Conditioned Aversion Research Articles

Distinct Encoding of Reward and Aversion by Peptidergic BNST Inputs to the VTA.

Neuropeptides play an important role in modulating mesolimbic system function. However, while synaptic inputs to the ventral tegmental area (VTA) have been extensively mapped, the sources of many neuropeptides are not well resolved. Here, we mapped the anatomical locations of three neuropeptide inputs to the VTA: neurotensin (NTS), corticotrophin releasing factor (CRF), and neurokinin B (NkB). Among numerous labeled inputs we identified the bed nucleus of the stria terminalis (BNST) as a major source of all three peptides, containing similar numbers of NTS, CRF, and NkB VTA projection neurons. Approximately 50% of BNST to VTA inputs co-expressed two or more of the peptides examined. Consistent with this expression pattern, analysis of calcium dynamics in the terminals of these inputs in the VTA revealed both common and distinct patterns of activation during appetitive and aversive conditioning. These data demonstrate additional diversification of the mesolimbic dopamine system through partially overlapping neuropeptidergic inputs.

Evaluation of taste aversion learning procedure for the generalization of aversion using palatable foods

An experiment to evaluate the effectiveness of the taste aversion conditioning paradigm in the generalization of aversion with palatable foods was performed. Ten experimentally naive females Wistar rats and three types of foods were used: a) standard purina rodent chow, b) vanilla flavor cookies and c) chocolate-flavored cookies. Subjects were divided into two groups. Using the taste aversion conditioning paradigm protocol, subjects were exposed to the types of food keeping an intake record. The experiment demonstrated that rats can acquire an aversion to palatable foods accompanied by a tendency to generalize, when using elements that share characteristics such as nutritional content and texture. In addition, the intake of a food that does not share the characteristics of texture, taste, smell and energy content with the one used for conditioning was not been affected. These findings indicate that the aversion generalization seems to depend on the properties of the food used.

Probing Neuro-Endocrine Interactions Through Remote Magnetothermal Adrenal Stimulation.

Exposure to stressful or traumatic stimuli may alter hypothalamic-pituitary-adrenal (HPA) axis and sympathoadrenal-medullary (SAM) reactivity. This altered reactivity may be a component or cause of mental illnesses. Dissecting these mechanisms requires tools to reliably probe HPA and SAM function, particularly the adrenal component, with temporal precision. We previously demonstrated magnetic nanoparticle (MNP) technology to remotely trigger adrenal hormone release by activating thermally sensitive ion channels. Here, we applied adrenal magnetothermal stimulation to probe stress-induced HPA axis and SAM changes. MNP and control nanoparticles were injected into the adrenal glands of outbred rats subjected to a tone-shock conditioning/extinction/recall paradigm. We measured MNP-triggered adrenal release before and after conditioning through physiologic (heart rate) and serum (epinephrine, corticosterone) markers. Aversive conditioning altered adrenal function, reducing corticosterone and blunting heart rate increases post-conditioning. MNP-based organ stimulation provides a novel approach to probing the function of SAM, HPA, and other neuro-endocrine axes and could help elucidate changes across stress and disease models.

Evaluating the efficacy of capture as aversive conditioning for American alligators in human‐dominated landscapes

AbstractAs anthropogenic impacts on ecosystems increase, novel solutions are needed to mitigate increasing human–wildlife conflict. Aversive conditioning is one strategy that can reduce the risks of humans living alongside wildlife by modifying the behavior of animals through their experiences with humans. Although considered rare, American alligator (Alligator mississippiensis) attacks on humans most often occur in human‐dominated landscapes and can be fatal. Our goal was to determine if capture and release protocols might serve as a form of aversive conditioning to reduce alligator tolerance of humans. Specifically, we compared the behavioral response of alligators in South Carolina, USA, in 2009–2018 to an approaching human for animals with 3 different levels of capture experience: alligators from a reference site where no captures occurred, alligators from a site where captures occurred that directly experienced capture and release, and alligators from the site where captures occurred that indirectly experienced capture and release (never captured but likely observed capture of others). We used a hurdle model and information‐theoretic approach to evaluate support for 8 hypotheses regarding factors that influence alligator probability of flight in response to an approaching human and the flight initiation distance (FID) of alligators that did flee. Our hypotheses considered the effects of capture experience, exposure to non‐capture (visual) surveys, alligator size, ambient temperature, and season. The best‐supported models provided strong evidence that capture experience increased the probability of flight and, to a lesser extent, increased FID of alligators that did flee, but that the strength of the effect varied with alligator size or some correlate. Furthermore, the effect of capture may extend beyond animals with direct experience. Capture and release protocols can result in an aversive conditioning response in alligators, effectively reducing habituation to humans. Given the geographic limitations of our study, more work is necessary to determine whether the utility of aversive conditioning may be site‐dependent, or similarly effective across a wider selection of developed landscapes.

