Peter C. Holland’s research while affiliated with Johns Hopkins University and other places

Prior exposure to a conditioned stimulus (CS) typically results in latent inhibition—slower acquisition of associative learning about that stimulus in subsequent training. Here, we found that CS preexposure had different effects on the appetitive conditioning of rats with a sucrose unconditioned stimulus (US) depending on training test procedures, the similarity of preexposure and training procedures, and the choice of response measure. Preexposure to a visual or an auditory stimulus produced facilitation of acquisition of food-cup-directed responding when both of those cues were (separately) paired with sucrose delivery in the training test (Experiments 1 and 3). By contrast, the same preexposure procedure resulted in latent inhibition of food-cup learning if the second stimulus in the test phase was of the same modality as the preexposed stimulus (Experiment 2). In Experiment 3, latent inhibition was enhanced if both phases included a single CS or both phases included both auditory and visual CSs, compared to treatments in which only one CS was presented in one phase but two CSs were presented in the other phase. In Experiment 4, preexposure of an auditory cue slowed subsequent learning about it if the context was salient but enhanced learning if the context was of weaker salience. Finally, a measure of general activity revealed latent inhibition after preexposure in all conditions in all 4 experiments. We discuss the results within several classes of latent inhibition theories, none of which provides a comprehensive account.

The surprising omission of a reinforcer can enhance the associability of the stimuli that were present when the reward prediction error was induced, so that they more readily enter into new associations in the future. Previous research from this laboratory identified brain circuit elements critical to the enhancement of stimulus associability by the omission of an expected event and to the subsequent expression of that altered associability in more rapid learning. These elements include the amygdala, the midbrain substantia nigra, the basal forebrain substantia innominata, the dorsolateral striatum, the secondary visual cortex, and the posterior parietal cortex. Here, we found that consolidation of a surprise-enhanced associability memory in a serial prediction task depends on processing in the amygdala central nucleus (CeA) after completion of sessions that included the surprising omission of an expected event. Post-surprise infusions of anisomycin, lidocaine, or muscimol prevented subsequent display of surprise-enhanced associability. Because previous studies indicated that CeA function is unnecessary for the expression of associability enhancements that were induced previously when CeA function was intact (Holland & Gallagher, 2006), we interpreted these results as indicating that post-surprise activity of CeA ("surprise replay") is necessary for the consolidation of altered associability memories elsewhere in the brain, such as the posterior parietal cortex (Schiffino, et al., 2014a).

Considerable evidence indicates that reinforcement prediction error, the difference between the obtained and expected reinforcer values, modulates attention to potential cues for reinforcement. The surprising delivery or omission of a reinforcer enhances the associability of the stimuli that were present when the error was induced, so that they more readily enter into new associations in the future. Previous research from our laboratory identified brain circuit elements critical to the enhancement of stimulus associability by the omission of an expected event and to the subsequent expression of that altered associability in more rapid learning. A key finding was that the rat posterior parietal cortex was essential during the encoding, consolidation, and retrieval of associability memories that were altered by the surprising omission of an expected event in a serial prediction task. Here, we found that function of the adjacent secondary visual cortex was critical only to the expression of altered cue associability in that same task. This specialization of function is discussed in the context of broader cortical and subcortical networks for modulation of attention in associative learning, as well as recent anatomical investigations that suggest that the rodent posterior parietal cortex overlaps with and may subsume secondary visual cortex. This article is protected by copyright. All rights reserved.

Prediction error (PE) plays a critical role in most modern theories of associative learning, by determining the effectiveness of conditioned stimuli (CS) or unconditioned stimuli (US). Here, we examined the effects of lesions of central (CeA) or basolateral (BLA) amygdala on performance in overexpectation tasks. In 2 experiments, after 2 CSs were separately paired with the US, they were combined and followed by the same US. In a subsequent test, we observed losses in strength of both CSs, as expected if the negative PE generated on reinforced compound trials encouraged inhibitory learning. CeA lesions, known to interfere with PE-induced enhancements in CS effectiveness, reduced those losses, suggesting that normally the negative PE also enhances cue associability in this task. BLA lesions had no effect. When a novel cue accompanied the reinforced compound, it acquired net conditioned inhibition, despite its consistent pairings with the US, consonant with US effectiveness models. That acquisition was unaffected by either CeA or BLA lesions, suggesting different rules for assignment of credit of changes in cue strength and cue associability. Finally, we examined a puzzling autoshaping phenomenon previously attributed to overexpectation effects. When a previously food-paired auditory cue was combined with the insertion of a lever and paired with the same food US, the auditory cue not only failed to block conditioning to the lever, but also lost strength, as in an overexpectation experiment. This effect was abolished by BLA lesions but unaffected by CeA lesions, suggesting it was unrelated to other overexpectation effects. (PsycINFO Database Record

Most modern theories of associative learning emphasize a critical role for prediction error (PE, the difference between received and expected events). One class of theories, exemplified by the Rescorla-Wagner (1972) model, asserts that PE determines the effectiveness of the reinforcer or unconditioned stimulus (US): surprising reinforcers are more effective than expected ones. A second class, represented by the Pearce-Hall (1980) model, argues that PE determines the associability of conditioned stimuli (CSs), the rate at which they may enter into new learning: the surprising delivery or omission of a reinforcer enhances subsequent processing of the CSs that were present when PE was induced. In this mini-review we describe evidence, mostly from our laboratory, for PE-induced changes in the associability of both CSs and USs, and the brain systems involved in the coding, storage and retrieval of these altered associability values. This evidence favors a number of modifications to behavioral models of how PE influences event processing, and suggests the involvement of widespread brain systems in animals' responses to PE.

