Social Behavior In Mice Research Articles

Microbial stimulation of oxytocin release from the intestinal epithelium via secretin signaling

ABSTRACT Intestinal microbes impact the health of the intestine and organs distal to the gut. Limosilactobacillus reuteri is a human intestinal microbe that promotes normal gut transit, the anti-inflammatory immune system, wound healing, normal social behavior in mice, and prevents bone reabsorption. Oxytocin impacts these functions and oxytocin signaling is required for L. reuteri-mediated wound healing and social behavior; however, the events in the gut leading to oxytocin stimulation and beneficial effects are unknown. Here we report evolutionarily conserved oxytocin production in the intestinal epithelium through analysis of single-cell RNA-Seq datasets and imaging of human and mouse intestinal tissues. Moreover, human intestinal organoids produce oxytocin, demonstrating that the intestinal epithelium is sufficient to produce oxytocin. We find that L. reuteri facilitates oxytocin secretion from human intestinal tissue and human intestinal organoids. Finally, we demonstrate that stimulation of oxytocin secretion by L. reuteri is dependent on the gut hormone secretin, which is produced in enteroendocrine cells, while oxytocin itself is produced in enterocytes. Altogether, this work demonstrates that oxytocin is produced and secreted from enterocytes in the intestinal epithelium in response to secretin stimulated by L. reuteri. This work thereby identifies oxytocin as an intestinal hormone and provides mechanistic insight into avenues by which gut microbes promote host health.

Knockout of Tmlhe in mice is not associated with autism spectrum disorder phenotypes or motor dysfunction despite low carnitine levels

Deletion of exon 2 of the trimethyllysine hydroxylase epsilon (TMLHE) gene was identified in probands with autism spectrum disorder (ASD). TMLHE encodes the first enzyme in carnitine biosynthesis, N6-trimethyllysine dioxygenase (TMLD). Researchers have suggested that carnitine depletion could be important for the development of ASD and cognitive, locomotor and social dysfunctions, but previous findings have been inconclusive regarding the specific role of endogenous carnitine. We developed a mouse knockout model with constitutive TMLD enzyme inactivation that exhibited a significant decrease in the carnitine by more than 90% compared to wild-type (WT) mice. However, we did not observe any significant social, cognitive, or repetitive-behavior changes associated with ASD in the knockout mice; muscle strength and coordination were also not affected. In addition, the life expectancy of knockout mice was similar to that of WT mice. In conclusion, knockout of Tmlh in mice does not induce an ASD phenotype or motor dysfunction despite extremely low carnitine and gamma-butyrobetaine concentrations. Moreover, inactivation of TMLD does not induce a phenotype similar to previously described primary carnitine deficiency; indeed, our results showed that low levels of carnitine sustained adequate energy production, muscle function and social behavior in mice.

Elevated levels of FMRP-target MAP1B impair human and mouse neuronal development and mouse social behaviors via autophagy pathway

Fragile X messenger ribonucleoprotein 1 protein (FMRP) binds many mRNA targets in the brain. The contribution of these targets to fragile X syndrome (FXS) and related autism spectrum disorder (ASD) remains unclear. Here, we show that FMRP deficiency leads to elevated microtubule-associated protein 1B (MAP1B) in developing human and non-human primate cortical neurons. Targeted MAP1B gene activation in healthy human neurons or MAP1B gene triplication in ASD patient-derived neurons inhibit morphological and physiological maturation. Activation of Map1b in adult male mouse prefrontal cortex excitatory neurons impairs social behaviors. We show that elevated MAP1B sequesters components of autophagy and reduces autophagosome formation. Both MAP1B knockdown and autophagy activation rescue deficits of both ASD and FXS patients’ neurons and FMRP-deficient neurons in ex vivo human brain tissue. Our study demonstrates conserved FMRP regulation of MAP1B in primate neurons and establishes a causal link between MAP1B elevation and deficits of FXS and ASD.

