Pain is aversive, but does the cessation of pain (‘relief’) have a reward-like effect? Indeed, fruitflies avoid an odour previously presented before a painful event, but approach an odour previously presented after a painful event. Thus, event-timing may turn punishment to reward. However, is event-timing also crucial in humans who can have explicit cognitions about associations? Here, we show that stimuli associated with pain-relief acquire positive implicit valence but are explicitly rated as aversive. Specifically, the startle response, an evolutionarily conserved defence reflex, is attenuated by stimuli that had previously followed a painful event, indicating implicit positive valence of the conditioned stimulus; nevertheless, participants explicitly evaluate these stimuli as ‘emotionally negative’. These results demonstrate a rift between the implicit and explicit conditioned valence induced by pain relief. They might explain why humans in some cases are attracted by conditioned stimuli despite explicitly judging them as negative.

Memories relating to a painful, negative event are adaptive and can be stored for a lifetime to support preemptive avoidance, escape, or attack behavior. However, under unfavorable circumstances such memories can become overwhelmingly powerful. They may trigger excessively negative psychological states and uncontrollable avoidance of locations, objects, or social interactions. It is therefore obvious that any process to counteract such effects will be of value. In this context, we stress from a basic-research perspective that painful, negative events are "Janus-faced" in the sense that there are actually two aspects about them that are worth remembering: What made them happen and what made them cease. We review published findings from fruit flies, rats, and man showing that both aspects, respectively related to the onset and the offset of the negative event, induce distinct and oppositely valenced memories: Stimuli experienced before an electric shock acquire negative valence as they signal upcoming punishment, whereas stimuli experienced after an electric shock acquire positive valence because of their association with the relieving cessation of pain. We discuss how memories for such punishment-and relief-learning are organized, how this organization fits into the threat-imminence model of defensive behavior, and what perspectives these considerations offer for applied psychology in the context of trauma, panic, and nonsuicidal self-injury.The acknowledged "negative" mnemonic effects of adverse experiences mostly relate to what happens before the onset of an aversive, painful event. However, there is a less widely acknowledged type of memory that relates to what happens after the offset of or after escape from such a painful event, at the moment of "relief" (Fig. 1) (we use "relief" to refer specifically to the acute effects of punishment offset; an equally legitimate yet broader use of the word in, e.g., "fear relief," encompasses any process that eases fear [Riebe et al. 2012]). Indeed, in experimental settings, it turns out that stimuli experienced before and during a punishing episode are later avoided as they signal upcoming punishment, whereas stimuli experienced after a painful episode can subsequently prompt approach behavior, arguably (Box 1) because of their association with the relieving cessation of pain (Konorski 1948;Smith and Buchanan 1954;Wolpe and Lazarus 1966;Zanna et al. 1970;Solomon and Corbit 1974;Schull 1979;Solomon 1980;Wagner 1981;Walasek et al. 1995;Tanimoto et al. 2004;Yarali et al. 2008Yarali et al. , 2009bAndreatta et al. 2010Andreatta et al. , 2012Yarali and Gerber 2010;Ilango et al. 2012;Navratilova et al. 2012;Diegelmann et al. 2013b); for a corresponding finding in the appetitive domain, see Hellstern et al. (1998) andFelsenberg et al. (2013). Such relief can both support the learning of the cues associated with the disappearance of the threat and reinforce those behaviors that helped to escape it. Obviously, the positive conditioned valence of and ensuing learned approach behavi...

Two things are worth remembering about an aversive event: What made it happen? What made it cease? If a stimulus precedes an aversive event, it becomes a signal for threat and will later elicit behavior indicating conditioned fear. However, if the stimulus is presented upon cessation of the aversive event, it elicits behavior indicating conditioned "relief." What are the neuronal bases for such learning? Using functional magnetic resonance imaging (fMRI) in humans we found that a fearconditioned stimulus activates amygdala but not striatum, whereas a relief-conditioned stimulus activates striatum but not amygdala. Correspondingly, acute inactivation of amygdala or of ventral striatum in rats respectively abolished only conditioned fear or only conditioned relief. Thus, the behaviorally opponent memories supported by onset and offset of aversive events engage and require fear and reward networks, respectively. This may explain attraction to stimuli associated with the cessation of trauma or of panic attacks. [Supplemental material is available for this article.]We avoid pain and seek reward. To this end, stimuli can become associated with these respective salient events (Pavlov 1927). For example, if a visual stimulus is repeatedly followed by an electric shock, it will be learned as a threat and will elicit conditioned fear. A behavioral indicator of such conditioned fear in humans and other mammals is increased "jumpiness" measured as an increased startle response in the presence of the learned stimulus (Davis et al. 1993;Fendt and Fanselow 1999;Grillon and Baas 2003). The neuronal basis of such conditioned fear and the crucial involvement of the amygdala is well examined in humans and rodents (Davis et

