Context extinction and associative learning in Lymnaea

Aerial respiratory behavior in the pond snail Lymnaea was operantly conditioned so that snails learned not to perform aerial respiration in a hypoxic environment. Snails were trained in either the standard context (no food odorant) or a carrot (food-odorant) context. An operant training procedure of two 45-min training sessions with a 1-h interval between the sessions followed by a third 45-min training session 18 h later was sufficient to produce associative learning and long-term memory (LTM) that persisted for at least 5 days. If, however, following the third operant training session snails received three 45-min extinction training sessions, with each extinction session separated by at least a 1-h interval, LTM was not observed when tested the following day. That is, the memory was extinguished. Extinction, however, did not occur if the context of the extinction training was different from the context of the associative training. That is, in the snails trained in the standard context, extinction did not occur if the extinction training sessions were performed in the food-odorant context and vice versa.     

Amygdala and hippocampal activity during acquisition and extinction of human fear conditioning

Previous functional magnetic resonance imaging (fMRI) studies have characterized brain systems involved in conditional response acquisition during Pavlovian fear conditioning. However, the functional neuroanatomy underlying the extinction of human conditional fear remains largely undetermined. The present study used fMRI to examine brain activity during acquisition and extinction of fear conditioning. During the acquisition phase, participants were either exposed to light (CS) presentations that signaled a brief electrical stimulation (paired group) or received light presentations that did not serve as a warning signal (control group). During the extinction phase, half of the paired group subjects continued to receive the same treatment, whereas the remainder received light alone. Control subjects also received light alone during the extinction phase. Changes in metabolic activity within the amygdala and hippocampus support the involvement of these regions in each of the procedural phases of fear conditioning. Hippocampal activity developed during acquisition of the fear response. Amygdala activity increased whenever experimental contingencies were altered, suggesting that this region is involved in processing changes in environmental relationships. The present data show learning-related amygdala and hippocampal activity during human Pavlovian fear conditioning and suggest that the amygdala is particularly important for forming new associations as relationships between stimuli change.     

Persistent up-regulation of polyribosomes at synapses during long-term memory,reconsolidation, and extinction of associative memory

Local protein synthesis at synapses can provide a rapid supply of proteins to support synaptic changes during consolidation of new memories, but its role in the maintenance or updating of established memories is unknown. Consolidation requires new protein synthesis in the period immediately following learning, whereas established memories are resistant to protein synthesis inhibitors. We have previously reported that polyribosomes are up-regulated in the lateral amygdala (LA) during consolidation of aversive-cued Pavlovian conditioning. In this study, we used serial section electron microscopy reconstructions to determine whether the distribution of dendritic polyribosomes returns to baseline during the long-term memory phase. Relative to control groups, long-term memory was associated with up-regulation of polyribosomes throughout dendrites, including in dendritic spines of all sizes. Retrieval of a consolidated memory by presentation of a small number of cues induces a new, transient requirement for protein synthesis to maintain the memory, while presentation of a large number of cues results in extinction learning, forming a new memory. One hour after retrieval or extinction training, the distribution of dendritic polyribosomes was similar except in the smallest spines, which had more polyribosomes in the extinction group. Our results demonstrate that the effects of learning on dendritic polyribosomes are not restricted to the transient translation-dependent phase of memory formation. Cued Pavlovian conditioning induces persistent synapse strengthening in the LA that is not reversed by retrieval or extinction, and dendritic polyribosomes may therefore correlate generally with synapse strength as opposed to recent activity or transient translational processes.

