Generation of memory cell-mediated immune responses after secondary infection of mice with pichinde virus

Pichinde virus (PV), a member of the arenavirus group, was found to elicit strong cell-mediated immune responses in various strains of mice. After primary i.v. inoculation, augmentation of natural killer (NK) cell activity occurred and peaked 3 to 4 days after infection. The NK response was followed by a second peak of cytotoxic activity that was found to be H-2 restricted, virus specific, and mediated by Thy-1.2+, Lyt-2.2+ lymphocytes. This cytotoxic T lymphocyte (CTL) response peaked 7 days post infection. Neutralizing antibodies were not detectable after PV infection of the mice. In light of this, we investigated the generation and kinetics of secondary cell-mediated immune responses after reinjection of homologous virus in vivo. Slight but significant augmentation of NK activity was observed 1 day after secondary virus challenge. As in the primary response, effectors of this NK activity rapidly became sensitive to anti-Thy-1.2 and complement treatment. NK activity rapidly returned to background levels and was followed by an anamnestic CTL response that peaked 4 days after reinjection of the virus. Thus, cell-mediated immune responses appeared more rapidly after secondary challenge in vivo, and the temporal relationship between NK and CTL generation was maintained. Both secondary NK and CTL responses were generated in mice that had been pretreated with cyclophosphamide (CY), suggesting that memory cell-mediated immune responses can be reactivated in vivo without undergoing cell division. In contrast, treatment with CY before primary infection delayed the appearance of virus-induced NK activity and abrogated the generation of H-2-restricted virus-specific CTL. Rechallenge of these CY-treated NK-primed mice resulted in the rapid generation of a secondary NK response that was not followed by either a primary or secondary CTL response. The data suggest that cells mediating a nonspecific effector function may possess specific memory. We discuss our results with respect to possible NK-CTL relationships.     

Supporting Evidence from Single Unit Experiments for the Cochlea as an Addressed Delay Line

WE have already outlined the principles of a theory of cochlear organization^{1, 2} whereby acoustic signal components in the low and mid frequency range—-that is to say, frequencies for which good or moderate phase locking of unit response is possible—are detected by the cochlea using an approximate cross-correlation mechanism which operates on the time varying signal displayed along the basilar membrane, the latter acting as an acoustic exponential delay line. The running correlations are performed using fixed patterns of control fibres addressed to the outer hair cells, the pattern of addressing for each control fibre group corresponding to an instantaneous wave pattern for a specific frequency defined by the location of the fibre system along the length of the membrane. The fibres of each control system synapse with the afferent dendrites associated with a definite inner hair cell and act as a frequency sensitive gate, the inner hair cell of the assembly providing generator current related to signal amplitude.     

Reconsidering the importance of the past in predator–prey models: both numerical and functional responses depend on delayed prey densities

We propose that delayed predator–prey models may provide superficially acceptable predictions for spurious reasons. Through experimentation and modelling, we offer a new approach: using a model experimental predator–prey system (the ciliates Didinium and Paramecium), we determine the influence of past-prey abundance at a fixed delay (approx. one generation) on both functional and numerical responses (i.e. the influence of present : past-prey abundance on ingestion and growth, respectively). We reveal a nonlinear influence of past-prey abundance on both responses, with the two responding differently. Including these responses in a model indicated that delay in the numerical response drives population oscillations, supporting the accepted (but untested) notion that reproduction, not feeding, is highly dependent on the past. We next indicate how delays impact short- and long-term population dynamics. Critically, we show that although superficially the standard (parsimonious) approach to modelling can reasonably fit independently obtained time-series data, it does so by relying on biologically unrealistic parameter values. By contrast, including our fully parametrized delayed density dependence provides a better fit, offering insights into underlying mechanisms. We therefore present a new approach to explore time-series data and a revised framework for further theoretical studies.     

