Error correction in latent inhibition and its disruption by opioid receptor blockade with naloxone.

Latent inhibition refers to the retardation in the development of conditioned responding when a pre-exposed stimulus is used to signal an unconditioned stimulus. This effect is described by error-correction models as an attentional deficit and is commonly used as an animal model of schizophrenia. A series of experiments studied the role of error-correction mechanism in latent inhibition and its interaction with the endogenous opioid system. Systemic administration of the competitive opioid receptor antagonist naloxone before rats were pre-exposed to a target stimulus prevented latent inhibition of its subsequent fear conditioning; it was without effect on a non-pre-exposed stimulus and did not produce state-dependent learning (Experiments 1a and 1b). Naloxone did not reverse the latent inhibitory effect already accrued to a pre-exposed target. However, it did prevent the enhancement of latent inhibition by a long retention interval interpolated between its initial exposure and re-exposure (Experiment 2) or by a novel stimulus compounded with the pre-exposed target during re-exposure (Experiment 3). These results provide evidence that attentional loss in latent inhibition is instructed by an opioid-mediated error signal which diminishes with repeated stimulus exposures but recovers with the passage of time or reintroduction of novelty.

A further assessment of the Hall-Rodriguez theory of latent inhibition.

The Hall-Rodriguez (G. Hall & G. Rodriguez, 2010, Associative and nonassociative processes in latent inhibition: An elaboration of the Pearce-Hall model, in R. E. Lubow & I. Weiner, Eds., Latent inhibition: Data, theories, and applications to schizophrenia, pp. 114-136, Cambridge, England: Cambridge University Press) theory of latent inhibition predicts that it will be deepened when a preexposed target stimulus is given additional preexposures in compound with (a) a novel stimulus or (b) another preexposed stimulus, and (c) that deepening will be greater when the compound contains a novel rather than another preexposed stimulus. A series of experiments studied these predictions using a fear conditioning procedure with rats. In each experiment, rats were preexposed to 3 stimuli, 1 (A) taken from 1 modality (visual or auditory) and the remaining 2 (X and Y) taken from another modality (auditory or visual). Then A was compounded with X, and Y was compounded with a novel stimulus (B) taken from the same modality as A. A previous series of experiments (H. T. Leung, A. S. Killcross, & R. F. Westbrook, 2011, Additional exposures to a compound of two preexposed stimuli deepen latent inhibition, Journal of Experimental Psychology: Animal Behavior Processes, Vol. 37, pp. 394-406) compared A with Y, finding that A was more latently inhibited than Y, the opposite of what was predicted. The present experiments confirmed that A was more latently inhibited than Y, showed that this was due to A entering the compound more latently inhibited than Y, and finally, that a comparison of X and Y confirmed the 3 predictions made by the theory.

Additional exposures to a compound of two preexposed stimuli deepen latent inhibition.

The present experiments studied the role of error correction mechanisms in the latent inhibition of conditioned fear responses by conditioned stimulus (CS) preexposure. They demonstrated that a preexposed CS subjected to additional exposures in compound with either another preexposed stimulus or a novel stimulus was more latently inhibited than a preexposed CS which received additional exposures in isolation. They also showed that a preexposed CS subjected to additional exposures in compound with another preexposed stimulus was more latently inhibited than a preexposed CS given additional exposures in compound with a novel stimulus. These results were discussed in terms of the Hall-Rodriguez (2010) model of latent inhibition.

Latent inhibition, learned irrelevance, and schizotypy: assessing their relationship.

INTRODUCTION: Previous research suggests that latent inhibition is reduced in patients with acute schizophrenia and in healthy participants with high levels of schizotypic characteristics. Other evidence indicates the disruption of a related effect (learned irrelevance) in patients with acute schizophrenia. METHOD: This study used a recently developed latent inhibition procedure, that avoids methodological limitations of previous studies, and a related learned irrelevance procedure to assess the relationship between these phenomena and schizotypic characteristics in undergraduate participants. RESULTS: Participants preexposed to a letter (S) learnt the predictive relationship between that letter and another letter (X) slower than the relationship between a novel letter and X (a latent inhibition effect). Experiment 1 found reduced latent inhibition in the high schizotypy group after 10, but not 20 preexposures. In Experiment 2, participants preexposed to both S and X learnt a subsequent relationship between them slower than the relationship between a novel letter and X (a learned irrelevance effect). This effect was abolished in participants with high levels of schizotypy. CONCLUSIONS: These results are both the first demonstration of abolished learned irrelevance and of a significant reduction in latent inhibition without employing an explicit masking task in participants with high levels of positive schizotypy.