Honey bees can store and retrieve independent memory traces after complex experiences that combine appetitive and aversive associations.

Real-world experiences often mix appetitive and aversive events. Understanding the ability of animals to extract, store and use this information is an important issue in neurobiology. We used honey bees as model organism to study learning and memory after a differential conditioning paradigm that combines appetitive and aversive training trials. First, we used an aversive conditioning paradigm that constitutes a clear opposite of the well-known appetitive olfactory conditioning of the proboscis extension response. A neutral odour is presented paired with the bitter substance quinine. Aversive memory is evidenced later as an odour-specific impairment in appetitive conditioning. Then, we tested the effect of mixing appetitive and aversive conditioning trials distributed along the same training session. Differential conditioning protocols like this were used previously to study the ability to discriminate odours; however, they were not focused on whether appetitive and aversive memories are formed. We found that after differential conditioning, honey bees establish independent appetitive and aversive memories that do not interfere with each other during acquisition or storage. Finally, we moved the question forward to retrieval and memory expression to evaluate what happens when appetitive and the aversive learned odours are mixed during a test. Interestingly, opposite memories compete in such a way that they do not cancel each other out. Honey bees showed the ability to switch from expressing appetitive to aversive memory depending on their satiation level.

Ludovico’s Technique: The Literary Depiction of Aversion Therapy in ‘A Clockwork Orange’

IntroductionAnthony Burgess’ novel ‘Clockwork Orange’ identifies the topical debates surrounding the use of aversion therapy (or aversive conditioning) as an effective treatment for addictive behaviours. Widely popularised in literature as ‘Ludovico’s Technique’, Burgess attempts to credit the misunderstanding and dramatization of its effects when the main protagonist is released from a prison sentence after undergoing this treatment.ObjectivesWe aimed to highlight the depictions of aversion therapy in modern popular literature.MethodsA narrative review of the current literature concerning aversion therapy and Anthony Burgess’s novel ‘A Clockwork Orange’ was conducted. Emphasis on the misinterpretation of aversive therapies was noted.Results Since the introduction of pharmacological alternatives and additional forms of psychological therapies, there has been a decline in the use of aversion therapy in recent decades. However, it is still effective when conceding the conditioning process. Likewise, its predecessor’ visual imagery’ is believed to be a more acceptable and effective form.Conclusions The depiction of aversion therapy in literature and media has played a role in shaping societal views on aversive conditioning techniques and the degree to which they are deemed acceptable forms of treatment. The “Ludovico Technique” featured in the novel ‘A Clockwork Orange’ and its film adaptation is arguably the most salient depiction of aversion therapy in popular culture.DisclosureNo significant relationships.

Conditional Regulation of Blood Pressure in Response to Emotional Stimuli by the Central Nucleus of the Amygdala in Rats.

