Oxytocin-induced facilitation of learning in a probabilistic task is associated with reduced feedback- and error-related negativity potentials.

BACKGROUND: Feedback evaluation of actions and error response detection are critical for optimizing behavioral adaptation. Oxytocin can facilitate learning following social feedback but whether its effects vary as a function of feedback valence remains unclear. AIMS: The present study aimed to investigate whether oxytocin would influence responses to positive and negative feedback differentially or equivalently. METHODS: The present study employed a randomized, double-blind, placebo controlled within-subject design to investigate whether intranasal oxytocin (24 IU) influenced behavioral and evoked electrophysiological potential responses to positive or negative feedback in a probabilistic learning task. RESULTS: Results showed that oxytocin facilitated learning and this effect was maintained in the absence of feedback. Using novel stimulus pairings, we found that oxytocin abolished bias towards learning more from negative feedback under placebo by increasing accuracy for positively reinforced stimuli. Oxytocin also decreased the feedback-related negativity difference (negative minus positive feedback) during learning, further suggesting that it rendered the evaluation of positive and negative feedback more equivalent. Additionally, post-learning oxytocin attenuated error-related negativity amplitudes but increased the late error positivity, suggesting that it may lower conflict detection between actual errors and expected correct responses at an early stage of processing but at a later stage increase error awareness and motivation for avoiding them. CONCLUSIONS: Oxytocin facilitates learning and subsequent performance by rendering the impact of positive relative to negative feedback more equivalent and also by reducing conflict detection and increasing error awareness, which may be beneficial for behavioral adaption.

Effects of chronic exposure to selenomethionine on social learning outcomes in zebrafish (Danio rerio): serotonergic dysregulation and oxidative stress in the brain.

For many species, social learning is crucial for fitness-related activities, but human-induced environmental changes can impair such learning processes. For instance, mining can release the element, selenium (Se), that is vital for physiological functions but also has toxicological properties at elevated concentrations. In this study, we investigated the effects of chronic exposure to Se on social learning outcomes and potential underlying molecular mechanisms in adult zebrafish. After exposure to different levels of dietary selenomethionine (control, 3.6, 12.8, 34.1 µg Se/g dry weight) for 90 days, we examined the ability of observer fish to follow demonstrators (experienced individuals) in escaping an oncoming trawl. Social learning outcomes were then assessed in the absence of demonstrators. Our results indicated that fish in the highest exposure group (34.1 µg/g) displayed significantly slower escape responses compared to fish in the control and lower exposure groups (3.6 and 12.8 µg Se/g). This impaired behavior was associated with higher oxidative stress and dysregulation in genes that are key in the serotonergic pathway, indicating that oxidative stress and alteration in the serotonergic system lead to impairment of social learning.

Combining oxytocin and cognitive bias modification training in a randomized controlled trial: Effects on trust in maternal support.

BACKGROUND AND OBJECTIVES: Research on the social effects of intranasal oxytocin in children is scarce. Oxytocin has been proposed to have clearer beneficial effects when added to social learning paradigms. The current study tested this proposition in middle childhood by assessing effects of cognitive bias modification (CBM) training and oxytocin on trust in maternal support. METHODS: Children (N = 100, 8-12 years) were randomly assigned to one of two training conditions: CBM training aimed at increasing trust or neutral placebo training. Within each training condition, half the participants received oxytocin and half a placebo. Main and interaction effects were assessed on measures of trust-related interpretation bias and trust. We explored whether child characteristics moderated intervention effects. RESULTS: Children in the CBM training were faster to interpret maternal behaviour securely versus insecurely. Effects did not generalize to interpretation bias measures or trust. There were no main or interaction effects of oxytocin. Exploratory moderation analyses indicated that combining CBM training with oxytocin had less positive effects on trust for children with more internalizing problems. LIMITATIONS: As this was the first study combining CBM and oxytocin, replication of the results is needed. CONCLUSIONS: This study combined a social learning paradigm with oxytocin in children. CBM training was effective at an automatic level of processing. Oxytocin did not enhance CBM effects or independently exert effects. Research in larger samples specifying when oxytocin might have beneficial effects is necessary before oxytocin can be used as intervention option in children.

