α-Synuclein aggregation decreases cortico-amygdala connectivity and impairs social behavior in mice.

Abnormal accumulation of insoluble α-synuclein (α-Syn) inclusions in neurons, neurites, and glial cells is the defining neuropathology of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy. Accumulation of α-Syn inclusions in the amygdala has been well-documented in post-mortem studies of PD and DLB brains, as well as preclinical animal models of these conditions. Though α-Syn pathology is closely associated with neurodegeneration, there is a poor correlation between neuronal loss in the amygdala and the clinical features of PD and DLB. Moreover, functional interaction between the cerebral cortex and the amygdala is critical to regulating emotion, motivation, and social behaviors. The cortico-amygdala functional interaction is likely to be disrupted by the development of α-Syn pathology in the brain. Thus, we hypothesize that neuronal α-Syn inclusions disrupt cortical modulation of the amygdala circuits and are sufficient to drive social behavioral deficits. In the present work, we designed a series of longitudinal studies to rigorously measure the time courses of neurodegeneration, functional impairment of cortico-amygdala connectivity, and development of amygdala-dependent social behavioral deficits to test this hypothesis. We injected α-Syn preformed fibrils (PFFs) into the dorsal striatum to induce α-Syn aggregation in the amygdala and the medial prefrontal cortex (mPFC) of C57BL6 mice of both sexes, followed by a detailed analysis of temporal development of α-Syn pathology, synaptic deficits, and neuronal loss in the amygdala, as well as behavioral deficits at 3-12 months post injections. Development of α-Syn inclusions caused losses of cortical axon terminals and cell death in the basolateral amygdala (BLA) at 6- and 12-months post injections, respectively. At a relatively early stage of 3 months post injections, the connection strength of the mPFC-BLA synapse was decreased in PFFs-injection mice compared to controls. Meanwhile, the PFFs-injected mice showed impaired social interaction behavior, which was rescued by chemogenetic stimulation of mPFC-BLA connections. Altogether, we presented a series of evidence to delineate circuit events in the amygdala associated with the accumulation of α-Syn inclusions in the mouse brain, highlighting that functional impairment of the amygdala is sufficient to cause social behavior deficits. The present work further suggests that early circuit modulation could be an effective approach to alleviate symptoms associated with α-Syn pathology, necessitating studies of functional consequences of α-Syn aggregation.

Behavioral and biochemical effects of environmental concentrations of caffeine in zebrafish after long-term exposure.

Caffeine (CAF) is widely detected in aquatic environments, serving as an indicator of anthropogenic contamination. Its high consumption, and persistence raise environmental concerns. This study was to evaluate the chronic effects in terms of growth rate, weight, behavior, and biochemical parameters of environmental concentrations of CAF on adult zebrafish. Adult zebrafish were exposed, for 30 d, to 0, 0.5, 1.5, and 300 µg L-1 CAF, with behavior (feeding latency, exploration, aggression, sociability, sound response) and biochemical endpoints (acetylcholinesterase (AChE), lactate dehydrogenase (LDH), and cortisol levels) assessed at the end of the exposure. CAF 0.5 µg L-1 increased feeding latency time, while 300 µg L-1 reduced growth and weight. Exposure to CAF affect fish behavior in terms of vertical exploration, aggressiveness, shoaling, and sound responses although were concentration specific. All concentrations tested increased social behavior, with fish swimming closer to the shoal. At a biochemical level, CAF exposed showed reduced AChE activity, while LDH activity, and cortisol levels increased at 300 µg L-1. Low concentrations of CAF caused neurotoxicity in zebrafish which may compromise their feeding behavior, and social interactions in the wild. These changes suggest potential ecological impacts of chronic exposure to CAF, such as impaired feeding and stress responses.

Interoception mediates the association between social support and sociability in patients with major depressive disorder.