Humans and animals can determine whether a situation is favorable to them and act accordingly. For this, the autonomic tuning of the cardiovascular system to supply energy to active skeletal muscles through the circulatory system is as important as motor control. However, how the autonomic cardiovascular responses are regulated in dynamically changing environments and the neuronal mechanisms underlying these responses remain unclear. To resolve these issues, we recorded the blood pressure and heart rate of head-restrained rats during dynamically changing appetitive and aversive classical conditioning tasks. The rats displayed various associations between conditioned stimuli and unconditioned stimuli in appetitive (sucrose water), neutral (no outcome), and aversive (air puff) blocks. The blood pressure and heart rate in the appetitive block gradually increased in response to the reward-predicting cue and the response to the actual reward vigorously increased. The reward-predictive response was significantly higher than the responses obtained in the neutral and aversive condition blocks. To investigate whether the reward-predictive pressor response was caused by orofacial movements such as anticipatory licking behavior, we separately analyzed high- and low-licking trials. The conditioned pressor response was observed even in trials with low-licking behaviors. Blood pressure and heart rate responses to the air puff-predicting cue in the aversive block were not significantly different from the responses in the neutral block. The conditioned blood pressure response rapidly changed with condition block switching. Furthermore, to examine the contribution of the amygdala as an emotion center to these conditioned responses, we bilaterally microinjected a GABAA receptor agonist, muscimol, into the central nucleus of the amygdala. Pharmacological inactivation of the central nucleus of the amygdala significantly decreased the reward-predictive pressor responses. These results suggest that the blood pressure is adaptively and rapidly regulated by emotional conditioned stimuli and that the central nucleus of the amygdala participates in regulating the pressor response in dynamically changing situations.

A Subregion of Insular Cortex Is Required for Rapid Taste-Visceral Integration and Consequent Conditioned Taste Aversion and Avoidance Expression in Rats.

Postingestive signals are important for shaping appetitive and consummatory responses, but the brain mechanisms required to assimilate interoceptive events with those at the frontlines of ingestion (taste-guided) are poorly understood. Here, we investigated whether an insular cortex (IC) region, which receives viscerosensory input, including gustatory, is required to modify taste-elicited consummatory reactions in response to a real-time interoceptive change using a serial taste reactivity (TR) test where the rats’ oromotor and somatic reactions to intraoral (IO) infusions of sucrose were periodically assessed over 45 min following lithium chloride (LiCl) administration. Results showed that neurally-intact rats shifted from an ingestive repertoire to an aversive one as LiCl took effect. Overall, this hedonic shift was delayed in rats with bilateral neurotoxic IC lesions. Rats with greater neuronal loss in posterior gustatory IC displayed fewer aversive reactions to sucrose following this initial LiCl injection. We further assessed whether the failure to integrate interoceptive feedback with ongoing taste-guided behavior impaired acquisition and/or expression of conditioned aversion and/or avoidance in these same rats. Although, as a group, LiCl-injected rats with IC lesions subsequently avoided the sugar in a 48-h two-bottle test, their preference for sucrose was significantly greater than that of the LiCl-injected neurally-intact rats. Overall lesion size, as well as proportion of the posterior gustatory and/or anterior visceral IC were each associated with impaired avoidance. These findings reveal new roles for the posterior gustatory and anterior visceral ICs in multisensory integrative function.

Phasic and Tonic Locus Coeruleus Stimulation Associated Valence Learning Engages Distinct Adrenoceptors in the Rat Basolateral Amygdala.

Reward exploitation and aversion are mediated in part by the locus coeruleus (LC), a brainstem structure significantly involved in learning and memory via the release of norepinephrine. Different LC firing patterns are associated with different functions. Previously, we have shown that high tonic and phasic LC activation signal negative and positive valence, respectively, via basolateral amygdala (BLA) circuitry. Tonic LC activation is associated preferentially with BLA-central amygdala (CeA) activation, while phasic LC stimulation preferentially recruits the BLA-nucleus accumbens (NAc) pathway. Here, we ask if phasic and tonic LC activation-associated valence learning requires different adrenoceptors in the BLA, in comparison with the odor valence learning induced by natural reward and aversive conditioning. Using optogenetic activation of the LC and local drug infusions in the BLA, we show that phasic LC activation-induced positive odor valence learning is dependent on both α1 and β-adrenoceptors, whereas tonic LC activation induced-negative odor valence learning depends on β-adrenoceptors only. In parallel, both α1 and β-adrenoceptors were required in the odor valence learning induced by reward while aversive conditioning was dependent on β-adrenoceptors. Phasic stimulation and reward conditioning likewise activated more NAc-projectors of the BLA, in comparison to tonic and aversive conditioning. There was a higher proportion of α1+ cells in the NAc-projectors compared to CeA-projectors in the BLA. Together, these results provide insight into the mechanisms underlying the effects of tonic and phasic activation of the LC, and more generally, negative and positive valence signaling.

