Social Approach Behavior Research Articles

Sociability development in mice with cell-specific deletion of the NMDA receptor NR1 subunit gene.

Social affiliative behavior is an important component of everyday life in many species and is likely to be disrupted in disabling ways in various neurodevelopmental and neuropsychiatric disorders. Therefore, determining the mechanisms involved in these processes is crucial. A link between N-methyl-d-aspartate (NMDA) receptor function and social behaviors has been clearly established. The cell types in which NMDA receptors are critical for social affiliative behavior, however, remain unclear. Here, we use mice carrying a conditional allele of the NMDA R1 subunit to address this question. Mice bearing a floxed NMDAR1 (NR1) allele were crossed with transgenic calcium/calmodulin-dependent kinase IIα (CaMKIIα)-Cre mice or parvalbumin (PV)-Cre mice targeting postnatal excitatory forebrain or PV-expressing interneurons, respectively, and assessed using the three-chambered Social Approach Test. We found that deletion of NR1 in PV-positive interneurons had no effect on social sniffing, but deletion of NR1 in glutamatergic pyramidal cells resulted in a significant increase in social approach behavior, regardless of age or sex. Therefore, forebrain excitatory neurons expressing NR1 play an important role in regulating social affiliative behavior.

Long-lasting pseudo-social aggressive behavior in opiate-withdrawn mice

Poor sociability and aggressive behavior are major clinical features of opiate use disorders that may contribute to the establishment and maintenance of these harmful diseases. The present study investigated the long-term effects of chronic morphine administration and withdrawal upon social and aggressive behavior as well as the interrelationship between these two behaviors. Thus, social behavior was measured in C57BL/6J male mice 7, 21, 35 and 49 days after cessation of escalating morphine doses (20–100 mg/kg, i.p.) administered during 6 consecutive days, using the three-chamber task for sociability (i.e., preference for an unfamiliar conspecific vs. an object) and social novelty preference (i.e., preference for a novel vs. a familiar conspecific). Moreover, aggressive biting behavior towards an unfamiliar conspecific was assessed throughout the three-chamber tests. Opiate withdrawal increased both social approach and aggressive biting behavior. Moreover, in morphine-withdrawn, but not in control, mice social approach and aggressive behavior followed a similar time-course and positively correlated one with each other, suggesting that social interest was mainly driven by aggressiveness. Aggressive biting behavior was still elevated 49 days after the last morphine administration, revealing that opiate withdrawal is followed by long-lasting aggressiveness. Throughout, opiate withdrawal did not affect social novelty preference, ruling out a role for olfactory or social discrimination dysfunction in the elevated social approach and aggressive behavior. The present findings of very long-lasting aggressive behavior and aggression-driven social approach in opiate-withdrawn mice might help understanding the behavioral and brain underpinnings of poor sociability and aggressiveness commonly observed in opiate use disorders patients.

Sociality deficits in serine racemase knockout mice.

BackgroundStudies of schizophrenia have pointed to the role of glutamate in its pathophysiology. Mice lacking D‐serine show impairments in neurotransmission through NMDA receptors and display behaviors consistent with features of schizophrenia. Yet, socio‐communicative deficits, a characteristic of schizophrenia, have not been reported in serine racemase knockout mice.MethodsWe use behavioral testing (the three‐chambered social approach task, the dyadic interaction task, and the novel object recognition task) to examine socio‐communicative behaviors in these mice.ResultsSerine racemase mice show abnormal social investigation and approach behavior, and differ from wild‐type controls in the duration and number of vocalizations they emit in the presence of a conspecific. Serine racemase knockout mice were not impaired in a cognitive test (novel object recognition), although they displayed abnormal behavior in the acquisition phase of the task.ConclusionsSerine racemase knockout mice demonstrate abnormalities in socio‐communicative behaviors consistent with an impairment in sociality, a negative symptom of schizophrenia.