BACKGROUND: Interoception dysfunction has an important impact on the onset and development of major depressive disorder (MDD). Social support serves as a protective factor against MDD, and sociability also plays a significant role in this condition. These interconnected constructs-social support and sociability-play pivotal roles in MDD. However, no research on the mechanisms underlying the associations between social support and sociability, particularly the potential role of interoception, have been reported. AIM: To investigate the mediating effect of interoception between social support and social ability and to explore the independent role of social support in sociability. METHODS: The participants included 292 patients with MDD and 257 healthy controls (HCs). The patient health questionnaire 9, the multidimensional assessment of interoception awareness, version 2 (MAIA-2), the social support rating scale (SSRS), and the Texas social behavior inventory (TSBI) were used to assess depression, interoception, social support, and sociability, respectively. A mediation analysis model for the eight dimensions of interoception (noticing, not distracting, not worrying, attention regulation, emotional awareness, self-regulation, body listening, and trust), social support, and sociability were established to evaluate the mediating effects. RESULTS: A partial correlation analysis of eight dimensions of the MAIA-2, SSRS, and TSBI scores, with demographic data as control variables, revealed pairwise correlations between the SSRS score and both the MAIA-2 score and TSBI score. In the major depression (MD) group, the SSRS score had a positive direct effect on the TSBI score, while the scores for body listening, emotional awareness, self-regulation, and trust in the MAIA-2C had indirect effects on the TSBI score. In the HC group, the SSRS score had a positive direct effect on the TSBI score, and the scores for attention regulation, emotional awareness, self-regulation, and trust in the MAIA-2C had indirect effects on the TSBI score. The proportion of mediators in the MD group was lower than that in the HC group. CONCLUSION: Interoceptive awareness is a mediating factor in the association between social support and sociability in both HCs and depressed patients. Training in interoceptive awareness might not only help improve emotional regulation in depressed patients but also enhance their social skills and support networks.

Deep learning-based scoring method of the three-chamber social behaviour test in a mouse model of alcohol intoxication. A comparative analysis of DeepLabCut, commercial automatic tracking and manual scoring.

Background: Alcohol consumption and withdrawal alter social behaviour in humans in a sex-dependent manner. The three-chamber test is a widely used paradigm to assess rodents' social behaviour, including sociability and social novelty. Automatic tracking systems are commonly used to score time spent with conspecifics, despite failing to score direct interaction time with conspecifics rather than time in the nearby zone. Thereby, the automatically scored results are usually inaccurate and need manual corrections. New method: New advances in artificial intelligence (AI) have been used recently to analyze complex behaviours. DeepLabCat is a pose-estimation toolkit that allows the tracking of animal body parts. Thus, we used DeepLabCut, to introduce a scoring model of the three-chamber test to investigate alcohol withdrawal effects on social behaviour in mice considering sex and withdrawal periods. We have compared the results of two automatic pose estimation methods: automatic tracking (AnyMaze) and DeepLabCut considering the manual scoring method, the current gold standard. Results: We have found that the automatic tracking method (AnyMaze) has failed to detect the significance of social deficits in female mice during acute withdrawal. However, tracking the animal's nose using DeepLabCut showed a significant social deficit in agreement with manual scoring. Interestingly, this social deficit was shown only in females during acute and recovered by the protracted withdrawal. DLC and manually scored results showed a higher Spearman correlation coefficient and a lower bias in the Bland-Altman analysis. Conclusion: our approach helps improve the accuracy of scoring the three-chamber test while outperforming commercial automatic tracking systems.

Early positive tactile stimulation reverses the increase of anxiety and decrease of sociality induced by early chronic mechanical pain in mandarin voles.