Integration of geometric with luminance information in the rat: evidence from within-compound associations.

In two experiments, rats first received preexposure to a rectangular arena in which the geometrically equivalent corner pairs (G1 and G2) were coincident with different luminance characteristics (C1 and C2, respectively). In Experiment 1, rats were then placed in a uniform gray rectangular arena where food was located in one geometrically equivalent pair of corners (G1), but not another (G2). Finally, rats were tested in a square arena with C1 and C2 and preferred to search in C1 rather than C2. In Experiment 2, following preexposure to G1C1 and G2C2, rats received pairings of C1 with food and C2 with no food in a square arena. During testing, rats preferred to search in G1 rather than G2 in a gray rectangular arena. These results demonstrate that reciprocal within-compound associations develop between geometric and luminance information and thereby challenge the view that there is a dedicated geometric module that is impenetrable to information that is not geometric.

Role of the medial prefrontal cortex in acquired distinctiveness and equivalence of cues.

In the present study, the authors examined the role of the medial prefrontal cortex in acquired equivalence and distinctiveness of cues. Rats were placed in 4 experimental contexts (A, B, C, and D) where they received presentations of 2 auditory stimuli (X and Y). In Contexts A and B, X was paired with food and Y was not, whereas in Contexts C and D, Y was paired with food and X was not. Rats that received sham lesions and those with lesions of the medial prefrontal cortex acquired this configural discrimination equally readily. Rats then received many pellets in A but not in C. After this training, sham-lesion rats exhibited more magazine activity in B than in D (an acquired distinctiveness/acquired equivalence effect), whereas those with medial prefrontal cortex lesions did not. These results indicate that the medial prefrontal cortex is involved in the process by which experience with stimuli influences the degree of generalization between them.

Lesions of rat infralimbic cortex result in disrupted retardation but normal summation test performance following training on a Pavlovian conditioned inhibition procedure.

The prefrontal cortex has a well-established role in the inhibition of inappropriate responding. Converging evidence implicates the infralimbic (IL) region of the rat medial prefrontal cortex (MPFC) in the maintenance of extinction [Quirk et al. (2000)J. Neurosci., 20, 6225-6231; Rhodes & Killcross (2004)Learn. Mem., 11, 611-616], a process generally considered to be mediated by the formation of inhibitory associations. An appetitive Pavlovian conditioned inhibition paradigm was used in order to investigate further the role of the IL MPFC in the control over behaviour by inhibitory associations. In two separate experiments, the effect of IL lesions on summation and retardation tests of conditioned inhibition was assessed. IL lesions did not affect summation test performance, indicating that lesioned animals were able to acquire inhibitory associations between a stimulus and reward and could express them normally when placed in competition with an excitatory cue. However, the retardation of excitatory conditioning that is normally seen when a stimulus with inhibitory properties is subsequently paired with reward was abolished in IL-lesioned animals. This suggests a selective role for the IL MPFC in the competition for behavioural control between the inhibitory and excitatory associations of a single stimulus.

Lesions of rat infralimbic cortex enhance renewal of extinguished appetitive Pavlovian responding.

