Biomedical subjects

Simon Killcross

Publications and source records attributed to Simon Killcross.

15 recordsLinked to original sources

PubMed2006

Clozapine but not haloperidol treatment reverses sub-chronic phencyclidine-induced disruption of conditional discrimination performance.

Abusers of phencyclidine (PCP) often present with a symptom profile similar to that exhibited by schizophrenic patients. Animal models utilising such psychotomimetics are currently informing research into the condition. Accumulating evidence suggests that a central cognitive deficit in schizophrenia is the inability to use task-setting cues to guide goal directed behaviour and that this ability is mediated by prefrontal dopamine (DA). The current study used the non-competitive NMDA antagonist phencyclidine (PCP) and Haloperidol (typical antipsychotic) and Clozapine (atypical antipsychotic) in order to further investigate the influence of DAergic manipulation on a task that requires the use of conditional information to inform goal-directed performance. An instrumental conditional discrimination task was employed in which rats learn to respond appropriately according to the presence of specific auditory conditional stimuli. Probe test 1 showed impaired conditional discrimination performance following sub-chronic PCP administration (seven twice-daily injection protocol) compared to control which was reversed by acute treatment with clozapine (5 mg/kg) but not haloperidol (0.1 mg/kg) both administered 60 min pre-test. Probe test 2 (8 days post-treatment) showed enduring deficits to conditional discrimination performance that were again reversed by clozapine but not haloperidol (injection procedures as above). These results show that tasks dependent upon conditional relationships are particularly sensitive to manipulation of DAergic systems as prolonged treatment with PCP has been shown to selectively reduce prefrontal cortex (PFC) DA activity and treatment with clozapine (known to ameliorate cognitive deficits) but not haloperidol has been shown to selectively restore PFC DA levels.

Analysis of Variance↗

PubMed2006

Differential attenuation of d-amphetamine-induced disruption of conditional discrimination performance by dopamine and serotonin antagonists.

RATIONALE: Recent experimental findings suggest that a core cognitive deficit of schizophrenia is the degraded ability to use task-setting cues to guide goal-directed behaviour, that this deficit is evident in acute as well as chronic schizophrenia, and that such deficits can me modelled in animals using conditional discrimination tasks. OBJECTIVE: To establish the reversal potential of D1, D2 and 5-HT receptor antagonists acutely, and D1 and D2 receptor antagonists chronically, on d-amphetamine-induced disruption of a conditional discrimination task that depends on the ability to use task-setting cues to direct goal directed performance. METHOD: A conditional discrimination paradigm was employed in which rats learned to respond on an appropriate lever, conditional upon specific auditory stimuli. RESULTS: d-Amphetamine (1.5 mg/kg) disruption of conditional discrimination was attenuated by acute pre-treatment with the selective D1 antagonist SCH 23390 and the atypical anti-psychotic clozapine (Cloz). Acute pre-treatment with the selective D2 antagonist eticlopride (Eti) and the anti-psychotic haloperidol (Hal) failed to reverse d-amphetamine disruption, as did pre-treatment with the selective 5HT1A antagonist WAY 100635 and the selective 5HT2A/C antagonist ritanserin. However, Eti and Hal did reverse d-amphetamine-induced task disruption when administered chronically (as did SCH 23390, alpha-flupenthixol and Cloz). CONCLUSIONS: These results suggest that D1 receptors are involved in tasks that require the use of conditional relationships and that D2 receptor antagonism can come to exert a similar influence after chronic treatment.

Animals↗

PubMed2006

Both motivational and training factors affect response conflict choice performance in rats.

Rats were trained on two biconditional discrimination tasks, in two different contexts, and were rewarded with two different outcomes. At test, they received presentations of audiovisual compounds of these training stimuli, in extinction. These compounds were formed in such way that the individual elements had dictated either the same (congruent trials) or different (incongruent trials) responses during training, and each stimulus element had previously been rewarded with a different outcome. Previous research has shown that rats use the contextual cues to disambiguate the conflicting response information provided by incongruent stimulus compounds. Experiment 1 demonstrated that this contextual control was goal-directed in the sense that it depended on the current value of the outcome and Experiment 2 demonstrated that both the training history of the biconditional stimuli and motivational influences influenced the contextual control of responding on incongruent trials. These results are discussed in relation to current models of choice behaviour.

Acoustic Stimulation↗

PubMed2006

Lesions of the basolateral amygdala disrupt conditioning based on the retrieved representations of motivationally significant events.

