The Role of Context Conditioning in the Reinstatement of Responding to an Alcohol-Predictive Conditioned Stimulus

Re-exposure to an unconditioned stimulus (US) can reinstate extinguished conditioned responding elicited by a conditioned stimulus (CS). We tested the hypothesis that the reinstatement of responding to an appetitive CS is driven by an excitatory association formed between the US and the context that the US was ingested in during US re-exposure. Male, Long-Evans rats were acclimated to drinking alcohol (15%, v/v) in the home-cage, then trained to associate an auditory CS with an alcohol-US that was delivered into a fluid port for oral intake. During subsequent extinction sessions, the CS was presented as before, but without alcohol. After extinction, rats were re-exposed to alcohol as in training, but without the CS (US re-exposure). 24 h later at test, the CS was presented as in training, but without alcohol. First, we tested the effect of extinguishing the context-alcohol association, formed during alcohol re-exposure, on reinstatement. Conducting four context extinction sessions across four days (spaced extinction) after the US re-exposure session did not impact reinstatement. However, four context extinction sessions conducted across two days (massed extinction) prevented reinstatement. Next, we conducted alcohol re-exposure in a context that either differed from, or was the same as, the test context. One alcohol re-exposure session in a different context did not affect reinstatement, however, three alcohol re-exposure sessions in a different context significantly reduced reinstatement during the first CS trial. These results partially support the view that a context-US association formed during US re-exposure drives the reinstatement of responding to an appetitive, alcohol-predictive CS.

Investigating the efficacy of the reminder-extinction procedure to disrupt contextual threat memories in humans using immersive Virtual Reality

Upon reactivation, consolidated memories can enter a temporary labile state and require restabilisation, known as reconsolidation. Interventions during this reconsolidation period can disrupt the reactivated memory. However, it is unclear whether different kinds of memory that depend on distinct brain regions all undergo reconsolidation. Evidence for reconsolidation originates from studies assessing amygdala-dependent memories using cue-conditioning paradigms in rodents, which were subsequently replicated in humans. Whilst studies providing evidence for reconsolidation of hippocampus-dependent memories in rodents have predominantly used context conditioning paradigms, studies in humans have used completely different paradigms such as tests for wordlists or stories. Here our objective was to bridge this paradigm gap between rodent and human studies probing reconsolidation of hippocampus-dependent memories. We modified a recently developed immersive Virtual Reality paradigm to test in humans whether contextual threat-conditioned memories can be disrupted by a reminder-extinction procedure that putatively targets reconsolidation. In contrast to our hypothesis, we found comparable recovery of contextual conditioned threat responses, and comparable retention of subjective measures of threat memory, episodic memory and exploration behaviour between the reminder-extinction and standard extinction groups. Our result provide no evidence that a reminder before extinction can prevent the return of context conditioned threat memories in humans.

Conjunctive and Elemental Representations of a Context in Humans

The dual-process theory assumes that contexts are encoded in an elemental and in a conjunctive representation. However, this theory was developed from animal studies, and we still have to explore if and how elemental and conjunctive representations contribute to, for example, contextual anxiety in humans. Therefore, 28 participants underwent differential context conditioning in a newly developed flip-book paradigm. Virtual rooms were presented similar to a flip-book, that is, as a stream of 49 consecutive screenshots creating the impression of walking through the rooms. This allowed registration of event-related brain potentials triggered by specific screenshots. During two acquisition phases, two rooms were shown in this way for six times each. In one room, the anxiety context (CTX+), mildly painful electric stimuli (unconditioned stimuli [USs]) were administered unpredictably after 12 distinct screenshots, which became threat elements, whereas 12 selected comparable screenshots became nonthreat elements (elemental representation); all screenshots represented the anxiety context (conjunctive representation). In the second room, the safety context (CTX−), no USs were applied; thus, all screenshots created the safety context whereby 12 preselected screenshots represented safety elements. Increased US expectancy ratings for threat versus nonthreat or safety elements reflected elemental representation. Conjunctive representation was evident in differential ratings (arousal and contingency) and increased P100 and early posterior negativity amplitudes for threat and nonthreat CTX+ versus safety CTX− screenshots. These differences disappeared during two test phases without US delivery indicating successful extinction. In summary, we revealed the first piece of evidence for the simultaneous contributions of elemental and conjunctive representation during context conditioning in humans.

