Extinction of conditioned defensive burying

Cerebellum (CB) interactions with forebrain systems contribute to learning cognitive and motor tasks, but the nature of these interactions is unknown. Trace eyeblink conditioning (EBC) is an excellent associative learning paradigm for examining interactions between forebrain systems and CB. The anterior cingulate cortex (ACC), central amygdala (AM), and CB are essential for trace EBC, and we previously recorded changes in neuronal activity in these areas during learning with paired presentations of the conditional stimulus (CS) and unconditional stimulus (US). We attributed changes in activity to learning CS-US contingency but did not report contingency manipulations. Here, we analyzed data from the same rats of both sexes during sessions with transitions from CS-US (paired) trials to CS-alone (extinction) trials and from CS-alone trials to CS-US trials. All three areas showed changes in activity with changes in contingency, during both stimuli and the intertrial interval (ITI). Subsets of ACC, AM, and CB neurons showed higher activity during paired trials, while others showed higher activity during extinction trials both during trial events and ITI. Within- and between-area neuronal synchrony and machine learning predictions of behavior from neuronal activity decreased during extinction trials relative to paired trials, indicating widespread effects of contingency change on the ACC-AM-CB network. The findings suggest that the ACC-AM-CB network encodes both within-trial stimulus contingency and between-trial task context. The transition from paired to extinction trials may decrease mossy fiber input consistency to CB from ACC and AM and decrease the likelihood of CRs.

A single experience of respiratory paralysis can be used to establish a conditioned response (CR) to a hitherto neutral stimulus. Respiratory paralysis to those undergoing it is horrific but not painful. The CR does not extinguish but becomes stronger as time passes despite repeated extinction trial

Accelerated life tests (ALTs) are used to make timely assessments of the life time distribution of highly reliable materials and components. Much of the previous work on ALTs has focused on constant-stress, step-stress, ramp-stress schemes and their various combinations. In the literature ramp-stress ALTs that have been formulated can be conducted when more than one test chambers are available; installation of which may prove to be costly. Even when one test chamber is used the stress rate remains constant throughout the duration of the experiment. It is not only necessary but imperative to examine if the test specimen is able to withstand differing stress conditions with the passage of time. This paper therefore, presents an optimal design of multi-objective modified ramp-stress ALT model with weighted goal programming approach. The modified ramp-stress uses one test chamber in place of the various chambers used in simple ramp-stress ALT thus saving experimental cost. With the market being increasingly competitive the emphasis today is on goal attainment with minimum deviations. Goal programming is a method to solve multi-objective problems that has applications in varied fields of engineering and operational research. The optimal plan consists in finding out relevant experimental variables, namely, stress rate, stress rate change point and warranty period, by using goal programming on weighted sum of variance of reliability function and expected warranty cost with pre-specified mission time under normal operating conditions. The Burr type XII life distribution and time-censored data have been used for the purpose. Burr type XII life distribution has been found appropriate for accelerated life testing experiments. The method developed has been explained using a numerical example and sensitivity analysis carried out. Comparative study has also been done to highlight the merits of the proposed model.

Qualitative properties of a niche-model

Toxin-induced conditioned disgust responses: Comparing emetine and scopolamine methyl nitrate (SMN) to lithium chloride (LiCl).

Differential involvement of medial prefrontal cortex and basolateral amygdala extracellular signal-regulated kinase in extinction of conditioned taste aversion is dependent on different intervals of extinction following conditioning

Extinction is a specific example of learning where a previously reinforced stimulus or response is no longer reinforced, and the previously learned behaviour is no longer necessary and must be modified. Current theories suggest extinction is not the erasure of the original learning but involves new learning that acts to suppress the original behaviour. Evidence for this can be found when the original behaviour recovers following the passage of time (spontaneous recovery) or reintroduction of the reinforcement (i.e. reinstatement). Recent studies have shown that pharmacological manipulation of noradrenaline (NA) or its receptors can influence appetitive extinction; however, the role and source of endogenous NA in these effects are unknown. Here, we examined the role of the locus coeruleus (LC) in appetitive extinction. Specifically, we tested whether optogenetic stimulation of LC neurons during extinction of a food-seeking behaviour would enhance extinction evidenced by reduced spontaneous recovery in future tests. LC stimulation during extinction trials did not change the rate of extinction but did serve to reduce subsequent spontaneous recovery, suggesting that stimulation of the LC can augment reward-related extinction. Optogenetic inhibition of the LC during extinction trials reduced responding during the trials where it was applied, but no long-lasting changes in the retention of extinction were observed. Since not all LC cells expressed halorhodopsin, it is possible that more complete LC inhibition or pathway-specific targeting would be more effective at suppressing extinction learning. These results provide further insight into the neural basis of appetitive extinction, and in particular the role of the LC. A deeper understanding of the physiological bases of extinction can aid development of more effective extinction-based therapies.