Differences in cocaine- and morphine-induced cognitive impairments and serum corticosterone between C57BL/6J and BALB/cJ mice.

Addictive drug exposure is associated with impairments in various cognitive domains. Murine models of drug-induced cognitive impairment have helped to inform research on interventions to attenuate such cognitive diminishment; however, while differences between the drug-induced cognitive impairments exhibited by C57BL/6J and BALB/cJ mice have been observed, they remain unclear. This study measured differences in cognitive behavior performance on the object recognition test (ORT) and social recognition test (SRT) and serum levels of corticosterone (CORT) between C57BL/6J and BALB/cJ mice after 14-day chronic exposure to either cocaine (5 mg/kg) or morphine (3 mg/kg) at a dosage of 10 ml/kg/day. The ORT revealed that cocaine and morphine exposure significantly reduced the discrimination ratio in both C57BL/6J and BALB/cJ mice, exploration time was only reduced in C57BL/6J mice: the exploration times of C57BL/6J mice from the control (p < 0.05), cocaine (p < 0.05), and morphine (p < 0.01) administration groups were significantly less than those of BALB/cJ mice. The SRT demonstrated that drug exposure significantly reduced exploration time (cocaine, p < 0.01; morphine, p < 0.01) and impaired social recognition in C57BL/6J mice. No significant effect in BALB/cJ mice was observed. Serum CORT levels were lower in control C57BL/6J mice than in control BALB/cJ mice (p < 0.05), but no difference was observed after drug administration. In conclusion, changes in object and social learning recognition indicate that C57BL/6J mice are more sensitive than BALB/cJ mice to chronic drug exposure, especially to cocaine; concomitant changes in serum CORT may mediate these effects.

Neural modulation of social reinforcement learning by intranasal oxytocin in male adults with high-functioning autism spectrum disorder: a randomized trial.

Reduced social motivation is a hallmark of individuals with autism spectrum disorders (ASDs). Although the exact neural mechanisms are unclear, oxytocin has been shown to enhance motivation and attention to social stimuli, suggesting a potential to augment social reinforcement learning as the central mechanism of behavioral interventions in ASD. We tested how reinforcement learning in social contexts and associated reward prediction error (RPE) signals in the nucleus accumbens (NAcc) were modulated by intranasal oxytocin. Male adults with a childhood diagnosis of ASD (n = 15) and healthy controls (n = 24; aged 18-26 years) performed a probabilistic reinforcement learning task during functional magnetic resonance imaging in a single-center (research center in Germany), randomized double-blind, placebo-controlled cross-over trial. The interventions were intranasal oxytocin (Syntocinon®, Novartis; 10 puffs = 20 international units (IUs) per treatment) and placebo spray. Using computational modeling of behavioral data, trial-by-trial RPE signals were assessed and related to brain activation in NAcc during reinforcing feedback in social and non-social contexts. The order of oxytocin/placebo was randomized for 60 participants. Twenty-one participants were excluded from analyses, leaving 39 for the final analysis. Behaviorally, individuals with ASD showed enhanced learning under oxytocin when the learning target as well as feedback was social as compared to non-social (social vs. non-social target: 87.09% vs. 71.29%, 95% confidence interval (CI): 7.28-24.33, p = .003; social vs. non-social feedback: 81.00% vs. 71.29%, 95% CI: 2.81-16.61, p = .027). Correspondingly, oxytocin enhanced the correlation of the RPE signal with NAcc activation during social (vs. non-social) feedback in ASD (3.48 vs. -1.12, respectively, 95% CI: 2.98-6.22, p = .000), whereas in controls, this effect was found in the placebo condition (2.90 vs. -1.14, respectively, 95% CI: 1.07-7.01, p = .010). In ASD, a similar pattern emerged when the learning target was social (3.00 vs. -0.64, respectively, 95% CI: -0.13 to 7.41, p = .057), whereas controls showed a reduced correlation for social learning targets under oxytocin (-0.70 vs. 2.72, respectively, 95% CI: -5.86 to 0.98, p = .008). The current data suggest that intranasal oxytocin has the potential to enhance social reinforcement learning in ASD. Future studies are warranted that investigate whether oxytocin can potentiate social learning when combined with behavioral therapies, resulting in greater treatment benefits than traditional behavior-only approaches.