Human sleep consolidates allergic responses conditioned to the environmental context of an allergen exposure

Allergies are highly prevalent, and allergic responses can be triggered even in the absence of allergens due to Pavlovian conditioning to a specific cue. Here we show in humans suffering from allergic rhinitis that merely reencountering the environmental context in which an allergen was administered a week earlier is sufficient to trigger an allergic response—but only if participants had slept after allergen exposure. This context-conditioning effect was entirely absent when participants stayed awake the night after allergen exposure or were tested in a different context. Unlike in context conditioning, cue conditioning (to an odor stimulus) occurred independently of sleep, a differential pattern that is likewise observed for conditioning in the behavioral domain. Our findings provide evidence that allergic responses can be conditioned to contextual information alone, even after only a single-trial conditioning procedure, and that sleep is necessary to consolidate this rapidly acquired maladaptive response. The results unravel a mechanism that could explain part of the strong psychological impact on allergic responses.

Generalization of Conditioned Contextual Anxiety and the Modulatory Effects of Anxiety Sensitivity

Anxiety patients overgeneralize fear responses, possibly because they cannot distinguish between cues never been associated with a threat (i.e., safe) and threat-associated cues. However, as contexts and not cues are discussed as the relevant triggers for prolonged anxiety responses characterizing many anxiety disorders, we speculated that it is rather overgeneralization of contextual anxiety, which constitutes a risk factor for anxiety disorders. To this end, we investigated generalization of conditioned contextual anxiety and explored modulatory effects of anxiety sensitivity, a risk factor for anxiety disorders. Fifty-five participants underwent context conditioning in a virtual reality paradigm. On Day 1 (acquisition), participants received unpredictable mildly painful electric stimuli (unconditioned stimulus, US) in one virtual office (anxiety context, CTX+), but never in a second office (safety context, CTX−). Successful acquisition of conditioned anxiety was indicated by aversive ratings and defensive physiological responses (i.e., SCR) to CTX+ vs CTX−. On Day 2 (generalization), participants re-visited both the anxiety and the safety contexts plus three generalization contexts (G-CTX), which were gradually dissimilar to CTX+ (from 75 to 25%). Generalization of conditioned anxiety was evident for ratings, but less clear for physiological responses. The observed dissociation between generalization of verbal and physiological responses suggests that these responses depend on two distinct context representations, likely elemental and contextual representations. Importantly, anxiety sensitivity was positively correlated with the generalization of reported contextual anxiety. Thus, this study demonstrates generalization gradients for conditioned contextual anxiety and that anxiety sensitivity facilitates such generalization processes suggesting the importance of generalization of contextual anxiety for the development of anxiety disorders.

Experimental boundary conditions of reinstatement induced return of fear in humans: Is reinstatement in humans what we think it is?

Experimental paradigms used to study reinstatement of fear in humans are characterized by procedural heterogeneity. Reinstatement protocols involve unexpected (re)-presentations of the unconditioned stimulus (USs) after fear extinction training. Here, we address the number of reinstatement USs administered as a potential boundary condition that may explain divergent findings in the field. A sample of 173 participants is exposed to a fear acquisition training, immediate extinction training, and reinstatement test experiment. Three groups differing in the number of reinstatement US are employed: one (n = 57) or four (n = 55) in experimental groups and zero (n = 61) in the control group. We adopt Bayesian statistical approaches beyond classical null hypothesis significance testing to qualify evidence for or against this potential methodological boundary condition in reinstatement-induced return of fear. Both groups exposed to reinstatement USs (RI-USone and RI-USfour) showed increased startle potentiation to the reinstatement administration context as compared to the RI-USzero group, supporting the role of context conditioning in reinstatement. This did however not transfer to responding to conditioned stimuli during the return of fear-test, as no evidence for an effect of the number of reinstatement USs (zero, one, four) was observed in either behavioral or physiological measures. In sum, our results speak against the number of reinstatement USs as a potential boundary condition in experimentally-induced return of fear in humans and may challenge what we think we know about the reinstatement phenomenon in humans and call for a critical reconsideration of paradigms as well as mechanisms that may underlie some reinstatement effects in the literature.