Extinction is a specific example of learning where a previously reinforced stimulus or response is no longer reinforced, and the previously learned behaviour is no longer necessary and must be modified. Current theories suggest extinction is not the erasure of the original learning but involves new learning that acts to suppress the original behaviour. Evidence for this can be found when the original behaviour recovers following the passage of time (spontaneous recovery) or reintroduction of the reinforcement (i.e. reinstatement). Recent studies have shown that pharmacological manipulation of noradrenaline (NA) or its receptors can influence appetitive extinction; however, the role and source of endogenous NA in these effects are unknown. Here, we examined the role of the locus coeruleus (LC) in appetitive extinction. Specifically, we tested whether optogenetic stimulation of LC neurons during extinction of a food-seeking behaviour would enhance extinction evidenced by reduced spontaneous recovery in future tests. LC stimulation during extinction trials did not change the rate of extinction but did serve to reduce subsequent spontaneous recovery, suggesting that stimulation of the LC can augment reward-related extinction. Optogenetic inhibition of the LC during extinction trials reduced responding during the trials where it was applied, but no long-lasting changes in the retention of extinction were observed. Since not all LC cells expressed halorhodopsin, it is possible that more complete LC inhibition or pathway-specific targeting would be more effective at suppressing extinction learning. These results provide further insight into the neural basis of appetitive extinction, and in particular the role of the LC. A deeper understanding of the physiological bases of extinction can aid development of more effective extinction-based therapies.

Many diverse species have demonstrated interval timing, the ability to respond appropriately to time in the range of seconds to minutes, suggesting that an ability to time is adaptive. The peak procedure is a common method of studying interval time perception. In the peak procedure, animals experience a mix of fixed-interval (FI) and extinction (EXT) trials. On EXT trials, responding typically increases to a peak at the time the FI schedule would normally deliver reinforcers before decreasing. Responding on different FI schedules within the peak procedure has been found to conform to Weber's law, whereby response variability is proportional to the length of the fixed interval. We conducted possibly the first investigation of the timing abilities of a marsupial common to Australia and New Zealand, the brushtail possum (Trichosurus vulpecula), using FI 15-, 30-, and 60-s schedules of reinforcement in the peak procedure. Response rates on EXT trials peaked at the time of usual reinforcer delivery, decreasing at longer time intervals, and were well fit by 3-parameter Gaussian curves, demonstrating the ability of possums to respond to time-based stimuli. Coefficients of variation suggested that the ability of possums to time was less accurate than that of mammals, but similar to that of birds, invertebrates, and reptiles. Coefficients of variation did not differ consistently over increasing FI intervals, showing that timing responses of possums likely conforms to the scalar property of timing also shown by other species. (PsycINFO Database Record

In honeybees, the proboscis extension response (PER) can be conditioned by associating an odor stimulus (CS) to a sucrose reward (US). Conditioned responses to the CS, which are acquired by most bees after a single CS-US pairing, disappear after repeated unrewarded presentations of the CS, a process called extinction. Extinction is usually thought to be based either on (1) the disruption of the stored CS-US association, or (2) the formation of an inhibitory "CS-no US" association that is better retrieved than the initial CS-US association. The observation of spontaneous recovery, i.e., the reappearance of responses to the CS after time passes following extinction, is traditionally interpreted as a proof for the formation of a transient inhibitory association. To provide a better understanding of extinction in honeybees, we examined whether time intervals during training and extinction or the number of conditioning and extinction trials have an effect on the occurrence of spontaneous recovery. We found that spontaneous recovery mostly occurs when conditioning and testing took place in a massed fashion (1-min intertrial intervals). Moreover, spontaneous recovery depended on the time elapsed since extinction, 1 h being an optimum. Increasing the number of conditioning trials improved the spontaneous recovery level, whereas increasing the number of extinction trials reduced it. Lastly, we show that after single-trial conditioning, spontaneous recovery appears only once after extinction. These elements suggest that in honeybees extinction of the PER actually reflects the impairment of the CS-US association, but that depending on training parameters different memory substrates are affected.