Oxytocin reduces interpersonal distance: Examining moderating effects of childrearing experiences and interpersonal context in virtual reality

Oxytocin has been shown to stimulate social approach behaviors, although effects may depend on contextual and individual difference factors. Here, we examined intranasal oxytocin effects on interpersonal distance using an immersive Virtual Reality paradigm, taking into account early caregiving experiences and interpersonal context as potential moderators. Participants were 180 women who received 24 IU oxytocin or a placebo and had reported how often their mother used love withdrawal as a disciplinary strategy, involving withholding love and affection after a failure or misbehavior. We used a virtual stop-distance paradigm, instructing participants to approach a virtual person or to stop an approaching virtual person at a preferred distance (passive approach). In order to examine the role of interpersonal context in shaping oxytocin effects, facial expressions and bodily gestures of the virtual person were manipulated. The person showed a dynamical expression of sadness, happiness, anger, fear, disgust, or no emotional expression in six different emotion conditions. We found that oxytocin reduced interpersonal distance across the different emotion conditions, but only in individuals with lower levels of love withdrawal. In addition, oxytocin reduced anxiety levels during passive approach, in particular in the disgust condition, but only in individuals with lower levels of maternal disciplinary love withdrawal. Individuals with more love withdrawal experienced more anxiety while being approached by a virtual person displaying disgust or fear, but benefitted less from anxiety-reducing oxytocin effects. These results are consistent with previous research showing a dysregulated oxytocinergic system after childhood adversity and indicate that oxytocin may be less effective for individuals who are most in need of an intervention because of a problematic family background.

Role of BDNF in the development of an OFC-amygdala circuit regulating sociability in mouse and human.

Social deficits are common in many psychiatric disorders. However, due to inadequate tools for manipulating circuit activity in humans and unspecific paradigms for modeling social behaviors in rodents, our understanding of the molecular and circuit mechanisms mediating social behaviors remains relatively limited. Using human functional neuroimaging and rodent fiber photometry, we identified a mOFC-BLA projection that modulates social approach behavior and influences susceptibility to social anxiety. In humans and knock-in mice with a loss of function BDNF SNP (Val66Met), the functionality of this circuit was altered, resulting in social behavioral changes in human and mice. We further showed that the development of this circuit is disrupted in BDNF Met carriers due to insufficient BDNF bioavailability, specifically during a peri-adolescent timeframe. These findings define one mechanism by which social anxiety may stem from altered maturation of orbitofronto-amygdala projections and identify a developmental window in which BDNF-based interventions may have therapeutic potential.

Abdominal vagal deafferentation alters affective behaviors in rats

BackgroundThere is growing evidence for a role of abnormal gut-brain signaling in disorders involving altered mood and affect, including depression. Studies using vagus nerve stimulation (VNS) suggest that the disruption of vagal afferent signaling may contribute to these abnormalities. To test this hypothesis, we used a rat model of subdiaphragmatic vagal deafferentation (SDA), the most complete and selective vagal deafferentation method existing to date, to study the consequences of complete disconnection of abdominal vagal afferents on affective behaviors. MethodsSDA- and Sham-operated male rats were subjected to several tests that are commonly used in preclinical rodent models to assess the presence of anhedonic behavior, namely the novel object-induced exploration test, the novelty-suppressed eating test, and the sucrose preference test. In addition, we compared SDA and Sham rats in a social interaction test and the forced swim test to assess sociability and behavioral despair, respectively. ResultsCompared to Sham controls, SDA rats consistently displayed signs of anhedonic behavior in all test settings used. SDA rats also showed increased immobility and reduced swimming in the forced swim test, whereas they did not differ from Sham controls with regards to social approach behavior. LimitationsThis study was conducted in male rats only. Hence, possible sex-specific effects of SDA on affective behaviors remained unexamined. ConclusionsOur findings demonstrate that hedonic behavior and behavioral despair are subject to visceral modulation through abdominal vagal afferents. These data are compatible with preclinical models and clinical trials showing beneficial effects of VNS on depression-like and affective behaviors.