Aversive conditioning: Principles of memory storage in sensory cortex

Sensory cortices exhibit plasticity after aversive learning and may have a crucial role in memory storage. A human neuroimaging study has now addressed neural principles underlying olfactory disgust conditioning.

Maternal stress, child behavior and the promotive role of older siblings

BackgroundIn the first years of their lives, children develop the cognitive, social and emotional skills that will provide the foundations for their lifelong health and achievements. To increase their life prospects and reduce the long-term effects of early aversive conditions, it is therefore crucial to understand the risk factors that negatively affect child development and the factors that are instead beneficial. In this study, we tested (i) the effects of different social and environmental stressors on maternal stress levels, (ii) the dynamic relationship between maternal stress and child behavior problems during development, and (iii) the potential promotive (i.e. main) or protective (i.e. buffering) effect of siblings on child behavior problems during development.MethodsWe used longitudinal data from 373 mother–child pairs (188 daughters, 185 sons) from pregnancy until 10 years of age. We assessed maternal stress and child behavior problems (internalizing and externalizing) with validated questionnaires, and then used linear mixed models, generalized linear mixed models and longitudinal cross-lagged models to analyze the data.ResultsOur results showed that higher maternal stress levels were predicted by socio-environmental stressors (i.e. the lack of sufficient social areas in the neighborhood). Moreover, prenatal maternal stress reliably predicted the occurrence of behavior problems during childhood. Finally, the presence of older siblings had a promotive function, by reducing the likelihood that children developed externalizing problems.ConclusionsOverall, our results confirm the negative effects that maternal stress during pregnancy may have on the offspring, and suggest an important main effect of older siblings in promoting a positive child development.

Countercontrol: A Relational Frame Theory (RFT) Account and Revival of a 70-Year-Old Skinnerian Term.

Countercontrol is a Skinnerian operant concept that posits that an individual’s attempts to exert control over another person’s behavior may evoke a countercontrolling response from the person being controlled that functions to avoid or escape the potentially aversive conditions generated by the controller. Despite Skinner’s historical concerns regarding the detrimental effects of countercontrol in terms of hindering optimal societal growth and cultural evolution, the concept has not been widely applied within behavior analysis. Drawing from recent developments in rule-governed behavior and relational frame theory, this article seeks to explicate countercontrol from a contemporary behavior analytic perspective and presents several modern-day societal applications. In particular, a relational frame theory account of rule-governed behavior is used as a framework to elucidate the behavioral processes by which rule-following occurs (or fails to occur) in the context of countercontrol. Implications of a renewed focus on countercontrol for understanding pressing societal issues are also discussed.

P107. The Role of Dopamine in Passive Aversive Conditioning – a Systematic Review

Research into the involvement of dopamine (DA) in passive aversive conditioning has exploded in the past three decades. However, to date, a systematic review of studies measuring or manipulating DA during fear conditioning does not exist. The objectives of this review were to compile the available data on DA measurements and manipulations during various phases of fear conditioning then to formulate data-driven conclusions and future hypotheses on this topic.

Sex Differences in the Spatial Behavior Functions of Adult-Born Neurons in Rats.

Adult neurogenesis modifies hippocampal circuits and behavior, but removing newborn neurons does not consistently alter spatial processing, a core function of the hippocampus. Additionally, little is known about sex differences in neurogenesis since few studies have compared males and females. Since adult-born neurons regulate the stress response, we hypothesized that spatial functions may be more prominent under aversive conditions and may differ between males and females given sex differences in stress responding. We therefore trained intact and neurogenesis-deficient rats in the spatial water maze at temperatures that vary in their degree of aversiveness. In the standard water maze, ablating neurogenesis did not alter spatial learning in either sex. However, in cold water, ablating neurogenesis had divergent sex-dependent effects: relative to intact rats, male neurogenesis-deficient rats were slower to escape the maze and female neurogenesis-deficient rats were faster. Neurogenesis promoted temperature-related changes in search strategy in females, but it promoted search strategy stability in males. Females displayed greater recruitment (Fos expression) of the dorsal hippocampus than males, particularly in cold water. However, blocking neurogenesis did not alter Fos expression in either sex. Finally, morphologic analyses revealed greater experience-dependent plasticity in males. Adult-born neurons in males and females had similar morphology at baseline but training increased spine density and reduced presynaptic terminal size, specifically in males. Collectively, these findings indicate that adult-born neurons contribute to spatial learning in stressful conditions and they provide new evidence for sex differences in their behavioral functions.