Re-evaluation of the absolute threshold and response mode of the most sensitive know “vibration” detector,the cockroach's subgenual organ: A cochlea-like displacement threshold and a direct response to sound

Earlier accounts claim from indirect measurements that the subgenual organ (SGO) in the proximal tibia of the cockroach leg can detect vibrational displacements down to 0.002 mm, two orders of magnitude below the threshold for vertebrate hair cells in the cochlea. The SGO vibration threshold is redetermined here more directly by a new method on a cantilever beam, while controlling for particular acoustic and vibrational artifacts that might have compromised earlier efforts. The threshold is revised upwards to about 0.2 mm in the most sensitive preparation, about the same as cochlea. Recently, it has been determined that the cockroach SGO also has an auditory response, and the data here on subthreshold summation and response-intensity relationships provide further evidence that sound and contact vibration are both sensed by the same receptor neurons. Direct measurements rule out the prevailing hypothesis that sound is detected indirectly as induced vibration of the ground, and also weigh strongly against any significant involvement of generalized leg resonance in acoustic pick-up. The results fit with a recent proposal that the auditory response is direct, and that acoustic fluctuations inside the tracheae may be the primary response mode in the transduction of both vibration and sound. 1994 John Wiley & Sons, Inc.     

The Role of Inhibition in a Computational Model of an Auditory Cortical Neuron during the Encoding of Temporal Information

In auditory cortex, temporal information within a sound is represented by two complementary neural codes: a temporal representation based on stimulus-locked firing and a rate representation, where discharge rate co-varies with the timing between acoustic events but lacks a stimulus-synchronized response. Using a computational neuronal model, we find that stimulus-locked responses are generated when sound-evoked excitation is combined with strong, delayed inhibition. In contrast to this, a non-synchronized rate representation is generated when the net excitation evoked by the sound is weak, which occurs when excitation is coincident and balanced with inhibition. Using single-unit recordings from awake marmosets (Callithrix jacchus), we validate several model predictions, including differences in the temporal fidelity, discharge rates and temporal dynamics of stimulus-evoked responses between neurons with rate and temporal representations. Together these data suggest that feedforward inhibition provides a parsimonious explanation of the neural coding dichotomy observed in auditory cortex.     

Impact of Morphometry,Myelinization and Synaptic Current Strength on Spike Conduction in Human and Cat Spiral Ganglion Neurons

Background

Our knowledge about the neural code in the auditory nerve is based to a large extent on experiments on cats. Several anatomical differences between auditory neurons in human and cat are expected to lead to functional differences in speed and safety of spike conduction.

Methodology/Principal Findings

Confocal microscopy was used to systematically evaluate peripheral and central process diameters, commonness of myelination and morphology of spiral ganglion neurons (SGNs) along the cochlea of three human and three cats. Based on these morphometric data, model analysis reveales that spike conduction in SGNs is characterized by four phases: a postsynaptic delay, constant velocity in the peripheral process, a presomatic delay and constant velocity in the central process. The majority of SGNs are type I, connecting the inner hair cells with the brainstem. In contrast to those of humans, type I neurons of the cat are entirely myelinated. Biophysical model evaluation showed delayed and weak spikes in the human soma region as a consequence of a lack of myelin. The simulated spike conduction times are in accordance with normal interwave latencies from auditory brainstem response recordings from man and cat. Simulated 400 pA postsynaptic currents from inner hair cell ribbon synapses were 15 times above threshold. They enforced quick and synchronous spiking. Both of these properties were not present in type II cells as they receive fewer and much weaker (^∼26 pA) synaptic stimuli.

Conclusions/Significance

Wasting synaptic energy boosts spike initiation, which guarantees the rapid transmission of temporal fine structure of auditory signals. However, a lack of myelin in the soma regions of human type I neurons causes a large delay in spike conduction in comparison with cat neurons. The absent myelin, in combination with a longer peripheral process, causes quantitative differences of temporal parameters in the electrically stimulated human cochlea compared to the cat cochlea.     

