects, acoustic communication is based on amplitude and frequency modulation of sound signals. Whereas frequency processing starts at the level of the hearing organs, temporal features of the sound amplitude such as rhythms or pulse rates require processing by central auditory neurons. Besides several theoretical concepts, brain circuits that detect temporal features of a sound signal are poorly understood. We focused on acoustically communicating field crickets and show how five neurons in the brain of females form an auditory feature detector circuit for the pulse pattern of the male calling song. The processing is based on a coincidence detector mechanism that selectively responds when a direct neural response and an intrinsically delayed response to the sound pulses coincide. This circuit provides the basis for auditory mate recognition in field crickets and reveals a principal mechanism of sensory processing underlying the perception of temporal patterns. PMID:26601259

  8. An auditory feature detection circuit for sound pattern recognition.

    PubMed

    Schöneich, Stefan; Kostarakos, Konstantinos; Hedwig, Berthold

    2015-09-01

    From human language to birdsong and the chirps of insects, acoustic communication is based on amplitude and frequency modulation of sound signals. Whereas frequency processing starts at the level of the hearing organs, temporal features of the sound amplitude such as rhythms or pulse rates require processing by central auditory neurons. Besides several theoretical concepts, brain circuits that detect temporal features of a sound signal are poorly understood. We focused on acoustically communicating field crickets and show how five neurons in the brain of females form an auditory feature detector circuit for the pulse pattern of the male calling song. The processing is based on a coincidence detector mechanism that selectively responds when a direct neural response and an intrinsically delayed response to the sound pulses coincide. This circuit provides the basis for auditory mate recognition in field crickets and reveals a principal mechanism of sensory processing underlying the perception of temporal patterns.

  9. Masking in three-dimensional auditory displays.

    PubMed

    Doll, T J; Hanna, T E; Russotti, J S

    1992-06-01

    The extent to which simultaneous inputs in a three-dimensional (3D) auditory display mask one another was studied in a simulated sonar task. The minimum signal-to-noise ratio (SNR) required to detect an amplitude-modulated 500-Hz tone in a background of broadband noise was measured using a loudspeaker array in a free field. Three aspects of the 3D array were varied: angular separation of the sources, degree of correlation of the background noises, and listener head movement. Masking was substantially reduced when the sources were uncorrelated. The SNR needed for detection decreased with source separation, and the rate of decrease was significantly greater with uncorrelated sources than with partially or fully correlated sources. Head movement had no effect on the SNR required for detection. Implications for the design and application of 3D auditory displays are discussed.

  10. Endodermal Wnt signaling is required for tracheal cartilage formation

    PubMed Central

    Snowball, John; Ambalavanan, Manoj; Whitsett, Jeffrey; Sinner, Debora

    2015-01-01

    Tracheobronchomalacia is a common congenital defect in which the walls of the trachea and bronchi lack of adequate cartilage required for support of the airways. Deletion of Wls, a cargo receptor mediating Wnt ligand secretion, in the embryonic endoderm using ShhCre mice inhibited formation of tracheal-bronchial cartilaginous rings. The normal dorsal-ventral patterning of tracheal mesenchyme was lost. Smooth muscle cells, identified by Acta2 staining, were aberrantly located in ventral mesenchyme of the trachea, normally the region of Sox9 expression in cartilage progenitors. Wnt/β-catenin activity, indicated by Axin2 LacZ reporter, was decreased in tracheal mesenchyme of Wlsf/f;ShhCre/+ embryos. Proliferation of chondroblasts was decreased and reciprocally, proliferation of smooth muscle cells was increased in Wlsf/f;ShhCre/+ tracheal tissue. Expression of Tbx4, Tbx5, Msx1 and Msx2, known to mediate cartilage and muscle patterning, were decreased in tracheal mesenchyme of Wlsf/f;ShhCre/+ embryos. Ex vivo studies demonstrated that Wnt7b and Wnt5a, expressed by the epithelium of developing trachea, and active Wnt/β-catenin signaling are required for tracheal chondrogenesis before formation of mesenchymal condensations. In conclusion, Wnt ligands produced by the tracheal epithelium pattern the tracheal mesenchyme via modulation of gene expression and cell proliferation required for proper tracheal cartilage and smooth muscle differentiation. PMID:26093309

  11. Myocardium and BMP signaling are required for endocardial differentiation.

    PubMed

    Palencia-Desai, Sharina; Rost, Megan S; Schumacher, Jennifer A; Ton, Quynh V; Craig, Michael P; Baltrunaite, Kristina; Koenig, Andrew L; Wang, Jinhu; Poss, Kenneth D; Chi, Neil C; Stainier, Didier Y R; Sumanas, Saulius

    2015-07-01

    Endocardial and myocardial progenitors originate in distinct regions of the anterior lateral plate mesoderm and migrate to the midline where they coalesce to form the cardiac tube. Endocardial progenitors acquire a molecular identity distinct from other vascular endothelial cells and initiate expression of specific genes such as nfatc1. Yet the molecular pathways and tissue interactions involved in establishing endocardial identity are poorly understood. The endocardium develops in tight association with cardiomyocytes. To test for a potential role of the myocardium in endocardial morphogenesis, we used two different zebrafish models deficient in cardiomyocytes: the hand2 mutant and a myocardial-specific genetic ablation method. We show that in hand2 mutants endocardial progenitors migrate to the midline but fail to assemble into a cardiac cone and do not express markers of differentiated endocardium. Endocardial differentiation defects were rescued by myocardial but not endocardial-specific expression of hand2. In metronidazole-treated myl7:nitroreductase embryos, myocardial cells were targeted for apoptosis, which resulted in the loss of endocardial nfatc1 expression. However, endocardial cells were present and retained expression of general vascular endothelial markers. We further identified bone morphogenetic protein (BMP) as a candidate myocardium-derived signal required for endocardial differentiation. Chemical and genetic inhibition of BMP signaling at the tailbud stage resulted in severe inhibition of endocardial differentiation while there was little effect on myocardial development. Heat-shock-induced bmp2b expression rescued endocardial nfatc1 expression in hand2 mutants and in myocardium-depleted embryos. Our results indicate that the myocardium is crucial for endocardial morphogenesis and differentiation, and identify BMP as a signal involved in endocardial differentiation.

  12. Auditory hallucinations.

    PubMed

    Blom, Jan Dirk

    2015-01-01

    Auditory hallucinations constitute a phenomenologically rich group of endogenously mediated percepts which are associated with psychiatric, neurologic, otologic, and other medical conditions, but which are also experienced by 10-15% of all healthy individuals in the general population. The group of phenomena is probably best known for its verbal auditory subtype, but it also includes musical hallucinations, echo of reading, exploding-head syndrome, and many other types. The subgroup of verbal auditory hallucinations has been studied extensively with the aid of neuroimaging techniques, and from those studies emerges an outline of a functional as well as a structural network of widely distributed brain areas involved in their mediation. The present chapter provides an overview of the various types of auditory hallucination described in the literature, summarizes our current knowledge of the auditory networks involved in their mediation, and draws on ideas from the philosophy of science and network science to reconceptualize the auditory hallucinatory experience, and point out directions for future research into its neurobiologic substrates. In addition, it provides an overview of known associations with various clinical conditions and of the existing evidence for pharmacologic and non-pharmacologic treatments.

  13. FES kinases are required for oncogenic FLT3 signaling.

    PubMed

    Voisset, E; Lopez, S; Chaix, A; Georges, C; Hanssens, K; Prébet, T; Dubreuil, P; De Sepulveda, P

    2010-04-01

    The closely related non-receptor tyrosine kinases FEline Sarcoma (FES) and FEs Related (FER) are activated by cell surface receptors in hematopoietic cells. Despite the early description of oncogenic viral forms of fes, v-fes, and v-fps, the implication of FES and FER in human pathology is not known. We have recently shown that FES but not FER is necessary for oncogenic KIT receptor signaling. Here, we report that both FES and FER kinases are activated in primary acute myeloid leukemia (AML) blasts and in AML cell lines. FES and FER activation is dependent on FLT3 in cell lines harboring constitutively active FLT3 mutants. Moreover, both FES and FER proteins are critical for FLT3-internal tandem duplication (ITD) signaling and for cell proliferation in relevant AML cell lines. FER is required for cell cycle transitions, whereas FES seems necessary for cell survival. We concluded that FES and FER kinases mediate essential non-redundant functions downstream of FLT3-ITD.

  14. Danger-associated peptide signaling in Arabidopsis requires clathrin.

    PubMed

    Ortiz-Morea, Fausto Andres; Savatin, Daniel V; Dejonghe, Wim; Kumar, Rahul; Luo, Yu; Adamowski, Maciej; Van den Begin, Jos; Dressano, Keini; Pereira de Oliveira, Guilherme; Zhao, Xiuyang; Lu, Qing; Madder, Annemieke; Friml, Jiří; Scherer de Moura, Daniel; Russinova, Eugenia

    2016-09-27

    The Arabidopsis thaliana endogenous elicitor peptides (AtPeps) are released into the apoplast after cellular damage caused by pathogens or wounding to induce innate immunity by direct binding to the membrane-localized leucine-rich repeat receptor kinases, PEP RECEPTOR1 (PEPR1) and PEPR2. Although the PEPR-mediated signaling components and responses have been studied extensively, the contributions of the subcellular localization and dynamics of the active PEPRs remain largely unknown. We used live-cell imaging of the fluorescently labeled and bioactive pep1 to visualize the intracellular behavior of the PEPRs in the Arabidopsis root meristem. We found that AtPep1 decorated the plasma membrane (PM) in a receptor-dependent manner and cointernalized with PEPRs. Trafficking of the AtPep1-PEPR1 complexes to the vacuole required neither the trans-Golgi network/early endosome (TGN/EE)-localized vacuolar H(+)-ATPase activity nor the function of the brefeldin A-sensitive ADP-ribosylation factor-guanine exchange factors (ARF-GEFs). In addition, AtPep1 and different TGN/EE markers colocalized only rarely, implying that the intracellular route of this receptor-ligand pair is largely independent of the TGN/EE. Inducible overexpression of the Arabidopsis clathrin coat disassembly factor, Auxilin2, which inhibits clathrin-mediated endocytosis (CME), impaired the AtPep1-PEPR1 internalization and compromised AtPep1-mediated responses. Our results show that clathrin function at the PM is required to induce plant defense responses, likely through CME of cell surface-located signaling components.

  15. Danger-associated peptide signaling in Arabidopsis requires clathrin.

    PubMed

    Ortiz-Morea, Fausto Andres; Savatin, Daniel V; Dejonghe, Wim; Kumar, Rahul; Luo, Yu; Adamowski, Maciej; Van den Begin, Jos; Dressano, Keini; Pereira de Oliveira, Guilherme; Zhao, Xiuyang; Lu, Qing; Madder, Annemieke; Friml, Jiří; Scherer de Moura, Daniel; Russinova, Eugenia

    2016-09-27

    The Arabidopsis thaliana endogenous elicitor peptides (AtPeps) are released into the apoplast after cellular damage caused by pathogens or wounding to induce innate immunity by direct binding to the membrane-localized leucine-rich repeat receptor kinases, PEP RECEPTOR1 (PEPR1) and PEPR2. Although the PEPR-mediated signaling components and responses have been studied extensively, the contributions of the subcellular localization and dynamics of the active PEPRs remain largely unknown. We used live-cell imaging of the fluorescently labeled and bioactive pep1 to visualize the intracellular behavior of the PEPRs in the Arabidopsis root meristem. We found that AtPep1 decorated the plasma membrane (PM) in a receptor-dependent manner and cointernalized with PEPRs. Trafficking of the AtPep1-PEPR1 complexes to the vacuole required neither the trans-Golgi network/early endosome (TGN/EE)-localized vacuolar H(+)-ATPase activity nor the function of the brefeldin A-sensitive ADP-ribosylation factor-guanine exchange factors (ARF-GEFs). In addition, AtPep1 and different TGN/EE markers colocalized only rarely, implying that the intracellular route of this receptor-ligand pair is largely independent of the TGN/EE. Inducible overexpression of the Arabidopsis clathrin coat disassembly factor, Auxilin2, which inhibits clathrin-mediated endocytosis (CME), impaired the AtPep1-PEPR1 internalization and compromised AtPep1-mediated responses. Our results show that clathrin function at the PM is required to induce plant defense responses, likely through CME of cell surface-located signaling components. PMID:27651494

  16. The small GTPase Rac1 regulates auditory hair cell morphogenesis

    PubMed Central

    Grimsley-Myers, Cynthia M.; Sipe, Conor W.; Géléoc, Gwenaëllle S.G.; Lu, Xiaowei

    2010-01-01

    Morphogenesis of sensory hair cells, in particular their mechanotransduction organelle, the stereociliary bundle, requires highly organized remodeling of the actin cytoskeleton. The roles of Rho family small GTPases during this process remain unknown. Here we show that deletion of Rac1 in the otic epithelium resulted in severe defects in cochlear epithelial morphogenesis. The mutant cochlea was severely shortened with a reduced number of auditory hair cells and cellular organization of the auditory sensory epithelium was abnormal. Rac1 mutant hair cells also displayed defects in planar cell polarity and morphogenesis of the stereociliary bundle, including bundle fragmentation or deformation, and mispositioning or absence of the kinocilium. We further demonstrate that a Rac-PAK signaling pathway mediates kinocilium-stereocilia interactions and is required for cohesion of the stereociliary bundle. Together, these results reveal a critical function of Rac1 in morphogenesis of the auditory sensory epithelium and stereociliary bundle. PMID:20016102

  17. Seeing the Song: Left Auditory Structures May Track Auditory-Visual Dynamic Alignment

    PubMed Central

    Mossbridge, Julia A.; Grabowecky, Marcia; Suzuki, Satoru

    2013-01-01

    Auditory and visual signals generated by a single source tend to be temporally correlated, such as the synchronous sounds of footsteps and the limb movements of a walker. Continuous tracking and comparison of the dynamics of auditory-visual streams is thus useful for the perceptual binding of information arising from a common source. Although language-related mechanisms have been implicated in the tracking of speech-related auditory-visual signals (e.g., speech sounds and lip movements), it is not well known what sensory mechanisms generally track ongoing auditory-visual synchrony for non-speech signals in a complex auditory-visual environment. To begin to address this question, we used music and visual displays that varied in the dynamics of multiple features (e.g., auditory loudness and pitch; visual luminance, color, size, motion, and organization) across multiple time scales. Auditory activity (monitored using auditory steady-state responses, ASSR) was selectively reduced in the left hemisphere when the music and dynamic visual displays were temporally misaligned. Importantly, ASSR was not affected when attentional engagement with the music was reduced, or when visual displays presented dynamics clearly dissimilar to the music. These results appear to suggest that left-lateralized auditory mechanisms are sensitive to auditory-visual temporal alignment, but perhaps only when the dynamics of auditory and visual streams are similar. These mechanisms may contribute to correct auditory-visual binding in a busy sensory environment. PMID:24194873

  18. The Drosophila Auditory System

    PubMed Central

    Boekhoff-Falk, Grace; Eberl, Daniel F.

    2013-01-01

    Development of a functional auditory system in Drosophila requires specification and differentiation of the chordotonal sensilla of Johnston’s organ (JO) in the antenna, correct axonal targeting to the antennal mechanosensory and motor center (AMMC) in the brain, and synaptic connections to neurons in the downstream circuit. Chordotonal development in JO is functionally complicated by structural, molecular and functional diversity that is not yet fully understood, and construction of the auditory neural circuitry is only beginning to unfold. Here we describe our current understanding of developmental and molecular mechanisms that generate the exquisite functions of the Drosophila auditory system, emphasizing recent progress and highlighting important new questions arising from research on this remarkable sensory system. PMID:24719289

  19. 49 CFR 236.568 - Difference between speeds authorized by roadway signal and cab signal; action required.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Difference between speeds authorized by roadway... Systems Rules and Instructions; Locomotives § 236.568 Difference between speeds authorized by roadway signal and cab signal; action required. If for any reason a cab signal authorizes a speed different...

  20. 49 CFR 236.568 - Difference between speeds authorized by roadway signal and cab signal; action required.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Difference between speeds authorized by roadway... Systems Rules and Instructions; Locomotives § 236.568 Difference between speeds authorized by roadway signal and cab signal; action required. If for any reason a cab signal authorizes a speed different...

  1. 49 CFR 236.568 - Difference between speeds authorized by roadway signal and cab signal; action required.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Difference between speeds authorized by roadway... Systems Rules and Instructions; Locomotives § 236.568 Difference between speeds authorized by roadway signal and cab signal; action required. If for any reason a cab signal authorizes a speed different...

  2. 49 CFR 236.568 - Difference between speeds authorized by roadway signal and cab signal; action required.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Difference between speeds authorized by roadway... Systems Rules and Instructions; Locomotives § 236.568 Difference between speeds authorized by roadway signal and cab signal; action required. If for any reason a cab signal authorizes a speed different...

  3. 49 CFR 236.568 - Difference between speeds authorized by roadway signal and cab signal; action required.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Difference between speeds authorized by roadway... Systems Rules and Instructions; Locomotives § 236.568 Difference between speeds authorized by roadway signal and cab signal; action required. If for any reason a cab signal authorizes a speed different...

  4. Requirement of TGFβ Signaling for SMO-mediated Carcinogenesis*

    PubMed Central

    Fan, Qipeng; He, Miao; Sheng, Tao; Zhang, Xiaoli; Sinha, Mala; Luxon, Bruce; Zhao, Xingbo; Xie, Jingwu

    2010-01-01

    Hedgehog (Hh) signaling, via the key signal transducer Smoothened (SMO) and Gli transcription factors, is essential for embryonic development and carcinogenesis. At present, the molecular mechanism of Hh signaling-mediated carcinogenesis is not completely understood. Using a mouse model (K14cre/R26SmoM2) of SMO-mediated basal cell carcinoma development, we identified TGFβ2 as a major Hh-regulated gene. TGFβ2 expression was high in the keratinocytes, with activated TGFβ signaling (indicated by elevated expression of phosphorylated SMAD2/3) detected in both tumor and stroma. The significance of TGFβ signaling for SMO function was demonstrated in two assays. Down-regulation of TGFβ2 expression prevented Hh signaling-dependent osteoblast differentiation and motor neuron differentiation. Furthermore, inhibition of TGFβ signaling by TGFβ receptor I inhibitor SD208 significantly reduced tumor area in K14cre/R26SmoM2 mice. Tumor shrinkage in mice was associated with an increased number of lymphocytes, suggesting an immune suppression role of TGFβ signaling. The relevance of our results to human cancer is reflected by the fact that human basal cell carcinomas, which almost always harbor activated Hh signaling, have activated TGFβ signaling, as indicated by high levels of phosphorylated SMAD2 and SMAD3 in tumor and stroma. Together, our data indicate that TGFβ signaling is critical for Hh signaling-mediated carcinogenesis. PMID:20858897

  5. Notch signaling from the endosome requires a conserved dileucine motif

    PubMed Central

    Zheng, Li; Saunders, Cosmo A.; Sorensen, Erika B.; Waxmonsky, Nicole C.; Conner, Sean D.

    2013-01-01

    Notch signaling is reliant on γ-secretase–mediated processing, although the subcellular location where γ-secretase cleaves Notch to initiate signaling remains unresolved. Accumulating evidence demonstrates that Notch signaling is modulated by endocytosis and endosomal transport. In this study, we investigated the relationship between Notch transport itinerary and signaling capacity. In doing so, we discovered a highly conserved dileucine sorting signal encoded within the cytoplasmic tail that directs Notch to the limiting membrane of the lysosome for signaling. Mutating the dileucine motif led to receptor accumulation in cation-dependent mannose-phosphate receptor–positive tubular early endosomes and a reduction in Notch signaling capacity. Moreover, truncated receptor forms that mimic activated Notch were readily cleaved by γ-secretase within the endosome; however, the cleavage product was proteasome-sensitive and failed to contribute to robust signaling. Collectively these results indicate that Notch signaling from the lysosome limiting membrane is conserved and that receptor targeting to this compartment is an active process. Moreover, the data support a model in which Notch signaling in mammalian systems is initiated from either the plasma membrane or lysosome, but not the early endosome. PMID:23171551

  6. Auditory synesthesias.

    PubMed

    Afra, Pegah

    2015-01-01

    Synesthesia is experienced when sensory stimulation of one sensory modality (the inducer) elicits an involuntary or automatic sensation in another sensory modality or different aspect of the same sensory modality (the concurrent). Auditory synesthesias (AS) occur when auditory stimuli trigger a variety of concurrents, or when non-auditory sensory stimulations trigger auditory synesthetic perception. The AS are divided into three types: developmental, acquired, and induced. Developmental AS are not a neurologic disorder but a different way of experiencing one's environment. They are involuntary and highly consistent experiences throughout one's life. Acquired AS have been reported in association with neurologic diseases that cause deafferentation of anterior optic pathways, with pathologic lesions affecting the central nervous system (CNS) outside of the optic pathways, as well as non-lesional cases associated with migraine, and epilepsy. It also has been reported with mood disorders as well as a single idiopathic case. Induced AS has been reported in experimental and postsurgical blindfolding, as well as intake of hallucinogenics or psychedelics. In this chapter the three different types of synesthesia, their characteristics, and phenomologic differences, as well as their possible neural mechanisms are discussed. PMID:25726281

  7. Auditory system

    NASA Technical Reports Server (NTRS)

    Ades, H. W.

    1973-01-01

    The physical correlations of hearing, i.e. the acoustic stimuli, are reported. The auditory system, consisting of external ear, middle ear, inner ear, organ of Corti, basilar membrane, hair cells, inner hair cells, outer hair cells, innervation of hair cells, and transducer mechanisms, is discussed. Both conductive and sensorineural hearing losses are also examined.

  8. RNA Type III Secretion Signals that require Hfq

    SciTech Connect

    Niemann, George; Brown, Roslyn N.; Mushamiri, Ivy T.; Nguyen, Nhu T.; Taiwo, Rukayat; Stufkens, Afke; Smith, Richard D.; Adkins, Joshua N.; McDermott, Jason E.; Heffron, Fred

    2013-05-01

    effector proteins from the bacterium to a host cell; however, the secretion signal is poorly defined. Effector N-termini are thought to contain the signal, but they lack homology, possess no identifiable motif, and adopt intrinsically disordered structures. We identified a panel of RNA secretion signals that facilitated reporter translocation into host cells via a mechanism dependent upon the RNA chaperone Hfq. Each of these signals was localized to an RNA leader sequence preceding the translational start codon. To obtain this panel of RNA signals, we fused untranslated leader sequences from 42 different Salmonella effector proteins to the adenylate cyclase reporter (CyaA'), and tested each of them for translocation into J774 macrophages. RNA sequences derived from five effectors, gtgA, cigR, gogB, sseL, and steD were sufficient for CyaA' injection into host cells. The gtgA RNA also directed translocation of the β-lactamase reporter. To determine the mechanism of signal recognition, we identified proteins that bound specifically to the gtgA RNA. One of the unique proteins identified was Hfq. Translocation of all five UTR fusions was abolished in the Hfq mutant, confirming the importance of Hfq. Our results suggest that Hfq may direct a subset of RNA transcripts to the T3S apparatus for translation and secretion. Signal diversity may explain why the T3S signal has been difficult to define.

  9. Sensory Processing of Backward-Masking Signals in Children with Language-Learning Impairment as Assessed with the Auditory Brainstem Response.

    ERIC Educational Resources Information Center

    Marler, Jeffrey A.; Champlin, Craig A.

    2005-01-01

    The purpose of this study was to examine the possible contribution of sensory mechanisms to an auditory processing deficit shown by some children with language-learning impairment (LLI). Auditory brainstem responses (ABRs) were measured from 2 groups of school-aged (8-10 years) children. One group consisted of 10 children with LLI, and the other…

  10. 49 CFR 236.12 - Spring switch signal protection; where required.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Spring switch signal protection; where required... Rules and Instructions: All Systems General § 236.12 Spring switch signal protection; where required. Signal protection shall be provided for facing and trailing movements through spring switch...

  11. 49 CFR 236.12 - Spring switch signal protection; where required.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Spring switch signal protection; where required... Rules and Instructions: All Systems General § 236.12 Spring switch signal protection; where required. Signal protection shall be provided for facing and trailing movements through spring switch...

  12. 49 CFR 236.12 - Spring switch signal protection; where required.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Spring switch signal protection; where required... Rules and Instructions: All Systems General § 236.12 Spring switch signal protection; where required. Signal protection shall be provided for facing and trailing movements through spring switch...

  13. 49 CFR 236.12 - Spring switch signal protection; where required.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Spring switch signal protection; where required... Rules and Instructions: All Systems General § 236.12 Spring switch signal protection; where required. Signal protection shall be provided for facing and trailing movements through spring switch...

  14. 47 CFR 11.52 - EAS code and Attention Signal Monitoring requirements.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 1 2011-10-01 2011-10-01 false EAS code and Attention Signal Monitoring... SYSTEM (EAS) Emergency Operations § 11.52 EAS code and Attention Signal Monitoring requirements. (a) EAS Participants must be capable of receiving the Attention Signal required by § 11.32(a)(9) and emergency...

  15. 47 CFR 11.52 - EAS code and Attention Signal Monitoring requirements.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 1 2014-10-01 2014-10-01 false EAS code and Attention Signal Monitoring... SYSTEM (EAS) Emergency Operations § 11.52 EAS code and Attention Signal Monitoring requirements. (a) EAS Participants must be capable of receiving the Attention Signal required by § 11.31(a)(2) and emergency...

  16. 47 CFR 11.52 - EAS code and Attention Signal Monitoring requirements.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 1 2013-10-01 2013-10-01 false EAS code and Attention Signal Monitoring... SYSTEM (EAS) Emergency Operations § 11.52 EAS code and Attention Signal Monitoring requirements. (a) EAS Participants must be capable of receiving the Attention Signal required by § 11.31(a)(2) and emergency...

  17. 33 CFR 150.720 - What are the requirements for sound signals?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 33 Navigation and Navigable Waters 2 2011-07-01 2011-07-01 false What are the requirements for sound signals? 150.720 Section 150.720 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF... are the requirements for sound signals? The sound signal on each pumping platform complex must...

  18. 33 CFR 150.720 - What are the requirements for sound signals?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 33 Navigation and Navigable Waters 2 2012-07-01 2012-07-01 false What are the requirements for sound signals? 150.720 Section 150.720 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF... are the requirements for sound signals? The sound signal on each pumping platform complex must...

  19. 33 CFR 150.720 - What are the requirements for sound signals?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 33 Navigation and Navigable Waters 2 2014-07-01 2014-07-01 false What are the requirements for sound signals? 150.720 Section 150.720 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF... are the requirements for sound signals? The sound signal on each pumping platform complex must...

  20. 33 CFR 150.720 - What are the requirements for sound signals?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false What are the requirements for sound signals? 150.720 Section 150.720 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF... are the requirements for sound signals? The sound signal on each pumping platform complex must...

  1. 33 CFR 150.720 - What are the requirements for sound signals?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 33 Navigation and Navigable Waters 2 2013-07-01 2013-07-01 false What are the requirements for sound signals? 150.720 Section 150.720 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF... are the requirements for sound signals? The sound signal on each pumping platform complex must...

  2. 14 CFR 171.311 - Signal format requirements.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... function transmitter must be capable of DPSK and continuous wave (CW) modulations of the RF carrier which... signal must be such that during the transmission time, the mean power density above a height of...

  3. 29 CFR 1926.1421 - Signals-voice signals-additional requirements.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... operations, the operator, signal person and lift director (if there is one), must contact each other and....), direction; distance and/or speed; function, stop command. (c) The operator, signal person and lift...

  4. Selective attention and the auditory vertex potential. I - Effects of stimulus delivery rate. II - Effects of signal intensity and masking noise

    NASA Technical Reports Server (NTRS)

    Schwent, V. L.; Hillyard, S. A.; Galambos, R.

    1976-01-01

    The effects of varying the rate of delivery of dichotic tone pip stimuli on selective attention measured by evoked-potential amplitudes and signal detectability scores were studied. The subjects attended to one channel (ear) of tones, ignored the other, and pressed a button whenever occasional targets - tones of a slightly higher pitch were detected in the attended ear. Under separate conditions, randomized interstimulus intervals were short, medium, and long. Another study compared the effects of attention on the N1 component of the auditory evoked potential for tone pips presented alone and when white noise was added to make the tones barely above detectability threshold in a three-channel listening task. Major conclusions are that (1) N1 is enlarged to stimuli in an attended channel only in the short interstimulus interval condition (averaging 350 msec), (2) N1 and P3 are related to different modes of selective attention, and (3) attention selectivity in multichannel listening task is greater when tones are faint and/or difficult to detect.

  5. Auditory orientation in crickets: Pattern recognition controls reactive steering

    NASA Astrophysics Data System (ADS)

    Poulet, James F. A.; Hedwig, Berthold

    2005-10-01

    Many groups of insects are specialists in exploiting sensory cues to locate food resources or conspecifics. To achieve orientation, bees and ants analyze the polarization pattern of the sky, male moths orient along the females' odor plume, and cicadas, grasshoppers, and crickets use acoustic signals to locate singing conspecifics. In comparison with olfactory and visual orientation, where learning is involved, auditory processing underlying orientation in insects appears to be more hardwired and genetically determined. In each of these examples, however, orientation requires a recognition process identifying the crucial sensory pattern to interact with a localization process directing the animal's locomotor activity. Here, we characterize this interaction. Using a sensitive trackball system, we show that, during cricket auditory behavior, the recognition process that is tuned toward the species-specific song pattern controls the amplitude of auditory evoked steering responses. Females perform small reactive steering movements toward any sound patterns. Hearing the male's calling song increases the gain of auditory steering within 2-5 s, and the animals even steer toward nonattractive sound patterns inserted into the speciesspecific pattern. This gain control mechanism in the auditory-to-motor pathway allows crickets to pursue species-specific sound patterns temporarily corrupted by environmental factors and may reflect the organization of recognition and localization networks in insects. localization | phonotaxis

  6. Brain Dynamics of Aging: Multiscale Variability of EEG Signals at Rest and during an Auditory Oddball Task(1,2,3).

    PubMed

    Sleimen-Malkoun, Rita; Perdikis, Dionysios; Müller, Viktor; Blanc, Jean-Luc; Huys, Raoul; Temprado, Jean-Jacques; Jirsa, Viktor K

    2015-01-01

    The present work focused on the study of fluctuations of cortical activity across time scales in young and older healthy adults. The main objective was to offer a comprehensive characterization of the changes of brain (cortical) signal variability during aging, and to make the link with known underlying structural, neurophysiological, and functional modifications, as well as aging theories. We analyzed electroencephalogram (EEG) data of young and elderly adults, which were collected at resting state and during an auditory oddball task. We used a wide battery of metrics that typically are separately applied in the literature, and we compared them with more specific ones that address their limits. Our procedure aimed to overcome some of the methodological limitations of earlier studies and verify whether previous findings can be reproduced and extended to different experimental conditions. In both rest and task conditions, our results mainly revealed that EEG signals presented systematic age-related changes that were time-scale-dependent with regard to the structure of fluctuations (complexity) but not with regard to their magnitude. Namely, compared with young adults, the cortical fluctuations of the elderly were more complex at shorter time scales, but less complex at longer scales, although always showing a lower variance. Additionally, the elderly showed signs of spatial, as well as between, experimental conditions dedifferentiation. By integrating these so far isolated findings across time scales, metrics, and conditions, the present study offers an overview of age-related changes in the fluctuation electrocortical activity while making the link with underlying brain dynamics. PMID:26464983

  7. Brain Dynamics of Aging: Multiscale Variability of EEG Signals at Rest and during an Auditory Oddball Task1,2,3

    PubMed Central

    Sleimen-Malkoun, Rita; Perdikis, Dionysios; Müller, Viktor; Blanc, Jean-Luc; Huys, Raoul; Temprado, Jean-Jacques

    2015-01-01

    Abstract The present work focused on the study of fluctuations of cortical activity across time scales in young and older healthy adults. The main objective was to offer a comprehensive characterization of the changes of brain (cortical) signal variability during aging, and to make the link with known underlying structural, neurophysiological, and functional modifications, as well as aging theories. We analyzed electroencephalogram (EEG) data of young and elderly adults, which were collected at resting state and during an auditory oddball task. We used a wide battery of metrics that typically are separately applied in the literature, and we compared them with more specific ones that address their limits. Our procedure aimed to overcome some of the methodological limitations of earlier studies and verify whether previous findings can be reproduced and extended to different experimental conditions. In both rest and task conditions, our results mainly revealed that EEG signals presented systematic age-related changes that were time-scale-dependent with regard to the structure of fluctuations (complexity) but not with regard to their magnitude. Namely, compared with young adults, the cortical fluctuations of the elderly were more complex at shorter time scales, but less complex at longer scales, although always showing a lower variance. Additionally, the elderly showed signs of spatial, as well as between, experimental conditions dedifferentiation. By integrating these so far isolated findings across time scales, metrics, and conditions, the present study offers an overview of age-related changes in the fluctuation electrocortical activity while making the link with underlying brain dynamics. PMID:26464983

  8. Fmrp is required for the establishment of the startle response during the critical period of auditory development.

    PubMed

    Yun, Seong-Wook; Platholi, Jimcy; Flaherty, Maria Sol; Fu, Weimin; Kottmann, Andreas H; Toth, Miklos

    2006-09-19

    Fragile X syndrome, the most common form of inherited mental retardation, is caused by the absence of the FMR-1 gene product FMRP. In addition to the hallmark cognitive defect, other symptoms are also apparent including hyperactivity, seizures and sensory abnormalities including a characteristic increase in sensitivity to auditory, tactile, visual, and olfactory stimuli. Fragile X is a developmental disorder with the first symptoms apparent in the first year of life but little is known about the role of FMRP in developmental processes. The sensory hyperreactivity of fragile X can be reproduced in fmr-1 knockout (KO) mice evident as abnormal audiogenic startle response and increased audiogenic seizure susceptibility. Here, we studied the onset and emergence of the startle deficit in fmr-1 KO mice during development. The startle response was first detectable at the end of the 2nd postnatal week in wild-type mice. The amplitude of startle response showed a substantial increase until the 4th postnatal week followed by a further but moderate increase up to adulthood. Expression of the fmr1 gene was detectable in the startle circuit before the onset and throughout the development of the startle response. Although the onset and amplitude of the startle response were not altered in fmr1 KO mice until the 3rd-4th postnatal week, beyond this age it failed to develop further resulting in an overall response deficit in adult KO mice. This indicates that although Fmrp is dispensable at the initial steps of startle response development, it is necessary for the full development of the response.

  9. Assessing effectiveness of various auditory warning signals in maintaining drivers' attention in virtual reality-based driving environments.

    PubMed

    Lin, Chin-Teng; Chiu, Tien-Ting; Huang, Teng-Yi; Chao, Chih-Feng; Liang, Wen-Chieh; Hsu, Shang-Hwa; Ko, Li-Wei

    2009-06-01

    Drivers' fatigue contributes to traffic accidents, so drivers must maintain adequate alertness. The effectiveness of audio alarms in maintaining driving performance and characteristics of alarms was studied in a virtural reality-based driving environment. Response time to the car's drifting was measured under seven conditions: with no warnings and with continuous warning tones (500 Hz, 1750 Hz, and 3000 Hz), and with tone bursts at 500 Hz, 1750 Hz, and 3000 Hz. Analyses showed the audio warning signals significantly improved driving. Further, the tones' spectral characteristics significantly influenced the effectiveness of the warning.

  10. 47 CFR 11.51 - EAS code and Attention Signal Transmission requirements.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Notification (EAN), Emergency Action Termination (EAT), and Required Monthly Test (RMT), and when the... messages and required tests by sending the EAS header codes, Attention Signal, emergency message and End of... EAS codes will become the minimum signaling requirement for National level messages and tests....

  11. 29 CFR 1926.1419 - Signals-general requirements.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ..., DEPARTMENT OF LABOR (CONTINUED) SAFETY AND HEALTH REGULATIONS FOR CONSTRUCTION Cranes and Derricks in... person may give signals to a crane/derrick at a time, except in circumstances covered by paragraph (j) of... given from the operator's direction perspective. (l) (m) Communication with multiple...

  12. 29 CFR 1926.1419 - Signals-general requirements.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ..., DEPARTMENT OF LABOR (CONTINUED) SAFETY AND HEALTH REGULATIONS FOR CONSTRUCTION Cranes and Derricks in... person may give signals to a crane/derrick at a time, except in circumstances covered by paragraph (j) of... given from the operator's direction perspective. (l) (m) Communication with multiple...

  13. 29 CFR 1926.1419 - Signals-general requirements.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ..., DEPARTMENT OF LABOR (CONTINUED) SAFETY AND HEALTH REGULATIONS FOR CONSTRUCTION Cranes and Derricks in... person may give signals to a crane/derrick at a time, except in circumstances covered by paragraph (j) of... given from the operator's direction perspective. (l) (m) Communication with multiple...

  14. Auditory short-term memory in the primate auditory cortex.

    PubMed

    Scott, Brian H; Mishkin, Mortimer

    2016-06-01

    Sounds are fleeting, and assembling the sequence of inputs at the ear into a coherent percept requires auditory memory across various time scales. Auditory short-term memory comprises at least two components: an active ׳working memory' bolstered by rehearsal, and a sensory trace that may be passively retained. Working memory relies on representations recalled from long-term memory, and their rehearsal may require phonological mechanisms unique to humans. The sensory component, passive short-term memory (pSTM), is tractable to study in nonhuman primates, whose brain architecture and behavioral repertoire are comparable to our own. This review discusses recent advances in the behavioral and neurophysiological study of auditory memory with a focus on single-unit recordings from macaque monkeys performing delayed-match-to-sample (DMS) tasks. Monkeys appear to employ pSTM to solve these tasks, as evidenced by the impact of interfering stimuli on memory performance. In several regards, pSTM in monkeys resembles pitch memory in humans, and may engage similar neural mechanisms. Neural correlates of DMS performance have been observed throughout the auditory and prefrontal cortex, defining a network of areas supporting auditory STM with parallels to that supporting visual STM. These correlates include persistent neural firing, or a suppression of firing, during the delay period of the memory task, as well as suppression or (less commonly) enhancement of sensory responses when a sound is repeated as a ׳match' stimulus. Auditory STM is supported by a distributed temporo-frontal network in which sensitivity to stimulus history is an intrinsic feature of auditory processing. This article is part of a Special Issue entitled SI: Auditory working memory.

  15. 33 CFR 175.110 - Visual distress signals required.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... passenger vessel subject to the requirements of 46 CFR chapter I, subchapter C, unless visual distress... onboard. Devices suitable for day use and devices suitable for night use, or devices suitable for both...

  16. 33 CFR 175.110 - Visual distress signals required.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... passenger vessel subject to the requirements of 46 CFR chapter I, subchapter C, unless visual distress... onboard. Devices suitable for day use and devices suitable for night use, or devices suitable for both...

  17. 33 CFR 175.110 - Visual distress signals required.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... passenger vessel subject to the requirements of 46 CFR chapter I, subchapter C, unless visual distress... onboard. Devices suitable for day use and devices suitable for night use, or devices suitable for both...

  18. 33 CFR 175.110 - Visual distress signals required.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... passenger vessel subject to the requirements of 46 CFR chapter I, subchapter C, unless visual distress... onboard. Devices suitable for day use and devices suitable for night use, or devices suitable for both...

  19. 33 CFR 149.585 - What are the requirements for sound signals?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... sound signals? 149.585 Section 149.585 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF... Navigation Miscellaneous § 149.585 What are the requirements for sound signals? (a) Each pumping platform complex must have a sound signal, approved under subpart 67.10 of this chapter, that has a 2-mile...

  20. 33 CFR 149.585 - What are the requirements for sound signals?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... sound signals? 149.585 Section 149.585 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF... Navigation Miscellaneous § 149.585 What are the requirements for sound signals? (a) Each pumping platform complex must have a sound signal, approved under subpart 67.10 of this chapter, that has a 2-mile...

  1. 33 CFR 149.585 - What are the requirements for sound signals?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... sound signals? 149.585 Section 149.585 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF... Navigation Miscellaneous § 149.585 What are the requirements for sound signals? (a) Each pumping platform complex must have a sound signal, approved under subpart 67.10 of this chapter, that has a 2-mile...

  2. 33 CFR 149.585 - What are the requirements for sound signals?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... sound signals? 149.585 Section 149.585 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF... Navigation Miscellaneous § 149.585 What are the requirements for sound signals? (a) Each pumping platform complex must have a sound signal, approved under subpart 67.10 of this chapter, that has a 2-mile...

  3. 33 CFR 149.585 - What are the requirements for sound signals?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... sound signals? 149.585 Section 149.585 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF... Navigation Miscellaneous § 149.585 What are the requirements for sound signals? (a) Each pumping platform complex must have a sound signal, approved under subpart 67.10 of this chapter, that has a 2-mile...

  4. A Model of Auditory-Cognitive Processing and Relevance to Clinical Applicability.

    PubMed

    Edwards, Brent

    2016-01-01

    Hearing loss and cognitive function interact in both a bottom-up and top-down relationship. Listening effort is tied to these interactions, and models have been developed to explain their relationship. The Ease of Language Understanding model in particular has gained considerable attention in its explanation of the effect of signal distortion on speech understanding. Signal distortion can also affect auditory scene analysis ability, however, resulting in a distorted auditory scene that can affect cognitive function, listening effort, and the allocation of cognitive resources. These effects are explained through an addition to the Ease of Language Understanding model. This model can be generalized to apply to all sounds, not only speech, representing the increased effort required for auditory environmental awareness and other nonspeech auditory tasks. While the authors have measures of speech understanding and cognitive load to quantify these interactions, they are lacking measures of the effect of hearing aid technology on auditory scene analysis ability and how effort and attention varies with the quality of an auditory scene. Additionally, the clinical relevance of hearing aid technology on cognitive function and the application of cognitive measures in hearing aid fittings will be limited until effectiveness is demonstrated in real-world situations. PMID:27355775

  5. The mechanism for stochastic resonance enhancement of mammalian auditory information processing

    PubMed Central

    Hong, Dawei; Martin, Joseph V; Saidel, William M

    2006-01-01

    Background In a mammalian auditory system, when intrinsic noise is added to a subthreshold signal, not only can the resulting noisy signal be detected, but also the information carried by the signal can be completely recovered. Such a phenomenon is called stochastic resonance (SR). Current analysis of SR commonly employs the energies of the subthreshold signal and intrinsic noise. However, it is difficult to explain SR when the energy addition of the signal and noise is not enough to lift the subthreshold signal over the threshold. Therefore, information modulation has been hypothesized to play a role in some forms of SR in sensory systems. Information modulation, however, seems an unlikely mechanism for mammalian audition, since it requires significant a priori knowledge of the characteristics of the signal. Results We propose that the analysis of SR cannot rely solely on the energies of a subthreshold signal and intrinsic noise or on information modulation. We note that a mammalian auditory system expends energy in the processing of a noisy signal. A part of the expended energy may therefore deposit into the recovered signal, lifting it over threshold. We propose a model that in a rigorous mathematical manner expresses this new theoretical viewpoint on SR in the mammalian auditory system and provide a physiological rationale for the model. Conclusion Our result indicates that the mammalian auditory system may be more active than previously described in the literature. As previously recognized, when intrinsic noise is used to generate a noisy signal, the energy carried by the noise is added to the original subthreshold signal. Furthermore, our model predicts that the system itself should deposit additional energy into the recovered signal. The additional energy is used in the processing of the noisy signal to recover the original subthreshold signal. PMID:17140437

  6. Nematode CLE signaling in Arabidopsis requires CLAVATA2 and CORYNE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Plant-parasitic cyst nematodes secrete CLAVATA3 (CLV3)/ESR(CLE)-like effector proteins. These proteins have been shown to act as ligand mimics of plant CLE peptides and are required for successful nematode infection; however, the receptors for nematode CLE-like peptides have not been identified. Her...

  7. 47 CFR 80.753 - Signal strength requirements at the service area contour.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 5 2011-10-01 2011-10-01 false Signal strength requirements at the service area contour. 80.753 Section 80.753 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED... Station VHF Coverage § 80.753 Signal strength requirements at the service area contour. (a)...

  8. 47 CFR 80.753 - Signal strength requirements at the service area contour.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 5 2014-10-01 2014-10-01 false Signal strength requirements at the service area contour. 80.753 Section 80.753 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED... Station VHF Coverage § 80.753 Signal strength requirements at the service area contour. (a)...

  9. 47 CFR 80.753 - Signal strength requirements at the service area contour.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 5 2010-10-01 2010-10-01 false Signal strength requirements at the service area contour. 80.753 Section 80.753 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED... Station VHF Coverage § 80.753 Signal strength requirements at the service area contour. (a)...

  10. 47 CFR 80.753 - Signal strength requirements at the service area contour.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 5 2013-10-01 2013-10-01 false Signal strength requirements at the service area contour. 80.753 Section 80.753 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED... Station VHF Coverage § 80.753 Signal strength requirements at the service area contour. (a)...

  11. 47 CFR 80.753 - Signal strength requirements at the service area contour.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 5 2012-10-01 2012-10-01 false Signal strength requirements at the service area contour. 80.753 Section 80.753 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED... Station VHF Coverage § 80.753 Signal strength requirements at the service area contour. (a)...

  12. Bat's auditory system: Corticofugal feedback and plasticity

    NASA Astrophysics Data System (ADS)

    Suga, Nobuo

    2001-05-01

    The auditory system of the mustached bat consists of physiologically distinct subdivisions for processing different types of biosonar information. It was found that the corticofugal (descending) auditory system plays an important role in improving and adjusting auditory signal processing. Repetitive acoustic stimulation, cortical electrical stimulation or auditory fear conditioning evokes plastic changes of the central auditory system. The changes are based upon egocentric selection evoked by focused positive feedback associated with lateral inhibition. Focal electric stimulation of the auditory cortex evokes short-term changes in the auditory cortex and subcortical auditory nuclei. An increase in a cortical acetylcholine level during the electric stimulation changes the cortical changes from short-term to long-term. There are two types of plastic changes (reorganizations): centripetal best frequency shifts for expanded reorganization of a neural frequency map and centrifugal best frequency shifts for compressed reorganization of the map. Which changes occur depends on the balance between inhibition and facilitation. Expanded reorganization has been found in different sensory systems and different species of mammals, whereas compressed reorganization has been thus far found only in the auditory subsystems highly specialized for echolocation. The two types of reorganizations occur in both the frequency and time domains. [Work supported by NIDCO DC00175.

  13. Transsynaptic EphB/Ephrin-B signaling regulates growth of presynaptic boutons required for classical conditioning.

    PubMed

    Li, Wei; Zheng, Zhaoqing; Keifer, Joyce

    2011-06-01

    Learning-related presynaptic remodeling has been documented in only a few systems, and its molecular mechanisms are largely unknown. Here we describe a role for the bidirectional EphB/ephrin-B signaling system in structural plasticity of presynaptic nerve terminals using an in vitro model of classical conditioning. Conditioning or BDNF application induced significant growth of auditory nerve presynaptic boutons that convey the conditioned stimulus to abducens motor neurons. Interestingly, bouton enlargement occurred only for those synapses apposed to motor neuron dendrites rather than to somata. Phosphorylation of ephrin-B1, but not EphB2, was induced by both conditioning and BDNF application and was inhibited by postsynaptic injections of ephrin-B antibody. Finally, suppression of postsynaptic ephrin-B function inhibited presynaptic bouton enlargement that was rescued by activation of EphB2 by ephrin-B1-Fc. These data provide evidence for ephrin-B-induced EphB2 forward signaling in presynaptic structural plasticity during classical conditioning. They also reveal a functional interaction between BDNF/TrkB and the Eph/ephrin signaling systems in the coordination of presynaptic and postsynaptic modifications during conditioning.

  14. Copper is required for oncogenic BRAF signaling and tumorigenesis

    PubMed Central

    Brady, Donita C.; Crowe, Matthew S.; Turski, Michelle L.; Hobbs, G. Aaron; Yao, Xiaojie; Chaikuad, Apirat; Knapp, Stefan; Xiao, Kunhong; Campbell, Sharon L.; Thiele, Dennis J.; Counter, Christopher M.

    2014-01-01

    The BRAF kinase is mutated, typically V600E, to induce an active oncogenic state in a large fraction of melanoma, thyroid, hairy cell leukemia, and to a lesser extent, a wide spectrum of other cancers1,2. BRAFV600E phosphorylates and activates the kinases MEK1 and MEK2, which in turn phosphorylate and activate the kinases ERK1 and ERK2, stimulating the MAPK pathway to promote cancer3. Targeting MEK1/2 is proving to be an important therapeutic strategy, as a MEK1/2 inhibitor provides a survival advantage in metastatic melanoma4, which is increased when co-administered with a BRAFV600E inhibitor5. In this regard, we previously found that copper (Cu) influx enhances MEK1 phosphorylation of ERK1/2 through a Cu-MEK1 interaction6. We now show that genetic loss of the high affinity Cu transporter Ctr1 or mutations in MEK1 that disrupt Cu binding reduced BRAFV600E-driven signaling and tumorigenesis. Conversely, a MEK1-MEK5 chimera that phosphorylates ERK1/2 independent of Cu or an active ERK2 restored tumor growth to cells lacking Ctr1. Importantly, Cu chelators used in the treatment of Wilson disease7 reduced tumor growth of both BRAFV600E-transformed cells and cells resistant to BRAF inhibition. Taken together, these results suggest that Cu-chelation therapy could be repurposed to treat BRAFV600E mutation-positive cancers. PMID:24717435

  15. Prefrontal D1 dopamine signaling is required for temporal control.

    PubMed

    Narayanan, Nandakumar S; Land, Benjamin B; Solder, John E; Deisseroth, Karl; DiLeone, Ralph J

    2012-12-11

    Temporal control, or how organisms guide movements in time to achieve behavioral goals, depends on dopamine signaling. The medial prefrontal cortex controls many goal-directed behaviors and receives dopaminergic input primarily from the midbrain ventral tegmental area. However, this system has never been linked with temporal control. Here, we test the hypothesis that dopaminergic projections from the ventral tegmental area to the prefrontal cortex influence temporal control. Rodents were trained to perform a fixed-interval timing task with an interval of 20 s. We report several results: first, that decreasing dopaminergic neurotransmission using virally mediated RNA interference of tyrosine hydroxylase impaired temporal control, and second that pharmacological disruption of prefrontal D1 dopamine receptors, but not D2 dopamine receptors, impaired temporal control. We then used optogenetics to specifically and selectively manipulate prefrontal neurons expressing D1 dopamine receptors during fixed-interval timing performance. Selective inhibition of D1-expressing prefrontal neurons impaired fixed-interval timing, whereas stimulation made animals more efficient during task performance. These data provide evidence that ventral tegmental dopaminergic projections to the prefrontal cortex influence temporal control via D1 receptors. The results identify a critical circuit for temporal control of behavior that could serve as a target for the treatment of dopaminergic diseases.

  16. Development and Fibronectin Signaling Requirements of the Zebrafish Interrenal Vessel

    PubMed Central

    Chiu, Chih-Hao; Chou, Chih-Wei; Takada, Shinji; Liu, Yi-Wen

    2012-01-01

    Background The early morphogenetic steps of zebrafish interrenal tissue, the teleostean counterpart of the mammalian adrenal gland, are modulated by the peri-interrenal angioblasts and blood vessels. While an organized distribution of intra-adrenal vessels and extracellular matrix is essential for the fetal adrenal cortex remodeling, whether and how an intra-interrenal buildup of vasculature and extracellular matrix forms and functions during interrenal organogenesis in teleosts remains unclear. Methodology and Principal Findings We characterized the process of interrenal gland vascularization by identifying the interrenal vessel (IRV); which develops from the axial artery through angiogenesis and is associated with highly enriched Fibronectin (Fn) accumulation at its microenvironment. The loss of Fn1 by either antisense morpholino (MO) knockdown or genetic mutation inhibited endothelial invasion and migration of the steroidogenic tissue. The accumulation of peri-IRV Fn requires Integrin α5 (Itga5), with its knockdown leading to interrenal and IRV morphologies phenocopying those in the fn1 morphant and mutant. fn1b, another known fn gene in zebrafish, is however not involved in the IRV formation. The distribution pattern of peri-IRV Fn could be modulated by the blood flow, while a lack of which altered angiogenic direction of the IRV as well as its ability to integrate with the steroidogenic tissue. The administration of Fn antagonist through microangiography exerted reducing effects on both interrenal vessel angiogenesis and steroidogenic cell migration. Conclusions and Significance This work is the first to identify the zebrafish IRV and to characterize how its integration into the developing interrenal gland requires the Fn-enriched microenvironment, which leads to the possibility of using the IRV formation as a platform for exploring organ-specific angiogenesis. In the context of other developmental endocrinology studies, our results indicate a highly dynamic

  17. Blood flow suppresses vascular Notch signalling via dll4 and is required for angiogenesis in response to hypoxic signalling

    PubMed Central

    Watson, Oliver; Novodvorsky, Peter; Gray, Caroline; Rothman, Alexander M.K.; Lawrie, Allan; Crossman, David C.; Haase, Andrea; McMahon, Kathryn; Gering, Martin; Van Eeden, Fredericus J.M.; Chico, Timothy J.A.

    2013-01-01

    Aims The contribution of blood flow to angiogenesis is incompletely understood. We examined the effect of blood flow on Notch signalling in the vasculature of zebrafish embryos, and whether blood flow regulates angiogenesis in zebrafish with constitutively up-regulated hypoxic signalling. Methods and results Developing zebrafish (Danio rerio) embryos survive via diffusion in the absence of circulation induced by knockdown of cardiac troponin T2 or chemical cardiac cessation. The absence of blood flow increased vascular Notch signalling in 48 h post-fertilization old embryos via up-regulation of the Notch ligand dll4. Despite this, patterning of the intersegmental vessels is not affected by absent blood flow. We therefore examined homozygous vhl mutant zebrafish that have constitutively up-regulated hypoxic signalling. These display excessive and aberrant angiogenesis from 72 h post-fertilization, with significantly increased endothelial number, vessel diameter, and length. The absence of blood flow abolished these effects, though normal vessel patterning was preserved. Conclusion We show that blood flow suppresses vascular Notch signalling via down-regulation of dll4. We have also shown that blood flow is required for angiogenesis in response to hypoxic signalling but is not required for normal vessel patterning. These data indicate important differences in hypoxia-driven vs. developmental angiogenesis. PMID:23812297

  18. Benign lesions of the external auditory canal.

    PubMed

    Tran, L P; Grundfast, K M; Selesnick, S H

    1996-10-01

    Benign mass lesions of the external auditory canal, such as exostoses and osteomas, are common findings on physical examination but most often do not require treatment. The differential diagnosis of lesions in the external auditory canal, however, should not be limited to those benign processes discussed here, but should also include infectious, dermatologic, congenital, and malignant processes.

  19. Auditory learning: a developmental method.

    PubMed

    Zhang, Yilu; Weng, Juyang; Hwang, Wey-Shiuan

    2005-05-01

    Motivated by the human autonomous development process from infancy to adulthood, we have built a robot that develops its cognitive and behavioral skills through real-time interactions with the environment. We call such a robot a developmental robot. In this paper, we present the theory and the architecture to implement a developmental robot and discuss the related techniques that address an array of challenging technical issues. As an application, experimental results on a real robot, self-organizing, autonomous, incremental learner (SAIL), are presented with emphasis on its audition perception and audition-related action generation. In particular, the SAIL robot conducts the auditory learning from unsegmented and unlabeled speech streams without any prior knowledge about the auditory signals, such as the designated language or the phoneme models. Neither available before learning starts are the actions that the robot is expected to perform. SAIL learns the auditory commands and the desired actions from physical contacts with the environment including the trainers.

  20. Sustainable Land Use Requires Attention to Ecological Signals

    USGS Publications Warehouse

    Halvorson, W.L.; Castellanos, A.E.; Murrieta-Saldivar, J.

    2003-01-01

    This case study details the difficulties of landscape management, highlighting the challenges inherent in managing natural resources when multiple agencies are involved, when the land users have no incentive for conservation, and when government agencies have too few resources for effective management. Pumping of groundwater from the aquifer of La Costa de Hermosillo in the state of Sonora, Mexico, began in 1945 and developed so quickly that by the late 1950s salinity intrusion from the Gulf of California was occurring in the wells. In the 1970s, the irrigatable land in La Costa peaked at 132,516 ha and the extracted volume of water from the aquifer peaked at around 1.14 billion cubic meters annually. By the 1980s, 105 wells of the total of 498 were contaminated with seawater and, therefore, identified for closure. At present La Costa de Hermosillo still represents 15% of the total harvested land, 16% of the total annual production, and 23% of the gross agricultural production of the state of Sonora. However, there are approximately 80,000 ha of abandoned fields due to salt water intension, lack of water and/or lack of credit available to individual farmers. This unstable situation resulted from the interplay of water management policies and practices, and farm-land policies and practices. While government agencies have been able to enforce better water use for agricultural production, there remains a significant area that requires restoration from its degraded state. For this piece of the ecosystem management puzzle, government agencies have thus far been unable to affect a solution.

  1. Sustainable land use requires attention to ecological signals.

    PubMed

    Halvorson, William L; Castellanos, Alejandro E; Murrieta-Saldivar, Joaquin

    2003-11-01

    This case study details the difficulties of landscape management, highlighting the challenges inherent in managing natural resources when multiple agencies are involved, when the land users have no incentive for conservation, and when government agencies have too few resources for effective management. Pumping of groundwater from the aquifer of La Costa de Hermosillo in the state of Sonora, Mexico, began in 1945 and developed so quickly that by the late 1950s salinity intrusion from the Gulf of California was occurring in the wells. In the 1970s, the irrigatable land in La Costa peaked at 132,516 ha and the extracted volume of water from the aquifer peaked at around 1.14 billion cubic meters annually. By the 1980s, 105 wells of the total of 498 were contaminated with seawater and, therefore, identified for closure. At present La Costa de Hermosillo still represents 15% of the total harvested land, 16% of the total annual production, and 23% of the gross agricultural production of the state of Sonora. However, there are approximately 80,000 ha of abandoned fields due to salt water intension, lack of water and/or lack of credit available to individual farmers. This unstable situation resulted from the interplay of water management policies and practices, and farm-land policies and practices. While government agencies have been able to enforce better water use for agricultural production, there remains a significant area that requires restoration from its degraded state. For this piece of the ecosystem management puzzle, government agencies have thus far been unable to affect a solution.