The formation of long-term memory involves a consolidation phase in the period immediately after learning, during which new proteins are required to stabilize learning-induced synapse remodeling (Davis and Squire 1984; Mayford et al. 2012; Rosenberg et al. 2014; Segal 2017). There is evidence that local protein synthesis in dendrites is essential for consolidation of long-term memory and related forms of synaptic plasticity (Holt and Schuman 2013), but its exact role is not well understood. Dendritic translation can supply new proteins to synapses rapidly, and potentially with synapse-specific spatial precision. Thousands of mRNAs have been identified in dendrites, many of which encode synaptic proteins (Poon et al. 2006; Zhong et al. 2006; Cajigas et al. 2012; Tushev et al. 2018; Middleton et al. 2019), and mRNA is present in dendritic spines (Tiruchinapalli et al. 2003; Hafner et al. 2019). The ability of dendritic mRNAs to remain dormant until they are unmasked by synaptic activity (Doyle and Kiebler 2011; Buxbaum et al. 2014; Hutten et al. 2014) provides a mechanism for rapid and targeted translation at synapses. Synaptic activity during learning triggers a transient up-regulation of new synaptic proteins in dendrites (Redondo and Morris 2011; Moncada et al. 2015), and the spatiotemporal constraints on these new proteins strongly suggest that they are translated locally (Sajikumar et al. 2007; Doyle and Kiebler 2011). We have previously found by serial section transmission electron microscopy (ssTEM) volume reconstruction that polyribosomes and translation factors are up-regulated in dendritic spines in the rat lateral amygdala (LA) 1 h after cued aversive Pavlovian conditioning (Ostroff et al. 2010, 2017; Gindina et al. 2021). These polyribosomes presumably represent translation supporting consolidation, but no studies have addressed whether dendritic translation remains elevated or returns to baseline in the long-term memory phase.Cued aversive Pavlovian conditioning, also referred to as fear or threat conditioning, is an extensively studied learning paradigm in which a sensory cue is paired with an unpleasant stimulus—typically an auditory cue with a mild shock—to create an associative memory between the two (LeDoux 2000; Maren 2001). There is strong evidence that this memory is mediated by protein synthesis-dependent strengthening of LA synapses during a short window after learning. Enhanced synaptic transmission is observed in the LA after conditioning (McKernan and Shinnick-Gallagher 1997; Rogan et al. 1997; Sah et al. 2008), and consolidation requires protein synthesis in the LA immediately after training, but not 6 or 24 h later (Nader et al. 2000; Schafe and LeDoux 2000; Maren et al. 2003). The extracellular signal-regulated/mitogen-activated protein kinase (ERK/MAPK), which regulates translation (Kelleher et al. 2004), is transiently phosphorylated in the LA 1 h after learning, and this phosphorylation is required for both memory consolidation (Schafe et al. 2000) and synaptic plasticity in the LA (Huang et al. 2000; Schafe et al. 2008).Although dormant long-term memories are stable, retrieval induces a new labile phase called reconsolidation, during which the memory can be updated, weakened, or strengthened (Dudai 2012). As in consolidation, postretrieval inhibition of protein synthesis or ERK/MAPK phosphorylation in the LA impairs reconsolidation of the memory and associated synaptic plasticity (Nader et al. 2000; Duvarci et al. 2005; Doyere et al. 2007). A transient supply of necessary new proteins is available to synapses during reconsolidation (Orlandi et al. 2020), but whether these proteins are synthesized in dendrites is unknown. Both consolidation and reconsolidation are impaired by broad protein synthesis inhibitors, and there is substantial evidence that consolidation requires translation initiation, the step in which polyribosomes are formed (Gkogkas et al. 2010; Santini et al. 2014). Interestingly, one study found that inhibition of the predominant initiation process impaired consolidation but not reconsolidation, suggesting that the role of translation differs between the two processes (Hoeffer et al. 2011). Since polyribosomes can be stalled for later reactivation (Richter and Coller 2015), reconsolidation could rely on translation of pre-existing polyribosomes.Reconsolidation is triggered by a small number of retrieval cues, but retrieval with a large number of cues induces extinction learning, in which the cue loses its ability to elicit defensive responses (Myers and Davis 2007). There is ample evidence that plasticity important for extinction occurs in the basolateral amygdala (BLA; which includes the LA), though it is unclear exactly how this relates to the original memory trace in the dorsal LA (Bouton et al. 2021). For instance, consolidation of extinction is impaired by pretraining systemic inhibition of protein synthesis (Suzuki et al. 2004) and by pretraining inhibition of protein synthesis or ERK/MAPK in the BLA (Lin et al. 2003c; Herry et al. 2006). However, the Lin et al. (2003c) study measured the effects of protein synthesis inhibition in the BLA 30 min after extinction training, which is typically thought to reflect short-term memory. Subsequent work by another group found that postextinction training inhibition of protein synthesis impaired reconsolidation, making it difficult to assess the effects on extinction consolidation (Duvarci et al. 2006). There are also ongoing debates about the relative contribution of “erasure” versus “new learning” processes in extinction. Evidence that protein synthesis-dependent depotentiation of CS inputs to the LA contributes to extinction suggests up-regulation of polyribosomes in the LA pyramidal cells storing the original trace (Lin et al. 2003a,b,c; Kim et al. 2009). However, up-regulation of polyribosomes is also possible if extinction plasticity occurs in other cells or regions of the brain, as repeated retrieval trials may strongly trigger reconsolidation processes. Complicating things further, it appears that extinction can halt reconsolidation (Suzuki et al. 2004).To investigate the dynamics of local translation in the context of an established memory, we used ssTEM to quantify dendritic polyribosome distribution in the LA during the long-term memory phase of Pavlovian conditioning, reconsolidation, and consolidation of extinction. We hypothesized that polyribosomes would not be up-regulated in the long-term memory condition relative to controls, since memory maintenance is resistant to protein synthesis inhibition at this time point. We also hypothesized that both retrieval and extinction would induce up-regulation of polyribosomes, but in different patterns; for example, reconsolidation processes could be reflected in polyribosomes near large synapses, but extinction could result in loss of these synapses and perhaps more generalized polyribosome distribution.     

