Nematospiroides dubius and Nippostrongylus brasiliensis: delayed type hypersensitivity responses to ovalbumin in the infected mouse

Mice (C57BL) infected with the intestinal nematode Nematospiroides dubius showed depressed delayed type hypersensitivity responses to ovalbumin administered subcutaneously in Freund's complete adjuvant. IgG and IgM responses to this inoculum were unaffected. It is unlikely that the depression arose from impairment of the ear test response because responses to an extract of the adult parasite were measurable and ear testing with lipopolysaccharide yielded normal responses in infected mice. Furthermore, mice immunized on the day of infection responded normally, whilst long term infected mice ear challenged with antigen pulsed macrophages gave depressed responses. The in vitro proliferative responses of cells from the spleens and from the lymph nodes draining the site of immunization were enhanced marginally by N. dubius infection. Furthermore, these cells induced normal or elevated adoptive delayed-type hypersensitivity and IgG responses in irradiated recipients. These findings suggest that N. dubius does not compromise the development of ovalbumin specific T cells involved in a delayed type hypersensitivity response. Evidence for the induction of suppressor cells by N. dubius is discussed, and the findings are compared with results obtained with Nippostrongylus brasiliensis, a parasite which is rejected rapidly from the mouse.     

A Novel Model of IgE-Mediated Passive Pulmonary Anaphylaxis in Rats

Mast cells are central effector cells in allergic asthma and are augmented in the airways of asthma patients. Attenuating mast cell degranulation and with it the early asthmatic response is an important intervention point to inhibit bronchoconstriction, plasma exudation and tissue oedema formation. To validate the efficacy of novel pharmacological interventions, appropriate and practicable in vivo models reflecting mast cell-dependent mechanisms in the lung, are missing. Thus, we developed a novel model of passive pulmonary anaphylaxis in rats. Rats were passively sensitized by concurrent intratracheal and intradermal (ear) application of an anti-DNP IgE antibody. Intravenous application of the antigen, DNP-BSA in combination with Evans blue dye, led to mast cell degranulation in both tissues. Quantification of mast cell degranulation in the lung was determined by (1) mediator release into bronchoalveolar lavage, (2) extravasation of Evans blue dye into tracheal and bronchial lung tissue and (3) invasive measurement of antigen-induced bronchoconstriction. Quantification of mast cell degranulation in the ear was determined by extravasation of Evans blue dye into ear tissue. We pharmacologically validated our model using the SYK inhibitor Fostamatinib, the H₁-receptor antagonist Desloratadine, the mast cell stabilizer disodium cromoglycate (DSCG) and the β₂-adrenergic receptor agonist Formoterol. Fostamatinib was equally efficacious in lung and ear. Desloratadine effectively inhibited bronchoconstriction and ear vascular leakage, but was less effective against pulmonary vascular leakage, perhaps reflecting the differing roles for histamine receptor sub-types. DSCG attenuated both vascular leakage in the lung and bronchoconstriction, but with a very short duration of action. As an inhaled approach, Formoterol was more effective in the lung than in the ear. This model of passive pulmonary anaphylaxis provides a tissue relevant readout of early mast cell activity and pharmacological benchmarking broadly reflects responses observed in patients with asthma.     

Potential anti-inflammatory actions of the elmiric (lipoamino) acids

A library of amino acid-fatty acid conjugates (elmiric acids) was synthesized and evaluated for activity as potential anti-inflammatory agents. The compounds were tested in vitro for their effects on cell proliferation and prostaglandin production, and compared with their effects on in vivo models of inflammation. LPS stimulated RAW 267.4 mouse macrophage cells were the in vitro model and phorbol ester-induced mouse ear edema served as the principal in vivo model. The prostaglandin responses were found to be strongly dependent on the nature of the fatty acid part of the molecule. Polyunsaturated acid conjugates produced a marked increase in media levels of i15-deoxy-PGJ(2) with minimal effects on PGE production. It is reported in the literature that prostaglandin ratios in which the J series predominates over the E series promote the resolution of inflammatory conditions. Several of the elmiric acids tested here produced such favorable ratios suggesting that their potential anti-inflammatory activity occurs via a novel mechanism of action. The ear edema assay results were generally in agreement with the prostaglandin assay findings indicating a connection between them.     