It is well established that extinction is highly context dependent, and several behavioural phenomena associated with the expression of extinction (spontaneous recovery, reinstatement and renewal) have been described as resulting from this context dependency. It has previously been shown that lesions of the infralimbic (IL) region of the medial prefrontal cortex result in increased levels of spontaneous recovery and reinstatement of an extinguished appetitive Pavlovian conditioned response. The current study shows that lesions of the IL cortex also result in increased renewal of a conditioned response when tested in the acquisition context. Thirteen IL-lesioned and 14 sham-lesioned rats were trained on an appetitive Pavlovian task in one context (Context A) followed by extinction in a different context (Context B); animals were then tested for renewal of responding in both Context A and B. Both groups demonstrated similarly low levels of responding when tested in the extinction context (B), and greater responding (i.e. renewal) when tested in the acquisition context (A). Further, the level of response renewal was greater in IL-lesioned animals. The results are discussed in relation to the possible role of the IL cortex in contextual control of extinction.

Excitotoxic lesions of the entorhinal cortex leave gustatory within-event learning intact.

The ability of rats with ibotenate lesions of the entorhinal cortex to form memories for events was assessed by using a gustatory within-event learning procedure. Rats first received exposure to 2 events, AX and BY, each composed of a pair of flavors. Following this exposure period, Flavor X alone was paired with the delivery of lithium chloride. Lesioned and control rats showed a greater aversion to A than to B and to AX than to BX. These results challenge theories that suppose that the entorhinal cortex plays a general role in forming representations of patterns of stimulation.

Medial prefrontal cortex lesions abolish contextual control of competing responses.

There is much debate as to the extent and nature of functional specialization within the different subregions of the prefrontal cortex. The current study was undertaken to investigate the effect of damage to medial prefrontal cortex subregions in the rat. Rats were trained on two biconditional discrimination tasks, one auditory and one visual, in two different contexts. At test, they received presentations of audiovisual compounds of these training stimuli in extinction. These compounds had dictated either the same (congruent trials) or different (incongruent trials) responses during training. In sham-operated controls, contextual cues came to control responding to conflicting information provided by incongruent stimulus compounds. Experiment 1 demonstrated that this contextual control of responding was not evident in individual rats with large amounts of damage that included the prelimbic and cingulate subregions of the prefrontal cortex. Experiment 2 further dissociated the result of Experiment 1, demonstrating that lesions specific to the anterior cingulate cortex were sufficient to produce a deficit early on during presentation of an incongruent stimulus compound but that performance was unimpaired as presentation progressed. This early deficit suggests a role for the anterior cingulate cortex in the detection of response conflict, and for the medial prefrontal cortex in the contextual control of competing responses, providing evidence for functional specialization within the rat prefrontal cortex.

Reinstatement of extinguished fear by beta-adrenergic arousal elicited by a conditioned context.

Five experiments examined the reinstatement of fear (freezing) produced by recent reexposure to a dangerous context. Rats were trained to fear a conditioned stimulus (CS) and a distinctive context with shock. The CS was then extinguished. A 2-min interval between reexposure to the dangerous context and presentation of the extinguished CS in a different context reinstated freezing when the CS was tested the next day. Propranolol (a beta-adrenergic antagonist) blocked reinstatement of extinguished fear without decreasing freezing to a nonextinguished CS. Administration of epinephrine (an adrenergic agonist) reinstated extinguished fear without reexposure to the dangerous context. The results suggest a role for beta-adrenergic activity elicited by exposure to a conditioned context in the reinstatement of extinguished fear.

Representational blending in human conditional learning: Implications for associative theory.

In two experiments, participants were presented with pictures of different foods (A, B, C, D, X,) and learned which combinations resulted in an allergic reaction in a fictitious patient, Mr X. In Problem 1, when A or B (but not C or D) was combined with food X an allergic reaction occurred, and when C or D (but not A or B) was combined with Y an allergic reaction occurred. In Experiment 1, participants also received Problem 2 in which A, B, C, and D interacted with foods V and W either in the same way as X and Y, respectively, or in a different way. Participants performed more proficiently in the former than in the latter condition. In Experiment 2, after training on Problem 1, participants judged whether or not novel combinations of foods (e.g., AB, CD, AD, CB) would cause an allergic reaction in Mr X. They were no more likely to indicate that AB or CD would cause an allergic reaction than AD or CB, but made their judgements more rapidly and with greater confidence on AB and CD trials than on AD and CB trials. These results (1) indicate that shared representations come to be addressed by the components of similar compounds (e.g., AX and BX) that have predicted the same outcome (an allergic reaction), and (2) are inconsistent with standard, associative theories of learning, but (3) are consistent with findings from nonhuman animals and with a connectionist interpretation of these findings.