  2. Low Power Adder Based Auditory Filter Architecture

    PubMed Central

    Jayanthi, V. S.

    2014-01-01

    Cochlea devices are powered up with the help of batteries and they should possess long working life to avoid replacing of devices at regular interval of years. Hence the devices with low power consumptions are required. In cochlea devices there are numerous filters, each responsible for frequency variant signals, which helps in identifying speech signals of different audible range. In this paper, multiplierless lookup table (LUT) based auditory filter is implemented. Power aware adder architectures are utilized to add the output samples of the LUT, available at every clock cycle. The design is developed and modeled using Verilog HDL, simulated using Mentor Graphics Model-Sim Simulator, and synthesized using Synopsys Design Compiler tool. The design was mapped to TSMC 65 nm technological node. The standard ASIC design methodology has been adapted to carry out the power analysis. The proposed FIR filter architecture has reduced the leakage power by 15% and increased its performance by 2.76%. PMID:25506073

  3. Low power adder based auditory filter architecture.

    PubMed

    Rahiman, P F Khaleelur; Jayanthi, V S

    2014-01-01

    Cochlea devices are powered up with the help of batteries and they should possess long working life to avoid replacing of devices at regular interval of years. Hence the devices with low power consumptions are required. In cochlea devices there are numerous filters, each responsible for frequency variant signals, which helps in identifying speech signals of different audible range. In this paper, multiplierless lookup table (LUT) based auditory filter is implemented. Power aware adder architectures are utilized to add the output samples of the LUT, available at every clock cycle. The design is developed and modeled using Verilog HDL, simulated using Mentor Graphics Model-Sim Simulator, and synthesized using Synopsys Design Compiler tool. The design was mapped to TSMC 65 nm technological node. The standard ASIC design methodology has been adapted to carry out the power analysis. The proposed FIR filter architecture has reduced the leakage power by 15% and increased its performance by 2.76%.

  4. Central auditory function of deafness genes.

    PubMed

    Willaredt, Marc A; Ebbers, Lena; Nothwang, Hans Gerd

    2014-06-01

    The highly variable benefit of hearing devices is a serious challenge in auditory rehabilitation. Various factors contribute to this phenomenon such as the diversity in ear defects, the different extent of auditory nerve hypoplasia, the age of intervention, and cognitive abilities. Recent analyses indicate that, in addition, central auditory functions of deafness genes have to be considered in this context. Since reduced neuronal activity acts as the common denominator in deafness, it is widely assumed that peripheral deafness influences development and function of the central auditory system in a stereotypical manner. However, functional characterization of transgenic mice with mutated deafness genes demonstrated gene-specific abnormalities in the central auditory system as well. A frequent function of deafness genes in the central auditory system is supported by a genome-wide expression study that revealed significant enrichment of these genes in the transcriptome of the auditory brainstem compared to the entire brain. Here, we will summarize current knowledge of the diverse central auditory functions of deafness genes. We furthermore propose the intimately interwoven gene regulatory networks governing development of the otic placode and the hindbrain as a mechanistic explanation for the widespread expression of these genes beyond the cochlea. We conclude that better knowledge of central auditory dysfunction caused by genetic alterations in deafness genes is required. In combination with improved genetic diagnostics becoming currently available through novel sequencing technologies, this information will likely contribute to better outcome prediction of hearing devices.

  5. How Does Auditory Training Work? Joined-Up Thinking and Listening.

    PubMed

    Ferguson, Melanie; Henshaw, Helen

    2015-11-01

    Auditory training aims to compensate for degradation in the auditory signal and is offered as an intervention to help alleviate the most common complaint in people with hearing loss, understanding speech in a background noise. Yet there remain many unanswered questions. This article reviews some of the key pieces of evidence that assess the evidence for whether, and how, auditory training benefits adults with hearing loss. The evidence supports that improvements occur on the trained task; however, transfer of that learning to generalized real-world benefit is much less robust. For more than a decade, there has been an increasing awareness of the role that cognition plays in listening. But more recently in the auditory training literature, there has been an increased focus on assessing how cognitive performance relevant for listening may improve with training. We argue that this is specifically the case for measures that index executive processes, such as monitoring, attention switching, and updating of working memory, all of which are required for successful listening and communication in challenging or adverse listening conditions. We propose combined auditory-cognitive training approaches, where training interventions develop cognition embedded within auditory tasks, which are most likely to offer generalized benefits to the real-world listening abilities of people with hearing loss. PMID:27587911

  6. Auditory processing efficiency deficits in children with developmental language impairments

    NASA Astrophysics Data System (ADS)

    Hartley, Douglas E. H.; Moore, David R.

    2002-12-01

    The ``temporal processing hypothesis'' suggests that individuals with specific language impairments (SLIs) and dyslexia have severe deficits in processing rapidly presented or brief sensory information, both within the auditory and visual domains. This hypothesis has been supported through evidence that language-impaired individuals have excess auditory backward masking. This paper presents an analysis of masking results from several studies in terms of a model of temporal resolution. Results from this modeling suggest that the masking results can be better explained by an ``auditory efficiency'' hypothesis. If impaired or immature listeners have a normal temporal window, but require a higher signal-to-noise level (poor processing efficiency), this hypothesis predicts the observed small deficits in the simultaneous masking task, and the much larger deficits in backward and forward masking tasks amongst those listeners. The difference in performance on these masking tasks is predictable from the compressive nonlinearity of the basilar membrane. The model also correctly predicts that backward masking (i) is more prone to training effects, (ii) has greater inter- and intrasubject variability, and (iii) increases less with masker level than do other masking tasks. These findings provide a new perspective on the mechanisms underlying communication disorders and auditory masking.

  7. The Very Large G-Protein-Coupled Receptor VLGR1: A Component of the Ankle Link Complex Required for the Normal Development of Auditory Hair Bundles

    PubMed Central

    McGee, JoAnn; Goodyear, Richard J.; McMillan, D. Randy; Stauffer, Eric A.; Holt, Jeffrey R.; Locke, Kirsten G.; Birch, David G.; Legan, P. Kevin; White, Perrin C.; Walsh, Edward J.; Richardson, Guy P.

    2009-01-01

    Sensory hair bundles in the inner ear are composed of stereocilia that can be interconnected by a variety of different link types, including tip links, horizontal top connectors, shaft connectors, and ankle links. The ankle link antigen is an epitope specifically associated with ankle links and the calycal processes of photoreceptors in chicks. Mass spectrometry and immunoblotting were used to identify this antigen as the avian ortholog of the very large G-protein-coupled receptor VLGR1, the product of the Usher syndrome USH2C (Mass1) locus. Like ankle links, Vlgr1 is expressed transiently around the base of developing hair bundles in mice. Ankle links fail to form in the cochleae of mice carrying a targeted mutation in Vlgr1 (Vlgr1/del7TM), and the bundles become disorganized just after birth. FM1-43 [N-(3-triethylammonium)propyl)-4-(4-(dibutylamino)styryl) pyridinium dibromide] dye loading and whole-cell recordings indicate mechanotransduction is impaired in cochlear, but not vestibular, hair cells of early postnatal Vlgr1/del7TM mutant mice. Auditory brainstem recordings and distortion product measurements indicate that these mice are severely deaf by the third week of life. Hair cells from the basal half of the cochlea are lost in 2-month-old Vlgr1/del7TM mice, and retinal function is mildly abnormal in aged mutants. Our results indicate that Vlgr1 is required for formation of the ankle link complex and the normal development of cochlear hair bundles. PMID:16775142

  8. Poor supplementary motor area activation differentiates auditory verbal hallucination from imagining the hallucination☆

    PubMed Central

    Raij, Tuukka T.; Riekki, Tapani J.J.

    2012-01-01

    Neuronal underpinnings of auditory verbal hallucination remain poorly understood. One suggested mechanism is brain activation that is similar to verbal imagery but occurs without the proper activation of the neuronal systems that are required to tag the origins of verbal imagery in one's mind. Such neuronal systems involve the supplementary motor area. The supplementary motor area has been associated with awareness of intention to make a hand movement, but whether this region is related to the sense of ownership of one's verbal thought remains poorly known. We hypothesized that the supplementary motor area is related to the distinction between one's own mental processing (auditory verbal imagery) and similar processing that is attributed to non-self author (auditory verbal hallucination). To test this hypothesis, we asked patients to signal the onset and offset of their auditory verbal hallucinations during functional magnetic resonance imaging. During non-hallucination periods, we asked the same patients to imagine the hallucination they had previously experienced. In addition, healthy control subjects signaled the onset and offset of self-paced imagery of similar voices. Both hallucinations and the imagery of hallucinations were associated with similar activation strengths of the fronto-temporal language-related circuitries, but the supplementary motor area was activated more strongly during the imagery than during hallucination. These findings suggest that auditory verbal hallucination resembles verbal imagery in language processing, but without the involvement of the supplementary motor area, which may subserve the sense of ownership of one's own verbal imagery. PMID:24179739

  9. Poor supplementary motor area activation differentiates auditory verbal hallucination from imagining the hallucination.

    PubMed

    Raij, Tuukka T; Riekki, Tapani J J

    2012-01-01

    Neuronal underpinnings of auditory verbal hallucination remain poorly understood. One suggested mechanism is brain activation that is similar to verbal imagery but occurs without the proper activation of the neuronal systems that are required to tag the origins of verbal imagery in one's mind. Such neuronal systems involve the supplementary motor area. The supplementary motor area has been associated with awareness of intention to make a hand movement, but whether this region is related to the sense of ownership of one's verbal thought remains poorly known. We hypothesized that the supplementary motor area is related to the distinction between one's own mental processing (auditory verbal imagery) and similar processing that is attributed to non-self author (auditory verbal hallucination). To test this hypothesis, we asked patients to signal the onset and offset of their auditory verbal hallucinations during functional magnetic resonance imaging. During non-hallucination periods, we asked the same patients to imagine the hallucination they had previously experienced. In addition, healthy control subjects signaled the onset and offset of self-paced imagery of similar voices. Both hallucinations and the imagery of hallucinations were associated with similar activation strengths of the fronto-temporal language-related circuitries, but the supplementary motor area was activated more strongly during the imagery than during hallucination. These findings suggest that auditory verbal hallucination resembles verbal imagery in language processing, but without the involvement of the supplementary motor area, which may subserve the sense of ownership of one's own verbal imagery. PMID:24179739

  10. Perception of stochastically undersampled sound waveforms: a model of auditory deafferentation

    PubMed Central

    Lopez-Poveda, Enrique A.; Barrios, Pablo

    2013-01-01

    Auditory deafferentation, or permanent loss of auditory nerve afferent terminals, occurs after noise overexposure and aging and may accompany many forms of hearing loss. It could cause significant auditory impairment but is undetected by regular clinical tests and so its effects on perception are poorly understood. Here, we hypothesize and test a neural mechanism by which deafferentation could deteriorate perception. The basic idea is that the spike train produced by each auditory afferent resembles a stochastically digitized version of the sound waveform and that the quality of the waveform representation in the whole nerve depends on the number of aggregated spike trains or auditory afferents. We reason that because spikes occur stochastically in time with a higher probability for high- than for low-intensity sounds, more afferents would be required for the nerve to faithfully encode high-frequency or low-intensity waveform features than low-frequency or high-intensity features. Deafferentation would thus degrade the encoding of these features. We further reason that due to the stochastic nature of nerve firing, the degradation would be greater in noise than in quiet. This hypothesis is tested using a vocoder. Sounds were filtered through ten adjacent frequency bands. For the signal in each band, multiple stochastically subsampled copies were obtained to roughly mimic different stochastic representations of that signal conveyed by different auditory afferents innervating a given cochlear region. These copies were then aggregated to obtain an acoustic stimulus. Tone detection and speech identification tests were performed by young, normal-hearing listeners using different numbers of stochastic samplers per frequency band in the vocoder. Results support the hypothesis that stochastic undersampling of the sound waveform, inspired by deafferentation, impairs speech perception in noise more than in quiet, consistent with auditory aging effects. PMID:23882176

  11. Estrogenic modulation of auditory processing: a vertebrate comparison

    PubMed Central

    Caras, Melissa L.

    2013-01-01

    Sex-steroid hormones are well-known regulators of vocal motor behavior in several organisms. A large body of evidence now indicates that these same hormones modulate processing at multiple levels of the ascending auditory pathway. The goal of this review is to provide a comparative analysis of the role of estrogens in vertebrate auditory function. Four major conclusions can be drawn from the literature: First, estrogens may influence the development of the mammalian auditory system. Second, estrogenic signaling protects the mammalian auditory system from noise- and age-related damage. Third, estrogens optimize auditory processing during periods of reproductive readiness in multiple vertebrate lineages. Finally, brain-derived estrogens can act locally to enhance auditory response properties in at least one avian species. This comparative examination may lead to a better appreciation of the role of estrogens in the processing of natural vocalizations and may provide useful insights toward alleviating auditory dysfunctions emanating from hormonal imbalances. PMID:23911849

  12. Neural mechanisms underlying auditory feedback control of speech.

    PubMed

    Tourville, Jason A; Reilly, Kevin J; Guenther, Frank H

    2008-02-01

    The neural substrates underlying auditory feedback control of speech were investigated using a combination of functional magnetic resonance imaging (fMRI) and computational modeling. Neural responses were measured while subjects spoke monosyllabic words under two conditions: (i) normal auditory feedback of their speech and (ii) auditory feedback in which the first formant frequency of their speech was unexpectedly shifted in real time. Acoustic measurements showed compensation to the shift within approximately 136 ms of onset. Neuroimaging revealed increased activity in bilateral superior temporal cortex during shifted feedback, indicative of neurons coding mismatches between expected and actual auditory signals, as well as right prefrontal and Rolandic cortical activity. Structural equation modeling revealed increased influence of bilateral auditory cortical areas on right frontal areas during shifted speech, indicating that projections from auditory error cells in posterior superior temporal cortex to motor correction cells in right frontal cortex mediate auditory feedback control of speech.

  13. Auditory Imagery: Empirical Findings

    ERIC Educational Resources Information Center

    Hubbard, Timothy L.

    2010-01-01

    The empirical literature on auditory imagery is reviewed. Data on (a) imagery for auditory features (pitch, timbre, loudness), (b) imagery for complex nonverbal auditory stimuli (musical contour, melody, harmony, tempo, notational audiation, environmental sounds), (c) imagery for verbal stimuli (speech, text, in dreams, interior monologue), (d)…

  14. Auditory Training for Central Auditory Processing Disorder.

    PubMed

    Weihing, Jeffrey; Chermak, Gail D; Musiek, Frank E

    2015-11-01

    Auditory training (AT) is an important component of rehabilitation for patients with central auditory processing disorder (CAPD). The present article identifies and describes aspects of AT as they relate to applications in this population. A description of the types of auditory processes along with information on relevant AT protocols that can be used to address these specific deficits is included. Characteristics and principles of effective AT procedures also are detailed in light of research that reflects on their value. Finally, research investigating AT in populations who show CAPD or present with auditory complaints is reported. Although efficacy data in this area are still emerging, current findings support the use of AT for treatment of auditory difficulties. PMID:27587909

  15. Auditory Training for Central Auditory Processing Disorder

    PubMed Central

    Weihing, Jeffrey; Chermak, Gail D.; Musiek, Frank E.

    2015-01-01

    Auditory training (AT) is an important component of rehabilitation for patients with central auditory processing disorder (CAPD). The present article identifies and describes aspects of AT as they relate to applications in this population. A description of the types of auditory processes along with information on relevant AT protocols that can be used to address these specific deficits is included. Characteristics and principles of effective AT procedures also are detailed in light of research that reflects on their value. Finally, research investigating AT in populations who show CAPD or present with auditory complaints is reported. Although efficacy data in this area are still emerging, current findings support the use of AT for treatment of auditory difficulties. PMID:27587909

  16. Wnt/β-catenin signaling in dermal condensates is required for hair follicle formation

    PubMed Central

    Tsai, Su-Yi; Sennett, Rachel; Rezza, Amélie; Clavel, Carlos; Grisanti, Laura; Zemla, Roland; Najam, Sara; Rendl, Michael

    2014-01-01

    Broad dermal Wnt signaling is required for patterned induction of hair follicle placodes and subsequent Wnt signaling in placode stem cells is essential for induction of dermal condensates, cell clusters of precursors for the hair follicle dermal papilla (DP). Progression of hair follicle formation then requires coordinated signal exchange between dermal condensates and placode stem cells. However, it remains unknown whether continued Wnt signaling in DP precursor cells plays a role in this process, largely due to the long-standing inability to specifically target dermal condensates for gene ablation. Here we use the Tbx18Cre knockin mouse line to ablate the Wnt-responsive transcription factor β-catenin specifically in these cells at E14.5 during the first wave of guard hair follicle formation. In the absence of β-catenin, canonical Wnt signaling is effectively abolished in these cells. Sox2+ dermal condensates initiate normally, however by E16.5 guard hair follicle numbers are strongly reduced and by E18.5 most whiskers and guard hair follicles are absent, suggesting that active Wnt signaling in dermal condensates is important for hair follicle formation to proceed after induction. To explore the molecular mechanisms by which Wnt signaling in dermal condensates regulates hair follicle formation, we analyze genome-wide the gene expression changes in embryonic β-catenin null DP precursor cells. We find altered expression of several signaling pathway genes, including Fgfs and Activin, both previously implicated in hair follicle formation. In summary, these data reveal a functional role of Wnt signaling in DP precursors for embryonic hair follicle formation and identify Fgf and Activin signaling as potential effectors of Wnt signaling-regulated events. PMID:24309208

  17. Wnt/β-catenin signaling in dermal condensates is required for hair follicle formation.

    PubMed

    Tsai, Su-Yi; Sennett, Rachel; Rezza, Amélie; Clavel, Carlos; Grisanti, Laura; Zemla, Roland; Najam, Sara; Rendl, Michael

    2014-01-15

    Broad dermal Wnt signaling is required for patterned induction of hair follicle placodes and subsequent Wnt signaling in placode stem cells is essential for induction of dermal condensates, cell clusters of precursors for the hair follicle dermal papilla (DP). Progression of hair follicle formation then requires coordinated signal exchange between dermal condensates and placode stem cells. However, it remains unknown whether continued Wnt signaling in DP precursor cells plays a role in this process, largely due to the long-standing inability to specifically target dermal condensates for gene ablation. Here we use the Tbx18(Cre) knockin mouse line to ablate the Wnt-responsive transcription factor β-catenin specifically in these cells at E14.5 during the first wave of guard hair follicle formation. In the absence of β-catenin, canonical Wnt signaling is effectively abolished in these cells. Sox2(+) dermal condensates initiate normally; however by E16.5 guard hair follicle numbers are strongly reduced and by E18.5 most whiskers and guard hair follicles are absent, suggesting that active Wnt signaling in dermal condensates is important for hair follicle formation to proceed after induction. To explore the molecular mechanisms by which Wnt signaling in dermal condensates regulates hair follicle formation, we analyze genome-wide the gene expression changes in embryonic β-catenin null DP precursor cells. We find altered expression of several signaling pathway genes, including Fgfs and Activin, both previously implicated in hair follicle formation. In summary, these data reveal a functional role of Wnt signaling in DP precursors for embryonic hair follicle formation and identify Fgf and Activin signaling as potential effectors of Wnt signaling-regulated events.

  18. Passive Auditory Stimulation Improves Vision in Hemianopia

    PubMed Central

    Lewald, Jörg; Tegenthoff, Martin; Peters, Sören; Hausmann, Markus

    2012-01-01

    Techniques employed in rehabilitation of visual field disorders such as hemianopia are usually based on either visual or audio-visual stimulation and patients have to perform a training task. Here we present results from a completely different, novel approach that was based on passive unimodal auditory stimulation. Ten patients with either left or right-sided pure hemianopia (without neglect) received one hour of unilateral passive auditory stimulation on either their anopic or their intact side by application of repetitive trains of sound pulses emitted simultaneously via two loudspeakers. Immediately before and after passive auditory stimulation as well as after a period of recovery, patients completed a simple visual task requiring detection of light flashes presented along the horizontal plane in total darkness. The results showed that one-time passive auditory stimulation on the side of the blind, but not of the intact, hemifield of patients with hemianopia induced an improvement in visual detections by almost 100% within 30 min after passive auditory stimulation. This enhancement in performance was reversible and was reduced to baseline 1.5 h later. A non-significant trend of a shift of the visual field border toward the blind hemifield was obtained after passive auditory stimulation. These results are compatible with the view that passive auditory stimulation elicited some activation of the residual visual pathways, which are known to be multisensory and may also be sensitive to unimodal auditory stimuli as were used here. Trial Registration DRKS00003577 PMID:22666311

  19. Synaptic plasticity and NO-cGMP-PKG signaling coordinately regulate ERK-driven gene expression in the lateral amygdala and in the auditory thalamus following Pavlovian fear conditioning.

    PubMed

    Ota, Kristie T; Monsey, Melissa S; Wu, Melissa S; Young, Grace J; Schafe, Glenn E

    2010-04-01

    We have recently hypothesized that NO-cGMP-PKG signaling in the lateral nucleus of the amygdala (LA) during auditory fear conditioning coordinately regulates ERK-driven transcriptional changes in both auditory thalamic (MGm/PIN) and LA neurons that serve to promote pre- and postsynaptic alterations at thalamo-LA synapses, respectively. In the present series of experiments, we show that N-methyl-D-aspartate receptor (NMDAR)-driven synaptic plasticity and NO-cGMP-PKG signaling in the LA regulate the training-induced expression of ERK and the ERK-driven immediate early genes (IEGs) Arc/Arg3.1, c-Fos, and EGR-1 in the LA and the MGm/PIN. Rats receiving intra-LA infusion of the NR2B selective antagonist Ifenprodil, the NOS inhibitor 7-Ni, or the PKG inhibitor Rp-8-Br-PET-cGMPS exhibited significant decreases in ERK activation and in the training-induced expression of all three IEGs in the LA and MGm/PIN while intra-LA infusion of the PKG activator 8-Br-cGMP had the opposite effect. Remarkably, those rats given intra-LA infusion of the membrane impermeable NO scavenger c-PTIO exhibited significant decreases in ERK activation and ERK-driven IEG expression in the MGm/PIN, but not in the LA. Together with our previous experiments, these results suggest that synaptic plasticity and the NO-cGMP-PKG signaling pathway promote fear memory consolidation, in part, by regulating ERK-driven transcription in both the LA and the MGm/PIN. They further suggest that synaptic plasticity in the LA during fear conditioning promotes ERK-driven transcription in MGm/PIN neurons via NO-driven "retrograde signaling."

  20. Improved Long-Term Memory via Enhancing cGMP-PKG Signaling Requires cAMP-PKA Signaling

    PubMed Central

    Bollen, Eva; Puzzo, Daniela; Rutten, Kris; Privitera, Lucia; De Vry, Jochen; Vanmierlo, Tim; Kenis, Gunter; Palmeri, Agostino; D'Hooge, Rudi; Balschun, Detlef; Steinbusch, Harry MW; Blokland, Arjan; Prickaerts, Jos

    2014-01-01

    Memory consolidation is defined by the stabilization of a memory trace after acquisition, and consists of numerous molecular cascades that mediate synaptic plasticity. Commonly, a distinction is made between an early and a late consolidation phase, in which early refers to the first hours in which labile synaptic changes occur, whereas late consolidation relates to stable and long-lasting synaptic changes induced by de novo protein synthesis. How these phases are linked at a molecular level is not yet clear. Here we studied the interaction of the cyclic nucleotide-mediated pathways during the different phases of memory consolidation in rodents. In addition, the same pathways were studied in a model of neuronal plasticity, long-term potentiation (LTP). We demonstrated that cGMP/protein kinase G (PKG) signaling mediates early memory consolidation as well as early-phase LTP, whereas cAMP/protein kinase A (PKA) signaling mediates late consolidation and late-phase-like LTP. In addition, we show for the first time that early-phase cGMP/PKG signaling requires late-phase cAMP/PKA-signaling in both LTP and long-term memory formation. PMID:24813825

  1. Drosophila PI4KIIIalpha is required in follicle cells for oocyte polarization and Hippo signaling

    PubMed Central

    Yan, Yan; Denef, Natalie; Tang, Charm; Schüpbach, Trudi

    2011-01-01

    In a genetic screen we isolated mutations in CG10260, which encodes a phosphatidylinositol 4-kinase (PI4KIIIalpha), and found that PI4KIIIalpha is required for Hippo signaling in Drosophila ovarian follicle cells. PI4KIIIalpha mutations in the posterior follicle cells lead to oocyte polarization defects similar to those caused by mutations in the Hippo signaling pathway. PI4KIIIalpha mutations also cause misexpression of well-established Hippo signaling targets. The Merlin-Expanded-Kibra complex is required at the apical membrane for Hippo activity. In PI4KIIIalpha mutant follicle cells, Merlin fails to localize to the apical domain. Our analysis of PI4KIIIalpha mutants provides a new link in Hippo signal transduction from the cell membrane to its core kinase cascade. PMID:21429988

  2. Representation of speech in human auditory cortex: Is it special?

    PubMed Central

    Steinschneider, Mitchell; Nourski, Kirill V.; Fishman, Yonatan I.

    2013-01-01

    Successful categorization of phonemes in speech requires that the brain analyze the acoustic signal along both spectral and temporal dimensions. Neural encoding of the stimulus amplitude envelope is critical for parsing the speech stream into syllabic units. Encoding of voice onset time (VOT) and place of articulation (POA), cues necessary for determining phonemic identity, occurs within shorter time frames. An unresolved question is whether the neural representation of speech is based on processing mechanisms that are unique to humans and shaped by learning and experience, or is based on rules governing general auditory processing that are also present in non-human animals. This question was examined by comparing the neural activity elicited by speech and other complex vocalizations in primary auditory cortex of macaques, who are limited vocal learners, with that in Heschl’s gyrus, the putative location of primary auditory cortex in humans. Entrainment to the amplitude envelope is neither specific to humans nor to human speech. VOT is represented by responses time-locked to consonant release and voicing onset in both humans and monkeys. Temporal representation of VOT is observed both for isolated syllables and for syllables embedded in the more naturalistic context of running speech. The fundamental frequency of male speakers is represented by more rapid neural activity phase-locked to the glottal pulsation rate in both humans and monkeys. In both species, the differential representation of stop consonants varying in their POA can be predicted by the relationship between the frequency selectivity of neurons and the onset spectra of the speech sounds. These findings indicate that the neurophysiology of primary auditory cortex is similar in monkeys and humans despite their vastly different experience with human speech, and that Heschl’s gyrus is engaged in general auditory, and not language-specific, processing. PMID:23792076

  3. Signaling required for blood vessel maintenance: molecular basis and pathological manifestations.

    PubMed

    Murakami, Masahiro

    2012-01-01

    As our understanding of molecular mechanisms leading to vascular formation increases, vessel maintenance including stabilization of new vessels and prevention of vessel regression began to be considered as an active process that requires specific cellular signaling. While signaling pathways such as VEGF, FGF, and angiopoietin-Tie2 are important for endothelial cell survival and junction stabilization, PDGF and TGF-β signaling modify mural cell (vascular smooth muscle cells and pericytes) functions, thus they fortify vessel integrity. Breakdown of these signaling systems results in pathological hyperpermeability and/or genetic vascular abnormalities such as vascular malformations, ultimately progressing to hemorrhage and edema. Hence, blood vessel maintenance is fundamental to controlling vascular homeostasis and tissue functions. This paper discusses signaling pathways essential for vascular maintenance and clinical conditions caused by deterioration of vessel integrity.

  4. Pre-LTP requires extracellular signal-regulated kinase in the ACC

    PubMed Central

    Yamanaka, Manabu; Tian, Zhen; Darvish-Ghane, Soroush

    2016-01-01

    The extracellular signal-regulated kinase is an important protein kinase for cortical plasticity. Long-term potentiation in the anterior cingulate cortex is believed to play important roles in chronic pain, fear, and anxiety. Previous studies of extracellular signal-regulated kinase are mainly focused on postsynaptic form of long-term potentiation (post-long-term potentiation). Little is known about the relationship between extracellular signal-regulated kinase and presynaptic long-term potentiation (pre-long-term potentiation) in cortical synapses. In this study, we examined whether pre-long-term potentiation in the anterior cingulate cortex requires the activation of presynaptic extracellular signal-regulated kinase. We found that p42/p44 mitogen-activated protein kinase inhibitors, PD98059 and U0126, suppressed the induction of pre-long-term potentiation. By contrast, these inhibitors did not affect the maintenance of pre-long-term potentiation. Using pharmacological inhibitors, we found that pre-long-term potentiation recorded for 1 h did not require transcriptional or translational processes. Our results strongly indicate that the activation of presynaptic extracellular signal-regulated kinase is required for the induction of pre-long-term potentiation, and this involvement may explain the contribution of extracellular signal-regulated kinase to mood disorders. PMID:27178245

  5. Conformational signaling required for synaptic plasticity by the NMDA receptor complex.

    PubMed

    Aow, Jonathan; Dore, Kim; Malinow, Roberto

    2015-11-24

    The NMDA receptor (NMDAR) is known to transmit important information by conducting calcium ions. However, some recent studies suggest that activation of NMDARs can trigger synaptic plasticity in the absence of ion flow. Does ligand binding transmit information to signaling molecules that mediate synaptic plasticity? Using Förster resonance energy transfer (FRET) imaging of fluorescently tagged proteins expressed in neurons, conformational signaling is identified within the NMDAR complex that is essential for downstream actions. Ligand binding transiently reduces FRET between the NMDAR cytoplasmic domain (cd) and the associated protein phosphatase 1 (PP1), requiring NMDARcd movement, and persistently reduces FRET between the NMDARcd and calcium/calmodulin-dependent protein kinase II (CaMKII), a process requiring PP1 activity. These studies directly monitor agonist-driven conformational signaling at the NMDAR complex required for synaptic plasticity.

  6. Magnetic resonance imaging of the internal auditory canal

    SciTech Connect

    Daniels, D.L.; Herfkins, R.; Koehler, P.R.; Millen, S.J.; Shaffer, K.A.; Williams, A.L.; Haughton, V.M.

    1984-04-01

    Three patients with exclusively or predominantly intracanalicular neuromas and 5 with presumably normal internal auditory canals were examined with prototype 1.4- or 1.5-tesla magnetic resonance (MR) scanners. MR images showed the 7th and 8th cranial nerves in the internal auditory canal. The intracanalicular neuromas had larger diameter and slightly greater signal strength than the nerves. Early results suggest that minimal enlargement of the nerves can be detected even in the internal auditory canal.

  7. Notch1 endocytosis is induced by ligand and is required for signal transduction.

    PubMed

    Chapman, G; Major, J A; Iyer, K; James, A C; Pursglove, S E; Moreau, J L M; Dunwoodie, S L

    2016-01-01

    The Notch signalling pathway is widely utilised during embryogenesis in situations where cell-cell interactions are important for cell fate specification and differentiation. DSL ligand endocytosis into the ligand-expressing cell is an important aspect of Notch signalling because it is thought to supply the force needed to separate the Notch heterodimer to initiate signal transduction. A functional role for receptor endocytosis during Notch signal transduction is more controversial. Here we have used live-cell imaging to examine trafficking of the Notch1 receptor in response to ligand binding. Contact with cells expressing ligands induced internalisation and intracellular trafficking of Notch1. Notch1 endocytosis was accompanied by transendocytosis of ligand into the Notch1-expressing signal-receiving cell. Ligand caused Notch1 endocytosis into SARA-positive endosomes in a manner dependent on clathrin and dynamin function. Moreover, inhibition of endocytosis in the receptor-expressing cell impaired ligand-induced Notch1 signalling. Our findings resolve conflicting observations from mammalian and Drosophila studies by demonstrating that ligand-dependent activation of Notch1 signalling requires receptor endocytosis. Endocytosis of Notch1 may provide a force on the ligand:receptor complex that is important for potent signal transduction.

  8. Spacecraft-spacecraft radio-metric tracking: Signal acquisition requirements and application to Mars approach navigation

    NASA Technical Reports Server (NTRS)

    Kahn, R. D.; Thurman, S.; Edwards, C.

    1994-01-01

    Doppler and ranging measurements between spacecraft can be obtained only when the ratio of the total received signal power to noise power density (P(sub t)/N(sub 0)) at the receiving spacecraft is sufficiently large that reliable signal detection can be achieved within a reasonable time period. In this article, the requirement on P(sub t)/N(sub 0) for reliable carrier signal detection is calculated as a function of various system parameters, including characteristics of the spacecraft computing hardware and a priori uncertainty in spacecraft-spacecraft relative velocity and acceleration. Also calculated is the P(sub t)/N(sub 0) requirements for reliable detection of a ranging signal, consisting of a carrier with pseudonoise (PN) phase modulation. Once the P(sub t)/N(sub 0) requirement is determined, then for a given set of assumed spacecraft telecommunication characteristics (transmitted signal power, antenna gains, and receiver noise temperatures) it is possible to calculate the maximum range at which a carrier signal or ranging signal may be acquired. For example, if a Mars lander and a spacecraft approaching Mars are each equipped with 1-m-diameter antennas, the transmitted power is 5 W, and the receiver noise temperatures are 350 K, then S-band carrier signal acquisition can be achieved at ranges exceeding 10 million km. An error covariance analysis illustrates the utility of in situ Doppler and ranging measurements for Mars approach navigation. Covariance analysis results indicate that navigation accuracies of a few km can be achieved with either data type. The analysis also illustrates dependency of the achievable accuracy on the approach trajectory velocity.

  9. Auditory-visual spatial interaction and modularity

    PubMed

    Radeau, M

    1994-02-01

    The results of dealing with the conditions for pairing visual and auditory data coming from spatially separate locations argue for cognitive impenetrability and computational autonomy, the pairing rules being the Gestalt principles of common fate and proximity. Other data provide evidence for pairing with several properties of modular functioning. Arguments for domain specificity are inferred from comparison with audio-visual speech. Suggestion of innate specification can be found in developmental data indicating that the grouping of visual and auditory signals is supported very early in life by the same principles that operate in adults. Support for a specific neural architecture comes from neurophysiological studies of the bimodal (auditory-visual) neurons of the cat superior colliculus. Auditory-visual pairing thus seems to present the four main properties of the Fodorian module.

  10. Distinct requirements for signal peptidase processing and function in the stable signal peptide subunit of the Junin virus envelope glycoprotein

    SciTech Connect

    York, Joanne; Nunberg, Jack H. . E-mail: jack.nunberg@umontana.edu

    2007-03-01

    The arenavirus envelope glycoprotein (GP-C) retains a cleaved and stable signal peptide (SSP) as an essential subunit of the mature complex. This 58-amino-acid residue peptide serves as a signal sequence and is additionally required to enable transit of the assembled GP-C complex to the Golgi, and for pH-dependent membrane fusion activity. We have investigated the C-terminal region of the Junin virus SSP to study the role of the cellular signal peptidase (SPase) in generating SSP. Site-directed mutagenesis at the cleavage site (positions - 1 and - 3) reveals a pattern of side-chain preferences consistent with those of SPase. Although position - 2 is degenerate for SPase cleavage, this residue in the arenavirus SSP is invariably a cysteine. In the Junin virus, this cysteine is not involved in disulfide bonding. We show that replacement with alanine or serine is tolerated for SPase cleavage but prevents the mutant SSP from associating with GP-C and enabling transport to the cell surface. Conversely, an arginine mutation at position - 1 that prevents SPase cleavage is fully compatible with GP-C-mediated membrane fusion activity when the mutant SSP is provided in trans. These results point to distinct roles of SSP sequences in SPase cleavage and GP-C biogenesis. Further studies of the unique structural organization of the GP-C complex will be important in identifying novel opportunities for antiviral intervention against arenaviral hemorrhagic disease.

  11. Does the whistling thorn acacia (Acacia drepanolobium) use auditory aposematism to deter mammalian herbivores?

    PubMed

    Lev-Yadun, Simcha

    2016-08-01

    Auditory signaling including aposematism characterizes many terrestrial animals. Auditory aposematism by which certain animals use auditory aposematic signals to fend off enemies is well known for instance in rattlesnakes. Auditory signaling by plants toward animals and other plants is an emerging area of plant biology that still suffers from limited amount of solid data. Here I propose that auditory aposematism operates in the African whistling thorn acacia (Acacia drepanolobium = Vachellia drepanolobium). In this tree, the large and hollow thorn bases whistle when wind blows. This type of aposematism compliments the well-known conspicuous thorn and mutualistic ant based aposematism during day and may operate during night when the conspicuous thorns are invisible.

  12. Requirement for nuclear calcium signaling in Drosophila long-term memory.

    PubMed

    Weislogel, Jan-Marek; Bengtson, C Peter; Müller, Michaela K; Hörtzsch, Jan N; Bujard, Martina; Schuster, Christoph M; Bading, Hilmar

    2013-05-07

    Calcium is used throughout evolution as an intracellular signal transducer. In the mammalian central nervous system, calcium mediates the dialogue between the synapse and the nucleus that is required for transcription-dependent persistent neuronal adaptations. A role for nuclear calcium signaling in similar processes in the invertebrate brain has yet to be investigated. Here, we show by in vivo calcium imaging of adult brain neurons of the fruit fly Drosophila melanogaster, that electrical foot shocks used in olfactory avoidance conditioning evoked transient increases in cytosolic and nuclear calcium concentrations in neurons. These calcium signals were detected in Kenyon cells of the flies' mushroom bodies, which are sites of learning and memory related to smell. Acute blockade of nuclear calcium signaling during conditioning selectively and reversibly abolished the formation of long-term olfactory avoidance memory, whereas short-term, middle-term, or anesthesia-resistant olfactory memory remained unaffected. Thus, nuclear calcium signaling is required in flies for the progression of memories from labile to transcription-dependent long-lasting forms. These results identify nuclear calcium as an evolutionarily conserved signal needed in both invertebrate and vertebrate brains for transcription-dependent memory consolidation.

  13. Calcium signaling and the MAPK cascade are required for sperm activation in Caenorhabditis elegans.

    PubMed

    Liu, Zhiyu; Wang, Bin; He, Ruijun; Zhao, Yanmei; Miao, Long

    2014-02-01

    In nematode, sperm activation (or spermiogenesis), a process in which the symmetric and non-motile spermatids transform into polarized and crawling spermatozoa, is critical for sperm cells to acquire fertilizing competence. SPE-8 dependent and SPE-8 independent pathways function redundantly during sperm activation in both males and hermaphrodites of Caenorhabditis elegans. However, the downstream signaling for both pathways remains unclear. Here we show that calcium signaling and the MAPK cascade are required for both SPE-8 dependent and SPE-8 independent sperm activation, implying that both pathways share common downstream signaling components during sperm activation. We demonstrate that activation of the MAPK cascade is sufficient to activate spermatids derived from either wild-type or spe-8 group mutant males and that activation of the MAPK cascade bypasses the requirement of calcium signal to induce sperm activation, indicating that the MAPK cascade functions downstream of or parallel with the calcium signaling during sperm activation. Interestingly, the persistent activation of MAPK in activated spermatozoa inhibits Major Sperm Protein (MSP)-based cytoskeleton dynamics. We demonstrate that MAPK plays dual roles in promoting pseudopod extension during sperm activation but also blocking the MSP-based, amoeboid motility of the spermatozoa. Thus, though nematode sperm are crawling cells, morphologically distinct from flagellated sperm, and the molecular machinery for motility of amoeboid and flagellated sperm is different, both types of sperm might utilize conserved signaling pathways to modulate sperm maturation.

  14. DARPP-32 is required for MAPK/ERK signaling in thyroid cells.

    PubMed

    Chocarro-Calvo, Ana; Zaballos, Miguel A; Santisteban, Pilar; García-Jiménez, Custodia

    2012-03-01

    Modulation of MAPK signaling duration by cAMP defines its physiological output by driving cells toward proliferation or differentiation. Understanding how the kinetics of MAPK signaling are integrated with other cellular signals is a key issue in development and cancer. Here we show that dopamine and cAMP-regulated neuronal phosphoprotein, 32 kDa (DARPP-32), a protein required for thyroid cell differentiation, determines whether MAPK/ERK activation is sustained or transient. Serum, a stimulus that activates MAPK signaling and does not independently increase DARPP-32 levels results in transient activation of the MAPK pathway. By contrast, TSH + (IGF-I) activate MAPK signaling but also independently increase DARPP-32 levels. Our results are consistent with a model in which maintenance of DARPP-32 expression by TSH + IGF-I leads to sustained MAPK signaling. Moreover, the sensitivity of MAPK/ERK signaling in thyroid cells is lost when de novo DARPP-32 expression is blocked by small interfering RNA. Because both DARPP-32 levels and function as inhibitor of protein phosphatase 1, a key inhibitor of MAPK kinase activity, are governed by cAMP/protein kinase A, the results may explain why in thyroid cells cAMP signaling downstream from TSH controls the duration of MAPK pathway activity. Thus, fine-tuning of DARPP-32 levels leads to changes in the kinetics or sensitivity of MAPK/ERK signaling. Given the implications of MAPK signaling in thyroid cancer and the loss of DARPP-32 in tumor and transformed thyroid cells, DARPP-32 may represent a key therapeutic target. PMID:22301787

  15. Auditory imagery: empirical findings.

    PubMed

    Hubbard, Timothy L

    2010-03-01

    The empirical literature on auditory imagery is reviewed. Data on (a) imagery for auditory features (pitch, timbre, loudness), (b) imagery for complex nonverbal auditory stimuli (musical contour, melody, harmony, tempo, notational audiation, environmental sounds), (c) imagery for verbal stimuli (speech, text, in dreams, interior monologue), (d) auditory imagery's relationship to perception and memory (detection, encoding, recall, mnemonic properties, phonological loop), and (e) individual differences in auditory imagery (in vividness, musical ability and experience, synesthesia, musical hallucinosis, schizophrenia, amusia) are considered. It is concluded that auditory imagery (a) preserves many structural and temporal properties of auditory stimuli, (b) can facilitate auditory discrimination but interfere with auditory detection, (c) involves many of the same brain areas as auditory perception, (d) is often but not necessarily influenced by subvocalization, (e) involves semantically interpreted information and expectancies, (f) involves depictive components and descriptive components, (g) can function as a mnemonic but is distinct from rehearsal, and (h) is related to musical ability and experience (although the mechanisms of that relationship are not clear). PMID:20192565

  16. Auditory imagery: empirical findings.

    PubMed

    Hubbard, Timothy L

    2010-03-01

    The empirical literature on auditory imagery is reviewed. Data on (a) imagery for auditory features (pitch, timbre, loudness), (b) imagery for complex nonverbal auditory stimuli (musical contour, melody, harmony, tempo, notational audiation, environmental sounds), (c) imagery for verbal stimuli (speech, text, in dreams, interior monologue), (d) auditory imagery's relationship to perception and memory (detection, encoding, recall, mnemonic properties, phonological loop), and (e) individual differences in auditory imagery (in vividness, musical ability and experience, synesthesia, musical hallucinosis, schizophrenia, amusia) are considered. It is concluded that auditory imagery (a) preserves many structural and temporal properties of auditory stimuli, (b) can facilitate auditory discrimination but interfere with auditory detection, (c) involves many of the same brain areas as auditory perception, (d) is often but not necessarily influenced by subvocalization, (e) involves semantically interpreted information and expectancies, (f) involves depictive components and descriptive components, (g) can function as a mnemonic but is distinct from rehearsal, and (h) is related to musical ability and experience (although the mechanisms of that relationship are not clear).

  17. Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal.

    PubMed

    Chamoun, Z; Mann, R K; Nellen, D; von Kessler, D P; Bellotto, M; Beachy, P A; Basler, K

    2001-09-14

    One of the most dominant influences in the patterning of multicellular embryos is exerted by the Hedgehog (Hh) family of secreted signaling proteins. Here, we identify a segment polarity gene in Drosophila melanogaster, skinny hedgehog (ski), and show that its product is required in Hh-expressing cells for production of appropriate signaling activity in embryos and in the imaginal precursors of adult tissues. The ski gene encodes an apparent acyltransferase, and we provide genetic and biochemical evidence that Hh proteins from ski mutant cells retain carboxyl-terminal cholesterol modification but lack amino-terminal palmitate modification. Our results suggest that ski encodes an enzyme that acts within the secretory pathway to catalyze amino-terminal palmitoylation of Hh, and further demonstrate that this lipid modification is required for the embryonic and larval patterning activities of the Hh signal.

  18. Two-signal requirement for growth-promoting function of Yap in hepatocytes

    PubMed Central

    Su, Tian; Bondar, Tanya; Zhou, Xu; Zhang, Cuiling; He, Hang; Medzhitov, Ruslan

    2015-01-01

    The transcriptional coactivator Yes-associated protein (Yap) promotes proliferation and inhibits apoptosis, suggesting that Yap functions as an oncogene. Most oncogenes, however, require a combination of at least two signals to promote proliferation. In this study, we present evidence that Yap activation is insufficient to promote growth in the otherwise normal tissue. Using a mosaic mouse model, we demonstrate that Yap overexpression in a fraction of hepatocytes does not lead to their clonal expansion, as proliferation is counterbalanced by increased apoptosis. To shift the activity of Yap towards growth, a second signal provided by tissue damage or inflammation is required. In response to liver injury, Yap drives clonal expansion, suppresses hepatocyte differentiation, and promotes a progenitor phenotype. These results suggest that Yap activation is insufficient to promote growth in the absence of a second signal thus coordinating tissue homeostasis and repair. DOI: http://dx.doi.org/10.7554/eLife.02948.001 PMID:25667983

  19. Controlled levels of canonical Wnt signaling are required for neural crest migration.

    PubMed

    Maj, Ewa; Künneke, Lutz; Loresch, Elisabeth; Grund, Anita; Melchert, Juliane; Pieler, Tomas; Aspelmeier, Timo; Borchers, Annette

    2016-09-01

    Canonical Wnt signaling plays a dominant role in the development of the neural crest (NC), a highly migratory cell population that generates a vast array of cell types. Canonical Wnt signaling is required for NC induction as well as differentiation, however its role in NC migration remains largely unknown. Analyzing nuclear localization of β-catenin as readout for canonical Wnt activity, we detect nuclear β-catenin in premigratory but not migratory Xenopus NC cells suggesting that canonical Wnt activity has to decrease to basal levels to enable NC migration. To define a possible function of canonical Wnt signaling in Xenopus NC migration, canonical Wnt signaling was modulated at different time points after NC induction. This was accomplished using either chemical modulators affecting β-catenin stability or inducible glucocorticoid fusion constructs of Lef/Tcf transcription factors. In vivo analysis of NC migration by whole mount in situ hybridization demonstrates that ectopic activation of canonical Wnt signaling inhibits cranial NC migration. Further, NC transplantation experiments confirm that this effect is tissue-autonomous. In addition, live-cell imaging in combination with biophysical data analysis of explanted NC cells confirms the in vivo findings and demonstrates that modulation of canonical Wnt signaling affects the ability of NC cells to perform single cell migration. Thus, our data support the hypothesis that canonical Wnt signaling needs to be tightly controlled to enable migration of NC cells. PMID:27341758

  20. Controlled levels of canonical Wnt signaling are required for neural crest migration.

    PubMed

    Maj, Ewa; Künneke, Lutz; Loresch, Elisabeth; Grund, Anita; Melchert, Juliane; Pieler, Tomas; Aspelmeier, Timo; Borchers, Annette

    2016-09-01

    Canonical Wnt signaling plays a dominant role in the development of the neural crest (NC), a highly migratory cell population that generates a vast array of cell types. Canonical Wnt signaling is required for NC induction as well as differentiation, however its role in NC migration remains largely unknown. Analyzing nuclear localization of β-catenin as readout for canonical Wnt activity, we detect nuclear β-catenin in premigratory but not migratory Xenopus NC cells suggesting that canonical Wnt activity has to decrease to basal levels to enable NC migration. To define a possible function of canonical Wnt signaling in Xenopus NC migration, canonical Wnt signaling was modulated at different time points after NC induction. This was accomplished using either chemical modulators affecting β-catenin stability or inducible glucocorticoid fusion constructs of Lef/Tcf transcription factors. In vivo analysis of NC migration by whole mount in situ hybridization demonstrates that ectopic activation of canonical Wnt signaling inhibits cranial NC migration. Further, NC transplantation experiments confirm that this effect is tissue-autonomous. In addition, live-cell imaging in combination with biophysical data analysis of explanted NC cells confirms the in vivo findings and demonstrates that modulation of canonical Wnt signaling affects the ability of NC cells to perform single cell migration. Thus, our data support the hypothesis that canonical Wnt signaling needs to be tightly controlled to enable migration of NC cells.

  1. 47 CFR 11.51 - EAS code and Attention Signal Transmission requirements.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... manually. (1) Automatic interrupt of programming and transmission of EAS messages are required when facilities are unattended. Automatic transmissions must include a permanent record that contains at a minimum... 47 Telecommunication 1 2011-10-01 2011-10-01 false EAS code and Attention Signal...

  2. Notch-signalling is required for head regeneration and tentacle patterning in Hydra.

    PubMed

    Münder, Sandra; Tischer, Susanne; Grundhuber, Maresa; Büchels, Nathalie; Bruckmeier, Nadine; Eckert, Stefanie; Seefeldt, Carolin A; Prexl, Andrea; Käsbauer, Tina; Böttger, Angelika

    2013-11-01

    Local self-activation and long ranging inhibition provide a mechanism for setting up organising regions as signalling centres for the development of structures in the surrounding tissue. The adult hydra hypostome functions as head organiser. After hydra head removal it is newly formed and complete heads can be regenerated. The molecular components of this organising region involve Wnt-signalling and β-catenin. However, it is not known how correct patterning of hypostome and tentacles are achieved in the hydra head and whether other signals in addition to HyWnt3 are needed for re-establishing the new organiser after head removal. Here we show that Notch-signalling is required for re-establishing the organiser during regeneration and that this is due to its role in restricting tentacle activation. Blocking Notch-signalling leads to the formation of irregular head structures characterised by excess tentacle tissue and aberrant expression of genes that mark the tentacle boundaries. This indicates a role for Notch-signalling in defining the tentacle pattern in the hydra head. Moreover, lateral inhibition by HvNotch and its target HyHes are required for head regeneration and without this the formation of the β-catenin/Wnt dependent head organiser is impaired. Work on prebilaterian model organisms has shown that the Wnt-pathway is important for setting up signalling centres for axial patterning in early multicellular animals. Our data suggest that the integration of Wnt-signalling with Notch-Delta activity was also involved in the evolution of defined body plans in animals.

  3. Auditory target detection in reverberation

    NASA Astrophysics Data System (ADS)

    Zurek, Patrick M.; Freyman, Richard L.; Balakrishnan, Uma

    2004-04-01

    Measurements and theoretical predictions of auditory target detection in simulated reverberant conditions are reported. The target signals were pulsed 13-octave bands of noise and the masker signal was a continuous wideband noise. Target and masker signals were passed through a software simulation of a reverberant room with a rigid sphere modeling a listener's head. The location of the target was fixed while the location of the masker was varied in the simulated room. Degree of reverberation was controlled by varying the uniform acoustic absorption of the simulated room's surfaces. The resulting target and masker signals were presented to the listeners over headphones in monaural-left, monaural-right, or binaural listening modes. Changes in detection performance in the monaural listening modes were largely predictable from the changes in target-to-masker ratio in the target band, but with a few dB of extra masking in reverberation. Binaural detection performance was generally well predicted by applying Durlach's [in Foundations of Modern Auditory Theory (Academic, New York, 1972)] equalization-cancellation theory to the direct-plus-reverberant ear signals. Predictions in all cases were based on a statistical description of room acoustics and on acoustic diffraction by a sphere. The success of these detection models in the present well-controlled reverberant conditions suggests that they can be used to incorporate listening mode and source location as factors in speech-intelligibility predictions.

  4. ABC Transporter Required for Intercellular Transfer of Developmental Signals in a Heterocystous Cyanobacterium

    PubMed Central

    Videau, Patrick; Rivers, Orion S.; Higa, Kelly C.

    2015-01-01

    ABSTRACT In the filamentous cyanobacterium Anabaena, patS and hetN encode peptide-derived signals with many of the properties of morphogens. These signals regulate the formation of a periodic pattern of heterocysts by lateral inhibition of differentiation. Here we show that intercellular transfer of the patS- and hetN-dependent developmental signals from heterocysts to vegetative cells requires HetC, a predicted ATP-binding cassette transporter (ABC transporter). Relative to the wild type, in a hetC mutant differentiation resulted in a reduced number of heterocysts that were incapable of nitrogen fixation, but deletion of patS or hetN restored heterocyst number and function in a hetC background. These epistasis results suggest that HetC is necessary for conferring self-immunity to the inhibitors on differentiating cells. Nine hours after induction of differentiation, HetC was required for neither induction of transcription of patS nor intercellular transfer of the patS-encoded signal to neighboring cells. Conversely, in strains lacking HetC, the patS- and hetN-encoded signals were not transferred from heterocyst cells to adjacent vegetative cells. The results support a model in which the patS-dependent signal is initially transferred between vegetative cells in a HetC-independent fashion, but some time before morphological differentiation of heterocysts is complete, transfer of both signals transitions to a HetC-dependent process. IMPORTANCE How chemical cues that regulate pattern formation in multicellular organisms move from one cell to another is a central question in developmental biology. In this study, we show that an ABC transporter, HetC, is necessary for transport of two developmental signals between different types of cells in a filamentous cyanobacterium. ABC transporters are found in organisms as diverse as bacteria and humans and, as the name implies, are often involved in the transport of molecules across a cellular membrane. The activity of HetC was

  5. Different Requirement for Wnt/β-Catenin Signaling in Limb Regeneration of Larval and Adult Xenopus

    PubMed Central

    Yokoyama, Hitoshi; Maruoka, Tamae; Ochi, Haruki; Aruga, Akio; Ohgo, Shiro; Ogino, Hajime; Tamura, Koji

    2011-01-01

    Background In limb regeneration of amphibians, the early steps leading to blastema formation are critical for the success of regeneration, and the initiation of regeneration in an adult limb requires the presence of nerves. Xenopus laevis tadpoles can completely regenerate an amputated limb at the early limb bud stage, and the metamorphosed young adult also regenerates a limb by a nerve-dependent process that results in a spike-like structure. Blockage of Wnt/β-catenin signaling inhibits the initiation of tadpole limb regeneration, but it remains unclear whether limb regeneration in young adults also requires Wnt/β-catenin signaling. Methodology/Principal Findings We expressed heat-shock-inducible (hs) Dkk1, a Wnt antagonist, in transgenic Xenopus to block Wnt/β-catenin signaling during forelimb regeneration in young adults. hsDkk1 did not inhibit limb regeneration in any of the young adult frogs, though it suppressed Wnt-dependent expression of genes (fgf-8 and cyclin D1). When nerve supply to the limbs was partially removed, however, hsDkk1 expression blocked limb regeneration in young adult frogs. Conversely, activation of Wnt/β-catenin signaling by a GSK-3 inhibitor rescued failure of limb-spike regeneration in young adult frogs after total removal of nerve supply. Conclusions/Significance In contrast to its essential role in tadpole limb regeneration, our results suggest that Wnt/β-catenin signaling is not absolutely essential for limb regeneration in young adults. The different requirement for Wnt/β-catenin signaling in tadpoles and young adults appears to be due to the projection of nerve axons into the limb field. Our observations suggest that nerve-derived signals and Wnt/β-catenin signaling have redundant roles in the initiation of limb regeneration. Our results demonstrate for the first time the different mechanisms of limb regeneration initiation in limb buds (tadpoles) and developed limbs (young adults) with reference to nerve-derived signals

  6. Feature Assignment in Perception of Auditory Figure

    PubMed Central

    Gregg, Melissa K.; Samuel, Arthur G.

    2012-01-01

    Because the environment often includes multiple sounds that overlap in time, listeners must segregate a sound of interest (the auditory figure) from other co-occurring sounds (the unattended auditory ground). We conducted a series of experiments to clarify the principles governing the extraction of auditory figures. We distinguish between auditory “objects” (relatively punctate events, such as a dog's bark) and auditory “streams” (sounds involving a pattern over time, such as a galloping rhythm). In Experiments 1 and 2, on each trial two sounds -- an object (a vowel) and a stream (a series of tones) – were presented with one target feature that could be perceptually grouped with either source. In each block of these experiments, listeners were required to attend to one of the two sounds, and report its perceived category. Across several experimental manipulations, listeners were more likely to allocate the feature to an impoverished object if the result of the grouping was a good, identifiable object. Perception of objects was quite sensitive to feature variation (noise masking), whereas perception of streams was more robust to feature variation. In Experiment 3, the number of sound sources competing for the feature was increased to three. This produced a shift toward relying more on spatial cues than on the potential contribution of the feature to an object's perceptual quality. The results support a distinction between auditory objects and streams, and provide new information about the way that the auditory world is parsed. PMID:22288691

  7. Auditory Dysfunction and Its Communicative Impact in the Classroom.

    ERIC Educational Resources Information Center

    Friedrich, Brad W.