Role of dopamine-dependent negative feedback in the hippocampal--basal ganglia--thalamo---hippocampal loop in response decrement

The mechanism of response decrement in hippocampal and dopaminergic neurons on repeating stimuli based on the dopamine-dependent negative feedback in the hippocampal--basal ganglia--thalamo--hippocampal loop is suggested. Activation of hippocampal neurons caused by new stimulus facilitates occurrence of reaction of dopaminergic cells due to their disinhibition through striatopallidal cells of nucleus accumbens and ventral pallidum. However, increase in dopamine level and activation accumbens and ventral pallidum. However, increase in dopamine level and activation of D2 receptors on the striatopallidal cell, while promoting depression of hippocampal inputs, prevents disinhibition of dopaminergic cells, and their reactions start their decrement. The subsequent decrease in D1 receptor activation leads to reduction of efficiency of neuron excitation in the hippocampal CA1 fields, as well as in striatonigral cells of nucleus accumbens. This leads to a decrease of disinhibition through a direct pathway via the basal ganglia of thalamic nucleus reunions which activates neurons of the CA1 field. This effect causes decrement of reactions of the hippocampal neurons, a subsequent reduction of dopaminergic cell disinhibition, and further decrement of their responses.     

Word retrieval learning modulates right frontal cortex in patients with left frontal damage

Previous studies have suggested that recovery or compensation of language function after a lesion in the left hemisphere may depend on mechanisms in the right hemisphere. However, a direct relationship between performance and right hemisphere activity has not been established. Here, we show that patients with left frontal lesions and partially recovered aphasia learn, at a normal rate, a novel word retrieval task that requires the damaged cortex. Verbal learning is accompanied by specific response decrements in right frontal and right occipital cortex, strongly supporting the compensatory role of the right hemisphere. Furthermore, responses in left occipital cortex are abnormal and not modulated by practice. These findings indicate that frontal cortex is a source of top-down signals during learning.     

Selective processing of calling songs by auditory interneurons in the female cricket, Gryllus pennsylvanicus: possible roles in behavior

Female crickets (Gryllus pennsylvanicus), caught in the field as nymphs, responded as adults in the laboratory with selective phonotaxis to model calling songs (CSs) that reproduced the dominant carrier frequencies and syllable periods (SPs) characteristic of the male's natural calling song. Extracellular recordings demonstrated two types of auditory interneurons in the female's cervical connectives that were very similar to the AN1 and AN2 neurons previously described in other gryllid species. The AN2 neuron responded to model CSs with a phasically encoded immediate response, and a more tonically encoded prolonged response. AN2's immediate response exhibited SP-dependent decreases (termed decrement) in its responses to sequential syllables of the CS that were greatest to CSs with the shortest SPs and diminished as SPs were lengthened, resulting in an SP-dependent habituation. Picrotoxin application transformed this SP-dependent habituation by AN2 to SP-selective responses in which the degree of decrement was greatest to SPs that were most phonotactically attractive. AN2's prolonged response was most sensitive to 5 kHz CSs and correlated with the carrier frequency tuning for the thresholds of phonotaxis by females. Thus, in females, AN2's immediate (in the presence of picrotoxin) and prolonged responses were selectively tuned to the SPs and carrier frequencies of the male's calls that were most attractive behaviorally. AN1's responses at threshold were also tuned to the dominant carrier frequencies of the male's CS.     

Neuromagnetic responses elicited by auditory stimuli in dichotic listening

We measured N1m and P2m components of the magnetic field responses that were elicited by random series of a tone burst given to the left ear and a monosyllabic speech sound given to the right ear. The magnetic responses had smaller amplitudes and/or longer peak latencies of the N1m and the P2m when the stimulus was preceded by a stimulus at the same ear than when preceded by a stimulus at the different ear. This reduction of the response by preceding stimulation of the same ear was significant over the hemisphere contralateral, but not ipsilateral, to the ear stimulated. The peak latencies of N1m and P2m were significantly longer in the response over the hemisphere contralateral than ipsilateral to the stimulated ear.     

Fatigue in isometric contraction in a single muscle fibre: a compartmental calcium ion flow model

Fatigue in muscle is a complex biological phenomenon which has so far eluded a definite explanation. Many biochemical and physiological models have been suggested in the literature to account for the decrement in the ability of muscle to sustain a given level of force for a long time. Some of these models have been critically analysed in this paper and are shown to be not able to explain all the experimental observations. A new compartmental model based on the intracellular calcium ion movement in muscle is proposed to study the mechanical responses of a muscle fibre. Computer simulation is performed to obtain model responses in isometric contraction to an impulse and a train of stimuli of long duration. The simulated curves have been compared with experimentally observed mechanical responses of the semitendinosus muscle fibre of Rana pipiens. The comparison of computed and observed responses indicates that the proposed calcium ion model indeed accounts very well for the muscle fatigue.     