Animals may experience early negative (mechanical pain: being retrieved using an incisor by parents or attacked) or positive stimulation (being licked and groomed) that may affect emotional and social behaviors in adulthood. Whether positive tactile stimulation can reverse adverse consequences on emotional and social behaviors in adulthood resulting from chronic mechanical pain and underlying mechanisms remain unclear. This study used a tail-pinching model during development to simulate mechanical pain experienced by pups in high-social mandarin voles (Microtus mandarinus). Subsequently, brush-like positive tactile stimuli were applied to the backs of the mandarin voles. Various behavioral tests were used to measure levels of anxiety, depression, and sociability. The results showed that early tail-pinching delayed the eye opening of pups, increased levels of anxiety, reduced levels of sociality in male mandarin voles, and impaired social cognition in females during adulthood. Brushing on the back reversed some of these effects. While mandarin voles that were exposed to tail-pinching during development were exposed to sub-threshold variable stress as adults, they were more likely to show a stress-induced increase of anxiety-like behavior, reduction of sociability, and impairment of social cognition, displaying heightened susceptibility to stress, particularly in males. However, back-brushing reversed some of these effects, implying that these adults display enhanced stress resilience. In addition, tail-pinching reduced levels of serum oxytocin and increased corticosterone levels in serum, but back-brushing reversed these effects. Overall, it was found that positive tactile stimulation reversed increases in anxiety and impairments of social behavior induced by negative stimulation in male mandarin voles via alteration of oxytocin and corticosterone levels.

Impact of Coffee Intake on Measures of Wellbeing in Mice.

Coffee intake is increasingly recognized as a life-style factor associated with the preservation of health, but there is still a debate on the relative effects of caffeinated and decaffeinated coffee. We now tested how the regular drinking of caffeinated and decaffeinated coffee for 3 weeks impacted on the behavior of male and female adult mice. Males drinking caffeinated coffee displayed statistically significant lower weight gain, increased sensorimotor coordination, greater motivation in the splash test, more struggling in the forced swimming test, faster onset of nest building, more marble burying and greater sociability. Females drinking caffeinated coffee displayed statistically significant increased hierarchy fighting, greater self-care and motivation in the splash test and faster onset of nest building. A post-hoc two-way ANOVA revealed sex-differences in the effects of caffeinated coffee (p values for interaction between the effect of caffeinated coffee and sex) on the hierarchy in the tube test (p = 0.044; dominance), in the time socializing (p = 0.044) and in the latency to grooming (p = 0.048; selfcare), but not in the marble burying test (p = 0.089). Intake of decaffeinated coffee was devoid of effects in males and females. Since caffeine targets adenosine receptors, we verified that caffeinated but not decaffeinated coffee intake increased the density of adenosine A1 receptors (A1R) and increased A1R-mediated tonic inhibition of synaptic transmission in the dorsolateral striatum and ventral but not dorsal hippocampus, the effects being more evident in the ventral hippocampus of females and striatum of males. In contrast, caffeinated and decaffeinated coffee both ameliorated the antioxidant status in the frontal cortex. It is concluded that caffeinated coffee increases A1R-mediated inhibition in mood-related areas bolstering wellbeing of both males and females, with increased sociability in males and hierarchy struggling and self-care in females.

Impacts of anthropogenic pollutants on social group cohesion and individual sociability in fish: A systematic review and meta-analysis.

Anthropogenic pollutants are near-ubiquitous in aquatic systems. Aquatic animals such as fishes are subject to physiological stress induced by pollution present in aquatic systems, which can translate to changes in behaviour. Key adaptive behaviours such as shoaling and schooling may be subject to change as a result of physiological or metabolic stress or neurosensory impacts of pollution. This can result in fitness and ecological impacts such as increased predation risk and reduced foraging success. Here, we conducted a systematic metanalysis of the existing literature, comprising 165 studies, on the effects of anthropogenic pollution on sociability and group cohesion in fish species. Both organic (number of studies = 92, posterior mean (PM) = -0.483, p < 0.01) and inorganic (n = 24, PM = -1.453, p < 0.001) chemical pollutants, as well as light exposure (n = 21, PM = -3.038, p < 0.01) were found to reduce sociability. These pollutants did not reduce group cohesion, indicating that effects may be masked in group settings, though fewer studies were carried out on group cohesion and this is a key area for future research. Mixtures of chemical pollutants (n = 16) were found to reduce cohesion (PM = -43.71, p < 0.01), but increase sociability (PM = 44.27, p < 0.01). Evidence was found that fish may behaviourally acclimate to two forms of pollutant, namely mixed chemical pollutants (PM = -0.668, p < 0.01) and noise exposure (n = 22, PM = -4.043, p < 0.01). While aquatic systems are often subject to pollution from multiple sources and of multiple types, very few studies investigated the effects of multiple stressors concurrently. This review identifies trends in the existing literature, and highlights areas where further research is required in order to understand the behavioural and ecological impacts of anthropogenic pollutants in aquatic systems.

