Adult norms for the decision-making MindPulse Digital Test.

We present adult normalized data for MindPulse (MP), a new tool evaluating attentional and executive functioning (AEF) in decision-making. We recruited 722 neurotypical participants (18-80 years), with 149 retested. The MP test includes three tasks: Simple Reaction Time (SRT), Go/No-go, and complex Go/No-go, involving perceptual components, motor responses, and measurements of reaction time (RT) and correctness. We compare responses, evaluating 14 cognitive indices (including new composite indices to describe AEF: Executive Speed and Reaction to Difficulty). We adjust for age/sex effects, introduce a difficulty scale, and consider standard deviations, aberrant times, and Spearman Correlation for speed-accuracy balance. Wilcoxon unpaired rank test is used to assess sex effects, and linear regression is employed to assess the age linear dependency model on the normalized database. The study demonstrated age and sex effects on RTs, in all three subtests, and the ability to correct it for individual results. The test showed excellent validity (Cronbach Alpha for the three subtasks is 92, 87, 95%) and high internal consistency (p < 0.001 for each subtask significantly faster than the more complex subtask) of the MP across the wide age range. Results showed correlation within the three RT parts of the test (p < .001 for each) and the independence of SRT, RD, and ES indices. The Retest effect was lower than intersubject variance, showing consistency over time. This study highlights the MP test's strong validity on a homogeneous, large adult sample. It emphasizes assessing AEF and Reaction to Difficulty dynamically with high sensitivity.

Endolysosomal TPCs regulate social behavior by controlling oxytocin secretion.

Oxytocin (OT) is a prominent regulator of many aspects of mammalian social behavior and stored in large dense-cored vesicles (LDCVs) in hypothalamic neurons. It is released in response to activity-dependent Ca2+ influx, but is also dependent on Ca2+ release from intracellular stores, which primes LDCVs for exocytosis. Despite its importance, critical aspects of the Ca2+-dependent mechanisms of its secretion remain to be identified. Here we show that lysosomes surround dendritic LDCVs, and that the direct activation of endolysosomal two-pore channels (TPCs) provides the critical Ca2+ signals to prime OT release by increasing the releasable LDCV pool without directly stimulating exocytosis. We observed a dramatic reduction in plasma OT levels in TPC knockout mice, and impaired secretion of OT from the hypothalamus demonstrating the importance of priming of neuropeptide vesicles for activity-dependent release. Furthermore, we show that activation of type 1 metabotropic glutamate receptors sustains somatodendritic OT release by recruiting TPCs. The priming effect could be mimicked by a direct application of nicotinic acid adenine dinucleotide phosphate, the endogenous messenger regulating TPCs, or a selective TPC2 agonist, TPC2-A1-N, or blocked by the antagonist Ned-19. Mice lacking TPCs exhibit impaired maternal and social behavior, which is restored by direct OT administration. This study demonstrates an unexpected role for lysosomes and TPCs in controlling neuropeptide secretion, and in regulating social behavior.

Characterization of social behavior in young and middle-aged ChAT-IRES-Cre mouse.

The cholinergic system is an important modulator of brain processes. It contributes to the regulation of several cognitive functions and emotional states, hence altering behaviors. Previous works showed that cholinergic (nicotinic) receptors of the prefrontal cortex are needed for adapted social behaviors. However, these data were obtained in mutant mice that also present alterations of several neurotransmitter systems, in addition to the cholinergic system. ChAT-IRES-Cre mice, that express the Cre recombinase specifically in cholinergic neurons, are useful tools to investigate the role of the cholinergic circuits in behavior. However, their own behavioral phenotype has not yet been fully characterized, in particular social behavior. In addition, the consequences of aging on the cholinergic system of ChAT-IRES-Cre mice has never been studied, despite the fact that aging is known to compromise the cholinergic system efficiency. The aim of the current study was thus to characterize the social phenotype of ChAT-IRES-Cre mice both at young (2-3 months) and middle (10-11 months) ages. Our results reveal an alteration of the cholinergic system, evidenced by a decrease of ChAT, CHT and VAChT gene expression in the striatum of the mice, that was accompanied by mild social disturbances and a tendency towards anxiety. Aging decreased social dominance, without being amplified by the cholinergic alterations. Altogether, this study shows that ChAT-IRES-Cre mice are useful models for studying the cholinergic system's role in social behavior using appropriate modulating technics (optogenetic or DREADD).