    1982-01-01

    The origins and nature of auditory dysfunction in school age children and the role of the audiologist in the evaluation of the learning disabled child are reviewed. Specific structures and mechanisms responsible for the reception and perception of auditory signals are specified. (Author/SEW)

  8. Auditory Temporal Processing Deficits in Children with Reading Disabilities

    ERIC Educational Resources Information Center

    Cohen-Mimran, Ravit; Sapir, Shimon

    2007-01-01

    The role of central auditory processing in reading skill development and reading disorders is unclear. The purpose of this study was to examine whether individuals with specific reading disabilities (SRD) have deficits in processing rapidly presented, serially ordered non-speech auditory signals. To this end, we compared 12 children with SRD and…

  9. Restoration of auditory nerve synapses in cats by cochlear implants.

    PubMed

    Ryugo, D K; Kretzmer, E A; Niparko, J K

    2005-12-01

    Congenital deafness results in abnormal synaptic structure in endings of the auditory nerve. If these abnormalities persist after restoration of auditory nerve activity by a cochlear implant, the processing of time-varying signals such as speech would likely be impaired. We stimulated congenitally deaf cats for 3 months with a six-channel cochlear implant. The device used human speech-processing programs, and cats responded to environmental sounds. Auditory nerve fibers exhibited a recovery of normal synaptic structure in these cats. This rescue of synapses is attributed to a return of spike activity in the auditory nerve and may help explain cochlear implant benefits in childhood deafness. PMID:16322457

  10. Layer specific and general requirements for ERK/MAPK signaling in the developing neocortex

    PubMed Central

    Xing, Lei; Larsen, Rylan S; Bjorklund, George Reed; Li, Xiaoyan; Wu, Yaohong; Philpot, Benjamin D; Snider, William D; Newbern, Jason M

    2016-01-01

    Aberrant signaling through the Raf/MEK/ERK (ERK/MAPK) pathway causes pathology in a family of neurodevelopmental disorders known as 'RASopathies' and is implicated in autism pathogenesis. Here, we have determined the functions of ERK/MAPK signaling in developing neocortical excitatory neurons. Our data reveal a critical requirement for ERK/MAPK signaling in the morphological development and survival of large Ctip2+ neurons in layer 5. Loss of Map2k1/2 (Mek1/2) led to deficits in corticospinal tract formation and subsequent corticospinal neuron apoptosis. ERK/MAPK hyperactivation also led to reduced corticospinal axon elongation, but was associated with enhanced arborization. ERK/MAPK signaling was dispensable for axonal outgrowth of layer 2/3 callosal neurons. However, Map2k1/2 deletion led to reduced expression of Arc and enhanced intrinsic excitability in both layers 2/3 and 5, in addition to imbalanced synaptic excitation and inhibition. These data demonstrate selective requirements for ERK/MAPK signaling in layer 5 circuit development and general effects on cortical pyramidal neuron excitability. DOI: http://dx.doi.org/10.7554/eLife.11123.001 PMID:26848828

  11. Effects of an Auditory Lateralization Training in Children Suspected to Central Auditory Processing Disorder

    PubMed Central

    Lotfi, Yones; Moosavi, Abdollah; Bakhshi, Enayatollah; Sadjedi, Hamed

    2016-01-01

    Background and Objectives Central auditory processing disorder [(C)APD] refers to a deficit in auditory stimuli processing in nervous system that is not due to higher-order language or cognitive factors. One of the problems in children with (C)APD is spatial difficulties which have been overlooked despite their significance. Localization is an auditory ability to detect sound sources in space and can help to differentiate between the desired speech from other simultaneous sound sources. Aim of this research was investigating effects of an auditory lateralization training on speech perception in presence of noise/competing signals in children suspected to (C)APD. Subjects and Methods In this analytical interventional study, 60 children suspected to (C)APD were selected based on multiple auditory processing assessment subtests. They were randomly divided into two groups: control (mean age 9.07) and training groups (mean age 9.00). Training program consisted of detection and pointing to sound sources delivered with interaural time differences under headphones for 12 formal sessions (6 weeks). Spatial word recognition score (WRS) and monaural selective auditory attention test (mSAAT) were used to follow the auditory lateralization training effects. Results This study showed that in the training group, mSAAT score and spatial WRS in noise (p value≤0.001) improved significantly after the auditory lateralization training. Conclusions We used auditory lateralization training for 6 weeks and showed that auditory lateralization can improve speech understanding in noise significantly. The generalization of this results needs further researches. PMID:27626084

  12. Effects of an Auditory Lateralization Training in Children Suspected to Central Auditory Processing Disorder

    PubMed Central

    Lotfi, Yones; Moosavi, Abdollah; Bakhshi, Enayatollah; Sadjedi, Hamed

    2016-01-01

    Background and Objectives Central auditory processing disorder [(C)APD] refers to a deficit in auditory stimuli processing in nervous system that is not due to higher-order language or cognitive factors. One of the problems in children with (C)APD is spatial difficulties which have been overlooked despite their significance. Localization is an auditory ability to detect sound sources in space and can help to differentiate between the desired speech from other simultaneous sound sources. Aim of this research was investigating effects of an auditory lateralization training on speech perception in presence of noise/competing signals in children suspected to (C)APD. Subjects and Methods In this analytical interventional study, 60 children suspected to (C)APD were selected based on multiple auditory processing assessment subtests. They were randomly divided into two groups: control (mean age 9.07) and training groups (mean age 9.00). Training program consisted of detection and pointing to sound sources delivered with interaural time differences under headphones for 12 formal sessions (6 weeks). Spatial word recognition score (WRS) and monaural selective auditory attention test (mSAAT) were used to follow the auditory lateralization training effects. Results This study showed that in the training group, mSAAT score and spatial WRS in noise (p value≤0.001) improved significantly after the auditory lateralization training. Conclusions We used auditory lateralization training for 6 weeks and showed that auditory lateralization can improve speech understanding in noise significantly. The generalization of this results needs further researches.

  13. FGF signaling is required for anterior but not posterior specification of the murine liver bud

    PubMed Central

    Wang, Jikui; Rhee, Siyeon; Palaria, Amrita; Tremblay, Kimberly D.

    2014-01-01

    Background The definitive endoderm arises as a naive epithelial sheet that produces the entire gut tube and associated organs including the liver, pancreas and lungs. Murine explant studies demonstrate that Fibroblast Growth Factor (FGF) signaling from adjacent tissues is required to induce hepatic gene expression from isolated foregut endoderm. The requirement of FGF signaling during liver development is examined via small molecule inhibition during whole embryo culture. Results Loss of FGF signaling prior to hepatic induction results in morphological defects and gene expression changes that are confined to the anterior liver bud. In contrast the posterior portion of the liver bud remains relatively unaffected. Because FGF is thought to act as a morphogen during endoderm organogenesis, the ventral pancreas was also examined after FGF inhibition. Although the size of the ventral pancreas is not affected, loss of FGF signaling results in a significantly higher density of ventral pancreas cells. Conclusions The requirement for FGF-mediated induction of hepatic gene expression differs across the anterior-posterior axis of the developing liver bud. These results underscore the importance of studying tissue differentiation in the context of the whole embryo. PMID:25302779

  14. Genetic requirements for signaling from an autoactive plant NB-LRR intracellular innate immune receptor.

    PubMed

    Roberts, Melinda; Tang, Saijun; Stallmann, Anna; Dangl, Jeffery L; Bonardi, Vera

    2013-01-01

    Plants react to pathogen attack via recognition of, and response to, pathogen-specific molecules at the cell surface and inside the cell. Pathogen effectors (virulence factors) are monitored by intracellular nucleotide-binding leucine-rich repeat (NB-LRR) sensor proteins in plants and mammals. Here, we study the genetic requirements for defense responses of an autoactive mutant of ADR1-L2, an Arabidopsis coiled-coil (CC)-NB-LRR protein. ADR1-L2 functions upstream of salicylic acid (SA) accumulation in several defense contexts, and it can act in this context as a "helper" to transduce specific microbial activation signals from "sensor" NB-LRRs. This helper activity does not require an intact P-loop. ADR1-L2 and another of two closely related members of this small NB-LRR family are also required for propagation of unregulated runaway cell death (rcd) in an lsd1 mutant. We demonstrate here that, in this particular context, ADR1-L2 function is P-loop dependent. We generated an autoactive missense mutation, ADR1-L2D484V, in a small homology motif termed MHD. Expression of ADR1-L2D848V leads to dwarfed plants that exhibit increased disease resistance and constitutively high SA levels. The morphological phenotype also requires an intact P-loop, suggesting that these ADR1-L2D484V phenotypes reflect canonical activation of this NB-LRR protein. We used ADR1-L2D484V to define genetic requirements for signaling. Signaling from ADR1-L2D484V does not require NADPH oxidase and is negatively regulated by EDS1 and AtMC1. Transcriptional regulation of ADR1-L2D484V is correlated with its phenotypic outputs; these outputs are both SA-dependent and -independent. The genetic requirements for ADR1-L2D484V activity resemble those that regulate an SA-gradient-dependent signal amplification of defense and cell death signaling initially observed in the absence of LSD1. Importantly, ADR1-L2D484V autoactivation signaling is controlled by both EDS1 and SA in separable, but linked pathways

  15. Ephrin-B2 Reverse Signaling Is Required for Topography but Not Pattern Formation of Lateral Superior Olivary Inputs to the Inferior Colliculus

    PubMed Central

    Wallace, Matthew M.; Kavianpour, Sarah M.; Gabriele, Mark L.

    2014-01-01

    Graded and modular expressions of Eph-ephrins are known to provide positional information for the formation of topographic maps and patterning in the developing nervous system. Previously we have shown that ephrin-B2 is expressed in a continuous gradient across the tonotopic axis of the central nucleus of the inferior colliculus (CNIC), whereas patterns are discontinuous and modular in the lateral cortex of the IC (LCIC). The present study explores the involvement of ephrin-B2 signaling in the development of projections to the CNIC and LCIC arising from the lateral superior olivary nuclei (LSO) prior to hearing onset. Anterograde and retrograde fluorescent tracing methods in neonatal fixed tissue preparations were used to compare topographic mapping and the establishment of LSO layers/modules in wild-type and ephrin-B2lacZ/+ mice (severely compromised reverse signaling). At birth, pioneer LSO axons occupy the ipsilateral IC in both groups but are delayed contralaterally in ephrin-B2lacZ/+ mutants. By the onset of hearing, both wild-type and mutant projections form discernible layers bilaterally in the CNIC and modular arrangements within the ipsilateral LCIC. In contrast, ephrin-B2lacZ/+ mice lack a reliable topography in LSO-IC projections, suggesting that fully functional ephrin-B2 reverse signaling is required for normal projection mapping. Taken together, these ephrin-B2 findings paired with known coexpression of EphA4 suggest the importance of these signaling proteins in establishing functional auditory circuits prior to experience. PMID:23042409

  16. Submandibular parasympathetic gangliogenesis requires Sprouty-dependent Wnt signals from epithelial progenitors

    PubMed Central

    Knosp, Wendy M.; Knox, Sarah M.; Lombaert, Isabelle M.A.; Haddox, Candace L.; Patel, Vaishali N.; Hoffman, Matthew P.

    2015-01-01

    Parasympathetic innervation is critical for submandibular gland (SMG) development and regeneration. Parasympathetic ganglia (PSG) are derived from Schwann cell precursors that migrate along nerves, differentiate into neurons, and coalesce within their target tissue to form ganglia. However, signals that initiate gangliogenesis after the precursors differentiate into neurons are unknown. We found deleting negative regulators of FGF signaling, Sprouty1 and Sprouty2 (Spry1/2DKO), resulted in a striking loss of gangliogenesis, innervation and keratin 5-positive (K5+) epithelial progenitors in the SMG. Here we identify Wnts produced by K5+ progenitors in the SMG as key mediators of gangliogenesis. Wnt signaling increases survival and proliferation of PSG neurons and inhibiting Wnt signaling disrupts gangliogenesis and organ innervation. Activating Wnt signaling and reducing FGF gene dosage rescues gangliogenesis and innervation in both the Spry1/2DKO SMG and pancreas. Thus K5+ progenitors produce Wnt signals to establish the PSG-epithelial communication required for organ innervation and progenitor cell maintenance. PMID:25805134

  17. Zebrafish con/disp1 reveals multiple spatiotemporal requirements for Hedgehog-signaling in craniofacial development

    PubMed Central

    2009-01-01

    Background The vertebrate head skeleton is derived largely from cranial neural crest cells (CNCC). Genetic studies in zebrafish and mice have established that the Hedgehog (Hh)-signaling pathway plays a critical role in craniofacial development, partly due to the pathway's role in CNCC development. Disruption of the Hh-signaling pathway in humans can lead to the spectral disorder of Holoprosencephaly (HPE), which is often characterized by a variety of craniofacial defects including midline facial clefting and cyclopia [1,2]. Previous work has uncovered a role for Hh-signaling in zebrafish dorsal neurocranium patterning and chondrogenesis, however Hh-signaling mutants have not been described with respect to the ventral pharyngeal arch (PA) skeleton. Lipid-modified Hh-ligands require the transmembrane-spanning receptor Dispatched 1 (Disp1) for proper secretion from Hh-synthesizing cells to the extracellular field where they act on target cells. Here we study chameleon mutants, lacking a functional disp1(con/disp1). Results con/disp1 mutants display reduced and dysmorphic mandibular and hyoid arch cartilages and lack all ceratobranchial cartilage elements. CNCC specification and migration into the PA primorida occurs normally in con/disp1 mutants, however disp1 is necessary for post-migratory CNCC patterning and differentiation. We show that disp1 is required for post-migratory CNCC to become properly patterned within the first arch, while the gene is dispensable for CNCC condensation and patterning in more posterior arches. Upon residing in well-formed pharyngeal epithelium, neural crest condensations in the posterior PA fail to maintain expression of two transcription factors essential for chondrogenesis, sox9a and dlx2a, yet continue to robustly express other neural crest markers. Histology reveals that posterior arch residing-CNCC differentiate into fibrous-connective tissue, rather than becoming chondrocytes. Treatments with Cyclopamine, to inhibit Hh-signaling

  18. Effects of multitasking on operator performance using computational and auditory tasks.

    PubMed

    Fasanya, Bankole K

    2016-09-01

    This study investigated the effects of multiple cognitive tasks on human performance. Twenty-four students at North Carolina A&T State University participated in the study. The primary task was auditory signal change perception and the secondary task was a computational task. Results showed that participants' performance in a single task was statistically significantly different from their performance in combined tasks: (a) algebra problems (algebra problem primary and auditory perception secondary); (b) auditory perception tasks (auditory perception primary and algebra problems secondary); and (c) mean false-alarm score in auditory perception (auditory detection primary and algebra problems secondary). Using signal detection theory (SDT), participants' performance measured in terms of sensitivity was calculated as -0.54 for combined tasks (algebra problems the primary task) and -0.53 auditory perceptions the primary task. During auditory perception tasks alone, SDT was found to be 2.51. Performance was 83% in a single task compared to 17% when combined tasks.

  19. Nodal signaling is required for closure of the anterior neural tube in zebrafish

    PubMed Central

    Aquilina-Beck, Allisan; Ilagan, Kristine; Liu, Qin; Liang, Jennifer O

    2007-01-01

    Background Nodals are secreted signaling proteins with many roles in vertebrate development. Here, we identify a new role for Nodal signaling in regulating closure of the rostral neural tube of zebrafish. Results We find that the neural tube in the presumptive forebrain fails to close in zebrafish Nodal signaling mutants. For instance, the cells that will give rise to the pineal organ fail to move from the lateral edges of the neural plate to the midline of the diencephalon. The open neural tube in Nodal signaling mutants may be due in part to reduced function of N-cadherin, a cell adhesion molecule expressed in the neural tube and required for neural tube closure. N-cadherin expression and localization to the membrane are reduced in fish that lack Nodal signaling. Further, N-cadherin mutants and morphants have a pineal phenotype similar to that of mutants with deficiencies in the Nodal pathway. Overexpression of an activated form of the TGFβ Type I receptor Taram-A (Taram-A*) cell autonomously rescues mesendoderm formation in fish with a severe decrease in Nodal signaling. We find that overexpression of Taram-A* also corrects their open neural tube defect. This suggests that, as in mammals, the mesoderm and endoderm have an important role in regulating closure of the anterior neural tube of zebrafish. Conclusion This work helps establish a role for Nodal signals in neurulation, and suggests that defects in Nodal signaling could underlie human neural tube defects such as exencephaly, a fatal condition characterized by an open neural tube in the anterior brain. PMID:17996054

  20. Vitamin D signaling in the bovine immune system: a model for understanding human vitamin D requirements.

    PubMed

    Nelson, Corwin D; Reinhardt, Timothy A; Lippolis, John D; Sacco, Randy E; Nonnecke, Brian J

    2012-03-01

    The endocrine physiology of vitamin D in cattle has been rigorously investigated and has yielded information on vitamin D requirements, endocrine function in health and disease, general metabolism, and maintenance of calcium homeostasis in cattle. These results are relevant to human vitamin D endocrinology. The current debate regarding vitamin D requirements is centered on the requirements for proper intracrine and paracrine vitamin D signaling. Studies in adult and young cattle can provide valuable insight for understanding vitamin D requirements as they relate to innate and adaptive immune responses during infectious disease. In cattle, toll-like receptor recognition activates intracrine and paracrine vitamin D signaling mechanism in the immune system that regulates innate and adaptive immune responses in the presence of adequate 25-hydroxyvitamin D. Furthermore, experiments with mastitis in dairy cattle have provided in vivo evidence for the intracrine vitamin D signaling mechanism in macrophages as well as vitamin D mediated suppression of infection. Epidemiological evidence indicates that circulating concentrations above 32 ng/mL of 25-hydroxyvitamin D are necessary for optimal vitamin D signaling in the immune system, but experimental evidence is lacking for that value. Experiments in cattle can provide that evidence as circulating 25-hydroxyvitamin D concentrations can be experimentally manipulated within ranges that are normal for humans and cattle. Additionally, young and adult cattle can be experimentally infected with bacteria and viruses associated with significant diseases in both cattle and humans. Utilizing the bovine model to further delineate the immunomodulatory role of vitamin D will provide potentially valuable insights into the vitamin D requirements of both humans and cattle, especially as they relate to immune response capacity and infectious disease resistance.

  1. Electromagnetic recording of the auditory system.

    PubMed

    Poeppel, David; Hickok, Gregory

    2015-01-01

    Auditory processing is remarkably fast and sensitive to the precise temporal structure of acoustic signals over a range of scales, from submillisecond phenomena such as localization to the construction of elementary auditory attributes at tens of milliseconds to basic properties of speech and music at hundreds of milliseconds. In light of the rapid (and often transitory) nature of auditory phenomena, in order to investigate the neurocomputational basis of auditory perception and cognition, a technique with high temporal resolution is appropriate. Here we briefly outline the utility of magnetoencephalography (MEG) for the study of the neural basis of audition. The basics of MEG are outlined in brief, and some of the most-used neural responses are described. We discuss the classic transient evoked fields (e.g., M100), responses elicited by change in a stimulus (e.g., pitch-onset response), the auditory steady-state response, and neural oscillations (e.g., theta-phase tracking). Because of the high temporal resolution and the good spatial resolution of MEG, paired with the convenient location of human auditory cortex for MEG-based recording, electromagnetic recording of this type is well suited to investigate various aspects from audition, from crafted laboratory experiments on pitch perception or scene analysis to naturalistic speech and music tasks.

  2. A circuit for motor cortical modulation of auditory cortical activity.

    PubMed

    Nelson, Anders; Schneider, David M; Takatoh, Jun; Sakurai, Katsuyasu; Wang, Fan; Mooney, Richard

    2013-09-01

    Normal hearing depends on the ability to distinguish self-generated sounds from other sounds, and this ability is thought to involve neural circuits that convey copies of motor command signals to various levels of the auditory system. Although such interactions at the cortical level are believed to facilitate auditory comprehension during movements and drive auditory hallucinations in pathological states, the synaptic organization and function of circuitry linking the motor and auditory cortices remain unclear. Here we describe experiments in the mouse that characterize circuitry well suited to transmit motor-related signals to the auditory cortex. Using retrograde viral tracing, we established that neurons in superficial and deep layers of the medial agranular motor cortex (M2) project directly to the auditory cortex and that the axons of some of these deep-layer cells also target brainstem motor regions. Using in vitro whole-cell physiology, optogenetics, and pharmacology, we determined that M2 axons make excitatory synapses in the auditory cortex but exert a primarily suppressive effect on auditory cortical neuron activity mediated in part by feedforward inhibition involving parvalbumin-positive interneurons. Using in vivo intracellular physiology, optogenetics, and sound playback, we also found that directly activating M2 axon terminals in the auditory cortex suppresses spontaneous and stimulus-evoked synaptic activity in auditory cortical neurons and that this effect depends on the relative timing of motor cortical activity and auditory stimulation. These experiments delineate the structural and functional properties of a corticocortical circuit that could enable movement-related suppression of auditory cortical activity. PMID:24005287

  3. Electrophysiological measurement of human auditory function

    NASA Technical Reports Server (NTRS)

    Galambos, R.

    1975-01-01

    Knowledge of the human auditory evoked response is reviewed, including methods of determining this response, the way particular changes in the stimulus are coupled to specific changes in the response, and how the state of mind of the listener will influence the response. Important practical applications of this basic knowledge are discussed. Measurement of the brainstem evoked response, for instance, can state unequivocally how well the peripheral auditory apparatus functions. It might then be developed into a useful hearing test, especially for infants and preverbal or nonverbal children. Clinical applications of measuring the brain waves evoked 100 msec and later after the auditory stimulus are undetermined. These waves are clearly related to brain events associated with cognitive processing of acoustic signals, since their properties depend upon where the listener directs his attention and whether how long he expects the signal.

  4. Phospholipid flippase ATP8A2 is required for normal visual and auditory function and photoreceptor and spiral ganglion cell survival

    PubMed Central

    Coleman, Jonathan A.; Zhu, Xianjun; Djajadi, Hidayat R.; Molday, Laurie L.; Smith, Richard S.; Libby, Richard T.; John, Simon W. M.; Molday, Robert S.

    2014-01-01

    ABSTRACT ATP8A2 is a P4-ATPase that is highly expressed in the retina, brain, spinal cord and testes. In the retina, ATP8A2 is localized in photoreceptors where it uses ATP to transport phosphatidylserine (PS) and phosphatidylethanolamine (PE) from the exoplasmic to the cytoplasmic leaflet of membranes. Although mutations in ATP8A2 have been reported to cause mental retardation in humans and degeneration of spinal motor neurons in mice, the role of ATP8A2 in sensory systems has not been investigated. We have analyzed the retina and cochlea of ATP8A2-deficient mice to determine the role of ATP8A2 in visual and auditory systems. ATP8A2-deficient mice have shortened photoreceptor outer segments, a reduction in photoresponses and decreased photoreceptor viability. The ultrastructure and phagocytosis of the photoreceptor outer segment appeared normal, but the PS and PE compositions were altered and the rhodopsin content was decreased. The auditory brainstem response threshold was significantly higher and degeneration of spiral ganglion cells was apparent. Our studies indicate that ATP8A2 plays a crucial role in photoreceptor and spiral ganglion cell function and survival by maintaining phospholipid composition and contributing to vesicle trafficking. PMID:24413176

  5. Antidepressant effects of sleep deprivation require astrocyte-dependent adenosine mediated signaling.

    PubMed

    Hines, D J; Schmitt, L I; Hines, R M; Moss, S J; Haydon, P G

    2013-01-01

    Major depressive disorder is a debilitating condition with a lifetime risk of ten percent. Most treatments take several weeks to achieve clinical efficacy, limiting the ability to bring instant relief needed in psychiatric emergencies. One intervention that rapidly alleviates depressive symptoms is sleep deprivation; however, its mechanism of action is unknown. Astrocytes regulate responses to sleep deprivation, raising the possibility that glial signaling mediates antidepressive-like actions of sleep deprivation. Here, we found that astrocytic signaling to adenosine (A1) receptors was required for the robust reduction of depressive-like behaviors following 12 hours of sleep deprivation. As sleep deprivation activates synaptic A1 receptors, we mimicked the effect of sleep deprivation on depression phenotypes by administration of the A1 agonist CCPA. These results provide the first mechanistic insight into how sleep deprivation impacts mood, and provide a novel pathway for rapid antidepressant development by modulation of glial signaling in the brain. PMID:23321809

  6. Antidepressant effects of sleep deprivation require astrocyte-dependent adenosine mediated signaling

    PubMed Central

    Hines, D J; Schmitt, L I; Hines, R M; Moss, S J; Haydon, P G

    2013-01-01

    Major depressive disorder is a debilitating condition with a lifetime risk of ten percent. Most treatments take several weeks to achieve clinical efficacy, limiting the ability to bring instant relief needed in psychiatric emergencies. One intervention that rapidly alleviates depressive symptoms is sleep deprivation; however, its mechanism of action is unknown. Astrocytes regulate responses to sleep deprivation, raising the possibility that glial signaling mediates antidepressive-like actions of sleep deprivation. Here, we found that astrocytic signaling to adenosine (A1) receptors was required for the robust reduction of depressive-like behaviors following 12 hours of sleep deprivation. As sleep deprivation activates synaptic A1 receptors, we mimicked the effect of sleep deprivation on depression phenotypes by administration of the A1 agonist CCPA. These results provide the first mechanistic insight into how sleep deprivation impacts mood, and provide a novel pathway for rapid antidepressant development by modulation of glial signaling in the brain. PMID:23321809

  7. Cue-elicited reward-seeking requires extracellular signal-regulated kinase activation in the nucleus accumbens.

    PubMed

    Shiflett, Michael W; Martini, Ross P; Mauna, Jocelyn C; Foster, Rebecca L; Peet, Eloise; Thiels, Edda

    2008-02-01

    The motivation to seek out rewards can come under the control of stimuli associated with reward delivery. The ability of cues to motivate reward-seeking behavior depends on the nucleus accumbens (NAcc). The molecular mechanisms in the NAcc that underlie the ability of a cue to motivate reward-seeking are not well understood. We examined whether extracellular signal-regulated kinase (ERK), an important intracellular signaling pathway in learning and memory, has a role in these motivational processes. We first examined p42 ERK (ERK2) activation in the NAcc after rats were trained to associate an auditory stimulus with food delivery and found that, as a consequence of training, presentation of the auditory cue itself was sufficient to increase ERK2 activation in the NAcc. To examine whether inhibition of ERK in the NAcc prevents cue-induced reward-seeking, we infused an inhibitor of ERK, U0126, into the NAcc before assessing rats' instrumental responding in the presence versus absence of the conditioned cue. We found that, whereas vehicle-infused rats showed increased instrumental responding during cue presentation, rats infused with U0126 showed a profound impairment in cue-induced instrumental responding. In contrast, intra-NAcc U0126 infusion had no effect on rats' food-reinforced instrumental responding or their ability to execute conditioned approach behavior. Our results demonstrate learning-related changes in ERK signaling in the NAcc, and that disruption of ERK activation in this structure interferes with the incentive-motivational effects of conditioned stimuli. The molecular mechanisms described here may have implications for cue-elicited drug craving after repeated exposure to drugs of abuse.

  8. Dendritic cell maturation requires STAT1 and is under feedback regulation by suppressors of cytokine signaling.

    PubMed

    Jackson, Sharon H; Yu, Cheng-Rong; Mahdi, Rashid M; Ebong, Samuel; Egwuagu, Charles E

    2004-02-15

    In this study we show that activation of STAT pathways is developmentally regulated and plays a role in dendritic cell (DC) differentiation and maturation. The STAT6 signaling pathway is constitutively activated in immature DC (iDC) and declines as iDCs differentiate into mature DCs (mDCs). However, down-regulation of this pathway during DC differentiation is accompanied by dramatic induction of suppressors of cytokine signaling 1 (SOCS1), SOCS2, SOCS3, and cytokine-induced Src homology 2-containing protein expression, suggesting that inhibition of STAT6 signaling may be required for DC maturation. In contrast, STAT1 signaling is most robust in mDCs and is not inhibited by the up-regulated SOCS proteins, indicating that STAT1 and STAT6 pathways are distinctly regulated in maturing DC. Furthermore, optimal activation of STAT1 during DC maturation requires both IL-4 and GM-CSF, suggesting that synergistic effects of both cytokines may in part provide the requisite STAT1 signaling intensity for DC maturation. Analyses of STAT1(-/-) DCs reveal a role for STAT1 in repressing CD86 expression in precursor DCs and up-regulating CD40, CD11c, and SOCS1 expression in mDCs. We further show that SOCS proteins are differentially induced by IL-4 and GM-CSF in DCs. SOCS1 is primarily induced by IL-4 through a STAT1-dependent mechanism, whereas SOCS3 is induced mainly by GM-CSF. Taken together, these results suggest that cytokine-induced maturation of DCs is under feedback regulation by SOCS proteins and that the switch from constitutive activation of the STAT6 pathway in iDCs to predominant use of STAT1 signals in mDC is mediated in part by STAT1-induced SOCS expression.

  9. The Human Brain Maintains Contradictory and Redundant Auditory Sensory Predictions

    PubMed Central

    Pieszek, Marika; Widmann, Andreas; Gruber, Thomas; Schröger, Erich

    2013-01-01

    Computational and experimental research has revealed that auditory sensory predictions are derived from regularities of the current environment by using internal generative models. However, so far, what has not been addressed is how the auditory system handles situations giving rise to redundant or even contradictory predictions derived from different sources of information. To this end, we measured error signals in the event-related brain potentials (ERPs) in response to violations of auditory predictions. Sounds could be predicted on the basis of overall probability, i.e., one sound was presented frequently and another sound rarely. Furthermore, each sound was predicted by an informative visual cue. Participants’ task was to use the cue and to discriminate the two sounds as fast as possible. Violations of the probability based prediction (i.e., a rare sound) as well as violations of the visual-auditory prediction (i.e., an incongruent sound) elicited error signals in the ERPs (Mismatch Negativity [MMN] and Incongruency Response [IR]). Particular error signals were observed even in case the overall probability and the visual symbol predicted different sounds. That is, the auditory system concurrently maintains and tests contradictory predictions. Moreover, if the same sound was predicted, we observed an additive error signal (scalp potential and primary current density) equaling the sum of the specific error signals. Thus, the auditory system maintains and tolerates functionally independently represented redundant and contradictory predictions. We argue that the auditory system exploits all currently active regularities in order to optimally prepare for future events. PMID:23308266

  10. Melanocortin 4 receptor signaling in dopamine 1 receptor neurons is required for procedural memory learning

    PubMed Central

    Cui, Huxing; Mason, Brittany L.; Lee, Charlotte; Nishi, Akinori; Elmquist, Joel K; Lutter, Michael

    2012-01-01

    It is now widely recognized that exposure to palatable foods engages reward circuits that promote over-eating and facilitate the development of obesity. While the melanocortin 4 receptor (MC4R) has previously been shown to regulate food intake and energy expenditure, little is known about its role in food reward. We demonstrate that MC4R is co-expressed with the dopamine 1 receptor (D1R) in the ventral striatum. While MC4R-null mice are hyperphagic and obese, they exhibit impairments in acquisition of operant responding for a high fat reinforcement. Restoration of MC4R signaling in D1R neurons normalizes procedural learning without affecting motivation to obtain high fat diet. MC4R signaling in D1R neurons is also required for learning in a non-food-reinforced version of the cued water maze. Finally, MC4R signaling in neostriatal slices increases phosphorylation of the Thr34 residue of DARPP-32, a protein phosphatase-1 inhibitor that regulates synaptic plasticity. These data identify a novel requirement for MC4R signaling in procedural memory learning. PMID:22342812

  11. Dissociation of two signals required for activation of resting B cells.

    PubMed Central

    Julius, M H; von Boehmer, H; Sidman, C L

    1982-01-01

    Cellular interactions involved in the T cell-dependent activation of B cells were analyzed by using lines and clones of helper T cells specific for determinants expressed on the B cell surface. Activation of male antigen-, M locus-, and H-2-specific T cells was shown to support polyclonal Ig production by a population of B cells that did not require T-cell-B-cell interaction for induction/amplification. However, these T cells alone did not activate gradient-purified small (resting) B cells. The activation of small B cells was shown to require not only a signal derived through an antigen-specific T-helper cell-B cell interaction but in addition a second signal that could be provided by anti-Ig antibodies. PMID:6979046

  12. Kit signaling is required for development of coordinated motility patterns in zebrafish gastrointestinal tract.

    PubMed

    Rich, Adam; Gordon, Scott; Brown, Chris; Gibbons, Simon J; Schaefer, Katherine; Hennig, Grant; Farrugia, Gianrico

    2013-06-01

    Interstitial cells of Cajal (ICC) provide a pacemaker signal for coordinated motility patterns in the mammalian gastrointestinal (GI) tract. Kit signaling is required for development and maintenance of ICC, and these cells can be identified by Kit-like immunoreactivity. The zebrafish GI tract has two distinct ICC networks similar to mammals, suggesting a similar role in the generation of GI motility; however, a functional role for Kit-positive cells in zebrafish has not been determined. Analysis of GI motility in intact zebrafish larvae was performed during development and after disruption of Kit signaling. Development of coordinated motility patterns occurred after 5 days post-fertilization (dpf) and correlated with appearance of Kit-positive cells. Disruptions of Kit signaling using the Kit antagonist imatinib mesylate, and in Sparse, a null kita mutant, also disrupted development of coordinated motility patterns. These data suggest that Kit signaling is necessary for development of coordinated motility patterns and that Kit-positive cells in zebrafish are necessary for coordinated motility patterns.

  13. Association of CD8 with p56lck is required for early T cell signalling events.

    PubMed Central

    Chalupny, N J; Ledbetter, J A; Kavathas, P

    1991-01-01

    The human CD8 glycoprotein functions as a co-receptor during T cell activation by both binding to MHC class I and transducing a transmembrane signal. The ability of CD8 to transduce a signal is mediated in part by its association with the protein tyrosine kinase p56lck. Using a panel of human CD8 alpha mutants, we demonstrated that the presence of a functional p56lck binding site is required for the early signalling events transduced by CD8, including increased [Ca2+]i and protein tyrosine phosphorylation. In addition, our results demonstrate that wild-type and all mutant forms of CD8 alpha have an inhibitory effect on signal transduction after CD3-CD3 or CD3-CD4 crosslinking when transfected into the (CD3+, CD4+, CD8-) H9 T cell line, suggesting that intermolecular associations of CD8, independent of its association with p56lck, are responsible for this effect. Signalling through CD4 or CD8 in a double positive thymocyte may therefore be different than in a single positive thymocyte or mature T cell. Images PMID:1902413

  14. Enhanced peripheral visual processing in congenitally deaf humans is supported by multiple brain regions, including primary auditory cortex

    PubMed Central

    Scott, Gregory D.; Karns, Christina M.; Dow, Mark W.; Stevens, Courtney; Neville, Helen J.

    2014-01-01

    Brain reorganization associated with altered sensory experience clarifies the critical role of neuroplasticity in development. An example is enhanced peripheral visual processing associated with congenital deafness, but the neural systems supporting this have not been fully characterized. A gap in our understanding of deafness-enhanced peripheral vision is the contribution of primary auditory cortex. Previous studies of auditory cortex that use anatomical normalization across participants were limited by inter-subject variability of Heschl's gyrus. In addition to reorganized auditory cortex (cross-modal plasticity), a second gap in our understanding is the contribution of altered modality-specific cortices (visual intramodal plasticity in this case), as well as supramodal and multisensory cortices, especially when target detection is required across contrasts. Here we address these gaps by comparing fMRI signal change for peripheral vs. perifoveal visual stimulation (11–15° vs. 2–7°) in congenitally deaf and hearing participants in a blocked experimental design with two analytical approaches: a Heschl's gyrus region of interest analysis and a whole brain analysis. Our results using individually-defined primary auditory cortex (Heschl's gyrus) indicate that fMRI signal change for more peripheral stimuli was greater than perifoveal in deaf but not in hearing participants. Whole-brain analyses revealed differences between deaf and hearing participants for peripheral vs. perifoveal visual processing in extrastriate visual cortex including primary auditory cortex, MT+/V5, superior-temporal auditory, and multisensory and/or supramodal regions, such as posterior parietal cortex (PPC), frontal eye fields, anterior cingulate, and supplementary eye fields. Overall, these data demonstrate the contribution of neuroplasticity in multiple systems including primary auditory cortex, supramodal, and multisensory regions, to altered visual processing in congenitally deaf

  15. Adenosine and the Auditory System

    PubMed Central

    Vlajkovic, Srdjan M; Housley, Gary D; Thorne, Peter R

    2009-01-01

    Adenosine is a signalling molecule that modulates cellular activity in the central nervous system and peripheral organs via four G protein-coupled receptors designated A1, A2A, A2B, and A3. This review surveys the literature on the role of adenosine in auditory function, particularly cochlear function and its protection from oxidative stress. The specific tissue distribution of adenosine receptors in the mammalian cochlea implicates adenosine signalling in sensory transduction and auditory neurotransmission although functional studies have demonstrated that adenosine stimulates cochlear blood flow, but does not alter the resting and sound-evoked auditory potentials. An interest in a potential otoprotective role for adenosine has recently evolved, fuelled by the capacity of A1 adenosine receptors to prevent cochlear injury caused by acoustic trauma and ototoxic drugs. The balance between A1 and A2A receptors is conceived as critical for cochlear response to oxidative stress, which is an underlying mechanism of the most common inner ear pathologies (e.g. noise-induced and age-related hearing loss, drug ototoxicity). Enzymes involved in adenosine metabolism, adenosine kinase and adenosine deaminase, are also emerging as attractive targets for controlling oxidative stress in the cochlea. Other possible targets include ectonucleotidases that generate adenosine from extracellular ATP, and nucleoside transporters, which regulate adenosine concentrations on both sides of the plasma membrane. Developments of selective adenosine receptor agonists and antagonists that can cross the blood-cochlea barrier are bolstering efforts to develop therapeutic interventions aimed at ameliorating cochlear injury. Manipulations of the adenosine signalling system thus hold significant promise in the therapeutic management of oxidative stress in the cochlea. PMID:20190966

  16. Auditory-motor learning influences auditory memory for music.

    PubMed

    Brown, Rachel M; Palmer, Caroline

    2012-05-01

    In two experiments, we investigated how auditory-motor learning influences performers' memory for music. Skilled pianists learned novel melodies in four conditions: auditory only (listening), motor only (performing without sound), strongly coupled auditory-motor (normal performance), and weakly coupled auditory-motor (performing along with auditory recordings). Pianists' recognition of the learned melodies was better following auditory-only or auditory-motor (weakly coupled and strongly coupled) learning than following motor-only learning, and better following strongly coupled auditory-motor learning than following auditory-only learning. Auditory and motor imagery abilities modulated the learning effects: Pianists with high auditory imagery scores had better recognition following motor-only learning, suggesting that auditory imagery compensated for missing auditory feedback at the learning stage. Experiment 2 replicated the findings of Experiment 1 with melodies that contained greater variation in acoustic features. Melodies that were slower and less variable in tempo and intensity were remembered better following weakly coupled auditory-motor learning. These findings suggest that motor learning can aid performers' auditory recognition of music beyond auditory learning alone, and that motor learning is influenced by individual abilities in mental imagery and by variation in acoustic features. PMID:22271265

  17. Auditory-motor learning influences auditory memory for music.

    PubMed

    Brown, Rachel M; Palmer, Caroline

    2012-05-01

    In two experiments, we investigated how auditory-motor learning influences performers' memory for music. Skilled pianists learned novel melodies in four conditions: auditory only (listening), motor only (performing without sound), strongly coupled auditory-motor (normal performance), and weakly coupled auditory-motor (performing along with auditory recordings). Pianists' recognition of the learned melodies was better following auditory-only or auditory-motor (weakly coupled and strongly coupled) learning than following motor-only learning, and better following strongly coupled auditory-motor learning than following auditory-only learning. Auditory and motor imagery abilities modulated the learning effects: Pianists with high auditory imagery scores had better recognition following motor-only learning, suggesting that auditory imagery compensated for missing auditory feedback at the learning stage. Experiment 2 replicated the findings of Experiment 1 with melodies that contained greater variation in acoustic features. Melodies that were slower and less variable in tempo and intensity were remembered better following weakly coupled auditory-motor learning. These findings suggest that motor learning can aid performers' auditory recognition of music beyond auditory learning alone, and that motor learning is influenced by individual abilities in mental imagery and by variation in acoustic features.

  18. Requirement for non-regulated, constitutive calcium influx in macrophage survival signaling

    SciTech Connect

    Tano, Jean-Yves; Vazquez, Guillermo

    2011-04-08

    Highlights: {yields} We examine the role of constitutive Ca{sup 2+} influx in macrophage survival. {yields} Survival signaling exhibits a mandatory requirement for constitutive Ca{sup 2+} influx. {yields} CAM/CAMKII couples constitutive Ca{sup 2+} influx to survival signaling. -- Abstract: The phosphatidylinositol-3-kinase (PI3K)/AKT axis and the Nuclear Factor kappa B (NF{kappa}B) pathway play critical roles in macrophage survival. In cells other than macrophages proper operation of those two pathways requires Ca{sup 2+} influx into the cell, but if that is the case in macrophages remains unexplored. In the present work we used THP-1-derived macrophages and a pharmacological approach to examine for the first time the role of constitutive, non-regulated Ca{sup 2+} influx in PI3K/AKT and NF{kappa}B signaling. Blocking constitutive function of Ca{sup 2+}-permeable channels with the organic channel blocker SKF96365 completely prevented phosphorylation of I{kappa}B{alpha}, AKT and its downstream target BAD in TNF{alpha}-treated macrophages. A similar effect was observed upon treating macrophages with the calmodulin (CAM) inhibitor W-7 or the calmodulin-dependent kinase II (CAMKII) inhibitor KN-62. In addition, pre-treating macrophages with SKF96365 significantly enhanced TNF{alpha}-induced apoptosis. Our findings suggest that in THP-1-derived macrophages survival signaling depends, to a significant extent, on constitutive Ca{sup 2+} influx presumably through a mechanism that involves the CAM/CAMKII axis as a coupling component between constitutive Ca{sup 2+} influx and activation of survival signaling.

  19. Auditory-somatosensory integration and cortical plasticity in musical training.

    PubMed

    Pantev, Christo; Lappe, Claudia; Herholz, Sibylle C; Trainor, Laurel

    2009-07-01

    Learning to play a musical instrument requires complex multimodal skills involving simultaneous perception of several sensory modalities: auditory, visual, and somatosensory as well as the motor system. Musical training thus provides an adequate neuroscientific model to study multimodal integration and plasticity in musical training. The aim of this study was to investigate the impact of short-term uni- and multimodal musical training on auditory-somatosensory integration and plasticity. Two groups of nonmusicians were musically trained. The first group (sensorimotor-auditory group, SA) learned to play a musical sequence on the piano, whereas the second one (auditory group, A) actively listened to and made judgments about the correctness of the music. The training-induced cortical plasticity effect was assessed by recording musically elicited mismatch negativity (MMN) from magnetoencephalographic (MEG) measurements before and after training. The SA group showed significant enlargement of MMN after training compared to the A group, reflecting greater enhancement of musical representations in auditory cortex after sensorimotor-auditory training compared to mere auditory training. This study demonstrates that the sensorimotor and auditory systems integrate and that this multimodal training causes cortical reorganizational changes in the auditory cortex over and above the changes introduced by auditory training alone.

  20. Amygdala upregulation of NCAM polysialylation induced by auditory fear conditioning is not required for memory formation, but plays a role in fear extinction.

    PubMed

    Markram, Kamila; Lopez Fernandez, Miguel Angel; Abrous, Djoher Nora; Sandi, Carmen

    2007-05-01

    There is much interest to understand the mechanisms leading to the establishment, maintenance, and extinction of fear memories. The amygdala has been critically involved in the processing of fear memories and a number of molecular changes have been implicated in this brain region in relation to fear learning. Although neural cell adhesion molecules (NCAMs) have been hypothesized to play a role, information available about their contribution to fear memories is scarce. We investigate here whether polysialylated NCAM (PSA-NCAM) contributes to auditory fear conditioning in the amygdala. First, PSA-NCAM expression was evaluated in different amygdala nuclei after auditory fear conditioning at two different shock intensities. Results showed that PSA-NCAM expression was increased 24 h post-training only in animals subjected to the highest shock intensity (1mA). Second, PSA-NCAM was cleaved in the basolateral amygdaloid complex through micro-infusions of the enzyme endoneuraminidase N, and the consequences of such treatment were investigated on the acquisition, consolidation, remote memory expression, and extinction of conditioned fear memories. Intra-amygdaloid cleavage of PSA-NCAM did not affect acquisition, consolidation or expression of remote fear memories. However, intra-amygdaloid PSA-NCAM cleavage enhanced fear extinction processes. These results suggest that upregulation of PSA-NCAM is a correlate of fear conditioning that is not necessary for the establishment of fear memory in the amygdala, but participates in mechanisms precluding fear extinction. These findings point out PSA-NCAM as a potential target for the treatment of psychopathologies that involve impairment in fear extinction.

  1. Elevated CO2-Induced Responses in Stomata Require ABA and ABA Signaling.

    PubMed

    Chater, Caspar; Peng, Kai; Movahedi, Mahsa; Dunn, Jessica A; Walker, Heather J; Liang, Yun-Kuan; McLachlan, Deirdre H; Casson, Stuart; Isner, Jean Charles; Wilson, Ian; Neill, Steven J; Hedrich, Rainer; Gray, Julie E; Hetherington, Alistair M

    2015-10-19

    An integral part of global environment change is an increase in the atmospheric concentration of CO2 ([CO2]) [1]. Increased [CO2] reduces leaf stomatal apertures and density of stomata that plays out as reductions in evapotranspiration [2-4]. Surprisingly, given the importance of transpiration to the control of terrestrial water fluxes [5] and plant nutrient acquisition [6], we know comparatively little about the molecular components involved in the intracellular signaling pathways by which [CO2] controls stomatal development and function [7]. Here, we report that elevated [CO2]-induced closure and reductions in stomatal density require the generation of reactive oxygen species (ROS), thereby adding a new common element to these signaling pathways. We also show that the PYR/RCAR family of ABA receptors [8, 9] and ABA itself are required in both responses. Using genetic approaches, we show that ABA in guard cells or their precursors is sufficient to mediate the [CO2]-induced stomatal density response. Taken together, our results suggest that stomatal responses to increased [CO2] operate through the intermediacy of ABA. In the case of [CO2]-induced reductions in stomatal aperture, this occurs by accessing the guard cell ABA signaling pathway. In both [CO2]-mediated responses, our data are consistent with a mechanism in which ABA increases the sensitivity of the system to [CO2] but could also be explained by requirement for a CO2-induced increase in ABA biosynthesis specifically in the guard cell lineage. Furthermore, the dependency of stomatal [CO2] signaling on ABA suggests that the ABA pathway is, in evolutionary terms, likely to be ancestral.

  2. Elevated CO2-Induced Responses in Stomata Require ABA and ABA Signaling.

    PubMed

    Chater, Caspar; Peng, Kai; Movahedi, Mahsa; Dunn, Jessica A; Walker, Heather J; Liang, Yun-Kuan; McLachlan, Deirdre H; Casson, Stuart; Isner, Jean Charles; Wilson, Ian; Neill, Steven J; Hedrich, Rainer; Gray, Julie E; Hetherington, Alistair M

    2015-10-19

    An integral part of global environment change is an increase in the atmospheric concentration of CO2 ([CO2]) [1]. Increased [CO2] reduces leaf stomatal apertures and density of stomata that plays out as reductions in evapotranspiration [2-4]. Surprisingly, given the importance of transpiration to the control of terrestrial water fluxes [5] and plant nutrient acquisition [6], we know comparatively little about the molecular components involved in the intracellular signaling pathways by which [CO2] controls stomatal development and function [7]. Here, we report that elevated [CO2]-induced closure and reductions in stomatal density require the generation of reactive oxygen species (ROS), thereby adding a new common element to these signaling pathways. We also show that the PYR/RCAR family of ABA receptors [8, 9] and ABA itself are required in both responses. Using genetic approaches, we show that ABA in guard cells or their precursors is sufficient to mediate the [CO2]-induced stomatal density response. Taken together, our results suggest that stomatal responses to increased [CO2] operate through the intermediacy of ABA. In the case of [CO2]-induced reductions in stomatal aperture, this occurs by accessing the guard cell ABA signaling pathway. In both [CO2]-mediated responses, our data are consistent with a mechanism in which ABA increases the sensitivity of the system to [CO2] but could also be explained by requirement for a CO2-induced increase in ABA biosynthesis specifically in the guard cell lineage. Furthermore, the dependency of stomatal [CO2] signaling on ABA suggests that the ABA pathway is, in evolutionary terms, likely to be ancestral. PMID:26455301

  3. ER Alpha Rapid Signaling Is Required for Estrogen Induced Proliferation and Migration of Vascular Endothelial Cells

    PubMed Central

    Lu, Qing; Schnitzler, Gavin R.; Ueda, Kazutaka; Iyer, Lakshmanan K.; Diomede, Olga I.; Andrade, Tiffany; Karas, Richard H.

    2016-01-01

    Estrogen promotes the proliferation and migration of vascular endothelial cells (ECs), which likely underlies its ability to accelerate re-endothelialization and reduce adverse remodeling after vascular injury. In previous studies, we have shown that the protective effects of E2 (the active endogenous form of estrogen) in vascular injury require the estrogen receptor alpha (ERα). ERα transduces the effects of estrogen via a classical DNA binding, “genomic” signaling pathway and via a more recently-described “rapid” signaling pathway that is mediated by a subset of ERα localized to the cell membrane. However, which of these pathways mediates the effects of estrogen on endothelial cells is poorly understood. Here we identify a triple point mutant version of ERα (KRR ERα) that is specifically defective in rapid signaling, but is competent to regulate transcription through the “genomic” pathway. We find that in ECs expressing wild type ERα, E2 regulates many genes involved in cell migration and proliferation, promotes EC migration and proliferation, and also blocks the adhesion of monocytes to ECs. ECs expressing KRR mutant ERα, however, lack all of these responses. These observations establish KRR ERα as a novel tool that could greatly facilitate future studies into the vascular and non-vascular functions of ERα rapid signaling. Further, they support that rapid signaling through ERα is essential for many of the transcriptional and physiological responses of ECs to E2, and that ERα rapid signaling in ECs, in vivo, may be critical for the vasculoprotective and anti-inflammatory effects of estrogen. PMID:27035664

  4. Human auditory evoked potentials. II - Effects of attention

    NASA Technical Reports Server (NTRS)

    Picton, T. W.; Hillyard, S. A.

    1974-01-01

    Attention directed toward auditory stimuli, in order to detect an occasional fainter 'signal' stimulus, caused a substantial increase in the N1 (83 msec) and P2 (161 msec) components of the auditory evoked potential without any change in preceding components. This evidence shows that human auditory attention is not mediated by a peripheral gating mechanism. The evoked response to the detected signal stimulus also contained a large P3 (450 msec) wave that was topographically distinct from the preceding components. This late positive wave could also be recorded in response to a detected omitted stimulus in a regular train and therefore seemed to index a stimulus-independent perceptual decision process.

  5. Biological impact of music and software-based auditory training.

    PubMed

    Kraus, Nina

    2012-01-01

    Auditory-based communication skills are developed at a young age and are maintained throughout our lives. However, some individuals - both young and old - encounter difficulties in achieving or maintaining communication proficiency. Biological signals arising from hearing sounds relate to real-life communication skills such as listening to speech in noisy environments and reading, pointing to an intersection between hearing and cognition. Musical experience, amplification, and software-based training can improve these biological signals. These findings of biological plasticity, in a variety of subject populations, relate to attention and auditory memory, and represent an integrated auditory system influenced by both sensation and cognition. PMID:22789822

  6. Biological impact of music and software-based auditory training.

    PubMed

    Kraus, Nina

    2012-01-01

    Auditory-based communication skills are developed at a young age and are maintained throughout our lives. However, some individuals - both young and old - encounter difficulties in achieving or maintaining communication proficiency. Biological signals arising from hearing sounds relate to real-life communication skills such as listening to speech in noisy environments and reading, pointing to an intersection between hearing and cognition. Musical experience, amplification, and software-based training can improve these biological signals. These findings of biological plasticity, in a variety of subject populations, relate to attention and auditory memory, and represent an integrated auditory system influenced by both sensation and cognition.

  7. Tankyrase Sterile α Motif Domain Polymerization Is Required for Its Role in Wnt Signaling.

    PubMed

    Riccio, Amanda A; McCauley, Michael; Langelier, Marie-France; Pascal, John M

    2016-09-01

    Tankyrase-1 (TNKS1/PARP-5a) is a poly(ADP-ribose) polymerase (PARP) enzyme that regulates multiple cellular processes creating a poly(ADP-ribose) posttranslational modification that can lead to target protein turnover. TNKS1 thereby controls protein levels of key components of signaling pathways, including Axin1, the limiting component of the destruction complex in canonical Wnt signaling that degrades β-catenin to prevent its coactivator function in gene expression. There are limited molecular level insights into TNKS1 regulation in cell signaling pathways. TNKS1 has a sterile α motif (SAM) domain that is known to mediate polymerization, but the functional requirement for SAM polymerization has not been assessed. We have determined the crystal structure of wild-type human TNKS1 SAM domain and used structure-based mutagenesis to disrupt polymer formation and assess the consequences on TNKS1 regulation of β-catenin-dependent transcription. Our data indicate the SAM polymer is critical for TNKS1 catalytic activity and allows TNKS1 to efficiently access cytoplasmic signaling complexes.

  8. Differential Requirements of TCR Signaling in Homeostatic Maintenance and Function of Dendritic Epidermal T Cells.

    PubMed

    Zhang, Baojun; Wu, Jianxuan; Jiao, Yiqun; Bock, Cheryl; Dai, Meifang; Chen, Benny; Chao, Nelson; Zhang, Weiguo; Zhuang, Yuan

    2015-11-01

    Dendritic epidermal T cells (DETCs) are generated exclusively in the fetal thymus and maintained in the skin epithelium throughout postnatal life of the mouse. DETCs have restricted antigenic specificity as a result of their exclusive usage of a canonical TCR. Although the importance of the TCR in DETC development has been well established, the exact role of TCR signaling in DETC homeostasis and function remains incompletely defined. In this study, we investigated TCR signaling in fully matured DETCs by lineage-restricted deletion of the Lat gene, an essential signaling molecule downstream of the TCR. We found that Lat deletion impaired TCR-dependent cytokine gene activation and the ability of DETCs to undergo proliferative expansion. However, linker for activation of T cells-deficient DETCs were able to maintain long-term population homeostasis, although with a reduced proliferation rate. Mice with Lat deletion in DETCs exhibited delayed wound healing accompanied by impaired clonal expansion within the wound area. Our study revealed differential requirements for TCR signaling in homeostatic maintenance of DETCs and in their effector function during wound healing. PMID:26408667

  9. Requirement of Stat3 Signaling in the Postnatal Development of Thymic Medullary Epithelial Cells.

    PubMed

    Satoh, Rumi; Kakugawa, Kiyokazu; Yasuda, Takuwa; Yoshida, Hisahiro; Sibilia, Maria; Katsura, Yoshimoto; Levi, Ben; Abramson, Jakub; Koseki, Yoko; Koseki, Haruhiko; van Ewijk, Willem; Hollander, Georg A; Kawamoto, Hiroshi

    2016-01-01

    Thymic medullary regions are formed in neonatal mice as islet-like structures, which increase in size over time and eventually fuse a few weeks after birth into a continuous structure. The development of medullary thymic epithelial cells (TEC) is dependent on NF-κB associated signaling though other signaling pathways may contribute. Here, we demonstrate that Stat3-mediated signals determine medullary TEC cellularity, architectural organization and hence the size of the medulla. Deleting Stat3 expression selectively in thymic epithelia precludes the postnatal enlargement of the medulla retaining a neonatal architecture of small separate medullary islets. In contrast, loss of Stat3 expression in cortical TEC neither affects the cellularity or organization of the epithelia. Activation of Stat3 is mainly positioned downstream of EGF-R as its ablation in TEC phenocopies the loss of Stat3 expression in these cells. These results indicate that Stat3 meditated signal via EGF-R is required for the postnatal development of thymic medullary regions. PMID:26789017

  10. Sex specific retinoic acid signaling is required for the initiation of urogenital sinus bud development.

    PubMed

    Bryant, Sarah L; Francis, Jeffrey C; Lokody, Isabel B; Wang, Hong; Risbridger, Gail P; Loveland, Kate L; Swain, Amanda

    2014-11-15

    The mammalian urogenital sinus (UGS) develops in a sex specific manner, giving rise to the prostate in the male and the sinus vagina in the embryonic female. Androgens, produced by the embryonic testis, have been shown to be crucial to this process. In this study we show that retinoic acid signaling is required for the initial stages of bud development from the male UGS. Enzymes involved in retinoic acid synthesis are expressed in the UGS mesenchyme in a sex specific manner and addition of ligand to female tissue is able to induce prostate-like bud formation in the absence of androgens, albeit at reduced potency. Functional studies in mouse organ cultures that faithfully reproduce the initiation of prostate development indicate that one of the roles of retinoic acid signaling in the male is to inhibit the expression of Inhba, which encodes the βA subunit of Activin, in the UGS mesenchyme. Through in vivo genetic analysis and culture studies we show that inhibition of Activin signaling in the female UGS leads to a similar phenotype to that of retinoic acid treatment, namely bud formation in the absence of androgens. Our data also reveals that both androgens and retinoic acid have extra independent roles to that of repressing Activin signaling in the development of the prostate during fetal stages. This study identifies a novel role for retinoic acid as a mesenchymal factor that acts together with androgens to determine the position and initiation of bud development in the male UGS epithelia. PMID:25261715

  11. A mouse model for Meckel syndrome reveals Mks1 is required for ciliogenesis and Hedgehog signaling

    PubMed Central

    Weatherbee, Scott D.; Niswander, Lee A.; Anderson, Kathryn V.