Cue-producing behavior in the Capuchin monkey during reversal, extinction, acquisition, and overtraining

In a two-choice discrimination situation, a cue-producing response produced the discriminanda for 0.05 sec. The cue-producing responses beyond those normally necessary to identify the discriminanda thus provided only redundant information. Two of the four Capuchin monkeys studied showed a large increase in cue-producing responses during reversal learning and extinction, and they reversed much faster than the two whose cue-producing responses showed little increase. During acquisition of a difficult discrimination, the cue-producing responses of the first two subjects reached a high level and during overtraining gradually reduced to their initial low level. The results were related to Wyckoff's theory of observing behavior and to the notions of uncertainty, reduction, and lack of information as extensions of the concepts of reinforcement and motivation.     

Generalization during acquisition, extinction, and transfer of matching with an adjustable comparison

Three groups of pigeons were given conditional discrimination training in which the number of standard stimuli was varied across groups. In the presence of each standard, a pigeon adjusted the comparison stimulus on a second key until the two keys matched. A report of this match (response on the first key) was reinforced. Transfer of the matching performance was investigated by adding new standards to the ones already available. All pigeons were exposed to two extinction sessions after 155 sessions of training. Rapidity of acquisition was inversely related to the number of standards presented. Generalization gradients derived from the several comparison stimuli showed that all pigeons reached a high level of accuracy in the presence of at least one standard, and some pigeons did so in the presence of as many as four of the six standards. There was no evidence of a systematic effect of extinction upon overall accuracy, or the individual generalization gradients. When a new standard was added, a given pigeon's performance (in terms of responding to the comparisons) was similar to performance in the presence of one of the old standards. However, the pigeons did not show evidence of confusion among the comparisons.     

Aging affects acquisition and reversal of reward-based associative learning

Reward-based associative learning is mediated by a distributed network of brain regions that are dependent on the dopaminergic system. Age-related changes in key regions of this system, the striatum and the prefrontal cortex, may adversely affect the ability to use reward information for the guidance of behavior. The present study investigated the effects of healthy aging on different components of reward learning, such as acquisition, reversal, effects of reward magnitude, and transfer of learning. A group of 30 young (mean age = 24.2 yr) and a group of 30 older subjects (mean age = 64.1 yr) completed two probabilistic reward-based stimulus association learning tasks. Older subjects showed poorer overall acquisition and impaired reversal learning, as well as deficits in transfer learning. When only those subjects who showed evidence of significant learning were considered, younger subjects showed equivalently fast learning irrespective of reward magnitude, while learning curves in older subjects were steeper for high compared to low reward magnitudes. Acquired equivalence learning, which requires generalization across stimuli and transfer of learned contingencies to new stimuli, was mildly impaired in older subjects.     

A partial reinforcement extinction effect despite equal rates of reinforcement during Pavlovian conditioning

In 4 experiments rats received appetitive Pavlovian conditioning followed by extinction. Food accompanied every trial with the conditioned stimulus (CS) for the continuously reinforced groups and only half of the trials for the partially reinforced groups. In contrast to previous experiments that have compared the effects of partial and continuous reinforcement, the rate at which food was delivered during the CS was the same for both groups. The strength of the conditioned response during extinction weakened more rapidly in the continuously than in the partially reinforced groups. The results demonstrate that the partial reinforcement extinction effect is a consequence of the nonreinforced trials with the CS, rather than the rate at which the unconditioned stimulus is delivered during the CS.     

Number and time in acquisition,extinction and recovery

We measured rate of acquisition, trials to extinction, cumulative responses in extinction, and the spontaneous recovery of anticipatory hopper poking in a Pavlovian protocol with mouse subjects. We varied by factors of 4 number of sessions, trials per session, intersession interval, and span of training (number of days over which training extended). We find that different variables affect each measure: Rate of acquisition [1/(trials to acquisition)] is faster when there are fewer trials per session. Terminal rate of responding is faster when there are more total training trials. Trials to extinction and amount of responding during extinction are unaffected by these variables. The number of training trials has no effect on recovery in a 4-trial probe session 21 days after extinction. However, recovery is greater when the span of training is greater, regardless of how many sessions there are within that span. Our results and those of others suggest that the numbers and durations and spacings of longer-duration “episodes” in a conditioning protocol (sessions and the spans in days of training and extinction) are important variables and that different variables affect different aspects of subjects' behavior. We discuss the theoretical and clinical implications of these and related findings and conclusions—for theories of conditioning and for neuroscience.     

疼痛恐惧的形成、泛化与消退

疼痛恐惧源于把疼痛等同于伤害的灾难化信念及对疼痛的负性解释, 它在慢性疼痛和能力丧失的发生和发展过程中起着重要作用。疼痛恐惧可以通过联合学习和观察学习等方式获得, 并且在具有相似特征的刺激中存在泛化现象。通过教育干预和等级暴露疗法等可以成功消退疼痛恐惧, 在消退过程中要控制安全信息等因素的不良影响。在疼痛恐惧的获得与消退中, 主要有杏仁核, 脑岛和前扣带皮层等脑区参与。未来的研究可以集中在深入探讨疼痛恐惧形成中的泛化及消退后的恢复、再巩固等现象, 加强其临床上的应用, 并综合心理、生物和认知神经科学, 研究疼痛恐惧的获得、泛化与消退的深层机制。