Social Phenotypes Research Articles

A comprehensive assay of social motivation reveals sex-specific roles of autism-associated genes and oxytocin

Social motivation is critical to the development of typical social functioning. Social motivation, specifically one or more of its components (e.g., social reward seeking or social orienting), could be relevant for understanding phenotypes related to autism. We developed a social operant conditioning task to quantify effort to access a social partner and concurrent social orienting in mice. We established that mice will work for access to a social partner, identified sex differences, and observed high test-retest reliability. We then benchmarked the method with two test-case manipulations. Shank3B mutants exhibited reduced social orienting and failed to show social reward seeking. Oxytocin receptor antagonism decreased social motivation, consistent with its role in social reward circuitry. Overall, we believe that this method provides a valuable addition to the assessment of social phenotypes in rodent models of autism and the mapping of potentially sex-specific social motivation neural circuits.

Variation in Group Composition Alters an Early-Stage Social Phenotype in hAPP-Transgenic J20 Mice.

Altered social behavior is one of the symptoms of Alzheimer's disease (AD) that results in social withdrawal and loneliness and provides a major burden on patients and their relatives. Furthermore, loneliness is associated with an increased risk to develop AD and related dementias. We aimed to investigate if altered social behavior is an early indicator of amyloid-β (Aβ) pathology in J20 mice, and if co-housing with wild type (WT) mice can positively influence this social phenotype. The social phenotype of group-housed mice was assessed using an automated behavioral scoring system for longitudinal recordings. Female mice were housed in a same-genotype (4 J20 or WT mice per colony) or mixed-genotype (2 J20 mice + 2 WT mice) colony. At 10 weeks of age, their behavior was assessed for five consecutive days. J20 mice showed increased locomotor activity and social sniffing, and reduced social contact compared to WT mice housed in same-genotype colonies. Mixed-genotype housing reduced the social sniffing duration of J20 mice, increased social contact frequency of J20 mice, and increased nest hide by WT mice. Thus, altered social behavior can be used as an early indicator of Aβ-pathology in female J20 mice. Additionally, when co-housed with WT mice, their social sniffing phenotype is not expressed and their social contact phenotype is reduced. Our findings highlight the presence of a social phenotype in the early stages of AD and indicate a role for social environment variation in the expression of social behavior of WT and J20 mice.

Behavioral profile of adult zebrafish acutely exposed to a selective dopamine uptake inhibitor, GBR 12909.

The dopamine transporter (DAT) is the main regulator of dopamine concentration in the extrasynaptic space. The pharmacological inhibition of the DAT results in a wide spectrum of behavioral manifestations, which have been identified so far in a limited number of species, mostly in rodents. Here, we used another well-recognized model organism, the zebrafish (Danio rerio), to explore the behavioral effects of GBR 12909, a highly-affine selective DAT blocker. We evaluated zebrafish locomotion, novelty-related exploration, spatial cognition, and social phenotypes in the novel tank, habituation and shoaling tests, following acute 20-min water immersion in GBR 12909. Our findings show hypolocomotion, anxiety-like state, and impaired spatial cognition in fish acutely treated with GBR 12909. This behavioral profile generally parallels that of the DAT knockout rodents and zebrafish, and it overlaps with behavioral effects of other DAT-inhibiting drugs of abuse, such as cocaine and D-amphetamine. Collectively, our data support the utility of zebrafish in translational studies on DAT targeting neuropharmacology and strongly implicate DAT aberration as an important mechanisms involved in neurological and psychiatric diseases.

AI-based analysis of social media language predicts addiction treatment dropout at 90 days.