Comparative study on picryl chloride (PCL)-induced contact dermatitis in female IQI/Jic and BALB/c mice.

Ear skin responses to picryl chloride (PCL)-induced contact dermatitis were compared in detail between IQI/Jic mice developed in Japan and BALB/c mice often used for the investigation of contact dermatitis. PCL was applied to the left ear of each mouse 4 (1st), 11 (2nd), 18 (3rd) and 25 days (4th) after sensitization of the abdominal skin with PCL. Time course examinations were carried out on the ear swelling responses, total IgE levels, skin histology and immunohistochemistry for infiltrated cells after the 1st and 4th application. In IQI mice, the peak time of the ear swelling responses tended to shift from 24 h to 9 h with marked elevation of total IgE levels and marked increase of mast cells showing degranulation after the 4th application when CD8(+) cells as well as CD4(+) cells also prominently increased. In BALB/c mice, except for the total IgE levels and the number of mast cells, the degrees of ear swelling responses, histological changes and increase of CD4(+) and CD8(+) cells were much less severe. Female IQI mice are considered to be a useful mouse strain for further investigations on the role of CD4(+) and CD8(+) T cells in the pathogenesis of contact dermatitis.     

Hearing in the African lungfish (Protopterus annectens): pre-adaptation to pressure hearing in tetrapods?

Lungfishes are the closest living relatives of the tetrapods, and the ear of recent lungfishes resembles the tetrapod ear more than the ear of ray-finned fishes and is therefore of interest for understanding the evolution of hearing in the early tetrapods. The water-to-land transition resulted in major changes in the tetrapod ear associated with the detection of air-borne sound pressure, as evidenced by the late and independent origins of tympanic ears in all of the major tetrapod groups. To investigate lungfish pressure and vibration detection, we measured the sensitivity and frequency responses of five West African lungfish (Protopterus annectens) using brainstem potentials evoked by calibrated sound and vibration stimuli in air and water. We find that the lungfish ear has good low-frequency vibration sensitivity, like recent amphibians, but poor sensitivity to air-borne sound. The skull shows measurable vibrations above 100 Hz when stimulated by air-borne sound, but the ear is apparently insensitive at these frequencies, suggesting that the lungfish ear is neither adapted nor pre-adapted for aerial hearing. Thus, if the lungfish ear is a model of the ear of early tetrapods, their auditory sensitivity was limited to very low frequencies on land, mostly mediated by substrate-borne vibrations.     

Muscimol infusions in the brain stem reticular formation reversibly block ingestion in the awake rat

Previous studies have localized a central pattern generator for mastication to the midline pontomedullary reticular formation (RF) based on cortically induced ororhythmic movements. The present study determined whether this same substrate mediated licking responses evoked by more natural stimuli. Licking in the awake rat was initiated either through an appetitive response to sucrose presented in a bottle or by intraoral (IO) infusions. Oral rejection responses also were obtained by IO infusions of quinine hydrochloride. Small volumes of the GABA(A) agonist muscimol bilaterally infused into the lateral medullary RF significantly reduced licking and oral rejection responses measured electromyographically from the anterior digastric and geniohyoid muscles. Other than the decrement or absence of ororhythmic activity, rats appeared normal and actively approached and probed the water bottle. The suppression was reversible and returned to baseline within 3 h. In contrast, midline infusions of muscimol did not affect licking or rejection responses. We postulate that the lateral medullary RF is an essential final common path for ingestive consummatory responses.     

The influence of muscles activation on the dynamical behaviour of the tympano-ossicular system of the middle ear

The human ear is a complex biomechanical system and is divided into three parts: outer, middle and inner ear. The middle ear is formed by ossicles (malleus, incus and stapes), ligaments, muscles and tendons, which transfers sound vibrations from the eardrum to the inner ear, linking with mastoid and Eustachian tube. In this work, a finite element modelling of the tympano-ossicular system of the middle ear was developed. A dynamic study based on a structural response to harmonic vibrations, for a sound pressure level (SPL) of 110, 120 and 130 dB SPL applied in the eardrum, is presented. The connection between the ossicles is made using a contact formulation. The model includes the different ligaments considering its hyperelastic behaviour. The activation of the muscles is based on the constitutive model proposed by previous work. The harmonic responses of displacement and pressure obtained on the stapes footplate, for a frequency range between 100 Hz and 10 kHz, are obtained simulating the muscle activation. The results are compared considering the passive and active states. The results are discussed and they are in accordance with audiological data published with reference to the effects of the middle ear muscles contraction.     

