Prediction, perception, and psychosis: Application of associative learning theories to schizophrenia research.

In recent years, there have been significant advances in our understanding of the positive symptoms of schizophrenia, such as hallucinations and delusions. This progress has been significantly aided by the use of associative learning-based approaches in human subjects and preclinical animal models. Here, we first review experimental research focusing on the abnormal processing of absent stimuli using three different conditioning phenomena: conditioned hallucinations, mediated conditioning, and trace conditioning.

Transition between habits and goal-directed actions in the renewal effect.

Three experiments with rats explored whether previously extinguished goal-directed and habitual responding recover with the same status using an ABA renewal preparation. In Experiments 1a and 1b, a lever-press response was minimally (four sessions) or extensively (16 sessions) trained in one context (Context A) and extinguished in another context (Context B). Then, outcome devaluation took place in either Context A or Context B in which a food pellet reinforcing the response was paired with lithium chloride (LiCl) for devalued groups and with saline for a control group.

Kamin blocking is disrupted by low-dose ketamine in mice: Further implications for aberrant stimulus processing in schizophrenia.

Previous studies have shown that low doses of ketamine, an N-methyl-D-aspartate receptor antagonist, produce aberrantly strong internal representations of associatively activated but absent stimuli in humans and nonhuman animals, suggesting the validity of ketamine treatment as a preclinical model of the positive symptoms of schizophrenia, including hallucinations and delusions. However, whether acute ketamine treatment also impairs the ability to ignore present but informationally redundant stimuli, which is another hallmark of schizophrenia, remains unclear. Accordingly, the present study investigated whether injections of low-dose ketamine attenuate Kamin blocking in an appetitive conditioning preparation in mice.

Resurgence of goal-directed actions and habits.

This study investigated how goal-directed and habitual behaviors recover after extinction within the context of the resurgence effect, a form of relapse induced by the removal or worsening of alternative reinforcement. Rats were trained to press a target lever with one reinforcer (O1) for either minimal (4) or extended (16) sessions. An extinction test after the completion of O1 devaluation confirmed that minimal and extended training formed goal-directed and habitual behaviors, respectively.

Ketamine facilitates appetitive trace conditioning in mice: Further evidence for abnormal stimulus representation in schizophrenia model animals.

Recent studies indicated that positive symptoms of schizophrenia, such as hallucination and delusion, can be modeled using Pavlovian conditioning procedures. Various schizophrenia model animals exhibit abnormally strong associative activations of absent stimuli (i.e.

Measurement of the exploration-exploitation response of dogs through a concurrent visual discrimination task.

In many species, the allocation of exploration and exploitation responses to environmental stimuli is important for survival. In this exploratory study, we determined whether dogs (Canis familiaris) explored novel stimuli in a visual discrimination task using food reinforcers. Initially, the dogs were trained with two pairs of simultaneous visual discrimination tasks.

Higher-Order Conditioning in the Spatial Domain.

Spatial learning and memory, the processes through which a wide range of living organisms encode, compute, and retrieve information from their environment to perform goal-directed navigation, has been systematically investigated since the early twentieth century to unravel behavioral and neural mechanisms of learning and memory. Early theories about learning to navigate space considered that animals learn through trial and error and develop responses to stimuli that guide them to a goal place. According to a trial-and error learning view, organisms can learn a sequence of motor actions that lead to a goal place, a strategy referred to as response learning, which contrasts with place learning where animals learn locations with respect to an allocentric framework.

Spontaneous object-location memory based on environmental geometry is impaired by both hippocampal and dorsolateral striatal lesions.

We examined the role of the hippocampus and the dorsolateral striatum in the representation of environmental geometry using a spontaneous object recognition procedure. Rats were placed in a kite-shaped arena and allowed to explore two distinctive objects in each of the right-angled corners. In a different room, rats were then placed into a rectangular arena with two identical copies of one of the two objects from the exploration phase, one in each of the two adjacent right-angled corners that were separated by a long wall.

Spatial inference without a cognitive map: the role of higher-order path integration.