    2009-01-01

    Meckel syndrome (MKS) is a rare autosomal recessive disease causing perinatal lethality associated with a complex syndrome that includes occipital meningoencephalocele, hepatic biliary ductal plate malformation, postaxial polydactyly and polycystic kidneys. The gene mutated in type 1 MKS encodes a protein associated with the base of the cilium in vertebrates and nematodes. However, shRNA knockdown studies in cell culture have reported conflicting results on the role of Mks1 in ciliogenesis. Here we show that loss of function of mouse Mks1 results in an accurate model of human MKS, with structural abnormalities in the neural tube, biliary duct, limb patterning, bone development and the kidney that mirror the human syndrome. In contrast to cell culture studies, loss of Mks1 in vivo does not interfere with apical localization of epithelial basal bodies but rather leads to defective cilia formation in most, but not all, tissues. Analysis of patterning in the neural tube and the limb demonstrates altered Hedgehog (Hh) pathway signaling underlies some MKS defects, although both tissues show an expansion of the domain of response to Shh signaling, unlike the phenotypes seen in other mutants with cilia loss. Other defects in the skull, lung, rib cage and long bones are likely to be the result of the disruption of Hh signaling, and the basis of defects in the liver and kidney require further analysis. Thus the disruption of Hh signaling can explain many, but not all, of the defects caused by loss of Mks1. PMID:19776033

  12. Maturation of a central brain flight circuit in Drosophila requires Fz2/Ca2+ signaling

    PubMed Central

    Agrawal, Tarjani; Hasan, Gaiti

    2015-01-01

    The final identity of a differentiated neuron is determined by multiple signaling events, including activity dependent calcium transients. Non-canonical Frizzled2 (Fz2) signaling generates calcium transients that determine neuronal polarity, neuronal migration, and synapse assembly in the developing vertebrate brain. Here, we demonstrate a requirement for Fz2/Ca2+ signaling in determining the final differentiated state of a set of central brain dopaminergic neurons in Drosophila, referred to as the protocerebral anterior medial (PAM) cluster. Knockdown or inhibition of Fz2/Ca2+ signaling during maturation of the flight circuit in pupae reduces Tyrosine Hydroxylase (TH) expression in the PAM neurons and affects maintenance of flight. Thus, we demonstrate that Fz2/Ca2+ transients during development serve as a pre-requisite for normal adult behavior. Our results support a neural mechanism where PAM neuron send projections to the α' and β' lobes of a higher brain centre, the mushroom body, and function in dopaminergic re-inforcement of flight. DOI: http://dx.doi.org/10.7554/eLife.07046.001 PMID:25955970

  13. Optogenetic stimulation of the auditory pathway

    PubMed Central

    Hernandez, Victor H.; Gehrt, Anna; Reuter, Kirsten; Jing, Zhizi; Jeschke, Marcus; Mendoza Schulz, Alejandro; Hoch, Gerhard; Bartels, Matthias; Vogt, Gerhard; Garnham, Carolyn W.; Yawo, Hiromu; Fukazawa, Yugo; Augustine, George J.; Bamberg, Ernst; Kügler, Sebastian; Salditt, Tim; de Hoz, Livia; Strenzke, Nicola; Moser, Tobias

    2014-01-01

    Auditory prostheses can partially restore speech comprehension when hearing fails. Sound coding with current prostheses is based on electrical stimulation of auditory neurons and has limited frequency resolution due to broad current spread within the cochlea. In contrast, optical stimulation can be spatially confined, which may improve frequency resolution. Here, we used animal models to characterize optogenetic stimulation, which is the optical stimulation of neurons genetically engineered to express the light-gated ion channel channelrhodopsin-2 (ChR2). Optogenetic stimulation of spiral ganglion neurons (SGNs) activated the auditory pathway, as demonstrated by recordings of single neuron and neuronal population responses. Furthermore, optogenetic stimulation of SGNs restored auditory activity in deaf mice. Approximation of the spatial spread of cochlear excitation by recording local field potentials (LFPs) in the inferior colliculus in response to suprathreshold optical, acoustic, and electrical stimuli indicated that optogenetic stimulation achieves better frequency resolution than monopolar electrical stimulation. Virus-mediated expression of a ChR2 variant with greater light sensitivity in SGNs reduced the amount of light required for responses and allowed neuronal spiking following stimulation up to 60 Hz. Our study demonstrates a strategy for optogenetic stimulation of the auditory pathway in rodents and lays the groundwork for future applications of cochlear optogenetics in auditory research and prosthetics. PMID:24509078

  14. Glial Cell Contributions to Auditory Brainstem Development

    PubMed Central

    Cramer, Karina S.; Rubel, Edwin W

    2016-01-01

    Glial cells, previously thought to have generally supporting roles in the central nervous system, are emerging as essential contributors to multiple aspects of neuronal circuit function and development. This review focuses on the contributions of glial cells to the development of auditory pathways in the brainstem. These pathways display specialized synapses and an unusually high degree of precision in circuitry that enables sound source localization. The development of these pathways thus requires highly coordinated molecular and cellular mechanisms. Several classes of glial cells, including astrocytes, oligodendrocytes and microglia, have now been explored in these circuits in both avian and mammalian brainstems. Distinct populations of astrocytes are found over the course of auditory brainstem maturation. Early appearing astrocytes are associated with spatial compartments in the avian auditory brainstem. Factors from late appearing astrocytes promote synaptogenesis and dendritic maturation, and astrocytes remain integral parts of specialized auditory synapses. Oligodendrocytes play a unique role in both birds and mammals in highly regulated myelination essential for proper timing to decipher interaural cues. Microglia arise early in brainstem development and may contribute to maturation of auditory pathways. Together these studies demonstrate the importance of non-neuronal cells in the assembly of specialized auditory brainstem circuits.

  15. Derivation of lung mesenchymal lineages from the fetal mesothelium requires hedgehog signaling for mesothelial cell entry

    PubMed Central

    Dixit, Radhika; Ai, Xingbin; Fine, Alan

    2013-01-01

    Recent studies have shown that mesothelial progenitors contribute to mesenchymal lineages of developing organs. To what extent the overlying mesothelium contributes to lung development remains unknown. To rigorously address this question, we employed Wt1CreERT2/+ mice for high-fidelity lineage tracing after confirming that Cre recombinase was mesothelial specific and faithfully recapitulated endogenous Wilms’ tumor 1 (Wt1) gene expression. We visualized WT1+ mesothelial cell entry into the lung by live imaging and identified their progenies in subpopulations of bronchial smooth muscle cells, vascular smooth muscle cells and desmin+ fibroblasts by lineage tagging. Derivation of these lineages was only observed with Cre recombinase activation during early lung development. Using loss-of-function assays in organ cultures, and targeted mesothelial-restricted hedgehog loss-of-function mice, we demonstrated that mesothelial cell movement into the lung requires the direct action of hedgehog signaling. By contrast, hedgehog signaling was not required for fetal mesothelial heart entry. These findings further support a paradigm wherein the mesothelium is a source of progenitors for mesenchymal lineages during organogenesis and indicate that signals controlling mesothelial cell entry are organ specific. PMID:24130328

  16. Notch signal reception is required in vascular smooth muscle cells for ductus arteriosus closure.

    PubMed

    Krebs, Luke T; Norton, Christine R; Gridley, Thomas

    2016-02-01

    The ductus arteriosus is an arterial vessel that shunts blood flow away from the lungs during fetal life, but normally occludes after birth to establish the adult circulation pattern. Failure of the ductus arteriosus to close after birth is termed patent ductus arteriosus, and is one of the most common congenital heart defects. Our previous work demonstrated that vascular smooth muscle cell expression of the Jag1 gene, which encodes a ligand for Notch family receptors, is essential for postnatal closure of the ductus arteriosus in mice. However, it was not known what cell population was responsible for receiving the Jag1-mediated signal. Here we show, using smooth muscle cell-specific deletion of the Rbpj gene, which encodes a transcription factor that mediates all canonical Notch signaling, that Notch signal reception in the vascular smooth muscle cell compartment is required for ductus arteriosus closure. These data indicate that homotypic vascular smooth muscle cell interactions are required for proper contractile smooth muscle cell differentiation and postnatal closure of the ductus arteriosus in mice.

  17. GLABROUS INFLORESCENCE STEMS (GIS) is required for trichome branching through gibberellic acid signaling in Arabidopsis.

    PubMed

    An, Lijun; Zhou, Zhongjing; Su, Sha; Yan, An; Gan, Yinbo

    2012-02-01

    Cell differentiation generally corresponds to the cell cycle, typically forming a non-dividing cell with a unique differentiated morphology, and Arabidopsis trichome is an excellent model system to study all aspects of cell differentiation. Although gibberellic acid is reported to be involved in trichome branching in Arabidopsis, the mechanism for such signaling is unclear. Here, we demonstrated that GLABROUS INFLORESCENCE STEMS (GIS) is required for the control of trichome branching through gibberellic acid signaling. The phenotypes of a loss-of-function gis mutant and an overexpressor showed that GIS acted as a repressor to control trichome branching. Our results also show that GIS is not required for cell endoreduplication, and our molecular and genetic study results have shown that GIS functions downstream of the key regulator of trichome branching, STICHEL (STI), to control trichome branching through the endoreduplication-independent pathway. Furthermore, our results also suggest that GIS controls trichome branching in Arabidopsis through two different pathways and acts either upstream or downstream of the negative regulator of gibbellic acid signaling SPINDLY (SPY).

  18. Formation of a Polarised Primitive Endoderm Layer in Embryoid Bodies Requires Fgfr/Erk Signalling

    PubMed Central

    Doughton, Gail; Wei, Jun; Tapon, Nicolas; Welham, Melanie J.; Chalmers, Andrew D.

    2014-01-01

    The primitive endoderm arises from the inner cell mass during mammalian pre-implantation development. It faces the blastocoel cavity and later gives rise to the extraembryonic parietal and visceral endoderm. Here, we investigate a key step in primitive endoderm development, the acquisition of apico-basolateral polarity and epithelial characteristics by the non-epithelial inner cell mass cells. Embryoid bodies, formed from mouse embryonic stem cells, were used as a model to study this transition. The outer cells of these embryoid bodies were found to gradually acquire the hallmarks of polarised epithelial cells and express markers of primitive endoderm cell fate. Fgf receptor/Erk signalling is known to be required for specification of the primitive endoderm, but its role in polarisation of this tissue is less well understood. To investigate the function of this pathway in the primitive endoderm, embryoid bodies were cultured in the presence of a small molecule inhibitor of Mek. This inhibitor caused a loss of expression of markers of primitive endoderm cell fate and maintenance of the pluripotency marker Nanog. In addition, a mislocalisation of apico-basolateral markers and disruption of the epithelial barrier, which normally blocks free diffusion across the epithelial cell layer, occurred. Two inhibitors of the Fgf receptor elicited similar phenotypes, suggesting that Fgf receptor signalling promotes Erk-mediated polarisation. This data shows that primitive endoderm cells of the outer layer of embryoid bodies gradually polarise, and formation of a polarised primitive endoderm layer requires the Fgf receptor/Erk signalling pathway. PMID:24752320

  19. The Distributed Auditory Cortex

    PubMed Central

    Winer, Jeffery A.; Lee, Charles C.

    2009-01-01

    A synthesis of cat auditory cortex (AC) organization is presented in which the extrinsic and intrinsic connections interact to derive a unified profile of the auditory stream and use it to direct and modify cortical and subcortical information flow. Thus, the thalamocortical input provides essential sensory information about peripheral stimulus events, which AC redirects locally for feature extraction, and then conveys to parallel auditory, multisensory, premotor, limbic, and cognitive centers for further analysis. The corticofugal output influences areas as remote as the pons and the cochlear nucleus, structures whose effects upon AC are entirely indirect, and has diverse roles in the transmission of information through the medial geniculate body and inferior colliculus. The distributed AC is thus construed as a functional network in which the auditory percept is assembled for subsequent redistribution in sensory, premotor, and cognitive streams contingent on the derived interpretation of the acoustic events. The confluence of auditory and multisensory streams likely precedes cognitive processing of sound. The distributed AC constitutes the largest and arguably the most complete representation of the auditory world. Many facets of this scheme may apply in rodent and primate AC as well. We propose that the distributed auditory cortex contributes to local processing regimes in regions as disparate as the frontal pole and the cochlear nucleus to construct the acoustic percept. PMID:17329049

  20. Beyond auditory cortex: working with musical thoughts.

    PubMed

    Zatorre, Robert J

    2012-04-01

    Musical imagery is associated with neural activity in auditory cortex, but prior studies have not examined musical imagery tasks requiring mental transformations. This paper describes functional magnetic resonance imaging (fMRI) studies requiring manipulation of musical information. In one set of experiments, listeners were asked to mentally reverse a familiar tune when presented backwards. This manipulation consistently elicits neural activity in the intraparietal sulcus (IPS). Separate experiments requiring judgments about melodies that have been transposed from one musical key to another also elicit IPS activation. Conjunction analyses indicate that the same portions of the IPS are recruited in both tasks. The findings suggest that the dorsal pathway of auditory processing is involved in the manipulation and transformation of auditory information, as has also been shown for visuomotor and visuospatial tasks. As such, it provides a substrate for the creation of new mental representations that are based on manipulation of previously experienced sensory events. PMID:22524363

  1. Electrophysiological measurement of human auditory function

    NASA Technical Reports Server (NTRS)

    Galambos, R.

    1975-01-01

    Contingent negative variations in the presence and amplitudes of brain potentials evoked by sound are considered. Evidence is produced that the evoked brain stem response to auditory stimuli is clearly related to brain events associated with cognitive processing of acoustic signals since their properties depend upon where the listener directs his attention, whether the signal is an expected event or a surprise, and when sound that is listened-for is heard at last.

  2. ERK signaling in the pituitary is required for female but not male fertility.

    PubMed

    Bliss, Stuart P; Miller, Andrew; Navratil, Amy M; Xie, Jianjun; McDonough, Sean P; Fisher, Patricia J; Landreth, Gary E; Roberson, Mark S

    2009-07-01

    Males and females require different patterns of pituitary gonadotropin secretion for fertility. The mechanisms underlying these gender-specific profiles of pituitary hormone production are unknown; however, they are fundamental to understanding the sexually dimorphic control of reproductive function at the molecular level. Several studies suggest that ERK1 and -2 are essential modulators of hypothalamic GnRH-mediated regulation of pituitary gonadotropin production and fertility. To test this hypothesis, we generated mice with a pituitary-specific depletion of ERK1 and 2 and examined a range of physiological parameters including fertility. We find that ERK signaling is required in females for ovulation and fertility, whereas male reproductive function is unaffected by this signaling deficiency. The effects of ERK pathway ablation on LH biosynthesis underlie this gender-specific phenotype, and the molecular mechanism involves a requirement for ERK-dependent up-regulation of the transcription factor Egr1, which is necessary for LHbeta expression. Together, these findings represent a significant advance in elucidating the molecular basis of gender-specific regulation of the hypothalamic-pituitary-gonadal axis and sexually dimorphic control of fertility.

  3. Canonical Wnt Signaling is Required for Ophthalmic Trigeminal Placode Cell Fate Determination and Maintenance

    PubMed Central

    Lassiter, Rhonda N.T.; Dude, Carolynn; Reynolds, Stephanie B.; Winters, Nichelle I.; Baker, Clare V.H.; Stark, Michael R.

    2014-01-01

    Cranial placodes are ectodermal regions that contribute extensively to the vertebrate peripheral sensory nervous system. The development of the ophthalmic trigeminal (opV) placode, which gives rise only to sensory neurons of the ophthalmic lobe of the trigeminal ganglion, is a useful model of sensory neuron development. While key differentiation processes have been characterized at the tissue and cellular levels, the signaling pathways governing opV placode development have not. Here, we tested in chick whether the canonical Wnt signaling pathway regulates opV placode development. By introducing a Wnt reporter into embryonic chick head ectoderm, we show that the canonical pathway is active in Pax3+ opV placode cells as, or shortly after, they are induced to express Pax3. Blocking the canonical Wnt pathway resulted in the failure of targeted cells to adopt or maintain an opV fate, as assayed by the expression of various markers including Pax3, FGFR4, Eya2, and the neuronal differentiation markers Islet1, neurofilament and NeuN, although, surprisingly, it led to upregulation of Neurogenin2, both in the opV placode and elsewhere in the ectoderm. Activating the canonical Wnt signaling pathway, however, was not sufficient to induce Pax3, the earliest specific marker of the opV placode. We conclude that canonical Wnt signaling is necessary for normal opV placode development, and propose that other molecular cues are required in addition to Wnt signaling to promote cells toward an opV placode fate. PMID:17604017

  4. Conserved mechanisms of vocalization coding in mammalian and songbird auditory midbrain

    PubMed Central

    Portfors, Christine V.

    2013-01-01

    The ubiquity of social vocalization among animals provides the opportunity to identify conserved mechanisms of auditory processing that subserve vocal communication. Identifying auditory coding properties that are shared across vocal communicators will provide insight into how human auditory processing leads to speech perception. Here, we compare auditory response properties and neural coding of social vocalizations in auditory midbrain neurons of mammalian and avian vocal communicators. The auditory midbrain is a nexus of auditory processing because it receives and integrates information from multiple parallel pathways and provides the ascending auditory input to the thalamus. The auditory midbrain is also the first region in the ascending auditory system where neurons show complex tuning properties that are correlated with the acoustics of social vocalizations. Single unit studies in mice, bats and zebra finches reveal shared principles of auditory coding including tonotopy, excitatory and inhibitory interactions that shape responses to vocal signals, nonlinear response properties that are important for auditory coding of social vocalizations and modulation tuning. Additionally, single neuron responses in the mouse and songbird midbrain are reliable, selective for specific syllables, and rely on spike timing for neural discrimination of distinct vocalizations. We propose that future research on auditory coding of vocalizations in mouse and songbird midbrain neurons adopt similar experimental and analytical approaches so that conserved principles of vocalization coding may be distinguished from those that are specialized for each species. PMID:23726970

  5. Conserved mechanisms of vocalization coding in mammalian and songbird auditory midbrain.

    PubMed

    Woolley, Sarah M N; Portfors, Christine V

    2013-11-01

    The ubiquity of social vocalizations among animals provides the opportunity to identify conserved mechanisms of auditory processing that subserve communication. Identifying auditory coding properties that are shared across vocal communicators will provide insight into how human auditory processing leads to speech perception. Here, we compare auditory response properties and neural coding of social vocalizations in auditory midbrain neurons of mammalian and avian vocal communicators. The auditory midbrain is a nexus of auditory processing because it receives and integrates information from multiple parallel pathways and provides the ascending auditory input to the thalamus. The auditory midbrain is also the first region in the ascending auditory system where neurons show complex tuning properties that are correlated with the acoustics of social vocalizations. Single unit studies in mice, bats and zebra finches reveal shared principles of auditory coding including tonotopy, excitatory and inhibitory interactions that shape responses to vocal signals, nonlinear response properties that are important for auditory coding of social vocalizations and modulation tuning. Additionally, single neuron responses in the mouse and songbird midbrain are reliable, selective for specific syllables, and rely on spike timing for neural discrimination of distinct vocalizations. We propose that future research on auditory coding of vocalizations in mouse and songbird midbrain neurons adopt similar experimental and analytical approaches so that conserved principles of vocalization coding may be distinguished from those that are specialized for each species. This article is part of a Special Issue entitled "Communication Sounds and the Brain: New Directions and Perspectives".

  6. Auditory motion affects visual biological motion processing.

    PubMed

    Brooks, A; van der Zwan, R; Billard, A; Petreska, B; Clarke, S; Blanke, O

    2007-02-01

    The processing of biological motion is a critical, everyday task performed with remarkable efficiency by human sensory systems. Interest in this ability has focused to a large extent on biological motion processing in the visual modality (see, for example, Cutting, J. E., Moore, C., & Morrison, R. (1988). Masking the motions of human gait. Perception and Psychophysics, 44(4), 339-347). In naturalistic settings, however, it is often the case that biological motion is defined by input to more than one sensory modality. For this reason, here in a series of experiments we investigate behavioural correlates of multisensory, in particular audiovisual, integration in the processing of biological motion cues. More specifically, using a new psychophysical paradigm we investigate the effect of suprathreshold auditory motion on perceptions of visually defined biological motion. Unlike data from previous studies investigating audiovisual integration in linear motion processing [Meyer, G. F. & Wuerger, S. M. (2001). Cross-modal integration of auditory and visual motion signals. Neuroreport, 12(11), 2557-2560; Wuerger, S. M., Hofbauer, M., & Meyer, G. F. (2003). The integration of auditory and motion signals at threshold. Perception and Psychophysics, 65(8), 1188-1196; Alais, D. & Burr, D. (2004). No direction-specific bimodal facilitation for audiovisual motion detection. Cognitive Brain Research, 19, 185-194], we report the existence of direction-selective effects: relative to control (stationary) auditory conditions, auditory motion in the same direction as the visually defined biological motion target increased its detectability, whereas auditory motion in the opposite direction had the inverse effect. Our data suggest these effects do not arise through general shifts in visuo-spatial attention, but instead are a consequence of motion-sensitive, direction-tuned integration mechanisms that are, if not unique to biological visual motion, at least not common to all types of

  7. Autophagy-associated alpha-arrestin signaling is required for conidiogenous cell development in Magnaporthe oryzae

    PubMed Central

    Dong, Bo; Xu, Xiaojin; Chen, Guoqing; Zhang, Dandan; Tang, Mingzhi; Xu, Fei; Liu, Xiaohong; Wang, Hua; Zhou, Bo

    2016-01-01

    Conidiation patterning is evolutionarily complex and mechanism concerning conidiogenous cell differentiation remains largely unknown. Magnaporthe oryzae conidiates in a sympodial way and uses its conidia to infect host and disseminate blast disease. Arrestins are multifunctional proteins that modulate receptor down-regulation and scaffold components of intracellular trafficking routes. We here report an alpha-arrestin that regulates patterns of conidiation and contributes to pathogenicity in M. oryzae. We show that disruption of ARRDC1 generates mutants which produce conidia in an acropetal array and ARRDC1 significantly affects expression profile of CCA1, a virulence-related transcription factor required for conidiogenous cell differentiation. Although germ tubes normally develop appressoria, penetration peg formation is dramatically impaired and Δarrdc1 mutants are mostly nonpathogenic. Fluorescent analysis indicates that EGFP-ARRDC1 puncta are well colocalized with DsRed2-Atg8, and this distribution profile could not be altered in Δatg9 mutants, suggesting ARRDC1 enters into autophagic flux before autophagosome maturation. We propose that M. oryzae employs ARRDC1 to regulate specific receptors in response to conidiation-related signals for conidiogenous cell differentiation and utilize autophagosomes for desensitization of conidiogenous receptor, which transmits extracellular signal to the downstream elements of transcription factors. Our investigation extends novel significance of autophagy-associated alpha-arrestin signaling to fungal parasites. PMID:27498554

  8. Efficient Tor Signaling Requires a Functional Class C Vps Protein Complex in Saccharomyces cerevisiae

    PubMed Central

    Zurita-Martinez, Sara A.; Puria, Rekha; Pan, Xuewen; Boeke, Jef D.; Cardenas, Maria E.

    2007-01-01

    The Tor kinases regulate responses to nutrients and control cell growth. Unlike most organisms that only contain one Tor protein, Saccharomyces cerevisiae expresses two, Tor1 and Tor2, which are thought to share all of the rapamycin-sensitive functions attributable to Tor signaling. Here we conducted a genetic screen that defined the global TOR1 synthetic fitness or lethal interaction gene network. This screen identified mutations in distinctive functional categories that impaired vacuolar function, including components of the EGO/Gse and PAS complexes that reduce fitness. In addition, tor1 is lethal in combination with mutations in class C Vps complex components. We find that Tor1 does not regulate the known function of the class C Vps complex in protein sorting. Instead class C vps mutants fail to recover from rapamycin-induced growth arrest or to survive nitrogen starvation and have low levels of amino acids. Remarkably, addition of glutamate or glutamine restores viability to a tor1 pep3 mutant strain. We conclude that Tor1 is more effective than Tor2 at providing rapamycin-sensitive Tor signaling under conditions of amino acid limitation, and that an intact class C Vps complex is required to mediate intracellular amino acid homeostasis for efficient Tor signaling. PMID:17565946

  9. Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-β-Catenin Signaling.

    PubMed

    Mariotti, Laura; Templeton, Catherine M; Ranes, Michael; Paracuellos, Patricia; Cronin, Nora; Beuron, Fabienne; Morris, Edward; Guettler, Sebastian

    2016-08-01

    The poly(ADP-ribose) polymerase (PARP) Tankyrase (TNKS and TNKS2) is paramount to Wnt-β-catenin signaling and a promising therapeutic target in Wnt-dependent cancers. The pool of active β-catenin is normally limited by destruction complexes, whose assembly depends on the polymeric master scaffolding protein AXIN. Tankyrase, which poly(ADP-ribosyl)ates and thereby destabilizes AXIN, also can polymerize, but the relevance of these polymers has remained unclear. We report crystal structures of the polymerizing TNKS and TNKS2 sterile alpha motif (SAM) domains, revealing versatile head-to-tail interactions. Biochemical studies informed by these structures demonstrate that polymerization is required for Tankyrase to drive β-catenin-dependent transcription. We show that the polymeric state supports PARP activity and allows Tankyrase to effectively access destruction complexes through enabling avidity-dependent AXIN binding. This study provides an example for regulated signal transduction in non-membrane-enclosed compartments (signalosomes), and it points to novel potential strategies to inhibit Tankyrase function in oncogenic Wnt signaling. PMID:27494558

  10. Dynamin II is required for 17β-estradiol signaling and autophagy-based ERα degradation.

    PubMed

    Totta, Pierangela; Busonero, Claudia; Leone, Stefano; Marino, Maria; Acconcia, Filippo

    2016-01-01

    17β-estradiol (E2) regulates diverse physiological effects, including cell proliferation, by binding to estrogen receptor α (ERα). ERα is both a transcription factor that drives E2-sensitive gene expression and an extra-nuclear localized receptor that triggers the activation of diverse kinase cascades. While E2 triggers cell proliferation, it also induces ERα degradation in a typical hormone-dependent feedback loop. Although ERα breakdown proceeds through the 26S proteasome, a role for lysosomes and for some endocytic proteins in controlling ERα degradation has been reported. Here, we studied the role of the endocytic protein dynamin II in E2-dependent ERα signaling and degradation. The results indicate that dynamin II siRNA-mediated knock-down partially prevents E2-induced ERα degradation through the inhibition of an autophagy-based pathway and impairs E2-induced cell proliferation signaling. Altogether, these data demonstrate that dynamin II is required for the E2:ERα signaling of physiological functions and uncovers a role for autophagy in the control of ERα turnover. PMID:27009360

  11. Dynamin II is required for 17β-estradiol signaling and autophagy-based ERα degradation

    PubMed Central

    Totta, Pierangela; Busonero, Claudia; Leone, Stefano; Marino, Maria; Acconcia, Filippo

    2016-01-01

    17β-estradiol (E2) regulates diverse physiological effects, including cell proliferation, by binding to estrogen receptor α (ERα). ERα is both a transcription factor that drives E2-sensitive gene expression and an extra-nuclear localized receptor that triggers the activation of diverse kinase cascades. While E2 triggers cell proliferation, it also induces ERα degradation in a typical hormone-dependent feedback loop. Although ERα breakdown proceeds through the 26S proteasome, a role for lysosomes and for some endocytic proteins in controlling ERα degradation has been reported. Here, we studied the role of the endocytic protein dynamin II in E2-dependent ERα signaling and degradation. The results indicate that dynamin II siRNA-mediated knock-down partially prevents E2-induced ERα degradation through the inhibition of an autophagy-based pathway and impairs E2-induced cell proliferation signaling. Altogether, these data demonstrate that dynamin II is required for the E2:ERα signaling of physiological functions and uncovers a role for autophagy in the control of ERα turnover. PMID:27009360

  12. A CRISPR screen defines a signal peptide processing pathway required by flaviviruses.

    PubMed

    Zhang, Rong; Miner, Jonathan J; Gorman, Matthew J; Rausch, Keiko; Ramage, Holly; White, James P; Zuiani, Adam; Zhang, Ping; Fernandez, Estefania; Zhang, Qiang; Dowd, Kimberly A; Pierson, Theodore C; Cherry, Sara; Diamond, Michael S

    2016-07-01

    Flaviviruses infect hundreds of millions of people annually, and no antiviral therapy is available. We performed a genome-wide CRISPR/Cas9-based screen to identify host genes that, when edited, resulted in reduced flavivirus infection. Here, we validated nine human genes required for flavivirus infectivity, and these were associated with endoplasmic reticulum functions including translocation, protein degradation, and N-linked glycosylation. In particular, a subset of endoplasmic reticulum-associated signal peptidase complex (SPCS) proteins was necessary for proper cleavage of the flavivirus structural proteins (prM and E) and secretion of viral particles. Loss of SPCS1 expression resulted in markedly reduced yield of all Flaviviridae family members tested (West Nile, Dengue, Zika, yellow fever, Japanese encephalitis, and hepatitis C viruses), but had little impact on alphavirus, bunyavirus, or rhabdovirus infection or the surface expression or secretion of diverse host proteins. We found that SPCS1 dependence could be bypassed by replacing the native prM protein leader sequences with a class I major histocompatibility complex (MHC) antigen leader sequence. Thus, SPCS1, either directly or indirectly via its interactions with unknown host proteins, preferentially promotes the processing of specific protein cargo, and Flaviviridae have a unique dependence on this signal peptide processing pathway. SPCS1 and other signal processing pathway members could represent pharmacological targets for inhibiting infection by the expanding number of flaviviruses of medical concern.

  13. A CRISPR screen defines a signal peptide processing pathway required by flaviviruses.

    PubMed

    Zhang, Rong; Miner, Jonathan J; Gorman, Matthew J; Rausch, Keiko; Ramage, Holly; White, James P; Zuiani, Adam; Zhang, Ping; Fernandez, Estefania; Zhang, Qiang; Dowd, Kimberly A; Pierson, Theodore C; Cherry, Sara; Diamond, Michael S

    2016-07-01

    Flaviviruses infect hundreds of millions of people annually, and no antiviral therapy is available. We performed a genome-wide CRISPR/Cas9-based screen to identify host genes that, when edited, resulted in reduced flavivirus infection. Here, we validated nine human genes required for flavivirus infectivity, and these were associated with endoplasmic reticulum functions including translocation, protein degradation, and N-linked glycosylation. In particular, a subset of endoplasmic reticulum-associated signal peptidase complex (SPCS) proteins was necessary for proper cleavage of the flavivirus structural proteins (prM and E) and secretion of viral particles. Loss of SPCS1 expression resulted in markedly reduced yield of all Flaviviridae family members tested (West Nile, Dengue, Zika, yellow fever, Japanese encephalitis, and hepatitis C viruses), but had little impact on alphavirus, bunyavirus, or rhabdovirus infection or the surface expression or secretion of diverse host proteins. We found that SPCS1 dependence could be bypassed by replacing the native prM protein leader sequences with a class I major histocompatibility complex (MHC) antigen leader sequence. Thus, SPCS1, either directly or indirectly via its interactions with unknown host proteins, preferentially promotes the processing of specific protein cargo, and Flaviviridae have a unique dependence on this signal peptide processing pathway. SPCS1 and other signal processing pathway members could represent pharmacological targets for inhibiting infection by the expanding number of flaviviruses of medical concern. PMID:27383988

  14. Lhx9 gene expression during early limb development in mice requires the FGF signalling pathway.

    PubMed

    Yang, Yisheng; Wilson, Megan J

    2015-01-01

    Lhx9 is a member of the LIM-homeodomain gene family necessary for the correct development of many organs including gonads, limbs, heart and the nervous system. In the context of limb development, Lhx9 has been implicated as an integrator for Fibroblast growth factor (FGF) and Sonic hedgehog (Shh) signalling required for proximal-distal (PD) and anterior-posterior (AP) development of the limb. Three splice variants of the Lhx9 transcript are expressed during development, two of which are predicted to act in a dominant negative fashion, competing with the DNA binding version of Lhx9 for binding to cofactors via the LIM-domain. We examined the expression pattern for the three alternative splice forms of Lhx9; Lhx9α, Lhx9β and Lhx9c during early limb development. We have found that of the three Lhx9 isoforms, only Lhx9α and Lhx9c (intact homeodomain) are expressed during early limb development, each with their own distinct expression pattern. Additionally we determined that Lhx9 expression overlaps with FGF10 expression in the developing limb bud mesenchyme. Limb bud explant cultures, in the presence of signalling pathway inhibitors, also indicated that Lhx9 mRNA expression in the limb bud was dependent on FGF signalling. PMID:26220830

  15. Autophagy-associated alpha-arrestin signaling is required for conidiogenous cell development in Magnaporthe oryzae.

    PubMed

    Dong, Bo; Xu, Xiaojin; Chen, Guoqing; Zhang, Dandan; Tang, Mingzhi; Xu, Fei; Liu, Xiaohong; Wang, Hua; Zhou, Bo

    2016-01-01

    Conidiation patterning is evolutionarily complex and mechanism concerning conidiogenous cell differentiation remains largely unknown. Magnaporthe oryzae conidiates in a sympodial way and uses its conidia to infect host and disseminate blast disease. Arrestins are multifunctional proteins that modulate receptor down-regulation and scaffold components of intracellular trafficking routes. We here report an alpha-arrestin that regulates patterns of conidiation and contributes to pathogenicity in M. oryzae. We show that disruption of ARRDC1 generates mutants which produce conidia in an acropetal array and ARRDC1 significantly affects expression profile of CCA1, a virulence-related transcription factor required for conidiogenous cell differentiation. Although germ tubes normally develop appressoria, penetration peg formation is dramatically impaired and Δarrdc1 mutants are mostly nonpathogenic. Fluorescent analysis indicates that EGFP-ARRDC1 puncta are well colocalized with DsRed2-Atg8, and this distribution profile could not be altered in Δatg9 mutants, suggesting ARRDC1 enters into autophagic flux before autophagosome maturation. We propose that M. oryzae employs ARRDC1 to regulate specific receptors in response to conidiation-related signals for conidiogenous cell differentiation and utilize autophagosomes for desensitization of conidiogenous receptor, which transmits extracellular signal to the downstream elements of transcription factors. Our investigation extends novel significance of autophagy-associated alpha-arrestin signaling to fungal parasites. PMID:27498554

  16. Spatial Learning Requires mGlu5 Signalling in the Dorsal Hippocampus.

    PubMed

    Tan, Shawn Zheng Kai; Ganella, Despina E; Dick, Alec Lindsay Ward; Duncan, Jhodie R; Ong-Palsson, Emma; Bathgate, Ross A D; Kim, Jee Hyun; Lawrence, Andrew J

    2015-06-01

    We examined the role of hippocampal metabotropic glutamate receptor 5 (mGlu5) in spatial learning and memory. Although it has been shown that mGlu5 signalling is required for certain forms of learning and memory, its role in spatial learning is unclear since studies using pharmacological or knockout mice models provide inconsistent findings. Additionally, the location in the brain where mGlu5 signalling may modulate such learning is yet to be precisely delineated. We stereotaxically injected rAAV-Cre into the dorsal hippocampus of mGlu5(loxP/loxP) mice to knockdown mGlu5 in that region. We show for the first time that knockdown of mGlu5 in the dorsal hippocampus is sufficient to impair spatial learning in Morris Water Maze. Locomotor activity and memory retrieval were unaffected by the mGlu5 knockdown. Taken together, these findings support a key role for dorsal hippocampal mGlu5 signalling in spatial learning.

  17. Cytoplasmic nanojunctions between lysosomes and sarcoplasmic reticulum are required for specific calcium signaling

    PubMed Central

    Fameli, Nicola; Ogunbayo, Oluseye A.

    2014-01-01

    Herein we demonstrate how nanojunctions between lysosomes and sarcoplasmic reticulum (L-SR junctions) serve to couple lysosomal activation to regenerative, ryanodine receptor-mediated cellular Ca 2+ waves. In pulmonary artery smooth muscle cells (PASMCs) it has been proposed that nicotinic acid adenine dinucleotide phosphate (NAADP) triggers increases in cytoplasmic Ca 2+ via L-SR junctions, in a manner that requires initial Ca 2+ release from lysosomes and subsequent Ca 2+-induced Ca 2+ release (CICR) via ryanodine receptor (RyR) subtype 3 on the SR membrane proximal to lysosomes. L-SR junction membrane separation has been estimated to be < 400 nm and thus beyond the resolution of light microscopy, which has restricted detailed investigations of the junctional coupling process. The present study utilizes standard and tomographic transmission electron microscopy to provide a thorough ultrastructural characterization of the L-SR junctions in PASMCs. We show that L-SR nanojunctions are prominent features within these cells and estimate that the junctional membrane separation and extension are about 15 nm and 300 nm, respectively. Furthermore, we develop a quantitative model of the L-SR junction using these measurements, prior kinetic and specific Ca 2+ signal information as input data. Simulations of NAADP-dependent junctional Ca 2+ transients demonstrate that the magnitude of these signals can breach the threshold for CICR via RyR3. By correlation analysis of live cell Ca 2+ signals and simulated Ca 2+ transients within L-SR junctions, we estimate that “trigger zones” comprising 60–100 junctions are required to confer a signal of similar magnitude. This is compatible with the 110 lysosomes/cell estimated from our ultrastructural observations. Most importantly, our model shows that increasing the L-SR junctional width above 50 nm lowers the magnitude of junctional [Ca 2+] such that there is a failure to breach the threshold for CICR via RyR3. L-SR junctions are

  18. [Central auditory prosthesis].

    PubMed

    Lenarz, T; Lim, H; Joseph, G; Reuter, G; Lenarz, M

    2009-06-01

    Deaf patients with severe sensory hearing loss can benefit from a cochlear implant (CI), which stimulates the auditory nerve fibers. However, patients who do not have an intact auditory nerve cannot benefit from a CI. The majority of these patients are neurofibromatosis type 2 (NF2) patients who developed neural deafness due to growth or surgical removal of a bilateral acoustic neuroma. The only current solution is the auditory brainstem implant (ABI), which stimulates the surface of the cochlear nucleus in the brainstem. Although the ABI provides improvement in environmental awareness and lip-reading capabilities, only a few NF2 patients have achieved some limited open set speech perception. In the search for alternative procedures our research group in collaboration with Cochlear Ltd. (Australia) developed a human prototype auditory midbrain implant (AMI), which is designed to electrically stimulate the inferior colliculus (IC). The IC has the potential as a new target for an auditory prosthesis as it provides access to neural projections necessary for speech perception as well as a systematic map of spectral information. In this paper the present status of research and development in the field of central auditory prostheses is presented with respect to technology, surgical technique and hearing results as well as the background concepts of ABI and AMI. PMID:19517084

  19. Auditory Spatial Layout

    NASA Technical Reports Server (NTRS)

    Wightman, Frederic L.; Jenison, Rick

    1995-01-01

    All auditory sensory information is packaged in a pair of acoustical pressure waveforms, one at each ear. While there is obvious structure in these waveforms, that structure (temporal and spectral patterns) bears no simple relationship to the structure of the environmental objects that produced them. The properties of auditory objects and their layout in space must be derived completely from higher level processing of the peripheral input. This chapter begins with a discussion of the peculiarities of acoustical stimuli and how they are received by the human auditory system. A distinction is made between the ambient sound field and the effective stimulus to differentiate the perceptual distinctions among various simple classes of sound sources (ambient field) from the known perceptual consequences of the linear transformations of the sound wave from source to receiver (effective stimulus). Next, the definition of an auditory object is dealt with, specifically the question of how the various components of a sound stream become segregated into distinct auditory objects. The remainder of the chapter focuses on issues related to the spatial layout of auditory objects, both stationary and moving.

  20. Altered auditory function in rats exposed to hypergravic fields

    NASA Technical Reports Server (NTRS)

    Jones, T. A.; Hoffman, L.; Horowitz, J. M.

    1982-01-01

    The effect of an orthodynamic hypergravic field of 6 G on the brainstem auditory projections was studied in rats. The brain temperature and EEG activity were recorded in the rats during 6 G orthodynamic acceleration and auditory brainstem responses were used to monitor auditory function. Results show that all animals exhibited auditory brainstem responses which indicated impaired conduction and transmission of brainstem auditory signals during the exposure to the 6 G acceleration field. Significant increases in central conduction time were observed for peaks 3N, 4P, 4N, and 5P (N = negative, P = positive), while the absolute latency values for these same peaks were also significantly increased. It is concluded that these results, along with those for fields below 4 G (Jones and Horowitz, 1981), indicate that impaired function proceeds in a rostro-caudal progression as field strength is increased.

  1. Insulin signaling is acutely required for long-term memory in Drosophila.

    PubMed

    Chambers, Daniel B; Androschuk, Alaura; Rosenfelt, Cory; Langer, Steven; Harding, Mark; Bolduc, Francois V

    2015-01-01

    Memory formation has been shown recently to be dependent on energy status in Drosophila. A well-established energy sensor is the insulin signaling (InS) pathway. Previous studies in various animal models including human have revealed the role of insulin levels in short-term memory but its role in long-term memory remains less clear. We therefore investigated genetically the spatial and temporal role of InS using the olfactory learning and long-term memory model in Drosophila. We found that InS is involved in both learning and memory. InS in the mushroom body is required for learning and long-term memory whereas long-term memory specifically is impaired after InS signaling disruption in the ellipsoid body, where it regulates the level of p70s6k, a downstream target of InS and a marker of protein synthesis. Finally, we show also that InS is acutely required for long-term memory formation in adult flies.

  2. Dehydroepiandrosterone Stimulation of Osteoblastogenesis in Human MSCs Requires IGF-I Signaling.

    PubMed

    Liang, Xiaonan; Glowacki, Julie; Hahne, Jochen; Xie, Li; LeBoff, Meryl S; Zhou, Shuanhu

    2016-08-01

    Dehydroepiandrosterone (DHEA) is an adrenal steroid that circulates in high concentrations in humans in its sulfated form, DHEAS. Clinical and epidemiological studies suggested that low DHEAS levels may be associated with low bone mass. Previously, we and others showed that the effects of DHEA on the skeleton may be conferred partly by their ability to inhibit skeletal catabolic agents, for example, bone resorptive cytokine IL-6. In this study, we tested the hypothesis that the anabolic effects of DHEA on osteoblastogenesis require IGF-I signaling pathways. Using both primary cultures and a cell line of human bone marrow-derived mesenchymal stem cells (hMSCs), we show that DHEA and other steroids stimulate osteoblastogenesis as shown by alkaline phosphatase activity and osteoblast gene induction. The stimulation by DHEA on both IGF-I gene expression and osteoblastogenesis in hMSCs requires IGF-I receptor, PI3K, p38 MAPK, or p42/44 MAPK signaling pathways. This study adds information to indicate that DHEA may be useful for treating bone diseases through its inhibition of skeletal catabolic IL-6 and stimulation of anabolic IGF-I-mediated mechanisms. J. Cell. Biochem. 117: 1769-1774, 2016. © 2015 Wiley Periodicals, Inc. PMID:26682953

  3. Hmga2 is required for canonical WNT signaling during lung development

    PubMed Central

    2014-01-01

    Background The high-mobility-group (HMG) proteins are the most abundant non-histone chromatin-associated proteins. HMG proteins are present at high levels in various undifferentiated tissues during embryonic development and their levels are strongly reduced in the corresponding adult tissues, where they have been implicated in maintaining and activating stem/progenitor cells. Here we deciphered the role of the high-mobility-group AT-hook protein 2 (HMGA2) during lung development by analyzing the lung of Hmga2-deficient mice (Hmga2 −/− ). Results We found that Hmga2 is expressed in the mouse embryonic lung at the distal airways. Analysis of Hmga2 −/− mice showed that Hmga2 is required for proper cell proliferation and distal epithelium differentiation during embryonic lung development. Hmga2 knockout led to enhanced canonical WNT signaling due to an increased expression of secreted WNT glycoproteins Wnt2b, Wnt7b and Wnt11 as well as a reduction of the WNT signaling antagonizing proteins GATA-binding protein 6 and frizzled homolog 2. Analysis of siRNA-mediated loss-of-function experiments in embryonic lung explant culture confirmed the role of Hmga2 as a key regulator of distal lung epithelium differentiation and supported the causal involvement of enhanced canonical WNT signaling in mediating the effect of Hmga2-loss-of-fuction. Finally, we found that HMGA2 directly regulates Gata6 and thereby modulates Fzd2 expression. Conclusions Our results support that Hmga2 regulates canonical WNT signaling at different points of the pathway. Increased expression of the secreted WNT glycoproteins might explain a paracrine effect by which Hmga2-knockout enhanced cell proliferation in the mesenchyme of the developing lung. In addition, HMGA2-mediated direct regulation of Gata6 is crucial for fine-tuning the activity of WNT signaling in the airway epithelium. Our results are the starting point for future studies investigating the relevance of Hmga2-mediated regulation of

  4. Gpr177-mediated Wnt Signaling Is Required for Secondary Palate Development.

    PubMed

    Liu, Y; Wang, M; Zhao, W; Yuan, X; Yang, X; Li, Y; Qiu, M; Zhu, X-J; Zhang, Z

    2015-07-01

    Cleft palate represents one of the major congenital birth defects in humans. Despite the essential roles of ectodermal canonical Wnt and mesenchymal Wnt signaling in the secondary palate development, the function of mesenchymal canonical Wnt activity in secondary palate development remains elusive. Here we show that Gpr177, a highly conserved transmembrane protein essential for Wnt trafficking, is required for secondary palate development. Gpr177 is expressed in both epithelium and mesenchyme of palatal shelves during mouse development. Wnt1(Cre)-mediated deletion of Gpr177 in craniofacial neural crest cells leads to a complete cleft secondary palate, which is formed mainly due to aberrant cell proliferation and increased cell death in palatal shelves. By BATGAL staining, we reveal an intense canonical Wnt activity in the anterior palate mesenchyme of E12.5 wild-type embryos but not in Gpr177(Wnt1-Cre) embryos, suggesting that mesenchymal canonical Wnt signaling activated by Gpr177-mediated mesenchymal Wnts is critical for secondary palate development. Moreover, phosphorylation of JNK and c-Jun is impaired in the Gpr177(Wnt1-Cre) palate and is restored by implantation of Wnt5a-soaked beads in the in vitro palate explants, suggesting that Gpr177 probably regulates palate development via the Wnt5a-mediated noncanonical Wnt pathway in which c-Jun and JNK are involved. Importantly, certain cellular processes and the altered gene expression in palates lacking Gpr177 are distinct from that of the Wnt5a mutant, further demonstrating involvement of other mesenchymal Wnts in the process of palate development. Together, these results suggest that mesenchymal Gpr177 is required for secondary palate development by regulating and integrating mesenchymal canonical and noncanonical Wnt signals.

  5. Neural crest induction by paraxial mesoderm in Xenopus embryos requires FGF signals.

    PubMed

    Monsoro-Burq, Anne-Hélène; Fletcher, Russell B; Harland, Richard M

    2003-07-01

    At the border of the neural plate, the induction of the neural crest can be achieved by interactions with the epidermis, or with the underlying mesoderm. Wnt signals are required for the inducing activity of the epidermis in chick and amphibian embryos. Here, we analyze the molecular mechanisms of neural crest induction by the mesoderm in Xenopus embryos. Using a recombination assay, we show that prospective paraxial mesoderm induces a panel of neural crest markers (Slug, FoxD3, Zic5 and Sox9), whereas the future axial mesoderm only induces a subset of these genes. This induction is blocked by a dominant negative (dn) form of FGFR1. However, neither dnFGFR4a nor inhibition of Wnt signaling prevents neural crest induction in this system. Among the FGFs, FGF8 is strongly expressed by the paraxial mesoderm. FGF8 is sufficient to induce the neural crest markers FoxD3, Sox9 and Zic5 transiently in the animal cap assay. In vivo, FGF8 injections also expand the Slug expression domain. This suggests that FGF8 can initiate neural crest formation and cooperates with other DLMZ-derived factors to maintain and complete neural crest induction. In contrast to Wnts, eFGF or bFGF, FGF8 elicits neural crest induction in the absence of mesoderm induction and without a requirement for BMP antagonists. In vivo, it is difficult to dissociate the roles of FGF and WNT factors in mesoderm induction and neural patterning. We show that, in most cases, effects on neural crest formation were parallel to altered mesoderm or neural development. However, neural and neural crest patterning can be dissociated experimentally using different dominant-negative manipulations: while Nfz8 blocks both posterior neural plate formation and neural crest formation, dnFGFR4a blocks neural patterning without blocking neural crest formation. These results suggest that different signal transduction mechanisms may be used in neural crest induction, and anteroposterior neural patterning. PMID:12783784

  6. Auditory processing deficits in reading disabled adults.

    PubMed

    Amitay, Sygal; Ahissar, Meray; Nelken, Israel

    2002-09-01

    The nature of the auditory processing deficit of disabled readers is still an unresolved issue. The quest for a fundamental, nonlinguistic, perceptual impairment has been dominated by the hypothesis that the difficulty lies in processing sequences of stimuli at presentation rates of tens of milliseconds. The present study examined this hypothesis using tasks that require processing of a wide range of stimulus time constants. About a third of the sampled population of disabled readers (classified as "poor auditory processors") had difficulties in most of the tasks tested: detection of frequency differences, detection of tones in narrowband noise, detection of amplitude modulation, detection of the direction of sound sources moving in virtual space, and perception of the lateralized position of tones based on their interaural phase differences. Nevertheless, across-channel integration was intact in these poor auditory processors since comodulation masking release was not reduced. Furthermore, phase locking was presumably intact since binaural masking level differences were normal. In a further examination of temporal processing, participants were asked to discriminate two tones at various intervals where the frequency difference was ten times each individual's frequency just noticeable difference (JND). Under these conditions, poor auditory processors showed no specific difficulty at brief intervals, contrary to predictions under a fast temporal processing deficit assumption. The complementary subgroup of disabled readers who were not poor auditory processors showed some difficulty in this condition when compared with their direct controls. However, they had no difficulty on auditory tasks such as amplitude modulation detection, which presumably taps processing of similar time scales. These two subgroups of disabled readers had similar reading performance but those with a generally poor auditory performance scored lower on some cognitive tests. Taken together, these

  7. Spatial auditory processing in pinnipeds

    NASA Astrophysics Data System (ADS)

    Holt, Marla M.

    Given the biological importance of sound for a variety of activities, pinnipeds must be able to obtain spatial information about their surroundings thorough acoustic input in the absence of other sensory cues. The three chapters of this dissertation address spatial auditory processing capabilities of pinnipeds in air given that these amphibious animals use acoustic signals for reproduction and survival on land. Two chapters are comparative lab-based studies that utilized psychophysical approaches conducted in an acoustic chamber. Chapter 1 addressed the frequency-dependent sound localization abilities at azimuth of three pinniped species (the harbor seal, Phoca vitulina, the California sea lion, Zalophus californianus, and the northern elephant seal, Mirounga angustirostris). While performances of the sea lion and harbor seal were consistent with the duplex theory of sound localization, the elephant seal, a low-frequency hearing specialist, showed a decreased ability to localize the highest frequencies tested. In Chapter 2 spatial release from masking (SRM), which occurs when a signal and masker are spatially separated resulting in improvement in signal detectability relative to conditions in which they are co-located, was determined in a harbor seal and sea lion. Absolute and masked thresholds were measured at three frequencies and azimuths to determine the detection advantages afforded by this type of spatial auditory processing. Results showed that hearing sensitivity was enhanced by up to 19 and 12 dB in the harbor seal and sea lion, respectively, when the signal and masker were spatially separated. Chapter 3 was a field-based study that quantified both sender and receiver variables of the directional properties of male northern elephant seal calls produce within communication system that serves to delineate dominance status. This included measuring call directivity patterns, observing male-male vocally-mediated interactions, and an acoustic playback study

  8. Auditory models for speech analysis

    NASA Astrophysics Data System (ADS)

    Maybury, Mark T.

    This paper reviews the psychophysical basis for auditory models and discusses their application to automatic speech recognition. First an overview of the human auditory system is presented, followed by a review of current knowledge gleaned from neurological and psychoacoustic experimentation. Next, a general framework describes established peripheral auditory models which are based on well-understood properties of the peripheral auditory system. This is followed by a discussion of current enhancements to that models to include nonlinearities and synchrony information as well as other higher auditory functions. Finally, the initial performance of auditory models in the task of speech recognition is examined and additional applications are mentioned.

  9. Biological impact of music and software-based auditory training

    PubMed Central

    Kraus, Nina

    2012-01-01

    Auditory-based communication skills are developed at a young age and are maintained throughout our lives. However, some individuals – both young and old – encounter difficulties in achieving or maintaining communication proficiency. Biological signals arising from hearing sounds relate to real-life communication skills such as listening to speech in noisy environments and reading, pointing to an intersection between hearing and cognition. Musical experience, amplification, and software-based training can improve these biological signals. These findings of biological plasticity, in a variety of subject populations, relate to attention and auditory memory, and represent an integrated auditory system influenced by both sensation and cognition. Learning outcomes The reader will (1) understand that the auditory system is malleable to experience and training, (2) learn the ingredients necessary for auditory learning to successfully be applied to communication, (3) learn that the auditory brainstem response to complex sounds (cABR) is a window into the integrated auditory system, and (4) see examples of how cABR can be used to track the outcome of experience and training. PMID:22789822

  10. Aspergillus nidulans Ambient pH Signaling Does Not Require Endocytosis.

    PubMed

    Lucena-Agell, Daniel; Galindo, Antonio; Arst, Herbert N; Peñalva, Miguel A

    2015-06-01

    Aspergillus nidulans (Pal) ambient pH signaling takes place in cortical structures containing components of the ESCRT pathway, which are hijacked by the alkaline pH-activated, ubiquitin-modified version of the arrestin-like protein PalF and taken to the plasma membrane. There, ESCRTs scaffold the assembly of dedicated Pal proteins acting downstream. The molecular details of this pathway, which results in the two-step proteolytic processing of the transcription factor PacC, have received considerable attention due to the key role that it plays in fungal pathogenicity. While current evidence strongly indicates that the pH signaling role of ESCRT complexes is limited to plasma membrane-associated structures where PacC proteolysis would take place, the localization of the PalB protease, which almost certainly catalyzes the first and only pH-regulated proteolytic step, had not been investigated. In view of ESCRT participation, this formally leaves open the possibility that PalB activation requires endocytic internalization. As endocytosis is essential for hyphal growth, nonlethal endocytic mutations are predicted to cause an incomplete block. We used a SynA internalization assay to measure the extent to which any given mutation prevents endocytosis. We show that none of the tested mutations impairing endocytosis to different degrees, including slaB1, conditionally causing a complete block, have any effect on the activation of the pathway. We further show that PalB, like PalA and PalC, localizes to cortical structures in an alkaline pH-dependent manner. Therefore, signaling through the Pal pathway does not involve endocytosis.

  11. Leptin signaling in GABA neurons, but not glutamate neurons, is required for reproductive function.

    PubMed

    Zuure, Wieteke A; Roberts, Amy L; Quennell, Janette H; Anderson, Greg M

    2013-11-01

    The adipocyte-derived hormone leptin acts in the brain to modulate the central driver of fertility: the gonadotropin releasing hormone (GnRH) neuronal system. This effect is indirect, as GnRH neurons do not express leptin receptors (LEPRs). Here we test whether GABAergic or glutamatergic neurons provide the intermediate pathway between the site of leptin action and the GnRH neurons. Leptin receptors were deleted from GABA and glutamate neurons using Cre-Lox transgenics, and the downstream effects on puberty onset and reproduction were examined. Both mouse lines displayed the expected increase in body weight and region-specific loss of leptin signaling in the hypothalamus. The GABA neuron-specific LEPR knock-out females and males showed significantly delayed puberty onset. Adult fertility observations revealed that these knock-out animals have decreased fecundity. In contrast, glutamate neuron-specific LEPR knock-out mice displayed normal fertility. Assessment of the estrogenic hypothalamic-pituitary-gonadal axis regulation in females showed that leptin action on GABA neurons is not necessary for estradiol-mediated suppression of tonic luteinizing hormone secretion (an indirect measure of GnRH neuron activity) but is required for regulation of a full preovulatory-like luteinizing hormone surge. In conclusion, leptin signaling in GABAergic (but not glutamatergic neurons) plays a critical role in the timing of puberty onset and is involved in fertility regulation throughout adulthood in both sexes. These results form an important step in explaining the role of central leptin signaling in the reproductive system. Limiting the leptin-to-GnRH mediators to GABAergic cells will enable future research to focus on a few specific types of neurons.

  12. Does murine spermatogenesis require WNT signalling? A lesson from Gpr177 conditional knockout mouse models.

    PubMed

    Chen, Su-Ren; Tang, J-X; Cheng, J-M; Hao, X-X; Wang, Y-Q; Wang, X-X; Liu, Y-X

    2016-01-01

    Wingless-related MMTV integration site (WNT) proteins and several other components of the WNT signalling pathway are expressed in the murine testes. However, mice mutant for WNT signalling effector β-catenin using different Cre drivers have phenotypes that are inconsistent with each other. The complexity and overlapping expression of WNT signalling cascades have prevented researchers from dissecting their function in spermatogenesis. Depletion of the Gpr177 gene (the mouse orthologue of Drosophila Wntless), which is required for the secretion of various WNTs, makes it possible to genetically dissect the overall effect of WNTs in testis development. In this study, the Gpr177 gene was conditionally depleted in germ cells (Gpr177(flox/flox), Mvh-Cre; Gpr177(flox/flox), Stra8-Cre) and Sertoli cells (Gpr177(flox/flox), Amh-Cre). No obvious defects in fertility and spermatogenesis were observed in these three Gpr177 conditional knockout (cKO) mice at 8 weeks. However, late-onset testicular atrophy and fertility decline in two germ cell-specific Gpr177 deletion mice were noted at 8 months. In contrast, we did not observe any abnormalities of spermatogenesis and fertility, even in 8-month-old Gpr177(flox/flox), Amh-Cre mice. Elevation of reactive oxygen species (ROS) was detected in Gpr177 cKO germ cells and Sertoli cells and exhibited an age-dependent manner. However, significant increase in the activity of Caspase 3 was only observed in germ cells from 8-month-old germ cell-specific Gpr177 knockout mice. In conclusion, GPR177 in Sertoli cells had no apparent influence on spermatogenesis, whereas loss of GPR177 in germ cells disrupted spermatogenesis in an age-dependent manner via elevating ROS levels and triggering germ cell apoptosis. PMID:27362799

  13. Differential Requirement for LAT and SLP-76 in GPVI versus T Cell Receptor Signaling

    PubMed Central

    Judd, Barbi A.; Myung, Peggy S.; Obergfell, Achim; Myers, Erin E.; Cheng, Alec M.; Watson, Stephen P.; Pear, Warren S.; Allman, David; Shattil, Sanford J.; Koretzky, Gary A.