The reoccurrence of use (relapse) and treatment dropout is frequently observed in substance use disorder (SUD) treatment. In the current paper, we evaluated the predictive capability of an AI-based digital phenotype using the social media language of patients receiving treatment for substance use disorders (N = 269). We found that language phenotypes outperformed a standard intake psychometric assessment scale when predicting patients' 90-day treatment outcomes. We also use a modern deep learning-based AI model, Bidirectional Encoder Representations from Transformers (BERT) to generate risk scores using pre-treatment digital phenotype and intake clinic data to predict dropout probabilities. Nearly all individuals labeled as low-risk remained in treatment while those identified as high-risk dropped out (risk score for dropout AUC = 0.81; p < 0.001). The current study suggests the possibility of utilizing social media digital phenotypes as a new tool for intake risk assessment to identify individuals most at risk of treatment dropout and relapse.

Axin2 coupled excessive Wnt‐glycolysis signaling mediates social defect in autism spectrum disorders

Social dysfunction is the core syndrome of autism spectrum disorder (ASD) and lacks effective medicine. Although numerous risk genes and relevant environmental factors have been identified, the convergent molecular mechanism underlying ASD‐associated social dysfunction remains largely elusive. Here, we report aberrant activation of canonical Wnt signaling and increased glycolysis in the anterior cingulate cortex (ACC, a key brain region of social function) of two ASD mouse models (Shank3−/− and valproic acid‐treated mice) and their corresponding human neurons. Overexpressing β‐catenin in the ACC of wild‐type mice induces both glycolysis and social deficits. Suppressing glycolysis in ASD mice partially rescued synaptic and social phenotype. Axin2, a key inhibitory molecule in Wnt signaling, interacts with the glycolytic enzyme enolase 1 (ENO1) in ASD neurons. Surprisingly, an Axin2 stabilizer, XAV939, effectively blocked Axin2/ENO1 interaction, switched glycolysis/oxidative phosphorylation balance, promoted synaptic maturation, and rescued social function. These data revealed excessive neuronal Wnt‐glycolysis signaling as an important underlying mechanism for ASD synaptic deficiency, indicating Axin2 as a potential therapeutic target for social dysfunction.

Behavioral Voluntary and Social Bioassays Enabling Identification of Complex and Sex-Dependent Pain-(-Related) Phenotypes in Rats with Bone Cancer.

Cancer-induced bone pain (CIBP) is a common and devastating symptom with limited treatment options in patients, significantly affecting their quality of life. The use of rodent models is the most common approach to uncovering the mechanisms underlying CIBP; however, the translation of results to the clinic may be hindered because the assessment of pain-related behavior is often based exclusively on reflexive-based methods, which are only partially indicative of relevant pain in patients. To improve the accuracy and strength of the preclinical, experimental model of CIBP in rodents, we used a battery of multimodal behavioral tests that were also aimed at identifying rodent-specific behavioral components by using a home-cage monitoring assay (HCM). Rats of all sexes received an injection with either heat-deactivated (sham-group) or potent mammary gland carcinoma Walker 256 cells into the tibia. By integrating multimodal datasets, we assessed pain-related behavioral trajectories of the CIBP-phenotype, including evoked and non-evoked based assays and HCM. Using principal component analysis (PCA), we discovered sex-specific differences in establishing the CIBP-phenotype, which occurred earlier (and differently) in males. Additionally, HCM phenotyping revealed the occurrence of sensory-affective states manifested by mechanical hypersensitivity in sham when housed with a tumor-bearing cagemate (CIBP) of the same sex. This multimodal battery allows for an in-depth characterization of the CIBP-phenotype under social aspects in rats. The detailed, sex-specific, and rat-specific social phenotyping of CIBP enabled by PCA provides the basis for mechanism-driven studies to ensure robustness and generalizability of results and provide information for targeted drug development in the future.

Emergent social structure is typically not associated with survival in a facultatively social mammal.

For social animals, group social structure has important consequences for disease and information spread. While prior studies showed individual connectedness within a group has fitness consequences, less is known about the fitness consequences of group social structure for the individuals who comprise the group. Using a long-term dataset on a wild population of facultatively social yellow-bellied marmots (Marmota flaviventer), we showed social structure had largely no relationship with survival, suggesting consequences of individual social phenotypes may not scale to the group social phenotype. An observed relationship for winter survival suggests a potentially contrasting direction of selection between the group and previous research on the individual level; less social individuals, but individuals in more social groups experience greater winter survival. This work provides valuable insights into evolutionary implications across social phenotypic scales.