Acquired equivalence and distinctiveness of cues: II. Neural manipulations and their implications.

Neural manipulations were used to examine the mechanisms that underlie the acquired equivalence and distinctiveness of cues in rats. Control rats and those with excitotoxic lesions of either the hippocampus (HPC) or entorhinal cortex (EC) acquired the following conditional discrimination: In Contexts A and B, Stimulus X-->food and Stimulus Y-->no food, and in Contexts C and D, Y-->food and X-->no food. Rats then received many food pellets in A but not in C. After this treatment, control rats showed more magazine activity in B than in D--an acquired equivalence-distinctiveness effect. This effect was also evident in HPC rats but not in EC rats. These results indicate that changes in stimulus distinctiveness are dissociable from the process of conditional learning.

Excitotoxic lesions of the hippocampus leave sensory preconditioning intact: implications for models of hippocampal function.

Learning about contextual cues is markedly disrupted in rats with hippocampal lesions. One analysis of this disruption is that it reflects a general failure to form associations between the elements of complex events. A straightforward prediction of this analysis is that sensory preconditioning will be disrupted by hippocampal lesions. This prediction was assessed by presenting rats with flavored solutions composed of 2 elements (A and X) before X was paired with an injection of the emetic, lithium chloride. A subsequent test revealed that rats were less willing to consume Solution A than they were to consume a control solution, B. This was true of rats with sham lesions and those with excitotoxic lesions of hippocampus. These findings fail to support the proposition that the hippocampus-dependent deficit in contextual conditioning is due to a general disruption to the process of associating the elements of complex events.

Dissociations in dopamine release in medial prefrontal cortex and ventral striatum during the acquisition and extinction of classical aversive conditioning in the rat.

Dual perfusion in vivo brain microdialysis was used to monitor extracellular levels of dopamine in the medial prefrontal cortex and ventral striatum during the acquisition and extinction of a classical aversive conditioning paradigm in rats. The main finding was a dissociation in the pattern of release in the two brain areas. The first stimulus-footshock pairing elicited large increases in cortical dopamine over baseline levels that were much greater than the increases elicited by different stimuli of equivalent salience that were unpaired with footshock. In contrast, dopamine levels in ventral striatum were unchanged under these conditions. Over the next two pairings, there was a decline in the cortical response and an increase in the response in ventral striatum. The first presentation of the aversive conditioned stimulus in a separate context elicited the largest response in ventral striatum. Post-conditioning, the cortical response to the conditioned stimulus was smaller than that elicited by the initial stimulus-footshock pairing and was equivalent in magnitude to that elicited by stimuli unpaired with footshock. Over the final two conditioned stimuli presentations, in the absence of the footshock reinforcer (extinction), responses declined in both brain areas. Simultaneous monitoring of behaviour indicated that the neurochemical events were accompanied by effective aversive learning, as indexed by conditioned freezing responses. The data are discussed in terms of the hypothesis that medial prefrontal cortex is especially engaged during novel circumstances which may, potentially, require new learning, whilst ventral striatal dopamine more closely follows the expression of conditioned responding during learning and extinction.

Effects of retention interval on latent inhibition and perceptual learning.

Repeated, non-reinforced preexposure to a context slowed development of conditioned freezing to that context when it was subsequently paired with footshock (latent inhibition) and enhanced discriminability of that context from a similar context (perceptual learning) whether assessed by a generalization test or by explicit discrimination training. Latent inhibition was eliminated by a delay between conditioning sessions and test (Experiments 1a and 1b) and reduced by a delay between preexposure and conditioning (Experiment 2). However, perceptual learning was unaffected by either of these intervals (Experiments 1b and 2). These results are discussed in terms their impact on theories that have latent inhibition as a possible mechanism of perceptual learning, and on theories of latent inhibition that consider the retardation of conditioned responding to be the result of an acquisition failure.