    2002-01-01

    Mice deficient in the adaptor Src homology 2 domain-containing leukocyte phosphoprotein of 76 kD (SLP-76) exhibit a bleeding disorder and lack T cells. Linker for activation of T cells (LAT)-deficient mice exhibit a similar T cell phenotype, but show no signs of hemorrhage. Both SLP-76 and LAT are important for optimal platelet activation downstream of the collagen receptor, GPVI. In addition, SLP-76 is involved in signaling mediated by integrin αIIbβ3. Because SLP-76 and LAT function coordinately in T cell signal transduction, yet their roles appear to differ in hemostasis, we investigated in detail the functional consequences of SLP-76 and LAT deficiencies in platelets. Previously we have shown that LAT−/− platelets exhibit defective responses to the GPVI-specific agonist, collagen-related peptide (CRP). Consistent with this, we find that surface expression of P-selectin in response to high concentrations of GPVI ligands is reduced in both LAT- and SLP-76–deficient platelets. However, platelets from LAT−/− mice, but not SLP-76−/− mice, aggregate normally in response to high concentrations of collagen and convulxin. Additionally, unlike SLP-76, LAT is not tyrosine phosphorylated after fibrinogen binding to integrin αIIbβ3, and collagen-stimulated platelets deficient in LAT spread normally on fibrinogen-coated surfaces. Together, these findings indicate that while LAT and SLP-76 are equally required for signaling via the T cell antigen receptor (TCR) and pre-TCR, platelet activation downstream of GPVI and αIIbβ3 shows a much greater dependency on SLP-76 than LAT. PMID:11901197

  14. Auxin binding protein 1 (ABP1) is not required for either auxin signaling or Arabidopsis development.

    PubMed

    Gao, Yangbin; Zhang, Yi; Zhang, Da; Dai, Xinhua; Estelle, Mark; Zhao, Yunde

    2015-02-17

    Auxin binding protein 1 (ABP1) has been studied for decades. It has been suggested that ABP1 functions as an auxin receptor and has an essential role in many developmental processes. Here we present our unexpected findings that ABP1 is neither required for auxin signaling nor necessary for plant development under normal growth conditions. We used our ribozyme-based CRISPR technology to generate an Arabidopsis abp1 mutant that contains a 5-bp deletion in the first exon of ABP1, which resulted in a frameshift and introduction of early stop codons. We also identified a T-DNA insertion abp1 allele that harbors a T-DNA insertion located 27 bp downstream of the ATG start codon in the first exon. We show that the two new abp1 mutants are null alleles. Surprisingly, our new abp1 mutant plants do not display any obvious developmental defects. In fact, the mutant plants are indistinguishable from wild-type plants at every developmental stage analyzed. Furthermore, the abp1 plants are not resistant to exogenous auxin. At the molecular level, we find that the induction of known auxin-regulated genes is similar in both wild-type and abp1 plants in response to auxin treatments. We conclude that ABP1 is not a key component in auxin signaling or Arabidopsis development. PMID:25646447

  15. Auxin binding protein 1 (ABP1) is not required for either auxin signaling or Arabidopsis development.

    PubMed

    Gao, Yangbin; Zhang, Yi; Zhang, Da; Dai, Xinhua; Estelle, Mark; Zhao, Yunde

    2015-02-17

    Auxin binding protein 1 (ABP1) has been studied for decades. It has been suggested that ABP1 functions as an auxin receptor and has an essential role in many developmental processes. Here we present our unexpected findings that ABP1 is neither required for auxin signaling nor necessary for plant development under normal growth conditions. We used our ribozyme-based CRISPR technology to generate an Arabidopsis abp1 mutant that contains a 5-bp deletion in the first exon of ABP1, which resulted in a frameshift and introduction of early stop codons. We also identified a T-DNA insertion abp1 allele that harbors a T-DNA insertion located 27 bp downstream of the ATG start codon in the first exon. We show that the two new abp1 mutants are null alleles. Surprisingly, our new abp1 mutant plants do not display any obvious developmental defects. In fact, the mutant plants are indistinguishable from wild-type plants at every developmental stage analyzed. Furthermore, the abp1 plants are not resistant to exogenous auxin. At the molecular level, we find that the induction of known auxin-regulated genes is similar in both wild-type and abp1 plants in response to auxin treatments. We conclude that ABP1 is not a key component in auxin signaling or Arabidopsis development.

  16. Learned stressor resistance requires extracellular signal-regulated kinase in the prefrontal cortex

    PubMed Central

    Christianson, John P.; Flyer-Adams, Johanna G.; Drugan, Robert C.; Amat, Jose; Daut, Rachel A.; Foilb, Allison R.; Watkins, Linda R.; Maier, Steven F.

    2014-01-01

    Behaviorally controllable stressors confer protection from the neurochemical and behavioral consequences of future uncontrollable stressors, a phenomenon termed “behavioral immunization”. Recent data implicate protein synthesis within the ventromedial prefrontal cortex (mPFC) as critical to behavioral immunization. Adult, male Sprague-Dawley rats were exposed to a series of controllable tailshocks and 1 week later to uncontrollable tailshocks, followed 24 h later by social exploration and shuttlebox escape tests. To test the involvement of N-methyl-D-aspartate receptors (NMDARs) and the extracellular signal-regulated kinase (ERK) cascade in behavioral immunization, either D-AP5 or the MEK inhibitor U0126 was injected to the prelimbic (PL) or infralimbic (IL) mPFC prior to controllable stress exposure. Phosphorylated ERK and P70S6K, regulators of transcription and translation, were quantified by Western blot or immunohistochemistry after controllable or uncontrollable tailshocks. Prior controllable stress prevented the social exploration and shuttlebox performance deficits caused by the later uncontrollable stressor, and this effect was blocked by injections of D-AP5 into mPFC. A significant increase in phosphorylated ERK1 and ERK2, but not P70S6K, occurred within the PL and IL in rats exposed to controllable stress, but not to uncontrollable stress. However, U0126 only prevented behavioral immunization when injected to the PL. We provide evidence that NMDAR and ERK dependent signaling within the PL region is required for behavioral immunization, a learned form of stressor resistance. PMID:25324750

  17. β1 integrin-mediated signals are required for platelet granule secretion and hemostasis in mouse.

    PubMed

    Petzold, Tobias; Ruppert, Raphael; Pandey, Dharmendra; Barocke, Verena; Meyer, Hannelore; Lorenz, Michael; Zhang, Lin; Siess, Wolfgang; Massberg, Steffen; Moser, Markus

    2013-10-10

    Integrins are critical for platelet adhesion and aggregation during arterial thrombosis and hemostasis. Although the platelet-specific αIIbβ3 integrin is known to be crucial for these processes, the in vivo role of β1 integrins is a matter of debate. Here we demonstrate that mice expressing reduced levels of β1 integrins or an activation-deficient β1 integrin show strongly reduced platelet adhesion to collagen in vitro and in a carotis ligation model in vivo. Interestingly, hypomorphic mice expressing only 3% of β1 integrins on platelets show normal bleeding times despite reduced platelet adhesion. The residual 3% of β1 integrins are able to trigger intracellular signals driving Rac-1-dependent granule release required for platelet aggregation and hemostasis. Our findings support a model, in which platelet β1 integrins serve as an important signaling receptor rather than an adhesion receptor in vivo and therefore promote β1 integrins as a promising and so far clinically unemployed antithrombotic target.

  18. A Supraphysiological Nuclear Export Signal Is Required for Parvovirus Nuclear Export

    PubMed Central

    Engelsma, Dieuwke; Valle, Noelia; Fish, Alexander; Salomé, Nathalie; Almendral, José M.

    2008-01-01

    CRM1 exports proteins that carry a short leucine-rich peptide signal, the nuclear export signal (NES), from the nucleus. Regular NESs must have low affinity for CRM1 to function optimally. We previously generated artificial NESs with higher affinities for CRM1, termed supraphysiological NESs. Here we identify a supraphysiological NES in an endogenous protein, the NS2 protein of parvovirus Minute Virus of Mice (MVM). NS2 interacts with CRM1 without the requirement of RanGTP, whereas addition of RanGTP renders the complex highly stable. Mutation of a single hydrophobic residue that inactivates regular NESs lowers the affinity of the NS2 NES for CRM1 from supraphysiological to regular. Mutant MVM harboring this regular NES is compromised in viral nuclear export and productivity. In virus-infected mouse fibroblasts we observe colocalization of NS2, CRM1 and mature virions, which is dependent on the supraphysiological NS2 NES. We conclude that supraphysiological NESs exist in nature and that the supraphysiological NS2 NES has a critical role in active nuclear export of mature MVM particles before cell lysis. PMID:18385513

  19. Gorab Is Required for Dermal Condensate Cells to Respond to Hedgehog Signals during Hair Follicle Morphogenesis.

    PubMed

    Liu, Ying; Snedecor, Elizabeth R; Choi, Yeon Ja; Yang, Ning; Zhang, Xu; Xu, Yuhuan; Han, Yunlin; Jones, Evan C; Shroyer, Kenneth R; Clark, Richard A; Zhang, Lianfeng; Qin, Chuan; Chen, Jiang

    2016-02-01

    GORAB is a golgin that localizes predominantly at the Golgi apparatus and physically interacts with small guanosine triphosphatases. GORAB is ubiquitously expressed in mammalian tissues, including the skin. However, the biological function of this golgin in skin is unknown. Here, we report that disrupting the expression of the Gorab gene in mice results in hair follicle morphogenesis defects that were characterized by impaired follicular keratinocyte differentiation. This hair follicle phenotype was associated with markedly suppressed hedgehog (Hh) signaling pathway in dermal condensates in vivo. Gorab-deficient dermal mesenchymal cells also displayed a significantly reduced capability to respond to Hh pathway activation in vitro. Furthermore, we found that the formation of the primary cilium, a cellular organelle that is essential for the Hh pathway, was impaired in mutant dermal condensate cells, suggesting that Gorab may be required for the Hh pathway through facilitating the formation of primary cilia. Thus, data obtained from this study provided insight into the biological functions of Gorab during embryonic morphogenesis of the skin in which Hh signaling and primary cilia exert important functions. PMID:26967474

  20. Gorab is required for dermal condensate cells to respond to hedgehog signals during hair follicle morphogenesis

    PubMed Central

    Liu, Ying; Snedecor, Elizabeth R.; Choi, Yeon Ja; Yang, Ning; Zhang, Xu; Xu, Yuhuan; Han, Yunlin; Jones, Evan C.; Shroyer, Kenneth R.; Clark, Richard A.; Zhang, Lianfeng; Qin, Chuan; Chen, Jiang

    2015-01-01

    GORAB is a golgin that localizes predominantly at the Golgi apparatus and physically interacts with small GTPases. GORAB is ubiquitously expressed in mammalian tissues, including the skin. However, the biological function of this golgin in skin is unknown. Here, we report that disrupting the expression of the Gorab gene in mice results in hair follicle morphogenesis defects that were characterized by impaired follicular keratinocyte differentiation. This hair follicle phenotype was associated with markedly suppressed hedgehog (Hh) signaling pathway in dermal condensates in vivo. Gorab-deficient dermal mesenchymal cells also displayed significantly reduced capability to respond to Hh pathway activation in vitro. Furthermore, we found that the formation of primary cilium, a cellular organelle that is essential for the Hh pathway, was impaired in mutant dermal papilla cells, suggesting that Gorab may be required for the Hh pathway through facilitating the formation of primary cilia. Thus, data obtained from this study provided insight onto the biological functions of Gorab during embryonic morphogenesis of skin in which Hh signaling and primary cilia exert important functions. PMID:26967474

  1. Analysis of satellite altimeter signal characteristics and investigation of sea-truth data requirements

    NASA Technical Reports Server (NTRS)

    1972-01-01

    Results are presented of analysis of satellite signal characteristics as influenced by ocean surface roughness and an investigation of sea truth data requirements. The first subject treated is that of postflight waveform reconstruction for the Skylab S-193 radar altimeter. Sea state estimation accuracies are derived based on analytical and hybrid computer simulation techniques. An analysis of near-normal incidence, microwave backscattering from the ocean's surface is accomplished in order to obtain the minimum sea truth data necessary for good agreement between theoretical and experimental scattering results. Sea state bias is examined from the point of view of designing an experiment which will lead to a resolution of the problem. A discussion is given of some deficiencies which were found in the theory underlying the Stilwell technique for spectral measurements.

  2. Clock signal requirement for high-frequency, high dynamic range acquisition systems

    SciTech Connect

    Viscor, Ivo; Halamek, Josef; Villa, Marco

    2005-11-15

    Analog-to-digital converters (ADC's) are increasingly replacing mixers in frequency conversion schemes. To achieve superior performances, in terms of bandwidth and dynamic range, a nearly ideal ADC clock is needed, with a spectral purity higher than the reference signal of the classical mixing scheme. These requirements of spectral purity for the ADC clock are discussed by analyzing in detail the nonuniform sampling process and by characterizing an actual acquisition system. The effect of clock phase imperfections on the output is proportional to the input frequency over sampling frequency ratio. Moreover, at the output we may have a multiple folding of the phase jitter spectrum. These effects are illustrated by three sets of measurements performed using our system: transfer of spurious clock components, aliasing of these components, and transfer of clock phase noise.

  3. Giant cholesteatoma of the external auditory canal.

    PubMed

    Sapçi, T; Uğur, G; Karavus, A; Ağrali, N; Akbulut, U G

    1997-06-01

    Cholesteatomas are found almost exclusively in the middle ear and mastoid. Occasionally this disease is seen in the external auditory canal. Cholesteatoma of the external auditory canal is a rare condition. Severe pain and profuse discharge associated with a normal eardrum and normal hearing are essential clinical features. In addition, we found facial paresis and conductive hearing loss in our case. Smaller cholesteatomas can be managed by frequent debridement in the office; larger lesions require surgical intervention. Surgery is successful in resolving otorrhea and relieving pain. In addition, our own experience has shown that surgery is successful in relieving facial paresis.

  4. Tuning out the noise: Limbic-auditory interactions in tinnitus

    PubMed Central

    Rauschecker, Josef P.; Leaver, Amber M.; Mühlau, Mark

    2010-01-01

    Tinnitus, the most common auditory disorder, affects about 40 million people in the United States alone, and its incidence is rising due to an aging population and increasing noise exposure. Although several approaches for the alleviation of tinnitus exist, there is as of yet no cure. The present article proposes a testable model for tinnitus that is grounded in recent findings from human imaging and focuses on brain areas in cortex, thalamus, and ventral striatum. Limbic and auditory brain areas are thought to interact at the thalamic level. While a tinnitus signal originates from lesion-induced plasticity of the auditory pathways, it can be tuned out by feedback connections from limbic regions, which block the tinnitus signal from reaching auditory cortex. If the limbic regions are compromised, this “noise-cancellation” mechanism breaks down, and chronic tinnitus results. Hopefully, this model will ultimately enable the development of effective treatment. PMID:20620868

  5. Auditory processing--speech, space and auditory objects.

    PubMed

    Scott, Sophie K

    2005-04-01

    There have been recent developments in our understanding of the auditory neuroscience of non-human primates that, to a certain extent, can be integrated with findings from human functional neuroimaging studies. This framework can be used to consider the cortical basis of complex sound processing in humans, including implications for speech perception, spatial auditory processing and auditory scene segregation. PMID:15831402

  6. Auditory perception bias in speech imitation

    PubMed Central

    Postma-Nilsenová, Marie; Postma, Eric

    2013-01-01

    In an experimental study, we explored the role of auditory perception bias in vocal pitch imitation. Psychoacoustic tasks involving a missing fundamental indicate that some listeners are attuned to the relationship between all the higher harmonics present in the signal, which supports their perception of the fundamental frequency (the primary acoustic correlate of pitch). Other listeners focus on the lowest harmonic constituents of the complex sound signal which may hamper the perception of the fundamental. These two listener types are referred to as fundamental and spectral listeners, respectively. We hypothesized that the individual differences in speakers' capacity to imitate F0 found in earlier studies, may at least partly be due to the capacity to extract information about F0 from the speech signal. Participants' auditory perception bias was determined with a standard missing fundamental perceptual test. Subsequently, speech data were collected in a shadowing task with two conditions, one with a full speech signal and one with high-pass filtered speech above 300 Hz. The results showed that perception bias toward fundamental frequency was related to the degree of F0 imitation. The effect was stronger in the condition with high-pass filtered speech. The experimental outcomes suggest advantages for fundamental listeners in communicative situations where F0 imitation is used as a behavioral cue. Future research needs to determine to what extent auditory perception bias may be related to other individual properties known to improve imitation, such as phonetic talent. PMID:24204361

  7. The Effects of Exercise on Synaptic Stripping Require Androgen Receptor Signaling

    PubMed Central

    Liu, Caiyue; Ward, Patricia J.; English, Arthur W.

    2014-01-01

    Following peripheral nerve injury, synapses are withdrawn from axotomized motoneurons. Moderate daily treadmill exercise, which promotes axon regeneration of cut peripheral nerves, also influences this synaptic stripping. Different exercise protocols are required to promote axon regeneration in male and female animals, but the sex requirements for an effect of exercise on synaptic stripping are unknown. In male and female C57BL/6 mice, the sciatic nerve was transected in the mid-thigh. Mice were then exercised five days per week for two weeks, beginning on the third post-transection day. Half of the exercised mice were trained by walking slowly (10 M/min) on a level treadmill for one hour per day (continuous training). Other mice were interval trained; four short (two min) sprints at 20 M/min separated by five minute rest periods. A third group was untrained. The extent of synaptic contacts made by structures immunoreactive to vesicular glutamate transporter 1 and glutamic acid decarboxylase 67 onto axotomized motoneurons was studied in confocal images of retrogradely labeled cells. Both types of presumed synaptic contacts were reduced markedly in unexercised mice following nerve transection, relative to intact mice. No significant reduction was found in continuous trained males or interval trained females. Reductions in these contacts in interval trained males and continuous trained females were identical to that observed in untrained mice. Treatments with the anti-androgen, flutamide, blocked the effect of sex-appropriate exercise on synaptic contacts in both males and females. Moderate daily exercise has a potent effect on synaptic inputs to axotomized motoneurons. Successful effects of exercise have different requirements in males and females, but require androgen receptor signaling in both sexes. PMID:24887087

  8. A signal sequence is not required for protein export in prlA mutants of Escherichia coli.

    PubMed Central

    Derman, A I; Puziss, J W; Bassford, P J; Beckwith, J

    1993-01-01

    The prlA/secY gene, which codes for an integral membrane protein component of the Escherichia coli protein export machinery, is the locus of the strongest suppressors of signal sequence mutations. We demonstrate that two exported proteins of E.coli, maltose-binding protein and alkaline phosphatase, each lacking its entire signal sequence, are exported to the periplasm in several prlA mutants. The export efficiency can be substantial; in a strain carrying the prlA4 allele, 30% of signal-sequenceless alkaline phosphatase is exported to the periplasm. Other components of the E.coli export machinery, including SecA, are required for this export. SecB is required for the export of signal-sequenceless alkaline phosphatase even though the normal export of alkaline phosphatase does not require this chaperonin. Our findings indicate that signal sequences confer speed and efficiency upon the export process, but that they are not always essential for export. Entry into the export pathway may involve components that so overlap in function that the absence of a signal sequence can be compensated for, or there may exist one or more means of entry that do not require signal sequences at all. Images PMID:8458344

  9. Ror2 signaling is required for local upregulation of GFD6 and activation of BMP signaling at the neural plate border.

    PubMed

    Schille, Carolin; Bayerlová, Michaela; Bleckmann, Annalen; Schambony, Alexandra

    2016-09-01

    The receptor tyrosine kinase Ror2 is a major Wnt receptor that activates β-catenin-independent signaling and plays a conserved role in the regulation of convergent extension movements and planar cell polarity in vertebrates. Mutations in the ROR2 gene cause recessive Robinow syndrome in humans, a short-limbed dwarfism associated with craniofacial malformations. Here, we show that Ror2 is required for local upregulation of gdf6 at the neural plate border in Xenopus embryos. Ror2 morphant embryos fail to upregulate neural plate border genes and show defects in the induction of neural crest cell fate. These embryos lack the spatially restricted activation of BMP signaling at the neural plate border at early neurula stages, which is required for neural crest induction. Ror2-dependent planar cell polarity signaling is required in the dorsolateral marginal zone during gastrulation indirectly to upregulate the BMP ligand Gdf6 at the neural plate border and Gdf6 is sufficient to rescue neural plate border specification in Ror2 morphant embryos. Thereby, Ror2 links Wnt/planar cell polarity signaling to BMP signaling in neural plate border specification and neural crest induction. PMID:27578181

  10. Ror2 signaling is required for local upregulation of GFD6 and activation of BMP signaling at the neural plate border.

    PubMed

    Schille, Carolin; Bayerlová, Michaela; Bleckmann, Annalen; Schambony, Alexandra

    2016-09-01

    The receptor tyrosine kinase Ror2 is a major Wnt receptor that activates β-catenin-independent signaling and plays a conserved role in the regulation of convergent extension movements and planar cell polarity in vertebrates. Mutations in the ROR2 gene cause recessive Robinow syndrome in humans, a short-limbed dwarfism associated with craniofacial malformations. Here, we show that Ror2 is required for local upregulation of gdf6 at the neural plate border in Xenopus embryos. Ror2 morphant embryos fail to upregulate neural plate border genes and show defects in the induction of neural crest cell fate. These embryos lack the spatially restricted activation of BMP signaling at the neural plate border at early neurula stages, which is required for neural crest induction. Ror2-dependent planar cell polarity signaling is required in the dorsolateral marginal zone during gastrulation indirectly to upregulate the BMP ligand Gdf6 at the neural plate border and Gdf6 is sufficient to rescue neural plate border specification in Ror2 morphant embryos. Thereby, Ror2 links Wnt/planar cell polarity signaling to BMP signaling in neural plate border specification and neural crest induction.

  11. Rho/Rock signal transduction pathway is required for MSC tenogenic differentiation

    PubMed Central

    Maharam, Edward; Yaport, Miguel; Villanueva, Nathaniel L; Akinyibi, Takintope; Laudier, Damien; He, Zhiyong; Leong, Daniel J; Sun, Hui B

    2015-01-01

    Mesenchymal stem cell (MSC)-based treatments have shown promise for improving tendon healing and repair. MSCs have the potential to differentiate into multiple lineages in response to select chemical and physical stimuli, including into tenocytes. Cell elongation and cytoskeletal tension have been shown to be instrumental to the process of MSC differentiation. Previous studies have shown that inhibition of stress fiber formation leads MSCs to default toward an adipogenic lineage, which suggests that stress fibers are required for MSCs to sense the environmental factors that can induce differentiation into tenocytes. As the Rho/ROCK signal transduction pathway plays a critical role in both stress fiber formation and in cell sensation, we examined whether the activation of this pathway was required when inducing MSC tendon differentiation using rope-like silk scaffolds. To accomplish this, we employed a loss-of-function approach by knocking out ROCK, actin and myosin (two other components of the pathway) using the specific inhibitors Y-27632, Latrunculin A and blebbistatin, respectively. We demonstrated that independently disrupting the cytoskeleton and the Rho/ROCK pathway abolished the expression of tendon differentiation markers and led to a loss of spindle morphology. Together, these studies suggest that the tension that is generated by MSC elongation is essential for MSC teno-differentiation and that the Rho/ROCK pathway is a critical mediator of tendon differentiation on rope-like silk scaffolds. PMID:26509098

  12. Transcription-dependent nuclear localization of DAZAP1 requires an N-terminal signal

    SciTech Connect

    Lin, Yi-Tzu; Wen, Wan-Ching; Yen, Pauline H.

    2012-11-23

    Highlights: Black-Right-Pointing-Pointer DAZAP1 shuttles between the nucleus and the cytoplasm. Black-Right-Pointing-Pointer DAZAP1 accumulates in the cytoplasm when the nuclear transcription is inhibited. Black-Right-Pointing-Pointer DAZAP1's transcription-dependent nuclear localization requires N-terminal N42. Black-Right-Pointing-Pointer SLIRP binds to N42 and may be involved in the process. -- Abstract: Deleted in Azoospermia Associated Protein 1 (DAZAP1) is a ubiquitous hnRNP protein required for normal development and spermatogenesis. It resides predominantly in the nucleus and moves between the nucleus and the cytoplasm via a ZNS shuttling signal at its C-terminus. DAZAP1 accumulates in the cytoplasm when RNA polymerase II activity is inhibited by actinomycin D. Here we report the mapping of a 42-amino acid segment (N42) at the N-terminus of DAZAP1 that is both necessary and sufficient for its transcription-dependent nuclear localization. In addition, using a yeast two-hybrid system, we have identified SLIRP as a N42-binding protein which may regulate DAZAP1 subcellular localization.

  13. Comparisons of memory for nonverbal auditory and visual sequential stimuli.

    PubMed

    McFarland, D J; Cacace, A T

    1995-01-01

    Properties of auditory and visual sensory memory were compared by examining subjects' recognition performance of randomly generated binary auditory sequential frequency patterns and binary visual sequential color patterns within a forced-choice paradigm. Experiment 1 demonstrated serial-position effects in auditory and visual modalities consisting of both primacy and recency effects. Experiment 2 found that retention of auditory and visual information was remarkably similar when assessed across a 10s interval. Experiments 3 and 4, taken together, showed that the recency effect in sensory memory is affected more by the type of response required (recognition vs. reproduction) than by the sensory modality employed. These studies suggest that auditory and visual sensory memory stores for nonverbal stimuli share similar properties with respect to serial-position effects and persistence over time.

  14. Central auditory neurons have composite receptive fields

    PubMed Central

    Kozlov, Andrei S.; Gentner, Timothy Q.

    2016-01-01

    High-level neurons processing complex, behaviorally relevant signals are sensitive to conjunctions of features. Characterizing the receptive fields of such neurons is difficult with standard statistical tools, however, and the principles governing their organization remain poorly understood. Here, we demonstrate multiple distinct receptive-field features in individual high-level auditory neurons in a songbird, European starling, in response to natural vocal signals (songs). We then show that receptive fields with similar characteristics can be reproduced by an unsupervised neural network trained to represent starling songs with a single learning rule that enforces sparseness and divisive normalization. We conclude that central auditory neurons have composite receptive fields that can arise through a combination of sparseness and normalization in neural circuits. Our results, along with descriptions of random, discontinuous receptive fields in the central olfactory neurons in mammals and insects, suggest general principles of neural computation across sensory systems and animal classes. PMID:26787894

  15. Impact of Educational Level on Performance on Auditory Processing Tests.

    PubMed

    Murphy, Cristina F B; Rabelo, Camila M; Silagi, Marcela L; Mansur, Letícia L; Schochat, Eliane

    2016-01-01

    Research has demonstrated that a higher level of education is associated with better performance on cognitive tests among middle-aged and elderly people. However, the effects of education on auditory processing skills have not yet been evaluated. Previous demonstrations of sensory-cognitive interactions in the aging process indicate the potential importance of this topic. Therefore, the primary purpose of this study was to investigate the performance of middle-aged and elderly people with different levels of formal education on auditory processing tests. A total of 177 adults with no evidence of cognitive, psychological or neurological conditions took part in the research. The participants completed a series of auditory assessments, including dichotic digit, frequency pattern and speech-in-noise tests. A working memory test was also performed to investigate the extent to which auditory processing and cognitive performance were associated. The results demonstrated positive but weak correlations between years of schooling and performance on all of the tests applied. The factor "years of schooling" was also one of the best predictors of frequency pattern and speech-in-noise test performance. Additionally, performance on the working memory, frequency pattern and dichotic digit tests was also correlated, suggesting that the influence of educational level on auditory processing performance might be associated with the cognitive demand of the auditory processing tests rather than auditory sensory aspects itself. Longitudinal research is required to investigate the causal relationship between educational level and auditory processing skills.

  16. Impact of Educational Level on Performance on Auditory Processing Tests

    PubMed Central

    Murphy, Cristina F. B.; Rabelo, Camila M.; Silagi, Marcela L.; Mansur, Letícia L.; Schochat, Eliane

    2016-01-01

    Research has demonstrated that a higher level of education is associated with better performance on cognitive tests among middle-aged and elderly people. However, the effects of education on auditory processing skills have not yet been evaluated. Previous demonstrations of sensory-cognitive interactions in the aging process indicate the potential importance of this topic. Therefore, the primary purpose of this study was to investigate the performance of middle-aged and elderly people with different levels of formal education on auditory processing tests. A total of 177 adults with no evidence of cognitive, psychological or neurological conditions took part in the research. The participants completed a series of auditory assessments, including dichotic digit, frequency pattern and speech-in-noise tests. A working memory test was also performed to investigate the extent to which auditory processing and cognitive performance were associated. The results demonstrated positive but weak correlations between years of schooling and performance on all of the tests applied. The factor “years of schooling” was also one of the best predictors of frequency pattern and speech-in-noise test performance. Additionally, performance on the working memory, frequency pattern and dichotic digit tests was also correlated, suggesting that the influence of educational level on auditory processing performance might be associated with the cognitive demand of the auditory processing tests rather than auditory sensory aspects itself. Longitudinal research is required to investigate the causal relationship between educational level and auditory processing skills. PMID:27013958

  17. GLP-1 receptor signaling is not required for reduced body weight after RYGB in rodents.

    PubMed

    Ye, Jianping; Hao, Zheng; Mumphrey, Michael B; Townsend, R Leigh; Patterson, Laurel M; Stylopoulos, Nicholas; Münzberg, Heike; Morrison, Christopher D; Drucker, Daniel J; Berthoud, Hans-Rudolf

    2014-03-01

    Exaggerated GLP-1 and PYY secretion is thought to be a major mechanism in the reduced food intake and body weight after Roux-en-Y gastric bypass surgery. Here, we use complementary pharmacological and genetic loss-of-function approaches to test the role of increased signaling by these gut hormones in high-fat diet-induced obese rodents. Chronic brain infusion of a supramaximal dose of the selective GLP-1 receptor antagonist exendin-9-39 into the lateral cerebral ventricle significantly increased food intake and body weight in both RYGB and sham-operated rats, suggesting that, while contributing to the physiological control of food intake and body weight, central GLP-1 receptor signaling tone is not the critical mechanism uniquely responsible for the body weight-lowering effects of RYGB. Central infusion of the selective Y2R-antagonist BIIE0246 had no effect in either group, suggesting that it is not critical for the effects of RYGB on body weight under the conditions tested. In a recently established mouse model of RYGB that closely mimics surgery and weight loss dynamics in humans, obese GLP-1R-deficient mice lost the same amount of body weight and fat mass and maintained similarly lower body weight compared with wild-type mice. Together, the results surprisingly provide no support for important individual roles of either gut hormone in the specific mechanisms by which RYGB rats settle at a lower body weight. It is likely that the beneficial effects of bariatric surgeries are expressed through complex mechanisms that require combination approaches for their identification.

  18. Interface Design Implications for Recalling the Spatial Configuration of Virtual Auditory Environments

    NASA Astrophysics Data System (ADS)

    McMullen, Kyla A.

    Although the concept of virtual spatial audio has existed for almost twenty-five years, only in the past fifteen years has modern computing technology enabled the real-time processing needed to deliver high-precision spatial audio. Furthermore, the concept of virtually walking through an auditory environment did not exist. The applications of such an interface have numerous potential uses. Spatial audio has the potential to be used in various manners ranging from enhancing sounds delivered in virtual gaming worlds to conveying spatial locations in real-time emergency response systems. To incorporate this technology in real-world systems, various concerns should be addressed. First, to widely incorporate spatial audio into real-world systems, head-related transfer functions (HRTFs) must be inexpensively created for each user. The present study further investigated an HRTF subjective selection procedure previously developed within our research group. Users discriminated auditory cues to subjectively select their preferred HRTF from a publicly available database. Next, the issue of training to find virtual sources was addressed. Listeners participated in a localization training experiment using their selected HRTFs. The training procedure was created from the characterization of successful search strategies in prior auditory search experiments. Search accuracy significantly improved after listeners performed the training procedure. Next, in the investigation of auditory spatial memory, listeners completed three search and recall tasks with differing recall methods. Recall accuracy significantly decreased in tasks that required the storage of sound source configurations in memory. To assess the impacts of practical scenarios, the present work assessed the performance effects of: signal uncertainty, visual augmentation, and different attenuation modeling. Fortunately, source uncertainty did not affect listeners' ability to recall or identify sound sources. The present

  19. Multivariate sensitivity to voice during auditory categorization

    PubMed Central

    Peelle, Jonathan E.; Kraemer, David; Lloyd, Samuel; Granger, Richard

    2015-01-01

    Past neuroimaging studies have documented discrete regions of human temporal cortex that are more strongly activated by conspecific voice sounds than by nonvoice sounds. However, the mechanisms underlying this voice sensitivity remain unclear. In the present functional MRI study, we took a novel approach to examining voice sensitivity, in which we applied a signal detection paradigm to the assessment of multivariate pattern classification among several living and nonliving categories of auditory stimuli. Within this framework, voice sensitivity can be interpreted as a distinct neural representation of brain activity that correctly distinguishes human vocalizations from other auditory object categories. Across a series of auditory categorization tests, we found that bilateral superior and middle temporal cortex consistently exhibited robust sensitivity to human vocal sounds. Although the strongest categorization was in distinguishing human voice from other categories, subsets of these regions were also able to distinguish reliably between nonhuman categories, suggesting a general role in auditory object categorization. Our findings complement the current evidence of cortical sensitivity to human vocal sounds by revealing that the greatest sensitivity during categorization tasks is devoted to distinguishing voice from nonvoice categories within human temporal cortex. PMID:26245316

  20. Multivariate sensitivity to voice during auditory categorization.

    PubMed

    Lee, Yune Sang; Peelle, Jonathan E; Kraemer, David; Lloyd, Samuel; Granger, Richard

    2015-09-01

    Past neuroimaging studies have documented discrete regions of human temporal cortex that are more strongly activated by conspecific voice sounds than by nonvoice sounds. However, the mechanisms underlying this voice sensitivity remain unclear. In the present functional MRI study, we took a novel approach to examining voice sensitivity, in which we applied a signal detection paradigm to the assessment of multivariate pattern classification among several living and nonliving categories of auditory stimuli. Within this framework, voice sensitivity can be interpreted as a distinct neural representation of brain activity that correctly distinguishes human vocalizations from other auditory object categories. Across a series of auditory categorization tests, we found that bilateral superior and middle temporal cortex consistently exhibited robust sensitivity to human vocal sounds. Although the strongest categorization was in distinguishing human voice from other categories, subsets of these regions were also able to distinguish reliably between nonhuman categories, suggesting a general role in auditory object categorization. Our findings complement the current evidence of cortical sensitivity to human vocal sounds by revealing that the greatest sensitivity during categorization tasks is devoted to distinguishing voice from nonvoice categories within human temporal cortex. PMID:26245316

  1. The influence of auditory-motor coupling on fractal dynamics in human gait.

    PubMed

    Hunt, Nathaniel; McGrath, Denise; Stergiou, Nicholas

    2014-01-01

    Humans exhibit an innate ability to synchronize their movements to music. The field of gait rehabilitation has sought to capitalize on this phenomenon by invoking patients to walk in time to rhythmic auditory cues with a view to improving pathological gait. However, the temporal structure of the auditory cue, and hence the temporal structure of the target behavior has not been sufficiently explored. This study reveals the plasticity of auditory-motor coupling in human walking in relation to 'complex' auditory cues. The authors demonstrate that auditory-motor coupling can be driven by different coloured auditory noise signals (e.g. white, brown), shifting the fractal temporal structure of gait dynamics towards the statistical properties of the signals used. This adaptive capability observed in whole-body movement, could potentially be harnessed for targeted neuromuscular rehabilitation in patient groups, depending on the specific treatment goal. PMID:25080936

  2. The influence of auditory-motor coupling on fractal dynamics in human gait

    PubMed Central

    Hunt, Nathaniel; McGrath, Denise; Stergiou, Nicholas

    2014-01-01

    Humans exhibit an innate ability to synchronize their movements to music. The field of gait rehabilitation has sought to capitalize on this phenomenon by invoking patients to walk in time to rhythmic auditory cues with a view to improving pathological gait. However, the temporal structure of the auditory cue, and hence the temporal structure of the target behavior has not been sufficiently explored. This study reveals the plasticity of auditory-motor coupling in human walking in relation to ‘complex' auditory cues. The authors demonstrate that auditory-motor coupling can be driven by different coloured auditory noise signals (e.g. white, brown), shifting the fractal temporal structure of gait dynamics towards the statistical properties of the signals used. This adaptive capability observed in whole-body movement, could potentially be harnessed for targeted neuromuscular rehabilitation in patient groups, depending on the specific treatment goal. PMID:25080936

  3. Auditory Channel Problems.

    ERIC Educational Resources Information Center

    Mann, Philip H.; Suiter, Patricia A.

    This teacher's guide contains a list of general auditory problem areas where students have the following problems: (a) inability to find or identify source of sound; (b) difficulty in discriminating sounds of words and letters; (c) difficulty with reproducing pitch, rhythm, and melody; (d) difficulty in selecting important from unimportant sounds;…

  4. Incidental Auditory Category Learning

    PubMed Central

    Gabay, Yafit; Dick, Frederic K.; Zevin, Jason D.; Holt, Lori L.

    2015-01-01

    Very little is known about how auditory categories are learned incidentally, without instructions to search for category-diagnostic dimensions, overt category decisions, or experimenter-provided feedback. This is an important gap because learning in the natural environment does not arise from explicit feedback and there is evidence that the learning systems engaged by traditional tasks are distinct from those recruited by incidental category learning. We examined incidental auditory category learning with a novel paradigm, the Systematic Multimodal Associations Reaction Time (SMART) task, in which participants rapidly detect and report the appearance of a visual target in one of four possible screen locations. Although the overt task is rapid visual detection, a brief sequence of sounds precedes each visual target. These sounds are drawn from one of four distinct sound categories that predict the location of the upcoming visual target. These many-to-one auditory-to-visuomotor correspondences support incidental auditory category learning. Participants incidentally learn categories of complex acoustic exemplars and generalize this learning to novel exemplars and tasks. Further, learning is facilitated when category exemplar variability is more tightly coupled to the visuomotor associations than when the same stimulus variability is experienced across trials. We relate these findings to phonetic category learning. PMID:26010588

  5. Using a Function Generator to Produce Auditory and Visual Demonstrations.

    ERIC Educational Resources Information Center

    Woods, Charles B.

    1998-01-01

    Identifies a function generator as an instrument that produces time-varying electrical signals of frequency, wavelength, and amplitude. Sending these signals to a speaker or a light-emitting diode can demonstrate how specific characteristics of auditory or visual stimuli relate to perceptual experiences. Provides specific instructions for using…

  6. Profile Analysis: A Different View of Auditory Intensity Discrimination.

    ERIC Educational Resources Information Center

    Green, David M.

    1983-01-01

    Analyzes a method of detecting changes in a particular frequency band by evaluating the overall shape or profile of the auditory signal spectrum. Claims that profile analysis is different from intensity discrimination, and applies the new method to detecting noise sinusoid and to results obtained when signal frequency is uncertain. (Author/AOS)

  7. Auditory-visual crossmodal integration in perception of face gender.

    PubMed

    Smith, Eric L; Grabowecky, Marcia; Suzuki, Satoru

    2007-10-01

    Whereas extensive neuroscientific and behavioral evidence has confirmed a role of auditory-visual integration in representing space [1-6], little is known about the role of auditory-visual integration in object perception. Although recent neuroimaging results suggest integrated auditory-visual object representations [7-11], substantiating behavioral evidence has been lacking. We demonstrated auditory-visual integration in the perception of face gender by using pure tones that are processed in low-level auditory brain areas and that lack the spectral components that characterize human vocalization. When androgynous faces were presented together with pure tones in the male fundamental-speaking-frequency range, faces were more likely to be judged as male, whereas when faces were presented with pure tones in the female fundamental-speaking-frequency range, they were more likely to be judged as female. Importantly, when participants were explicitly asked to attribute gender to these pure tones, their judgments were primarily based on relative pitch and were uncorrelated with the male and female fundamental-speaking-frequency ranges. This perceptual dissociation of absolute-frequency-based crossmodal-integration effects from relative-pitch-based explicit perception of the tones provides evidence for a sensory integration of auditory and visual signals in representing human gender. This integration probably develops because of concurrent neural processing of visual and auditory features of gender.

  8. A corollary discharge maintains auditory sensitivity during sound production.

    PubMed

    Poulet, James F A; Hedwig, Berthold

    2002-08-22

    Speaking and singing present the auditory system of the caller with two fundamental problems: discriminating between self-generated and external auditory signals and preventing desensitization. In humans and many other vertebrates, auditory neurons in the brain are inhibited during vocalization but little is known about the nature of the inhibition. Here we show, using intracellular recordings of auditory neurons in the singing cricket, that presynaptic inhibition of auditory afferents and postsynaptic inhibition of an identified auditory interneuron occur in phase with the song pattern. Presynaptic and postsynaptic inhibition persist in a fictively singing, isolated cricket central nervous system and are therefore the result of a corollary discharge from the singing motor network. Mimicking inhibition in the interneuron by injecting hyperpolarizing current suppresses its spiking response to a 100-dB sound pressure level (SPL) acoustic stimulus and maintains its response to subsequent, quieter stimuli. Inhibition by the corollary discharge reduces the neural response to self-generated sound and protects the cricket's auditory pathway from self-induced desensitization.

  9. The neglected neglect: auditory neglect.

    PubMed

    Gokhale, Sankalp; Lahoti, Sourabh; Caplan, Louis R

    2013-08-01

    Whereas visual and somatosensory forms of neglect are commonly recognized by clinicians, auditory neglect is often not assessed and therefore neglected. The auditory cortical processing system can be functionally classified into 2 distinct pathways. These 2 distinct functional pathways deal with recognition of sound ("what" pathway) and the directional attributes of the sound ("where" pathway). Lesions of higher auditory pathways produce distinct clinical features. Clinical bedside evaluation of auditory neglect is often difficult because of coexisting neurological deficits and the binaural nature of auditory inputs. In addition, auditory neglect and auditory extinction may show varying degrees of overlap, which makes the assessment even harder. Shielding one ear from the other as well as separating the ear from space is therefore critical for accurate assessment of auditory neglect. This can be achieved by use of specialized auditory tests (dichotic tasks and sound localization tests) for accurate interpretation of deficits. Herein, we have reviewed auditory neglect with an emphasis on the functional anatomy, clinical evaluation, and basic principles of specialized auditory tests.

  10. Integration and segregation in auditory scene analysis

    NASA Astrophysics Data System (ADS)

    Sussman, Elyse S.

    2005-03-01

    Assessment of the neural correlates of auditory scene analysis, using an index of sound change detection that does not require the listener to attend to the sounds [a component of event-related brain potentials called the mismatch negativity (MMN)], has previously demonstrated that segregation processes can occur without attention focused on the sounds and that within-stream contextual factors influence how sound elements are integrated and represented in auditory memory. The current study investigated the relationship between the segregation and integration processes when they were called upon to function together. The pattern of MMN results showed that the integration of sound elements within a sound stream occurred after the segregation of sounds into independent streams and, further, that the individual streams were subject to contextual effects. These results are consistent with a view of auditory processing that suggests that the auditory scene is rapidly organized into distinct streams and the integration of sequential elements to perceptual units takes place on the already formed streams. This would allow for the flexibility required to identify changing within-stream sound patterns, needed to appreciate music or comprehend speech..

  11. STAT1 Signaling within Macrophages Is Required for Antifungal Activity against Cryptococcus neoformans

    PubMed Central

    Leopold Wager, Chrissy M.; Hole, Camaron R.; Wozniak, Karen L.; Olszewski, Michal A.; Mueller, Mathias

    2015-01-01

    Cryptococcus neoformans, the predominant etiological agent of cryptococcosis, is an opportunistic fungal pathogen that primarily affects AIDS patients and patients undergoing immunosuppressive therapy. In immunocompromised individuals, C. neoformans can lead to life-threatening meningoencephalitis. Studies using a virulent strain of C. neoformans engineered to produce gamma interferon (IFN-γ), denoted H99γ, demonstrated that protection against pulmonary C. neoformans infection is associated with the generation of a T helper 1 (Th1)-type immune response and signal transducer and activator of transcription 1 (STAT1)-mediated classical (M1) macrophage activation. However, the critical mechanism by which M1 macrophages mediate their anti-C. neoformans activity remains unknown. The current studies demonstrate that infection with C. neoformans strain H99γ in mice with macrophage-specific STAT1 ablation resulted in severely increased inflammation of the pulmonary tissue, a dysregulated Th1/Th2-type immune response, increased fungal burden, deficient M1 macrophage activation, and loss of protection. STAT1-deficient macrophages produced significantly less nitric oxide (NO) than STAT1-sufficient macrophages, correlating with an inability to control intracellular cryptococcal proliferation, even in the presence of reactive oxygen species (ROS). Furthermore, macrophages from inducible nitric oxide synthase knockout mice, which had intact ROS production, were deficient in anticryptococcal activity. These data indicate that STAT1 activation within macrophages is required for M1 macrophage activation and anti-C. neoformans activity via the production of NO. PMID:26351277

  12. α2δ-3 Is Required for Rapid Transsynaptic Homeostatic Signaling.

    PubMed

    Wang, Tingting; Jones, Ryan T; Whippen, Jenna M; Davis, Graeme W

    2016-09-13

    The homeostatic modulation of neurotransmitter release, termed presynaptic homeostatic potentiation (PHP), is a fundamental type of neuromodulation, conserved from Drosophila to humans, that stabilizes information transfer at synaptic connections throughout the nervous system. Here, we demonstrate that α2δ-3, an auxiliary subunit of the presynaptic calcium channel, is required for PHP. The α2δ gene family has been linked to chronic pain, epilepsy, autism, and the action of two psychiatric drugs: gabapentin and pregabalin. We demonstrate that loss of α2δ-3 blocks both the rapid induction and sustained expression of PHP due to a failure to potentiate presynaptic calcium influx and the RIM-dependent readily releasable vesicle pool. These deficits are independent of α2δ-3-mediated regulation of baseline calcium influx and presynaptic action potential waveform. α2δ proteins reside at the extracellular face of presynaptic release sites throughout the nervous system, a site ideal for mediating rapid, transsynaptic homeostatic signaling in health and disease. PMID:27626659

  13. Tomato root penetration in soil requires a coaction between ethylene and auxin signaling.

    PubMed

    Santisree, Parankusam; Nongmaithem, Sapana; Vasuki, Himabindu; Sreelakshmi, Yellamaraju; Ivanchenko, Maria G; Sharma, Rameshwar

    2011-07-01

    During seed germination, emerging roots display positive gravitropism and penetrate into the soil for nutrition and anchorage. Tomato (Solanum lycopersicum) seeds germinated in the presence of 1-methylcyclopropene (1-MCP), an inhibitor of ethylene action, failed to insert roots into Soilrite and grew in the air, forming loops. Time-lapse video imaging showed that 1-MCP-grown root tips retained positive gravitropism and made contact with the surface of Soilrite but failed to penetrate into the Soilrite. Time-course studies revealed that the effect of 1-MCP was most prominent when seed imbibition and germination were carried out in the continual presence of 1-MCP. Conversely, 1-MCP was ineffective when applied postgermination after penetration of roots in the Soilrite. Furthermore, treatment with 1-MCP caused a reduction in DR5::β-glucuronidase auxin-reporter activity and modified the expression of SlIAA3 and SlIAA9 transcripts, indicating interference with auxin signaling. The reduced ethylene perception mutant, Never-ripe, displayed decreased ability for root penetration, and the enhanced polar auxin transport mutant, polycotyledon, showed a nearly normal root penetration in the presence of 1-MCP, which could be reversed by application of auxin transport inhibitors. Our results indicate that during tomato seed germination, a coaction between ethylene and auxin is required for root penetration into the soil.

  14. PSYCHOACOUSTICS: a comprehensive MATLAB toolbox for auditory testing.

    PubMed

    Soranzo, Alessandro; Grassi, Massimo

    2014-01-01

    PSYCHOACOUSTICS is a new MATLAB toolbox which implements three classic adaptive procedures for auditory threshold estimation. The first includes those of the Staircase family (method of limits, simple up-down and transformed up-down); the second is the Parameter Estimation by Sequential Testing (PEST); and the third is the Maximum Likelihood Procedure (MLP). The toolbox comes with more than twenty built-in experiments each provided with the recommended (default) parameters. However, if desired, these parameters can be modified through an intuitive and user friendly graphical interface and stored for future use (no programming skills are required). Finally, PSYCHOACOUSTICS is very flexible as it comes with several signal generators and can be easily extended for any experiment.

  15. PSYCHOACOUSTICS: a comprehensive MATLAB toolbox for auditory testing

    PubMed Central

    Soranzo, Alessandro; Grassi, Massimo

    2014-01-01

    PSYCHOACOUSTICS is a new MATLAB toolbox which implements three classic adaptive procedures for auditory threshold estimation. The first includes those of the Staircase family (method of limits, simple up-down and transformed up-down); the second is the Parameter Estimation by Sequential Testing (PEST); and the third is the Maximum Likelihood Procedure (MLP). The toolbox comes with more than twenty built-in experiments each provided with the recommended (default) parameters. However, if desired, these parameters can be modified through an intuitive and user friendly graphical interface and stored for future use (no programming skills are required). Finally, PSYCHOACOUSTICS is very flexible as it comes with several signal generators and can be easily extended for any experiment. PMID:25101013

  16. The Essential Complexity of Auditory Receptive Fields

    PubMed Central

    Thorson, Ivar L.; Liénard, Jean; David, Stephen V.

    2015-01-01

    Encoding properties of sensory neurons are commonly modeled using linear finite impulse response (FIR) filters. For the auditory system, the FIR filter is instantiated in the spectro-temporal receptive field (STRF), often in the framework of the generalized linear model. Despite widespread use of the FIR STRF, numerous formulations for linear filters are possible that require many fewer parameters, potentially permitting more efficient and accurate model estimates. To explore these alternative STRF architectures, we recorded single-unit neural activity from auditory cortex of awake ferrets during presentation of natural sound stimuli. We compared performance of > 1000 linear STRF architectures, evaluating their ability to predict neural responses to a novel natural stimulus. Many were able to outperform the FIR filter. Two basic constraints on the architecture lead to the improved performance: (1) factorization of the STRF matrix into a small number of spectral and temporal filters and (2) low-dimensional parameterization of the factorized filters. The best parameterized model was able to outperform the full FIR filter in both primary and secondary auditory cortex, despite requiring fewer than 30 parameters, about 10% of the number required by the FIR filter. After accounting for noise from finite data sampling, these STRFs were able to explain an average of 40% of A1 response variance. The simpler models permitted more straightforward interpretation of sensory tuning properties. They also showed greater benefit from incorporating nonlinear terms, such as short term plasticity, that provide theoretical advances over the linear model. Architectures that minimize parameter count while maintaining maximum predictive power provide insight into the essential degrees of freedom governing auditory cortical function. They also maximize statistical power available for characterizing additional nonlinear properties that limit current auditory models. PMID:26683490

  17. The Essential Complexity of Auditory Receptive Fields.

    PubMed

    Thorson, Ivar L; Liénard, Jean; David, Stephen V

    2015-12-01

    Encoding properties of sensory neurons are commonly modeled using linear finite impulse response (FIR) filters. For the auditory system, the FIR filter is instantiated in the spectro-temporal receptive field (STRF), often in the framework of the generalized linear model. Despite widespread use of the FIR STRF, numerous formulations for linear filters are possible that require many fewer parameters, potentially permitting more efficient and accurate model estimates. To explore these alternative STRF architectures, we recorded single-unit neural activity from auditory cortex of awake ferrets during presentation of natural sound stimuli. We compared performance of > 1000 linear STRF architectures, evaluating their ability to predict neural responses to a novel natural stimulus. Many were able to outperform the FIR filter. Two basic constraints on the architecture lead to the improved performance: (1) factorization of the STRF matrix into a small number of spectral and temporal filters and (2) low-dimensional parameterization of the factorized filters. The best parameterized model was able to outperform the full FIR filter in both primary and secondary auditory cortex, despite requiring fewer than 30 parameters, about 10% of the number required by the FIR filter. After accounting for noise from finite data sampling, these STRFs were able to explain an average of 40% of A1 response variance. The simpler models permitted more straightforward interpretation of sensory tuning properties. They also showed greater benefit from incorporating nonlinear terms, such as short term plasticity, that provide theoretical advances over the linear model. Architectures that minimize parameter count while maintaining maximum predictive power provide insight into the essential degrees of freedom governing auditory cortical function. They also maximize statistical power available for characterizing additional nonlinear properties that limit current auditory models. PMID:26683490

  18. Unconscious learning of auditory discrimination using mismatch negativity (MMN) neurofeedback.

    PubMed

    Chang, Ming; Iizuka, Hiroyuki; Naruse, Yasushi; Ando, Hideyuki; Maeda, Taro

    2014-10-24

    Neurofeedback is a strong direct training method for brain function, wherein brain activity patterns are measured and displayed as feedback, and trainees try to stabilize the feedback signal onto certain desirable states to regulate their own mental states. Here, we introduce a novel neurofeedback method, using the mismatch negativity (MMN) responses elicited by similar sounds that cannot be consciously discriminated. Through neurofeedback training, without participants' attention to the auditory stimuli or awareness of what was to be learned, we found that the participants could unconsciously achieve a significant improvement in the auditory discrimination of the applied stimuli. Our method has great potential to provide effortless auditory perceptual training. Based on this method, participants do not need to make an effort to discriminate auditory stimuli, and can choose tasks of interest without boredom due to training. In particular, it could be used to train people to recognize speech sounds that do not exist in their native language and thereby facilitate foreign language learning.

  19. Cranial nerve development requires co-ordinated Shh and canonical Wnt signaling.

    PubMed

    Kurosaka, Hiroshi; Trainor, Paul A; Leroux-Berger, Margot; Iulianella, Angelo

    2015-01-01

    Cranial nerves govern sensory and motor information exchange between the brain and tissues of the head and neck. The cranial nerves are derived from two specialized populations of cells, cranial neural crest cells and ectodermal placode cells. Defects in either cell type can result in cranial nerve developmental defects. Although several signaling pathways are known to regulate cranial nerve formation our understanding of how intercellular signaling between neural crest cells and placode cells is coordinated during cranial ganglia morphogenesis is poorly understood. Sonic Hedgehog (Shh) signaling is one key pathway that regulates multiple aspects of craniofacial development, but whether it co-ordinates cranial neural crest cell and placodal cell interactions during cranial ganglia formation remains unclear. In this study we examined a new Patched1 (Ptch1) loss-of-function mouse mutant and characterized the role of Ptch1 in regulating Shh signaling during cranial ganglia development. Ptch1(Wig/ Wig) mutants exhibit elevated Shh signaling in concert with disorganization of the trigeminal and facial nerves. Importantly, we discovered that enhanced Shh signaling suppressed canonical Wnt signaling in the cranial nerve region. This critically affected the survival and migration of cranial neural crest cells and the development of placodal cells as well as the integration between neural crest and placodes. Collectively, our findings highlight a novel and critical role for Shh signaling in cranial nerve development via the cross regulation of canonical Wnt signaling. PMID:25799573

  20. Cranial Nerve Development Requires Co-Ordinated Shh and Canonical Wnt Signaling

    PubMed Central

    Kurosaka, Hiroshi; Trainor, Paul A.; Leroux-Berger, Margot; Iulianella, Angelo

    2015-01-01

    Cranial nerves govern sensory and motor information exchange between the brain and tissues of the head and neck. The cranial nerves are derived from two specialized populations of cells, cranial neural crest cells and ectodermal placode cells. Defects in either cell type can result in cranial nerve developmental defects. Although several signaling pathways are known to regulate cranial nerve formation our understanding of how intercellular signaling between neural crest cells and placode cells is coordinated during cranial ganglia morphogenesis is poorly understood. Sonic Hedgehog (Shh) signaling is one key pathway that regulates multiple aspects of craniofacial development, but whether it co-ordinates cranial neural crest cell and placodal cell interactions during cranial ganglia formation remains unclear. In this study we examined a new Patched1 (Ptch1) loss-of-function mouse mutant and characterized the role of Ptch1 in regulating Shh signaling during cranial ganglia development. Ptch1Wig/ Wig mutants exhibit elevated Shh signaling in concert with disorganization of the trigeminal and facial nerves. Importantly, we discovered that enhanced Shh signaling suppressed canonical Wnt signaling in the cranial nerve region. This critically affected the survival and migration of cranial neural crest cells and the development of placodal cells as well as the integration between neural crest and placodes. Collectively, our findings highlight a novel and critical role for Shh signaling in cranial nerve development via the cross regulation of canonical Wnt signaling. PMID:25799573

  1. Psychophysical and Neural Correlates of Auditory Attraction and Aversion

    NASA Astrophysics Data System (ADS)

    Patten, Kristopher Jakob

    This study explores the psychophysical and neural processes associated with the perception of sounds as either pleasant or aversive. The underlying psychophysical theory is based on auditory scene analysis, the process through which listeners parse auditory signals into individual acoustic sources. The first experiment tests and confirms that a self-rated pleasantness continuum reliably exists for 20 various stimuli (r = .48). In addition, the pleasantness continuum correlated with the physical acoustic characteristics of consonance/dissonance (r = .78), which can facilitate auditory parsing processes. The second experiment uses an fMRI block design to test blood oxygen level dependent (BOLD) changes elicited by a subset of 5 exemplar stimuli chosen from Experiment 1 that are evenly distributed over the pleasantness continuum. Specifically, it tests and confirms that the pleasantness continuum produces systematic changes in brain activity for unpleasant acoustic stimuli beyond what occurs with pleasant auditory stimuli. Results revealed that the combination of two positively and two negatively valenced experimental sounds compared to one neutral baseline control elicited BOLD increases in the primary auditory cortex, specifically the bilateral superior temporal gyrus, and left dorsomedial prefrontal cortex; the latter being consistent with a frontal decision-making process common in identification tasks. The negatively-valenced stimuli yielded additional BOLD increases in the left insula, which typically indicates processing of visceral emotions. The positively-valenced stimuli did not yield any significant BOLD activation, consistent with consonant, harmonic stimuli being the prototypical acoustic pattern of auditory objects that is optimal for auditory scene analysis. Both the psychophysical findings of Experiment 1 and the neural processing findings of Experiment 2 support that consonance is an important dimension of sound that is processed in a manner that aids

  2. Repression of Hedgehog signalling is required for the acquisition of dorsolateral cell fates in the zebrafish otic vesicle

    PubMed Central

    Hammond, Katherine L.; van Eeden, Fredericus J. M.; Whitfield, Tanya T.

    2010-01-01

    In zebrafish, Hedgehog (Hh) signalling from ventral midline structures is necessary and sufficient to specify posterior otic identity. Loss of Hh signalling gives rise to mirror symmetric ears with double anterior character, whereas severe upregulation of Hh signalling leads to double posterior ears. By contrast, in mouse and chick, Hh is predominantly required for dorsoventral otic patterning. Whereas a loss of Hh function in zebrafish does not affect dorsoventral and mediolateral otic patterning, we now show that a gain of Hh signalling activity causes ventromedial otic territories to expand at the expense of dorsolateral domains. In a panel of lines carrying mutations in Hh inhibitor genes, Hh pathway activity is increased throughout the embryo, and dorsolateral otic structures are lost or reduced. Even a modest increase in Hh signalling has consequences for patterning the ear. In ptc1–/– and ptc2–/– mutant embryos, in which Hh signalling is maximal throughout the embryo, the inner ear is severely ventralised and medialised, in addition to displaying the previously reported double posterior character. Transplantation experiments suggest that the effects of the loss of Hh pathway inhibition on the ear are mediated directly. These new data suggest that Hh signalling must be kept tightly repressed for the correct acquisition of dorsolateral cell fates in the zebrafish otic vesicle, revealing distinct similarities between the roles of Hh signalling in zebrafish and amniote inner ear patterning. PMID:20223756

  3. Auditory pathways: anatomy and physiology.

    PubMed

    Pickles, James O

    2015-01-01

    This chapter outlines the anatomy and physiology of the auditory pathways. After a brief analysis of the external, middle ears, and cochlea, the responses of auditory nerve fibers are described. The central nervous system is analyzed in more detail. A scheme is provided to help understand the complex and multiple auditory pathways running through the brainstem. The multiple pathways are based on the need to preserve accurate timing while extracting complex spectral patterns in the auditory input. The auditory nerve fibers branch to give two pathways, a ventral sound-localizing stream, and a dorsal mainly pattern recognition stream, which innervate the different divisions of the cochlear nucleus. The outputs of the two streams, with their two types of analysis, are progressively combined in the inferior colliculus and onwards, to produce the representation of what can be called the "auditory objects" in the external world. The progressive extraction of critical features in the auditory stimulus in the different levels of the central auditory system, from cochlear nucleus to auditory cortex, is described. In addition, the auditory centrifugal system, running from cortex in multiple stages to the organ of Corti of the cochlea, is described.