Maternal immune activation impairs cognitive flexibility and alters transcription in frontal cortex

BackgroundEpidemiological studies suggest that the risk of neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia is increased by prenatal exposure to viral or bacterial infection during pregnancy. It is still unclear how activation of the maternal immune response interacts with underlying genetic factors to influence observed ASD phenotypes. MethodsThe current study investigated how maternal immune activation (MIA) in mice impacts gene expression in the frontal cortex in adulthood, and how these molecular changes relate to deficits in cognitive flexibility and social behavior, and increases in repetitive behavior that are prevalent in ASD. Poly(I:C) (20 mg/kg) was administered to dams on E12.5 and offspring were tested for social approach behavior, repetitive grooming, and probabilistic reversal learning in adulthood (n = 8 vehicle; n = 9 Poly(I:C)). We employed next-generation high-throughput mRNA sequencing (RNA-seq) to comprehensively investigate the transcriptome profile in frontal cortex of adult offspring of Poly(I:C)-exposed dams. ResultsExposure to poly(I:C) during gestation impaired probabilistic reversal learning and decreased social approach in MIA offspring compared to controls. We found long-term effects of MIA on expression of 24 genes, including genes involved in glutamatergic neurotransmission, mTOR signaling and potassium ion channel activity. Correlations between gene expression and specific behavioral measures provided insight into genes that may be responsible for ASD-like behavioral alterations. ConclusionsThese findings suggest that MIA can lead to impairments in cognitive flexibility in mice similar to those exhibited in ASD individuals, and that these impairments are associated with altered gene expression in frontal cortex.

Sex-dependent effects of Cacna1c haploinsufficiency on juvenile social play behavior and pro-social 50-kHz ultrasonic communication in rats.

As cross-disorder risk gene, CACNA1C is implicated in the etiology of all major neuropsychiatric disorders characterized by deficits in social behavior and communication and there is evidence for sex-dependent influences of single-nucleotide polymorphisms within CACNA1C on diagnosis, course, and recovery in humans. In this study, we aimed, therefore, at further exploring the role of Cacna1c in regulating behavioral phenotypes, focusing on sex-specific differences in social behavior and communication during the critical developmental period of adolescence in rats. Specifically, we compared rough-and-tumble play, concomitant emission of pro-social 50-kHz ultrasonic vocalizations, and social approach behavior in response to playback of 50-kHz ultrasonic vocalizations between constitutive heterozygous Cacna1c +/- females and wildtype Cacna1c +/+ littermate controls, and contrasted present female findings to data previously reported in males. Our results show for the first time that partial depletion of Cacna1c leads to sex-dependent alterations in social behavior and communication in rats. In females, Cacna1c haploinsufficiency led to hypermasculinization, with rough-and-tumble play behavior, in general, and pinning behavior, in particular, being even higher than in males without affecting concomitant 50-kHz ultrasonic vocalizations. In males, in contrast, rough-and-tumble play behavior was not altered, yet emission of 50-kHz ultrasonic vocalizations was diminished following partial Cacna1c depletion. The behavioral responses elicited by playback of 50-kHz ultrasonic vocalizations were reduced upon partial Cacna1c depletion in both sexes. It thus can be concluded that Cacna1c plays a prominent sex-dependent role in regulating juvenile rat social play behavior and pro-social 50-kHz ultrasonic communication with relevance to sex-specific effects seen in neuropsychiatric disorders.

Intranasal oxytocin modulates higher order social cognition in body dysmorphic disorder.

Body dysmorphic disorder (BDD) is a psychiatric disorder with specific impairments in social cognition related to excessive concerns about one's appearance. Individuals with BDD have difficulty identifying emotional expressions and attribute internal factors for others' emotional expressions in self-referent (but not other-referent) scenarios. Given the role of oxytocin in regulating social approach behavior and social salience, we hypothesized that oxytocin would improve biases in emotion recognition, attributions, and threat interpretations in individuals with BDD, compared to healthy controls (HCs). This is the first study to examine the effects of oxytocin in people with BDD. Eighteen participants with BDD and 16 HCs received a single dose of 24 international units of intranasal oxytocin (Syntocinon®) or matching placebo in a randomized, placebo-controlled, within-subject crossover design. Participants completed the Emotion Recognition Task and Interpretation Questionnaire 45min after administration. Oxytocin, relative to placebo, did not improve emotion recognition accuracy in either self-referent or other-referent contexts for individuals with BDD. However, oxytocin led to greater internal attributions in other-referent contexts for those with BDD compared to HCs. Rather than reducing self-blame, oxytocin led to other-directed blame. Oxytocin did not impact threat interpretations in BDD. Oxytocin may only impact specific aspects of higher order social cognition in BDD and may have unwanted effects on emotion attributions. Our results caution its clinical use in BDD.