Human MECP2 transgenic rats show increased anxiety, severe social deficits, and abnormal prefrontal neural oscillation stability.

Methylated CpG binding protein 2 (MeCP2) plays an important role in the development and normal function of the neural system. Abnormally high expression of MECP2 leads to a subtype of autism called MECP2 duplication syndrome and MECP2 is considered one of the key pathogenic genes for autism spectrum disorders. However, the effect of MECP2 overexpression on neural activity is still not fully understood. Thus, transgenic (TG) animals that abnormally overexpress MeCP2 are important disease models in research on neurological function and autism. To create an animal model with a stronger and more stable autism phenotype, this study established a human MECP2 TG rat model and evaluated its movement ability, anxiety, and social behavior through behavioral tests. The results showed that MECP2 TG rats had an abnormally increased anxiety phenotype and social deficits in terms of abnormal social approach and social novelty preference, but no movement disorder. These autism-like behavioral phenotypes suggest that human MECP2 TG rats are suitable models for studying autism as they show more severe social deficit phenotypes and without interference from movement disorders affecting other phenotypes, which is an issue for mouse models with MECP2 duplication. In addition, this study performed preliminary exploration of the influence of the human MECP2 transgene on neural oscillation stability of the medial prefrontal cortex (mPFC), which is an important brain region for social interactions. Oscillation stability in MECP2 TG rats showed abnormal responses to social conditions. Overall, the results of this study provide a new research tool for understanding the mechanism of social impairment and treatment of autism. The results also provide evidence for the influence of MECP2 duplication on mPFC neural activity.

Social attention and social-emotional modulation of attention in Angelman syndrome: an eye-tracking study

Individuals with Angelman syndrome (AS) present with severe intellectual disability alongside a social phenotype characterised by social communication difficulties and an increased drive for social engagement. As the social phenotype in this condition is poorly understood, we examined patterns of social attention and social modulation of attention in AS. Twenty-four individuals with AS and twenty-one young children with similar mental age were shown videos featuring unfamiliar actors who performed simple actions across two conditions: a playful condition, in which the actor showed positive facial emotions, and a neutral condition, in which the actor showed a neutral facial expression. During the passive observation of the videos, participants’ proportion of time spent watching the two areas of interest (faces and actions) was examined using eye-tracking technology. We found that the playful condition elicited increased proportion of fixations duration to the actor’s face compared to the neutral condition similarly across groups. Additionally, the proportion of fixations duration to the action area was similar across groups in the two conditions. However, children with AS looked towards the actor’s face for a shorter duration compared to the comparison group across conditions. This pattern of similarities and differences provides novel insight on the complex social phenotype of children with AS.

NRXN1 depletion in the medial prefrontal cortex induces anxiety-like behaviors and abnormal social phenotypes along with impaired neurite outgrowth in rat

BackgroundNeurodevelopmental disorders (NDDs) are a group of disorders induced by abnormal brain developmental processes. The prefrontal cortex (PFC) plays an essential role in executive function, and its role in NDDs has been reported. NDDs are associated with high-risk gene mutations and share partially overlapping genetic abnormalities.MethodsNeurexins (NRXNs) are related to autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). NRXN1, an essential susceptibility gene for NDDs, has been reported to be associated with NDDs. However, little is known about its key role in NDDs.ResultsNRXN1 downregulation in the medial PFC induced anxiety-like behaviors and abnormal social phenotypes with impaired neurite outgrowth in Sh-NRXN1 in prefrontal neurons. Moreover, tandem mass tag (TMT)-based proteomic analysis of rat brain samples showed that NRXN1 downregulation led to significant proteome alterations, including pathways related to the extracellular matrix, cell membrane, and morphologic change. Furthermore, full-automatic immunoblotting analysis verified the differently expressed proteins related to cell morphology and membrane structure.ConclusionsOur results confirmed the association of NRXN1 with abnormal behaviors in NDDs and provided richer insights into specific prefrontal knockdown in adolescence, potentially expanding the NRXN1 interactome and contributing to human health.Graphical abstract