Rapid effects of estrogens on short-term memory: Possible mechanisms.

Contribution to Special Issue on Fast effects of steroids. Estrogens affect learning and memory through rapid and delayed mechanisms. Here we review studies on rapid effects on short-term memory. Estradiol rapidly improves social and object recognition memory, spatial memory, and social learning when administered systemically. The dorsal hippocampus mediates estrogen rapid facilitation of object, social and spatial short-term memory. The medial amygdala mediates rapid facilitation of social recognition. The three estrogen receptors, α (ERα), ß (ERß) and the G-protein coupled estrogen receptor (GPER) appear to play different roles depending on the task and brain region. Both ERα and GPER agonists rapidly facilitate short-term social and object recognition and spatial memory when administered systemically or into the dorsal hippocampus and facilitate social recognition in the medial amygdala. Conversely, only GPER can facilitate social learning after systemic treatment and an ERß agonist only rapidly improved short-term spatial memory when given systemically or into the hippocampus, but also facilitates social recognition in the medial amygdala. Investigations into the mechanisms behind estrogens' rapid effects on short term memory showed an involvement of the extracellular signal-regulated kinase (ERK) and the phosphoinositide 3-kinase (PI3K) kinase pathways. Recent evidence also showed that estrogens interact with the neuropeptide oxytocin in rapidly facilitating social recognition. Estrogens can increase the production and/or release of oxytocin and other neurotransmitters, such as dopamine and acetylcholine. Therefore, it is possible that estrogens' rapid effects on short-term memory may occur through the regulation of various neurotransmitters, although more research is need on these interactions as well as the mechanisms of estrogens' actions on short-term memory.

Social Learning Requires Plasticity Enhanced by Fluoxetine Through Prefrontal Bdnf-TrkB Signaling to Limit Aggression Induced by Post-Weaning Social Isolation.

Escalated or abnormal aggression induced by early adverse experiences is a growing issue of social concern and urges the development of effective treatment strategies. Here we report that synergistic interactions between psychosocial and biological factors specifically ameliorate escalated aggression induced by early adverse experiences. Rats reared in isolation from weaning until early adulthood showed abnormal forms of aggression and social deficits that were temporarily ameliorated by re-socialization, but aggression again escalated in a novel environment. We demonstrate that when re-socialization was combined with the antidepressant fluoxetine, which has been shown to reactivate juvenile-like state of plasticity, escalated aggression was greatly attenuated, while neither treatment alone was effective. Early isolation induced a permanent, re-socialization-resistant reduction in Bdnf expression in the amygdala and the infralimbic cortex. Only the combined treatment of fluoxetine and re-socialization was able to recover Bdnf expression via epigenetic regulation. Moreover, the behavior improvement after the combined treatment was dependent on TrkB activity. Combined treatment specifically strengthened the input from the ventral hippocampus to the mPFC, suggesting that this pathway is an important mediator of the beneficial behavioral effects of the combined psychosocial and pharmacological treatment of abnormal aggression. Our findings suggest that synergy between pharmacological induction of plasticity and psychosocial rehabilitation could enhance the efficacy of therapies for pathological aggression.

Prosocial effects of prolactin in male rats: Social recognition, social approach and social learning.

Prolactin (PRL) and oxytocin (OT) are pituitary hormones essential for lactation, but also promote sexual behavior. OT stimulates social behaviors, such as recognition, approach, and learning, but less is known about PRL in these behaviors. Since PRL and OT have complementary functions in reproduction, we hypothesized that PRL increases social recognition, approach, and learning. Male Long-Evans rats received ovine PRL (oPRL; 0.5, 2.0 or 5.0mg/kg), the PRL antagonist bromocriptine (0.1, 3.0 or 5.0mg/kg) or saline 20 mins before testing for recognition of familiar vs. unfamiliar stimulus males. Saline controls preferred the unfamiliar male (p<0.05), while bromocriptine blocked this preference. oPRL did not increase preference. To measure social approach, we determined if PRL restores approach 2h after defeat by an aggressive male. Defeated rats avoided the aggressive male. 2mg/kg oPRL, before or after defeat, restored approach towards the aggressive male (p<0.05). In non-defeated rats, oPRL or 3mg/kg bromocriptine had no effect. To determine if PRL increases social learning, we tested social transmission of food preference. Rats choose between two unfamiliar flavors, one of which they have previously been exposed to through interaction with a demonstrator rat. Vehicle controls preferred chow with the demonstrated flavor over the novel flavor. oPRL-treated rats were similar. Bromocriptine-treated rats failed to show a preference. When tested one week later, only oPRL-treated rats preferred the demonstrated flavor. The results suggest that PRL is required for social recognition and learning, and that increasing PRL enhances social memory and approach, similar to OT.