耳蜗电位的持续反应与其中单个脉冲的反应

研究了豚鼠耳蜗电位中持续反应与其中的单个脉冲反应的关系。由于听学系统存在着非线性,因此仅仅知道由单个短声诱发的耳蜗电位脉冲反应还无法预测一串等间隔重复短声诱发的持续反应。然而,等间隔重复短声串中第5个以后的每个短声受前面所有短声的掩蔽都相同,诱发的反应都相同,因此持续反应的稳态部分可以由掩蔽作用达到饱和时单个短声的反应通过延时相加得到。本文在时间域和频率域上定量地证明了这点。     

Relationships between cell-mediated immunity and the IgE antibody response: II. Delayed hypersensitivity and antibody production to DNP-Ascaris conjugates

Rats of the W/F strain were immunized with DNP-Ascaris conjugates using complete Freund's adjuvant (CFA), Al(OH)₃ gel (alum), or B. pertussis vaccine as adjuvants. Cell-mediated immunity was assessed by lymphotoxin in vitro and by delayed hypersensitivity in vivo. IgE and IgG antibody determinations were made on serum pools obtained at various times during the primary and secondary responses. Although delayed hypersensitivity appeared earlier than lymphotoxin, these two parameters correlated during the primary but not during the secondary response. The discrepancies suggested that different cells may be responsible for these two phenomena. Antibody production was influenced by the adjuvant used. CFA led to IgG antibody responses to both hapten and carrier but not to IgE antibody production. The use of B. pertussis resulted in both IgE and IgG antibody production. In the case of alum, anti-hapten antibodies appeared during the primary response while anti-carrier antibodies of both IgE and IgG classes were detected after booster. The results indicated that cell-mediated immunity, IgE, and IgG antibodies appeared independently in an ordered, temporal sequence, and that these responses were not mutually exclusive but were under strong modulatory influences of the various adjuvants used.     

综述: 初级视皮层的亮度信息加工

亮度(luminance)是最基本的视觉信息.与其他视觉特征相比,由于视神经元对亮度刺激的反应较弱,并且许多神经元对均匀亮度无反应,对亮度信息编码的神经机制知之甚少.初级视皮层部分神经元对亮度的反应要慢于对比度反应,被认为是由边界对比度诱导的亮度知觉(brightness)的神经基础.我们的研究表明,初级视皮层许多神经元的亮度反应要快于对比度反应,并且这些神经元偏好低的空间频率、高的时间频率和高的运动速度,提示皮层下具有低空间频率和高运动速度通路的信息输入对产生初级视皮层神经元的亮度反应有贡献.已经知道初级视皮层神经元对空间频率反应的时间过程是从低空间频率到高空间频率,我们发现的早期亮度反应是对极低空间频率的反应,与这一时间过程是一致的,是这一从粗到细的视觉信息加工过程的第一步,揭示了处理最早的粗的视觉信息的神经基础.另外,初级视皮层含有偏好亮度下降和高运动速度的神经元,这群神经元的活动有助于在光照差的环境中检测高速运动的低亮度物体.     

Response variability in the mammalian auditory cortex: an objection to feature detection?

Research strategy in the auditory system has tended to parallel that in the visual system, where neurons have been shown to respond selectively to specific stimulus parameters. Auditory neurons have been shown to be sensitive to changes in acoustic parameters, but only rarely have neurons been reported that respond exclusively to only one biologically significant sound. Even at higher levels of the auditory system very few cells have been found that could be described as "vocalization detectors." In addition, variability in responses to artificial sounds have been reported for auditory cortical neurons similar to the response variability that has been reported in the visual system. Recent evidence indicates that the responses of auditory cortical neurons to species-specific vocalizations can also be labile, varying in both strength and selectivity. This is especially true of the secondary auditory cortex. This variability, coupled with the lack of extreme specificity in the secondary auditory cortex, suggests that secondary cortical neurons are not well suited for the role of "vocalization detectors."     