Active crocodiles are less sociable.

How animals move and associate with conspecifics is rarely random, with a population's spatial structure forming the foundation on which the social behaviours of individuals form. Studies examining the spatial-social interface typically measure averaged behavioural differences between individuals; however, this neglects the inherent variation present within individuals and how it may impact the spatial-social interface. Here, we investigated differences in among-individual (co)variance in sociability, activity and site fidelity in a population of wild estuarine crocodiles, Crocodylus porosus, across a 10-year period. By monitoring 118 crocodiles using coded acoustic transmitters and an array of fixed underwater receivers, we discovered that not only did individual crocodiles repeatably differ (among-individual variation) in each behaviour measured but also in how consistently they expressed these behaviours through time (within-individual variation). As expected, crocodile activity and sociability formed a behavioural syndrome, with more active individuals being less sociable. Interestingly, we also found that individuals that were either more sociable or displayed greater site fidelity were also more specialized (lower within-individual variation) in these behaviours. Together, our results provide important empirical evidence for the interplay between spatial, temporal and social individual-level behavioural variation and how these contribute to forming behavioural niches. This article is part of the theme issue 'The spatial-social interface: a theoretical and empirical integration'.

Korean Red Ginseng and Rb1 restore altered social interaction, gene expressions in the medial prefrontal cortex, and gut metabolites under post-weaning social isolation in mice.

Background: Post-weaning social isolation (SI) reduces sociability, gene expressions including myelin genes in the medial prefrontal cortex (mPFC), and alters microbiome compositions in rodent models. Korean Red Ginseng (KRG) and its major ginsenoside Rb1 have been reported to affect myelin formation and gut metabolites. However, their effects under post-weaning SI have not been investigated. This study investigated the effects of KRG and Rb1 on sociability, gene expressions in the mPFC, and gut metabolites under post-weaning SI. Methods: C57BL/6J mice were administered with water or KRG (150, 400 mg/kg) or Rb1 (0.1 mg/kg) under SI or regular environment (RE) for 2 weeks during the post-weaning period (P21-P35). After this period, mice underwent a sociability test, and then brains and ceca were collected for qPCR/immunohistochemistry and non-targeted metabolomics, respectively. Results: SI reduced sociability compared to RE; however, KRG (400 mg/kg) and Rb1 significantly restored sociability under SI. In the mPFC, expressions of genes related to myelin, neurotransmitter, and oxidative stress were significantly reduced in mice under SI compared to RE conditions. Under SI, KRG and Rb1 recovered the altered expressions of several genes in the mPFC. In gut metabolomics, 313 metabolites were identified as significant among 3027 detected metabolites. Among the significantly changed metabolites in SI, some were recovered by KRG or Rb1, including metabolites related to stress axis, inflammation, and DNA damage. Conclusion: Altered sociability, gene expression levels in the mPFC, and gut metabolites induced by two weeks of post-weaning SI were at least partially recovered by KRG and Rb1.

Serotonin release by parachloroamphetamine in rats with high and low sociability: High prefrontal release capacity in sociable females.

