Stimulus control over induction produced by upcoming food-pellet reinforcement

Research has demonstrated that rats increase their rate of lever pressing for sucrose reinforcement when food-pellet reinforcement will soon be available within the session. Recent results suggest that this increase occurs because stimuli in the session come to signal different levels of overall reinforcement. The present experiment tested this idea by having rats respond in two types of session. In one, they pressed lever A for 1% sucrose reinforcers in the first half of the session and lever B for food-pellet reinforcers in the second half (the opposing lever was retracted in the respective half). In the other, they pressed lever B for 1% sucrose reinforcers in the first half and lever A for 1% sucrose reinforcers in the second. Thus, the presence of lever A in the first half of the session was predictive of upcoming food-pellet reinforcement, but only lever B was ever used to obtain food pellets. Subjects responded at a higher rate on lever B in the first half of the session than on lever A, despite food-pellet reinforcement being unavailable in such sessions. Furthermore, they responded at a higher rate on lever B during probe sessions in which both levers were available. These results demonstrate that stimulus control over induction occurs when a stimulus becomes differentially associated with a heightened level of reinforcement. However, questions remain as to whether this association is Pavlovian or whether stimuli with "predictive value" may ever lead to induction.     

Adrenoreceptors are involved in the stimulation of neutrophils by exercise-induced circulating concentrations of Hsp72: cAMP as a potential "intracellular danger signal"

Recently, the terms "stress mediators" or "danger signals" have come to be used to describe endogenous molecules that can be released in stress situations and activate the innate immune system even in the absence of antigenic stimuli. There is evidence suggesting that extracellular heat shock proteins of 72 kDa (eHsp72), together with noradrenaline (NA), are candidates as danger signals during exercise-induced stress, interacting in the activation of neutrophils. Previous studies have shown that the post-exercise circulating concentration of eHsp72 activates the phagocytic process of neutrophils with the participation of toll-like receptor 2, but that other receptors must also be involved. The present investigation evaluates the role of adrenoreceptors in the activation of the chemotaxis, phagocytosis, and fungicidal capacity of neutrophils by the post-exercise circulating concentration of eHsp72. The results showed that intact α- and β-adrenoreceptors are necessary for the stimulation of all stages of the phagocytic process by eHsp72. Also, eHsp72 increased the intracellular levels of cAMP, suggesting that it is an "intracellular danger signal" during stress-induced activation of neutrophils mediated by extracellular heat shock proteins. These results can contribute to better understanding the mechanisms involved in the regulation of the innate immune response mediated by "danger signals" during exercise, and probably during other stress situations.     

The NADPH oxidase of human polymorphonuclear leukocytes. Evidence for regulation by multiple signals

Activation of the membrane-bound NADPH oxidase in human polymorphonuclear leukocytes can be triggered by chemoattractants, the tumor promoter phorbol myristate acetate or the calcium ionophore A23187. We have shown previously that these stimuli have markedly different temporal patterns of oxidase activation (McPhail, L. C., and Snyderman, R. (1983) J. Clin. Invest. 72, 192-200), suggesting that each follows, at least in part, a unique transductional pathway. We now report that if leukocytes were sequentially exposed to any of several combinations of heterologous stimuli, the pattern of activation by the second stimulus was strikingly altered, resulting in a more rapid rate and enhanced level of oxidase activation by the second stimulus. This suggests that exposure of cells to the first stimulus (priming) had influenced an intermediate also used by the second stimulus. The signal for priming could be clearly distinguished from the signal causing oxidase activation by the dose-response curves for each, as well as by the use of several pharmacologic agents. In addition, if leukocytes were given sequential doses of homologous stimuli, either partial (phorbol myristate acetate) or full (N-formyl-methionyl-leucyl -phenylalanine and A23187) desensitization of oxidase activation was observed. These results demonstrate that these stimuli share a common intermediate in the pathway of oxidase activation. Moreover, the data indicate that NADPH oxidase activation is regulated by at least three distinct signals: signal 1 (priming), signal 2 (activation), and signal 3 (inactivation). It is likely that more than one intracellular messenger exerts a modulating influence on NADPH oxidase activity and that its regulation involves the interplay between several cellular control proteins.     