Cholinergic neurons in the basal forebrain are involved in behavioral abnormalities associated with Cul3 deficiency: Role of prefrontal cortex projections in cognitive deficits

Loss-of-function mutations of the gene Cul3 have been identified as a risk factor for autism-spectrum disorder (ASD), but the pathogenic mechanisms are not well understood. Conditional Cul3 ablation in cholinergic neurons of mice (ChatCRECul3F/+) recapitulated ASD-like social and sensory gating phenotypes and caused significant cognitive impairments, with diminished activity of cholinergic neurons in the basal forebrain (BF). Chemogenetic inhibition of BF cholinergic neurons in healthy mice induced similar social and cognitive deficits. Conversely, chemogenetic stimulation of BF cholinergic neurons in ChatCRECul3F/+ mice reversed abnormalities in sensory gating and cognition. Cortical hypofunction was also found after ChAT-specific Cul3 ablation and stimulation of cholinergic projections from the BF to the prefrontal cortex (PFC) mitigated cognitive deficits. Overall, we demonstrate that cholinergic dysfunction due to Cul3 deficiency is involved in ASD-like behavioral abnormalities, and that BF cholinergic neurons are particularly critical for cognitive component through their projections to the PFC.

Standardization and normative data of the 48-item Yoni short version for the assessment of theory of mind in typical and atypical conditions.

The Yoni task is a computerized tool assessing first-and second-order affective and cognitive Theory of Mind (ToM), accounting for the multidimensional and multi-level mentalizing features. The Italian Yoni task has been validated and standardized in its 98-item version, and a 48-item short version has been proposed for a quick digital evaluation of ToM in clinical contexts. The present study aimed to test the Yoni-48's convergent validity, correlating the tool score with the Reading the Mind in the Eyes test (ET) and Gender Test (GT), its items discrimination ability through the Classical Test Theory, and Rash model, its reliability by evaluating the internal consistency (McDonald's ω, Cronbach's α, Guttman's λ 2, and Guttman's λ 6) and Spearman-Brown ϱSP split-half analysis, and to provide standardization and normative data in the Italian population. Results suggested a good convergent validity with a statistically significant association with ET (p < 0.001), while a null correlation was observed with GT (p = 0.947). The Classical Test Theory and Rash model confirmed a good discrimination ability of the Yoni-48's second-order affective and cognitive ToM items, while weaker discrimination capacity was registered for the first-order ToM items. The inter-item reliability was optimal for clinical purposes (ω, α, λ 2, λ 6 ≥ 0.90). Also, the split-half reliability was high (Spearman-Brown ϱSP = 0.90). For standardization, age and education were revealed as significant predictors of Yoni accuracy scores, except for the first-order ToM score. Instead, age was the only predictor of Yoni's response speed score. The Italian normative data showed a high Yoni accuracy in healthy adults (mean accuracy = 0.85) and speed (mean response time = 0.92). Finally, both accuracy and response time level was balanced between the affective and cognitive components of ToM. This study supports the psychometric properties of the Yoni-48 and provides normative data for the Italian population. Further studies are needed to test the suitability of this short version for profiling the social cognition neurocognitive phenotype.