BACKGROUND: Social behaviour is the expression of one of the most generally accepted independent dimensions of personality. Serotonergic neurotransmission has been implicated in typical social response and drugs that promote serotonin (5-hydroxytryptamine (5-HT)) release have prosocial effects. By using the social interaction test, we have previously demonstrated sociability as a temperamental trait in male Wistar rats. AIMS: To assess sociability in male rats of the Sprague-Dawley strain and in female rats of both Wistar and Sprague-Dawley strain, and extracellular levels of 5-HT in rats with high and low sociability (high sociability (HS)- and low sociability (LS)-rats). METHODS: Social interaction test conducted with different weight-matched partners was used to assess sociability, and in vivo, microdialysis was performed before and after administration of a low dose (2 mg/kg) of parachloroamphetamine (PCA) in the prefrontal cortex, dorsamedial striatum and ventral tegmental area. RESULTS: Similarly to male Wistar rats, female Wistars and Sprague-Dawley rats of both sexes displayed trait-wise sociability. Male Wistar HS-rats had lower extracellular levels of 5-HT in prefrontal cortex at baseline and after administration of PCA, and higher PCA-induced increase of extracellular 5-HT in ventral tegmental area. In dorsomedial striatum, PCA elicited a comparable increase in extracellular dopamine in HS- and LS-rats, but higher release of 5-HT in HS-rats. Comparison of PCA-induced 5-HT release in prefrontal cortex of male and female Sprague-Dawley rats revealed a larger 5-HT response in female HS-rats. CONCLUSIONS: 5-HT release potential is higher in rats with high expression of sociability trait, whereas some regionally variable differences may be related to relative contributions of social motivation and anxiety in shaping social behaviour.

Canine hyper-sociability structural variants associated with altered three-dimensional chromatin state.

Strong selection on complex traits can lead to skewed trait means and reduced trait variability in populations. An example of this phenomenon can be evidenced in allele frequency changes and skewed trait distributions driven by persistent human-directed selective pressures in domesticated species. Dog domestication is linked to several genomic variants; however, the functional impacts of these variants may not always be straightforward when found in non-coding regions of the genome. Four polymorphic transposable elements (TE) found within non-coding sites along a 5 Mb region on canine CFA6 have evolved due to directional selection associated with heightened human-directed hyper-sociability in domesticated dogs. We found that the polymorphic TE in intron 17 of the canine GTF2I gene, which was previously reported to be negatively correlated with canid human-directed hyper-sociability, is associated with altered chromatin looping and hence distinct cis-regulatory landscapes. We reported supporting evidence of an E2F1-DNA binding peak concordant with the altered loop and higher expression of GTF2I exon 18, indicative of alternative splicing. Globally, we discovered differences in pathways regulating the extra-cellular matrix with respect to TE copy number. Overall, we reported evidence suggesting an intriguing molecular convergence between the emergence of hypersocial behaviors in dogs and the same genes that, when hemizygous, produce human Williams Beuren Syndrome characterized by cranio-facial defects and heightened social behaviors. Our results additionally emphasize the often-overlooked potential role of chromatin architecture in social evolution.

Quantitative evaluation of a theoretical-conceptual model based on affective and socio-behavioral dimensions to explain the academic performance of mathematics students.

Objective: There is evidence that suggests that affective dimensions, personality traits, as well as students' cooperative interpersonal interactions, are an important element in the students learning process. In this work we propose a theoretical model, based on evidence, that shows the direct and indirect relationships between these factors and academic performance in mathematics courses, in undergraduate and school students. Methods: To understand the type of relationships between these variables, the PANAS psychometric test of positive and negative affect, the BIG FIVE personality test and the economic decision game DUPLES GAME were applied. The study sample was 130 students between 17 and 22 years of age from undergraduate and school (M ± SD = 20.1 ± 3.99). Results: From a path analysis, statistically significant relationships were found, for example, a direct relationship between neuroticism and positive affect, which in turn is related to academic performance. We also found a direct relationship between neuroticism and negative affect, extraversion and positive affect. This allows us to propose that some of the independent variables of the model directly and indirectly influence the academic performance of students in the subject of mathematics. Conclusion: Positive affect and negative affect directly affect academic performance in mathematics, neuroticism has a direct impact on negative affect and extraversion direct impact on positive affect. Consequently, there are direct and indirect relationships between personality traits and affective dimensions, which affect the academic performance of mathematics students.

Mobile sensing-based depression severity assessment in participants with heterogeneous mental health conditions.