Oxytocin attenuates deficits in social interaction but not recognition memory in a prenatal valproic acid-induced mouse model of autism.

Recent studies have reported that oxytocin ameliorates behavioral abnormalities in both animal models and individuals with autism spectrum disorders (ASD). However, the mechanisms underlying the ameliorating effects of oxytocin remain unclear. In this study, we examined the effects of intranasal oxytocin on impairments in social interaction and recognition memory in an ASD mouse model in which animals are prenatally exposed to valproic acid (VPA). We found that a single intranasal administration of oxytocin restored social interaction deficits for up to 2h in mice prenatally exposed to VPA, but there was no effect on recognition memory impairments. Additionally, administration of oxytocin across 2weeks improved prenatal VPA-induced social interaction deficits for at least 24h. In contrast, there were no effects on the time spent sniffing in control mice. Immunohistochemical analysis revealed that intranasal administration of oxytocin increased c-Fos expression in the paraventricular nuclei (PVN), prefrontal cortex, and somatosensory cortex, but not the hippocampal CA1 and CA3 regions of VPA-exposed mice, suggesting the former regions may underlie the effects of oxytocin. These findings suggest that oxytocin attenuates social interaction deficits through the activation of higher cortical areas and the PVN in an ASD mouse model.

IGF1-Dependent Synaptic Plasticity of Mitral Cells in Olfactory Memory during Social Learning.

During social transmission of food preference (STFP), mice form long-term memory of food odors presented by a social partner. How does the brain associate a social context with odor signals to promote memory encoding? Here we show that odor exposure during STFP, but not unconditioned odor exposure, induces glomerulus-specific long-term potentiation (LTP) of synaptic strength selectively at the GABAergic component of dendrodendritic synapses of granule and mitral cells in the olfactory bulb. Conditional deletion of synaptotagmin-10, the Ca2+ sensor for IGF1 secretion from mitral cells, or deletion of IGF1 receptor in the olfactory bulb prevented the socially relevant GABAergic LTP and impaired memory formation after STFP. Conversely, the addition of IGF1 to acute olfactory bulb slices elicited the GABAergic LTP in mitral cells by enhancing postsynaptic GABA receptor responses. Thus, our data reveal a synaptic substrate for a socially conditioned long-term memory that operates at the level of the initial processing of sensory information.

Endogenous opioids regulate social threat learning in humans.

Many fearful expectations are shaped by observation of aversive outcomes to others. Yet, the neurochemistry regulating social learning is unknown. Previous research has shown that during direct (Pavlovian) threat learning, information about personally experienced outcomes is regulated by the release of endogenous opioids, and activity within the amygdala and periaqueductal gray (PAG). Here we report that blockade of this opioidergic circuit enhances social threat learning through observation in humans involving activity within the amygdala, midline thalamus and the PAG. In particular, anticipatory responses to learned threat cues (CS) were associated with temporal dynamics in the PAG, coding the observed aversive outcomes to other (observational US). In addition, pharmacological challenge of the opioid receptor function is classified by distinct brain activity patterns during the expression of conditioned threats. Our results reveal an opioidergic circuit that codes the observed aversive outcomes to others into threat responses and long-term memory in the observer.

The Role of Dorsal Hippocampal Dopamine D1-Type Receptors in Social Learning, Social Interactions, and Food Intake in Male and Female Mice.