The BDNF Val68Met polymorphism causes a sex specific alcohol preference over social interaction and also acute tolerance to the anxiolytic effects of alcohol, a phenotype driven by malfunction of BDNF in the ventral hippocampus of male mice

BackgroundThe brain-derived neurotrophic factor (BDNF) Valine 66 to Methionine human polymorphism results in impaired activity-dependent BDNF release and has been linked to psychiatric disorders including depression and anxiety. We previously showed that male knock-in mice carrying the mouse Methionine homolog (Met68BDNF) exhibit excessive and compulsive alcohol drinking behaviors as compared to the wild-type Val68BDNF mice.ObjectiveHere, we set out to determine the potential mechanism for the heightened and compulsive alcohol drinking phenotypes detected in Met68BDNF mice.ResultsWe found that male, but not female Met68BDNF mice exhibit social anxiety-like behaviors. We further show that male Met68BDNF mice exhibit a preference for alcohol over social interaction. In contrast, alcohol place preference without an alternative social reward, is similar in male Met68BDNF and Val68BDNF mice. Since the Met68BDNF mice show social anxiety phenotypes, we tested whether alcohol reliefs anxiety similarly in Met68BDNF and Val68BDNF mice and found that male, but not female Met68BDNF mice are insensitive to the acute anxiolytic action of alcohol. Finally, we show that this acute tolerance to alcohol-dependent anxiolysis can be restored by overexpressing wild-type Val68BDNF in the ventral hippocampus (vHC) of Met68BDNF mice.ConclusionsTogether, our results suggest that excessive alcohol drinking in the Met68BDNF may be attributed, in part, to heighted social anxiety and a lack of alcohol-dependent anxiolysis, a phenotype that is associated with malfunction of BDNF signaling in the vHC of male Met68BDNF mice.

Social behavioral profiling by unsupervised deep learning reveals a stimulative effect of dopamine D3 agonists on zebrafish sociality

It has been a major challenge to systematically evaluate and compare how pharmacological perturbations influence social behavioral outcomes. Although some pharmacological agents are known to alter social behavior, precise description and quantification of such effects have proven difficult. We developed a scalable social behavioral assay for zebrafish named ZeChat based on unsupervised deep learning to characterize sociality at high resolution. High-dimensional and dynamic social behavioral phenotypes are automatically classified using this method. By screening a neuroactive compound library, we found that different classes of chemicals evoke distinct patterns of social behavioral fingerprints. By examining these patterns, we discovered that dopamine D3 agonists possess a social stimulative effect on zebrafish. The D3 agonists pramipexole, piribedil, and 7-hydroxy-DPAT-HBr rescued social deficits in a valproic-acid-induced zebrafish autism model. The ZeChat platform provides a promising approach for dissecting the pharmacology of social behavior and discovering novel social-modulatory compounds.

Co-expression Gene Networks and Machine-learning Algorithms Unveil a Core Genetic Toolkit for Reproductive Division of Labour in Rudimentary Insect Societies.

The evolution of eusociality requires that individuals forgo some or all their own reproduction to assist the reproduction of others in their group, such as a primary egg-laying queen. A major open question is how genes and genetic pathways sculpt the evolution of eusociality, especially in rudimentary forms of sociality-those with smaller cooperative nests when compared with species such as honeybees that possess large societies. We lack comprehensive comparative studies examining shared patterns and processes across multiple social lineages. Here we examine the mechanisms of molecular convergence across two lineages of bees and wasps exhibiting such rudimentary societies. These societies consist of few individuals and their life histories range from facultative to obligately social. Using six species across four independent origins of sociality, we conduct a comparative meta-analysis of publicly available transcriptomes. Standard methods detected little similarity in patterns of differential gene expression in brain transcriptomes among reproductive and non-reproductive individuals across species. By contrast, both supervised machine learning and consensus co-expression network approaches uncovered sets of genes with conserved expression patterns among reproductive and non-reproductive phenotypes across species. These sets overlap substantially, and may comprise a shared genetic "toolkit" for sociality across the distantly related taxa of bees and wasps and independently evolved lineages of sociality. We also found many lineage-specific genes and co-expression modules associated with social phenotypes and possible signatures of shared life-history traits. These results reveal how taxon-specific molecular mechanisms complement a core toolkit of molecular processes in sculpting traits related to the evolution of eusociality.