Postural Correlates of Pollution Perception.

In our contemporary societies, environmental issues are more and more important. An increasing number of studies explore the biological processes involved in environment perception and in particular try to highlight the mechanisms underlying the perception of environmental scenes by our brain. The main objective of the present study was to establish whether the visualization of clean and polluted environmental scenes would lead to differential postural reactions. Our hypothesis was based on a differential postural modulation that could be recorded when the subject is confronted with images representing a "polluted" environment, differential modulation which has been reported in previous studies in response to painful-scenes compared to non-painful scenes visualization.Thirty-one subjects participated in this study. Physiological measurements [heart rate variability (HRV) and electrodermal activity] and postural responses (Center Of Pression-COP-displacements) were recorded in response to perception of polluted or clean environmental scenes. We show, for the first time, that images representing polluted scenes evoke a weaker approach movement than images representing clean scenes. The displacement of the COP in the anteroposterior axis reflects an avoidance when subjects visualize "polluted" scenes. Our results demonstrate a clear distinction between "clean" and "polluted" environments according to the postural change they induce, correlated with the ratings of pleasure and approach evoked by images.

Inter-Individual Differences in Cognitive Tasks: Focusing on the Shaping of Decision-Making Strategies.

In this paper, we review recent (published and novel) data showing inter-individual variation in decision-making strategies established by mice in a gambling task (MGT for Mouse Gambling Task). It may look intriguing, at first, that congenic animals develop divergent behaviors. However, using large groups of mice, we show that individualities emerge in the MGT, with about 30% of healthy mice displaying risk-averse choices while about 20-25% of mice make risk-prone choices. These strategies are accompanied by different brain network mobilization and individual levels of regional -prefrontal and striatal- monoamines. We further illustrate three ecological ways that influence drastically cognitive strategies in healthy adult mice: sleep deprivation, sucrose or artificial sweetener exposure, and regular exposure to stimulating environments. Questioning how to unmask individual strategies, what are their neural/neurochemical bases and whether we can shape or reshape them with different environmental manipulations is of great value, first to understand how the brain may build flexible decisions, and second to study behavioral plasticity, in healthy adult, as well as in developing brains. The latter may open new avenues for the identification of vulnerability traits to adverse events, before the emergence of mental pathologies.

Prolonged Consumption of Sweetened Beverages Lastingly Deteriorates Cognitive Functions and Reward Processing in Mice.

We investigated the detrimental effects of chronic consumption of sweet or sweetened beverages in mice. We report that consumption of beverages containing small amounts of sucrose during several weeks impaired reward systems. This is evidenced by robust changes in the activation pattern of prefrontal brain regions associated with abnormal risk-taking and delayed establishment of decision-making strategy. Supporting these findings, we find that chronic consumption of low doses of artificial sweeteners such as saccharin disrupts brain regions' activity engaged in decision-making and reward processes. Consequently, this leads to the rapid development of inflexible decisions, particularly in a subset of vulnerable individuals. Our data also reveal that regular consumption, even at low doses, of sweet or sweeteners dramatically alters brain neurochemistry, i.e., dopamine content and turnover, and high cognitive functions, while sparing metabolic regulations. Our findings suggest that it would be relevant to focus on long-term consequences on the brain of sweet or sweetened beverages in humans, especially as they may go metabolically unnoticed.

Brain adaptation to acute stress: effect of time, social buffering, and nicotinic cholinergic system.

Both social behavior and stress responses rely on the activity of the prefrontal cortex (PFC) and basolateral nucleus of the amygdala (BLA) and on cholinergic transmission. We previously showed in adult C57BL/6J (B6) mice that social interaction has a buffering effect on stress-related prefrontal activity, depending on the ß2-/- cholinergic nicotinic receptors (nAChRs, ß2-/- mice). The latency for this buffer to emerge being short, we question here whether the associated brain plasticity, as reflected by regional c-fos protein quantification and PFC-BLA functional connectivity, is modulated by time. Overall, we show that time normalized the stress-induced PFC hyperactivation in B6 mice and PFC hypo-activation in ß2-/- mice, with no effect on BLA. It also triggered a multitude of functional links between PFC subareas, and between PFC and BLA in B6 mice but not ß2-/- mice, showing a central role of nAChRs in this plasticity. Coupled with social interaction and time, stress led to novel and drastic diminution of functional connectivity within the PFC in both genotypes. Thus, time, emotional state, and social behavior induced dissociated effects on PFC and BLA activity and important cortico-cortical reorganizations. Both activity and plasticity were under the control of the ß2-nAChRs.

