Deficits in acquisition and extinction of conditioned responses in mGluR7 knockout mice

Metabotropic glutamate receptor 7 (mGluR7) is expressed in brain regions implicated in emotional learning and working memory, and previous behavioral experiments indicated contributions of mGluR7 to various complex behaviors. In the present study, we investigated the specific effects of mGluR7 deletion on a variety of conditioning paradigms that model crucial neurocognitive and psychopathological behavioral phenomena. Null-mutant mGluR7^−/− mice displayed defects during scheduled appetitive conditioning, acquisition and extinction of appetitive odor conditioning, extinction of response suppression-based conditioned emotional responding (CER), acquisition of discriminative CER, and contextual fear conditioning. mGluR7^−/− animals were slower to acquire the association between a conditioned stimulus and a positive or negative reinforcer, but eventually reached similar performance levels to their wildtype littermates. Notably, extinction learning of conditioned responses was slower in mGluR7^−/− compared to wildtype animals. The observed delays in the acquisition of complicated stimulus associations across conditioning procedures may suggest a critical role for mGluR7 in neurocognitive functions and psychopathology.     

Non-differential return of fear in humans after a reinstatement procedure

The present experiment investigated reinstatement of fear in humans using a differential fear conditioning preparation. In this experiment, one neutral stimulus (conditioned stimulus; CS+) was paired with an aversive stimulus (unconditioned stimulus; US) during the acquisition phase, while another neutral stimulus was not (CS−). This procedure led to a difference in responding between the CS+ and the CS− (i.e., differential conditioning). After this acquisition phase, an extinction phase followed, during which both CSs were presented without the US, resulting in a decrease in differential conditioned responding. Reinstatement refers to the return of extinguished conditioned responses due to the experience of US-only trials after the extinction phase. This phenomenon was investigated by presenting half of the participants (reinstatement group) with unpredictable USs after the extinction phase. The control group did not receive these USs after the extinction procedure. The results show that return of fear was clearly apparent after the reinstating USs. This return of fear was, however, not limited to the CS+. An increase in ‘conditioned’ responding was also observed for the control stimulus. This interesting observation will be discussed against the background of a number of recent theoretical conceptualizations of reinstatement.     

Reinstatement of extinguished conditioned responses and negative stimulus valence as a pathway to return of fear in humans

The present study investigated reinstatement of conditioned responses in humans by using a differential Pavlovian conditioning procedure. Evidence for reinstatement was established in a direct (fear rating) and in an indirect measure (secondary reaction time task) of conditioning. Moreover, the amount of reinstatement in the secondary reaction time task was significantly correlated with the difference in valence between the conditioned stimulus (CS)+ and the CS-after extinction. These data provide clear evidence for reinstatement and for the role of negative stimulus valence in the return of conditioned responding after extinction.     

Differential acquisition, extinction, and reinstatement of conditioned suppression in mice

In animals, the reappearance of conditioned fear responses after extinction has been primarily investigated using single-cue conditioning paradigms. However, a differential paradigm can overcome several of the disadvantages associated with a single-cue procedure. In the present study, the reinstatement phenomenon was assessed in mice using a differential conditioned suppression paradigm. In a first phase, one conditioned stimulus (CS + ) was consistently paired with an unconditioned stimulus (US; footshock) while another CS (CS-) was not, resulting in selective suppression of previously trained instrumental behaviour during the CS + . After the extinction phase, half of the animals (reinstatement group) were presented with unsignalled USs, while the other half were not (control group). A differential return of conditioned responding was observed in the reinstatement group, but not in the control group. The implications of these findings for future conditioning research are discussed.     

The development of cued versus contextual conditioning in a predictable and an unpredictable human fear conditioning preparation

In this human fear conditioning study, the online development of conditioned US-expectancy to discrete cues and background contexts was measured in two groups. In the paired group (n=30), the CS was systematically followed by an aversive shock (US). In the unpaired group (n=30), CS and US were presented explicitly unpaired. Using US-expectancy ratings, we replicated the basic finding already illustrated in humans with startle modulation. In the paired group, the CS elicited more US-expectancy than the context, whereas in the unpaired group, the context elicited more US-expectancy than the CS. Interestingly, we also observed a trial-by-trial development of conditioning to the context in the unpaired group as indicated by a significant linear trend. This gradual development and the evidence for the role of US-expectancy in contextual fear add to the idea that cued and contextual fear rely on the same basic associative processes.     

Reinstatement of fear responses in human aversive conditioning

The treatment of choice for a number of anxiety disorders is exposure therapy. However, successful reduction of fear through exposure is sometimes followed by a (partial) return of symptoms of fear (return of fear, ROF; Clin. Psychol. Rev. 9 (1989) 147). Several possible learning mechanisms have been suggested to explain ROF (e.g. mechanisms related to spontaneous recovery, renewal, reacquisition and reinstatement). The present study focuses on reinstatement, which refers to the observation that mere US-only presentations can 'reinstate' previously extinguished fear responses. Although animal research has repeatedly demonstrated this phenomenon, little is known about fear reinstatement in humans. The present study employed a differential aversive conditioning procedure: after acquisition and a subsequent extinction procedure, a series of four unpredicted US-only trials was scheduled in the reinstatement group. The control group did not receive additional US presentations. A significant reinstatement effect was observed for US-expectancy ratings and fear ratings in the reinstatement group, but not in the control group. No differences were observed in a reaction time measure of resource allocation to the conditioned stimuli. These findings constitute a first demonstration of reinstatement of conditioned fear responses in humans. Implications for exposure treatment and suggestions for future research are discussed.