Social attention during object engagement: toward a cross-species measure of preferential social orienting

BackgroundA central challenge in preclinical research investigating the biology of autism spectrum disorder (ASD) is the translation of ASD-related social phenotypes across humans and animal models. Social orienting, an observable, evolutionarily conserved behavior, represents a promising cross-species ASD phenotype given that disrupted social orienting is an early-emerging ASD feature with evidence for predicting familial recurrence. Here, we adapt a competing-stimulus social orienting task from domesticated dogs to naturalistic play behavior in human toddlers and test whether this approach indexes decreased social orienting in ASD.MethodsPlay behavior was coded from the Autism Diagnostic Observation Schedule (ADOS) in two samples of toddlers, each with and without ASD. Sample 1 (n = 16) consisted of community-ascertained research participants, while Sample 2 involved a prospective study of infants at a high or low familial liability for ASD (n = 67). Coding quantified the child’s looks towards the experimenter and caregiver, a social stimulus, while playing with high-interest toys, a non-social stimulus. A competing-stimulus measure of “Social Attention During Object Engagement” (SADOE) was calculated by dividing the number of social looks by total time spent playing with toys. SADOE was compared based on ASD diagnosis and differing familial liability for ASD.ResultsIn both samples, toddlers with ASD exhibited significantly lower SADOE compared to toddlers without ASD, with large effect sizes (Hedges’ g ≥ 0.92) driven by a lower frequency of child-initiated spontaneous looks. Among toddlers at high familial likelihood of ASD, toddlers with ASD showed lower SADOE than toddlers without ASD, while SADOE did not differ based on presence or absence of familial ASD risk alone. SADOE correlated negatively with ADOS social affect calibrated severity scores and positively with the Communication and Symbolic Behavior Scales social subscale. In a binary logistic regression model, SADOE alone correctly classified 74.1% of cases, which rose to 85.2% when combined with cognitive development.ConclusionsThis work suggests that a brief behavioral measure pitting a high-interest nonsocial stimulus against the innate draw of social partners can serve as a feasible cross-species measure of social orienting, with implications for genetically informative behavioral phenotyping of social deficits in ASD and other neurodevelopmental disorders.

Behavioral trajectories of aging prairie voles (Microtus ochrogaster): Adapting behavior to social context wanes with advanced age

Several studies using mice have examined the effects of aging on cognitive tasks, as well as sensory and motor functions. However, few studies have examined the influence of aging on social behavior. Prairie voles (Microtus ochrogaster) are a socially monogamous and biparental rodent that live in small family groups and are now among the most popular rodent models for studies examining social behavior. Although the social behavioral trajectories of early-life development in prairie voles have been well-studied, how social behavior may change throughout adulthood remains unknown. Here we examined behavior in virgin male and female prairie voles in four different age groups: postnatal day (PND) 60-80, 140-160, 220-240, and 300-320. All animals underwent testing in a novel object task, a dominance test, a resident-intruder test, and several iterations of social approach and social interaction tests with varying types of social stimuli (i.e., novel same-sex conspecific, novel opposite-sex conspecific, familiar same-sex sibling/cagemate, small group of novel same-sex conspecifics). We found that age influenced neophobia and dominance, but not social approach behavior. Further, we found that young adult, but not older adult, prairie voles adapt prosocial and aggressive behavior relative to social context, and that selective aggression occurs in relation to age even in the absence of a pair bond. Our results suggest that prairie voles calibrate social phenotype in a context-dependent manner in young adulthood and stop adjusting behavior to social context in advanced age, demonstrating that social behavior is plastic not only throughout early development, but also well into adulthood. Together, this study provides insight into age-related changes in social behavior in prairie voles and shows that prairie voles may be a viable model for studying the cognitive and physiological benefits of social relationships and social engagement in advanced age.