Investigation of social, affective, and locomotor behavior of adolescent Brattleboro rats reveals a link between vasopressin's actions on arousal and social behavior

Arginine vasopressin (AVP) has recently been implicated in juvenile and adolescent social development. How AVP influences social development, however, is not understood. Adolescent homozygous Brattleboro rats (Hom), which lack AVP due to a mutation in the Avp gene, exhibit fewer active social behaviors (e.g., social play) but more passive social behaviors (e.g., huddling) than their wild type and heterozygous (Het) littermates, raising the possibility that AVP impacts social development through an arousal mechanism. Here, we test whether the atypical social phenotype of adolescent Hom rats is associated with altered behavioral arousal, social approach, or affective behaviors and whether Brattleboro mothers impact these behavioral phenotypes. Male and female Het and Hom adolescents born to Het or Hom mothers were tested in social interaction, open field, novelty-seeking, social approach, and marble burying tests. As reported previously, Hom rats played less and emitted fewer 50 kHz ultrasonic vocalizations while huddling more than their Het littermates. No genotype differences were detected in novelty seeking or social approach, nor were consistent differences found between offspring from Het and Hom mothers. However, Hom rats were less active in the open field and buried fewer marbles than Het rats indicating a hypoaroused, low anxiety phenotype. Open field activity correlated with levels of social play indicating that the effects of the Brattleboro mutation on arousal and social behavior are linked. These data demonstrate that chronic AVP deficiency impacts behavioral arousal during adolescence and support the hypothesis that AVP influences adolescent social development, in part, through its regulation of arousal.

A common polymorphism on the oxytocin receptor gene (rs2268498) and resting-state functional connectivity of amygdala subregions - A genetic imaging study

Across species, the neuropeptide oxytocin has been associated with affiliative and social approach behavior. It has been suggested to exert its effects by modulating neural circuitry underlying anxiety, affiliative motivation, and social salience. The present study aims to investigate differences in subregional amygdala resting-state connectivity in healthy adult carriers of different genotypes of the oxytocin receptor (OXTR) gene polymorphism rs2268498. Previous studies have associated this polymorphic locus with social cognitive and affiliative phenotypes. The amygdala qualifies as a reasonable target due to its broad implication in emotional and social cognitive processing as well as its key role in mediating the behavioral effects of oxytocin. Whole brain seed-based functional connectivity analyses for the basolateral, centromedial and superficial amygdala revealed stronger resting-state connectivity of all amygdala subregions to the fusiform and inferior occipital gyrus in TT-carriers compared to C-allele carriers. Additional modulations were found for the centromedial amygdala which showed stronger resting-state connectivity to inferior frontal regions and the insula in C-allele carriers and to brainstem regions in TT-carriers. Our findings not only show the importance of oxytocin functioning in amygdalar neuronal signaling but also emphasize the need to investigate the amygdalar subregions individually instead of the amygdala as a whole. In summary, the present study is the first to characterize the impact of genetic variation of the OXTR gene with known functional consequences on widespread changes in a functional brain network originating from the amygdala.

Effects of light and dark phase testing on the investigation of behavioural paradigms in mice: Relevance for behavioural neuroscience