Pigeons' timing of an arbitrary and a naturalistic auditory stimulus: tone versus cooing

Previous animal research has traditionally used arbitrary stimuli to investigate timing in a temporal bisection procedure. The current study compared the timing of the duration of an arbitrary, auditory stimulus (a 500-Hz tone) to the timing of the duration of a naturalistic, auditory stimulus (a pigeon cooing). In the first phase of this study, temporal perception was assessed by comparing psychophysical functions for the duration of tone and cooing signals. In the first set of tests, the point of subjective equality (PSE) was significantly lower for the tone than for the cooing stimulus, indicating that tones were judged longer than equivalent durations of cooing. In the second set of tests, gaps were introduced in the tone signal to match those present in the cooing signal, and no significant difference in the PSE for the tone or the cooing signal was found. A repetition of the testing conducted with gaps removed from the tone signal, failed to replicate the difference in the PSEs for the tone and cooing signals originally obtained. In the second phase of the study, memory for the duration of tone and cooing was examined, and a choose-long bias was found for both signals. Based on these results, it appears that, for pigeons, there may be no significant differences in either temporal perception or temporal memory for arbitrary, auditory signals and more complex, naturalistic, auditory signals.     

The motor dominant in man]

Study of the motor dominant in man has shown that in aftereffect of rhythmic electrocutaneous stimulation of hand, a latent focus of excitation is formed in the CNS. When using sensory stimuli (light, sound) and also stimuli, addressed to the second signal system, a hand motor reaction appears in the rhythm of earlier electrocutaneous stimulation, what testifies to preservation of rhythmic nature of excitation in the dominant focus. Summation process in the dominant focus is not reflected in human consciousness. Study of the brain biopotentials has shown that at formation of human motor dominant, typical changes of spectral-coherent characteristics of the neocortex electrical activity appear: within the "dominant" hemisphere, the spectrum power, increases in the range of low frequencies; highly coherent connections of electrical processes appear in the delta-range of the frontal-parietal area at conjugate decrease of combination of processes in the parietal-occipital area of the cerebral cortex. Formation of the dominant focus in one hemisphere causes general reconstruction of the structure of intercentral relations of both hemispheres electrical activity.     

The influence of serotonin on fear learning

Learning of associations between aversive stimuli and predictive cues is the basis of Pavlovian fear conditioning and is driven by a mismatch between expectation and outcome. To investigate whether serotonin modulates the formation of such aversive cue-outcome associations, we used functional magnetic resonance imaging (fMRI) and dietary tryptophan depletion to reduce brain serotonin (5-HT) levels in healthy human subjects. In a Pavlovian fear conditioning paradigm, 5-HT depleted subjects compared to a non-depleted control group exhibited attenuated autonomic responses to cues indicating the upcoming of an aversive event. These results were closely paralleled by reduced aversive learning signals in the amygdala and the orbitofrontal cortex, two prominent structures of the neural fear circuit. In agreement with current theories of serotonin as a motivational opponent system to dopamine in fear learning, our data provide first empirical evidence for a role of serotonin in representing formally derived learning signals for aversive events.     

Ghrelin regulates phasic dopamine and nucleus accumbens signaling evoked by food‐predictive stimuli