FRI-352 - Cholestatic liver disease enhances sociability and leads to significant adaptative changes in amygdala neural circuits regulating social behavior in mice

FRI-352 - Cholestatic liver disease enhances sociability and leads to significant adaptative changes in amygdala neural circuits regulating social behavior in mice

Balance Between Projecting Neuronal Populations of the Nucleus Accumbens Controls Social Behavior in Mice

BackgroundDeficient social interactions are a hallmark of major neuropsychiatric disorders, and accumulating evidence points to altered social reward and motivation as key underlying mechanisms of these pathologies. In the present study, we further explored the role of the balance of activity between D1 and D2 receptor–expressing striatal projection neurons (D1R- and D2R-SPNs) in the control of social behavior, challenging the hypothesis that excessive D2R-SPN activity, rather than deficient D1R-SPN activity, compromises social behavior. MethodsWe selectively ablated D1R- and D2R-SPNs using an inducible diphtheria toxin receptor–mediated cell targeting strategy and assessed social behavior as well as repetitive/perseverative behavior, motor function, and anxiety levels. We tested the effects of optogenetic stimulation of D2R-SPNs in the nucleus accumbens (NAc) and pharmacological compounds repressing D2R-SPN. ResultsTargeted deletion of D1R-SPNs in the NAc blunted social behavior in mice, facilitated motor skill learning, and increased anxiety levels. These behaviors were normalized by pharmacological inhibition of D2R-SPN, which also repressed transcription in the efferent nucleus, the ventral pallidum. Ablation of D1R-SPNs in the dorsal striatum had no impact on social behavior but impaired motor skill learning and decreased anxiety levels. Deletion of D2R-SPNs in the NAc produced motor stereotypies but facilitated social behavior and impaired motor skill learning. We mimicked excessive D2R-SPN activity by optically stimulating D2R-SPNs in the NAc and observed a severe deficit in social interaction that was prevented by D2R-SPN pharmacological inhibition. ConclusionsRepressing D2R-SPN activity may represent a promising therapeutic strategy to relieve social deficits in neuropsychiatric disorders.

Exposure to polystyrene particles causes anxiety-, depression-like behavior and abnormal social behavior in mice

In the era of plastic use, organisms are constantly exposed to polystyrene particles (PS-Ps). PS-Ps accumulated in living organisms exert negative effects on the body, although studies evaluating their effects on brain development are scarce. In this study, the effects of PS-Ps on nervous system development were investigated using cultured primary cortical neurons and mice exposed to PS-Ps at different stages of brain development. The gene expression associated with brain development was downregulated in embryonic brains following PS-Ps exposure, and Gabra2 expression decreased in the embryonic and adult mice exposed to PS-Ps. Additionally, offspring of PS-Ps-treated dams exhibited signs of anxiety- and depression-like behavior, and abnormal social behavior. We propose that PS-Ps accumulation in the brain disrupts brain development and behavior in mice. This study provides novel information regarding PS-Ps toxicity and its harmful effects on neural development and behavior in mammals.

An Insula-Enriched Regulator of Retinoic Acid Marks a New Intersection in the Neural Circuitry of Mouse Social Behavior

An Insula-Enriched Regulator of Retinoic Acid Marks a New Intersection in the Neural Circuitry of Mouse Social Behavior

An operant social self-administration and choice model in mice.

Little is known about how social factors contribute to neurobiology or neuropsychiatric disorders. The use of mice allows one to probe the neurobiological bases of social interaction, offering the genetic diversity and versatility to identify cell types and neural circuits of social behavior. However, mice typically show lower social motivation compared with rats, leading to the question of whether mice should be used to model complex social behaviors displayed by humans. Studies on mouse social behavior often rely on measures such as time spent in contact with a social partner or preference for a social-paired context, but fail to assess volitional (subject-controlled) rewarding social interaction. Here, we describe a volitional social self-administration and choice model that is an extension of our previous work on rats. Using mice, we systematically compared female adolescent and adult C57BL/6 mice and outbred CD1 mice, showing that operant social self-administration, social seeking during periods of isolation and choice of social interaction over palatable food is significantly stronger in female CD1 mice than in female C57BL/6J mice, independently of age. We describe the requirements for building the social self-administration and choice apparatus and we provide guidance for studying the role of operant social reward in mice. We also discuss its use to study brain mechanisms of operant social reward, potentially extending its application to mouse models of neuropsychiatric disorders. The training commonly requires ~4 weeks for stable social self-administration and 3-4 additional weeks for tests, including social seeking and choice.