Loss of latent inhibition of contextual conditioning following non-reinforced context exposure in rats.

Three experiments with rats demonstrated that preexposure to an experimental environment retarded the level of conditioned freezing observed on a test in that environment after it had been paired with mild footshock. Furthermore, Experiment 1 demonstrated that this latent inhibition effect could be abolished if preexposed rats were exposed to a second experimental environment following conditioning to the preexposed environment. Experiments 2 and 3 demonstrated that this second environment had to be similar, but not identical, to the preexposed environment, and that the influence of exposure to the second environment on latent inhibition could be abolished by exposure to that environment prior to footshock conditioning. These results are considered in terms of the Dickinson-Burke (1996) theory of retrospective revaluation, and their implications for experiments demonstrating a loss of latent inhibition across a delay are considered.

WAY100635 and latent inhibition in the rat: selective effects at preexposure.

The influence of the selective, silent 5HT1a antagonist WAY100635 (Wyeth Research Ltd) on the latent inhibition effect was examined in a within-subject, on-baseline conditioned suppression procedure in rats. WAY100635 was found to enhance the latent inhibition effect, producing a retardation in the acquisition of conditioned suppression following a level of stimulus preexposure known to be insufficient to produce a latent inhibition effect in control animals. This influence of the drug was restricted to its actions during the preexposure phase of the experiment, and the drug also abolished the unconditioned suppression of lever pressing that occurs on the first presentation of a novel auditory stimulus. These findings are discussed in terms of the possible influence of serotonergic manipulations on contextual processing, and also have important implications for current animal models of schizophrenia which stress the role of dopaminergic mechanisms in latent inhibition.

Symmetrical effects of amphetamine and alpha-flupenthixol on conditioned punishment and conditioned reinforcement: contrasts with midazolam.

In a test of conditioned punishment, saline-treated controls showed a moderate bias in responding away from a lever producing a response-contingent auditory conditioned stimulus (CS) that had been paired with mild footshock during training and towards a lever producing a neutral auditory CS. Systemic treatment with the indirect dopamine (DA) agonist amphetamine (0.25-1.0 mg/kg) produced a dose-dependent increase in the punishing effect of the aversive CS, whilst responding on the neutral CS lever was unchanged. Treatment with the dopamine-receptor antagonist alpha-flupenthixol (0.125, 0.25 mg/kg) decreased the efficacy of the punishing CS, but again left responding on the neutral lever unchanged. The benzodiazepine midazolam (0.1, 0.3 mg/kg) had a similar effect to alpha-flupenthixol, but treated animals showed a preference for the aversive CS. Parallel results were observed with amphetamine (0.25 mg/kg) and alpha-flupenthixol (0.125, 0.25 mg/kg) in a matched test of positive conditioned reinforcement, with amphetamine enhancing, and alpha-flupenthixol reducing, the efficacy of the CS paired with food. Midazolam treatment (0.1-1.0 mg/kg) had no effect on the reinforcing impact of an appetitive CS. Thus dopaminergic agents modulate the behavioural impact of both appetitively and aversively motivated conditioned stimuli on instrumental performance, whilst the benzodiazepine midazolam has a selective impact on aversively-motivated stimuli that is qualitatively distinct from that of the dopaminergic antagonist alpha-flupenthixol.

Deficits in memory and hippocampal long-term potentiation in mice with reduced calbindin D28K expression.

The influx of calcium into the postsynaptic neuron is likely to be an important event in memory formation. Among the mechanisms that nerve cells may use to alter the time course or size of a spike of intracellular calcium are cytosolic calcium binding or "buffering" proteins. To consider the role in memory formation of one of these proteins, calbindin D28K, which is abundant in many neurons, including the CA1 pyramidal cells of the hippocampus, transgenic mice deficient in calbindin D28K have been created. These mice show selective impairments in spatial learning paradigms and fail to maintain long-term potentiation. These results suggest a role for calbindin D28K protein in temporally extending a neuronal calcium signal, allowing the activation of calcium-dependent intracellular signaling pathways underlying memory function.