Unexpected Interacting Effects of Physical (Radiation) and Chemical (Bisphenol A) Treatments on Male Reproductive Functions in Mice.

For decades, numerous chemical pollutants have been described to interfere with endogenous hormone metabolism/signaling altering reproductive functions. Among these endocrine disrupting substances, Bisphenol A (BPA), a widely used compound, is known to negatively impact germ and somatic cells in the testis. Physical agents, such as ionizing radiation, were also described to perturb spermatogenesis. Despite the fact that we are constantly exposed to numerous environmental chemical and physical compounds, very few studies explore the impact of combined exposure to chemical and physical pollutants on reproductive health. The aim of this study was to describe the impact of fetal co-exposure to BPA and IR on testicular function in mice. We exposed pregnant mice to 10 µM BPA (corresponding to 0.5 mg/kg/day) in drinking water from 10.5 dpc until birth, and we irradiated mice with 0.2 Gy (γ-ray, RAD) at 12.5 days post-conception. Co-exposure to BPA and γ-ray induces DNA damage in fetal germ cells in an additive manner, leading to a long-lasting decrease in germ cell abundance. We also observed significant alteration of adult steroidogenesis by RAD exposure independently of the BPA exposure. This is illustrated by the downregulation of steroidogenic genes and the decrease of the number of adult Leydig cells. As a consequence, courtship behavior is modified, and male ultrasonic vocalizations associated with courtship decreased. In conclusion, this study provides evidence for the importance of broadening the concept of endocrine disruptors to include physical agents, leading to a reevaluation of risk management and regulatory decisions.

A Dissociation of Attention, Executive Function and Reaction to Difficulty: Development of the MindPulse Test, a Novel Digital Neuropsychological Test for Precise Quantification of Perceptual-Motor Decision-Making Processes.

Traditionally, neuropsychological testing has assessed processing speed and precision, closely related to the ability to perform high-order cognitive tasks. An individual making a decision under time pressure must constantly rebalance its speed to action in order to account for possible errors. A deficit in processing speed appears to be afrequent disorder caused by cerebral damage - but it can be hard to pinpoint the exact cause of the slowdown. It is therefore important to separate the perceptual-motor component of processing speed from the decision-time component. We present a technique to isolate Reaction Times (RTs): a short digital test to assess the decision-making abilities of individuals by gauging their ability to balance between speed and precision. Our hypothesis is that some subjects willaccelerate, and others slow down in the face of the difficulty. This pilot study, conducted on 83 neurotypical adult volunteers, used images stimuli. The test was designed to measure RTs and correctness. After learning release gesture, the subjects were presented with three tasks: a simple Reaction Time task, a Go/No-Go, and a complex Go/No-Go with 2 simultaneous Choices. All three tasks have in common a perceptual component and a motor response. By measuring the 3 reference points requiring attentional and executive processing, while progressively increasing the conceptual complexity of the task, we were able to compare the processing times for different tasks - thus calculating the deceleration specific to the reaction time linked to difficulty. We defined the difficulty coefficient of a task as being the ratio of the group average time of this task minus the base time/average time of the unit task minus the base time. We found that RTs can be broken down into three elementary, uncorrelated components: Reaction Time, Executive Speed, and Reaction to Difficulty (RD). We hypothesized that RD reflects how the subject reacts to difficulty by accelerating (RD < 0) or decelerating (RD > 0). Thus we provide here a first proof of concept: the ability to measure four axes of the speed-precision trade-off inherent in a subject's fundamental decision making: perceptual-motor speed, executive speed, subject accuracy, and reaction to difficulty.

Postural correlates of painful stimuli exposure: impact of mental simulation processes and pain-level of the stimuli.