The cognitive map has been taken as the standard model for how agents infer the most efficient route to a goal location. Alternatively, path integration - maintaining a homing vector during navigation - constitutes a primitive and presumably less-flexible strategy than cognitive mapping because path integration relies primarily on vestibular stimuli and pace counting. The historical debate as to whether complex spatial navigation is ruled by associative learning or cognitive map mechanisms has been challenged by experimental difficulties in successfully neutralizing path integration.

En route to delineating hippocampal roles in spatial learning.

The precise role played by the hippocampus in spatial learning tasks, such as the Morris Water Maze (MWM), is not fully understood. One theory is that the hippocampus is not required for 'knowing where' but rather is crucial in 'getting there'. To explore this idea in the MWM, we manipulated 'getting there' variables, such as passive transport or active swimming towards the hidden platform, in rats with and without hippocampal lesions.

The response strategy and the place strategy in a plus-maze have different sensitivities to devaluation of expected outcome.

Previous studies have suggested that spatial navigation can be achieved with at least two distinct learning processes, involving either cognitive map-like representations of the local environment, referred to as the "place strategy", or simple stimulus-response (S-R) associations, the "response strategy". A similar distinction between cognitive/behavioral processes has been made in the context of non-spatial, instrumental conditioning, with the definition of two processes concerning the sensitivity of a given behavior to the expected value of its outcome as well as to the response-outcome contingency ("goal-directed action" and "S-R habit"). Here we investigated whether these two versions of dichotomist definitions of learned behavior, one spatial and the other non-spatial, correspond to each other in a formal way.

Striatonigral direct pathway activation is sufficient to induce repetitive behaviors.

Pharmacological intervention in the substantia nigra is known to induce repetitive behaviors in rodents, but a direct causal relationship between a specific neural circuit and repetitive behavior has not yet been established. Here we demonstrate that optogenetic activation of dopamine D1 receptor-expressing MSNs terminals in the substantia nigra pars reticulata resulted in sustained and chronic repetitive behaviors. These data show for the first time that activation of the striatonigral direct pathway is sufficient to generate motor stereotypies.

Mice lacking hippocampal left-right asymmetry show non-spatial learning deficits.

Left-right asymmetry is known to exist at several anatomical levels in the brain and recent studies have provided further evidence to show that it also exists at a molecular level in the hippocampal CA3-CA1 circuit. The distribution of N-methyl-d-aspartate (NMDA) receptor NR2B subunits in the apical and basal synapses of CA1 pyramidal neurons is asymmetrical if the input arrives from the left or right CA3 pyramidal neurons. In the present study, we examined the role of hippocampal asymmetry in cognitive function using β2-microglobulin knock-out (β2m KO) mice, which lack hippocampal asymmetry.

Impaired Pavlovian predictive learning between temporally phasic but not static events in autism-model strain mice.

Autism-spectrum disorder (ASD) is a multi-aspect developmental disorder characterised by various social and non-social behavioural abnormalities. Using BTBR T+ tf mouse strain (BTBR), a promising animal model displaying a number of behavioural and neural characteristics associated with ASD, we tested the hypothesis that at the core of various symptoms of ASD lies a fundamental deficit in predictive learning between events. In five experiments, we conducted a variety of Pavlovian conditioning tasks, some requiring the establishment of associations between temporally phasic events and others involving static events.

Conditioned social preference, but not place preference, produced by intranasal oxytocin in female mice.

Oxytocin (OT) has been implicated in a variety of mammalian reproductive and social behaviors, and the use of intranasal OT for clinical purposes is on the rise. However, basic actions of OT, including the rewarding or reinforcing properties of the drug, are currently not fully understood. In this study, the authors investigated whether intranasally administered OT has different reinforcing properties for social and nonsocial stimuli and whether such effects are variable between male and female subjects.

Asymmetrical generalization of length in the rat.

Two groups of rats in Experiment 1 were required to escape from a square pool by swimming to 1 of 2 submerged platforms that were situated beside the centers of 2 opposite walls. To help rats find a platform, black panels of equal width were pasted to the middle of the walls that were adjacent to the platforms. The width of the 2 panels was 50 cm for Group 50, and 100 cm for Group 100.

Evidence for concrete but not abstract representation of length during spatial learning in rats.