Environmental stimuli that signal food availability hold powerful sway over motivated behavior and promote feeding, in part, by activating the mesolimbic system. These food‐predictive cues evoke brief (phasic) changes in nucleus accumbens (NAc) dopamine concentration and in the activity of individual NAc neurons. Phasic fluctuations in mesolimbic signaling have been directly linked to goal‐directed behaviors, including behaviors elicited by food‐predictive cues. Food‐seeking behavior is also strongly influenced by physiological state (i.e., hunger vs. satiety). Ghrelin, a stomach hormone that crosses the blood‐brain barrier, is linked to the perception of hunger and drives food intake, including intake potentiated by environmental cues. Notwithstanding, whether ghrelin regulates phasic mesolimbic signaling evoked by food‐predictive stimuli is unknown. Here, rats underwent Pavlovian conditioning in which one cue predicted the delivery of rewarding food (CS+) and a second cue predicted nothing (CS?). After training, we measured the effect of ghrelin infused into the lateral ventricle (LV) on sub‐second fluctuations in NAc dopamine using fast‐scan cyclic voltammetry and individual NAc neuron activity using in vivo electrophysiology in separate groups of rats. LV ghrelin augmented both phasic dopamine and phasic increases in the activity of NAc neurons evoked by the CS+. Importantly, ghrelin did not affect the dopamine nor NAc neuron response to the CS?, suggesting that ghrelin selectively modulated mesolimbic signaling evoked by motivationally significant stimuli. These data demonstrate that ghrelin, a hunger signal linked to physiological state, can regulate cue‐evoked mesolimbic signals that underlie food‐directed behaviors.

     

Analysis of the neuronal selectivity underlying low fMRI signals

BACKGROUND: A prevailing assumption in neuroimaging studies is that relatively low fMRI signals are due to weak neuronal activation, and, therefore, they are commonly ignored. However, lower fMRI signals may also result from intense activation by highly selective, albeit small, subsets of neurons in the imaged voxel. We report on an approach that could form a basis for resolving this ambiguity imposed by the low (mm range) spatial resolution of fMRI. Our approach employs fMR-adaptation as an indicator for highly active neuronal populations even when the measured fMRI signal is low.RESULTS: In this study, we first showed that fMRI-adaptation is diminished when overall neuronal activity is lowered substantially by reducing image contrast. We then applied the same adaptation paradigm, but this time we lowered the fMRI signal by changing object shape. While the overall fMRI signal in category-related regions such as the face-related pFs was drastically reduced for non-face stimuli, the adaptation level obtained for these stimuli remained high. We hypothesize that the relatively greater adaptation level following exposure to "nonoptimal" object shapes is indicative of small subsets of neurons responding vigorously to these "nonoptimal" objects even when the overall fMRI activity is low.CONCLUSIONS: Our results show that fMR-adaptation can be used to differentiate between neuronal activation patterns that appear similar in the overall fMRI signal. The results suggest that it may be possible to employ fMR-adaptation to reveal functionally heterogeneous islands of activity, which are too small to image using conventional imaging methods.     

Evolution of talking plants in a tritrophic context: conditions for uninfested plants to attract predators prior to herbivore attack

Herbivory induces plants to emit volatile chemicals that attract enemies of the herbivores (bodyguards of plants). In this way, the plant acquires protection and the bodyguards gain food. These plant signals cause neighboring plants, not under attack, to release signals as well. We hypothesize that such "secondary" signals help to reduce damage from future herbivore attacks by the protection received from the bodyguards. By modeling we explore the conditions for such secondary signals to evolve. Three kinds of strategies are considered: plants of the first strategy always emit a signal, those of the second strategy emit a signal only when infested, and those of the third strategy emit a signal not only when infested, but also when a certain number of neighbors are infested (i.e. secondary signaling). When signaling is much less (much more) costly than damage from herbivory, the first (second) strategy will be favored by selection, whereas for intermediate costs the third strategy, i.e. secondary signaling, will evolve. However, secondary signaling will not evolve when the primary signals lure the bodyguards too effectively. This is because the undamaged plant gains associational defense when the infested individual is defending very well; therefore, the need for secondary signaling decreases.     