Previous studies have reported (i) freezing-like posturographic correlates in response to painful as compared to non-painful scenes vision (Lelard et al., Front Hum Neurosci 7:4, 2013) and (ii) an increase of this response during the mental simulation as compared to the passive viewing of the painful scenes (Lelard et al., Front Psychol 8:2012, 2017). The main objective of the present study was to explore the modulation of posturographic correlates of painful scenes vision by the level of depicted pain and the influence of mental simulation on this modulation. Thirty-six participants (36.3 ± 11.4 years old) were included in this study. During the experiment, participants had to stand on a posturographic platform. Three types of static visual stimuli were randomly depicting different pain-level situations: no-pain, low-pain, high-pain. In a first run, participants watched these stimuli passively (passive condition); in a second run, they were asked to "imagine that they were personally experiencing the situations they were about to see" (mental simulation condition). For each picture, subjective ratings were recorded for displeasure and desire to avoid at the end of the posturographic session. Results support an approach-type behavior in response to high-pain stimuli in the passive condition which becomes a withdrawal-type behavior in the mental simulation condition. Moreover, this withdrawal-type behavior is modulated by the level of depicted pain and this modulation does not appear for the subjective data. As a conclusion, these results are in accordance with those of previous studies showing the modulation of posturographic correlates of pain perception by mental simulation and report, for the first time, modulation of this effect by the level of depicted pain. The dichotomy of this modulatory effect between subjective and objective data is discussed as well as the finding of an approach-type behavior towards painful stimuli when passively viewing them becoming a withdrawal-type behavior when mental simulation is applied to the same stimuli.

Effects of water restriction on social behavior and 5-HT neurons density in the dorsal and median raphe nuclei in mice.

We explored here the hypothesis that temporary chronic water restriction in mice affects social behavior, via its action on the density of 5-HT neurons in dorsal and median raphe nuclei (DRN and MRN). For that, we submitted adult C57BL/6 J mice to mild and controlled temporary dehydration, i.e., 6 h of water access every 48 h for 15 days. We investigated their social behavior in a social interaction task known to allow free and reciprocal social contact. Results showed that temporary dehydration increases significantly time spent in social contact and social dominance. It also expands 5-HT neuron density within both DRN and MRN and the behavioral and neuronal plasticity were positively correlated. Our findings suggest that disturbance in 5-HT neurotransmission caused by temporary dehydration stress unbalances choice processes of animals in social context.

Evoked pleasure and approach-avoidance in response to pollution.

From year-to-year, environment is becoming one of the major concerns of human societies. Few studies have investigated the biological processes involved in environmental scene perception. Here, we initiate a line of research by beginning to study emotional processes involved in this perception. Our results demonstrate a clear distinction between "Clean" and "Polluted" environments according to the pleasure and approach desire ratings they induced. Moreover, women expressed higher pleasure in the "Clean" condition, as did older participants. Finally, rural scenes induced higher pleasure in participants than urban ones.

The Mouse Gambling Task: Assessing Individual Decision-making Strategies in Mice.

Decision-making is a complex cognitive process which consists of choosing one option among several alternatives. In humans, this process is featured in the Iowa gambling task (IGT), a decision-making task that mimics real life situations by reproducing uncertain conditions based on probabilistic rewards or penalties (see Background). Several authors wanted to adapt the IGT in rodents with subtle differences in protocols that match various aspects of the human task. Here we propose, for the first time in mice, a protocol that contains the most important characteristics of the IGT: 4 different options, choices based on 4 ambiguous outcomes with immediate and long term rewards, a total of 100 trials, no learning of the contingency before the task, and presence of both a certain reward and a probable penalty. During this task, mice have to choose between options more or less advantageous in the short and long term by developing a decision-making strategy that differs between individuals. Therefore, the strength of this protocol is that it is one of the first to enable the study of decision-making in a complex situation, and demonstrates inter-individual differences regarding decision-making strategies in mice.

Reduced adolescent risk-assessment and lower nicotinic beta-2 expression in rats exposed to nicotine through lactation by forcedly drinking dams.