Different timing and light phases are critical factors in behavioural neuroscience, which can greatly affect the experimental outcomes of the performed tests. Despite the fact that time of testing is one of the most common factors that varies across behavioural laboratories, knowledge about the consequences of testing time on behavioural readouts is limited. Thus, in this study we systematically assessed the effect of this factor on the readout of a variety of elementary and recurrent behavioural paradigms in C57Bl/6 mice. Furthermore, we investigated potential neuronal correlates of this phenomenon by analysing how testing time influences the expression pattern of genes relevant for neuronal activation functions and the control of brain circadian rhythms. We show that animals tested in the light phase display reduced social approach behaviour and sensorimotor gating and increased locomotor activity, whereas anxiety-related behaviour and working memory are not affected. In addition, animals tested in the light phase also exhibit increased locomotor response to systemic amphetamine treatment, which is paralleled by alterations in the expression patterns of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in the Nucleus Accumbens (NAc) and/or Midbrain (Mid). Lastly, we observed that neuronal activation, indexed by the gene expression levels of cFos, was increased in the NAc and Mid of animals tested during the light phase. Our data thus suggest that daily alterations in gene expression in mesolimbic brain structures might be involved in the different behavioural responses of mice tested in the light- versus the dark-phase. At the same time, our study adds further weight to the notion that the specific timing of testing can indeed strongly affect the readout of a given test. As comparison and reproducibility of findings is pivotal in science, experimental protocols should be clarified in detail to allow appropriate data comparison across different laboratories.

Placebo treatment facilitates social trust and approach behavior

Placebo effect refers to beneficial changes induced by the use of inert treatment, such as placebo-induced relief of physical pain and attenuation of negative affect. To date, we know little about whether placebo treatment could facilitate social functioning, a crucial aspect for well-being of a social species. In the present study, we develop and validate a paradigm to induce placebo effects on social trust and approach behavior (social placebo effect), and show robust evidence that placebo treatment promotes trust in others and increases preference for a closer interpersonal distance. We further examine placebo effects in real-life social interaction and show that placebo treatment makes single, but not pair-bonded, males keep closer to an attractive first-met female and perceive less social anxiety in the female. Finally, we show evidence that the effects of placebo treatment on social trust and approach behavior can be as strong as the effect of intranasal administration of oxytocin, a neuropeptide known for its function in facilitating social cognition and behavior. The finding of the social placebo effect extends our understanding of placebo effects on improvement of physical, mental, and social well-being and suggests clinical potentials in the treatment of social dysfunction.

Decreased Density of Cholinergic Interneurons in the Medial Caudate Nucleus in Humans with Williams Syndrome

Williams syndrome (WS) is a rare neurodevelopmental disorder caused by the hemideletion of approximately 25–28 genes at 7q11.23. Its unusual social and cognitive phenotype is most strikingly characterized by the disinhibition of social behavior, in addition to reduced global IQ, with a relative sparing of language ability. Hypersociality and increased social approach behavior in WS may represent a unique inability to inhibit responses to specifically social stimuli, and is likely rooted in part in abnormalities of frontostriatal circuitry. Recent research has demonstrated that selective ablation of striatal cholinergic interneurons (SCINs) results in significant increases in compulsive conspecific‐directed, but not object‐focused, exploratory behavior in mice, indicating a role for SCINs in social approach behavior. Here, we examined the density of SCINs and parvalbumin‐positive interneurons in the striatum of five postmortem specimens from subjects with WS and five typically‐developing (TD) subjects. We found a significant reduction in the density of SCINs in the medial caudate nucleus, an important region receiving cortical projections from the orbitofrontal and ventromedial prefrontal cortex in circuitry involved in language and reward systems. This pattern of decreased SCIN density in WS is contrasted by anatomical findings in other disorders, including Tourette syndrome and schizophrenia, where differing patterns of SCIN depletion are found. Taken together with findings from neuroimaging, differences in the brains of individuals with WS at both the macro‐ and microstructural level further indicate a role for frontostriatal circuitry in the disorder's distinctive behavioral phenotype.Support or Funding InformationThis research is supported in part by NIH #P01NICHD033113, #1R03MH103697‐01(KS), and a Wenner Gren Dissertation Fieldwork Grant (KLH).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Specificity in Sociality: Mice and Prairie Voles Exhibit Different Patterns of Peer Affiliation.

