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Biomedical subjects

A S Killcross

Publications and source records attributed to A S Killcross.

16 recordsLinked to original sources
PubMed2005

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.

Analysis of Variance↗
PubMed2005

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.

Adrenergic Agents↗
PubMed2005

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.

Animals↗
PubMed2003

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.

Association↗
PubMed2002

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.

Analysis of Variance↗
PubMed2001

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.

Animals↗
PubMed1998

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.

Animals↗
PubMed1998

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.

Animals↗
PubMed1998

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.

Animals↗
PubMed1997

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.

Amphetamine↗
PubMed1997

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.

Acoustic Stimulation↗
PubMed1996

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.

Animals↗
PubMed1994

Amphetamine-induced disruptions of latent inhibition are reinforcer mediated: implications for animal models of schizophrenic attentional dysfunction.

Latent inhibition (LI) is a phenomenon observed when repeated, non-reinforced presentation of a stimulus results in a retardation of subsequent conditioning to that stimulus. Several recent experiments have suggested that LI is abolished in conditioned suppression paradigms following acute, low doses of amphetamine given during pre-exposure and conditioning. Experiment 1 sought to increase the generality of this finding in an appetitive LI paradigm, using a dose of amphetamine previously shown to disrupt the LI effect in an aversive paradigm (Killcross and Robbins 1993). However, no evidence for any disruption of LI was found. Experiment 2 extended this investigation to additional, higher doses of d-amphetamine, and also examined the role of reinforcer magnitude in the effect. A non-significant trend towards an attenuated LI effect was found, which was reversed by decreases in the concentration of the sucrose reinforcer. Experiments 3 and 4 investigated the influence of systemic amphetamine in aversive paradigms, with specific attention to the increased response to the aversive foot-shock reinforcer found in amphetamine-treated animals. These experiments revealed that the influence of amphetamine on the LI effect in conditioned suppression paradigms could be reversed by reducing the intensity of footshock used in conditioning, thereby paralleling the effect found in the appetitive paradigm. Therefore it is unlikely that a simple attentional account of the abolition of the LI effect in previous experiments can be sustained.

Amphetamine↗
PubMed1994

Effects of the neuroleptic alpha-flupenthixol on latent inhibition in aversively- and appetitively-motivated paradigms: evidence for dopamine-reinforcer interactions.

Three experiments examined the influence of the dopamine (DA) D1/D2 receptor antagonist alpha-flupenthixol on the latent inhibition (LI) effect. LI is a phenomenon which is manifest when non-reinforced pre-exposure to a stimulus retards subsequent conditioning to that stimulus, and has been proposed as an animal model of the selective attentional processes that are disrupted in acute schizophrenia. Experiment 1 extended previous findings that neuroleptics enhance the LI effect in conditioned suppression paradigms in rats to alpha-flupenthixol (0.23 mg/kg). Experiment 2 demonstrated that this enhancement of the LI effect was also seen in a parallel appetitively-motivated conditioning paradigm at the same dose. In both Experiment 1 and Experiment 2, the enhancement of the LI effect by alpha-flupenthixol appeared to be accompanied by a decrease in the impact of the reinforcer (be it appetitive or aversive). Experiment 3 investigated the possible role of the reinforcer in the effect of alpha-flupenthixol on the LI effect in the aversive, conditioned suppression paradigm by increasing the intensity of footshock in rats treated with alpha-flupenthixol. Increasing the intensity of the footshock completely abolished the enhancement of LI found following injection of alpha-flupenthixol, a result which could not be attributed to a floor effect. The results provide no support for interpretations of the influence of DA manipulations on the LI effect that draw parallels with deficits in selective attention observed in acute schizophrenia.

Acoustic Stimulation↗
PubMed1993

Differential effects of intra-accumbens and systemic amphetamine on latent inhibition using an on-baseline, within-subject conditioned suppression paradigm.

Latent inhibition (LI) is a phenomenon in which repeated, non-reinforced presentation of a stimulus retards subsequent conditioning to that stimulus. Several recent experiments have suggested that LI is abolished following acute, low doses of amphetamine given during pre-exposure and conditioning, and this effect has been attributed to amphetamine-induced changes in dopamine levels in the nucleus accumbens. Experiments 1 and 2 examined the effects of two doses of intra-accumbens d-amphetamine (10 micrograms/microliters and 3 micrograms/microliters) on LI in an on-baseline, within-subject conditioned suppression paradigm. There was no effect of either dose on LI, but a significant disinhibition of conditioned suppression resulted in a retardation of learning. In experiment 3 the effects of a low dose of systemic d-amphetamine (0.5 mg/kg) on latent inhibition were examined. The results replicated the abolition of LI found in previous studies, and demonstrated enhanced post-shock suppression in amphetamine-treated animals. These data provide no evidence for the involvement of the mesolimbic dopamine system in LI.

Acoustic Stimulation↗