One recent perspective (Blundell et al., 2001; 2003; Killcross and Blundell, 2002; Balleine et al. 2003) on the function of the basolateral region of the amygdala (BLA) suggests that it plays an important role in the representation of the sensory features of motivationally significant events. This predicts that lesions of the BLA will not produce a decrement in performance in conditioning procedures based on the formation of associations between the sensory aspects of neutral events but will interfere with conditioning based on associations between neutral cues and motivationally significant events. This prediction is supported by the evidence that BLA lesions were without effect on a sensory preconditioning procedure (experiment 1A) that used neutral cues but that BLA lesions did significantly impair representation-mediated conditioning (experiment 1B) when the target cues were motivationally significant at the time of training. These results demonstrate that animals with lesions of the BLA can represent the sensory aspects of neutral events but not the sensory aspects of motivationally significant events.

Amygdala↗

PubMed2006

Amphetamine exposure enhances habit formation.

Performance of instrumental actions in rats is initially sensitive to postconditioning changes in reward value, but after more extended training, behavior comes to be controlled by stimulus-response (S-R) habits that are no longer goal directed. To examine whether sensitization of dopaminergic systems leads to a more rapid transition from action-outcome processes to S-R habits, we examined performance of amphetamine-sensitized rats in an instrumental devaluation task. Animals were either sensitized (7 d, 2 mg/kg/d) before training (experiment 1) or sensitized between training and testing (experiment 2). Rats were trained to press a lever for a reward (three sessions) and were then given a test of goal sensitivity by devaluation of the instrumental outcome before testing in extinction. Control animals showed selective sensitivity to devaluation of the instrumental outcome. However, amphetamine sensitization administered before training caused the animals' responding to persist despite the changed value of the reinforcer. This deficit resulted from an inability to use representations of the outcome to guide behavior, because a reacquisition test confirmed that all of the animals had acquired an aversion to the reinforcer. In experiment 2, post-training sensitization did not disrupt normal goal-directed behavior. These findings indicate that amphetamine sensitization leads to a rapid progression from goal-directed to habit-based responding but does not affect the performance of established goal-directed actions.

Amphetamine↗

PubMed2006

Parallel incentive processing: an integrated view of amygdala function.

The amygdala is a heterogeneous structure that has been implicated in a wide variety of functions, most notably in fear conditioning. From this research, an influential serial model of amygdala processes has emerged in which aversive learning is mediated by the amygdala basolateral nucleus whereas performance, in this case of various defensive reflexes, is mediated by the central nucleus. By contrast, recent evidence from appetitive conditioning studies suggests that the basolateral and central nuclei operate in parallel to mediate distinct incentive processes: the basolateral nucleus encodes emotional events with reference to their particular sensory-specific features, whereas the central nucleus encodes their more general motivational or affective significance. Given that there is little if any direct behavioral evidence for the serial model, we suggest that more attention should be given to the claims of the parallel view.

Amygdala↗

PubMed2006

Prefrontal cortex lesions disrupt the contextual control of response conflict.

The prefrontal cortex has been implicated in multiple forms of goal-directed behavior. Rats with pretraining lesions to the prefrontal cortex (PFC) or specific lesions to the anterior cingulate cortex (ACC) were trained and tested on a novel behavioral procedure measuring aspects of cue and response competition typical of tests of prefrontal function in humans. Rats were trained on two biconditional discrimination tasks, one auditory and one visual, in two discriminably different contexts. At test, they received presentations of audiovisual compounds of these training stimuli in both contexts, in extinction. These compounds were formed in such way that the individual elements had dictated either the same (congruent trials) or different (incongruent trials) responses during training. Sham-operated rats used the contextual cues to disambiguate the conflicting response information provided by incongruent stimulus compounds. ACC lesions impaired the contextual control of instrumental responding during incongruent cues during only the initial period of cue presentation, whereas larger PFC lesions abolished incongruent cue performance completely. Neither biconditional discrimination acquisition, nor test performance during congruent stimulus compounds, were affected by the lesions. These findings are consistent with human and nonhuman primate studies, indicating a role for the PFC in the processes by which cues come to control behavior in the face of conflicting information and the ACC specifically in processes such as detection of response conflict. This procedure provides a good foundation for an improved understanding of the disruption to goal-directed behavior seen with frontal dysfunction in a number of neuropsychological disorders including schizophrenia.

Acoustic Stimulation↗

PubMed2004

Attenuation of d-amphetamine-induced disruption of conditional discrimination performance by alpha-flupenthixol.