In 4 experiments, rats had to discriminate between the lengths of 2 objects of the same color, black or white, before a test trial with the same objects but of opposite color. The experiments took place in a pool from which rats had to escape by swimming to 1 of 2 submerged platforms. For Experiments 1 and 2, the platforms were situated near the centers of panels of 1 length, but not another, that were pasted onto the gray walls of a square arena.

Dorsolateral striatal lesions impair navigation based on landmark-goal vectors but facilitate spatial learning based on a "cognitive map".

In three experiments, the nature of the interaction between multiple memory systems in rats solving a variation of a spatial task in the water maze was investigated. Throughout training rats were able to find a submerged platform at a fixed distance and direction from an intramaze landmark by learning a landmark-goal vector. Extramaze cues were also available for standard place learning, or "cognitive mapping," but these cues were valid only within each session, as the position of the platform moved around the pool between sessions together with the intramaze landmark.

The role of the hippocampus in passive and active spatial learning.

Rats with lesions of the hippocampus or sham lesions were required in four experiments to escape from a square swimming pool by finding a submerged platform. Experiments 1 and 2 commenced with passive training in which rats were repeatedly placed on the platform in one corner-the correct corner-of a pool with distinctive walls. A test trial then revealed a strong preference for the correct corner in the sham but not the hippocampal group.

Asymmetry in the discrimination of length during spatial learning.

The ability of rats to solve a discrimination between two objects that differ in length was investigated in five experiments. Using a rectangular swimming pool, Experiment 1 revealed it is easier to locate a submerged platform when it is near the center of a long rather than a short wall. For Experiments 2-4, the objects were black or white panels pasted onto the gray walls of a square pool, with two long panels pasted to two opposing walls and two short panels pasted to the remaining walls.

Within-compound associations explain potentiation and failure to overshadow learning based on geometry by discrete landmarks.

In three experiments, rats were trained to locate a submerged platform in one of the base corners of a triangular arena above each of which was suspended one of two distinctive landmarks. In Experiment 1, it was established that these landmarks differed in their salience by the differential control they gained over behavior after training in compound with geometric cues. In Experiment 2, it was shown that locating the platform beneath the less salient landmark potentiated learning based on geometry compared with control rats for which landmarks provided ambiguous information about the location of the platform.

Overshadowing of geometry learning by discrete landmarks in the water maze: effects of relative salience and relative validity of competing cues.

The effects of stimulus salience and cue validity in the overshadowing of geometric features of an enclosed arena by discrete landmarks were investigated in rats using the water maze paradigm. Experiment 1 established that in a rhomboid-shaped arena, the acute corner was more salient than the obtuse corner. In Experiment 2, rats were trained to find a submerged platform either in one of the acute, or obtuse, corners.

Spontaneous object recognition memory is maintained following transformation of global geometric properties.

Studies of spontaneous behavior to assess memory are widespread, but often the relationships of objects to contexts and spatial locations are poorly defined. We examined whether object-location memory was maintained following global, but not local, changes to the geometric shape of an arena. Rats explored two trial-unique objects in a distinctively shaped arena before being exposed to two identical copies of one of these objects in a different shape in a different physical location.

Dissociable roles of the medial prefrontal cortex, the anterior cingulate cortex, and the hippocampus in behavioural flexibility revealed by serial reversal of three-choice discrimination in rats.

Contributions of different limbic cortical areas to mediation of behavioural flexibility were examined using repeated acquisition of three-choice discrimination in operant chambers. Rats were trained on a series of positional discrimination tasks with three levers, where position of the correct lever remained the same within a task but shifted across tasks. Ibotenic acid lesions of the medial prefrontal cortex impaired acquisition of each discrimination task by increasing errors specifically in the early phase of each task.

Choice and contingency in the development of behavioral autonomy during instrumental conditioning.

In two experiments hungry rats received extensive training to lever press for food outcomes before one outcome was devalued by aversion conditioning and responding tested in extinction. If the rats were trained on a concurrent schedule in which two responses yielded different outcomes, performance during the extinction test was reduced by devaluation of the associated outcome. By contrast, if a single response was trained concurrently with the noncontingent presentations of the other outcome, test performance was insensitive to devaluation of the contingent outcome.