Infrasonic hearing in birds: a review of audiometry and hypothesized structure–function relationships

The perception of airborne infrasound (sounds below 20 Hz, inaudible to humans except at very high levels) has been documented in a handful of mammals and birds. While animals that produce vocalizations with infrasonic components (e.g. elephants) present conspicuous examples of potential use of infrasound in the context of communication, the extent to which airborne infrasound perception exists among terrestrial animals is unclear. Given that most infrasound in the environment arises from geophysical sources, many of which could be ecologically relevant, communication might not be the only use of infrasound by animals. Therefore, infrasound perception could be more common than currently realized. At least three bird species, each of which do not communicate using infrasound, are capable of detecting infrasound, but the associated auditory mechanisms are not well understood. Here we combine an evaluation of hearing measurements with anatomical observations to propose and evaluate hypotheses supporting avian infrasound detection. Environmental infrasound is mixed with non‐acoustic pressure fluctuations that also occur at infrasonic frequencies. The ear can detect such non‐acoustic pressure perturbations and therefore, distinguishing responses to infrasound from responses to non‐acoustic perturbations presents a great challenge. Our review shows that infrasound could stimulate the ear through the middle ear (tympanic) route and by extratympanic routes bypassing the middle ear. While vibration velocities of the middle ear decline towards infrasonic frequencies, whole‐body vibrations – which are normally much lower amplitude than that those of the middle ear in the ‘audible’ range (i.e. >20 Hz) – do not exhibit a similar decline and therefore may reach vibration magnitudes comparable to the middle ear at infrasonic frequencies. Low stiffness in the middle and inner ear is expected to aid infrasound transmission. In the middle ear, this could be achieved by large air cavities in the skull connected to the middle ear and low stiffness of middle ear structures; in the inner ear, the stiffness of round windows and cochlear partitions are key factors. Within the inner ear, the sizes of the helicotrema and cochlear aqueduct are expected to play important roles in shunting low‐frequency vibrations away from low‐frequency hair‐cell sensors in the cochlea. The basilar papilla, the auditory organ in birds, responds to infrasound in some species, and in pigeons, infrasonic‐sensitive neurons were traced back to the apical, abneural end of the basilar papilla. Vestibular organs and the paratympanic organ, a hair cell organ outside of the inner ear, are additional untested candidates for infrasound detection in birds. In summary, this review brings together evidence to create a hypothetical framework for infrasonic hearing mechanisms in birds and other animals.     

An Effective 3D Ear Acquisition System

The human ear is a new feature in biometrics that has several merits over the more common face, fingerprint and iris biometrics. It can be easily captured from a distance without a fully cooperative subject. Also, the ear has a relatively stable structure that does not change much with the age and facial expressions. In this paper, we present a novel method of 3D ear acquisition system by using triangulation imaging principle, and the experiment results show that this design is efficient and can be used for ear recognition.     

Membrane parameters,signal transmission,and the design of a graded potential neuron

1. The large monopolar cells (LMCs) of the fly, Calliphora vicina, visual system transmit graded potentials over distances of up to 1.0 mm. An electrical model was constructed to investigate the design principles relating their membrane parameters to signal transmission and filtering. 2. Using existing anatomical measurements, a cable model (van Hateren 1986) was fitted to the measured intracellular responses of the cells to injected current. The LMC has three functional components: a distal synaptic zone of low impedance, an axon with high specific membrane resistance (greater than 50.10(5) M omega.micron 2), and a high impedance proximal terminal. These components interact to transmit information efficiently. The low input impedance synaptic zone charges and discharges the axon rapidly, ensuring a good frequency response. The high resistance axon conducts signals with little decrement. The model shows that graded potential transmission in LMCs selectively filters synaptic noise and predicts the changes in response waveform that occur during transmission. 3. The parameters of the model were adjusted to determine the relative costs and benefits of alternative cable designs. The design used in LMCs is the most expensive and the most effective. It requires the largest currents to generate responses but transmits signals with least decrement. Parallel neurons in the fly visual system have fewer input synapses and this could low-pass filter their graded response.     

