Simon Killcross

Different types of fear-conditioned behaviour mediated by separate nuclei within amygdala

The amygdala has long been thought to be involved in emotional behaviour, and its role in anxiety and conditioned fear has been highlighted. Individual amygdaloid nuclei have been shown to project to various cortical and subcortical regions implicated in affective processing. Here we show that some of these nuclei have separate roles in distinct mechanisms underlying conditioned fear responses. Rats with lesions of the central nucleus exhibited reduction in the suppression of behaviour elicited by a conditioned fear stimulus, but were simultaneously able to direct their actions to avoid further presentations of this aversive stimulus. In contrast, animals with lesions of the basolateral amygdala were unable to avoid the conditioned aversive stimulus by their choice behaviour, but exhibited normal conditioned suppression to this stimulus. This double dissociation demonstrates that distinct neural systems involving separate amygdaloid nuclei mediate different types of conditioned fear behaviour. We suggest that theories of amygdala function should take into account the roles of discrete amygdala subsystems in controlling different components of integrated emotional responses.

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.

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.

Social isolation in the rat produces developmentally specific deficits in prepulse inhibition of the acoustic startle response without disrupting latent inhibition

A series of experiments examined the effects of 8 weeks of social isolation on spontaneous locomotor activity, prepulse inhibition (PPI) of the acoustic startle response, latent inhibition (LI) in a conditioned suppression paradigm, and basal and d-amphetamine stimulated dopamine (DA) release in the ventral striatum, as measured by in vivo microdialysis. Both isolation-reared animals (those isolated from the weaning age) and isolation-housed animals (those isolated as adults) were hyperactive when placed in a novel environment. Social isolation also led to deficits in PPI of the acoustic startle response that were specific to isolation-reared animals. Isolation rearing was without effect on the expression of LI but did lead to an enhanced response to systemic d-amphetamine in terms of striatal DA release. The data are discussed with respect to the involvement of ventral striatal DA mechanisms in the expression of PPI and LI, differences in the impact of social isolation in young and adult animals, and the utility of social isolation model as a nonlesion, nonpharmacologic means of perturbing ventral striatal DA function.

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.

Dopaminergic Mechanisms in Actions and Habits

Recent studies suggest new ways to interpret dopaminergic actions in goal-directed performance and habitual responding. In the early stages of learning dopamine plays an essential role, but with extended training dopamine appears to play a decreasing role in response expression. Experimental manipulation of dopamine levels alters the correlation of cortical and striatal neural activity in behaving animals, and these dopamine-dependent changes in corticostriatal correlations may be reflected in changes in action selection in the basal ganglia. Consistent with this hypothesis, changes in dopamine signaling brought about by sensitization with amphetamine mimic the transition from goal-directed to habit-based instrumental performance. At the cellular level, dopamine-dependent synaptic plasticity may be important initially, and subsequently lead to more persistent changes that no longer require dopamine. The locus of these actions within the cortical and corticostriatal circuitry is a focus on ongoing research.

Effects of ibotenic acid lesions of the Nucleus Accumbens on instrumental action

In a series of studies, we assessed the effects of ibotenic acid lesions of the nucleus accumbens on instrumental performance in hungry rats. Although these lesions were found to generally impair lever press performance for both food pellets and a sucrose solution, they did not affect sensitivity to changes in the incentive value of the outcome induced either by a shift in food deprivation or a shift in the sucrose concentration. Further, these lesions did not affect sensitivity to a change in the instrumental contingency from response-contingent to non-contingent outcome delivery. In contrast, concurrent assessment of food magazine approach responses found that the lesion induced both a deficit in magazine entry and marked insensitivity to shifts in the incentive value of the outcome and to the changed situation that accompanied the change in instrumental contingency. These results are interpreted as suggesting (1) that nucleus accumbens lesions produce a general deficit in affective arousal; and (2) that the influence of affective mechanisms on instrumental performance may be structurally dissociated from the control of performance mediated by the action-outcome relation.

Associative learning mechanisms underpinning the transition from recreational drug use to addiction

Learning theory proposes that drug seeking is a synthesis of multiple controllers. Whereas goal‐directed drug seeking is determined by the anticipated incentive value of the drug, habitual drug seeking is elicited by stimuli that have formed a direct association with the response. Moreover, drug‐paired stimuli can transfer control over separately trained drug seeking responses by retrieving an expectation of the drugs identity (specific transfer) or incentive value (general transfer). This review covers outcome devaluation and transfer of stimulus‐control procedures in humans and animals, which isolate the differential governance of drug seeking by these four controllers following various degrees of contingent and noncontingent drug exposure. The neural mechanisms underpinning these four controllers are also reviewed. These studies suggest that although initial drug seeking is goal‐directed, chronic drug exposure confers a progressive loss of control over action selection by specific outcome representations (impaired outcome devaluation and specific transfer), and a concomitant increase in control over action selection by antecedent stimuli (enhanced habit and general transfer). The prefrontal cortex and mediodorsal thalamus may play a role in this drug‐induced transition to behavioral autonomy.

Inactivation of the prelimbic, but not infralimbic, prefrontal cortex impairs the contextual control of response conflict in rats

One fundamental function of the prefrontal cortex (PFC) is to guide context‐appropriate behaviour in situations of response conflict. Haddon and Killcross recently developed a task in rats which mimics some aspects of response conflict seen in human cognitive paradigms such as the Stroop task. Using this paradigm they demonstrated that large PFC lesions including the prelimbic (PL), infralimbic (IL) and anterior cingulate cortices (ACC) selectively impaired performance on incongruent trials which required the use of task‐setting contextual cues to control responding in the face of ambiguous response information. The current experiment was conducted to determine whether specific PFC regions were responsible for the deficit in incongruent performance. Rats were trained on two instrumental biconditional discriminations, one auditory and one visual, in two different contexts. Following acquisition, rats were implanted with guide cannulae aimed at the PL or the IL cortices of the rat prefrontal cortex. Following retraining, rats received microinfusions of the GABAA agonist muscimol or artificial cerebrospinal fluid (aCSF) into either the PL or the IL prior to presentations of novel congruent and incongruent audiovisual compounds of the training stimuli in extinction. Results showed that temporary inactivation of the PL cortex led to a selective deficit on incongruent compound trials, but left congruent, and hence biconditional task performance intact. By contrast, IL inactivation had no effect on the accuracy of responding during either congruent or incongruent trials. These results suggest that the PL cortex is necessary for the use of task‐setting contextual cues to control responding to conflicting information.

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.