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-o-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 beta 2-microglobulin knock-out (Pm KO) mice, which lack hippocampal asymmetry. We tested beta 2m KO mice in a series of spatial and non-spatial learning tasks and compared the performances of beta 2m KO and C57BL6/J wild-type (WT) mice. The beta 2m KO mice appeared normal in both spatial reference memory and spatial working memory tasks but they took more time than WT mice in learning the two non-spatial learning tasks (i.e., a differential reinforcement of lower rates of behavior (DRL) task and a straight runway task). The beta 2m KO mice also showed less precision in their response timing in the DRL task and showed weaker spontaneous recovery during extinction in the straight runway task. These results indicate that hippocampal asymmetry is important for certain characteristics of non spatial learning.

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. BTBR mice were impaired in the acquisition of conditioned magazine approach responses with an appetitive unconditioned stimulus (US) (Experiment 1) and conditioned freezing with an electric shock US (Experiment 2). Both of these tasks had temporally phasic conditioned stimuli (CSs). Conversely, these mice showed normal acquisition of conditioned place preference (CPP), whether the US was a systemic injection of methamphetamine (Experiment 3A) or the presence of food (Experiment 3B). Experiment 4 showed normal acquisition of conditioned taste aversion (CTA) to a flavour-taste compound CS, although BTBR mice still exhibited an abnormal stimulus selection when learning for each element of the compound CS was assessed separately. Experiment 5 revealed a weaker latent inhibition of CTA in BTBR mice. The BTBR mouse's impaired predictive learning between phasic events and intact associations between static events are discussed in terms of dysfunctional contingency-based, but not contiguity based learning, which may accompany abnormal selective attention to relevant cues. We propose that such dysfunctional contingency learning mechanisms may underlie the development of various social and non-social symptoms of ASD. (C) 2016 Elsevier Inc. All rights reserved.

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. Conditioned social preference (CSP) and conditioned place preference (CPP) paradigms were used to examine social and nonsocial reinforcing properties of OT. In CSP, the presence of a same-sex unfamiliar conspecific was repeatedly paired with intranasal OT, while a different conspecific was associated with saline. The reinforcing effect of OT was assessed in a postconditioning choice test under a drug-free condition. In CPP, the 2 conspecifics were replaced with nonsocial black and white compartments. The authors found that intranasal OT (12 mu g) in females supported the formation of CSP (Experiment 1) but not CPP (Experiment 3). Neither CSP (Experiment 2) nor CPP (Experiment 4) was formed in males. Extended conditioning with higher dose OT (36 mu g), however, abolished the initial CSP in females and produced an aversion to the OT-paired stimulus mouse. Experiment 5 indicated that it was the repeated administrations rather than the higher dose that produced the abolition of the original preference. Overall, the current results demonstrate for the first time a sex-and stimulus-dependent reinforcing property of intranasal OT in mice.

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. Test trials were then conducted in the same pool, but with the platforms removed and with a 50-cm panel on 1 wall and a 100-cm panel on the opposite wall. Group 50 expressed a stronger preference for the 100-cm than the 50-cm panel during the test, whereas Group 100 expressed a similar preference for both panels. Thus the degree of generalization from the short to the long panel was greater than from the long to the short panel. Experiments 2 and 3 pointed to the same conclusion. They were of a similar design to Experiment 1, except that the lengths of the panels for the 2 groups were 25 and 50 cm in Experiment 2, and 25 and 100 cm in Experiment 3. The results are explained by assuming the original training results in the walls without black panels entering into inhibitory associations. This inhibition is then assumed to generalize more to the short than the long test panels and thereby result in an asymmetry in the gradients of generalization between the different lengths.

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. Test trials were then conducted in the same pool, but with the platforms removed and with a 50-cm panel on 1 wall and a 100-cm panel on the opposite wall. Group 50 expressed a stronger preference for the 100-cm than the 50-cm panel during the test, whereas Group 100 expressed a similar preference for both panels. Thus the degree of generalization from the short to the long panel was greater than from the long to the short panel. Experiments 2 and 3 pointed to the same conclusion. They were of a similar design to Experiment 1, except that the lengths of the panels for the 2 groups were 25 and 50 cm in Experiment 2, and 25 and 100 cm in Experiment 3. The results are explained by assuming the original training results in the walls without black panels entering into inhibitory associations. This inhibition is then assumed to generalize more to the short than the long test panels and thereby result in an asymmetry in the gradients of generalization between the different lengths.

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. Animals could therefore learn the position of the platform by taking the consistent vector from the landmark across sessions or by rapidly encoding the new platform position on each session with reference to the extramaze cues. Excitotoxic lesions of the dorsolateral striatum impaired vector-based learning but facilitated cognitive map-based rapid place learning when the extramaze cues were relatively poor (Experiment 1) but not when they were more salient (Experiments 2 and 3). The way the lesion effects interacted with cue availability is consistent with the idea that the memory systems involved in the current navigation task are functionally cooperative yet associatively competitive in nature.