Drug-inducible,dendritic cell-based genetic immunization

Determining the mechanism of Ag loading of Langerhans cells (LC) for genetic immunization (GI) is complicated by the inability to distinguish between the response generated by direct transfection of LC from that due to exogenous uptake. To unravel this mechanism, we examined the impact of gene gun treatment on LC with respect to their activation and migration from skin, transgene expression, and ability to initiate humoral and cellular immune responses upon transfer to naive mice. To assess responses generated by direct LC transfection, an RU486-inducible expression system was used as a GI vector. In vitro skin organ cultures were developed from gene gun immunized mouse ear specimens to obtain LC. Gene gun treatment markedly augmented (3-fold) LC migration from ear skin, and these LC expressed the transgene at RNA and protein levels. Transfer of 2 x 10(5) migratory cells resulted in identical cellular responses to, but 10-fold lower humoral responses than, standard GI. Using an RU486-inducible system, we were able to measure responses generated by directly transfected LC. Our results indicate that direct transfection is a predominant pathway for LC Ag loading. The ability to regulate transgene expression with inducible DC-based vaccines demonstrates a new level of immunological control.     

Recording Single Neurons' Action Potentials from Freely Moving Pigeons Across Three Stages of Learning

While the subject of learning has attracted immense interest from both behavioral and neural scientists, only relatively few investigators have observed single-neuron activity while animals are acquiring an operantly conditioned response, or when that response is extinguished. But even in these cases, observation periods usually encompass only a single stage of learning, i.e. acquisition or extinction, but not both (exceptions include protocols employing reversal learning; see Bingman et al.¹ for an example). However, acquisition and extinction entail different learning mechanisms and are therefore expected to be accompanied by different types and/or loci of neural plasticity.Accordingly, we developed a behavioral paradigm which institutes three stages of learning in a single behavioral session and which is well suited for the simultaneous recording of single neurons'' action potentials. Animals are trained on a single-interval forced choice task which requires mapping each of two possible choice responses to the presentation of different novel visual stimuli (acquisition). After having reached a predefined performance criterion, one of the two choice responses is no longer reinforced (extinction). Following a certain decrement in performance level, correct responses are reinforced again (reacquisition). By using a new set of stimuli in every session, animals can undergo the acquisition-extinction-reacquisition process repeatedly. Because all three stages of learning occur in a single behavioral session, the paradigm is ideal for the simultaneous observation of the spiking output of multiple single neurons. We use pigeons as model systems, but the task can easily be adapted to any other species capable of conditioned discrimination learning.     

Electrophysiological correlates of local muscular fatigue effects upon human visual reaction time.

A study of the neurophysiological basis of reaction time change was undertaken as a means of exploring the physiological mechanisms of local muscular fatigue effects upon sensorimotor performance. The identification of electrophysiological indices of central and peripheral processes within the human electroencephalogram and electromyogram, enabled a fractionation of total reaction time into component latencies measuring sensory reception time, sensorimotor integration time, central motor outflow time and peripheral motor contraction time. Simple foot dorsiflexion reactions to visual stimuli were observed in 18 male college students. Foot responses under one condition were performed against a resistance which necessitated a moderate degree of muscular tension before movement could occur while a second condition required normal unresisted responses. Two intensities of serial isometric work resulting in the order of a 38% decrement in maximum voluntary contractile capability (MVC) were performed by each subject. While the rate and extent of MVC decrement varied with the inherent strength of the subject and the intensity of the exercise performed, unconditional changes were observed in the spatiotemporal dimensions of reaction time performance following exercise-induced fatigue. The quality of total reaction time was found to deteriorate, particularly when responses were resisted. Peripheral deficiencies, suggestive of a decreased rate of tension development, were evidenced by a marked elongation of resisted motor times, and less vigorous and extensive unresisted responses. Insofar as the energy of response electromyograms was also diminished, central mechanisms were implicated, possible due to a shift in motor unit recruitment. Concomitant changes were also observed in central processing.     

Temporal generalization and diffusion in forgetting

Two processes may contribute to the decrement in discriminability with increasing temporal distance between the occasioning event and later choice. One is the length of the interval and the other is generalization decrement. In the model described by White and Wixted [J. Exp. Anal. Behav. 71 (1999) 91-113], choice was predicted by the relative payoff for correct delayed matching responses, conditional on the current value of the stimulus sampled from Thurstone-like probability distributions of the effect of the sample stimuli. In the model, discriminability decreased with increasing temporal distance because the variance of the distributions increased with time. However, White and Wixted did not specify the function relating variance to temporal distance. If a diffusion process is assumed, and if diffusion increases exponentially with time, the resulting forgetting function is a negative exponential. An additional process involves exponential generalization of remembering from one time to other times. Alternative diffusion functions result in hyperbolic or power forgetting functions. The combination of two exponential processes yields forgetting functions that are double exponential in form and which appear consistent with a wide range of data.