Dynamic changes to signal allocation rules in response to variable social environments in house mice

Urine marking is central to mouse social behavior. Males use depletable and costly urine marks in intrasexual competition and mate attraction. We investigate how males alter signaling decisions across variable social landscapes using thermal imaging to capture spatiotemporal marking data. Thermal recording reveals fine-scale adjustments in urinary motor patterns in response to competition and social odors. Males demonstrate striking winner-loser effects in scent mark allocation effort and timing. Competitive experience primes temporal features of marking and modulates responses to scent familiarity. Males adjust signaling effort, mark latency, and marking rhythm, depending on the scent identities in the environment. Notably, recent contest outcome affects how males respond to familiar and unfamiliar urine. Winners increase marking effort toward unfamiliar relative to familiar male scents, whereas losers reduce marking effort to unfamiliar but increase to familiar rival scents. All males adjust their scent mark timing after a contest regardless of fight outcome, and deposit marks in more rapid bursts during marking bouts. In contrast to this dynamism, initial signal investment predicts aspects of scent marking days later, revealing the possibility of alternative marking strategies among competitive males. These data show that mice flexibly update their signaling decisions in response to changing social landscapes.

Effects of Assisted Reproductive Technologies on Social Behavior of BTBR Mice – A Model of Autism Spectrum Disorder

The present work is the first attempt to study the effect of such assisted reproductive technologies (ARTs), as in vitro culture of preimplantation embryos on the social behavior of offspring, using BTBR mice (BTBR T+Itpr3tf/J) as an idiopathic model of a-utism. The C57BL/6J mice were used as controls. Social behavior was studied in adult offspring mice obtained after in vitro culture and embryo transfer (ET) (groups ET-C57BL/6J and ET-BTBR). The BTBR mice demonstrated the reduced levels of social recognition and affiliation compared to C57BL/6J mice. The social affiliation and recognition test revealed that ET-C57BL/6J males had a high level of social interaction, which was of similar magnitude as in naturally conceived C57BL/6J males. However, ET-C57BL/6J and ET-BTBR females demonstrated a decrease in interest to a new stranger compared to naturally conceived controls of the same sex, which was revealed in a social recognition session of this test. Thus, the in vitro culture affected the social recognition in the offspring of C57BL/6J and BTBR mice, but only in females.

Effects of Assisted Reproductive Technologies on Social Behavior of BTBR Mice, a Model of Autism Spectrum Disorders

Effects of Assisted Reproductive Technologies on Social Behavior of BTBR Mice, a Model of Autism Spectrum Disorders

Early growth response 2 in the mPFC regulates mouse social and cooperative behaviors.

Adolescent social neglect impairs social performance, but the underlying molecular mechanisms remain unclear. Here we report that isolation rearing of juvenile mice caused cooperation defects that were rescued by immediate social reintroduction. We also identified the transcription factor early growth response 2 (Egr2) in the medial prefrontal cortex (mPFC) as a major target of social isolation and resocialization. Isolation rearing increased corticosteroid production, which reduced the expression of Egr2 in the mPFC, including in oligodendrocytes. Overexpressing Egr2 ubiquitously in the mPFC, but not specifically in neurons nor in oligodendroglia, protected mice from the isolation rearing-induced cooperation defect. In addition to synapse integrity, Egr2 also regulated the development of oligodendroglia, specifically the transition from undifferentiated oligodendrocyte precursor cells to premyelinating oligodendrocytes. In conclusion, this study reveals the importance of mPFC Egr2 in the cooperative behavior that is modulated by social experience, and its unexpected role in oligodendrocyte development.

In the pursuit of new social neurons. Neurogenesis and social behavior in mice: A systematic review.

Social behaviors have become more relevant to our understanding of the human nervous system because relationships with our peers may require and modulate adult neurogenesis. Here, we review the pieces of evidence we have to date for the divergence of social behaviors in mice by modulation of adult neurogenesis or if social behaviors and the social environment can drive a change in neurogenic processes. Social recognition and memory are deeply affected by antimitotic drugs and irradiation, while NSC transgenic mice may run with lower levels of social discrimination. Interestingly, social living conditions can create a big impact on neurogenesis. Social isolation and social defeat reduce the number of new neurons, while social dominance and enrichment of the social environment increase their number. These new "social neurons" trigger functional modifications with amazing transgenerational effects. All of these suggest that we are facing two bidirectional intertwined variables, and the great challenge now is to understand the cellular and genetic mechanisms that allow this relationship to be used therapeutically.

Assessing the effect of compounds from plantar foot sweat, nesting material, and urine on social behavior in male mice, Mus musculus.