Evidence for Persistence of Sexual Evaluative Learning Effects

Overcoming our fears is on everyone’s “to do” list. However, this is more difficult for some than others, especially those suffering from posttraumatic stress disorder (PTSD). To understand how the brain learns to feel safe, researchers have turned to extinction of classically conditioned fear. In extinction, mice learn that a tone previously paired with a footshock no longer predicts the shock and is therefore no longer dangerous. One promise of extinction research is the possibility of accelerating extinction learning, with the hope of facilitating extinction-based exposure therapy used to treat PTSD sufferers. In this issue of Learning and Memory, Cain et al. (2004) make good on that promise by showing that the noradrenergic antagonist yohimbine accelerates extinction learning in mice. Yohimbine increases release of norepinephrine from nerve terminals by blocking 2 autoreceptors. Mice given systemic yohimbine extinguished their conditioned freezing responses in far fewer trials than controls. Mice injected with saline required 30 trials to extinguish freezing to the level that yohimbine-injected rats reached after only five trials. Interestingly, yohimbine did not increase the maximal level of extinction achieved after 30 trials, suggesting that norepinephrine modulates but does not mediate extinction. In support of this, blocking noradrenergic receptors with propranolol did not have a significant effect on the rate of extinction. A clue to how yohimbine might affect extinction comes from another recent study from the same authors (Cain et al. 2003). They found, somewhat counterintuitively, that rats learned extinction better if the interval between extinction trials was short (trial massing). Increasing the delay between extinction trials (trial spacing) decreased the effectiveness of extinction. In fact, with an intertrial interval of 10 min, rats actually increased their fear during extinction training. Because extinction trials can also serve as reminders of conditioning, Cain et al. (2003) suggest that extinction can trigger two opposing processes: fear incubation or fear extinction, depending on the intertrial interval. In the present study, Cain et al. (2004) replicated their observation that fear was not reduced by spaced extinction training. Spaced training with yohimbine, however, resulted in significant extinction, whereas spaced training with propranolol led to increased fear. Thus, noradrenergic activity (or trial massing) appears to tip the scales in favor of extinction, but noradrenergic blockade (or trial spacing) favors incubation (see Fig. 1). These findings suggest the interesting possibility that incubation acts as a safeguard against accidental learning of extinction; incubation must be overcome before extinction can be initiated. An obvious implication for exposure therapy is that exposure sessions might be more effective if given frequently over a short period, to “kick-start” the extinction process. Yohimbine given in conjunction with exposure therapy might reduce the number of sessions needed, or might convert unsuccessful therapies into successful ones. However, yohimbine might not be popular as an adjunct to exposure therapy because it has been shown to be anxiogenic in both people (Charney et al. 1984) and mice (Blanchard et al. 1993). This could be another clue to its acceleration of extinction, as it is well known that factors increasing conditioned responding during extinction strengthen subsequent memory for extinction (Rescorla 2000). For extinction of fear, this might mean “no pain, no gain.” These findings also offer a cautionary note to those considering using propranolol as a treatment for PTSD (Pitman et al. 2002), at least with patients undergoing exposure therapy. Other recent studies have used different approaches to accelerate extinction of fear. As in many types of learning, longterm retention of extinction requires activation of NMDA glutamate receptors. NMDA antagonists given systemically (Santini et al. 2001) or microinfused into the amygdala (Falls et al. 1992) prevent extinction of conditioned fear. By the same logic, could facilitating NMDA receptors strengthen extinction? The answer appears to be yes. Davis and colleagues showed that microinfusing the partial agonist D-cycloserine into the amygdala strengthened extinction of fear-potentiated startle in rats (Walker et al. 2002). This finding, which has been replicated for extinction of conditioned freezing (Ledgerwood et al. 2003), suggests that extinction may be consolidated in the amygdala via NMDAdependent mechanisms. D-cycloserine, which has been used for decades as a treatment for tuberculosis, is well tolerated and may be another useful adjunct to exposure therapy. Increasing evidence suggests that consolidation of extinction also involves the medial prefrontal cortex (mPFC). Rats with lesions of mPFC can extinguish fear responses normally, but are unable to recall extinction learning the following day (Morgan et al. 1993; Quirk et al. 2000). This is the same time at which mPFC neurons show increased tone responses (Milad and Quirk 2002), suggesting that mPFC signals extinction memory. Interestingly, high-frequency stimulation of mPFC, either directly (Milad and Quirk 2002) or via its thalamic inputs (Herry and Garcia 2002), strengthens extinction memory. Thus, consolidation of extinction may involve NMDA-mediated long-term potentiation of the

Dose response effects of lithium chloride on conditioned place aversions and locomotor activity in rats

Although long-delay learning has been demonstrated numerous times in the conditioned taste avoidance procedure, the empirical evidence showing this is almost exclusively limited to studies using emetics. Given that compounds outside the emetic class (e.g. drugs of abuse) are also effective in inducing conditioned taste avoidances, the present study assessed the ability of cocaine, a non-emetic psychoactive compound, to support long-delay conditioning as the unconditioned stimulus in conditioned taste avoidance preparation. Using saccharin as the conditioned stimulus, two taste-drug pairings were followed by six extinction trials during which saccharin was presented without subsequent injections of cocaine. During the two conditioning trials, animals were injected subcutaneously with cocaine (32 mg/kg) at different conditioned stimulus-unconditioned stimulus intervals, that is, 10, 60, 120, 180, 240, 300, 420 and 540 min. A control group of animals was given an equi-volume injection of the drug vehicle at the 10-min conditioned stimulus-unconditioned stimulus interval. After two conditioning trials, all treatment groups consumed significantly less saccharin than controls, with the magnitude of the effect decreasing as the conditioned stimulus-unconditioned stimulus interval increased. After six extinction trials, animals injected with cocaine at 10, 60 and 120 min conditioned stimulus-unconditioned stimulus intervals still consumed significantly less than controls. These results with cocaine suggest that taste avoidance learning over long delays is not limited to classical emetic compounds and may, in fact, be characteristic of taste avoidance learning in general.

Ventral medial prefrontal cortex and emotional perseveration: the memory for prior extinction training