Because the occurrence of primary reinforcers in natural environments is relatively rare, conditioned reinforcement plays an important role in many accounts of behavior, including pathological behaviors such as the abuse of alcohol or drugs. As a result of pairing with natural or drug reinforcers, initially neutral cues acquire the ability to serve as reinforcers for subsequent learning. Accepting a major role for conditioned reinforcement in everyday learning is complicated by the often-evanescent nature of this phenomenon in the laboratory, especially when primary reinforcers are entirely absent from the test situation. Here, I found that under certain conditions, the impact of conditioned reinforcement could be extended by lesions of the basolateral amygdala (BLA). Rats received first-order Pavlovian conditioning pairings of 1 visual conditioned stimulus (CS) with food prior to receiving excitotoxic or sham lesions of the BLA, and first-order pairings of another visual CS with food after that surgery. Finally, each rat received second-order pairings of a different auditory cue with each visual first-order CS. As in prior studies, relative to sham-lesioned control rats, lesioned rats were impaired in their acquisition of second-order conditioning to the auditory cue paired with the first-order CS that was trained after surgery. However, lesioned rats showed enhanced and prolonged second-order conditioning to the auditory cue paired with the first-order CS that was trained before amygdala damage was made. Implications for an enhanced role for conditioned reinforcement by drug-related cues after drug-induced alterations in neural plasticity are discussed. (PsycINFO Database Record

The rapid increase in obesity may be partly mediated by an increase in the exposure to cues for food. Food-paired cues play a role in food procurement and intake under conditions of satiety. The mechanism by which this occurs requires characterization, but may involve ghrelin. This orexigenic peptide alters the response to food-paired conditioned stimuli, and neural responses to food images in reward nuclei. Therefore, we tested whether a ghrelin receptor antagonist alters the influence of food-paired cues on the performance of instrumental responses that earn food and the consumption of food itself using tests of Pavlovian-to-instrumental transfer (PIT) and cue potentiated feeding (CPF), respectively. Food-deprived rats received Pavlovian conditioning where an auditory cue was paired with delivery of sucrose solution followed by instrumental conditioning to lever press for sucrose. Following training, rats were given ad libitum access to chow. On test day, rats were injected with the ghrelin receptor antagonist GHRP-6 [D-Lys3], and then tested for PIT or CPF. Disruption with ghrelin signaling enhanced expression of PIT. In addition, GHRP-6 [D-Lys3] impaired the initiation of feeding behavior in CPF without influencing overall intake of sucrose. Finally, in PIT tested rats, enhanced FOS immunoreactivity was revealed following the antagonist in regions thought to underlie PIT; however, the antagonist had no effect on FOS immunoreactivity in CPF tested rats.

The dorsolateral striatum (DLS) is frequently implicated in sensory-motor integration, including the performance of sensory orienting responses and learned stimulus-response habits. Our laboratory previously identified a role for the DLS in rats' performance of conditioned orienting responses (ORs) to Pavlovian cues for food delivery. Here, we considered whether DLS is also critical to another aspect of attention in associative learning, the surprise-induced enhancement of cue associability. A large behavioral literature shows that a cue present when an expected event is omitted enters into new associations more rapidly, when that cue is subsequently paired with food. Research from our laboratory has shown that both cue associability enhancements and conditioned ORs depend on the function of a circuit that includes the amygdala central nucleus and the substantia nigra pars compacta. In three experiments, we explored the involvement of DLS in surprise-induced associability enhancements, using a three-stage serial prediction task that permitted separation of DLS function in registering surprise (prediction error) and enhancing cue associability, and in using that increased associability to learn more rapidly about that cue later. The results showed that DLS is critical to the expression, but not the establishment, of the enhanced cue associability normally produced by surprise in this task. They extend the role of DLS and the amygdalo-nigro-striatal circuit underlying learned orienting to more subtle aspects of attention in associative learning, but are consistent with the general notion that DLS is more important in the expression of previously-acquired tendencies than in their acquisition. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Exposure to environmental cues associated with food can evoke eating behavior in the absence of hunger. This capacity for reward cues to promote feeding behaviors under sated conditions can be examined in the laboratory using cue-potentiated feeding (CPF). The orexigenic neuropeptide Melanin Concentrating Hormone is expressed throughout brain circuitry critical for CPF. We examined whether deletion of the MCH receptor, MCH-1R, would in KO mice disrupt overeating in the presence of a Pavlovian CS+ associated with sucrose delivery. While both wild-type controls and KO mice showed comparable food magazine approach responses during the CPF test, MCH-1R deletion significantly impaired the ability of the CS+ to evoke overeating of sucrose. Through the use of a refined analysis of meal intake, it was revealed that this disruption to overeating behavior in KO mice reflected a reduction in the capacity for the CS+ to initiate and maintain bursts of licking behavior. These findings suggest that overeating during CPF requires intact MCH-1R signaling and may be due to an influence of the CS+ on the palatability of food and on regulatory mechanisms of peripheral control. Thus, disruptions to MCH-1R signaling may be a useful pharmacological tool to inhibit this form of overeating behavior. Copyright © 2015. Published by Elsevier Inc.