Home cage aggression causes poor welfare in male laboratory mice and reduces data quality. One of the few proven strategies to reduce aggression involves preserving used nesting material at cage change. Volatile organic compounds from the nesting material and several body fluids not only correlate with less home cage aggression, but with more affiliative allo-grooming behavior. To date, these compounds have not been tested for a direct influence on male mouse social behavior. This study aimed to determine if 4 previously identified volatile compounds impact home cage interactions. A factorial design was used with cages equally split between C57BL/6N and SJL male mice (N = 40). Treatments were randomly assigned across cages and administered by spraying one compound solution on each cage's nesting material. Treatments were refreshed after day 3 and during cage change on day 7. Home cage social behavior was observed throughout the study week and immediately after cage change. Several hours after cage change, feces were collected from individual mice to measure corticosterone metabolites as an index of social stress. Wound severity was also assessed after euthanasia. Measures were analyzed with mixed models. Compound treatments did not impact most study measures. For behavior, SJL mice performed more aggression and submission, and C57BL/6N mice performed more allo-grooming. Wound severity was highest in the posterior region of both strains, and the middle back region of C57BL/6N mice. Posterior wounding also increased with more observed aggression. Corticosterone metabolites were higher in C57BL/6N mice and in mice treated with 3,4-dimethyl-1,2-cyclopentanedione with more wounding. These data confirm previous strain patterns in social behavior and further validates wound assessment as a measure of escalated aggression. The lack of observed treatment effects could be due to limitations in the compound administration procedure and/or the previous correlation study, which is further discussed.

Amygdala neural ensemble mediates mouse social investigation behaviors.

Innate social investigation behaviors are critical for animal survival and are regulated by both neural circuits and neuroendocrine factors. Our understanding of how neuropeptides regulate social interest, however, is incomplete at the current stage. In this study, we identified the expression of secretin (SCT) in a subpopulation of excitatory neurons in the basolateral amygdala. With distinct molecular and physiological features, BLASCT+ cells projected to the medial prefrontal cortex and were necessary and sufficient for promoting social investigation behaviors, whilst other basolateral amygdala neurons were anxiogenic and antagonized social behaviors. Moreover, the exogenous application of secretin effectively promoted social interest in both healthy and autism spectrum disorder model mice. These results collectively demonstrate a previously unrecognized group of amygdala neurons for mediating social behaviors and suggest promising strategies for social deficits.

Bio-inspired navigation and exploration system for a hexapod robotic platform

This paper presents a biologically inspired system for guiding and controlling a virtual hexapod robot. Our navigation and exploration system is composed of subsystems that execute processes of path integration, action selection, actuator control and correction of the robot’s orientation. For the subsystem that serves the path integration function we modified an existing model of bio-inspired vector summation by adding the capability of performing online calculation. For the action selection subsystem that allows to switch between the behaviors of exploration, approaching a target and homing we modified an existing model of decision making for mediating social behaviors in mice. We added an additional circuit that projects a signal to the units representing each of the behaviors. In the case of the actuator control subsystem, the structure of a central pattern generator model that incorporates feedback and adaptation was used as the base for generating and transforming signals for the actuators. Finally, the orientation correction subsystem is a novel model that determines an error value from a desired and the current orientations. The proposed models were simulated as independent scripts and then implemented as ROS (Robot Operating System) nodes for controlling a robot simulation in Gazebo.

Phase separation and zinc-induced transition modulate synaptic distribution and association of autism-linked CTTNBP2 and SHANK3

Many synaptic proteins form biological condensates via liquid-liquid phase separation (LLPS). Synaptopathy, a key feature of autism spectrum disorders (ASD), is likely relevant to the impaired phase separation and/or transition of ASD-linked synaptic proteins. Here, we report that LLPS and zinc-induced liquid-to-gel phase transition regulate the synaptic distribution and protein-protein interaction of cortactin-binding protein 2 (CTTNBP2), an ASD-linked protein. CTTNBP2 forms self-assembled condensates through its C-terminal intrinsically disordered region and facilitates SHANK3 co-condensation at dendritic spines. Zinc binds the N-terminal coiled-coil region of CTTNBP2, promoting higher-order assemblies. Consequently, it leads to reduce CTTNBP2 mobility and enhance the stability and synaptic retention of CTTNBP2 condensates. Moreover, ASD-linked mutations alter condensate formation and synaptic retention of CTTNBP2 and impair mouse social behaviors, which are all ameliorated by zinc supplementation. Our study suggests the relevance of condensate formation and zinc-induced phase transition to the synaptic distribution and function of ASD-linked proteins.