Social behavior is often described as a unified concept, but highly social (group-living) species exhibit distinct social structures and may make different social decisions. Prairie voles (Microtus ochrogaster) are socially monogamous rodents that often reside in extended family groups, and exhibit robust preferences for familiar social partners (same- and opposite-sex) during extended choice tests, although short-term preferences are not known. Mice (Mus musculus) are gregarious and colonial, but in brief laboratory tests of social preference they typically prefer social novelty. This preference for novel vs. familiar peers may represent a species-specific difference in social decision-making between mice and prairie voles. However, the tests used to measure preferences in each species differ markedly in duration and degree of contact, such that the behaviors cannot be directly compared. We assessed whether social preferences for novelty or familiarity differed between mice and prairie voles of both sexes when assessed with matching protocols: the sociability/social preference test (SPT) typically used in mice (short, no direct contact), and the partner preference test (PPT) used in voles (long, direct contact). A subset of voles also underwent a PPT using barriers (long, no direct contact). In the short SPT, behavior did not differ between species. In the longer test, pronounced partner preferences emerged in prairie voles, but mice exhibited no social preferences and rarely huddled. No sex differences were evident in either test. Direct physical contact was required for partner preferences in huddling time in voles, but preference for the partner chamber was evident with or without contact. Both prairie voles and mice are social, but they exhibit important differences in the specificity and extent of their social behavior. While mice are often used to study social approach and other behaviors, voles are a more suitable species for the study of selective social relationships. Consideration of these differences will be important for studies examining the neural mechanisms supporting different kinds of peer social behavior.

Recovery of stress-impaired social behavior by an antagonist of the CRF binding protein, CRF6−33, in the bed nucleus of the stria terminalis of male rats

Social stress is recognized to promote the development of neuropsychiatric and mood disorders. Corticotropin releasing factor (CRF) is an important neuropeptide activated by social stress, and it contributes to neural and behavioral adaptations, as indicated by impaired social interactions and anhedonic effects. Few studies have focused on the role of the CRF binding protein (CRFBP), a component of the CRF system, and its activity in the bed nucleus of stria terminalis (BNST), a limbic structure connecting amygdala and hypothalamus. In this study, animals’ preference for sweet solutions was examined as an index of stress-induced anhedonic responses in Wistar rats subjected to four brief intermittent episodes of social defeat. Next, social approach was assessed after local infusions of the CRFBP antagonist, CRF fragment 6–33 (CRF6–33) into the BNST. The experience of brief episodes of social defeat impaired social approach behaviors in male rats. However, intra-BNST CRF6–33 infusions restored social approach in stressed animals to the levels of non-stressed rats. CRF6–33 acted selectively on social interaction and did not alter general exploration in nether stressed nor non-stressed rats. These findings suggest that BNST CRFBP is involved in the modulation of anxiety-like responses induced by social stress.

Cacna1c haploinsufficiency leads to pro-social 50-kHz ultrasonic communication deficits in rats.

ABSTRACTThe cross-disorder risk gene CACNA1C is strongly implicated in multiple neuropsychiatric disorders, including autism spectrum disorder (ASD), bipolar disorder (BPD) and schizophrenia (SCZ), with deficits in social functioning being common for all major neuropsychiatric disorders. In the present study, we explored the role of Cacna1c in regulating disorder-relevant behavioral phenotypes, focusing on socio-affective communication after weaning during the critical developmental period of adolescence in rats. To this aim, we used a newly developed genetic Cacna1c rat model and applied a truly reciprocal approach for studying communication through ultrasonic vocalizations, including both sender and receiver. Our results show that a deletion of Cacna1c leads to deficits in social behavior and pro-social 50-kHz ultrasonic communication in rats. Reduced levels of 50-kHz ultrasonic vocalizations emitted during rough-and-tumble play may suggest that Cacna1c haploinsufficient rats derive less reward from playful social interactions. Besides the emission of fewer 50-kHz ultrasonic vocalizations in the sender, Cacna1c deletion reduced social approach behavior elicited by playback of 50-kHz ultrasonic vocalizations. This indicates that Cacna1c haploinsufficiency has detrimental effects on 50-kHz ultrasonic communication in both sender and receiver. Together, these data suggest that Cacna1c plays a prominent role in regulating socio-affective communication in rats with relevance for ASD, BPD and SCZ.This article has an associated First Person interview with the first author of the paper.

Mapping trait-like socio-affective phenotypes in rats through 50-kHz ultrasonic vocalizations.