Temperature dependence of temporal resolution in an insect nervous system

The vast majority of animals are poikilotherms, and thus face the problem that the temperature of their nervous systems rather smoothly follows the temperature changes imposed by their environment. Since basic properties of nerve cells, e.g., the time constants of ion channels, strongly depend on temperature, a temperature shift likely affects the processing of the temporal structure of sensory stimuli. This can be critical in acoustic communication systems in which time patterns of signals are decisive for recognition by the receiver. We investigated the temperature dependence of the responses of locust auditory receptors and interneurons by varying the temperature of the experimental animals during intracellular recordings. The resolution of fast amplitude modulations of acoustic signals was determined in a gap detection paradigm. In auditory receptors and local (second order) interneurons, temporal resolution was improved at higher temperatures. This gain could be attributed to a higher precision of spike timing. In a third-order neuron, a rise in temperature affected the interactions of inhibition and excitation in a complex manner, also resulting in a better resolution of gaps in the millisecond range.     

Adult Plasticity in the Subcortical Auditory Pathway of the Maternal Mouse

Subcortical auditory nuclei were traditionally viewed as non-plastic in adulthood so that acoustic information could be stably conveyed to higher auditory areas. Studies in a variety of species, including humans, now suggest that prolonged acoustic training can drive long-lasting brainstem plasticity. The neurobiological mechanisms for such changes are not well understood in natural behavioral contexts due to a relative dearth of in vivo animal models in which to study this. Here, we demonstrate in a mouse model that a natural life experience with increased demands on the auditory system – motherhood – is associated with improved temporal processing in the subcortical auditory pathway. We measured the auditory brainstem response to test whether mothers and pup-naïve virgin mice differed in temporal responses to both broadband and tone stimuli, including ultrasonic frequencies found in mouse pup vocalizations. Mothers had shorter latencies for early ABR peaks, indicating plasticity in the auditory nerve and the cochlear nucleus. Shorter interpeak latency between waves IV and V also suggest plasticity in the inferior colliculus. Hormone manipulations revealed that these cannot be explained solely by estrogen levels experienced during pregnancy and parturition in mothers. In contrast, we found that pup-care experience, independent of pregnancy and parturition, contributes to shortening auditory brainstem response latencies. These results suggest that acoustic experience in the maternal context imparts plasticity on early auditory processing that lasts beyond pup weaning. In addition to establishing an animal model for exploring adult auditory brainstem plasticity in a neuroethological context, our results have broader implications for models of perceptual, behavioral and neural changes that arise during maternity, where subcortical sensorineural plasticity has not previously been considered.     

Cell-cycle checkpoints that ensure coordination between nuclear and cytoplasmic events in Saccharomyces cerevisiae

Cytoskeletal organization is crucial for several aspects of cell-cycle progression but cytoskeletal elements are quite sensitive to environmental perturbations. Two novel checkpoint controls monitor the function of the actin and microtubule systems in budding yeast and operate to delay cell-cycle progression in response to cytoskeletal perturbations. In cells whose actin cytoskeleton has been perturbed, bud formation is frequently delayed and the morphogenesis checkpoint introduces a compensatory delay of nuclear division until a bud has been formed. In cells whose microtubule cytoskeleton has been perturbed, anaphase spindle elongation often occurs entirely within the mother cell, and the post-anaphase nuclear migration checkpoint introduces a compensatory delay of cytokinesis until one pole of the anaphase nucleus enters the bud. Recent studies indicate that regulators of entry into mitosis are localized to the daughter side of the mother-bud neck whereas regulators of exit from mitosis are localized to the spindle pole bodies. Thus, specific cell-cycle regulators are well-placed to monitor whether a cell has formed a bud and whether a daughter nucleus has been delivered accurately to the bud following mitosis.     

Interleukin-4 causes delayed virus clearance in influenza virus-infected mice.