Mobile sensing-based depression severity assessment could complement the subjective questionnaires-based assessment currently used in practice. However, previous studies on mobile sensing for depression severity assessment were conducted on homogeneous mental health condition participants; evaluation of possible generalization across heterogeneous groups has been limited. Similarly, previous studies have not investigated the potential of free-living audio data for depression severity assessment. Audio recordings from free-living could provide rich sociability features to characterize depressive states. We conducted a study with 11 healthy individuals, 13 individuals with major depressive disorder, and eight individuals with schizoaffective disorders. Communication logs and location data from the participants' smartphones and continuous audio recordings of free-living from a wearable audioband were obtained over a week for each participant. The depression severity prediction model trained using communication log and location data features had a root mean squared error (rmse) of 6.80. Audio-based sociability features further reduced the rmse to 6.07 (normalized rmse of 0.22). Audio-based sociability features also improved the F1 score in the five-class depression category classification model from 0.34 to 0.46. Thus, free-living audio-based sociability features complement the commonly used mobile sensing features to improve depression severity assessment. The prediction results obtained with mobile sensing-based features are better than the rmse of 9.83 (normalized rmse of 0.36) and the F1 score of 0.25 obtained with a baseline model. Additionally, the predicted depression severity had a significant correlation with reported depression severity (correlation coefficient of 0.76, p < 0.001). Thus, our work shows that mobile sensing could model depression severity across participants with heterogeneous mental health conditions, potentially offering a screening tool for depressive symptoms monitoring in the broader population.

Early social isolation disrupts adult personality expression in group-living mites.

Animal personalities are characterized by intra-individual consistency and consistent inter-individual variability in behaviour across time and contexts. Personalities abound in animals, ranging from sea anemones to insects, arachnids, birds, fish and primates, yet the pathways mediating personality formation and expression remain elusive. Social conditions during the early postnatal period are known determinants of mean behavioural trait expressions later in life, but their relevance in shaping personality trajectories is unknown. Here, we investigated the consequences of early social isolation on adult personality expression in plant-inhabiting predatory mites Phytoseiulus persimilis. These mites are adapted to live in groups. We hypothesized that transient experience of social isolation early in life, that is, deprivation of any social contact during a sensitive window in the post-hatching phase, has enduring adverse effects on adult personality expression. Newly hatched mites were transiently reared in isolation or in groups and tested as adults for repeatability of various within-group behaviours, such as movement patterns and mutual interactions including sociability, defined as the propensity to associate and interact benignly with conspecifics, and activity patterns when alone. Groups composed of individuals with the same or different early-life experiences were repeatedly videotaped and individual behaviours were automatically analysed using AnimalTA. Social experiences early in life had persistent effects on mean behavioural traits as well as adult personality expression, as measured by intraclass correlation coefficients (indicating repeatability). On average, isolation-reared females moved at higher speeds, meandered less, kept greater distances from others and had fewer immediate neighbours than group-reared females. Group-reared females were highly repeatable in inter-individual distance, moving speed, meandering and area explored, whereas isolation-reared females were repeatable only in the number of immediate neighbours. Activity, quantified as the proportion of time spent moving within groups, was only repeatable in group-reared females, whereas activity, quantified as the proportion of time spent moving when alone, was only repeatable in females reared in isolation. Strikingly, also the early-life experiences of male mates influenced personality expression of mated females, with isolation-reared males boosting the repeatability of behavioural traits of group-reared females. Overall, our study provides evidence that a transient phase of social isolation during a critical period early in life has lasting effects that extend into adulthood, impairing adult personality expression. These effects should cascade upward, changing the phenotypic composition and diversity within populations.

Vasostatin-1 restores autistic disorders in an idiopathic autism model (BTBR T+ Itpr3tf/J mice) by decreasing hippocampal neuroinflammation.