The neurobiological mechanisms underlying social learning (ie, in which an animal's learning is influenced by another) are slowly being unraveled. Previous work with systemic treatments shows that dopamine (DA) D1-type receptors mediate social learning in the social transmission of food preferences (STFP) in mice. This study examines the involvement of one brain region underlying this effect. The ventral tegmental area has dopaminergic projections to many limbic structures, including the hippocampus-a site important for social learning in the STFP in rodents. In this study, adult male and female CD-1 mice received a dorsal hippocampal microinfusion of the D1-like receptor antagonist SCH23390 at 1, 2, 4, or 6 µg/µl 15 min before a 30 min social interaction with a same-sex conspecific, in which mice had the opportunity to learn a socially transmitted food preference. Results show that social learning was blocked in female mice microinfused with 6 µg/µl, and in males infused with 1, 4, or 6 µg/µl of SCH23390. This social learning impairment could not be explained by changes in total food intake, or olfactory discrimination. A detailed analysis of the social interactions also revealed that although SCH23390 did not affect oronasal investigation for either sex, drug treatments affected other social behaviors in a sex-specific manner; there was primarily a reduction in agonistic-related behaviors among males, and social investigatory-related behaviors among females. Thus, this study shows that dorsal hippocampal D1-type receptors mediate social learning and social behaviors in male and female mice.

Apoptotic Process Induced by Oxaliplatin in Rat Hippocampus Causes Memory Impairment.

Aspects of memory involved in cognitive mechanisms were investigated in rat after oxaliplatin (OX) chemotherapy using animal behavioural assessment of passive avoidance and social learning paradigms, which are both hippocampus-sensitive. Rodents, previously subjected to 2-week OX treatment, showed passive avoidance and social learning impairment and apoptotic processes in the hippocampus. Apoptosis rate significantly increased in cultured hippocampal cells exposed to OX at increasing doses, and this effect was dose-dependent. Ex vivo experiments showed that cell damage and apoptosis were blocked in the hippocampus from OX rats cotreated with copper sulphate (CS) which precludes OX transport inside the cell. In vivo, passive avoidance and social learning impairment could not be observed in OX rats co-administered with CS. Thus, a site of action of OX treatment on memory impairment appears to be located at the hippocampus. These findings strongly support that cellular damage induced by OX in rodent hippocampus underlies the weakening of some memory functions.

Activation of the G protein-coupled estrogen receptor, but not estrogen receptor α or ß, rapidly enhances social learning.

Social learning is a highly adaptive process by which an animal acquires information from a conspecific. While estrogens are known to modulate learning and memory, much of this research focuses on individual learning. Estrogens have been shown to enhance social learning on a long-term time scale, likely via genomic mechanisms. Estrogens have also been shown to affect individual learning on a rapid time scale through cell-signaling cascades, rather than via genomic effects, suggesting they may also rapidly influence social learning. We therefore investigated the effects of 17ß-estradiol and involvement of the estrogen receptors (ERs) using the ERα agonist propyl pyrazole triol, the ERß agonist diarylpropionitrile, and the G protein-coupled ER 1 (GPER1) agonist G1 on the social transmission of food preferences (STFP) task, within a time scale that focused on the rapid effects of estrogens. General ER activation with 17ß-estradiol resulted in a modest facilitation of social learning, with mice showing a preference up to 30min of testing. Specific activation of the GPER1 also rapidly enhanced social learning, with mice showing a socially learned preference up to 2h of testing. ERα activation instead shortened the expression of a socially learned food preference, while ERß activation had little to no effects. Thus, rapid estrogenic modulation of social learning in the STFP may be the outcome of competing action at the three main receptors. Hence, estrogens' rapid effects on social learning likely depend on the specific ERs present in brain regions recruited during social learning.

Memantine improves observational learning in day-old chicks.

Evidence of observational learning (social learning) is present in many species. One such task is the one-trial taste-avoidance task, in which Actor chicks peck a bead coated with an aversant substance. Observer chicks learn to avoid beads that are similar in appearance to the one presented to the Actors. It has been firmly established that active learning of the one-trial taste-avoidance task is dependent on a constrained level of glutamate receptor activation. The current study examined the effects of memantine, a noncompetitive N-methyl-D-aspartate receptor antagonist, on the learning by Observers. Memantine produced an inverted U-shaped dose-dependent response curve; 1.0 mmol/l memantine produced significant improvement. These results demonstrate that memantine influences memory formation for observational learning in the day-old chick and support the hypothesis that memantine can improve memories by altering levels of glutamate during memory formation.