Few animal studies focus on consequences of nicotine postnatal exposure, particularly through lactation. We have recently shown that forced nicotine drinking elevates maternal care, paradoxically provoking arousal and stress in pups. Present work aimed to evaluate the specific contribution of altered maternal cares, compared to the sequelae merely due to nicotine effects. Two groups were compared to water-drinking control dams: (i) free-choice dams (H2O+NIC group) drinking from two bottles, containing either nicotine or water; (ii) forced dams (NIC+NIC group) drinking from two bottles, both containing nicotine. We previously demonstrated that nicotine was indeed transferred to the lactating offspring. Regarding behavioural consequences at adolescence, both H2O+NIC and NIC+NIC rats were slower than controls in discovering a novel over a familiar compartment, whilst only NIC+NIC rats exhibited reduced risk-related avoidance and assessment behaviour. Brain analyses at adulthood suggest that, in prefrontal cortex, nicotine per se reduced serotonin, while the maternal overcare reduced CHRN-B2 gene-expression. As a whole, unescapable nicotine-enhanced maternal care could have an impact on the offspring arousal by acting on prefrontal CHRN-B2 gene-expression. When present results are translated to consequences of non-voluntary exposure in humans, we propose that children receiving altered attentions by a smoking caregiver might undergo a neuro-behavioural development biased towards emotional shyness.

A multiscale analysis in CD38-/- mice unveils major prefrontal cortex dysfunctions.

Autism spectrum disorder (ASD) is characterized by early onset of behavioral and cognitive alterations. Low plasma levels of oxytocin (OT) have also been found in ASD patients; recently, a critical role for the enzyme CD38 in the regulation of OT release was demonstrated. CD38 is important in regulating several Ca2+-dependent pathways, but beyond its role in regulating OT secretion, it is not known whether a deficit in CD38 expression leads to functional modifications of the prefrontal cortex (PFC), a structure involved in social behavior. Here, we report that CD38-/- male mice show an abnormal cortex development, an excitation-inhibition balance shifted toward a higher excitation, and impaired synaptic plasticity in the PFC such as those observed in various mouse models of ASD. We also show that a lack of CD38 alters social behavior and emotional responses. Finally, examining neuromodulators known to control behavioral flexibility, we found elevated monoamine levels in the PFC of CD38-/- adult mice. Overall, our study unveiled major changes in PFC physiologic mechanisms and provides new evidence that the CD38-/- mouse could be a relevant model to study pathophysiological brain mechanisms of mental disorders such as ASD.-Martucci, L. L., Amar, M., Chaussenot, R., Benet, G., Bauer, O., de Zélicourt, A., Nosjean, A., Launay, J.-M., Callebert, J., Sebrié, C., Galione, A., Edeline, J.-M., de la Porte, S., Fossier, P., Granon, S., Vaillend, C., Cancela, J.-M., A multiscale analysis in CD38-/- mice unveils major prefrontal cortex dysfunctions.

Ultrasonic vocalizations as a tool in studying emotional states in rodent models of social behavior and brain disease.

Rodents emit ultrasonic vocalizations (USVs) to communicate the presence of positive or negative emotional states and to coordinate social interactions. On this basis, USVs are increasingly being used as a behavioral readout in rodent studies of affect, motivation and social behavior. Notably, several investigations have demonstrated that rodents emit USVs when tested in experimental paradigms that are used in preclinical studies of psychiatric and neurological diseases. Moreover, it has been shown that calling behavior may be influenced by genetic and/or environmental factors (i.e., stress), early rearing conditions that have been implicated in brain disease, as well as psychoactive drugs. Hence, measuring USV emissions has emerged as a useful tool in studying the mechanisms that underlie the emotional disturbances featuring certain brain diseases, as well as in the development of suited pharmacological therapies. This review provides an overview of the behavioral significance of USV emissions and describes the contexts that promote calling behavior in rats and mice. Moreover, the review summarizes the current evidence concerning the use of USVs as a marker of affect in rat and mouse models of sociability, psychiatric diseases and neurological diseases, and discusses the strengths and current limitations of using USVs as a behavioral readout in rodent studies of emotional behavior. This article is part of the Special Issue entitled 'The neuropharmacology of social behavior: from bench to bedside'.

Dissociated features of social cognition altered in mouse models of schizophrenia: Focus on social dominance and acoustic communication.