Chromogranin A (CgA), a âˆ¼ 49 kDa acidic secretory protein, is ubiquitously distributed in endocrine and neuroendocrine cells and neurons. As a propeptide, CgA is proteolytically cleaved to generate several peptides of biological importance, including pancreastatin (PST: hCgA250-301), Vasostatin 1 (VS1: hCgA1-76), and catestatin (CST: CgA 352-372). VS1 represents the most conserved fragment of CgA. A 20 amino acid domain within VS1 (CgA 47-66) exhibits potent antimicrobial and anti-inflammatory activities. Autism is known to be associated with inflammation. Therefore, we seek to test the hypothesis that VS1 modulates autism behaviors by reducing inflammation in the hippocampus. Treatment of C57BL/6 (B6) and BTBR (a mouse model of idiopathic autism) mice with VS1 revealed the following: BTBR mice showed a significant decrease in chamber time in the presence of a stranger or a novel object. Treatment with VS1 significantly increased chamber time in both cases, underscoring a crucial role for VS1 in improving behavioral deficits in BTBR mice. In contrast to chamber time, sniffing time in BTBR mice in the presence of a stranger was less compared to B6 control mice. VS1 did not improve this latter parameter. Surprisingly, sniffing time in BTBR mice in the presence of a novel object was comparable with B6 mice. Proinflammatory cytokines such as IL-6 and IL-1b, as well as other inflammatory markers, were elevated in BTBR mice, which were dramatically reduced after supplementation with VS1. Interestingly, even Beclin-1/p62, pAKT/AKT, and p-p70-S6K/p70-S6K ratios were notably reduced by VS1. We conclude that VS1 plays a crucial role in restoring autistic spectrum disorders (ASD) plausibly by attenuating neuroinflammation.

Pannexin1 Mediates Early-Life Seizure-Induced Social Behavior Deficits.

There is a high co-morbidity between childhood epilepsy and autism spectrum disorder (ASD), with age of seizure onset being a critical determinant of behavioral outcomes. The interplay between these comorbidities has been investigated in animal models with results showing that the induction of seizures at early post-natal ages leads to learning and memory deficits and to autistic-like behavior in adulthood. Modifications of the excitation/inhibition (glutamate/GABA, ATP/adenosine) balance that follows early-life seizures (ELS) are thought to be the physiological events that underlie neuropsychiatric and neurodevelopmental disorders. Although alterations in purinergic/adenosinergic signaling have been implicated in seizures and ASD, it is unknown whether the ATP release channels, Pannexin1 (Panx1), contribute to ELS-induced behavior changes. To tackle this question, we used the ELS-kainic acid model in transgenic mice with global and cell type specific deletion of Panx1 to evaluate whether these channels were involved in behavioral deficits that occur later in life. Our studies show that ELS results in Panx1 dependent social behavior deficits and also in poor performance in a spatial memory test that does not involve Panx1. These findings provide support for a link between ELS and adult behavioral deficits. Moreover, we identify neuronal and not astrocyte Panx1 as a potential target to specifically limit astrogliosis and social behavioral deficits resultant from early-life seizures.

Sociability across Eastern-Western cultures: Is it the same underlying construct?

In this study, we examined cross-cultural differences in sociability, a core personality facet of the higher order extraversion trait, which has been reported at lower levels in Eastern versus Western cultures several decades ago. Up until now, however, East-West cultural comparisons on the Western-defined construct of sociability have been limited, despite the extensive research published on extraversion indicating that this personality dimension is globally relevant across cultures. Following current practices, we first assessed for measurement invariance (MI) on the Cheek and Buss sociability scale between Chinese (n = 816, 47.2% male, M = 18.51 years, SD = 1.26 years) and Canadian (n = 995, 30.8% male, M = 19.62 years, SD = 1.25 years) young adult samples to ensure any comparisons would be valid and meaningful. Results from a multigroup confirmatory factor analysis (exact invariance) showed that there was measurement non-invariance at the scalar level in the sociability construct across country and country by sex, and the newer alignment method (approximate invariance) confirmed these results, suggesting that mean level comparisons of sociability were biased and noninformative. Our findings indicated that although a few of the higher-level personality dimensions such as extraversion are considered universal, the facets underlying their meaning, like sociability, are not as clearly delineated between cultures. Alongside the present-day pursuit of understanding personality across cultures through an indigenous measurement lens in tandem with the notion of universality, researchers should also consider narrowing their focus onto lower-level facets, each of which is likely to be uniquely embedded into a cultural context.

Intermittent Fasting Improves Social Interaction and Decreases Inflammatory Markers in Cortex and Hippocampus.