Direct and feedback temporary connections between unfamiliar visual stimuli]

Recording of averaged evoked potentials to two successive visual stimuli shows that associations, temporary connections, direct and feedback, can be elaborated in man between two unrecognized stimuli. The magnitude of cortical late response to the first stimulus in the complex diminishes as a result of action of the inhibitory feedback temporary connection. This inhibitory effect is more pronounced when the second stimulus is emotionally significant for the subject. The evoked potential to the second stimulus in the association between unrecognized visual stimuli is considerably facilitated. The role is discussed of direct and feedback temporary connections between unrecognized stimuli in some unconscious psychic phenomena in man.     

Sensory information in local field potentials and spikes from visual and auditory cortices: time scales and frequency bands

Studies analyzing sensory cortical processing or trying to decode brain activity often rely on a combination of different electrophysiological signals, such as local field potentials (LFPs) and spiking activity. Understanding the relation between these signals and sensory stimuli and between different components of these signals is hence of great interest. We here provide an analysis of LFPs and spiking activity recorded from visual and auditory cortex during stimulation with natural stimuli. In particular, we focus on the time scales on which different components of these signals are informative about the stimulus, and on the dependencies between different components of these signals. Addressing the first question, we find that stimulus information in low frequency bands (<12 Hz) is high, regardless of whether their energy is computed at the scale of milliseconds or seconds. Stimulus information in higher bands (>50 Hz), in contrast, is scale dependent, and is larger when the energy is averaged over several hundreds of milliseconds. Indeed, combined analysis of signal reliability and information revealed that the energy of slow LFP fluctuations is well related to the stimulus even when considering individual or few cycles, while the energy of fast LFP oscillations carries information only when averaged over many cycles. Addressing the second question, we find that stimulus information in different LFP bands, and in different LFP bands and spiking activity, is largely independent regardless of time scale or sensory system. Taken together, these findings suggest that different LFP bands represent dynamic natural stimuli on distinct time scales and together provide a potentially rich source of information for sensory processing or decoding brain activity.     

Signal integration by the Cpx-envelope stress system

The Cpx-envelope stress system coordinates the expression and assembly of surface structures important for the virulence of Gram-negative pathogenic bacteria. It is comprised of the membrane-anchored sensor kinase CpxA, the cytosolic response regulator CpxR and the accessory protein CpxP. Characteristic of the group of two-component systems, the Cpx system responds to a broad range of stimuli including pH, salt, metals, lipids and misfolded proteins that cause perturbation in the envelope. Moreover, the Cpx system has been linked to inter-kingdom signalling and bacterial cell death. However, although signal specificity has been assumed, for most signals the mechanism of signal integration is not understood. Recent structural and functional studies provide the first insights into how CpxP inhibits CpxA and serves as sensor for misfolded pilus subunits, pH and salt. Here, we summarize and reflect on the current knowledge on signal integration by the Cpx-envelope stress system.     

Attenuation of the responses to repeated cholinergic interventions in the isolated dog atrium

In the isolated, blood-perfused canine right atrium, which was pretreated with propranolol, negative chronotropic and inotropic responses were evoked by stimulation of the intramural parasympathetic nerve fibers or by intra-arterial infusion of acetylcholine (ACh). Successive cholinergic interventions were applied; first, a conditioning intervention for 2 min was given, then this was followed by a test intervention for 4 min. The two interventions were separated by a rest period that varied from 15 to 240 s. The cardiac responses to the conditioning parasympathetic nerve stimulation quickly reached maximum levels, and then they "faded" or progressively diminished back toward the control level. The inotropic responses to the conditioning infusion of ACh (1 microgram/min) faded slightly but the chronotropic response did not. After the rest period, the test nerve stimulation evoked responses that also gradually faded with time. The maximal amplitude of the responses to the test stimuli were less than those to the conditioning stimuli. This reduction in the maximal amplitude of the cardiac responses to the test stimuli was more pronounced with high frequency stimulation (30 Hz) than with low frequency stimulation (5 Hz). The decrement was also more pronounced the shorter the rest period, and it was greater at earlier times after beginning the stimulation. Conversely, the maximal cardiac responses to test infusions of ACh were not appreciably less than the responses to the conditioning infusions. We conclude, therefore, that the diminution of the cardiac responses to the second test stimulation of the parasympathetic nerve fibers was mainly ascribable to a prejunctional rather than to a postjunctional mechanism.     