Social and communication impairments are common features of psychiatric disorders. Animal models of schizophrenia display various social deficits due to difference in tests, mouse strains and drugs. Moreover, communication deficits have not been studied. Our objectives were to assess and compare three major features of social cognition in different mouse models of schizophrenia: interest for a social stimulus, organization and acceptance of social contact, and acoustic communication to question whether mouse models for schizophrenia with social dysfunction also exhibit vocal communication defects. To achieve these aims we treated acutely C57BL/6J mice either with MK-801 or ketamine and tested WT and microtubule-associated protein 6 -MAP6- KO mice in two complementary social tasks: the 3-chamber test which measures social motivation and the social interaction task -SIT- which relies on prefrontal cortex activity and measures the ability to organize and respond to a real interaction, and which promotes ultrasonic vocalizations. Our results reveal that schizophrenia models have intact interest for a social stimulus in the 3-chamber test. However, thanks to principal component analyses of social interaction data, we demonstrate that social motivation and the ability to act socially rely on distinct mechanisms in revealing a decrease in dominance and communication in pharmacological schizophrenia models along with social withdraw, classically observed in schizophrenia, in MK-801 model. In this latter model, some social parameters can be significantly improved by aripiprazole, an atypical antipsychotic. Our social protocol, combined with fine-tuned analysis, is expected to provide an innovative framework for testing future treatments in preclinical models. This article is part of the Special Issue entitled 'The neuropharmacology of social behavior: from bench to bedside'.

Altered social behavior in mice carrying a cortical Foxp2 deletion.

Genetic disruptions of the forkhead box transcription factor FOXP2 in humans cause an autosomal-dominant speech and language disorder. While FOXP2 expression pattern are highly conserved, its role in specific brain areas for mammalian social behaviors remains largely unknown. Here we studied mice carrying a homozygous cortical Foxp2 deletion. The postnatal development and gross morphological architecture of mutant mice was indistinguishable from wildtype (WT) littermates. Unbiased behavioral profiling of adult mice revealed abnormalities in approach behavior towards conspecifics as well as in the reciprocal responses of WT interaction partners. Furthermore mutant mice showed alterations in acoustical parameters of ultrasonic vocalizations, which also differed in function of the social context. Cell type-specific gene expression profiling of cortical pyramidal neurons revealed aberrant regulation of genes involved in social behavior. In particular Foxp2 mutants showed the downregulation of Mint2 (Apba2), a gene involved in approach behavior in mice and autism spectrum disorder in humans. Taken together these data demonstrate that cortical Foxp2 is required for normal social behaviors in mice.

Mouse Gambling Task reveals differential effects of acute sleep debt on decision-making and associated neurochemical changes.

Sleep loss is associated with sleepiness, sustained attention, and memory deficits. However, vulnerability of higher cognitive processes (i.e. decision making) to sleep debt is less understood. Therefore, a major challenge is to understand why and how higher cognitive processes are affected by sleep debt. We had established in mice correlations between individual decision-making strategies, prefrontal activity, and regional monoaminergic levels. Now, we show that acute sleep debt (ASD) disturbs decision-making processes and provokes brain regional modifications of serotonin and dopamine that could explain why ASD promotes inflexible and more risk-prone behaviors. Finally, we highlight, for the first time, that in a large group of healthy inbred mice some of them are more sensitive to ASD by showing inflexible behavior and decision-making deficits. We were also able to predict mice that would be the most vulnerable to ASD depending of their behavior before ASD exposure.

Stress-induced brain activation: buffering role of social behavior and neuronal nicotinic receptors.

Social behavior and stress responses both rely on activity in the prefrontal cortex (PFC) and amygdala. We previously reported that acute stress exposure impoverishes social repertoire and triggers behavioral rigidity, and that both effects are modulated by ß2-containing nicotinic receptors. We, therefore, hypothesized that the activity of brain regions associated with the integration of social cues will be modulated by stress exposure. We mapped the expression of c-fos protein in all subregions of the PFC and basolateral (BLA) and central (Ce) areas of the amygdala in C57BL/6J (B6) and ß2-/- mice. We show altered brain activity and differences in functional connectivity between the two genotypes after stress: the PFC and BLA were hyperactivated in B6 and hypo-activated in ß2-/- mice, showing that the impact of stress on brain activity and functional organization depends on the nicotinic system. We also show that the effects of the opportunity to explore a novel environment or interact socially after acute stress depended on genotype: exploration induced only marginal PFC activation in both genotypes relative to stress alone, excluding a major role for ß2 receptors in this process. However, social interaction following stress only activated the rostral and caudolateral areas of the PFC in B6 mice, while it induced a kindling of activation in all PFC and amygdalar areas in ß2-/- mice. These results indicate that acute stress triggers important PFC-amygdala plasticity, social interaction has a buffering role during stress-induced brain activation, and ß2 receptors contribute to the effects of social interaction under stress.