Fifty-kilohertz ultrasonic vocalizations (USV) in rats are believed to express inter-individual differences in trait-like positive affective phenotypes. Emission of 50-kHz USV can be induced by amphetamine (AMPH) to model mania-like positive affect, raising the possibility that predispositions for high 50-kHz USV production confer susceptibility to mania-like states. Such 50-kHz USV presumably express the sender's motivation for social contact and elicit social approach behavior in receivers. We recently showed that AMPH-induced 50-kHz USV are paralleled by mania-like patterns of enhanced social approach behavior towards playback of 50-kHz USV. Here, we assessed whether these AMPH effects are dependent on trait-like inter-individual differences in 50-kHz USV production. To this aim, we subdivided juvenile rats into those emitting low (LC) and high (HC) rates of baseline 50-kHz USV and compared them across four AMPH dosage conditions: 0.0, 0.5, 1.0, and 2.5mg/kg. HC rats were considerably more susceptible to AMPH in inducing 50-kHz USV than LC rats, consistently across all examined doses. They further appeared to attribute more incentive salience to signals of rewarding social contact, as evidenced by enhanced social approach behavior towards 50-kHz USV playback, a response pattern also seen in LC rats after receiving AMPH treatment. HC but not LC rats emitted aversive 22-kHz USV following 50-kHz USV playback, indicating increased proneness to experience negative affective states if no actual social consequence followed the incentive signal. Inter-individual differences in 50-kHz USV map onto a unique trait-like socio-affective phenotype associated with enhanced emotional reactivity towards social and non-social reward, possibly conferring risk to mania-like states.

Aberrant cognitive phenotypes and altered hippocampal BDNF expression related to epigenetic modifications in mice lacking the post-synaptic scaffolding protein SHANK1: Implications for autism spectrum disorder.

Autism spectrum disorder (ASD) is a class of neurodevelopmental disorders characterized by persistent deficits in social communication/interaction, together with restricted/repetitive patterns of behavior. ASD is among the most heritable neuropsychiatric conditions, and while available evidence points to a complex set of genetic factors, the SHANK gene family has emerged as one of the most promising candidates. Here, we assessed ASD-related phenotypes with particular emphasis on social behavior and cognition in Shank1 mouse mutants in comparison to heterozygous and wildtype littermate controls across development in both sexes. While social approach behavior was evident in all experimental conditions and social recognition was only mildly affected by genotype, Shank1-/- null mutant mice were severely impaired in object recognition memory. This effect was particularly prominent in juveniles, not due to impairments in object discrimination, and replicated in independent mouse cohorts. At the neurobiological level, object recognition deficits were paralleled by increased brain-derived neurotrophic factor (BDNF) protein expression in the hippocampus of Shank1-/- mice; yet BDNF levels did not differ under baseline conditions. We therefore investigated changes in the epigenetic regulation of hippocampal BDNF expression and detected an enrichment of histone H3 acetylation at the Bdnf promoter1 in Shank1-/- mice, consistent with increased learning-associated BDNF. Together, our findings indicate that Shank1 deletions lead to an aberrant cognitive phenotype characterized by severe impairments in object recognition memory and increased hippocampal BDNF levels, possibly due to epigenetic modifications. This result supports the link between ASD and intellectual disability, and suggests epigenetic regulation as a potential therapeutic target.

Three-dimensional computer graphic animations for studying social approach behaviour in medaka fish: Effects of systematic manipulation of morphological and motion cues.

We studied social approach behaviour in medaka fish using three-dimensional computer graphic (3DCG) animations based on the morphological features and motion characteristics obtained from real fish. This is the first study which used 3DCG animations and examined the relative effects of morphological and motion cues on social approach behaviour in medaka. Various visual stimuli, e.g., lack of motion, lack of colour, alternation in shape, lack of locomotion, lack of body motion, and normal virtual fish in which all four features (colour, shape, locomotion, and body motion) were reconstructed, were created and presented to fish using a computer display. Medaka fish presented with normal virtual fish spent a long time in proximity to the display, whereas time spent near the display was decreased in other groups when compared with normal virtual medaka group. The results suggested that the naturalness of visual cues contributes to the induction of social approach behaviour. Differential effects between body motion and locomotion were also detected. 3DCG animations can be a useful tool to study the mechanisms of visual processing and social behaviour in medaka.