A study of the complex of vegetative-somatic components during elaboration of the generalized meaning of words]

Characteristics of interrelations in the complex of vegetative-somatic components (cardio-vascular, respiratory and motor) in conditioning to verbal signals denoting action were studied in children aged from one year nine months up to two years six months. The formation of a signal significance of verbal stimuli is accompanied by a progressive rise in the level of synchronous interrelations between vegetative components.     

Raised Middle-Finger: Electrocortical Correlates of Social Conditioning with Nonverbal Affective Gestures

Humans form impressions of others by associating persons (faces) with negative or positive social outcomes. This learning process has been referred to as social conditioning. In everyday life, affective nonverbal gestures may constitute important social signals cueing threat or safety, which therefore may support aforementioned learning processes. In conventional aversive conditioning, studies using electroencephalography to investigate visuocortical processing of visual stimuli paired with danger cues such as aversive noise have demonstrated facilitated processing and enhanced sensory gain in visual cortex. The present study aimed at extending this line of research to the field of social conditioning by pairing neutral face stimuli with affective nonverbal gestures. To this end, electro-cortical processing of faces serving as different conditioned stimuli was investigated in a differential social conditioning paradigm. Behavioral ratings and visually evoked steady-state potentials (ssVEP) were recorded in twenty healthy human participants, who underwent a differential conditioning procedure in which three neutral faces were paired with pictures of negative (raised middle finger), neutral (pointing), or positive (thumbs-up) gestures. As expected, faces associated with the aversive hand gesture (raised middle finger) elicited larger ssVEP amplitudes during conditioning. Moreover, theses faces were rated as to be more arousing and unpleasant. These results suggest that cortical engagement in response to faces aversively conditioned with nonverbal gestures is facilitated in order to establish persistent vigilance for social threat-related cues. This form of social conditioning allows to establish a predictive relationship between social stimuli and motivationally relevant outcomes.     

Neural Correlates of Central Inhibition during Physical Fatigue

Central inhibition plays a pivotal role in determining physical performance during physical fatigue. Classical conditioning of central inhibition is believed to be associated with the pathophysiology of chronic fatigue. We tried to determine whether classical conditioning of central inhibition can really occur and to clarify the neural mechanisms of central inhibition related to classical conditioning during physical fatigue using magnetoencephalography (MEG). Eight right-handed volunteers participated in this study. We used metronome sounds as conditioned stimuli and maximum handgrip trials as unconditioned stimuli to cause central inhibition. Participants underwent MEG recording during imagery of maximum grips of the right hand guided by metronome sounds for 10 min. Thereafter, fatigue-inducing maximum handgrip trials were performed for 10 min; the metronome sounds were started 5 min after the beginning of the handgrip trials. The next day, neural activities during imagery of maximum grips of the right hand guided by metronome sounds were measured for 10 min. Levels of fatigue sensation and sympathetic nerve activity on the second day were significantly higher relative to those of the first day. Equivalent current dipoles (ECDs) in the posterior cingulated cortex (PCC), with latencies of approximately 460 ms, were observed in all the participants on the second day, although ECDs were not identified in any of the participants on the first day. We demonstrated that classical conditioning of central inhibition can occur and that the PCC is involved in the neural substrates of central inhibition related to classical conditioning during physical fatigue.     

Heptahelical terpsichory. Who calls the tune?