Two different subsets of T cells, Th1 and Th2 cells, have been demonstrated to secrete different profiles of cytokines and to influence various infections in different ways. Whereas cytokines secreted by Th1 cells, particularly gamma interferon, promote the generation of cell-mediated immunity, Th2 cells and their cytokines (interleukin-4 [IL-4], IL-5, IL-10, and IL-13) have been shown to function in recovery from parasitic infections and in antibody responses. In this study, we analyzed the effects of the dominant Th2 cytokine, IL-4, on immunity to virus infection. We assessed the effects of IL-4 on both secondary immune responses by an adoptive transfer assay and primary immune responses by in vivo treatment of influenza virus-infected mice with IL-4. The results demonstrated that IL-4 can function to inhibit antiviral immunity at both stages. We found that IL-4 treatment of sensitized cells during secondary stimulation in vitro had little effect on their ability to lyse virus-infected target cells in a 51Cr release assay. Nevertheless, the clearance of influenza A/PR/8/34 (H1N1) virus from the lungs of infected BALB/c mice was significantly delayed after the transfer of virus-specific T cells secondarily stimulated in the presence of IL-4 in comparison to virus clearance in recipients of cells stimulated in the absence of IL-4. In contrast to the adoptive transfer results, the treatment of PR8 virus-infected mice with IL-4 during primary infection greatly suppressed the generation of cytotoxic T-cell precursors, as assessed by secondary stimulation in vitro. In addition, culture supernatants of secondarily stimulated spleen cells from IL-4-treated mice contained significantly less gamma interferon and more IL-4 than did spleen cells from controls. More importantly, the treatment of mice with IL-4 resulted in an extremely significant delay in virus clearance. Thus, IL-4 can inhibit both primary and secondary antiviral immune responses.     

Temporal parameters of male—female sound communication in Leptophyes punctatissima

ABSTRACT. Quantitative information is presented about acoustic communication between the sexes of the speckled bush cricket Leptophyes punctatissima Bosc (Orthoptera: Tettigoniidae). The male song elicits an acoustic response from a receptive female with a net delay (excluding the travelling time of the sound) of about 25 ms depending upon ambient temperature. Only when the female responses fall within the narrow temporal window between 20 and 50 ms after the onset of his song does the male perform phonotaxis. The precise timing of this duet is described, and its advantages and disadvantages are discussed.     

Impulse control: temporal dynamics in gene transcription

Regulatory circuits controlling gene expression constantly rewire to adapt to environmental stimuli, differentiation cues, and disease. We review our current understanding of the temporal dynamics of gene expression in eukaryotes and prokaryotes and the molecular mechanisms that shape them. We delineate several prototypical temporal patterns, including "impulse" (or single-pulse) patterns in response to transient environmental stimuli, sustained (or state-transitioning) patterns in response to developmental cues, and oscillating patterns. We focus on impulse responses and their higher-order temporal organization in regulons and cascades and describe how core protein circuits and cis-regulatory sequences in promoters integrate with chromatin architecture to generate these responses.     

Relation between potassium-channel kinetics and the intrinsic dynamics in isolated retinal bipolar cells

Characterization of the intrinsic dynamics of isolated retinal bipolar cells by a whole-cell patch-clamp technique combined with estimation of effective impulse responses across a range of mean injected currents reveals strikingly adaptive behavior. At resting potential, bipolar cells' effective impulse response is slow, high gain, and low pass. Depolarization speeds up response, decreases gain, and, in most cells, induces bandpass behavior.This adaptive behavior involves two K⁺ currents. The delayed-rectifier accounts for the observed gain reduction, speed increase, and bandpass behavior. The A-channel further shortens the impulse responses but suppresses bandpass features. Computer simulations of model neurons with a delayed-rectifier and varying A-channel conductances reveal that impulse responses largely reflect the flux of electrical charge through the two K⁺ channels. The A-channel broadens the frequency response and preempts the action of the delayed-rectifier, thereby reducing the associated bandpass features. Admixtures of the two K⁺ channels produce the observed variety of dynamics of retinal bipolar cells.     

Wideband acoustic energy studies of pulmonary airways

The impulse response of the pulmonary system has been measured by exciting the system with wideband acoustic noise introduced through the mouth. The transmitted sound is detected using microphones placed on the patient's back at appropriate locations. A specially designed analog correlator is used to obtain the impulse response of the pulmonary system through cross-correlation techniques. Uniquely characteristic responses have been obtained from smoking and nonsmoking patient groups.