RATIONALE: Previous evidence suggests that manipulation of forebrain dopamine (DA) systems may impair the use of conditional information to inform goal-directed performance, and this may be related to impairments in the ability to use task-setting cues in schizophrenia. OBJECTIVE: To investigate, using the indirect DA agonist d-amphetamine and the D1/D2 receptor antagonist alpha-flupenthixol, the influence of DAergic manipulation on discrimination performance that requires the use of conditional information to inform goal-directed performance. METHODS: Both instrumental and Pavlovian conditional discriminations were employed in which rats learned to respond appropriately according to the presence of auditory conditional stimuli, and results from these experiments were contrasted with a control Pavlovian-instrumental transfer task. RESULTS: Experiment 1 showed a disruption of instrumental conditional discrimination performance by d-amphetamine at 1.5 mg/kg and attenuation of correct responding following 1.0 mg/kg. Disruption with both doses was observed in experiment 2 using a conditional discrimination based on Pavlovian, conditioned responding. Results from a control Pavlovian-instrumental transfer task (experiment 3) revealed that d-amphetamine (0.5, 1.0 and 1.5 mg/kg) did not have any detrimental effect on subjects' basic sensory, motor or motivational processes. Experiment 4 showed that d-amphetamine disruption of instrumental conditional discrimination was attenuated by pre-treatment with the D1/D2 receptor antagonist alpha-flupenthixol. CONCLUSION: These results demonstrate that tasks dependent on conditional relationships are highly sensitive to manipulation of DAergic systems.

Animals↗

PubMed2003

Inactivation of the infralimbic prefrontal cortex reinstates goal-directed responding in overtrained rats.

Over the course of extended training, instrumental responding in rats shows a transition from goal-dependent performance to goal-independent performance, as assessed by sensitivity to reward-devaluation induced by taste aversions or specific satiety. It has been suggested that this reflects the gradual dominance of reflexive, habit-based responding over voluntary, goal-directed actions. Previous research suggests that lesions of the medial prefrontal cortex disrupt this interaction between goal-directed and habitual responding. More specifically, whereas lesions of the prelimbic prefrontal cortex appear to disrupt normal goal-directed responding, lesions of the infralimbic prefrontal cortex cause animals to remain goal-directed even after substantial overtraining. The current experiment explored further the nature of this interaction between actions and habits. Rats were given extended training of an instrumental lever press response before bilateral intracerebral cannulae giving access to the infralimbic cortex were implanted. Following further reminder training all animals were given a test of goal sensitivity by specific-satiety devaluation of the instrumental outcome, or a matched reward, prior to extinction tests. Before these tests, half of the animals received bilateral infusions of muscimol into the infralimbic cortex, and the remainder, control vehicle infusions. As expected after extended instrumental training, control-infused animals showed habitual performance that was not selectively influenced by devaluation of the instrumental outcome. In contrast, animals receiving temporary inactivation of the infralimbic cortex by muscimol showed selective sensitivity to devaluation of the instrumental outcome, indicating a reinstatement of goal-directed responding in these animals. This suggests that the development of habitual responding reflects the active inhibition of goal-directed responses that are mediated by action-outcome associations.

Analysis of Variance↗

PubMed2003

Preserved sensitivity to outcome value after lesions of the basolateral amygdala.

Recent work (Blundell et al., 2001; Balleine et al., 2003) has suggested that the basolateral region of the amygdala (BLA) is important in the representation of the sensory and incentive aspects of motivationally significant events. In common with other theories of function of the BLA, this predicts that lesions of the BLA will interfere with reinforcer devaluation after appetitive Pavlovian or instrumental conditioning. However, this hypothesis also predicts that BLA lesions will be without effect on postconditioning changes in reinforcer value if initial learning is only about the sensory aspects of otherwise neutral events. This interpretation is supported by evidence for significant detrimental effects of BLA lesions on reinforcer devaluation in a Pavlovian autoshaping procedure, but no effect of postconditioning devaluation using a sensory preconditioning procedure. These results demonstrate that animals with BLA lesions can remain sensitive to post-training changes in the motivational value of outcomes.

Amygdala↗

PubMed2003

Glucocorticoid receptor agonist enhances pavlovian appetitive conditioning but disrupts outcome-specific associations.