Alpha-band EEG suppression as a neural marker of sustained attentional engagement to conditioned threat stimuli.

Attention helps us to be aware of the external world, and this may be especially important when a threat stimulus predicts an aversive outcome. Electroencephalogram (EEG) alpha-band suppression has long been considered as a neural signature of attentional engagement. The present study was designed to test whether attentional engagement, as indexed by alpha-band suppression, is increased in a sustained manner following a conditioned stimulus (CS) that is paired with an aversive (CS+) vs neutral (CS-) outcome. We tested 70 healthy young adults in aversive conditioning and extinction paradigms. One of three colored circles served as the CS+, which was paired in 50% of the trials with a noise burst (unconditioned stimulus, US). The other colored circles (CS-) were never paired with the US. For conditioning, we found greater alpha-band suppression for the CS+ compared to the CS-; this suppression was sustained through the time of the predicted US. This effect was significantly reduced for extinction. These results indicate that conditioned threat stimuli trigger an increase in attentional engagement as subjects monitor the environment for the predicted aversive stimulus. Moreover, this alpha-band suppression effect may be valuable for future studies examining normal or pathological increases in attentional monitoring following threat stimuli.

Avoidance of neonicotinoid-treated seeds and cotyledons by captive eared doves (Zenaida auriculata, Columbidae)

Farmland birds can be exposed to neonicotinoids through the ingestion of treated unburied seeds and cotyledons. The aim of this study was to evaluate the avoidance of sorghum with imidacloprid, clothianidin or thiamethoxam, soybean with imidacloprid, and soybean cotyledons with imidacloprid or thiamethoxam on eared doves (Zenaida auriculata). Doves were fed with test food (untreated and neonicotinoid-treated sorghum, soybean or soybean cotyledons) and maintenance food (seed mix) for 3–5 days to study the repellency (primary repellency and conditioned aversion) and anorexia caused by neonicotinoid-treated food, followed by a 7-day period on maintenance food to study the persistence of the anorexic effect after neonicotinoid exposure. Immediately afterward, the same doves were exposed to treated test food during a second period of 3–5 days to study the potential reinforcement of food avoidance. Finally, doves were fed with untreated test food to test the capacity of the pesticide to induce conditioned food aversion against untreated food in subsequent encounters. Intoxication signs and differences of body weight were determined. With sorghum, the three neonicotinoids produced a decrease in the consumption of treated seeds by >97% compared to control birds. However, this was not enough to prevent the death of 3/8 and 1/8 of the doves exposed to imidacloprid and clothianidin, respectively. Anorexia was clearly observed with neonicotinoid-treated sorghum. The birds did not avoid the untreated sorghum after exposure to the treated sorghum, indicating that avoidance is not generalized to the type of food without an associated sensory cue. The results obtained with soybean seeds and cotyledons were less conclusive because captive doves hardly consumed these foods, even without neonicotinoid treatment. The avoidance of sorghum seeds treated with neonicotinoids was insufficient to prevent poisoning and death of eared doves.

Memory retention of conditioned aversion training in New Zealand's alpine parrot, the kea

AbstractNew Zealand pest control operations commonly deploy toxic sodium fluoroacetate (1080) baits to control introduced mammalian predators and protect vulnerable native fauna, yet the highly intelligent kea (Nestor notabilis) is at risk of mortality following ingestion of toxic baits intended for their protection. We tested the retention of conditioned aversion in 11 captive kea that had learned to avoid baits containing the bird repellent anthraquinone alongside color, olfactory, and taste cues. We revisited kea over increasing time intervals (3 days, 5 weeks, 3 months, 6 months, and 1 yr) offering them otherwise identical non‐repellent baits. Kea retained their aversion until the final session, 1 year after previous exposure to reinforcement, and almost 2 years since previous exposure to repellent. Whether the kea forgot their aversion or the repeated exposures to non‐repellent baits resulted in extinction of the aversion, our results indicate that kea are capable of remembering an aversion for long enough to be of practical use to conservation managers in reducing kea mortality through 1080 operations.