  4. Auditory object cognition in dementia

    PubMed Central

    Goll, Johanna C.; Kim, Lois G.; Hailstone, Julia C.; Lehmann, Manja; Buckley, Aisling; Crutch, Sebastian J.; Warren, Jason D.

    2011-01-01

    The cognition of nonverbal sounds in dementia has been relatively little explored. Here we undertook a systematic study of nonverbal sound processing in patient groups with canonical dementia syndromes comprising clinically diagnosed typical amnestic Alzheimer's disease (AD; n = 21), progressive nonfluent aphasia (PNFA; n = 5), logopenic progressive aphasia (LPA; n = 7) and aphasia in association with a progranulin gene mutation (GAA; n = 1), and in healthy age-matched controls (n = 20). Based on a cognitive framework treating complex sounds as ‘auditory objects’, we designed a novel neuropsychological battery to probe auditory object cognition at early perceptual (sub-object), object representational (apperceptive) and semantic levels. All patients had assessments of peripheral hearing and general neuropsychological functions in addition to the experimental auditory battery. While a number of aspects of auditory object analysis were impaired across patient groups and were influenced by general executive (working memory) capacity, certain auditory deficits had some specificity for particular dementia syndromes. Patients with AD had a disproportionate deficit of auditory apperception but preserved timbre processing. Patients with PNFA had salient deficits of timbre and auditory semantic processing, but intact auditory size and apperceptive processing. Patients with LPA had a generalised auditory deficit that was influenced by working memory function. In contrast, the patient with GAA showed substantial preservation of auditory function, but a mild deficit of pitch direction processing and a more severe deficit of auditory apperception. The findings provide evidence for separable stages of auditory object analysis and separable profiles of impaired auditory object cognition in different dementia syndromes. PMID:21689671

  5. Mitogen-activated protein kinases with distinct requirements for Ste5 scaffolding influence signaling specificity in Saccharomyces cerevisiae.

    PubMed

    Flatauer, Laura J; Zadeh, Sheena F; Bardwell, Lee

    2005-03-01

    Scaffold proteins are believed to enhance specificity in cell signaling when different pathways share common components. The prototype scaffold Ste5 binds to multiple components of the Saccharomyces cerevisiae mating pheromone response pathway, thereby conducting the mating signal to the Fus3 mitogen-activated protein kinase (MAPK). Some of the kinases that Ste5 binds to, however, are also shared with other pathways. Thus, it has been presumed that Ste5 prevents its bound kinases from transgressing into other pathways and protects them from intrusions from those pathways. Here we found that Fus3MAPK required Ste5 scaffolding to receive legitimate signals from the mating pathway as well as misdirected signals leaking from other pathways. Furthermore, increasing the cellular concentration of active Ste5 enhanced the channeling of inappropriate stimuli to Fus3. This aberrant signal crossover resulted in the erroneous induction of cell cycle arrest and mating. In contrast to Fus3, the Kss1 MAPK did not require Ste5 scaffolding to receive either authentic or leaking signals. Furthermore, the Ste11 kinase, once activated via Ste5, was able to signal to Kss1 independently of Ste5 scaffolding. These results argue that Ste5 does not act as a barrier that actively prevents signal crossover to Fus3 and that Ste5 may not effectively sequester its activated kinases away from other pathways. Rather, we suggest that specificity in this network is promoted by the selective activation of Ste5 and the distinct requirements of the MAPKs for Ste5 scaffolding. PMID:15713635

  6. Rac1 protein signaling is required for DNA damage response stimulated by topoisomerase II poisons.

    PubMed

    Huelsenbeck, Stefanie C; Schorr, Anne; Roos, Wynand P; Huelsenbeck, Johannes; Henninger, Christian; Kaina, Bernd; Fritz, Gerhard

    2012-11-01

    To investigate the potency of the topoisomerase II (topo II) poisons doxorubicin and etoposide to stimulate the DNA damage response (DDR), S139 phosphorylation of histone H2AX (γH2AX) was analyzed using rat cardiomyoblast cells (H9c2). Etoposide caused a dose-dependent increase in the γH2AX level as shown by Western blotting. By contrast, the doxorubicin response was bell-shaped with high doses failing to increase H2AX phosphorylation. Identical results were obtained by immunohistochemical analysis of γH2AX focus formation, comet assay-based DNA strand break analysis, and measuring the formation of the topo II-DNA cleavable complex. At low dose, doxorubicin activated ataxia telangiectasia mutated (ATM) but not ATM and Rad3-related (ATR). Both the lipid-lowering drug lovastatin and the Rac1-specific inhibitor NSC23766 attenuated doxorubicin- and etoposide-stimulated H2AX phosphorylation, induction of DNA strand breaks, and topo II-DNA complex formation. Lovastatin and NSC23766 acted in an additive manner. They did not attenuate doxorubicin-induced increase in p-ATM and p-Chk2 levels. DDR stimulated by topo II poisons was partially blocked by inhibition of type I p21-associated kinases. DDR evoked by the topoisomerase I poison topotecan remained unaffected by lovastatin. The data show that the mechanisms involved in DDR stimulated by topo II poisons are agent-specific with anthracyclines lacking DDR-stimulating activity at high doses. Pharmacological inhibition of Rac1 signaling counteracts doxorubicin- and etoposide-stimulated DDR by disabling the formation of the topo II-DNA cleavable complex. Based on the data we suggest that Rac1-regulated mechanisms are required for DNA damage induction and subsequent activation of the DDR following treatment with topo II but not topo I poisons.

  7. Erythropoietin enhancement of rat pancreatic tumor cell proliferation requires the activation of ERK and JNK signals.

    PubMed

    Bose, Chhanda; Udupa, Kodetthoor B

    2008-08-01

    Erythropoietin (EPO) regulates the proliferation and differentiation of erythroid cells by binding to its specific transmembrane receptor EPOR. Recent studies, however, have shown that the EPOR is additionally present in various cancer cells and EPO induces the proliferation of these cells, suggesting a different function for EPO other than erythropoiesis. Therefore, the purpose of the present study was to examine EPOR expression and the role of EPO in the proliferation and signaling cascades involved in this process, using the rat pancreatic tumor cell line AR42J. Our results showed that AR42J cells expressed EPOR, and EPO significantly enhanced their proliferation. Cell cycle analysis of EPO-treated cells indicated an increased percentage of cells in the S phase, whereas cell numbers in G0/G1 phase were significantly reduced. Phosphorylation of extracellular regulatory kinase 1/2 (ERK1/2) and c-Jun NH(2) terminal kinase 1/2 (JNK1/2) was rapidly stimulated and sustained after EPO addition. Treatment of cells with mitogen-activated protein/ERK kinase (MEK) inhibitor PD98059 or JNK inhibitor SP600125 significantly inhibited EPO-enhanced proliferation and also increased the fraction of cells in G0/G1 phase. Furthermore, the inhibition of JNK using small interference RNA (siRNA) suppressed EPO-enhanced proliferation of AR42J cells. Taken together, our results indicate that AR42J cells express EPOR and that the activation of both ERK1/2 and JNK1/2 by EPO is essential in regulating proliferation and the cell cycle. Thus both appear to play a key role in EPO-enhanced proliferation and suggest that the presence of both is required for EPO-mediated proliferation of AR42J cells.

  8. Rice Rab11 is required for JA-mediated defense signaling

    SciTech Connect

    Hong, Min Ji; Lee, Yun mi; Son, Young Sim; Im, Chak Han; Yi, Young Byung; Rim, Yeong Gil; Bahk, Jeong Dong; Heo, Jae Bok

    2013-05-17

    Highlights: •OsRab11 interacts with OsOPR8. •OsOPR8 is localized in the cytosol and peroxisome. •OsRab11 enhances the NADPH consumption by OsOPR8. •Transgenic Arabidopsis overexpressing OsRab11 represents a pathogen-resistant phenotype. -- Abstract: Rab proteins play an essential role in regulating vesicular transport in eukaryotic cells. Previously, we characterized OsRab11, which in concert with OsGAP1 and OsGDI3 regulates vesicular trafficking from the trans-Golgi network (TGN) to the plasma membrane or vacuole. To further elucidate the physiological function of OsRab11 in plants, we performed yeast two-hybrid screens using OsRab11 as bait. OsOPR8 was isolated and shown to interact with OsRab11. A co-immunoprecipitation assay confirmed this interaction. The green fluorescent protein-OsOPR8 fusion product was targeted to the cytoplasm and peroxisomes of protoplasts from Arabidopsis thaliana. OsOPR8 exhibited NADPH-dependent reduction activity when 2-cyclohexen-1-one (CyHE) and 12-oxo-phytodienoic acid (OPDA) were supplied as possible substrates. Interestingly, NADPH oxidation by OsOPR8 was increased when wild-type OsRab11 or the constitutively active form of OsRab11 (Q78L) were included in the reaction mix, but not when the dominant negative form of OsRab11 (S28N) was included. OsRab11 was expressed broadly in plants and both OsRab11 and OsOPR8 were induced by jasmonic acid (JA) and elicitor treatments. Overexpressed OsRab11 transgenic plants showed resistance to pathogens through induced expression of JA-responsive genes. In conclusion, OsRab11 may be required for JA-mediated defense signaling by activating the reducing activity of OsOPR8.

  9. Auditory alert systems with enhanced detectability

    NASA Technical Reports Server (NTRS)

    Begault, Durand R. (Inventor)

    2008-01-01

    Methods and systems for distinguishing an auditory alert signal from a background of one or more non-alert signals. In a first embodiment, a prefix signal, associated with an existing alert signal, is provided that has a signal component in each of three or more selected frequency ranges, with each signal component in each of three or more selected level at least 3-10 dB above an estimated background (non-alert) level in that frequency range. The alert signal may be chirped within one or more frequency bands. In another embodiment, an alert signal moves, continuously or discontinuously, from one location to another over a short time interval, introducing a perceived spatial modulation or jitter. In another embodiment, a weighted sum of background signals adjacent to each ear is formed, and the weighted sum is delivered to each ear as a uniform background; a distinguishable alert signal is presented on top of this weighted sum signal at one ear, or distinguishable first and second alert signals are presented at two ears of a subject.

  10. Does the whistling thorn acacia (Acacia drepanolobium) use auditory aposematism to deter mammalian herbivores?

    PubMed

    Lev-Yadun, Simcha

    2016-08-01

    Auditory signaling including aposematism characterizes many terrestrial animals. Auditory aposematism by which certain animals use auditory aposematic signals to fend off enemies is well known for instance in rattlesnakes. Auditory signaling by plants toward animals and other plants is an emerging area of plant biology that still suffers from limited amount of solid data. Here I propose that auditory aposematism operates in the African whistling thorn acacia (Acacia drepanolobium = Vachellia drepanolobium). In this tree, the large and hollow thorn bases whistle when wind blows. This type of aposematism compliments the well-known conspicuous thorn and mutualistic ant based aposematism during day and may operate during night when the conspicuous thorns are invisible. PMID:27359246

  11. Early hominin auditory capacities.

    PubMed

    Quam, Rolf; Martínez, Ignacio; Rosa, Manuel; Bonmatí, Alejandro; Lorenzo, Carlos; de Ruiter, Darryl J; Moggi-Cecchi, Jacopo; Conde Valverde, Mercedes; Jarabo, Pilar; Menter, Colin G; Thackeray, J Francis; Arsuaga, Juan Luis

    2015-09-01

    Studies of sensory capacities in past life forms have offered new insights into their adaptations and lifeways. Audition is particularly amenable to study in fossils because it is strongly related to physical properties that can be approached through their skeletal structures. We have studied the anatomy of the outer and middle ear in the early hominin taxa Australopithecus africanus and Paranthropus robustus and estimated their auditory capacities. Compared with chimpanzees, the early hominin taxa are derived toward modern humans in their slightly shorter and wider external auditory canal, smaller tympanic membrane, and lower malleus/incus lever ratio, but they remain primitive in the small size of their stapes footplate. Compared with chimpanzees, both early hominin taxa show a heightened sensitivity to frequencies between 1.5 and 3.5 kHz and an occupied band of maximum sensitivity that is shifted toward slightly higher frequencies. The results have implications for sensory ecology and communication, and suggest that the early hominin auditory pattern may have facilitated an increased emphasis on short-range vocal communication in open habitats. PMID:26601261

  12. Early hominin auditory capacities

    PubMed Central

    Quam, Rolf; Martínez, Ignacio; Rosa, Manuel; Bonmatí, Alejandro; Lorenzo, Carlos; de Ruiter, Darryl J.; Moggi-Cecchi, Jacopo; Conde Valverde, Mercedes; Jarabo, Pilar; Menter, Colin G.; Thackeray, J. Francis; Arsuaga, Juan Luis

    2015-01-01

    Studies of sensory capacities in past life forms have offered new insights into their adaptations and lifeways. Audition is particularly amenable to study in fossils because it is strongly related to physical properties that can be approached through their skeletal structures. We have studied the anatomy of the outer and middle ear in the early hominin taxa Australopithecus africanus and Paranthropus robustus and estimated their auditory capacities. Compared with chimpanzees, the early hominin taxa are derived toward modern humans in their slightly shorter and wider external auditory canal, smaller tympanic membrane, and lower malleus/incus lever ratio, but they remain primitive in the small size of their stapes footplate. Compared with chimpanzees, both early hominin taxa show a heightened sensitivity to frequencies between 1.5 and 3.5 kHz and an occupied band of maximum sensitivity that is shifted toward slightly higher frequencies. The results have implications for sensory ecology and communication, and suggest that the early hominin auditory pattern may have facilitated an increased emphasis on short-range vocal communication in open habitats. PMID:26601261

  13. Early hominin auditory capacities.

    PubMed

    Quam, Rolf; Martínez, Ignacio; Rosa, Manuel; Bonmatí, Alejandro; Lorenzo, Carlos; de Ruiter, Darryl J; Moggi-Cecchi, Jacopo; Conde Valverde, Mercedes; Jarabo, Pilar; Menter, Colin G; Thackeray, J Francis; Arsuaga, Juan Luis

    2015-09-01

    Studies of sensory capacities in past life forms have offered new insights into their adaptations and lifeways. Audition is particularly amenable to study in fossils because it is strongly related to physical properties that can be approached through their skeletal structures. We have studied the anatomy of the outer and middle ear in the early hominin taxa Australopithecus africanus and Paranthropus robustus and estimated their auditory capacities. Compared with chimpanzees, the early hominin taxa are derived toward modern humans in their slightly shorter and wider external auditory canal, smaller tympanic membrane, and lower malleus/incus lever ratio, but they remain primitive in the small size of their stapes footplate. Compared with chimpanzees, both early hominin taxa show a heightened sensitivity to frequencies between 1.5 and 3.5 kHz and an occupied band of maximum sensitivity that is shifted toward slightly higher frequencies. The results have implications for sensory ecology and communication, and suggest that the early hominin auditory pattern may have facilitated an increased emphasis on short-range vocal communication in open habitats.

  14. Call sign intelligibility improvement using a spatial auditory display

    NASA Technical Reports Server (NTRS)

    Begault, Durand R.

    1993-01-01

    A spatial auditory display was used to convolve speech stimuli, consisting of 130 different call signs used in the communications protocol of NASA's John F. Kennedy Space Center, to different virtual auditory positions. An adaptive staircase method was used to determine intelligibility levels of the signal against diotic speech babble, with spatial positions at 30 deg azimuth increments. Non-individualized, minimum-phase approximations of head-related transfer functions were used. The results showed a maximal intelligibility improvement of about 6 dB when the signal was spatialized to 60 deg or 90 deg azimuth positions.

  15. Call sign intelligibility improvement using a spatial auditory display

    NASA Astrophysics Data System (ADS)

    Begault, Durand R.

    1993-04-01

    A spatial auditory display was used to convolve speech stimuli, consisting of 130 different call signs used in the communications protocol of NASA's John F. Kennedy Space Center, to different virtual auditory positions. An adaptive staircase method was used to determine intelligibility levels of the signal against diotic speech babble, with spatial positions at 30 deg azimuth increments. Non-individualized, minimum-phase approximations of head-related transfer functions were used. The results showed a maximal intelligibility improvement of about 6 dB when the signal was spatialized to 60 deg or 90 deg azimuth positions.

  16. Specification of auditory sensitivity by Drosophila TRP channels.

    PubMed

    Göpfert, Martin C; Albert, Jörg T; Nadrowski, B; Kamikouchi, A

    2006-08-01

    Ears achieve their exquisite sensitivity by means of mechanical feedback: motile mechanosensory cells through their active motion boost the mechanical input from the ear. Examination of the auditory mechanics in Drosophila melanogaster mutants shows that the transient receptor potential (TRP) channel NompC is required to promote this feedback, whereas the TRP vanilloid (TRPV) channels Nan and Iav serve to control the feedback gain. The combined function of these channels specifies the sensitivity of the fly auditory organ. PMID:16819519

  17. Clinical assessment of auditory dysfunction.

    PubMed Central

    Thomas, W G

    1982-01-01

    Many drugs, chemical substances and agents are potentially toxic to the human auditory system. The extent of toxicity depends on numerous factors. With few exceptions, toxicity in the auditory system affects various organs or cells within the cochlea or vestibular system, with brain stem and other central nervous system involvement reported with some chemicals and agents. This ototoxicity usually presents as a decrease in auditory sensitivity, tinnitus and/or vertigo or loss of balance. Classical and newer audiological techniques used in clinical assessment are beneficial in specifying the site of lesion in the cochlea, although auditory test results, themselves, give little information regarding possible pathology or etiology within the cochlea. Typically,, ototoxicity results in high frequency hearing loss, progressive as a function of frequency, usually accompanied by tinnitus and occasionally by vertigo or loss of balance. Auditory testing protocols are necessary to document this loss in auditory function. PMID:7044778

  18. Localized Cell and Drug Delivery for Auditory Prostheses

    PubMed Central

    Hendricks, Jeffrey L.; Chikar, Jennifer A.; Crumling, Mark A.; Raphael, Yehoash; Martin, David C.

    2011-01-01

    Localized cell and drug delivery to the cochlea and central auditory pathway can improve the safety and performance of implanted auditory prostheses (APs). While generally successful, these devices have a number of limitations and adverse effects including limited tonal and dynamic ranges, channel interactions, unwanted stimulation of non-auditory nerves, immune rejection, and infections including meningitis. Many of these limitations are associated with the tissue reactions to implanted auditory prosthetic devices and the gradual degeneration of the auditory system following deafness. Strategies to reduce the insertion trauma, degeneration of target neurons, fibrous and bony tissue encapsulation, and immune activation can improve the viability of tissue required for AP function as well as improve the resolution of stimulation for reduced channel interaction and improved place-pitch and level discrimination. Many pharmaceutical compounds have been identified that promote the viability of auditory tissue and prevent inflammation and infection. Cell delivery and gene therapy have provided promising results for treating hearing loss and reversing degeneration. Currently, many clinical and experimental methods can produce extremely localized and sustained drug delivery to address AP limitations. These methods provide better control over drug concentrations while eliminating the adverse effects of systemic delivery. Many of these drug delivery techniques can be integrated into modern auditory prosthetic devices to optimize the tissue response to the implanted device and reduce the risk of infection or rejection. Together, these methods and pharmaceutical agents can be used to optimize the tissue-device interface for improved AP safety and effectiveness. PMID:18573323

  19. Neural responses in songbird forebrain reflect learning rates, acquired salience, and stimulus novelty after auditory discrimination training.

    PubMed

    Bell, Brittany A; Phan, Mimi L; Vicario, David S

    2015-03-01

    How do social interactions form and modulate the neural representations of specific complex signals? This question can be addressed in the songbird auditory system. Like humans, songbirds learn to vocalize by imitating tutors heard during development. These learned vocalizations are important in reproductive and social interactions and in individual recognition. As a model for the social reinforcement of particular songs, male zebra finches were trained to peck for a food reward in response to one song stimulus (GO) and to withhold responding for another (NoGO). After performance reached criterion, single and multiunit neural responses to both trained and novel stimuli were obtained from multiple electrodes inserted bilaterally into two songbird auditory processing areas [caudomedial mesopallium (CMM) and caudomedial nidopallium (NCM)] of awake, restrained birds. Neurons in these areas undergo stimulus-specific adaptation to repeated song stimuli, and responses to familiar stimuli adapt more slowly than to novel stimuli. The results show that auditory responses differed in NCM and CMM for trained (GO and NoGO) stimuli vs. novel song stimuli. When subjects were grouped by the number of training days required to reach criterion, fast learners showed larger neural responses and faster stimulus-specific adaptation to all stimuli than slow learners in both areas. Furthermore, responses in NCM of fast learners were more strongly left-lateralized than in slow learners. Thus auditory responses in these sensory areas not only encode stimulus familiarity, but also reflect behavioral reinforcement in our paradigm, and can potentially be modulated by social interactions.

  20. A study on the influence of headphones in auditory perceptual function.

    PubMed

    Horie, Yoshinori; Toriizuka, Takashi

    2012-01-01

    The focus of this study is a human's ability to make full use of listening and hearing. This ability consists of dividing auditory information into a signal and a noise. To evaluate the risk of using headphones, the study investigated the auditory perception when a warning sound is given in the presence of environmental noise.

  1. Auditory and Visual Differences in Time Perception? An Investigation from a Developmental Perspective with Neuropsychological Tests

    ERIC Educational Resources Information Center

    Zelanti, Pierre S.; Droit-Volet, Sylvie

    2012-01-01

    Adults and children (5- and 8-year-olds) performed a temporal bisection task with either auditory or visual signals and either a short (0.5-1.0s) or long (4.0-8.0s) duration range. Their working memory and attentional capacities were assessed by a series of neuropsychological tests administered in both the auditory and visual modalities. Results…

  2. Direct Hepatocyte Insulin Signaling Is Required for Lipogenesis but Is Dispensable for the Suppression of Glucose Production.

    PubMed

    Titchenell, Paul M; Quinn, William J; Lu, Mingjian; Chu, Qingwei; Lu, Wenyun; Li, Changhong; Chen, Helen; Monks, Bobby R; Chen, Julia; Rabinowitz, Joshua D; Birnbaum, Morris J

    2016-06-14

    During insulin-resistant states such as type II diabetes mellitus (T2DM), insulin fails to suppress hepatic glucose production (HGP) yet promotes lipid synthesis. This metabolic state has been termed "selective insulin resistance" to indicate a defect in one arm of the insulin-signaling cascade, potentially downstream of Akt. Here we demonstrate that Akt-dependent activation of mTORC1 and inhibition of Foxo1 are required and sufficient for de novo lipogenesis, suggesting that hepatic insulin signaling is likely to be intact in insulin-resistant states. Moreover, cell-nonautonomous suppression of HGP by insulin depends on a reduction of adipocyte lipolysis and serum FFAs but is independent of vagal efferents or glucagon signaling. These data are consistent with a model in which, during T2DM, intact liver insulin signaling drives enhanced lipogenesis while excess circulating FFAs become a dominant inducer of nonsuppressible HGP. PMID:27238637

  3. ZINC-INDUCED EGF RECEPTOR SIGNALING REQUIRES SRC-MEDIATED PHOSPHORYLATION OF THE EGF RECEPTOR ON TYROSINE 845 (Y845)

    EPA Science Inventory

    ZINC-INDUCED EGF RECEPTOR SIGNALING REQUIRES Src-MEDIATED PHOSPHORYLATION OF THE EGF RECEPTOR ON TYROSINE 845 (Y845)
    Weidong Wu1, Lee M. Graves2, Gordon N. Gill3 and James M. Samet4 1Center for Environmental Medicine and Lung Biology; 2Department of Pharmacology, University o...

  4. Auditory interfaces: The human perceiver

    NASA Technical Reports Server (NTRS)

    Colburn, H. Steven

    1991-01-01

    A brief introduction to the basic auditory abilities of the human perceiver with particular attention toward issues that may be important for the design of auditory interfaces is presented. The importance of appropriate auditory inputs to observers with normal hearing is probably related to the role of hearing as an omnidirectional, early warning system and to its role as the primary vehicle for communication of strong personal feelings.

  5. Modeling neural adaptation in the frog auditory system

    NASA Astrophysics Data System (ADS)

    Wotton, Janine; McArthur, Kimberly; Bohara, Amit; Ferragamo, Michael; Megela Simmons, Andrea

    2005-09-01

    Extracellular recordings from the auditory midbrain, Torus semicircularis, of the leopard frog reveal a wide diversity of tuning patterns. Some cells seem to be well suited for time-based coding of signal envelope, and others for rate-based coding of signal frequency. Adaptation for ongoing stimuli plays a significant role in shaping the frequency-dependent response rate at different levels of the frog auditory system. Anuran auditory-nerve fibers are unusual in that they reveal frequency-dependent adaptation [A. L. Megela, J. Acoust. Soc. Am. 75, 1155-1162 (1984)], and therefore provide rate-based input. In order to examine the influence of these peripheral inputs on central responses, three layers of auditory neurons were modeled to examine short-term neural adaptation to pure tones and complex signals. The response of each neuron was simulated with a leaky integrate and fire model, and adaptation was implemented by means of an increasing threshold. Auditory-nerve fibers, dorsal medullary nucleus neurons, and toral cells were simulated and connected in three ascending layers. Modifying the adaptation properties of the peripheral fibers dramatically alters the response at the midbrain. [Work supported by NOHR to M.J.F.; Gustavus Presidential Scholarship to K.McA.; NIH DC05257 to A.M.S.

  6. Hippo signaling mediators Yap and Taz are required in the epicardium for coronary vasculature development

    PubMed Central

    Singh, Anamika; Ramesh, Sindhu; Cibi, Dasan Mary; Yun, Lim Sze; Li, Jun; Li, Li; Manderfield, Lauren J.; Olson, Eric N.; Epstein, Jonathan A.; Singh, Manvendra K.

    2016-01-01

    Summary Formation of the coronary vasculature is a complex and precisely coordinated morphogenetic process that begins with the formation of epicardium. The epicardium gives rise to many components of the coronary vasculature, including fibroblasts, smooth muscle cells and endothelium. Hippo signaling components have been implicated in cardiac development and regeneration. However a role of Hippo signaling in the epicardium has not been explored. Employing a combination of genetic and pharmacological approaches, we demonstrate that inhibition of Hippo signaling mediators Yap and Taz leads to impaired epicardial epithelial-to-mesenchymal transition (EMT) and a reduction in epicardial cell proliferation and differentiation into coronary endothelial cells. We provide evidence that Yap and Taz control epicardial cell behavior, in part by regulating Tbx18 and Wt1 expression. Our findings show a role for Hippo signaling in epicardial cell proliferation, EMT and cell fate specification during cardiac organogenesis. PMID:27160901

  7. Epsin is required for Dishevelled stability and Wnt signaling activation in colon cancer development

    PubMed Central

    Chang, Baojun; Tessneer, Kandice L.; McManus, John; Liu, Xiaolei; Hahn, Scott; Pasula, Satish; Wu, Hao; Song, Hoogeun; Chen, Yiyuan; Cai, Xiaofeng; Dong, Yunzhou; Brophy, Megan L.; Rahman, Ruby; Ma, Jian-Xing; Xia, Lijun; Chen, Hong

    2015-01-01

    Uncontrolled canonical Wnt signaling supports colon epithelial tumor expansion and malignant transformation. Understanding the regulatory mechanisms involved is crucial for elucidating the pathogenesis of and will provide new therapeutic targets for colon cancer. Epsins are ubiquitin-binding adaptor proteins upregulated in several human cancers; however, epsins’ involvement in colon cancer is unknown. Here we show that loss of intestinal epithelial epsins protects against colon cancer by significantly reducing the stability of the crucial Wnt signaling effector, dishevelled (Dvl2), and impairing Wnt signaling. Consistently, epsins and Dvl2 are correspondingly upregulated in colon cancer. Mechanistically, epsin binds Dvl2 via its epsin N-terminal homology domain and ubiquitin-interacting motifs and prohibits Dvl2 polyubiquitination and degradation. Our findings reveal an unconventional role for epsins in stabilizing Dvl2 and potentiating Wnt signaling in colon cancer cells to ensure robust colon cancer progression. Epsins’ pro-carcinogenic role suggests they are potential therapeutic targets to combat colon cancer. PMID:25871009

  8. An NB-LRR protein required for HR signalling mediated by both extra- and intracellular resistance proteins.

    PubMed

    Gabriëls, Suzan H E J; Vossen, Jack H; Ekengren, Sophia K; van Ooijen, Gerben; Abd-El-Haliem, Ahmed M; van den Berg, Grardy C M; Rainey, Daphne Y; Martin, Gregory B; Takken, Frank L W; de Wit, Pierre J G M; Joosten, Matthieu H A J

    2007-04-01

    Tomato (Solanum lycopersicum) Cf resistance genes confer hypersensitive response (HR)-associated resistance to strains of the pathogenic fungus Cladosporium fulvum that express the matching avirulence (Avr) gene. Previously, we identified an Avr4-responsive tomato (ART) gene that is required for Cf-4/Avr4-induced HR in Nicotiana benthamiana as demonstrated by virus-induced gene silencing (VIGS). The gene encodes a CC-NB-LRR type resistance (R) protein analogue that we have designated NRC1 (NB-LRR protein required for HR-associated cell death 1). Here we describe that knock-down of NRC1 in tomato not only affects the Cf-4/Avr4-induced HR but also compromises Cf-4-mediated resistance to C. fulvum. In addition, VIGS using NRC1 in N. benthamiana revealed that this protein is also required for the HR induced by the R proteins Cf-9, LeEix, Pto, Rx and Mi. Transient expression of NRC1(D481V), which encodes a constitutively active NRC1 mutant protein, triggers an elicitor-independent HR. Subsequently, we transiently expressed this auto-activating protein in N. benthamiana silenced for genes known to be involved in HR signalling, thereby allowing NRC1 to be positioned in an HR signalling pathway. We found that NRC1 requires RAR1 and SGT1 to be functional, whereas it does not require NDR1 and EDS1. As the Cf-4 protein requires EDS1 for its function, we hypothesize that NRC1 functions downstream of EDS1. We also found that NRC1 acts upstream of a MAP kinase pathway. We conclude that Cf-mediated resistance signalling requires a downstream NB-LRR protein that also functions in cell death signalling pathways triggered by other R proteins.

  9. Requirement of cAMP Signaling for Schwann Cell Differentiation Restricts the Onset of Myelination

    PubMed Central

    Bacallao, Ketty; Monje, Paula V.

    2015-01-01

    Isolated Schwann cells (SCs) respond to cAMP elevation by adopting a differentiated post-mitotic state that exhibits high levels of Krox-20, a transcriptional enhancer of myelination, and mature SC markers such as the myelin lipid galactocerebroside (O1). To address how cAMP controls myelination, we performed a series of cell culture experiments which compared the differentiating responses of isolated and axon-related SCs to cAMP analogs and ascorbate, a known inducer of axon ensheathment, basal lamina formation and myelination. In axon-related SCs, cAMP induced the expression of Krox-20 and O1 without a concomitant increase in the expression of myelin basic protein (MBP) and without promoting axon ensheathment, collagen synthesis or basal lamina assembly. When cAMP was provided together with ascorbate, a dramatic enhancement of MBP expression occurred, indicating that cAMP primes SCs to form myelin only under conditions supportive of basal lamina formation. Experiments using a combination of cell permeable cAMP analogs and type-selective adenylyl cyclase (AC) agonists and antagonists revealed that selective transmembrane AC (tmAC) activation with forskolin was not sufficient for full SC differentiation and that the attainment of an O1 positive state also relied on the activity of the soluble AC (sAC), a bicarbonate sensor that is insensitive to forskolin and GPCR activation. Pharmacological and immunological evidence indicated that SCs expressed sAC and that sAC activity was required for morphological differentiation and the expression of myelin markers such as O1 and protein zero. To conclude, our data indicates that cAMP did not directly drive myelination but rather the transition into an O1 positive state, which is perhaps the most critical cAMP-dependent rate limiting step for the onset of myelination. The temporally restricted role of cAMP in inducing differentiation independently of basal lamina formation provides a clear example of the uncoupling of signals

  10. Requirement of cAMP signaling for Schwann cell differentiation restricts the onset of myelination.

    PubMed

    Bacallao, Ketty; Monje, Paula V

    2015-01-01

    Isolated Schwann cells (SCs) respond to cAMP elevation by adopting a differentiated post-mitotic state that exhibits high levels of Krox-20, a transcriptional enhancer of myelination, and mature SC markers such as the myelin lipid galactocerebroside (O1). To address how cAMP controls myelination, we performed a series of cell culture experiments which compared the differentiating responses of isolated and axon-related SCs to cAMP analogs and ascorbate, a known inducer of axon ensheathment, basal lamina formation and myelination. In axon-related SCs, cAMP induced the expression of Krox-20 and O1 without a concomitant increase in the expression of myelin basic protein (MBP) and without promoting axon ensheathment, collagen synthesis or basal lamina assembly. When cAMP was provided together with ascorbate, a dramatic enhancement of MBP expression occurred, indicating that cAMP primes SCs to form myelin only under conditions supportive of basal lamina formation. Experiments using a combination of cell permeable cAMP analogs and type-selective adenylyl cyclase (AC) agonists and antagonists revealed that selective transmembrane AC (tmAC) activation with forskolin was not sufficient for full SC differentiation and that the attainment of an O1 positive state also relied on the activity of the soluble AC (sAC), a bicarbonate sensor that is insensitive to forskolin and GPCR activation. Pharmacological and immunological evidence indicated that SCs expressed sAC and that sAC activity was required for morphological differentiation and the expression of myelin markers such as O1 and protein zero. To conclude, our data indicates that cAMP did not directly drive myelination but rather the transition into an O1 positive state, which is perhaps the most critical cAMP-dependent rate limiting step for the onset of myelination. The temporally restricted role of cAMP in inducing differentiation independently of basal lamina formation provides a clear example of the uncoupling of signals

  11. Increased signaling entropy in cancer requires the scale-free property of protein interaction networks.

    PubMed

    Teschendorff, Andrew E; Banerji, Christopher R S; Severini, Simone; Kuehn, Reimer; Sollich, Peter

    2015-04-28

    One of the key characteristics of cancer cells is an increased phenotypic plasticity, driven by underlying genetic and epigenetic perturbations. However, at a systems-level it is unclear how these perturbations give rise to the observed increased plasticity. Elucidating such systems-level principles is key for an improved understanding of cancer. Recently, it has been shown that signaling entropy, an overall measure of signaling pathway promiscuity, and computable from integrating a sample's gene expression profile with a protein interaction network, correlates with phenotypic plasticity and is increased in cancer compared to normal tissue. Here we develop a computational framework for studying the effects of network perturbations on signaling entropy. We demonstrate that the increased signaling entropy of cancer is driven by two factors: (i) the scale-free (or near scale-free) topology of the interaction network, and (ii) a subtle positive correlation between differential gene expression and node connectivity. Indeed, we show that if protein interaction networks were random graphs, described by Poisson degree distributions, that cancer would generally not exhibit an increased signaling entropy. In summary, this work exposes a deep connection between cancer, signaling entropy and interaction network topology.

  12. Increased signaling entropy in cancer requires the scale-free property of protein interaction networks

    PubMed Central

    Teschendorff, Andrew E.; Banerji, Christopher R. S.; Severini, Simone; Kuehn, Reimer; Sollich, Peter

    2015-01-01

    One of the key characteristics of cancer cells is an increased phenotypic plasticity, driven by underlying genetic and epigenetic perturbations. However, at a systems-level it is unclear how these perturbations give rise to the observed increased plasticity. Elucidating such systems-level principles is key for an improved understanding of cancer. Recently, it has been shown that signaling entropy, an overall measure of signaling pathway promiscuity, and computable from integrating a sample's gene expression profile with a protein interaction network, correlates with phenotypic plasticity and is increased in cancer compared to normal tissue. Here we develop a computational framework for studying the effects of network perturbations on signaling entropy. We demonstrate that the increased signaling entropy of cancer is driven by two factors: (i) the scale-free (or near scale-free) topology of the interaction network, and (ii) a subtle positive correlation between differential gene expression and node connectivity. Indeed, we show that if protein interaction networks were random graphs, described by Poisson degree distributions, that cancer would generally not exhibit an increased signaling entropy. In summary, this work exposes a deep connection between cancer, signaling entropy and interaction network topology. PMID:25919796

  13. Continuous auditory monitoring--how much information do we register?

    PubMed

    Craven, R M; McIndoe, A K

    1999-11-01

    We have studied response times of 30 anaesthetists to a standardized episode of arterial oxygen desaturation in a simulated patient, randomized to the use of either a fixed or variable pitch pulse oximeter. We wished to determine if a variable auditory signal was important in detecting adverse events. A variable pitch pulse signal had a shorter time to recognition of desaturation (P < 0.0001), with a mean response time of 32 s, compared with 129 s for the fixed pitch signal.

  14. Synaptic generation of an intracellular retrograde signal requires activation of the tyrosine kinase and mitogen-activated protein kinase signaling cascades in Aplysia.

    PubMed

    Stough, Shara; Kopec, Ashley M; Carew, Thomas J

    2015-11-01

    Cellular changes underlying memory formation can be generated in an activity-dependent manner at specific synapses. Thus an important question concerns the mechanisms by which synaptic signals communicate with the cell body to mediate these cellular changes. A monosynaptic circuit that is enhanced by sensitization in Aplysia is well-suited to study this question because three different subcellular compartments: (i) the sensorimotor SN-MN synapses, (ii) the SN projections to MNs via axonal connections, (iii) the SN cell bodies, can all be manipulated and studied independently. Here, we report that activity-dependent (AD) training in either the entire SN-MN circuit or in only the synaptic compartment, activates MAPK in a temporally and spatially specific pattern. Specifically, we find (i) MAPK activation is first transiently generated at SN-MN synapses during training, (ii) immediately after training MAPK is transiently activated in SN-MN axonal connections and persistently activated in SN cell bodies, and finally, (iii) MAPK is activated in SN cell bodies and SN-MN synapses 1h after training. These data suggest that there is an intracellularly transported retrograde signal generated at the synapse which is later responsible for delayed MAPK activation at SN somata. Finally, we find that this retrograde signal requires activation of tyrosine kinase (TK) and MEK signaling cascades at the synapses.

  15. ROS-Induced JNK and p38 Signaling Is Required for Unpaired Cytokine Activation during Drosophila Regeneration

    PubMed Central

    Santabárbara-Ruiz, Paula; López-Santillán, Mireya; Martínez-Rodríguez, Irene; Binagui-Casas, Anahí; Pérez, Lídia; Milán, Marco; Corominas, Montserrat; Serras, Florenci

    2015-01-01

    Upon apoptotic stimuli, epithelial cells compensate the gaps left by dead cells by activating proliferation. This has led to the proposal that dying cells signal to surrounding living cells to maintain homeostasis. Although the nature of these signals is not clear, reactive oxygen species (ROS) could act as a signaling mechanism as they can trigger pro-inflammatory responses to protect epithelia from environmental insults. Whether ROS emerge from dead cells and what is the genetic response triggered by ROS is pivotal to understand regeneration of Drosophila imaginal discs. We genetically induced cell death in wing imaginal discs, monitored the production of ROS and analyzed the signals required for repair. We found that cell death generates a burst of ROS that propagate to the nearby surviving cells. Propagated ROS activate p38 and induce tolerable levels of JNK. The activation of JNK and p38 results in the expression of the cytokines Unpaired (Upd), which triggers the JAK/STAT signaling pathway required for regeneration. Our findings demonstrate that this ROS/JNK/p38/Upd stress responsive module restores tissue homeostasis. This module is not only activated after cell death induction but also after physical damage and reveals one of the earliest responses for imaginal disc regeneration. PMID:26496642

  16. ROS-Induced JNK and p38 Signaling Is Required for Unpaired Cytokine Activation during Drosophila Regeneration.

    PubMed

    Santabárbara-Ruiz, Paula; López-Santillán, Mireya; Martínez-Rodríguez, Irene; Binagui-Casas, Anahí; Pérez, Lídia; Milán, Marco; Corominas, Montserrat; Serras, Florenci

    2015-10-01

    Upon apoptotic stimuli, epithelial cells compensate the gaps left by dead cells by activating proliferation. This has led to the proposal that dying cells signal to surrounding living cells to maintain homeostasis. Although the nature of these signals is not clear, reactive oxygen species (ROS) could act as a signaling mechanism as they can trigger pro-inflammatory responses to protect epithelia from environmental insults. Whether ROS emerge from dead cells and what is the genetic response triggered by ROS is pivotal to understand regeneration of Drosophila imaginal discs. We genetically induced cell death in wing imaginal discs, monitored the production of ROS and analyzed the signals required for repair. We found that cell death generates a burst of ROS that propagate to the nearby surviving cells. Propagated ROS activate p38 and induce tolerable levels of JNK. The activation of JNK and p38 results in the expression of the cytokines Unpaired (Upd), which triggers the JAK/STAT signaling pathway required for regeneration. Our findings demonstrate that this ROS/JNK/p38/Upd stress responsive module restores tissue homeostasis. This module is not only activated after cell death induction but also after physical damage and reveals one of the earliest responses for imaginal disc regeneration.

  17. Mouse nasal epithelial innate immune responses to Pseudomonas aeruginosa quorum-sensing molecules require taste signaling components

    PubMed Central

    Lee, Robert J.; Chen, Bei; Redding, Kevin M.; Margolskee, Robert F.; Cohen, Noam A.

    2016-01-01

    We previously observed that the human bitter taste receptor T2R38 is an important component of upper respiratory innate defense because it detects acyl homoserine lactone (AHL) quorum sensing molecules secreted by gram-negative bacteria. T2R38 activation in human sinonasal epithelial cells stimulates calcium and nitric oxide signals that increase mucociliary clearance, the major physical respiratory defense against inhaled pathogens. While mice do not have a clear T2R38 orthologue, they do have bitter taste receptors capable of responding to T2R38 agonists, suggesting that T2R-mediated innate immune mechanisms may be conserved in mice. We examined whether AHLs activate calcium and nitric oxide signaling in mouse nasal epithelial cells and utilized pharmacology as well as cells from knockout mice lacking important components of canonical taste signal transduction pathways to determine if AHL-stimulated responses require taste signaling molecules. We found that AHLs stimulate calcium-dependent NO production that increases mucociliary clearance and thus likely serves an innate immune role against gram-negative bacteria. These responses require PLCβ2 and TRPM5 taste signaling components, but not α-gustducin. These data suggest the mouse may be a useful model for further studies of T2R-mediated innate immunity. PMID:24045336

  18. NK cell-extrinsic IL-18 signaling is required for efficient NK-cell activation by vaccinia virus.

    PubMed

    Brandstadter, Joshua D; Huang, Xiaopei; Yang, Yiping

    2014-09-01

    NK cells are important for the control of vaccinia virus (VV) in vivo. Recent studies have shown that multiple pathways are required for effective activation of NK cells. These include both TLR-dependent and -independent pathways, as well as the NKG2D activating receptor that recognizes host stress-induced NKG2D ligands. However, it remains largely unknown what controls the upregulation of NKG2D ligands in response to VV infection. In this study using C57BL/6 mice, we first showed that IL-18 is critical for NK-cell activation and viral clearance. We then demonstrated that IL-18 signaling on both NK cells and DCs is required for efficient NK-cell activation upon VV infection in vitro. We further showed in vivo that efficient NK-cell activation in response to VV is dependent on DCs and IL-18 signaling in non-NK cells, suggesting an essential role for NK cell-extrinsic IL-18 signaling in NK-cell activation. Mechanistically, IL-18 signaling in DCs promotes expression of Rae-1, an NKG2D ligand. Collectively, our data reveal a previously unrecognized role for NK cell-extrinsic IL-18 signaling in NK-cell activation through upregulation of NKG2D ligands. These observations may provide insights into the design of effective NK-cell-based therapies for viral infections and cancer.

  19. Using an auditory sensory substitution device to augment vision: evidence from eye movements.

    PubMed

    Wright, Thomas D; Margolis, Aaron; Ward, Jamie

    2015-03-01

    Sensory substitution devices convert information normally associated with one sense into another sense (e.g. converting vision into sound). This is often done to compensate for an impaired sense. The present research uses a multimodal approach in which both natural vision and sound-from-vision ('soundscapes') are simultaneously presented. Although there is a systematic correspondence between what is seen and what is heard, we introduce a local discrepancy between the signals (the presence of a target object that is heard but not seen) that the participant is required to locate. In addition to behavioural responses, the participants' gaze is monitored with eye-tracking. Although the target object is only presented in the auditory channel, behavioural performance is enhanced when visual information relating to the non-target background is presented. In this instance, vision may be used to generate predictions about the soundscape that enhances the ability to detect the hidden auditory object. The eye-tracking data reveal that participants look for longer in the quadrant containing the auditory target even when they subsequently judge it to be located elsewhere. As such, eye movements generated by soundscapes reveal the knowledge of the target location that does not necessarily correspond to the actual judgment made. The results provide a proof of principle that multimodal sensory substitution may be of benefit to visually impaired people with some residual vision and, in normally sighted participants, for guiding search within complex scenes.

  20. A Novel 9-Class Auditory ERP Paradigm Driving a Predictive Text Entry System

    PubMed Central

    Höhne, Johannes; Schreuder, Martijn; Blankertz, Benjamin; Tangermann, Michael

    2011-01-01

    Brain–computer interfaces (BCIs) based on event related potentials (ERPs) strive for offering communication pathways which are independent of muscle activity. While most visual ERP-based BCI paradigms require good control of the user's gaze direction, auditory BCI paradigms overcome this restriction. The present work proposes a novel approach using auditory evoked potentials for the example of a multiclass text spelling application. To control the ERP speller, BCI users focus their attention to two-dimensional auditory stimuli that vary in both, pitch (high/medium/low) and direction (left/middle/right) and that are presented via headphones. The resulting nine different control signals are exploited to drive a predictive text entry system. It enables the user to spell a letter by a single nine-class decision plus two additional decisions to confirm a spelled word. This paradigm – called PASS2D – was investigated in an online study with 12 healthy participants. Users spelled with more than 0.8 characters per minute on average (3.4 bits/min) which makes PASS2D a competitive method. It could enrich the toolbox of existing ERP paradigms for BCI end users like people with amyotrophic lateral sclerosis disease in a late stage. PMID:21909321

  1. Adaptive, behaviorally-gated, persistent encoding of task-relevant auditory information in ferret frontal cortex

    PubMed Central

    Fritz, Jonathan B.; David, Stephen V.; Radtke-Schuller, Susanne; Yin, Pingbo; Shamma, Shihab A.

    2010-01-01

    Top-down signals from frontal cortex (FC) are conjectured to play a critical role in cognitive control of sensory processing. To explore this interaction, we compared activity in ferret FC and primary auditory cortex (A1) during auditory and visual tasks requiring discrimination between classes of reference and target stimuli. FC responses were behaviorally-gated, selectively encoded the timing and invariant behavioral meaning of target stimuli, could be rapid in onset, and sometimes persisted for hours following behavior. This mirrors earlier findings in A1that attention triggered rapid, selective, persistent, task-related changes in spectrotemporal receptive fields. Simultaneously recorded local field potentials (LFPs) revealed behaviorally-gated changes in inter-areal coherence, selectively modulated between FC and focal regions of A1 responsive to target sounds. These results suggest that A1 and FC dynamically establish a functional connection during auditory behavior that shapes the flow of sensory information and maintains a persistent trace of recent task-relevant stimulus features. PMID:20622871

  2. Characterization of auditory synaptic inputs to gerbil perirhinal cortex

    PubMed Central

    Kotak, Vibhakar C.; Mowery, Todd M.; Sanes, Dan H.

    2015-01-01

    The representation of acoustic cues involves regions downstream from the auditory cortex (ACx). One such area, the perirhinal cortex (PRh), processes sensory signals containing mnemonic information. Therefore, our goal was to assess whether PRh receives auditory inputs from the auditory thalamus (MG) and ACx in an auditory thalamocortical brain slice preparation and characterize these afferent-driven synaptic properties. When the MG or ACx was electrically stimulated, synaptic responses were recorded from the PRh neurons. Blockade of type A gamma-aminobutyric acid (GABA-A) receptors dramatically increased the amplitude of evoked excitatory potentials. Stimulation of the MG or ACx also evoked calcium transients in most PRh neurons. Separately, when fluoro ruby was injected in ACx in vivo, anterogradely labeled axons and terminals were observed in the PRh. Collectively, these data show that the PRh integrates auditory information from the MG and ACx and that auditory driven inhibition dominates the postsynaptic responses in a non-sensory cortical region downstream from the ACx. PMID:26321918

  3. Corticofugal regulation of auditory sensitivity in the bat inferior colliculus.

    PubMed

    Jen, P H; Chen, Q C; Sun, X D

    1998-12-01

    Under free-field stimulation conditions, corticofugal regulation of auditory sensitivity of neurons in the central nucleus of the inferior colliculus of the big brown bat, Eptesicus fuscus, was studied by blocking activities of auditory cortical neurons with Lidocaine or by electrical stimulation in auditory cortical neuron recording sites. The corticocollicular pathway regulated the number of impulses, the auditory spatial response areas and the frequency-tuning curves of inferior colliculus neurons through facilitation or inhibition. Corticofugal regulation was most effective at low sound intensity and was dependent upon the time interval between acoustic and electrical stimuli. At optimal inter-stimulus intervals, inferior colliculus neurons had the smallest number of impulses and the longest response latency during corticofugal inhibition. The opposite effects were observed during corticofugal facilitation. Corticofugal inhibitory latency was longer than corticofugal facilitatory latency. Iontophoretic application of gamma-aminobutyric acid and bicuculline to inferior colliculus recording sites produced effects similar to what were observed during corticofugal inhibition and facilitation. We suggest that corticofugal regulation of central auditory sensitivity can provide an animal with a mechanism to regulate acoustic signal processing in the ascending auditory pathway.

  4. Heritability of Non-Speech Auditory Processing Skills

    PubMed Central

    Brewer, Carmen C.; Zalewski, Christopher K.; King, Kelly A.; Zobay, Oliver; Riley, Alison; Ferguson, Melanie A.; Bird, Jonathan E.; McCabe, Margaret M.; Hood, Linda J.; Drayna, Dennis; Griffith, Andrew J.; Morell, Robert J.; Friedman, Thomas B.; Moore, David R.

    2015-01-01

    Recent insight into the genetic bases for autism spectrum disorder, dyslexia, stuttering and language disorders suggest that neurogenetic approaches may also reveal at least one etiology of auditory processing disorder (APD). A person with an APD typically has difficulty understanding speech in background noise despite having normal pure-tone hearing sensitivity. The estimated prevalence of APD may be as high as 10% in the pediatric population, yet the causes are unknown and have not been explored by molecular or genetic approaches. The aim of our study was to determine the heritability of frequency and temporal resolution for auditory signals and speech recognition in noise in 96 identical or fraternal twin-pairs, aged 6-11 years. Measures of auditory processing of non-speech sounds included backward masking (temporal resolution), notched noise masking (spectral resolution), pure-tone frequency discrimination (temporal fine structure sensitivity), and nonsense syllable recognition in noise. We provide evidence of significant heritability, ranging from 0.32-0.74, for individual measures of these non-speech based auditory processing skills that are crucial for understanding of spoken language. Identification of specific heritable auditory processing traits such as these serve as a basis to pursue the genetic underpinnings of APD by identifying genetic variants associated with common auditory processing disorders in children and adults. PMID:26883091

  5. Auditory Discrimination and Auditory Sensory Behaviours in Autism Spectrum Disorders

    ERIC Educational Resources Information Center

    Jones, Catherine R. G.; Happe, Francesca; Baird, Gillian; Simonoff, Emily; Marsden, Anita J. S.; Tregay, Jenifer; Phillips, Rebecca J.; Goswami, Usha; Thomson, Jennifer M.; Charman, Tony

    2009-01-01

    It has been hypothesised that auditory processing may be enhanced in autism spectrum disorders (ASD). We tested auditory discrimination ability in 72 adolescents with ASD (39 childhood autism; 33 other ASD) and 57 IQ and age-matched controls, assessing their capacity for successful discrimination of the frequency, intensity and duration…

  6. The Central Auditory Processing Kit[TM]. Book 1: Auditory Memory [and] Book 2: Auditory Discrimination, Auditory Closure, and Auditory Synthesis [and] Book 3: Auditory Figure-Ground, Auditory Cohesion, Auditory Binaural Integration, and Compensatory Strategies.

    ERIC Educational Resources Information Center

    Mokhemar, Mary Ann

    This kit for assessing central auditory processing disorders (CAPD), in children in grades 1 through 8 includes 3 books, 14 full-color cards with picture scenes, and a card depicting a phone key pad, all contained in a sturdy carrying case. The units in each of the three books correspond with auditory skill areas most commonly addressed in…

  7. Hippo signaling is required for Notch-dependent smooth muscle differentiation of neural crest

    PubMed Central

    Manderfield, Lauren J.; Aghajanian, Haig; Engleka, Kurt A.; Lim, Lillian Y.; Liu, Feiyan; Jain, Rajan; Li, Li; Olson, Eric N.; Epstein, Jonathan A.

    2015-01-01

    Notch signaling has well-defined roles in the assembly of arterial walls and in the development of the endothelium and smooth muscle of the vasculature. Hippo signaling regulates cellular growth in many tissues, and contributes to regulation of organ size, in addition to other functions. Here, we show that the Notch and Hippo pathways converge to regulate smooth muscle differentiation of the neural crest, which is crucial for normal development of the aortic arch arteries and cranial vasculature during embryonic development. Neural crest-specific deletion of the Hippo effectors Yap and Taz produces neural crest precursors that migrate normally, but fail to produce vascular smooth muscle, and Notch target genes such as Jagged1 fail to activate normally. We show that Yap is normally recruited to a tissue-specific Jagged1 enhancer by directly interacting with the Notch intracellular domain (NICD). The Yap-NICD complex is recruited to chromatin by the DNA-binding protein Rbp-J in a Tead-independent fashion. Thus, Hippo signaling can modulate Notch signaling outputs, and components of the Hippo and Notch pathways physically interact. Convergence of Hippo and Notch pathways by the mechanisms described here might be relevant for the function of these signaling cascades in many tissues and in diseases such as cancer. PMID:26253400

  8. VISA is an adapter protein required for virus-triggered IFN-beta signaling.

    PubMed

    Xu, Liang-Guo; Wang, Yan-Yi; Han, Ke-Jun; Li, Lian-Yun; Zhai, Zhonghe; Shu, Hong-Bing

    2005-09-16

    Viral infection or stimulation of TLR3 triggers signaling cascades, leading to activation of the transcription factors IRF-3 and NF-kappaB, which collaborate to induce transcription of type I interferon (IFN) genes. In this study, we identified a protein termed VISA (for virus-induced signaling adaptor) as a critical component in the IFN-beta signaling pathways. VISA recruits IRF-3 to the cytoplasmic viral dsRNA sensor RIG-I. Depletion of VISA inhibits virus-triggered and RIG-I-mediated activation of IRF-3, NF-kappaB, and the IFN-beta promoter, suggesting that VISA plays a central role in virus-triggered TLR3-independent IFN-beta signaling. Our data also indicate that VISA interacts with TRIF and TRAF6 and mediates bifurcation of the TLR3-triggered NF-kappaB and IRF-3 activation pathways. These findings suggest that VISA is critically involved in both virus-triggered TLR3-independent and TLR3-mediated antiviral IFN signaling.