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. The acquired preference for the correct length was eliminated by changing the color of the panels. In Experiment 3, the platforms were situated near the middle of the long walls of a rectangular pool, and in Experiment 4 they were situated in 1 pair of diagonally opposite corners of the same pool. Changing the color of the walls markedly disrupted the effects of the original training in both experiments. The results indicate that rats represent the length of objects not by their abstract, geometric attributes but in a more concrete fashion such as by a mental snapshot or by the amount of color stimulation they provide.

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. The acquired preference for the correct length was eliminated by changing the color of the panels. In Experiment 3, the platforms were situated near the middle of the long walls of a rectangular pool, and in Experiment 4 they were situated in 1 pair of diagonally opposite corners of the same pool. Changing the color of the walls markedly disrupted the effects of the original training in both experiments. The results indicate that rats represent the length of objects not by their abstract, geometric attributes but in a more concrete fashion such as by a mental snapshot or by the amount of color stimulation they provide.

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 cornerthe correct cornerof 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. Subsequent active training of being required to swim to the platform resulted in both groups acquiring a preference for the correct corner in the two experiments. In Experiments 3 and 4, rats were required to solve a discrimination between different panels pasted to the walls of the pool, by swimming to the middle of a correct panel. Hippocampal lesions prevented a discrimination being formed between panels of different lengths (Experiment 3), but not between panels showing lines of different orientations (Experiment 4); rats with sham lesions mastered both problems. It is suggested that an intact hippocampus is necessary for the formation of stimulus-goal associations that permit successful passive spatial leaning. It is further suggested that an intact hippocampus is not necessary for the formation of stimulus-response associations, except when they involve information about length or distance. (c) 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.

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. The platform was easier to locate when it was placed near the middle of a long rather than a short panel. This effect was found when the long panels were twice (Experiments 2-4) or four times the length of the short panels (Experiment 4). Experiment 5 demonstrated that rats can solve a discrimination between panels of length 15 and 45 cm more readily than when they are 70 and 100 cm. The results are consistent with the claim that generalization gradients based on stimulus magnitude are steeper for stimuli that are weaker rather than stronger than the stimulus used for the original training.

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. The presence of the more salient landmark above the platform for another group of animals appeared to have no effect on learning based on geometry. Experiment 3 established that these landmark and geometry cues entered into within-compound associations during compound training. We argue that these within-compound associations can account for the potentiation seen in Experiment 2, as well as previous failures to demonstrate overshadowing of geometric cues. We also suggest that these within-compound associations need not be of different magnitudes, despite the different effects of each of the landmarks on learning based on geometry seen in Experiment 2. Instead, within-compound associations appear to mitigate the overshadowing effects that traditional theories of associative learning would predict.

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 h 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. In addition to the information provided by corner angle, the platform was also signaled by the presence of a spherical landmark suspended above the platform for rats in the experimental group. The landmark was a more valid cue for predicting the location of the platform than the angle of the corner. This training resulted in overshadowing of learning about the angle of the corner by the presence of the landmark. The final experiment extended this result by showing that when the predictive validities of the angle and the landmark were matched in the experimental group, learning about geometry was still overshadowed by the presence of landmarks, but only in animals that were trained with the platform at an obtuse, but not acute, corner. These results uniquely demonstrate that learning about geometry can be overshadowed by discrete landmarks, and also that whether overshadowing is observed depends on the stimulus salience and the relative validity of the competing cues. These findings imply that learning based on geometric cues follows the same basic rules that apply to a wide range of other learning paradigms.

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. These errors were characterised by perseveration to the previously correct lever. By contrast, lesions of the anterior cingulate cortex resulted in the impairment of discrimination in general without inducing perseveration; the impairment was instead characterised by disruption of general error-correction processes. Hippocampal lesions severely impaired learning by increasing perseverative tendencies that were present throughout the learning stages in each task. These results extend our understanding of the contributions of the different nodes of the limbic cortico-striatal circuit to different aspects of behavioural flexibility. (C) 2011 Elsevier B.V. All rights reserved.

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. This finding demonstrates that training on a schedule that offers a choice between responses that yield different outcomes prevents the onset of behavioral autonomy.

Different groups of rats received different amounts of training to lever press for a food reinforcer before an aversion was conditioned to the food. This devaluation of the reinforcer reduced responding in both subsequent extinction and reinforced tests of responding to a degree that was independent of the amount of instrumental training. Moreover, interpolating context extinction between aversion conditioning and the extinction test reduced the magnitude of the devaluation effect, thereby indicating that Pavlovian contextual conditioning may play a role in the instrumental devaluation effect. (C) 2010 Elsevier B.V. All rights reserved.

The capacity for goal-directed behavior requires not only the encoding of the response-outcome relationship but also the ability to resolve conflict induced by competing responses. Recent neuroimaging studies have identified the prefrontal cortex as critical for resolving conflict between competing responses. At present, however, much of this evidence is indirect, and the necessity of dorsomedial prefrontal cortex (dmPFC) function for the resolution of conflict in goal-directed behavior has not been assessed. Here, we develop a rodent paradigm to investigate response conflict caused by the concurrent activation of a correct and incorrect response. In this paradigm, the outcome of one response also acts as a discriminative stimulus signaling that the other response is correct. Whereas rats with a functional dmPFC are able to resolve this conflict, inactivation of dmPFC using an infusion of muscimol produced a deficit by selectively interfering with their ability to inhibit the incorrect, competing response.