Gastrointestinal mechanosensation affects the activity of prefrontal cortical neurons mediating social behavior in mice

Social cognition requires integration of sensory modalities with emotion and experience to plan and engage in appropriate social behavior. Oxytocin is a neuropeptide that shapes the perception of social stimuli by activating the oxytocin receptor (Oxtr). Neurons within the medial prefrontal cortex (mPFC) that express Oxtr(s) (referred to as mPFCOxtr) integrate these complex systems. Oxytocin acts within the brain to influence the perception of the external environment; however, Oxtr(s) are also expressed on vagal sensory afferents, suggesting that oxytocin may also influence interoception or the ability to sense one’s internal state. To better understand the role of interoception in social cognition, we examined the structure and function of the neurons within the nodose ganglia that express the Oxtr (referred to as NDGOxtr). To visualize NDGOxtr, we bilaterally injected Cre‐inducible adeno‐associated virus (AAV) synthesizing mCherry or tdTomato into the nodose ganglia (NDG) of mice with Cre‐recombinase directed to the Oxtr gene (Oxtr‐Cre mice). We found that NDGOxtr expressed mRNAs for the mechanically gated ion channels, Piezo 1/2, and sent fibers to the stomach and duodenum that formed intramuscular arrays or intraganglionic laminar endings. These results suggest that NDGOxtr function as mechanoreceptors that detect distention of the gastrointestinal tract. Next, we used in vivo Ca2+ imaging to determine the effect that gastric distention has on mPFCOxtr that mediate social behavior. Oxtr‐Cre mice were delivered Cre‐inducible AAV expressing the fluorescent Ca2+ indicator, GCaMPf, into the mPFC, and subsequently, implanted with a GRIN lens. After habituation to the head mounted miniscope, mice were tested in the social interaction paradigm and Ca2+ events were recorded. Receiver operating characteristic analysis revealed that ≍30% of mPFCOxtr couple firing to social interaction. Next, we evaluated how gastric distention may influence the activity of mPFCOxtr. Mice were given a sham gavage or a gavage of methylcellulose and Ca2+ events from mPFCOxtr were recorded. Differences in Ca2+ events were calculated using a Wilcoxon rank sum test to the classify individual neurons as inhibited, excited, or unchanged by the stimulus. Intriguingly, gavage of methylcellulose robustly inhibited mPFCOxtr relative to the sham‐treated control. To determine whether NDGOxtrmediate this inhibition, Oxtr‐Cre mice outfitted for in vivo Ca2+ imaging were given Cre‐inducible AAV expressing channelrhodopsin2 into the NDG and a fiber optic was implanted into the nucleus of the solitary tract (NTS). This approach enables optogenetic excitation of axons in the NTS originating from NDGOxtr during simultaneous Ca2+ imaging of mPFCOxtr. Preliminary results indicate that optogenetic excitation of NDGOxtr also inhibit mPFCOxtr. Collectively, our results suggest that mechanosensation of the gastrointestinal tract may have a profound influence over the perception of social stimuli.

Mucosal fungi promote gut barrier function and social behavior via Type 17 immunity

Fungal communities (the mycobiota) are an integral part of the gut microbiota, and the disruption of their integrity contributes to local and gut-distal pathologies. Yet, the mechanisms by which intestinal fungi promote homeostasis remain unclear. We characterized the mycobiota biogeography along the gastrointestinal tract and identified a subset of fungi associated with the intestinal mucosa of mice and humans. Mucosa-associated fungi (MAF) reinforced intestinal epithelial function and protected mice against intestinal injury and bacterial infection. Notably, intestinal colonization with a defined consortium of MAF promoted social behavior in mice. The gut-local effects on barrier function were dependent on IL-22 production by CD4+ T helper cells, whereas the effects on social behavior were mediated through IL-17R-dependent signaling in neurons. Thus, the spatial organization of the gut mycobiota is associated with host-protective immunity and epithelial barrier function and might be a driver of the neuroimmune modulation of mouse behavior through complementary Type 17 immune mechanisms.

Immune gene tied to social behavior in autism mouse model

Activating the immune system blunts social behavior in mice missing a copy of the autism-linked gene SHANK3, according to a new study. Blocking TRPV4, which encodes an ion channel involved in inflammatory responses, can reverse this effect.