  9. Activation of Notch1 signaling is required for β-catenin–mediated human primary melanoma progression

    PubMed Central

    Balint, Klara; Xiao, Min; Pinnix, Chelsea C.; Soma, Akinobu; Veres, Imre; Juhasz, Istvan; Brown, Eric J.; Capobianco, Anthony J.; Herlyn, Meenhard; Liu, Zhao-Jun

    2005-01-01

    Notch is a highly conserved transmembrane receptor that determines cell fate. Notch signaling denotes cleavage of the Notch intracellular domain, its translocation to the nucleus, and subsequent activation of target gene transcription. Involvement of Notch signaling in several cancers is well known, but its role in melanoma remains poorly characterized. Here we show that the Notch1 pathway is activated in human melanoma. Blocking Notch signaling suppressed whereas constitutive activation of the Notch1 pathway enhanced primary melanoma cell growth both in vitro and in vivo yet had little effect on metastatic melanoma cells. Activation of Notch1 signaling enabled primary melanoma cells to gain metastatic capability. Furthermore, the oncogenic effect of Notch1 on primary melanoma cells was mediated by β-catenin, which was upregulated following Notch1 activation. Inhibiting β-catenin expression reversed Notch1-enhanced tumor growth and metastasis. Our data therefore suggest a β-catenin–dependent, stage-specific role for Notch1 signaling in promoting the progression of primary melanoma. PMID:16239965

  10. Balanced Shh signaling is required for proper formation and maintenance of dorsal telencephalic midline structures

    PubMed Central

    2010-01-01

    Background The rostral telencephalic dorsal midline is an organizing center critical for the formation of the future cortex and hippocampus. While the intersection of WNTs, BMPs, and FGFs establishes boundaries within this critical center, a direct role of Shh signaling in this region remains controversial. In this paper we show that both increased and decreased Shh signaling directly affects boundary formation within the telencephalic dorsal midline. Results Viral over-expression of Shh in the embryonic telencephalon prevents formation of the cortical hem and choroid plexus, while expanding the roof plate. In a transgenic model where cholesterol-lacking ShhN is expressed from one allele (ShhN/+), genes expressed in all three domains, cortical hem, choroid plexus and roof plate expand. In Gli1/2 -/- mutant brains, where Shh signaling is reduced, the roof plate expands, again at the expense of cortical hem and plexus. Cell autonomous activation of Shh signaling in the dorsal midline through Gdf7-driven activated Smoothened expression results in expansion of the Wnt3a-expressing cortical hem into the plexus domain. In addition, developmental stage determines dorsal midline responsiveness to Shh. Conclusions Together, these data demonstrate that balanced Shh signaling is critical for maintaining regional boundaries within the dorsal midline telencephalic organizing center. PMID:21114856

  11. STIM1-dependent Ca2+ microdomains are required for myofilament remodeling and signaling in the heart

    PubMed Central

    Parks, Cory; Alam, Mohammad Afaque; Sullivan, Ryan; Mancarella, Salvatore

    2016-01-01

    In non-excitable cells stromal interaction molecule 1 (STIM1) is a key element in the generation of Ca2+ signals that lead to gene expression, migration and cell proliferation. A growing body of literature suggests that STIM1 plays a key role in the development of pathological cardiac hypertrophy. However, the precise mechanisms involving STIM-dependent Ca2+ signaling in the heart are not clearly established. Here, we have investigated the STIM1-associated Ca2+ signals in cardiomyocytes and their relevance to pathological cardiac remodeling. We show that mice with inducible, cardiac-restricted, ablation of STIM1 exhibited left ventricular reduced contractility, which was corroborated by impaired single cell contractility. The spatial properties of STIM1-dependent Ca2+ signals determine restricted Ca2+ microdomains that regulate myofilament remodeling and activate spatially segregated pro-hypertrophic factors. Indeed, mice lacking STIM1 showed less adverse structural remodeling in response to pressure overload-induced cardiac hypertrophy. These results highlight how STIM1-dependent Ca2+ microdomains have a major impact on intracellular Ca2+ homeostasis, cytoskeletal remodeling and cellular signaling, even when excitation-contraction coupling is present. PMID:27150728

  12. IGF signaling between blastema and wound epidermis is required for fin regeneration.

    PubMed

    Chablais, Fabian; Jazwinska, Anna

    2010-03-01

    In mammals, the loss of a limb is irreversible. By contrast, urodele amphibians and teleost fish are capable of nearly perfect regeneration of lost appendages. This ability depends on direct interaction between the wound epithelium and mesenchymal progenitor cells of the blastema. It has been known for decades that contact between the wound epithelium and the underlying blastema is essential for successful regeneration. However, the underlying mechanisms are poorly understood. Here, we show that upon amputation the blastema induces expression of the ligand Igf2b, which then activates IGF signaling specifically in cells of the adjacent apical epithelium. Inhibition of IGF signaling by either morpholino antisense technology, or by specific chemical inhibitors of Igf1 receptor function NVP-AEW541 and NVP-ADW742, impairs fin regeneration. At the cellular level, this block in regeneration is reflected by a lack of the distinctive basal epithelium, increased apoptosis in the wound epidermis and reduced proliferation of blastema cells. Furthermore, induction of the blastemal and wound epidermal markers cannot be supported in the absence of IGF signaling. These data provide evidence that Igf2b expressed in the blastema promotes the properties of the adjacent wound epidermis, which subsequently are necessary for blastema function. Thus, IGF signaling upregulated upon fin amputation represents a signal from the blastema to the wound epithelium, a crucial step in appendage regeneration.

  13. DAT isn’t all that: cocaine reward and reinforcement requires Toll Like Receptor 4 signaling

    PubMed Central

    Northcutt, A.L.; Hutchinson, M.R.; Wang, X.; Baratta, M.V.; Hiranita, T.; Cochran, T.A.; Pomrenze, M.B.; Galer, E.L.; Kopajtic, T.A.; Li, C.M.; Amat, J.; Larson, G.; Cooper, D.C.; Huang, Y.; O’Neill, C.E.; Yin, H.; Zahniser, N.R.; Katz, J.L.; Rice, K.C.; Maier, S.F.; Bachtell, R.K.; Watkins, L.R.

    2014-01-01

    The initial reinforcing properties of drugs of abuse, such as cocaine, are largely attributed to their ability to activate the mesolimbic dopamine system. Resulting increases in extracellular dopamine in the nucleus accumbens (NAc) are traditionally thought to result from cocaine’s ability to block dopamine transporters (DATs). Here we demonstrate that cocaine also interacts with the immunosurveillance receptor complex, Toll-Like Receptor 4 (TLR4), on microglial cells to initiate central innate immune signaling. Disruption of cocaine signaling at TLR4 suppresses cocaine-induced extracellular dopamine in the NAc, as well as cocaine conditioned place preference and cocaine self-administration. These results provide a novel understanding of the neurobiological mechanisms underlying cocaine reward/reinforcement that includes a critical role for central immune signaling, and offer a new target for medication development for cocaine abuse treatment. PMID:25644383

  14. Lens regeneration from the cornea requires suppression of Wnt/β-catenin signaling.

    PubMed

    Hamilton, Paul W; Sun, Yu; Henry, Jonathan J

    2016-04-01

    The frog, Xenopus laevis, possesses a high capacity to regenerate various larval tissues, including the lens, which is capable of complete regeneration from the cornea epithelium. However, the molecular signaling mechanisms of cornea-lens regeneration are not fully understood. Previous work has implicated the involvement of the Wnt signaling pathway, but molecular studies have been very limited. Iris-derived lens regeneration in the newt (Wolffian lens regeneration) has shown a necessity for active Wnt signaling in order to regenerate a new lens. Here we provide evidence that the Wnt signaling pathway plays a different role in the context of cornea-lens regeneration in Xenopus. We examined the expression of frizzled receptors and wnt ligands in the frog cornea epithelium. Numerous frizzled receptors (fzd1, fzd2, fzd3, fzd4, fzd6, fzd7, fzd8, and fzd10) and wnt ligands (wnt2b.a, wnt3a, wnt4, wnt5a, wnt5b, wnt6, wnt7b, wnt10a, wnt11, and wnt11b) are expressed in the cornea epithelium, demonstrating that this tissue is transcribing many of the ligands and receptors of the Wnt signaling pathway. When compared to flank epithelium, which is lens regeneration incompetent, only wnt11 and wnt11b are different (present only in the cornea epithelium), identifying them as potential regulators of cornea-lens regeneration. To detect changes in canonical Wnt/β-catenin signaling occurring within the cornea epithelium, axin2 expression was measured over the course of regeneration. axin2 is a well-established reporter of active Wnt/β-catenin signaling, and its expression shows a significant decrease at 24 h post-lentectomy. This decrease recovers to normal endogenous levels by 48 h. To test whether this signaling decrease was necessary for lens regeneration to occur, regenerating eyes were treated with either 6-bromoindirubin-3'-oxime (BIO) or 1-azakenpaullone - both activators of Wnt signaling - resulting in a significant reduction in the percentage of cases with successful

  15. The plastic ear and perceptual relearning in auditory spatial perception.

    PubMed

    Carlile, Simon

    2014-01-01

    The auditory system of adult listeners has been shown to accommodate to altered spectral cues to sound location which presumably provides the basis for recalibration to changes in the shape of the ear over a life time. Here we review the role of auditory and non-auditory inputs to the perception of sound location and consider a range of recent experiments looking at the role of non-auditory inputs in the process of accommodation to these altered spectral cues. A number of studies have used small ear molds to modify the spectral cues that result in significant degradation in localization performance. Following chronic exposure (10-60 days) performance recovers to some extent and recent work has demonstrated that this occurs for both audio-visual and audio-only regions of space. This begs the questions as to the teacher signal for this remarkable functional plasticity in the adult nervous system. Following a brief review of influence of the motor state in auditory localization, we consider the potential role of auditory-motor learning in the perceptual recalibration of the spectral cues. Several recent studies have considered how multi-modal and sensory-motor feedback might influence accommodation to altered spectral cues produced by ear molds or through virtual auditory space stimulation using non-individualized spectral cues. The work with ear molds demonstrates that a relatively short period of training involving audio-motor feedback (5-10 days) significantly improved both the rate and extent of accommodation to altered spectral cues. This has significant implications not only for the mechanisms by which this complex sensory information is encoded to provide spatial cues but also for adaptive training to altered auditory inputs. The review concludes by considering the implications for rehabilitative training with hearing aids and cochlear prosthesis.

  16. The plastic ear and perceptual relearning in auditory spatial perception

    PubMed Central

    Carlile, Simon

    2014-01-01

    The auditory system of adult listeners has been shown to accommodate to altered spectral cues to sound location which presumably provides the basis for recalibration to changes in the shape of the ear over a life time. Here we review the role of auditory and non-auditory inputs to the perception of sound location and consider a range of recent experiments looking at the role of non-auditory inputs in the process of accommodation to these altered spectral cues. A number of studies have used small ear molds to modify the spectral cues that result in significant degradation in localization performance. Following chronic exposure (10–60 days) performance recovers to some extent and recent work has demonstrated that this occurs for both audio-visual and audio-only regions of space. This begs the questions as to the teacher signal for this remarkable functional plasticity in the adult nervous system. Following a brief review of influence of the motor state in auditory localization, we consider the potential role of auditory-motor learning in the perceptual recalibration of the spectral cues. Several recent studies have considered how multi-modal and sensory-motor feedback might influence accommodation to altered spectral cues produced by ear molds or through virtual auditory space stimulation using non-individualized spectral cues. The work with ear molds demonstrates that a relatively short period of training involving audio-motor feedback (5–10 days) significantly improved both the rate and extent of accommodation to altered spectral cues. This has significant implications not only for the mechanisms by which this complex sensory information is encoded to provide spatial cues but also for adaptive training to altered auditory inputs. The review concludes by considering the implications for rehabilitative training with hearing aids and cochlear prosthesis. PMID:25147497

  17. Retinoic Acid Stimulates Regeneration of Mammalian Auditory Hair Cells

    NASA Astrophysics Data System (ADS)

    Lefebvre, Philippe P.; Malgrange, Brigitte; Staecker, Hinrich; Moonen, Gustave; van de Water, Thomas R.

    1993-04-01

    Sensorineural hearing loss resulting from the loss of auditory hair cells is thought to be irreversible in mammals. This study provides evidence that retinoic acid can stimulate the regeneration in vitro of mammalian auditory hair cells in ototoxic-poisoned organ of Corti explants in the rat. In contrast, treatment with retinoic acid does not stimulate the formation of extra hair cells in control cultures of Corti's organ. Retinoic acid-stimulated hair cell regeneration can be blocked by cytosine arabinoside, which suggests that a period of mitosis is required for the regeneration of auditory hair cells in this system. These results provide hope for a recovery of hearing function in mammals after auditory hair cell damage.

  18. Listening to Another Sense: Somatosensory Integration in the Auditory System

    PubMed Central

    Wu, Calvin; Stefanescu, Roxana A.; Martel, David T.

    2014-01-01

    Conventionally, sensory systems are viewed as separate entities, each with its own physiological process serving a different purpose. However, many functions require integrative inputs from multiple sensory systems, and sensory intersection and convergence occur throughout the central nervous system. The neural processes for hearing perception undergo significant modulation by the two other major sensory systems, vision and somatosensation. This synthesis occurs at every level of the ascending auditory pathway: the cochlear nucleus, inferior colliculus, medial geniculate body, and the auditory cortex. In this review, we explore the process of multisensory integration from 1) anatomical (inputs and connections), 2) physiological (cellular responses), 3) functional, and 4) pathological aspects. We focus on the convergence between auditory and somatosensory inputs in each ascending auditory station. This review highlights the intricacy of sensory processing, and offers a multisensory perspective regarding the understanding of sensory disorders. PMID:25526698

  19. Deficient auditory interhemispheric transfer in patients with PAX6 mutations.

    PubMed

    Bamiou, Doris-Eva; Musiek, Frank E; Sisodiya, Sanjay M; Free, Samantha L; Davies, Rosalyn A; Moore, Anthony; van Heyningen, Veronica; Luxon, Linda M

    2004-10-01

    PAX6 mutations are associated with absence/hypoplasia of the anterior commissure and reduction in the callosal area in humans. Both of these structures contain auditory interhemispheric fibers. The aim of this study was to characterize central auditory function in patients with a PAX6 mutation. We conducted central auditory tests (dichotic speech, pattern, and gaps in noise tests) on eight subjects with a PAX6 mutation and eight age- and sex-matched controls. Brain magnetic resonance imaging showed absent/hypoplastic anterior commissure in six and a hypoplastic corpus callosum in three PAX6 subjects. The control group gave normal central auditory tests results. All the PAX6 subjects gave abnormal results in at least two tests that require interhemispheric transfer, and all but one gave normal results in a test not requiring interhemispheric transfer. The left ear scores in the dichotic speech tests was significantly lower in the PAX6 than in the control group. These results are consistent with deficient auditory interhemispheric transfer in patients with a PAX6 mutation, which may be attributable to structural and/or functional abnormalities of the anterior commisure and corpus callosum, although the exact contribution of these two formations to our findings remains unclear. Our unique findings broaden the possible functions of PAX6 to include neurodevelopmental roles in higher order auditory processing. PMID:15389894

  20. Sorting Signals Required for Trafficking of the Cysteine-Rich Acidic Repetitive Transmembrane Protein in Trypanosoma brucei

    PubMed Central

    Qiao, Xugang; Chuang, Bin-Fay; Jin, Yamei; Muranjan, Madhavi; Hung, Chien-Hui; Lee, Pei-Tseng; Lee, Mary Gwo-Shu

    2006-01-01

    In trypanosomatids, endocytosis and exocytosis are restricted to the flagellar pocket (FP). The cysteine-rich acidic repetitive transmembrane (CRAM) protein is located at the FP of Trypanosoma brucei and potentially functions as a receptor or an essential component for lipoprotein uptake. We characterized sorting determinants involved in efficient trafficking of CRAM to and from the FP of T. brucei. Previous studies indicated the presence of signals in the CRAM C terminus, specific for its localization to the FP and for efficient endocytosis (H. Yang, D. G. Russell, B. Zeng, M. Eiki, and M.G.-S. Lee, Mol. Cell. Biol. 20:5149-5163, 2000.) To delineate functional domains of putative sorting signals, we performed a mutagenesis series of the CRAM C terminus. Subcellular localization of CRAM mutants demonstrated that the amino acid sequence between −5 and −14 (referred to as a transport signal) is essential for exporting CRAM from the endoplasmic reticulum to the FP, and mutations of amino acids at −12 (V), −10 (V), or −5 (D) led to retention of CRAM in the endoplasmic reticulum. Comparison of the endocytosis efficiency of CRAM mutants demonstrated that the sequence from amino acid −5 to −23 (referred to as a putative endocytosis signal) is required for efficient endocytosis and overlaps with the transport signal. Apparently the CRAM-derived sorting signal can efficiently interact with the T. brucei μ1 adaptin, and mutations at amino acids essential for the function of the transport signal abolished the interaction of the signal with T. brucei μ1, strengthening the hypothesis of the involvement of the clathrin- and adaptor-dependent pathway in trafficking of CRAM via the FP. PMID:16896208

  1. PV plasticity sustained through D1/5 dopamine signaling required for long-term memory consolidation.

    PubMed

    Karunakaran, Smitha; Chowdhury, Ananya; Donato, Flavio; Quairiaux, Charles; Michel, Christoph M; Caroni, Pico

    2016-03-01

    Long-term consolidation of memories depends on processes occurring many hours after acquisition. Whether this involves plasticity that is specifically required for long-term consolidation remains unclear. We found that learning-induced plasticity of local parvalbumin (PV) basket cells was specifically required for long-term, but not short/intermediate-term, memory consolidation in mice. PV plasticity, which involves changes in PV and GAD67 expression and connectivity onto PV neurons, was regulated by cAMP signaling in PV neurons. Following induction, PV plasticity depended on local D1/5 dopamine receptor signaling at 0-5 h to regulate its magnitude, and at 12-14 h for its continuance, ensuring memory consolidation. D1/5 dopamine receptor activation selectively induced DARPP-32 and ERK phosphorylation in PV neurons. At 12-14 h, PV plasticity was required for enhanced sharp-wave ripple densities and c-Fos expression in pyramidal neurons. Our results reveal general network mechanisms of long-term memory consolidation that requires plasticity of PV basket cells induced after acquisition and sustained subsequently through D1/5 receptor signaling.

  2. Requirement of Smad4-mediated signaling in odontoblast differentiation and dentin matrix formation

    PubMed Central

    Yun, Chi-Young; Choi, Hwajung; You, Young-Jae; Yang, Jin-Young

    2016-01-01

    Dentin is the major part of tooth and formed by odontoblasts. Under the influence of the inner enamel epithelium, odontoblasts differentiate from ectomesenchymal cells of the dental papilla and secrete pre-dentin which then undergo mineralization into dentin. Transforming growth factor-beta (TGF-β)/bone morphogenetic protein (BMP) signaling is essential for dentinogenesis; however, the precise molecular mechanisms remain unclear. To understand the role of TGF-β/BMP signaling in odontoblast differentiation and dentin formation, we generated mice with conditional ablation of Smad4, a key intracellular mediator of TGF-β/BMP signaling, using Osr2 or OC-Cre mice. Here we found the molars of Osr2CreSmad4 mutant mice exhibited impaired odontoblast differentiation, and normal dentin was replaced by ectopic bone-like structure. In Osr2CreSmad4 mutant mice, cell polarity of odontoblast was lost, and the thickness of crown dentin was decreased in later stage compared to wild type. Moreover, the root dentin was also impaired and showed ectopic bone-like structure similar to Osr2CreSmad4 mutant mice. Taken together, our results suggest that Smad4-dependent TGF-β/BMP signaling plays a critical role in odontoblast differentiation and dentin formation during tooth development. PMID:27722013

  3. Epsin is required for Dishevelled stability and Wnt signalling activation in colon cancer development.

    PubMed

    Chang, Baojun; Tessneer, Kandice L; McManus, John; Liu, Xiaolei; Hahn, Scott; Pasula, Satish; Wu, Hao; Song, Hoogeun; Chen, Yiyuan; Cai, Xiaofeng; Dong, Yunzhou; Brophy, Megan L; Rahman, Ruby; Ma, Jian-Xing; Xia, Lijun; Chen, Hong

    2015-03-16

    Uncontrolled canonical Wnt signalling supports colon epithelial tumour expansion and malignant transformation. Understanding the regulatory mechanisms involved is crucial for elucidating the pathogenesis of and will provide new therapeutic targets for colon cancer. Epsins are ubiquitin-binding adaptor proteins upregulated in several human cancers; however, the involvement of epsins in colon cancer is unknown. Here we show that loss of intestinal epithelial epsins protects against colon cancer by significantly reducing the stability of the crucial Wnt signalling effector, dishevelled (Dvl2), and impairing Wnt signalling. Consistently, epsins and Dvl2 are correspondingly upregulated in colon cancer. Mechanistically, epsin binds Dvl2 via its epsin N-terminal homology domain and ubiquitin-interacting motifs and prohibits Dvl2 polyubiquitination and degradation. Our findings reveal an unconventional role for epsins in stabilizing Dvl2 and potentiating Wnt signalling in colon cancer cells to ensure robust colon cancer progression. The pro-carcinogenic role of Epsins suggests that they are potential therapeutic targets to combat colon cancer.

  4. NMDA receptor signaling in oligodendrocyte progenitors is not required for oligodendrogenesis and myelination

    PubMed Central

    De Biase, L. M.; Kang, S. H.; Baxi, E. G.; Fukaya, M.; Pucak, M. L.; Mishina, M.; Calabresi, P. A.; Bergles, D. E.

    2011-01-01

    Oligodendrocyte precursor cells (OPCs) express NMDA receptors (NMDARs) and form synapses with glutamatergic neurons throughout the central nervous system (CNS). Although glutamate influences the proliferation and maturation of these progenitors in vitro, the role of NMDAR signaling in oligodendrogenesis and myelination in vivo is not known. Here, we investigated the consequences of genetically deleting the obligatory NMDAR subunit NR1 from OPCs and their oligodendrocyte progeny in the CNS of developing and mature mice. NMDAR-deficient OPCs proliferated normally, achieved appropriate densities in gray and white matter, and differentiated to form major white matter tracts without delay. OPCs also retained their characteristic physiological and morphological properties in the absence of NMDAR signaling, and were able to form synapses with glutamatergic axons. However, expression of calcium permeable AMPA receptors was enhanced in NMDAR-deficient OPCs. These results suggest that NMDAR signaling is not used to control OPC development, but to regulate AMPAR-dependent signaling with surrounding axons, pointing to additional functions for these ubiquitous glial cells. PMID:21880926

  5. Notch Signalling Is Required for the Formation of Structurally Stable Muscle Fibres in Zebrafish

    PubMed Central

    Pascoal, Susana; Esteves de Lima, Joana; Leslie, Jonathan D.; Hughes, Simon M.; Saúde, Leonor

    2013-01-01

    Background Accurate regulation of Notch signalling is central for developmental processes in a variety of tissues, but its function in pectoral fin development in zebrafish is still unknown. Methodology/Principal Findings Here we show that core elements necessary for a functional Notch pathway are expressed in developing pectoral fins in or near prospective muscle territories. Blocking Notch signalling at different levels of the pathway consistently leads to the formation of thin, wavy, fragmented and mechanically weak muscles fibres and loss of stress fibres in endoskeletal disc cells in pectoral fins. Although the structural muscle genes encoding Desmin and Vinculin are normally transcribed in Notch-disrupted pectoral fins, their proteins levels are severely reduced, suggesting that weak mechanical forces produced by the muscle fibres are unable to stabilize/localize these proteins. Moreover, in Notch signalling disrupted pectoral fins there is a decrease in the number of Pax7-positive cells indicative of a defect in myogenesis. Conclusions/Significance We propose that by controlling the differentiation of myogenic progenitor cells, Notch signalling might secure the formation of structurally stable muscle fibres in the zebrafish pectoral fin. PMID:23840804

  6. Leptin receptor signaling in T cells is required for Th17 differentiation

    PubMed Central

    Reis, Bernardo S; Lee, Kihyun; Fanok, Melania H; Mascaraque, Cristina; Amoury, Manal; Cohn, Lillian; Rogoz, Aneta; Dallner, Olof S; Moraes-Vieira, Pedro M; Domingos, Ana I; Mucida, Daniel

    2015-01-01

    The hormone leptin plays a key role in energy homeostasis, and the absence of either leptin or its receptor (lepR) leads to severe obesity and metabolic disorders. To avoid indirect effects and to address the cell-intrinsic role of leptin signaling in the immune system, we conditionally targeted lepR in T cells. In contrast to pleiotropic immune disorders reported in obese mice with leptin or lepR deficiency, we found that lepR deficiency in CD4+ T cells resulted in a selective defect in both autoimmune and protective Th17 responses. Reduced capacity for differentiation towards a Th17 phenotype by lepr-deficient T cells was attributed to reduced activation of the signal transducer and activator of transcription 3 (STAT3) and its downstream targets. This study establishes cell-intrinsic roles for leptin receptor signaling in the immune system and suggests that leptin signaling during T cell differentiation plays a crucial role in T cell peripheral effector function. PMID:25917102

  7. Issues in Human Auditory Development

    ERIC Educational Resources Information Center

    Werner, Lynne A.

    2007-01-01

    The human auditory system is often portrayed as precocious in its development. In fact, many aspects of basic auditory processing appear to be adult-like by the middle of the first year of postnatal life. However, processes such as attention and sound source determination take much longer to develop. Immaturity of higher-level processes limits the…

  8. Word Recognition in Auditory Cortex

    ERIC Educational Resources Information Center

    DeWitt, Iain D. J.

    2013-01-01

    Although spoken word recognition is more fundamental to human communication than text recognition, knowledge of word-processing in auditory cortex is comparatively impoverished. This dissertation synthesizes current models of auditory cortex, models of cortical pattern recognition, models of single-word reading, results in phonetics and results in…

  9. Auditory neglect and related disorders.

    PubMed

    Gutschalk, Alexander; Dykstra, Andrew

    2015-01-01

    Neglect is a neurologic disorder, typically associated with lesions of the right hemisphere, in which patients are biased towards their ipsilesional - usually right - side of space while awareness for their contralesional - usually left - side is reduced or absent. Neglect is a multimodal disorder that often includes deficits in the auditory domain. Classically, auditory extinction, in which left-sided sounds that are correctly perceived in isolation are not detected in the presence of synchronous right-sided stimulation, has been considered the primary sign of auditory neglect. However, auditory extinction can also be observed after unilateral auditory cortex lesions and is thus not specific for neglect. Recent research has shown that patients with neglect are also impaired in maintaining sustained attention, on both sides, a fact that is reflected by an impairment of auditory target detection in continuous stimulation conditions. Perhaps the most impressive auditory symptom in full-blown neglect is alloacusis, in which patients mislocalize left-sided sound sources to their right, although even patients with less severe neglect still often show disturbance of auditory spatial perception, most commonly a lateralization bias towards the right. We discuss how these various disorders may be explained by a single model of neglect and review emerging interventions for patient rehabilitation.

  10. Auditory short-term memory activation during score reading.

    PubMed

    Simoens, Veerle L; Tervaniemi, Mari

    2013-01-01

    Performing music on the basis of reading a score requires reading ahead of what is being played in order to anticipate the necessary actions to produce the notes. Score reading thus not only involves the decoding of a visual score and the comparison to the auditory feedback, but also short-term storage of the musical information due to the delay of the auditory feedback during reading ahead. This study investigates the mechanisms of encoding of musical information in short-term memory during such a complicated procedure. There were three parts in this study. First, professional musicians participated in an electroencephalographic (EEG) experiment to study the slow wave potentials during a time interval of short-term memory storage in a situation that requires cross-modal translation and short-term storage of visual material to be compared with delayed auditory material, as it is the case in music score reading. This delayed visual-to-auditory matching task was compared with delayed visual-visual and auditory-auditory matching tasks in terms of EEG topography and voltage amplitudes. Second, an additional behavioural experiment was performed to determine which type of distractor would be the most interfering with the score reading-like task. Third, the self-reported strategies of the participants were also analyzed. All three parts of this study point towards the same conclusion according to which during music score reading, the musician most likely first translates the visual score into an auditory cue, probably starting around 700 or 1300 ms, ready for storage and delayed comparison with the auditory feedback.

  11. Phosphorylation of Sox9 is required for neural crest delamination and is regulated downstream of BMP and canonical Wnt signaling.

    PubMed

    Liu, Jessica A J; Wu, Ming-Hoi; Yan, Carol H; Chau, Bolton K H; So, Henry; Ng, Alvis; Chan, Alan; Cheah, Kathryn S E; Briscoe, James; Cheung, Martin

    2013-02-19

    Coordination of neural crest cell (NCC) induction and delamination is orchestrated by several transcription factors. Among these, Sry-related HMG box-9 (Sox9) and Snail2 have been implicated in both the induction of NCC identity and, together with phoshorylation, NCC delamination. How phosphorylation effects this function has not been clear. Here we show, in the developing chick neural tube, that phosphorylation of Sox9 on S64 and S181 facilitates its SUMOylation, and the phosphorylated forms of Sox9 are essential for trunk neural crest delamination. Both phosphorylation and to a lesser extent SUMOylation, of Sox9 are required to cooperate with Snail2 to promote delamination. Moreover, bone morphogenetic protein and canonical Wnt signaling induce phosphorylation of Sox9, thereby connecting extracellular signals with the delamination of NCCs. Together the data suggest a model in which extracellular signals initiate phosphorylation of Sox9 and its cooperation with Snail2 to induce NCC delamination. PMID:23382206

  12. Phosphorylation of Sox9 is required for neural crest delamination and is regulated downstream of BMP and canonical Wnt signaling

    PubMed Central

    Liu, Jessica A. J.; Wu, Ming-Hoi; Yan, Carol H.; Chau, Bolton K. H.; So, Henry; Chan, Alan; Cheah, Kathryn S. E.; Briscoe, James; Cheung, Martin

    2013-01-01

    Coordination of neural crest cell (NCC) induction and delamination is orchestrated by several transcription factors. Among these, Sry-related HMG box-9 (Sox9) and Snail2 have been implicated in both the induction of NCC identity and, together with phoshorylation, NCC delamination. How phosphorylation effects this function has not been clear. Here we show, in the developing chick neural tube, that phosphorylation of Sox9 on S64 and S181 facilitates its SUMOylation, and the phosphorylated forms of Sox9 are essential for trunk neural crest delamination. Both phosphorylation and to a lesser extent SUMOylation, of Sox9 are required to cooperate with Snail2 to promote delamination. Moreover, bone morphogenetic protein and canonical Wnt signaling induce phosphorylation of Sox9, thereby connecting extracellular signals with the delamination of NCCs. Together the data suggest a model in which extracellular signals initiate phosphorylation of Sox9 and its cooperation with Snail2 to induce NCC delamination. PMID:23382206

  13. Recording of electrically evoked auditory brainstem responses (E-ABR) with an integrated stimulus generator in Matlab.

    PubMed

    Bahmer, Andreas; Peter, Otto; Baumann, Uwe

    2008-08-30

    Electrical auditory brainstem responses (E-ABRs) of subjects with cochlear implants are used for monitoring the physiologic responses of early signal processing of the auditory system. Additionally, E-ABR measurements allow the diagnosis of retro-cochlear diseases. Therefore, E-ABR should be available in every cochlear implant center as a diagnostic tool. In this paper, we introduce a low-cost setup designed to perform an E-ABR as well as a conventional ABR for research purposes. The distributable form was developed with Matlab and the Matlab Compiler (The Mathworks Inc.). For the ABR, only a PC with a soundcard, conventional system headphones, and an EEG pre-amplifier are necessary; for E-ABR, in addition, an interface to the cochlea implant is required. For our purposes, we implemented an interface for the Combi 40+/Pulsar implant (MED-EL, Innsbruck).

  14. Effects of the audiovisual conflict on auditory early processes.

    PubMed

    Scannella, Sébastien; Causse, Mickaël; Chauveau, Nicolas; Pastor, Josette; Dehais, Frédéric

    2013-07-01

    Auditory alarm misperception is one of the critical events that lead aircraft pilots to an erroneous flying decision. The rarity of these alarms associated with their possible unreliability may play a role in this misperception. In order to investigate this hypothesis, we manipulated both audiovisual conflict and sound rarity in a simplified landing task. Behavioral data and event related potentials (ERPs) of thirteen healthy participants were analyzed. We found that the presentation of a rare auditory signal (i.e., an alarm), incongruent with visual information, led to a smaller amplitude of the auditory N100 (i.e., less negative) compared to the condition in which both signals were congruent. Moreover, the incongruity between the visual information and the rare sound did not significantly affect reaction times, suggesting that the rare sound was neglected. We propose that the lower N100 amplitude reflects an early visual-to-auditory gating that depends on the rarity of the sound. In complex aircraft environments, this early effect might be partly responsible for auditory alarm insensitivity. Our results provide a new basis for future aeronautic studies and the development of countermeasures.

  15. The Perception of Auditory Motion

    PubMed Central

    Leung, Johahn

    2016-01-01

    The growing availability of efficient and relatively inexpensive virtual auditory display technology has provided new research platforms to explore the perception of auditory motion. At the same time, deployment of these technologies in command and control as well as in entertainment roles is generating an increasing need to better understand the complex processes underlying auditory motion perception. This is a particularly challenging processing feat because it involves the rapid deconvolution of the relative change in the locations of sound sources produced by rotational and translations of the head in space (self-motion) to enable the perception of actual source motion. The fact that we perceive our auditory world to be stable despite almost continual movement of the head demonstrates the efficiency and effectiveness of this process. This review examines the acoustical basis of auditory motion perception and a wide range of psychophysical, electrophysiological, and cortical imaging studies that have probed the limits and possible mechanisms underlying this perception. PMID:27094029

  16. Midbrain auditory selectivity to natural sounds

    PubMed Central

    Moss, Cynthia F.

    2016-01-01

    This study investigated auditory stimulus selectivity in the midbrain superior colliculus (SC) of the echolocating bat, an animal that relies on hearing to guide its orienting behaviors. Multichannel, single-unit recordings were taken across laminae of the midbrain SC of the awake, passively listening big brown bat, Eptesicus fuscus. Species-specific frequency-modulated (FM) echolocation sound sequences with dynamic spectrotemporal features served as acoustic stimuli along with artificial sound sequences matched in bandwidth, amplitude, and duration but differing in spectrotemporal structure. Neurons in dorsal sensory regions of the bat SC responded selectively to elements within the FM sound sequences, whereas neurons in ventral sensorimotor regions showed broad response profiles to natural and artificial stimuli. Moreover, a generalized linear model (GLM) constructed on responses in the dorsal SC to artificial linear FM stimuli failed to predict responses to natural sounds and vice versa, but the GLM produced accurate response predictions in ventral SC neurons. This result suggests that auditory selectivity in the dorsal extent of the bat SC arises through nonlinear mechanisms, which extract species-specific sensory information. Importantly, auditory selectivity appeared only in responses to stimuli containing the natural statistics of acoustic signals used by the bat for spatial orientation—sonar vocalizations—offering support for the hypothesis that sensory selectivity enables rapid species-specific orienting behaviors. The results of this study are the first, to our knowledge, to show auditory spectrotemporal selectivity to natural stimuli in SC neurons and serve to inform a more general understanding of mechanisms guiding sensory selectivity for natural, goal-directed orienting behaviors. PMID:26884152

  17. Idealized computational models for auditory receptive fields.

    PubMed

    Lindeberg, Tony; Friberg, Anders

    2015-01-01

    We present a theory by which idealized models of auditory receptive fields can be derived in a principled axiomatic manner, from a set of structural properties to (i) enable invariance of receptive field responses under natural sound transformations and (ii) ensure internal consistency between spectro-temporal receptive fields at different temporal and spectral scales. For defining a time-frequency transformation of a purely temporal sound signal, it is shown that the framework allows for a new way of deriving the Gabor and Gammatone filters as well as a novel family of generalized Gammatone filters, with additional degrees of freedom to obtain different trade-offs between the spectral selectivity and the temporal delay of time-causal temporal window functions. When applied to the definition of a second-layer of receptive fields from a spectrogram, it is shown that the framework leads to two canonical families of spectro-temporal receptive fields, in terms of spectro-temporal derivatives of either spectro-temporal Gaussian kernels for non-causal time or a cascade of time-causal first-order integrators over the temporal domain and a Gaussian filter over the logspectral domain. For each filter family, the spectro-temporal receptive fields can be either separable over the time-frequency domain or be adapted to local glissando transformations that represent variations in logarithmic frequencies over time. Within each domain of either non-causal or time-causal time, these receptive field families are derived by uniqueness from the assumptions. It is demonstrated how the presented framework allows for computation of basic auditory features for audio processing and that it leads to predictions about auditory receptive fields with good qualitative similarity to biological receptive fields measured in the inferior colliculus (ICC) and primary auditory cortex (A1) of mammals. PMID:25822973

  18. Midbrain auditory selectivity to natural sounds.

    PubMed

    Wohlgemuth, Melville J; Moss, Cynthia F

    2016-03-01

    This study investigated auditory stimulus selectivity in the midbrain superior colliculus (SC) of the echolocating bat, an animal that relies on hearing to guide its orienting behaviors. Multichannel, single-unit recordings were taken across laminae of the midbrain SC of the awake, passively listening big brown bat, Eptesicus fuscus. Species-specific frequency-modulated (FM) echolocation sound sequences with dynamic spectrotemporal features served as acoustic stimuli along with artificial sound sequences matched in bandwidth, amplitude, and duration but differing in spectrotemporal structure. Neurons in dorsal sensory regions of the bat SC responded selectively to elements within the FM sound sequences, whereas neurons in ventral sensorimotor regions showed broad response profiles to natural and artificial stimuli. Moreover, a generalized linear model (GLM) constructed on responses in the dorsal SC to artificial linear FM stimuli failed to predict responses to natural sounds and vice versa, but the GLM produced accurate response predictions in ventral SC neurons. This result suggests that auditory selectivity in the dorsal extent of the bat SC arises through nonlinear mechanisms, which extract species-specific sensory information. Importantly, auditory selectivity appeared only in responses to stimuli containing the natural statistics of acoustic signals used by the bat for spatial orientation-sonar vocalizations-offering support for the hypothesis that sensory selectivity enables rapid species-specific orienting behaviors. The results of this study are the first, to our knowledge, to show auditory spectrotemporal selectivity to natural stimuli in SC neurons and serve to inform a more general understanding of mechanisms guiding sensory selectivity for natural, goal-directed orienting behaviors. PMID:26884152

  19. Response recovery in the locust auditory pathway.

    PubMed

    Wirtssohn, Sarah; Ronacher, Bernhard

    2016-01-01

    Temporal resolution and the time courses of recovery from acute adaptation of neurons in the auditory pathway of the grasshopper Locusta migratoria were investigated with a response recovery paradigm. We stimulated with a series of single click and click pair stimuli while performing intracellular recordings from neurons at three processing stages: receptors and first and second order interneurons. The response to the second click was expressed relative to the single click response. This allowed the uncovering of the basic temporal resolution in these neurons. The effect of adaptation increased with processing layer. While neurons in the auditory periphery displayed a steady response recovery after a short initial adaptation, many interneurons showed nonlinear effects: most prominent a long-lasting suppression of the response to the second click in a pair, as well as a gain in response if a click was preceded by a click a few milliseconds before. Our results reveal a distributed temporal filtering of input at an early auditory processing stage. This set of specified filters is very likely homologous across grasshopper species and thus forms the neurophysiological basis for extracting relevant information from a variety of different temporal signals. Interestingly, in terms of spike timing precision neurons at all three processing layers recovered very fast, within 20 ms. Spike waveform analysis of several neuron types did not sufficiently explain the response recovery profiles implemented in these neurons, indicating that temporal resolution in neurons located at several processing layers of the auditory pathway is not necessarily limited by the spike duration and refractory period.

  20. Idealized Computational Models for Auditory Receptive Fields

    PubMed Central

    Lindeberg, Tony; Friberg, Anders

    2015-01-01

    We present a theory by which idealized models of auditory receptive fields can be derived in a principled axiomatic manner, from a set of structural properties to (i) enable invariance of receptive field responses under natural sound transformations and (ii) ensure internal consistency between spectro-temporal receptive fields at different temporal and spectral scales. For defining a time-frequency transformation of a purely temporal sound signal, it is shown that the framework allows for a new way of deriving the Gabor and Gammatone filters as well as a novel family of generalized Gammatone filters, with additional degrees of freedom to obtain different trade-offs between the spectral selectivity and the temporal delay of time-causal temporal window functions. When applied to the definition of a second-layer of receptive fields from a spectrogram, it is shown that the framework leads to two canonical families of spectro-temporal receptive fields, in terms of spectro-temporal derivatives of either spectro-temporal Gaussian kernels for non-causal time or a cascade of time-causal first-order integrators over the temporal domain and a Gaussian filter over the logspectral domain. For each filter family, the spectro-temporal receptive fields can be either separable over the time-frequency domain or be adapted to local glissando transformations that represent variations in logarithmic frequencies over time. Within each domain of either non-causal or time-causal time, these receptive field families are derived by uniqueness from the assumptions. It is demonstrated how the presented framework allows for computation of basic auditory features for audio processing and that it leads to predictions about auditory receptive fields with good qualitative similarity to biological receptive fields measured in the inferior colliculus (ICC) and primary auditory cortex (A1) of mammals. PMID:25822973

  1. Midbrain auditory selectivity to natural sounds.

    PubMed

    Wohlgemuth, Melville J; Moss, Cynthia F

    2016-03-01

    This study investigated auditory stimulus selectivity in the midbrain superior colliculus (SC) of the echolocating bat, an animal that relies on hearing to guide its orienting behaviors. Multichannel, single-unit recordings were taken across laminae of the midbrain SC of the awake, passively listening big brown bat, Eptesicus fuscus. Species-specific frequency-modulated (FM) echolocation sound sequences with dynamic spectrotemporal features served as acoustic stimuli along with artificial sound sequences matched in bandwidth, amplitude, and duration but differing in spectrotemporal structure. Neurons in dorsal sensory regions of the bat SC responded selectively to elements within the FM sound sequences, whereas neurons in ventral sensorimotor regions showed broad response profiles to natural and artificial stimuli. Moreover, a generalized linear model (GLM) constructed on responses in the dorsal SC to artificial linear FM stimuli failed to predict responses to natural sounds and vice versa, but the GLM produced accurate response predictions in ventral SC neurons. This result suggests that auditory selectivity in the dorsal extent of the bat SC arises through nonlinear mechanisms, which extract species-specific sensory information. Importantly, auditory selectivity appeared only in responses to stimuli containing the natural statistics of acoustic signals used by the bat for spatial orientation-sonar vocalizations-offering support for the hypothesis that sensory selectivity enables rapid species-specific orienting behaviors. The results of this study are the first, to our knowledge, to show auditory spectrotemporal selectivity to natural stimuli in SC neurons and serve to inform a more general understanding of mechanisms guiding sensory selectivity for natural, goal-directed orienting behaviors.

  2. Auditory selective attention to speech modulates activity in the visual word form area.

    PubMed

    Yoncheva, Yuliya N; Zevin, Jason D; Maurer, Urs; McCandliss, Bruce D

    2010-03-01

    Selective attention to speech versus nonspeech signals in complex auditory input could produce top-down modulation of cortical regions previously linked to perception of spoken, and even visual, words. To isolate such top-down attentional effects, we contrasted 2 equally challenging active listening tasks, performed on the same complex auditory stimuli (words overlaid with a series of 3 tones). Instructions required selectively attending to either the speech signals (in service of rhyme judgment) or the melodic signals (tone-triplet matching). Selective attention to speech, relative to attention to melody, was associated with blood oxygenation level-dependent (BOLD) increases during functional magnetic resonance imaging (fMRI) in left inferior frontal gyrus, temporal regions, and the visual word form area (VWFA). Further investigation of the activity in visual regions revealed overall deactivation relative to baseline rest for both attention conditions. Topographic analysis demonstrated that while attending to melody drove deactivation equivalently across all fusiform regions of interest examined, attending to speech produced a regionally specific modulation: deactivation of all fusiform regions, except the VWFA. Results indicate that selective attention to speech can topographically tune extrastriate cortex, leading to increased activity in VWFA relative to surrounding regions, in line with the well-established connectivity between areas related to spoken and visual word perception in skilled readers.

  3. HSPG synthesis by zebrafish Ext2 and Extl3 is required for Fgf10 signalling during limb development.

    PubMed

    Norton, William H J; Ledin, Johan; Grandel, Heiner; Neumann, Carl J

    2005-11-01

    Heparan sulphate proteoglycans (HSPGs) are known to be crucial for signalling by the secreted Wnt, Hedgehog, Bmp and Fgf proteins during invertebrate development. However, relatively little is known about their effect on developmental signalling in vertebrates. Here, we report the analysis of daedalus, a novel zebrafish pectoral fin mutant. Positional cloning identified fgf10 as the gene disrupted in daedalus. We find that fgf10 mutants strongly resemble zebrafish ext2 and extl3 mutants, which encode glycosyltransferases required for heparan sulphate biosynthesis. This suggests that HSPGs are crucial for Fgf10 signalling during limb development. Consistent with this proposal, we observe a strong genetic interaction between fgf10 and extl3 mutants. Furthermore, application of Fgf10 protein can rescue target gene activation in fgf10, but not in ext2 or extl3 mutants. By contrast, application of Fgf4 protein can activate target genes in both ext2 and extl3 mutants, indicating that ext2 and extl3 are differentially required for Fgf10, but not Fgf4, signalling during limb development. This reveals an unexpected specificity of HSPGs in regulating distinct vertebrate Fgfs. PMID:16221725

  4. Continuous inhibitory signaling by both SHP-1 and SHIP-1 pathways is required to maintain unresponsiveness of anergic B cells

    PubMed Central

    Getahun, Andrew; Beavers, Nicole A.; Larson, Sandy R.; Shlomchik, Mark J.

    2016-01-01

    Many autoreactive B cells persist in the periphery in a state of unresponsiveness called anergy. This unresponsiveness is rapidly reversible, requiring continuous BCR interaction with self-antigen and resultant regulatory signaling for its maintenance. Using adoptive transfer of anergic B cells with subsequent acute induction of gene deletion or expression, we demonstrate that the continuous activities of independent inhibitory signaling pathways involving the tyrosine phosphatase SHP-1 and the inositol phosphatase SHIP-1 are required to maintain anergy. Acute breach of anergy by compromise of either of these pathways leads to rapid cell activation, proliferation, and generation of short-lived plasma cells that reside in extrafollicular foci. Results are consistent with predicted/observed reduction in the Lyn–SHIP-1–PTEN–SHP-1 axis function in B cells from systemic lupus erythematosus patients. PMID:27114609

  5. The novel SAM domain protein Aveugle is required for Raf activation in the Drosophila EGF receptor signaling pathway

    PubMed Central

    Roignant, Jean-Yves; Hamel, Sophie; Janody, Florence; Treisman, Jessica E.

    2006-01-01

    Activation of the Raf kinase by GTP-bound Ras is a poorly understood step in receptor tyrosine kinase signaling pathways. One such pathway, the epidermal growth factor receptor (EGFR) pathway, is critical for cell differentiation, survival, and cell cycle regulation in many systems, including the Drosophila eye. We have identified a mutation in a novel gene, aveugle, based on its requirement for normal photoreceptor differentiation. The phenotypes of aveugle mutant cells in the eye and wing imaginal discs resemble those caused by reduction of EGFR pathway function. We show that aveugle is required between ras and raf for EGFR signaling in the eye and for mitogen-activated protein kinase phosphorylation in cell culture. aveugle encodes a small protein with a sterile α motif (SAM) domain that can physically interact with the scaffold protein connector enhancer of Ksr (Cnk). We propose that Aveugle acts together with Cnk to promote Raf activation, perhaps by recruiting an activating kinase. PMID:16600911

  6. Receptor tyrosine phosphatase psi is required for Delta/Notch signalling and cyclic gene expression in the presomitic mesoderm.

    PubMed

    Aerne, Birgit; Ish-Horowicz, David

    2004-07-01

    Segmentation in vertebrate embryos is controlled by a biochemical oscillator ('segmentation clock') intrinsic to the cells in the unsegmented presomitic mesoderm, and is manifested in cyclic transcription of genes involved in establishing somite polarity and boundaries. We show that the receptor protein tyrosine phosphatase psi (RPTPpsi) gene is essential for normal functioning of the somitogenesis clock in zebrafish. We show that reduction of RPTPpsi activity using morpholino antisense oligonucleotides results in severe disruption of the segmental pattern of the embryo, and loss of cyclic gene expression in the presomitic mesoderm. Analysis of cyclic genes in RPTPpsi morphant embryos indicates an important requirement for RPTPpsi in the control of the somitogenesis clock upstream of or in parallel with Delta/Notch signalling. Impairing RPTPpsi activity also interferes with convergent extension during gastrulation. We discuss this dual requirement for RPTPpsi in terms of potential functions in Notch and Wnt signalling. PMID:15226256

  7. Lys63-linked polyubiquitination of BRAF at lysine 578 is required for BRAF-mediated signaling

    PubMed Central

    An, Lei; Jia, Wei; Yu, Yang; Zou, Ning; Liang, Li; Zhao, Yanling; Fan, Yihui; Cheng, Jin; Shi, Zhongcheng; Xu, Gufeng; Li, Grace; Yang, Jianhua; Zhang, Hong

    2013-01-01

    The RAF kinase family is essential in mediating signal transduction from RAS to ERK. BRAF constitutively active mutations correlate with human cancer development. However, the precise molecular regulation of BRAF activation is not fully understood. Here we report that BRAF is modified by Lys63-linked polyubiquitination at lysine 578 within its kinase domain once it is activated by gain of constitutively active mutation or epidermal growth factor (EGF) stimulation. Substitution of BRAF lysine 578 with arginine (K578R) inhibited BRAF-mediated ERK activation. Furthermore, ectopic expression of BRAF K578R mutant inhibited anchorage-independent colony formation of MCF7 breast cancer cell line. Our studies have identified a previously unrecognized regulatory role of Lys63-linked polyubiquitination in BRAF-mediated normal and oncogenic signalings. PMID:23907581

  8. Epithelial-Specific Requirement of FGFR2 Signaling During Tooth and Palate Development

    PubMed Central

    HOSOKAWA, RYOICHI; DENG, XUEMEI; TAKAMORI, KAZUNORI; XU, XUN; URATA, MARK; BRINGAS, PABLO; CHAI, YANG

    2010-01-01

    Reciprocal interactions between epithelium and mesenchyme are crucial for embryonic development. Fibroblast growth factors (FGFs) are a growth factor family that play an important role in epithelial–mesenchymal tissue interaction. We have generated epithelial-specific conditional knockout mice targeting Fibroblast growth factor receptor 2 (Fgfr2) to investigate the function of FGF signaling during craniofacial development. K14-Cre;Fgfr2fl/fl mice have skin defects, retarded tooth formation, and cleft palate. During the formation of the tooth primordium and palatal processes, cell proliferation in the epithelial cells of K14-Cre;Fgfr2fl/fl mice is reduced. Thus, FGF signaling via FGFR2 in the epithelium is crucial for cell proliferation activity during tooth and palate development. PMID:19235875

  9. Time-sharing visual and auditory tracking tasks

    NASA Technical Reports Server (NTRS)

    Tsang, Pamela S.; Vidulich, Michael A.

    1987-01-01

    An experiment is described which examined the benefits of distributing the input demands of two tracking tasks as a function of task integrality. Visual and auditory compensatory tracking tasks were utilized. Results indicate that presenting the two tracking signals in two input modalities did not improve time-sharing efficiency. This was attributed to the difficulty insensitivity phenomenon.

  10. Stuttering Inhibition via Altered Auditory Feedback during Scripted Telephone Conversations

    ERIC Educational Resources Information Center

    Hudock, Daniel; Kalinowski, Joseph

    2014-01-01

    Background: Overt stuttering is inhibited by approximately 80% when people who stutter read aloud as they hear an altered form of their speech feedback to them. However, levels of stuttering inhibition vary from 60% to 100% depending on speaking situation and signal presentation. For example, binaural presentations of delayed auditory feedback…

  11. Rhythmic versus Phonemic Interference in Delayed Auditory Feedback

    ERIC Educational Resources Information Center

    Kaspar, Kai; Rubeling, Hartmut

    2011-01-01

    Purpose: Delayed auditory feedback (DAF) of a speaker's voice disturbs normal speech production. Various traditional theories assume that the content of the delayed feedback signal interferes with the actual production of a particular speech unit ("phonemic content hypothesis"). The "displaced rhythm hypothesis" as an alternative explanation…

  12. Biological Impact of Music and Software-Based Auditory Training

    ERIC Educational Resources Information Center

    Kraus, Nina

    2012-01-01

    Auditory-based communication skills are developed at a young age and are maintained throughout our lives. However, some individuals--both young and old--encounter difficulties in achieving or maintaining communication proficiency. Biological signals arising from hearing sounds relate to real-life communication skills such as listening to speech in…

  13. Eukaryotic G Protein Signaling Evolved to Require G Protein–Coupled Receptors for Activation

    PubMed Central

    Bradford, William; Buckholz, Adam; Morton, John; Price, Collin; Jones, Alan M.; Urano, Daisuke

    2016-01-01

    Although bioinformatic analysis of the increasing numbers of diverse genome sequences and amount of functional data has provided insight into the evolution of signaling networks, bioinformatics approaches have limited application for understanding the evolution of highly divergent protein families. We used biochemical analyses to determine the in vitro properties of selected divergent components of the heterotrimeric guanine nucleotide–binding protein (G protein) signaling network to investigate signaling network evolution. In animals, G proteins are activated by cell-surface seven-transmembrane (7TM) receptors, which are named G protein–coupled receptors (GPCRs) and function as guanine nucleotide exchange factors (GEFs). In contrast, the plant G protein is intrinsically active, and a 7TM protein terminates G protein activity by functioning as a guanosine triphosphatase–activating protein (GAP). We showed that ancient regulation of the G protein active state is GPCR-independent and “self-activating,” a property that is maintained in Bikonts, one of the two fundamental evolutionary clades containing eukaryotes, whereas G proteins of the other clade, the Unikonts, evolved from being GEF-independent to being GEF-dependent. Self-activating G proteins near the base of the Eukaryota are controlled by 7TM-GAPs, suggesting that the ancestral regulator of G protein activation was a GAP-functioning receptor, not a GEF-functioning GPCR. Our findings indicate that the GPCR paradigm describes a recently evolved network architecture found in a relatively small group of Eukaryota and suggest that the evolution of signaling network architecture is constrained by the availability of molecules that control the activation state of nexus proteins. PMID:23695163

  14. Mas Oncogene Signaling and Transformation Require the Small GTP-Binding Protein Rac

    PubMed Central

    Zohn, Irene E.; Symons, Marc; Chrzanowska-Wodnicka, Magdalena; Westwick, John K.; Der, Channing J.

    1998-01-01

    The Mas oncogene encodes a novel G-protein-coupled receptor that was identified originally as a transforming protein when overexpressed in NIH 3T3 cells. The mechanism and signaling pathways that mediate Mas transformation have not been determined. We observed that the foci of transformed NIH 3T3 cells caused by Mas were similar to those caused by activated Rho and Rac proteins. Therefore, we determined if Mas signaling and transformation are mediated through activation of a specific Rho family protein. First, we observed that, like activated Rac1, Mas cooperated with activated Raf and caused synergistic transformation of NIH 3T3 cells. Second, both Mas- and Rac1-transformed NIH 3T3 cells retained actin stress fibers and showed enhanced membrane ruffling. Third, like Rac, Mas induced lamellipodium formation in porcine aortic endothelial cells. Fourth, Mas and Rac1 strongly activated the JNK and p38, but not ERK, mitogen-activated protein kinases. Fifth, Mas and Rac1 stimulated transcription from common DNA promoter elements: NF-κB, serum response factor (SRF), Jun/ATF-2, and the cyclin D1 promoter. Finally, Mas transformation and some of Mas signaling (SRF and cyclin D1 but not NF-κB activation) were blocked by dominant negative Rac1. Taken together, these observations suggest that Mas transformation is mediated in part by activation of Rac-dependent signaling pathways. Thus, Rho family proteins are common mediators of transformation by a diverse variety of oncogene proteins that include Ras, Dbl family, and G-protein-coupled oncogene proteins. PMID:9488437

  15. MRTF-SRF signaling is required for seeding of HSC/Ps in bone marrow during development.

    PubMed

    Costello, Patrick; Sargent, Mathew; Maurice, Diane; Esnault, Cyril; Foster, Katie; Anjos-Afonso, Fernando; Treisman, Richard

    2015-02-19

    Chemokine signaling is important for the seeding of different sites by hematopoietic stem cells (HSCs) during development. Serum response factor (SRF) controls multiple genes governing adhesion and migration, mainly by recruiting members of the myocardin-related transcription factor (MRTF) family of G-actin-regulated cofactors. We used vav-iCre to inactivate MRTF-SRF signaling early during hematopoietic development. In both Srf- and Mrtf-deleted animals, hematopoiesis in fetal liver and spleen is intact but does not become established in fetal bone marrow. Srf-null HSC progenitor cells (HSC/Ps) fail to effectively engraft in transplantation experiments, exhibiting normal proximal signaling responses to SDF-1, but reduced adhesiveness, F-actin assembly, and reduced motility. Srf-null HSC/Ps fail to polarize in response to SDF-1 and cannot migrate through restrictive membrane pores to SDF-1 or Scf in vitro. Mrtf-null HSC/Ps were also defective in chemotactic responses to SDF-1. Srf-null HSC/Ps exhibit substantial deficits in cytoskeletal gene expression. MRTF-SRF signaling is thus critical for expression of genes required for the response to chemokine signaling during hematopoietic development. PMID:25573994

  16. ERK1/ERK2 MAPK signaling is required to increase myelin thickness independent of oligodendrocyte differentiation and initiation of myelination.

    PubMed

    Ishii, Akihiro; Fyffe-Maricich, Sharyl L; Furusho, Miki; Miller, Robert H; Bansal, Rashmi

    2012-06-27

    Wrapping of the myelin sheath around axons by oligodendrocytes is critical for the rapid conduction of electrical signals required for the normal functioning of the CNS. Myelination is a multistep process where oligodendrocytes progress through a well coordinated differentiation program regulated by multiple extracellular growth and differentiation signals. The intracellular transduction of the extracellular signals that regulate myelination is poorly understood. Here we demonstrate a critical role for two important signaling molecules, extracelluar signal-regulated protein kinases 1 and 2 (ERK1/ERK2), downstream mediators of mitogen-activated protein kinases, in the control of CNS myelin thickness. We generated and analyzed two lines of mice lacking both ERK1/ERK2 function specifically in oligodendrocyte-lineage cells. In the absence of ERK1/ERK2 signaling NG2⁺ oligodendrocyte progenitor cells proliferated and differentiated on schedule. Mutant oligodendrocytes also ensheathed axons normally and made a few wraps of compact myelin. However, the subsequent increase in myelination that correlated myelin thickness in proportion to the axon caliber failed to occur. Furthermore, although the numbers of differentiated oligodendrocytes in the adult mutants were unchanged, they showed an inability to upregulate the transcription of major myelin genes that normally occurs during active myelination. Similarly, in vitro ERK1/ERK2-deficient oligodendrocytes differentiated normally but failed to form typical myelin-like membrane sheets. None of these effects were observed in single ERK1 or ERK2 mutants. These studies suggest that the predominant role of ERK1/ERK2 signaling in vivo is in promoting rapid myelin growth to increase its thickness, subsequent to oligodendrocyte differentiation and the initiation of myelination.

  17. Vangl-dependent planar cell polarity signalling is not required for neural crest migration in mammals.

    PubMed

    Pryor, Sophie E; Massa, Valentina; Savery, Dawn; Andre, Philipp; Yang, Yingzi; Greene, Nicholas D E; Copp, Andrew J

    2014-08-01

    The role of planar cell polarity (PCP) signalling in neural crest (NC) development is unclear. The PCP dependence of NC cell migration has been reported in Xenopus and zebrafish, but NC migration has not been studied in mammalian PCP mutants. Vangl2(Lp/Lp) mouse embryos lack PCP signalling and undergo almost complete failure of neural tube closure. Here we show, however, that NC specification, migration and derivative formation occur normally in Vangl2(Lp/Lp) embryos. The gene family member Vangl1 was not expressed in NC nor ectopically expressed in Vangl2(Lp/Lp) embryos, and doubly homozygous Vangl1/Vangl2 mutants exhibited normal NC migration. Acute downregulation of Vangl2 in the NC lineage did not prevent NC migration. In vitro, Vangl2(Lp/Lp) neural tube explants generated emigrating NC cells, as in wild type. Hence, PCP signalling is not essential for NC migration in mammals, in contrast to its essential role in neural tube closure. PCP mutations are thus unlikely to mediate NC-related birth defects in humans.