Group social structure has limited impact on reproductive success in a wild mammal

Abstract The frequency and type of dyadic social interactions individuals partake in has important fitness consequences. Social network analysis is an effective tool to quantify the complexity and consequences of these behaviors on the individual level. Less work has used social networks to quantify the social structure—specific attributes of the pattern of all social interactions in a network—of animal social groups, and its fitness consequences for those individuals who comprise the group. We studied the association between social structure, quantified via five network measures, and annual reproductive success in wild, free-living female yellow-bellied marmots (Marmota flaviventer). We quantified reproductive success in two ways: (1) if an individual successfully weaned a litter and (2) how many pups were weaned. Networks were constructed from 38 968 interactions between 726 unique individuals in 137 social groups across 19 years. Using generalized linear mixed models, we found largely no relationship between either measure of reproductive success and social structure. We found a modest relationship that females residing in more fragmentable social groups (i.e., groups breakable into two or more separate groups of two or more individuals) weaned larger litters. Prior work showed that yellow-bellied marmots residing in more fragmentable groups gained body mass faster—another important fitness correlate. Interestingly, we found no strong relationships between other attributes of social group structure, suggesting that in this facultatively social mammal, the position of individuals within their group, the individual social phenotype, may be more important for fitness than the emergent group social phenotype.

Social phenotype-dependent selection of social environment in wild great and blue tits: an experimental study.

There is growing evidence that individuals actively assess the match between their phenotype and their environment when making habitat choice decisions (so-called matching habitat choice). However, to our knowledge, no studies have considered how the social environment may interact with social phenotype in determining habitat choice, despite habitat choice being an inherently social process and growing evidence for individual variation in sociability. We conducted an experiment using wild great and blue tits to understand how birds integrate their social phenotype and social environment when choosing where and how to feed. We used programmable feeders to (i) record social interactions and estimate social phenotype, and (ii) experimentally manipulate the local density experienced by birds of differing social phenotype. By tracking feeder usage, we estimated how social environment and social phenotype predicted feeder choice and feeding behaviour. Both social environment and social phenotype predicted feeder usage, but a bird's decision to remain in a particular social environment did not depend on their social phenotype. By contrast, for feeding behaviour, responses to the social environment depended on social phenotype. Our results provide rare evidence of matching habitat choice and shed light on the dependence of habitat choice on between-individual differences in social phenotype.

Prebiotic supplementation modulates selective effects of stress on behavior and brain metabolome in aged mice

Aging has a significant impact on physiology with implications for central nervous system function coincident with increased vulnerability to stress exposures. A number of stress-sensitive molecular mechanisms are hypothesized to underpin age-related changes in brain function. Recent cumulative evidence also suggests that aging impacts gut microbiota composition. However, the impact of such effects on the ability of mammals to respond to stress in aging is still relatively unexplored. Therefore, in this study we assessed the ability of a microbiota-targeted intervention (the prebiotic FOS-Inulin) to alleviate age-related responses to stress. Exposure of aged C57BL/6 mice to social defeat led to an altered social interaction phenotype in the social interaction test, which was reversed by FOS-Inulin supplementation. Interestingly, this occured independent of affecting social defeat-induced elevations in the stress hormone corticosterone. Additionally, the behavioral modifications following FOS-Inulin supplementation were also not coincident with improvement of pro-inflammatory markers. Metabolomics analysis was performed and intriguingly, age associated metabolites were shown to be reduced in the prefrontal cortex of stressed aged mice and this deficit was recovered by FOS-Inulin supplementation. Taken together these results suggest that prebiotic dietary intervention rescued the behavioral response to stress in aged mice, not through amelioration of the inflammatory response, but by restoring the levels of key metabolites in the prefrontal cortex of aged animals. Therefore, dietary interventions could be a compelling avenue to improve the molecular and behavioral manifestations of chronic stress exposures in aging via targeting the microbiota-gut brain axis.