Autism spectrum disorder (ASD) is a psychiatric condition characterized by reduced social interaction, anxiety, and stereotypic behaviors related to neuroinflammation and microglia activation. We demonstrated that maternal exposure to Western diet (cafeteria diet or CAF) induced microglia activation, systemic proinflammatory profile, and ASD-like behavior in the offspring. Here, we aimed to identify the effect of alternate day fasting (ADF) as a non-pharmacologic strategy to modulate neuroinflammation and ASD-like behavior in the offspring prenatally exposed to CAF diet. We found that ADF increased plasma beta-hydroxybutyrate (BHB) levels in the offspring exposed to control and CAF diets but not in the cortex (Cx) and hippocampus (Hpp). We observed that ADF increased the CD45 + cells in Cx of both groups; In control individuals, ADF promoted accumulation of CD206 + microglia cells in choroid plexus (CP) and increased in CD45 + macrophages cells and lymphocytes in the Cx. Gestational exposure to CAF diet promoted defective sociability in the offspring; ADF improved social interaction and increased microglia CD206 + in the Hpp and microglia complexity in the dentate gyrus. Additionally, ADF led to attenuation of the ER stress markers (Bip/ATF6/p-JNK) in the Cx and Hpp. Finally, biological modeling showed that fasting promotes higher microglia complexity in Cx, which is related to improvement in social interaction, whereas in dentate gyrus sociability is correlated with less microglia complexity. These data suggest a contribution of intermittent fasting as a physiological stimulus capable of modulating microglia phenotype and complexity in the brain, and social interaction in male mice.

miRNA-mediated inhibition of an actomyosin network in hippocampal pyramidal neurons restricts sociability in adult male mice.

Social deficits are frequently observed in patients suffering from neurodevelopmental disorders, but the molecular mechanisms regulating sociability are still poorly understood. We recently reported that the loss of the microRNA (miRNA) cluster miR-379-410 leads to hypersocial behavior and anxiety in mice. Here, we show that ablating miR-379-410 in excitatory neurons of the postnatal mouse hippocampus recapitulates hypersociability, but not anxiety. At the cellular level, miR-379-410 loss in excitatory neurons leads to larger dendritic spines, increased excitatory synaptic transmission, and upregulation of an actomyosin gene network. Re-expression of three cluster miRNAs, as well as pharmacological inhibition of the actomyosin activator ROCK, is sufficient to reinstate normal sociability in miR-379-410 knockout mice. Several actomyosin genes and miR-379-410 family members are reciprocally dysregulated in isogenic human induced pluripotent stem cell (iPSC)-derived neurons harboring a deletion present in patients with Williams-Beuren syndrome, characterized by hypersocial behavior. Together, our results show an miRNA-actomyosin pathway involved in social behavior regulation.

Glyphosate-based herbicide exposure affects cognitive flexibility and social cognition in adult mice.

Glyphosate (Gly) is the active ingredient of several widely used herbicide formulations. Studies on Gly and glyphosate-based herbicide (GBH) exposure in different experimental models have suggested that the nervous system represented a key target for its toxicity, especially the prefrontal cortex (PFC). However, it is still unknown whether exposure to GBH affects higher brain functions dependent on PFC circuitry. The present work aimed to examine the effects of subtoxic doses of GBH on social cognition and cognitive flexibility as two functions belonging to higher brain function in mice. To do so, adult male mice were exposed daily to GBH by gavage at doses of 250 or 500 mg/kg for a sub-chronic period lasting 6 weeks. Then, mice were subjected to behavioral testing using the three-chamber and the Barnes maze paradigms. Our results indicate that GBH did not affect sociability. However, we found that GBH affects social cognition expressed by a lower discrimination index in the three-chamber test. Moreover, spatial memories evaluated during the probe trial, and cognitive flexibility evaluated during the reversal probe, were affected in mice exposed to GBH. Based on these results, exposure to subtoxic doses of GBH led to neurobehavioral alterations affecting the integrity of social cognition and cognitive flexibility functions. Finally, these data urge a thorough investigation of the cellular and molecular mechanisms underlying these alterations.