Octopaminergic neurons function in appetitive but not aversive olfactory learning and memory in Bactrocera dorsalis.

The biogenic amine octopamine (OA, invertebrate counterpart of noradrenaline) plays critical roles in the regulation of olfactory behavior. Historically, OA has been thought to mediate appetitive but not aversive learning in honeybees, fruit flies (Drosophila), and crickets. However, this viewpoint has recently been challenged because OA activity through a β-adrenergic-like receptor drives both appetitive and aversive learning. Here, we explored the roles of OA neurons in olfactory learning and memory retrieval in Bactrocera dorsalis. We trained flies to associate an orange odor with a sucrose reward or to associate methyl eugenol, a male lure, with N,N-diethyl-3-methyl benzoyl amide (DEET) punishment. We then treated flies with OA receptor antagonists before appetitive or aversive conditioning and a memory retention test. Injection of OA receptor antagonist mianserin or epinastine into the abdomen of flies led to impaired of appetitive learning and memory retention with a sucrose reward, while aversive learning and memory retention with DEET punishment remained intact. Our results suggest that the OA signaling participates in appetitive but not aversive learning and memory retrieval in B. dorsalis through OA receptors.

High trait anxiety blocks olfactory plasticity induced by aversive learning

Aversive learning normally induces alterations in sensory function as the brain’s sensory systems are tuned to optimize detection and discrimination of threat-predictive stimuli. Anxiety disorders can disrupt behavioral discrimination between threat-predictive and neutral stimuli, resulting in overgeneralization of negative affective responses to non-threatening situations. We thus hypothesized that anxiety could disrupt learning-induced improvement in sensory discrimination. We tested perceptual discrimination between similar odorants before and after discriminative aversive conditioning. Participants exhibiting normal levels of trait anxiety developed a larger skin conductance response (SCR) to the shock-predictive odorant and substantial improvement in their perceptual discrimination between the two odors. Repeated exposure to the odors without shock partially extinguished the SCRs but the perceptual effect persisted. By contrast, participants with high levels of trait anxiety developed comparably sized SCRs to both odors and displayed no perceptual improvement. Learning-induced perceptual plasticity can thus be impaired in people with high levels of trait anxiety.

Strong Aversive Conditioning Triggers a Long-Lasting Generalized Aversion.

Generalization is an adaptive mnemonic process in which an animal can leverage past learning experiences to navigate future scenarios, but overgeneralization is a hallmark feature of anxiety disorders. Therefore, understanding the synaptic plasticity mechanisms that govern memory generalization and its persistence is an important goal. Here, we demonstrate that strong CTA conditioning results in a long-lasting generalized aversion that persists for at least 2 weeks. Using brain slice electrophysiology and activity-dependent labeling of the conditioning-active neuronal ensemble within the gustatory cortex, we find that strong CTA conditioning induces a long-lasting increase in synaptic strengths that occurs uniformly across superficial and deep layers of GC. Repeated exposure to salt, the generalized tastant, causes a rapid attenuation of the generalized aversion that correlates with a reversal of the CTA-induced increases in synaptic strength. Unlike the uniform strengthening that happens across layers, reversal of the generalized aversion results in a more pronounced depression of synaptic strengths in superficial layers. Finally, the generalized aversion and its reversal do not impact the acquisition and maintenance of the aversion to the conditioned tastant (saccharin). The strong correlation between the generalized aversion and synaptic strengthening, and the reversal of both in superficial layers by repeated salt exposure, strongly suggests that the synaptic changes in superficial layers contribute to the formation and reversal of the generalized aversion. In contrast, the persistence of synaptic strengthening in deep layers correlates with the persistence of CTA. Taken together, our data suggest that layer-specific synaptic plasticity mechanisms separately govern the persistence and generalization of CTA memory.