The discovery that arrestins can function as ligand-regulated signaling scaffolds has revealed a previously unappreciated level of complexity in G protein-coupled receptor (GPCR) signal transduction. Because arrestin-bound GPCRs are uncoupled from G proteins, arrestin binding can be viewed as switching receptors between two temporally and spatially distinct signaling modes. Recent work has established two factors that underscore this duality of GPCR signaling and suggest it may ultimately have therapeutic significance. The first is that signaling by receptor-arrestin "signalsomes" does not require heterotrimeric G protein activation. The second is that arrestin-dependent signals can be initiated by pathway-specific "biased agonists," creating the potential for drugs that selectively modulate different aspects of GPCR function. Currently, however, little is known about the physiological relevance of G protein-independent signals at the cellular or whole animal levels, and additional work is needed to determine whether arrestin pathway-selective drugs will find clinical application.     

Competition between functional signal peptides demonstrates variation in affinity for the secretion pathway.

We have developed a system for examining the relative affinity of two different signal peptides for the protein secretion pathway in Escherichia coli. This system involves the expression of a modified alkaline phosphatase which possesses two signal peptides arranged in tandem. When both signal peptides have the wild-type sequence, cleavage after the first and cleavage after the second occur with nearly equal frequency. In both cases the remainder of the protein is transported to the periplasm. Thus both signal peptides effectively compete with each other for entrance to the secretion pathway. When the hydrophobicity of the second signal peptide is altered by small increments, we find that the more hydrophobic signal peptide is preferentially utilized. Thus, a more hydrophobic signal peptide can outcompete even an efficient wild-type signal sequence. The crossover point, for utilization of the second to the first signal peptide, is marked and occurs over a very small change in hydrophobicity. Our results suggest that the small differences in the hydrophobicity of wild-type signal peptides may have critical consequences: preproteins with the more hydrophobic signals could dominate one pathway, leaving those with only slightly less hydrophobic signals to require additional factors such as chaperonins, SecB, and other binding proteins.     

Production of tumor necrosis factor by rIFN-gamma-primed C3H/HeJ (Lpsd) macrophages requires the presence of lipid A-associated proteins

Previous studies have shown that the activation of murine macrophages to a fully tumoricidal state requires that specific environmental signals be delivered to the macrophage in a step-wise manner: a "priming" signal first renders the macrophage stimulated, but not cytolytic. The addition of a second or "trigger" signal to the primed macrophage results in tumoricidal activity. One potent priming signal has been identified as IFN-gamma and one often used trigger signal for endotoxin-responsive (Lpsn) macrophages is LPS. In contrast to LPS-responsive macrophage, rIFN-gamma-primed C3H/HeJ (Lpsd) macrophages fail to become cytolytic in response to protein-free, phenol-water-extracted LPS preparations, but become tumoricidal when exposed in vitro to protein-rich butanol-extracted LPS or purified lipid A-associated proteins. Further characterization of the activation requirements of the C3H/HeJ macrophages revealed that for optimal elaboration of TNF in vitro, two signals were also required: rIFN-gamma and a second signal that contained LAP. C3H/HeJ macrophages macrophages primed with rIFN-gamma failed to produce TNF in response to any concentration of protein-free phenol-water extracted LPS, even when supernatants were concentrated before assaying for functional activity in a standard TNF L929 fibroblast assay. Although exposure of rIFN-gamma-primed C3H/HeJ macrophages to LAP resulted in a fully tumoricidal state equivalent to that exhibited by C3H/OuJ macrophages, the levels of TNF produced remained discrepant. Under identical conditions, C3H/OuJ macrophages produced approximately fivefold more TNF (11,776 U/ml) than C3H/HeJ macrophages (2,399 U/ml). This suggests that although C3H/HeJ macrophages can respond functionally in a "normal" manner given the correct signals, they remain quantitatively deficient in the production of certain proteins. In this system, the elaboration of TNF and macrophage-mediated tumor cell lysis were shown to be dissociable events. The tumor target used in these studies (P815) was shown to be resistant to as much as 40,000 U/ml of purified rTNF. In addition, C3H/OuJ macrophage cultures exposed to LPS only (which resulted in the production of high levels of TNF), failed to lyse these targets. Lastly, anti-mouse TNF antibody added to macrophage cultures had no effect on the induction of tumor cell lysis.