Opportunistic infections are common in HIV-infected patients; they activate HIV replication and contribute to disease progression. In the present study we examined the role of Toll-like receptor 2 (TLR2) and TLR9 in HIV-long terminal repeat (HIV-LTR) trans-activation and assessed whether TLR4 synergized with TLR2 or TLR9 to induce HIV replication. Soluble Mycobacterium tuberculosis factor (STF) and phenol-soluble modulin from Staphylococcus epidermidis induced HIV-LTR trans-activation in human microvessel endothelial cells cotransfected with TLR2 cDNA. Stimulation of ex vivo spleen cells from HIV-1 transgenic mice with TLR4, TLR2, and TLR9 ligands (LPS, STF, and CpG DNA, respectively) induced p24 Ag production in a dose-dependent manner. Costimulation of HIV-1 transgenic mice spleen cells with LPS and STF or CpG DNA induced TNF-α and IFN-γ production in a synergistic manner and p24 production in an additive fashion. In the THP-1 human monocytic cell line stably expressing the HIV-LTR-luciferase construct, LPS and STF also induced HIV-LTR trans-activation in an additive manner. This is the first time that TLR2 and TLR9 and costimulation of TLRs have been shown to induce HIV replication. Together these results underscore the importance of TLRs in bacterial Ag- and CpG DNA-induced HIV-LTR trans-activation and HIV replication. These observations may be important in understanding the role of the innate immune system and the molecular mechanisms involved in the increased HIV replication and HIV disease progression associated with multiple opportunistic infections.

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Gustatory stimuli have at least 2 kinds of function: They can support immediate, reflexive responses (such as substrate choice and feeding) and they can drive internal reinforcement. We provide behavioral analyses of these functions with respect to sweet taste in larval Drosophila. The idea is to use the dose–effect characteristics as behavioral “fingerprints” to dissociate reflexive and reinforcing functions. For glucose and trehalose, we uncover relatively weak preference. In contrast, for fructose and sucrose, preference responses are strong and the effects on feeding pronounced. Specifically, larvae are attracted to, and feeding is stimulated most strongly for, intermediate concentrations of either sugar: Using very high concentrations (4 M) results in weakened preference and suppression of feeding. In contrast to such an optimum function regarding choice and feeding, an asymptotic dose–effect function is found for reinforcement learning: Learning scores reach asymptote at 2 M and remain stable for a 4-M concentration. A similar parametric discrepancy between the reflexive (choice and feeding) and reinforcing function is also seen for sodium chloride (Niewalda T, Singhal S, Fiala A, Saumweber T, Wegener S, Gerber B, in preparation). We discuss whether these discrepancies are based either on inhibition from high-osmolarity sensors upon specifically the reflexive pathways or whether different sensory pathways, with different effective dose–response characteristics, may have preferential access to drive either reflex responses or modulatory neurons mediating internal reinforcement, respectively.

An experience with electric shock can support two opposing kinds of behavioral effects: Stimuli that precede shock during training are subsequently avoided as predictors for punishment, whereas stimuli that follow shock during training are later on approached, as they predict relief. We show here, for the fruit fly Drosophila, that upon the loss of white-function, the balance between these two kinds of learning is distorted in favor of punishment learning: white 1118 mutants show stronger punishment learning and weaker relief learning, as compared to wild type flies. Thus, white 1118 mutants establish, overall, more ''negative'' memories for the shock experience. This only concerns the mnemonic effects of the shock; the immediate, reflexive responsiveness to shock remains unaltered. Also, learning about reward is apparently unaffected, both in adult and larval Drosophila. Prompted by the proposed function of the White protein as the transporter for biogenic amine precursors, we probed the brains of white 1118 mutants for the amounts of biogenic amines (octopamine, tyramine, dopamine, and serotonin) by using high-pressure liquid chromatography coupled to mass spectrometry. Using this method, we found, however, no difference between white 1118 and wild type flies for any of the probed amines. In any event, analyses of how the white 1118 mutation affects the balance between punishment and relief learning should provide a study case of how heritable distortions of such balance can come about. Finally, the effects of the white 1118 mutation should be considered as a source of confound when using white-as the ''marker gene'' in behavior-genetic analyses of any sort.

Animals' behaviour towards odours depends on both odour quality and odour intensity. While neuronal coding of odour quality is fairly well studied, how odour intensity is treated by olfactory systems is less clear. Here we study odour intensity processing at the behavioural level, using the fruit fly Drosophila melanogaster. We trained flies by pairing a MEDIUM intensity of an odour with electric shock, and then, at a following test phase, measured flies' conditioned avoidance of either this previously trained MEDIUM intensity or a LOWer or a HIGHer intensity. With respect to 3-octanol, n-amylacetate and 4-methylcyclohexanol, we found that conditioned avoidance is strongest when training and test intensities match, speaking for intensity-specific memories. With respect to a fourth odour, benzaldehyde, on the other hand, we found no such intensity specificity. These results form the basis for further studies of odour intensity processing at the behavioural, neuronal and molecular level.