  18. Distinct Signaling Requirements for the Establishment of ESC Pluripotency in Late-Stage EpiSCs

    PubMed Central

    Illich, Damir Jacob; Zhang, Miao; Ursu, Andrei; Osorno, Rodrigo; Kim, Kee-Pyo; Yoon, Juyong; Araúzo-Bravo, Marcos J.; Wu, Guangming; Esch, Daniel; Sabour, Davood; Colby, Douglas; Grassme, Kathrin S.; Chen, Jiayu; Greber, Boris; Höing, Susanne; Herzog, Wiebke; Ziegler, Slava; Chambers, Ian; Gao, Shaorong; Waldmann, Herbert; Schöler, Hans R.

    2016-01-01

    Summary It has previously been reported that mouse epiblast stem cell (EpiSC) lines comprise heterogeneous cell populations that are functionally equivalent to cells of either early- or late-stage postimplantation development. So far, the establishment of the embryonic stem cell (ESC) pluripotency gene regulatory network through the widely known chemical inhibition of MEK and GSK3beta has been impractical in late-stage EpiSCs. Here, we show that chemical inhibition of casein kinase 1alpha (CK1alpha) induces the conversion of recalcitrant late-stage EpiSCs into ESC pluripotency. CK1alpha inhibition directly results in the simultaneous activation of the WNT signaling pathway, together with inhibition of the TGFbeta/SMAD2 signaling pathway, mediating the rewiring of the gene regulatory network in favor of an ESC-like state. Our findings uncover a molecular mechanism that links CK1alpha to ESC pluripotency through the direct modulation of WNT and TGFbeta signaling. PMID:27149845

  19. PDK1 is required for the hormonal signaling pathway leading to meiotic resumption in starfish oocytes.

    PubMed

    Hiraoka, Daisaku; Hori-Oshima, Sawako; Fukuhara, Takeshi; Tachibana, Kazunori; Okumura, Eiichi; Kishimoto, Takeo

    2004-12-15

    Meiotic resumption is generally under the control of an extracellular maturation-inducing hormone. It is equivalent to the G2-M phase transition in somatic cell mitosis and is regulated by cyclin B-Cdc2 kinase. However, the complete signaling pathway from the hormone to cyclin B-Cdc2 is yet unclear in any organism. A model system to analyze meiotic resumption is the starfish oocyte, in which Akt/protein kinase B (PKB) plays a key mediator in hormonal signaling that leads to cyclin B-Cdc2 activation. Here we show in starfish oocytes that when PDK1 activity is inhibited by a neutralizing antibody, maturation-inducing hormone fails to induce cyclin B-Cdc2 activation at the meiotic G2-M phase transition, even though PDK2 activity becomes detectable. These observations assign a novel role to PDK1 for a hormonal signaling intermediate toward meiotic resumption. They further support that PDK2 is a molecule distinct from PDK1 and Akt, and that PDK2 activity is not sufficient for the full activation of Akt in the absence of PDK1 activity. PMID:15581868

  20. Human neural stem cell-induced endothelial morphogenesis requires autocrine/paracrine and juxtacrine signaling

    PubMed Central

    Chou, Chung-Hsing; Modo, Michel

    2016-01-01

    Transplanted neural stem cells (NSC) interact with the host brain microenvironment. A neovascularization is commonly observed in the vicinity of the cell deposit, which is correlated with behavioral improvements. To elucidate the signaling mechanisms between human NSCs and endothelial cells (ECs), these were cocultured in an in vitro model in which NSC-induced endothelial morphogenesis produced a neurovascular environment. Soluble (autocrine/paracrine) and contact–mediated (juxtacrine) signaling molecules were evaluated for two conditionally immortalized fetal NSC lines derived from the cortical anlage (CTXOE03) and ganglionic eminence (STROC05), as well as an adult EC line (D3) derived from the cerebral microvasculature of a hippocampal biopsy. STROC05 were 4 times as efficient to induce endothelial morphogenesis compared to CTXOE03. The cascade of reciprocal interactions between NSCs and ECs in this process was determined by quantifying soluble factors, receptor mapping, and immunocytochemistry for extracellular matrix molecules. The mechanistic significance of these was further evaluated by pharmacological blockade. The sequential cell-specific regulation of autocrine/paracrine and juxtacrine signaling accounted for the differential efficiency of NSCs to induce endothelial morphogenesis. These in vitro studies shed new light on the reciprocal interactions between NSCs and ECs, which are pivotal for our mechanistic understanding of the efficacy of NSC transplantation. PMID:27374240

  1. Virus-induced gene silencing reveals signal transduction components required for the Pvr9-mediated hypersensitive response in Nicotiana benthamiana.

    PubMed

    Tran, Phu-Tri; Choi, Hoseong; Choi, Doil; Kim, Kook-Hyung

    2016-08-01

    Resistance to pathogens mediated by plant resistance (R) proteins requires different signaling transduction components and pathways. Our previous studies revealed that a potyvirus resistance gene in pepper, Pvr9, confers a hypersensitive response (HR) to pepper mottle virus in Nicotiana benthamiana. Our results show that the Pvr9-mediated HR against pepper mottle virus infection requires HSP90, SGT1, NDR1, but not EDS1. These results suggest that the Pvr9-mediated HR is possibly related to the SA pathway but not the ET, JA, ROS or NO pathways.

  2. Auditory brainstem response in dolphins.

    PubMed

    Ridgway, S H; Bullock, T H; Carder, D A; Seeley, R L; Woods, D; Galambos, R

    1981-03-01

    We recorded the auditory brainstem response (ABR) in four dolphins (Tursiops truncatus and Delphinus delphis). The ABR evoked by clicks consists of seven waves within 10 msec; two waves often contain dual peaks. The main waves can be identified with those of humans and laboratory mammals; in spite of a much longer path, the latencies of the peaks are almost identical to those of the rat. The dolphin ABR waves increase in latency as the intensity of a sound decreases by only 4 microseconds/decibel(dB) (for clicks with peak power at 66 kHz) compared to 40 microseconds/dB in humans (for clicks in the sonic range). Low-frequency clicks (6-kHz peak power) show a latency increase about 3 times (12 microseconds/dB) as great. Although the dolphin brainstem tracks individual clicks to at least 600 per sec, the latency increases and amplitude decreases with increasing click rates. This effect varies among different waves of the ABR; it is around one-fifth the effect seen in man. The dolphin brain is specialized for handling brief, frequent clicks. A small latency difference is seen between clicks 180 degrees different in phase--i.e., with initial compression vs. initial rarefaction. The ABR can be used to test theories of dolphin sonar signal processing. Hearing thresholds can be evaluated rapidly. Cetaceans that have not been investigated can now be examined, including the great whales, a group for which data are now completely lacking.

  3. Are you listening? Brain activation associated with sustained nonspatial auditory attention in the presence and absence of stimulation.

    PubMed

    Seydell-Greenwald, Anna; Greenberg, Adam S; Rauschecker, Josef P

    2014-05-01

    Neuroimaging studies investigating the voluntary (top-down) control of attention largely agree that this process recruits several frontal and parietal brain regions. Since most studies used attention tasks requiring several higher-order cognitive functions (e.g. working memory, semantic processing, temporal integration, spatial orienting) as well as different attentional mechanisms (attention shifting, distractor filtering), it is unclear what exactly the observed frontoparietal activations reflect. The present functional magnetic resonance imaging study investigated, within the same participants, signal changes in (1) a "Simple Attention" task in which participants attended to a single melody, (2) a "Selective Attention" task in which they simultaneously ignored another melody, and (3) a "Beep Monitoring" task in which participants listened in silence for a faint beep. Compared to resting conditions with identical stimulation, all tasks produced robust activation increases in auditory cortex, cross-modal inhibition in visual and somatosensory cortex, and decreases in the default mode network, indicating that participants were indeed focusing their attention on the auditory domain. However, signal increases in frontal and parietal brain areas were only observed for tasks 1 and 2, but completely absent for task 3. These results lead to the following conclusions: under most conditions, frontoparietal activations are crucial for attention since they subserve higher-order cognitive functions inherently related to attention. However, under circumstances that minimize other demands, nonspatial auditory attention in the absence of stimulation can be maintained without concurrent frontal or parietal activations. PMID:23913818

  4. Intratympanic manganese administration revealed sound intensity and frequency dependent functional activity in rat auditory pathway.

    PubMed

    Jin, Seong-Uk; Lee, Jae-Jun; Hong, Kwan Soo; Han, Mun; Park, Jang-Woo; Lee, Hui Joong; Lee, Sangheun; Lee, Kyu-Yup; Shin, Kyung Min; Cho, Jin Ho; Cheong, Chaejoon; Chang, Yongmin

    2013-09-01

    The cochlear plays a vital role in the sense and sensitivity of hearing; however, there is currently a lack of knowledge regarding the relationships between mechanical transduction of sound at different intensities and frequencies in the cochlear and the neurochemical processes that lead to neuronal responses in the central auditory system. In the current study, we introduced manganese-enhanced MRI (MEMRI), a convenient in vivo imaging method, for investigation of how sound, at different intensities and frequencies, is propagated from the cochlear to the central auditory system. Using MEMRI with intratympanic administration, we demonstrated differential manganese signal enhancements according to sound intensity and frequencies in the ascending auditory pathway of the rat after administration of intratympanic MnCl2.Compared to signal enhancement without explicit sound stimuli, auditory structures in the ascending auditory pathway showed stronger signal enhancement in rats who received sound stimuli of 10 and 40 kHz. In addition, signal enhancement with a stimulation frequency of 40 kHz was stronger than that with 10 kHz. Therefore, the results of this study seem to suggest that, in order to achieve an effective response to high sound intensity or frequency, more firing of auditory neurons, or firing of many auditory neurons together for the pooled neural activity is needed.

  5. Sost downregulation and local Wnt signaling are required for the osteogenic response to mechanical loading.

    PubMed

    Tu, Xiaolin; Rhee, Yumie; Condon, Keith W; Bivi, Nicoletta; Allen, Matthew R; Dwyer, Denise; Stolina, Marina; Turner, Charles H; Robling, Alexander G; Plotkin, Lilian I; Bellido, Teresita

    2012-01-01

    Sclerostin, the Wnt signaling antagonist encoded by the Sost gene, is secreted by osteocytes and inhibits bone formation by osteoblasts. Mechanical stimulation reduces sclerostin expression, suggesting that osteocytes might coordinate the osteogenic response to mechanical force by locally unleashing Wnt signaling. To investigate whether sclerostin downregulation is a pre-requisite for load-induced bone formation, we conducted experiments in transgenic mice (TG) engineered to maintain high levels of SOST expression during mechanical loading. This was accomplished by introducing a human SOST transgene driven by the 8 kb fragment of the DMP1 promoter that also provided osteocyte specificity of the transgene. Right ulnae were subjected to in vivo cyclic axial loading at equivalent strains for 1 min/day at 2 Hz; left ulnae served as internal controls. Endogenous murine Sost mRNA expression measured 24 h after 1 loading bout was decreased by about 50% in TG and wild type (WT) littermates. In contrast, human SOST, only expressed in TG mice, remained high after loading. Mice were loaded on 3 consecutive days and bone formation was quantified 16 days after initiation of loading. Periosteal bone formation in control ulnae was similar in WT and TG mice. Loading induced the expected strain-dependent increase in bone formation in WT mice, resulting from increases in both mineralizing surface (MS/BS) and mineral apposition rate (MAR). In contrast, load-induced bone formation was reduced by 70-85% in TG mice, due to lower MS/BS and complete inhibition of MAR. Moreover, Wnt target gene expression induced by loading in WT mice was absent in TG mice. Thus, downregulation of Sost/sclerostin in osteocytes is an obligatory step in the mechanotransduction cascade that activates Wnt signaling and directs osteogenesis to where bone is structurally needed.

  6. Processing by Convertases Is Required for Glypican-3-induced Inhibition of Hedgehog Signaling*

    PubMed Central

    Capurro, Mariana; Shi, Wen; Izumikawa, Tomomi; Kitagawa, Hiroshi; Filmus, Jorge

    2015-01-01

    Glypican-3 (GPC3) is one of the six members of the mammalian glypican family. We have previously reported that GPC3 inhibits Hedgehog (Hh) signaling by competing with Patched (Ptc) for Hh binding. We also showed that GPC3 binds with high affinity to Hh through its core protein, but that it does not interact with Ptc. Several members of the glypican family, including GPC3, are subjected to an endoproteolytic cleavage by the furin-like convertase family of endoproteases. Surprisingly, however, we have found that a mutant GPC3 that cannot be processed by convertases is as potent as wild-type GPC3 in stimulating Wnt activity in hepatocellular carcinoma cell lines and 293T cells and in promoting hepatocellular carcinoma growth. In this study, we show that processing by convertases is essential for GPC3-induced inhibition of Hh signaling. Moreover, we show that a convertase-resistant GPC3 stimulates Hh signaling by increasing the binding of this growth factor to Ptc. Consistent with this, we show that the convertase-resistant mutant binds to both Hh and Ptc through its heparan sulfate (HS) chains. Unexpectedly, we found that the mutant core protein does not bind to Hh. We also report that the convertase-resistant mutant GPC3 carries HS chains with a significantly higher degree of sulfation than those of wild-type GPC3. We propose that the structural changes generated by the lack of cleavage determine a change in the sulfation of the HS chains and that these hypersulfated chains mediate the interaction of the mutant GPC3 with Ptc. PMID:25653284

  7. AtLAZY1 is a signaling component required for gravitropism of the Arabidopsis thaliana inflorescence.

    PubMed

    Yoshihara, Takeshi; Spalding, Edgar P; Iino, Moritoshi

    2013-04-01

    The present study identified a family of six A. thaliana genes that share five limited regions of sequence similarity with LAZY1, a gene in Oryza sativa (rice) shown to participate in the early gravity signaling for shoot gravitropism. A T-DNA insertion into the Arabidopsis gene (At5g14090) most similar to LAZY1 increased the inflorescence branch angle to 81° from the wild type value of 42°. RNA interference lines and molecular rescue experiments confirmed the linkage between the branch-angle phenotype and the gene consequently named AtLAZY1. Time-resolved gravitropism measurements of atlazy1 hypocotyls and primary inflorescence stems showed a significantly reduced bending rate during the first hour of response. The subcellular localization of AtLAZY1 protein was investigated to determine if the nuclear localization predicted from the gene sequence was observable and important to its function in shoot gravity responses. AtLAZY1 fused to green fluorescent protein largely rescued the branch-angle phenotype of atlazy1, and was observed by confocal microscopy at the cell periphery and within the nucleus. Mutation of the nuclear localization signal prevented detectable levels of AtLAZY1 in the nucleus without affecting the ability of the gene to rescue the atlazy1 branch-angle phenotype. These results indicate that AtLAZY1 functions in gravity signaling during shoot gravitropism, being a functional ortholog of rice LAZY1. The nuclear pool of the protein appears to be unnecessary for this function, which instead relies on a pool that appears to reside at the cell periphery.

  8. Auditory hallucinations treated by radio headphones.

    PubMed

    Feder, R

    1982-09-01

    A young man with chronic auditory hallucinations was treated according to the principle that increasing external auditory stimulation decreases the likelihood of auditory hallucinations. Listening to a radio through stereo headphones in conditions of low auditory stimulation eliminated the patient's hallucinations.

  9. Language Development Activities through the Auditory Channel.

    ERIC Educational Resources Information Center

    Fitzmaurice, Peggy, Comp.; And Others

    Presented primarily for use with educable mentally retarded and learning disabled children are approximately 100 activities for language development through the auditory channel. Activities are grouped under the following three areas: receptive skills (auditory decoding, auditory memory, and auditory discrimination); expressive skills (auditory…

  10. Fumonisin B1-induced cell death in arabidopsis protoplasts requires jasmonate-, ethylene-, and salicylate-dependent signaling pathways.

    PubMed

    Asai, T; Stone, J M; Heard, J E; Kovtun, Y; Yorgey, P; Sheen, J; Ausubel, F M

    2000-10-01

    We have established an Arabidopsis protoplast model system to study plant cell death signaling. The fungal toxin fumonisin B1 (FB1) induces apoptosis-like programmed cell death (PCD) in wild-type protoplasts. FB1, however, only marginally affects the viability of protoplasts isolated from transgenic NahG plants, in which salicylic acid (SA) is metabolically degraded; from pad4-1 mutant plants, in which an SA amplification mechanism is thought to be impaired; or from jar1-1 or etr1-1 mutant plants, which are insensitive to jasmonate (JA) or ethylene (ET), respectively. FB1 susceptibility of wild-type protoplasts decreases in the dark, as does the cellular content of phenylalanine ammonia-lyase, a light-inducible enzyme involved in SA biosynthesis. Interestingly, however, FB1-induced PCD does not require the SA signal transmitter NPR1, given that npr1-1 protoplasts display wild-type FB1 susceptibility. Arabidopsis cpr1-1, cpr6-1, and acd2-2 protoplasts, in which the SA signaling pathway is constitutively activated, exhibit increased susceptibility to FB1. The cpr6-1 and acd2-2 mutants also constitutively express the JA and ET signaling pathways, but only the acd2-2 protoplasts undergo PCD in the absence of FB1. These results demonstrate that FB1 killing of Arabidopsis is light dependent and requires SA-, JA-, and ET-mediated signaling pathways as well as one or more unidentified factors activated by FB1 and the acd2-2 mutation.

  11. Effects of Presentation Rate and Attention on Auditory Discrimination: A Comparison of Long-Latency Auditory Evoked Potentials in School-Aged Children and Adults

    PubMed Central

    Choudhury, Naseem A.; Parascando, Jessica A.; Benasich, April A.

    2015-01-01

    Decoding human speech requires both perception and integration of brief, successive auditory stimuli that enter the central nervous system as well as the allocation of attention to language-relevant signals. This study assesses the role of attention on processing rapid transient stimuli in adults and children. Cortical responses (EEG/ERPs), specifically mismatch negativity (MMN) responses, to paired tones (standard 100–100Hz; deviant 100–300Hz) separated by a 300, 70 or 10ms silent gap (ISI) were recorded under Ignore and Attend conditions in 21 adults and 23 children (6–11 years old). In adults, an attention-related enhancement was found for all rate conditions and laterality effects (L>R) were observed. In children, 2 auditory discrimination-related peaks were identified from the difference wave (deviant-standard): an early peak (eMMN) at about 100–300ms indexing sensory processing, and a later peak (LDN), at about 400–600ms, thought to reflect reorientation to the deviant stimuli or “second-look” processing. Results revealed differing patterns of activation and attention modulation for the eMMN in children as compared to the MMN in adults: The eMMN had a more frontal topography as compared to adults and attention played a significantly greater role in childrens’ rate processing. The pattern of findings for the LDN was consistent with hypothesized mechanisms related to further processing of complex stimuli. The differences between eMMN and LDN observed here support the premise that separate cognitive processes and mechanisms underlie these ERP peaks. These findings are the first to show that the eMMN and LDN differ under different temporal and attentional conditions, and that a more complete understanding of children’s responses to rapid successive auditory stimulation requires an examination of both peaks. PMID:26368126

  12. Effects of Presentation Rate and Attention on Auditory Discrimination: A Comparison of Long-Latency Auditory Evoked Potentials in School-Aged Children and Adults.

    PubMed

    Choudhury, Naseem A; Parascando, Jessica A; Benasich, April A

    2015-01-01

    Decoding human speech requires both perception and integration of brief, successive auditory stimuli that enter the central nervous system as well as the allocation of attention to language-relevant signals. This study assesses the role of attention on processing rapid transient stimuli in adults and children. Cortical responses (EEG/ERPs), specifically mismatch negativity (MMN) responses, to paired tones (standard 100-100 Hz; deviant 100-300 Hz) separated by a 300, 70 or 10 ms silent gap (ISI) were recorded under Ignore and Attend conditions in 21 adults and 23 children (6-11 years old). In adults, an attention-related enhancement was found for all rate conditions and laterality effects (L>R) were observed. In children, 2 auditory discrimination-related peaks were identified from the difference wave (deviant-standard): an early peak (eMMN) at about 100-300 ms indexing sensory processing, and a later peak (LDN), at about 400-600 ms, thought to reflect reorientation to the deviant stimuli or "second-look" processing. Results revealed differing patterns of activation and attention modulation for the eMMN in children as compared to the MMN in adults: The eMMN had a more frontal topography as compared to adults and attention played a significantly greater role in childrens' rate processing. The pattern of findings for the LDN was consistent with hypothesized mechanisms related to further processing of complex stimuli. The differences between eMMN and LDN observed here support the premise that separate cognitive processes and mechanisms underlie these ERP peaks. These findings are the first to show that the eMMN and LDN differ under different temporal and attentional conditions, and that a more complete understanding of children's responses to rapid successive auditory stimulation requires an examination of both peaks. PMID:26368126

  13. Effects of multitasking on operator performance using computational and auditory tasks.

    PubMed

    Fasanya, Bankole K

    2016-09-01

    This study investigated the effects of multiple cognitive tasks on human performance. Twenty-four students at North Carolina A&T State University participated in the study. The primary task was auditory signal change perception and the secondary task was a computational task. Results showed that participants' performance in a single task was statistically significantly different from their performance in combined tasks: (a) algebra problems (algebra problem primary and auditory perception secondary); (b) auditory perception tasks (auditory perception primary and algebra problems secondary); and (c) mean false-alarm score in auditory perception (auditory detection primary and algebra problems secondary). Using signal detection theory (SDT), participants' performance measured in terms of sensitivity was calculated as -0.54 for combined tasks (algebra problems the primary task) and -0.53 auditory perceptions the primary task. During auditory perception tasks alone, SDT was found to be 2.51. Performance was 83% in a single task compared to 17% when combined tasks. PMID:26886505

  14. Hedgehog signaling is required for cranial neural crest morphogenesis and chondrogenesis at the midline in the zebrafish skull.

    PubMed

    Wada, Naoyuki; Javidan, Yashar; Nelson, Sarah; Carney, Thomas J; Kelsh, Robert N; Schilling, Thomas F

    2005-09-01

    Neural crest cells that form the vertebrate head skeleton migrate and interact with surrounding tissues to shape the skull, and defects in these processes underlie many human craniofacial syndromes. Signals at the midline play a crucial role in the development of the anterior neurocranium, which forms the ventral braincase and palate, and here we explore the role of Hedgehog (Hh) signaling in this process. Using sox10:egfp transgenics to follow neural crest cell movements in the living embryo, and vital dye labeling to generate a fate map, we show that distinct populations of neural crest form the two main cartilage elements of the larval anterior neurocranium: the paired trabeculae and the midline ethmoid. By analyzing zebrafish mutants that disrupt sonic hedgehog (shh) expression, we demonstrate that shh is required to specify the movements of progenitors of these elements at the midline, and to induce them to form cartilage. Treatments with cyclopamine, to block Hh signaling at different stages, suggest that although requirements in morphogenesis occur during neural crest migration beneath the brain, requirements in chondrogenesis occur later, as cells form separate trabecular and ethmoid condensations. Cell transplantations indicate that these also reflect different sources of Shh, one from the ventral neural tube that controls trabecular morphogenesis and one from the oral ectoderm that promotes chondrogenesis. Our results suggest a novel role for Shh in the movements of neural crest cells at the midline, as well as in their differentiation into cartilage, and help to explain why both skeletal fusions and palatal clefting are associated with the loss of Hh signaling in holoprosencephalic humans.

  15. Rectification is required to extract oscillatory envelope modulation from surface electromyographic signals.

    PubMed

    Dakin, Christopher J; Dalton, Brian H; Luu, Billy L; Blouin, Jean-Sébastien

    2014-10-01

    Rectification of surface electromyographic (EMG) recordings prior to their correlation with other signals is a widely used form of preprocessing. Recently this practice has come into question, elevating the subject of EMG rectification to a topic of much debate. Proponents for rectifying suggest it accentuates the EMG spike timing information, whereas opponents indicate it is unnecessary and its nonlinear distortion of data is potentially destructive. Here we examine the necessity of rectification on the extraction of muscle responses, but for the first time using a known oscillatory input to the muscle in the form of electrical vestibular stimulation. Participants were exposed to sinusoidal vestibular stimuli while surface and intramuscular EMG were recorded from the left medial gastrocnemius. We compared the unrectified and rectified surface EMG to single motor units to determine which method best identified stimulus-EMG coherence and phase at the single-motor unit level. Surface EMG modulation at the stimulus frequency was obvious in the unrectified surface EMG. However, this modulation was not identified by the fast Fourier transform, and therefore stimulus coherence with the unrectified EMG signal failed to capture this covariance. Both the rectified surface EMG and single motor units displayed significant coherence over the entire stimulus bandwidth (1-20 Hz). Furthermore, the stimulus-phase relationship for the rectified EMG and motor units shared a moderate correlation (r = 0.56). These data indicate that rectification of surface EMG is a necessary step to extract EMG envelope modulation due to motor unit entrainment to a known stimulus.

  16. TIM-1 signaling is required for maintenance and induction of regulatory B cells.

    PubMed

    Yeung, M Y; Ding, Q; Brooks, C R; Xiao, S; Workman, C J; Vignali, D A A; Ueno, T; Padera, R F; Kuchroo, V K; Najafian, N; Rothstein, D M

    2015-04-01

    Apart from their role in humoral immunity, B cells can exhibit IL-10-dependent regulatory activity (Bregs). These regulatory subpopulations have been shown to inhibit inflammation and allograft rejection. However, our understanding of Bregs has been hampered by their rarity, lack of a specific marker, and poor insight into their induction and maintenance. We previously demonstrated that T cell immunoglobulin mucin domain-1 (TIM-1) identifies over 70% of IL-10-producing B cells, irrespective of other markers. We now show that TIM-1 is the primary receptor responsible for Breg induction by apoptotic cells (ACs). However, B cells that express a mutant form of TIM-1 lacking the mucin domain (TIM-1(Δmucin) ) exhibit decreased phosphatidylserine binding and are unable to produce IL-10 in response to ACs or by specific ligation with anti-TIM-1. TIM-1(Δmucin) mice also exhibit accelerated allograft rejection, which appears to be due in part to their defect in both baseline and induced IL-10(+) Bregs, since a single transfer of WT TIM-1(+) B cells can restore long-term graft survival. These data suggest that TIM-1 signaling plays a direct role in Breg maintenance and induction both under physiological conditions (in response to ACs) and in response to therapy through TIM-1 ligation. Moreover, they directly demonstrate that the mucin domain regulates TIM-1 signaling.

  17. Follow-the-leader cell migration requires biased cell-cell contact and local microenvironmental signals.

    PubMed

    Wynn, Michelle L; Rupp, Paul; Trainor, Paul A; Schnell, Santiago; Kulesa, Paul M

    2013-06-01

    Directed cell migration often involves at least two types of cell motility that include multicellular streaming and chain migration. However, what is unclear is how cell contact dynamics and the distinct microenvironments through which cells travel influence the selection of one migratory mode or the other. The embryonic and highly invasive neural crest (NC) are an excellent model system to study this question since NC cells have been observed in vivo to display both of these types of cell motility. Here, we present data from tissue transplantation experiments in chick and in silico modeling that test our hypothesis that cell contact dynamics with each other and the microenvironment promote and sustain either multicellular stream or chain migration. We show that when premigratory cranial NC cells (at the pre-otic level) are transplanted into a more caudal region in the head (at the post-otic level), cells alter their characteristic stream behavior and migrate in chains. Similarly, post-otic NC cells migrate in streams after transplantation into the pre-otic hindbrain, suggesting that local microenvironmental signals dictate the mode of NC cell migration. Simulations of an agent-based model (ABM) that integrates the NC cell behavioral data predict that chain migration critically depends on the interplay of biased cell-cell contact and local microenvironment signals. Together, this integrated modeling and experimental approach suggests new experiments and offers a powerful tool to examine mechanisms that underlie complex cell migration patterns.

  18. cAMP-Signalling Regulates Gametocyte-Infected Erythrocyte Deformability Required for Malaria Parasite Transmission

    PubMed Central

    Thompson, Eloise; Breil, Florence; Lorthiois, Audrey; Dupuy, Florian; Cummings, Ross; Duffier, Yoann; Corbett, Yolanda; Mercereau-Puijalon, Odile; Vernick, Kenneth; Taramelli, Donatella; Baker, David A.; Langsley, Gordon; Lavazec, Catherine

    2015-01-01

    Blocking Plasmodium falciparum transmission to mosquitoes has been designated a strategic objective in the global agenda of malaria elimination. Transmission is ensured by gametocyte-infected erythrocytes (GIE) that sequester in the bone marrow and at maturation are released into peripheral blood from where they are taken up during a mosquito blood meal. Release into the blood circulation is accompanied by an increase in GIE deformability that allows them to pass through the spleen. Here, we used a microsphere matrix to mimic splenic filtration and investigated the role of cAMP-signalling in regulating GIE deformability. We demonstrated that mature GIE deformability is dependent on reduced cAMP-signalling and on increased phosphodiesterase expression in stage V gametocytes, and that parasite cAMP-dependent kinase activity contributes to the stiffness of immature gametocytes. Importantly, pharmacological agents that raise cAMP levels in transmissible stage V gametocytes render them less deformable and hence less likely to circulate through the spleen. Therefore, phosphodiesterase inhibitors that raise cAMP levels in P. falciparum infected erythrocytes, such as sildenafil, represent new candidate drugs to block transmission of malaria parasites. PMID:25951195

  19. Protein-tyrosine-phosphatase SHPTP2 is a required positive effector for insulin downstream signaling.

    PubMed Central

    Yamauchi, K; Milarski, K L; Saltiel, A R; Pessin, J E

    1995-01-01

    SHPTP2 is a ubiquitously expressed tyrosine-specific protein phosphatase that contains two amino-terminal Src homology 2 (SH2) domains responsible for its association with tyrosine-phosphorylated proteins. In this study, expression of dominant interfering mutants of SHPTP2 was found to inhibit insulin stimulation of c-fos reporter gene expression and activation of the 42-kDa (Erk2) and 44-kDa (Erk1) mitogen-activated protein kinases. Cotransfection of dominant interfering SHPTP2 mutants with v-Ras or Grb2 indicated that SHPTP2 regulated insulin signaling either upstream of or in parallel to Ras function. Furthermore, phosphotyrosine blotting and immunoprecipitation identified the 125-kDa focal adhesion kinase (pp125FAK) as a substrate for insulin-dependent tyrosine dephosphorylation. These data demonstrate that SHPTP2 functions as a positive regulator of insulin action and that insulin signaling results in the dephosphorylation of tyrosine-phosphorylated pp125FAK. Images Fig. 2 Fig. 4 Fig. 5 PMID:7531337

  20. Cortical auditory disorders: clinical and psychoacoustic features.

    PubMed Central

    Mendez, M F; Geehan, G R

    1988-01-01

    The symptoms of two patients with bilateral cortical auditory lesions evolved from cortical deafness to other auditory syndromes: generalised auditory agnosia, amusia and/or pure word deafness, and a residual impairment of temporal sequencing. On investigation, both had dysacusis, absent middle latency evoked responses, acoustic errors in sound recognition and matching, inconsistent auditory behaviours, and similarly disturbed psychoacoustic discrimination tasks. These findings indicate that the different clinical syndromes caused by cortical auditory lesions form a spectrum of related auditory processing disorders. Differences between syndromes may depend on the degree of involvement of a primary cortical processing system, the more diffuse accessory system, and possibly the efferent auditory system. Images PMID:2450968

  1. Object continuity enhances selective auditory attention.

    PubMed

    Best, Virginia; Ozmeral, Erol J; Kopco, Norbert; Shinn-Cunningham, Barbara G

    2008-09-01

    In complex scenes, the identity of an auditory object can build up across seconds. Given that attention operates on perceptual objects, this perceptual buildup may alter the efficacy of selective auditory attention over time. Here, we measured identification of a sequence of spoken target digits presented with distracter digits from other directions to investigate the dynamics of selective attention. Performance was better when the target location was fixed rather than changing between digits, even when listeners were cued as much as 1 s in advance about the position of each subsequent digit. Spatial continuity not only avoided well known costs associated with switching the focus of spatial attention, but also produced refinements in the spatial selectivity of attention across time. Continuity of target voice further enhanced this buildup of selective attention. Results suggest that when attention is sustained on one auditory object within a complex scene, attentional selectivity improves over time. Similar effects may come into play when attention is sustained on an object in a complex visual scene, especially in cases where visual object formation requires sustained attention.

  2. Testing multi-scale processing in the auditory system

    PubMed Central

    Teng, Xiangbin; Tian, Xing; Poeppel, David

    2016-01-01

    Natural sounds contain information on multiple timescales, so the auditory system must analyze and integrate acoustic information on those different scales to extract behaviorally relevant information. However, this multi-scale process in the auditory system is not widely investigated in the literature, and existing models of temporal integration are mainly built upon detection or recognition tasks on a single timescale. Here we use a paradigm requiring processing on relatively ‘local’ and ‘global’ scales and provide evidence suggesting that the auditory system extracts fine-detail acoustic information using short temporal windows and uses long temporal windows to abstract global acoustic patterns. Behavioral task performance that requires processing fine-detail information does not improve with longer stimulus length, contrary to predictions of previous temporal integration models such as the multiple-looks and the spectro-temporal excitation pattern model. Moreover, the perceptual construction of putatively ‘unitary’ auditory events requires more than hundreds of milliseconds. These findings support the hypothesis of a dual-scale processing likely implemented in the auditory cortex. PMID:27713546

  3. 47 CFR 11.52 - EAS code and Attention Signal Monitoring requirements.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... requirements. 11.52 Section 11.52 Telecommunication FEDERAL COMMUNICATIONS COMMISSION GENERAL EMERGENCY ALERT... Integrated Public Alert and Warning System (IPAWS) to enable (whether through “pull” interface technologies... technologies, such as instant messaging and email) the distribution of Common Alert Protocol...

  4. 47 CFR 11.52 - EAS code and Attention Signal Monitoring requirements.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Action Notification (EAN), Emergency Action Termination (EAT), and Required Monthly Test (RMT) for their... Event code must be transmitted immediately and Monthly EAS test messages within 60 minutes. All actions... for the EAN and EAT Event header codes for National level emergencies and the RMT and RWT Event...

  5. Distinct requirements for TrkB and TrkC signaling in target innervation by sensory neurons

    NASA Technical Reports Server (NTRS)

    Postigo, Antonio; Calella, Anna Maria; Fritzsch, Bernd; Knipper, Marlies; Katz, David; Eilers, Andreas; Schimmang, Thomas; Lewin, Gary R.; Klein, Rudiger; Minichiello, Liliana

    2002-01-01

    Signaling by brain-derived neurotrophic factor (BDNF) via the TrkB receptor, or by neurotrophin-3 (NT3) through the TrkC receptor support distinct populations of sensory neurons. The intracellular signaling pathways activated by Trk (tyrosine kinase) receptors, which in vivo promote neuronal survival and target innervation, are not well understood. Using mice with TrkB or TrkC receptors lacking the docking site for Shc adaptors (trkB(shc/shc) and trkC(shc/shc) mice), we show that TrkB and TrkC promote survival of sensory neurons mainly through Shc site-independent pathways, suggesting that these receptors use similar pathways to prevent apoptosis. In contrast, the regulation of target innervation appears different: in trkB(shc/shc) mice neurons lose target innervation, whereas in trkC(shc/shc) mice the surviving TrkC-dependent neurons maintain target innervation and function. Biochemical analysis indicates that phosphorylation at the Shc site positively regulates autophosphorylation of TrkB, but not of TrkC. Our findings show that although TrkB and TrkC signals mediating survival are largely similar, TrkB and TrkC signals required for maintenance of target innervation in vivo are regulated by distinct mechanisms.

  6. The Putzig-NURF Nucleosome Remodeling Complex Is Required for Ecdysone Receptor Signaling and Innate Immunity in Drosophila melanogaster

    PubMed Central

    Kugler, Sabrina J.; Gehring, Eva-Maria; Wallkamm, Veronika; Krüger, Victoria; Nagel, Anja C.

    2011-01-01

    Putzig (Pzg) was originally identified as being an integral component of the TRF2/DREF complex in Drosophila melanogaster, thereby regulating the transcriptional activation of replication-related genes. In a DREF-independent manner, Pzg was shown to mediate Notch target gene activation. This function of Pzg entails an association with the nucleosome remodeling factor complex NURF, which directly binds the ecdysone receptor EcR and coregulates targets of the EcR via the NURF-specific subunit Nurf-301. In contrast, Nurf-301 acts as a negative regulator of JAK/STAT signaling. Here, we provide evidence to show that Pzg is fundamental for these functions of NURF, apart from the regulation of Notch signaling activity. A jump-out mutagenesis provided us with a pzg null mutant displaying early larval lethality, defects in growth, and molting accompanied by aberrant feeding behavior. We show that Pzg is associated with EcR in vivo and required for the transcriptional induction of EcR target genes, whereas reduced ecdysteroid levels imply a NURF-independent function of Pzg. Moreover, pzg interferes with JAK/STAT-signaling activity by acting as a corepressor of Ken. Lamellocyte differentiation was consistently affected in a JAK/STAT mutant background and the expression level of defense response genes was elevated in pzg mutants, leading to the formation of melanotic tumors. Our results suggest that Pzg acts as an important partner of NURF in the regulation of EcR and JAK/STAT signaling. PMID:21385730

  7. Neuronal STAT5 signaling is required for maintaining lactation but not for postpartum maternal behaviors in mice.

    PubMed

    Buonfiglio, Daniella C; Ramos-Lobo, Angela M; Silveira, Marina A; Furigo, Isadora C; Hennighausen, Lothar; Frazão, Renata; Donato, Jose

    2015-05-01

    Prolactin and placental lactogens control mammary development and lactation as well as play an important role in maternal behaviors. However, the molecular mechanisms in the brain responsible for this regulation remain largely unknown. Therefore, the present study investigated whether Signal Transducer and Activator of Transcription 5 (STAT5) signaling in the brain, the key transcriptional factor recruited by prolactin receptor and other hormones, is required for postpartum maternal behavior, maintenance of lactation and offspring growth. Neuronal ablation of STAT5 impaired the control of prolactin secretion and reduced the hypothalamic expression of suppressors of cytokine signaling (i.e., SOCS3 and CISH). In addition, neuronal STAT5 deletion attenuated the hyperphagia commonly observed during lactation by decreasing the hypothalamic expression of orexigenic neurotransmitters such as the neuropeptide Y and agouti-related protein. The lower food intake of lactating neuron-specific STAT5 knockout females resulted in reduced milk production and offspring growth. Unexpectedly, postpartum maternal behavior expression was not impaired in neuron-specific STAT5 knockout females. On the contrary, the latency to retrieve and group the pups into the nest was reduced in mutant dams. Finally, we demonstrated that approximately 30% of recorded neurons in the medial preoptic area were acutely depolarized by prolactin suggesting that fast STAT5-independent signaling pathways may be involved in the regulation of maternal behaviors. Overall, our results revealed important information about the molecular mechanisms recruited by hormones to orchestrate the activation of neural circuitries engaged in the induction of maternal care.

  8. The putative lipid transporter, Arv1, is required for activating pheromone-induced MAP kinase signaling in Saccharomyces cerevisiae.

    PubMed

    Villasmil, Michelle L; Ansbach, Alison; Nickels, Joseph T

    2011-02-01

    Saccharomyces cerevisiae haploid cells respond to extrinsic mating signals by forming polarized projections (shmoos), which are necessary for conjugation. We have examined the role of the putative lipid transporter, Arv1, in yeast mating, particularly the conserved Arv1 homology domain (AHD) within Arv1 and its role in this process. Previously it was shown that arv1 cells harbor defects in sphingolipid and glycosylphosphatidylinositol (GPI) biosyntheses and may harbor sterol trafficking defects. Here we demonstrate that arv1 cells are mating defective and cannot form shmoos. They lack the ability to initiate pheromone-induced G1 cell cycle arrest, due to failure to polarize PI(4,5)P(2) and the Ste5 scaffold, which results in weakened MAP kinase signaling activity. A mutant Ste5, Ste5(Q59L), which binds more tightly to the plasma membrane, suppresses the MAP kinase signaling defects of arv1 cells. Filipin staining shows arv1 cells contain altered levels of various sterol microdomains that persist throughout the mating process. Data suggest that the sterol trafficking defects of arv1 affect PI(4,5)P(2) polarization, which causes a mislocalization of Ste5, resulting in defective MAP kinase signaling and the inability to mate. Importantly, our studies show that the AHD of Arv1 is required for mating, pheromone-induced G1 cell cycle arrest, and for sterol trafficking.

  9. The Putative Lipid Transporter, Arv1, Is Required for Activating Pheromone-Induced MAP Kinase Signaling in Saccharomyces cerevisiae

    PubMed Central

    Villasmil, Michelle L.; Ansbach, Alison; Nickels, Joseph T.

    2011-01-01

    Saccharomyces cerevisiae haploid cells respond to extrinsic mating signals by forming polarized projections (shmoos), which are necessary for conjugation. We have examined the role of the putative lipid transporter, Arv1, in yeast mating, particularly the conserved Arv1 homology domain (AHD) within Arv1 and its role in this process. Previously it was shown that arv1 cells harbor defects in sphingolipid and glycosylphosphatidylinositol (GPI) biosyntheses and may harbor sterol trafficking defects. Here we demonstrate that arv1 cells are mating defective and cannot form shmoos. They lack the ability to initiate pheromone-induced G1 cell cycle arrest, due to failure to polarize PI(4,5)P2 and the Ste5 scaffold, which results in weakened MAP kinase signaling activity. A mutant Ste5, Ste5Q59L, which binds more tightly to the plasma membrane, suppresses the MAP kinase signaling defects of arv1 cells. Filipin staining shows arv1 cells contain altered levels of various sterol microdomains that persist throughout the mating process. Data suggest that the sterol trafficking defects of arv1 affect PI(4,5)P2 polarization, which causes a mislocalization of Ste5, resulting in defective MAP kinase signaling and the inability to mate. Importantly, our studies show that the AHD of Arv1 is required for mating, pheromone-induced G1 cell cycle arrest, and for sterol trafficking. PMID:21098723

  10. Extracellular matrix-dependent tissue-specific gene expression in mammary epithelial cells requires both physical and biochemical signal transduction

    SciTech Connect

    Roskelley, C.D.; Desprez, P.Y.; Bissell, M.J. )

    1994-12-20

    Extracellular matrix (ECM) profoundly influences the growth and differentiation of the mammary gland epithelium, both in culture and in vivo. Utilizing a clonal population of mouse mammary epithelial cells that absolutely requires an exogenous ECM for function, we developed a rapid assay to study signal transduction by ECM. Two components of the cellular response to a basement membrane overlay that result in the expression of the milk protein [beta]-casein were defined. The first component of this response involves a rounding and clustering of the cells that can be physically mimicked by plating the cells on a nonadhesive substratum. The second component is biochemical in nature, and it is associated with [beta][sub 1] integrin clustering and increased tyrosine phosphorylation. The second component is initiated in a morphology-independent manner, but the proper translation of this biochemical signal into a functional response requires cell rounding and cell clustering. Thus, physical and biochemical signal transduction events contribute to the ECM-dependent regulation of tissue-specific gene expression in mouse mammary epithelial cells. 44 refs., 6 figs.

  11. Auditory-olfactory synesthesia coexisting with auditory-visual synesthesia.

    PubMed

    Jackson, Thomas E; Sandramouli, Soupramanien

    2012-09-01

    Synesthesia is an unusual condition in which stimulation of one sensory modality causes an experience in another sensory modality or when a sensation in one sensory modality causes another sensation within the same modality. We describe a previously unreported association of auditory-olfactory synesthesia coexisting with auditory-visual synesthesia. Given that many types of synesthesias involve vision, it is important that the clinician provide these patients with the necessary information and support that is available.

  12. Auditory Sketches: Very Sparse Representations of Sounds Are Still Recognizable.

    PubMed

    Isnard, Vincent; Taffou, Marine; Viaud-Delmon, Isabelle; Suied, Clara

    2016-01-01

    Sounds in our environment like voices, animal calls or musical instruments are easily recognized by human listeners. Understanding the key features underlying this robust sound recognition is an important question in auditory science. Here, we studied the recognition by human listeners of new classes of sounds: acoustic and auditory sketches, sounds that are severely impoverished but still recognizable. Starting from a time-frequency representation, a sketch is obtained by keeping only sparse elements of the original signal, here, by means of a simple peak-picking algorithm. Two time-frequency representations were compared: a biologically grounded one, the auditory spectrogram, which simulates peripheral auditory filtering, and a simple acoustic spectrogram, based on a Fourier transform. Three degrees of sparsity were also investigated. Listeners were asked to recognize the category to which a sketch sound belongs: singing voices, bird calls, musical instruments, and vehicle engine noises. Results showed that, with the exception of voice sounds, very sparse representations of sounds (10 features, or energy peaks, per second) could be recognized above chance. No clear differences could be observed between the acoustic and the auditory sketches. For the voice sounds, however, a completely different pattern of results emerged, with at-chance or even below-chance recognition performances, suggesting that the important features of the voice, whatever they are, were removed by the sketch process. Overall, these perceptual results were well correlated with a model of auditory distances, based on spectro-temporal excitation patterns (STEPs). This study confirms the potential of these new classes of sounds, acoustic and auditory sketches, to study sound recognition.

  13. Auditory Sketches: Very Sparse Representations of Sounds Are Still Recognizable

    PubMed Central

    Isnard, Vincent; Taffou, Marine; Viaud-Delmon, Isabelle; Suied, Clara

    2016-01-01

    Sounds in our environment like voices, animal calls or musical instruments are easily recognized by human listeners. Understanding the key features underlying this robust sound recognition is an important question in auditory science. Here, we studied the recognition by human listeners of new classes of sounds: acoustic and auditory sketches, sounds that are severely impoverished but still recognizable. Starting from a time-frequency representation, a sketch is obtained by keeping only sparse elements of the original signal, here, by means of a simple peak-picking algorithm. Two time-frequency representations were compared: a biologically grounded one, the auditory spectrogram, which simulates peripheral auditory filtering, and a simple acoustic spectrogram, based on a Fourier transform. Three degrees of sparsity were also investigated. Listeners were asked to recognize the category to which a sketch sound belongs: singing voices, bird calls, musical instruments, and vehicle engine noises. Results showed that, with the exception of voice sounds, very sparse representations of sounds (10 features, or energy peaks, per second) could be recognized above chance. No clear differences could be observed between the acoustic and the auditory sketches. For the voice sounds, however, a completely different pattern of results emerged, with at-chance or even below-chance recognition performances, suggesting that the important features of the voice, whatever they are, were removed by the sketch process. Overall, these perceptual results were well correlated with a model of auditory distances, based on spectro-temporal excitation patterns (STEPs). This study confirms the potential of these new classes of sounds, acoustic and auditory sketches, to study sound recognition. PMID:26950589

  14. Prkci is required for a non-autonomous signal that coordinates cell polarity during cavitation.

    PubMed

    Mah, In Kyoung; Soloff, Rachel; Izuhara, Audrey K; Lakeland, Daniel L; Wang, Charles; Mariani, Francesca V

    2016-08-01

    Polarized epithelia define boundaries, spaces, and cavities within organisms. Cavitation, a process by which multicellular hollow balls or tubes are produced, is typically associated with the formation of organized epithelia. In order for these epithelial layers to form, cells must ultimately establish a distinct apical-basal polarity. Atypical PKCs have been proposed to be required for apical-basal polarity in diverse species. Here we show that while cells null for the Prkci isozyme exhibit some polarity characteristics, they fail to properly segregate apical-basal proteins, form a coordinated ectodermal epithelium, or participate in normal cavitation. A failure to cavitate could be due to an overgrowth of interior cells or to an inability of interior cells to die. Null cells however, do not have a marked change in proliferation rate and are still capable of undergoing cell death, suggesting that alterations in these processes are not the predominant cause of the failed cavitation. Overexpression of BMP4 or EZRIN can partially rescue the phenotype possibly by promoting cell death, polarity, and differentiation. However, neither is sufficient to provide the required cues to generate a polarized epithelium and fully rescue cavitation. Interestingly, when wildtype and Prkci(-/-) ES cells are mixed together, a polarized ectodermal epithelium forms and cavitation is rescued, likely due to the ability of wildtype cells to produce non-autonomous polarity cues. We conclude that Prkci is not required for cells to respond to these cues, though it is required to produce them. Together these findings indicate that environmental cues can facilitate the formation of polarized epithelia and that cavitation requires the proper coordination of multiple basic cellular processes including proliferation, differentiation, cell death, and apical-basal polarization. PMID:27312576

  15. Prkci is required for a non-autonomous signal that coordinates cell polarity during cavitation.

    PubMed

    Mah, In Kyoung; Soloff, Rachel; Izuhara, Audrey K; Lakeland, Daniel L; Wang, Charles; Mariani, Francesca V

    2016-08-01

    Polarized epithelia define boundaries, spaces, and cavities within organisms. Cavitation, a process by which multicellular hollow balls or tubes are produced, is typically associated with the formation of organized epithelia. In order for these epithelial layers to form, cells must ultimately establish a distinct apical-basal polarity. Atypical PKCs have been proposed to be required for apical-basal polarity in diverse species. Here we show that while cells null for the Prkci isozyme exhibit some polarity characteristics, they fail to properly segregate apical-basal proteins, form a coordinated ectodermal epithelium, or participate in normal cavitation. A failure to cavitate could be due to an overgrowth of interior cells or to an inability of interior cells to die. Null cells however, do not have a marked change in proliferation rate and are still capable of undergoing cell death, suggesting that alterations in these processes are not the predominant cause of the failed cavitation. Overexpression of BMP4 or EZRIN can partially rescue the phenotype possibly by promoting cell death, polarity, and differentiation. However, neither is sufficient to provide the required cues to generate a polarized epithelium and fully rescue cavitation. Interestingly, when wildtype and Prkci(-/-) ES cells are mixed together, a polarized ectodermal epithelium forms and cavitation is rescued, likely due to the ability of wildtype cells to produce non-autonomous polarity cues. We conclude that Prkci is not required for cells to respond to these cues, though it is required to produce them. Together these findings indicate that environmental cues can facilitate the formation of polarized epithelia and that cavitation requires the proper coordination of multiple basic cellular processes including proliferation, differentiation, cell death, and apical-basal polarization.

  16. Lymphotoxin β receptor signaling is required for inflammatory lymphangiogenesis in the thyroid

    PubMed Central

    Furtado, Glaucia C.; Marinkovic, Tatjana; Martin, Andrea P.; Garin, Alexandre; Hoch, Benjamin; Hubner, Wolfgang; Chen, Benjamin K.; Genden, Eric; Skobe, Mihaela; Lira, Sergio A.

    2007-01-01

    Infiltration of lymphocytes into the thyroid gland and formation of lymph node-like structures is a hallmark of Hashimoto's thyroiditis. Here we demonstrate that lymphatic vessels are present within these infiltrates. Mice overexpressing the chemokine CCL21 in the thyroid (TGCCL21 mice) developed similar lymphoid infiltrates and lymphatic vessels. TGCCL21 mice lacking mature T and B cells (RAGTGCCL21 mice) did not have cellular infiltrates or increased number of lymphatic vessels compared with controls. Transfer of CD3+CD4+ T cells into RAGTGCCL21 mice promoted the development of LYVE-1+podoplanin+Prox-1+ vessels in the thyroid. Genetic deletion of lymphotoxin β receptor or lymphotoxin α abrogated development of lymphatic vessels in the inflamed areas in the thyroid but did not affect development of neighboring lymphatics. These results define a model for the study of inflammatory lymphangiogenesis in the thyroid and implicate lymphotoxin β receptor signaling in this process. PMID:17360402

  17. An essential requirement for the SCAP/SREBP signaling axis to protect cancer cells from lipotoxicity

    PubMed Central

    Williams, Kevin J.; Argus, Joseph P.; Zhu, Yue; Wilks, Moses Q.; Marbois, Beth N.; York, Autumn G.; Kidani, Yoko; Pourzia, Alexandra L.; Akhavan, David; Lisiero, Dominique N.; Komisopoulou, Evangelia; Henkin, Amy H.; Soto, Horacio; Chamberlain, Brian T.; Vergnes, Laurent; Jung, Michael E.; Torres, Jorge Z.; Liau, Linda M.; Christofk, Heather R.; Prins, Robert M.; Mischel, Paul S.; Reue, Karen; Graeber, Thomas G.; Bensinger, Steven J.

    2014-01-01

    SREBPs are key transcriptional regulators of lipid metabolism and cellular growth. It has been proposed that SREBP signaling regulates cellular growth through its ability to drive lipid biosynthesis. Unexpectedly, we find that loss of SREBP activity inhibits cancer cell growth and viability by uncoupling fatty acid synthesis from desaturation. Integrated lipid profiling and metabolic flux analysis revealed that cancer cells with attenuated SREBP activity maintain long-chain saturated fatty acid synthesis, while losing fatty acid desaturation capacity. We traced this defect to the uncoupling of Fatty Acid Synthase activity from SCD1-mediated desaturation. This deficiency in desaturation drives an imbalance between the saturated and monounsaturated fatty acid pools resulting in severe lipotoxicity. Importantly, replenishing the monounsaturated fatty acid pool restored growth to SREBP-inhibited cells. These studies highlight the importance of fatty acid desaturation in cancer growth and provide a novel mechanistic explanation for the role of SREBPs in cancer metabolism. PMID:23440422

  18. Role of Estrogen Receptor Signaling Required for Endometriosis-Like Lesion Establishment in a Mouse Model

    PubMed Central

    Burns, Katherine A.; Rodriguez, Karina F.; Hewitt, Sylvia C.; Janardhan, Kyathanahalli S.; Young, Steven L.

    2012-01-01

    Endometriosis results from ectopic invasion of endometrial tissue within the peritoneal cavity. Aberrant levels of the estrogen receptor (ER), ERα and ERβ, and higher incidence of autoimmune disorders are observed in women with endometriosis. An immunocompetent mouse model of endometriosis was used in which minced uterine tissue from a donor was dispersed into the peritoneal cavity of a recipient. Wild-type (WT), ERα-knockout (αERKO), and βERKO mice were donors or recipients to investigate the roles of ERα, ERβ, and estradiol-mediated signaling on endometriosis-like disease. Mice were treated with vehicle or estradiol, and resulting location, number, and size of endometriosis-like lesions were assessed. In comparison with WT lesions in WT hosts, αERKO lesions in WT hosts were smaller and fewer in number. The effect of ER status and estradiol treatment on nuclear receptor status, proliferation, organization, and inflammation within lesions were examined. αERKO lesions in WT hosts did not form distal to the incision site, respond to estradiol, or proliferate but did have increased inflammation. WT lesions in αERKO hosts did respond to estradiol, proliferate, and show decreased inflammation with treatment, but surprisingly, progesterone receptor expression and localization remained unchanged. Only minor differences were observed between WT lesions in βERKO hosts and βERKO lesions in WT hosts, demonstrating the estradiol-mediated signaling responses are predominately through ERα. In sum, these results suggest ER in both endometriosis-like lesions and their environment influence lesion characteristics, and understanding these interactions may play a critical role in elucidating this enigmatic disease. PMID:22700766

  19. Gap junction signalling mediated through connexin-43 is required for chick limb development.

    PubMed

    Makarenkova, H; Patel, K

    1999-03-15

    During chick limb development the gap junction protein Connexin-43 (Cx43) is expressed in discrete spatially restricted domains in the apical ectodermal ridge (AER) and mesenchyme of the zone of polarising activity. Antisense oligonucleotides (ODNs) were used to investigate the role of Connexin-43 (Cx43) in the development of the chick limb bud. We have used unmodified ODNs in Pluronic F-127 gel, which is liquid at low temperature but sets at room temperature and so remains situated at the point of application. As a mild surfactant, the gel increases antisense ODN penetration and supplies ODNs to the embryo continually for 12-18 h. We have shown a strong decrease in Cx43 protein expression after application of specific antisense oligonucleotides but the abundance of a closely related protein, Connexin-32 (Cx32), was not affected. Application of antisense Cx43 ODNs at stages 8-15 HH before limb outgrowth resulted in dramatic limb phenotypes. About 40% of treated embryos exhibited defects such as truncation of the limb bud, fragmentation into two or more domains, or complete splitting of the limb bud into two or three branches. Molecular analysis of antisense treated embryos failed to detect Shh or Bmp-2 in anterior structures and suggested that extra lobes seen in nicked and split limbs were not a result of establishment of new signalling centres as found after the application of FGF to the flank. However, examination of markers for the AER showed a number of abnormalities. In severely truncated specimens we were unable to detect the expression of either Fgf-4 or Fgf-8. In both nicked and split limbs the expression of these genes was discontinuous. Down-regulation of Cx43 after the antisense application could be comparable to AER removal and results in distal truncation of the limb bud. Taken together these data suggest the existence of a feedback loop between the FGFs and signalling mediated by Cx43.

  20. Evaluation of Central Auditory Discrimination Abilities in Older Adults

    PubMed Central

    Freigang, Claudia; Schmidt, Lucas; Wagner, Jan; Eckardt, Rahel; Steinhagen-Thiessen, Elisabeth; Ernst, Arne; Rübsamen, Rudolf

    2011-01-01

    The present study focuses on auditory discrimination abilities in older adults aged 65–89 years. We applied the “Leipzig inventory for patient psychoacoustic” (LIPP), a psychoacoustic test battery specifically designed to identify deficits in central auditory processing. These tests quantify the just noticeable differences (JND) for the three basic acoustic parameters (i.e., frequency, intensity, and signal duration). Three different test modes [monaural, dichotic signal/noise (s/n) and interaural] were used, stimulus level was 35 dB sensation level. The tests are designed as three-alternative forced-choice procedure with a maximum-likelihood procedure estimating p = 0.5 correct response value. These procedures have proven to be highly efficient and provide a reliable outcome. The measurements yielded significant age-dependent deteriorations in the ability to discriminate single acoustic features pointing to progressive impairments in central auditory processing. The degree of deterioration was correlated to the different acoustic features and to the test modes. Most prominent, interaural frequency and signal duration discrimination at low test frequencies was elevated which indicates a deterioration of time- and phase-dependent processing at brain stem and cortical levels. LIPP proves to be an effective tool to identify basic pathophysiological mechanisms and the source of a specific impairment in auditory processing of the elderly. PMID:21577251