A Pavlovian-instrumental transfer design was used to investigate the impact of the glucocorticoid receptor agonist dexamethasone (dex) on Pavlovian associations involving the sensory and motivational aspects of rewards. Rats were trained with 2 lever responses, R1 and R2, for different rewards, Outcome (O)1 and O2. In separate Pavlovian training sessions. Stimulus A was paired with O1 and Stimulus B with O2. Administration of dex after A-O1 sessions enhanced A-O1 associations measured in extinction, relative to B-O2 pairings that were followed by saline. In lever-press transfer tests, presentation of Stimuli A or B enhanced general responding to the same degree. However, outcome-specific transfer (selectively greater enhancement of R1 during A and R2 during B) was abolished for Stimulus A. This suggests that memory enhancement by posttraining dex is simultaneously detrimental to processing of outcome-specific sensory information.

Animals↗

PubMed2003

Discrimination between outcomes in instrumental learning: effects of preexposure to the reinforcers.

In two experiments rats received instrumental training with two response levers, one response being reinforced by sucrose solution and the other by sucrose pellets. Prior to a test session, on which both levers were made available in the absence of reinforcement, the rats were given free access to one of the reinforcers, a procedure known to reduce its value. It was found that the rats responded at a lower rate on the lever that had produced the now-devalued reinforcer, but that this effect was substantial only in rats that had received preexposure to the two reinforcers before instrumental training was begun (Experiment 1). Experiment 2 demonstrated that this effect was obtained only when presentations of the two reinforcers were presented according to an inter-mixed schedule during preexposure. It is suggested that this result constitutes an instance of the perceptual learning effect in which intermixed preexposure to similar events enhances their discriminability.

Animals↗

PubMed2003

Coordination of actions and habits in the medial prefrontal cortex of rats.

As animals learn novel behavioural responses, performance is maintained by two dissociable influences. Initial responding is goal-directed and under voluntary control, but overtraining of the same response routine leads to behavioural autonomy and the development of habits that are no longer voluntary or goal-directed. Rats normally show goal-directed performance after limited training, indexed by sensitivity to changes in the value of reward, but this sensitivity to goal value is lost with extended training. Rats with selective lesions of the prelimbic medial prefrontal cortex showed no sensitivity to goal value after either limited or extended training, whereas rats with lesions of the infralimbic region of the medial prefrontal cortex showed the opposite pattern of deficit, a marked sensitivity to goal value after both limited and extended training. This double-dissociation suggests that the prelimbic region is responsible for voluntary response performance and the infralimbic cortex mediates the incremental ability of extended training to override this goal-directed behaviour.

Animals↗

PubMed2002

Posttraining glucocorticoid receptor agonist enhances memory in appetitive and aversive Pavlovian discrete-cue conditioning paradigms.

Glucocorticoid modulation of emotional memory has repeatedly been shown in aversive learning paradigms, but has received little attention in appetitive tasks. It has also been suggested that it may be selective for contextual cues. In order to investigate if glucocorticoids can modulate memory in discrete-cue conditioning of both appetitive and aversive tasks, two experiments were carried out. Male Lister-Hooded rats received pairings of an auditory cue and either food-reward (experiment 1) or footshock (experiment 2), followed immediately by posttraining injections of the glucocorticoid receptor agonist dexamethasone (0.3, 0.6, and 1.2 mg/kg) or vehicle. Dexamethasone (1.2 mg/kg) led to significantly enhanced learning. These results give support to the notion that glucocorticoids play a role in the modulation of both appetitive and aversive emotional memories and show that their role in learning goes beyond the construction of context representations. The modulation of appetitive and aversive discrete-cue learning may be subserved by a common mechanism.

Animals↗

PubMedDate not supplied

Lesions of rat infralimbic cortex enhance recovery and reinstatement of an appetitive Pavlovian response.

The prefrontal cortex (PFC) has a well-established role in the inhibition of inappropriate responding, and evidence suggests that the infralimbic (IL) region of the rat medial PFC (MPFC) may be involved in some aspects of extinction of conditioned fear. MPFC lesions including, but not those sparing the IL cortex increase spontaneous recovery of extinguished conditioned fear when tested 24 h after an initial extinction session. The current experiment extended these findings by use of appetitive rather than aversive conditioning. Ten IL-lesioned and 11 sham-operated rats were trained on a Pavlovian task in which a conditioned stimulus (CS) was followed by food pellets (the unconditioned stimulus or US). IL lesions had no effect on extinction of the conditioned response (CR, magazine entries) during the first extinction session. However, the level of spontaneous recovery between the first extinction session and a second, 24 h later, was increased in IL-lesioned rats relative to sham animals. In contrast, evidence of savings measured between the extinction sessions did not differ between groups. Furthermore, reinstatement of the CR following unsignaled delivery of the US was also increased in IL-lesioned rats.

Animals↗