Social Novelty Preference Research Articles

Oxytocin neurons mediate the effect of social isolation via the VTA circuits.

Social interaction during adolescence strongly influences brain function and behavior, and the recent pandemic has emphasized the devastating effect of social distancing on mental health. While accumulating evidence has shown the importance of the reward system in encoding specific aspects of social interaction, the consequences of social isolation on the reward system and the development of social skills later in adulthood are still largely unknown. Here, we found that 1 week of social isolation during adolescence in male mice increased social interaction at the expense of social habituation and social novelty preference. Behavioral changes were accompanied by the acute hyperexcitability of putative dopamine (pDA) neurons in the ventral tegmental area and long-lasting expression of GluA2-lacking AMPARs at excitatory inputs onto pDA neurons that project to the prefrontal cortex. Social isolation-dependent behavioral deficits and changes in neural activity and synaptic plasticity were reversed by chemogenetic inhibition of oxytocin neurons in the paraventricular nucleus of the hypothalamus. These results demonstrate that social isolation in male mice has acute and long-lasting effects on social interaction and suggest that homeostatic adaptations mediate these effects within the reward circuit.

Interspecific differences in sociability, social novelty preference, anxiety- and depression-like behaviors between Brandt's voles and C57BL/6J mice

The three-chamber test has been widely used to investigate social approach/novelty preference in rodents. Most studies have used the briefly familiar and unfamiliar individuals as stimuli to examine social recognition; however, little is known about the effects of long-term familiar peers in this paradigm. In the present study, we made a slight modification to it: the first phase measured preference for a cage-mate (not a novel individual) over an identical wire cage without an individual stimulus; the later phase measured preference for a novel individual placed in the previous empty wire cage compared to the cage-mate (not the briefly familiar individual). The present study aimed to compare differences in sociability and social recognition between Brandt's voles (Lasiopodomys brandtii) and C57BL/6J mice using this modified three-chamber test. The levels of anxiety-, depression-, and anhedonia-like behaviors were also examined in both species. We found that Brandt’s voles preferred the cage-mate over the empty cage in phase 1 and showed a preference for the novel individual in phase 2. In C57BL/6J mice, males showed no preference for familiar peers in phase 1, whereas females failed to show a preference for the novel individual in phase 2, showing a sex-specific difference. Furthermore, Brandt’s voles displayed higher levels of locomotor activity and sociability as well as lower levels of anxiety-, depression-, and anhedonia-like behaviors than C57BL/6J mice. Interestingly, sociability and social approach correlated with depression-like behavior, whereas social novelty preference correlated with anhedonia-like behavior. Together, these data indicate that Brandt’s voles and C57BL/6J mice show significant differences in sociability, social recognition, and levels of anxiety- and depression-like behaviors. Furthermore, Brandt’s voles are more suitable for the study of selective social relationships.

Adult resocialization restores sociability, reduced by adolescent social isolation in rats

We aimed to assess the effect of 6-week adolescent social isolation on sociability and social novelty preference in male Wistar rats. In addition, we examined whether isolation effects would persist after adult resocialization. Our findings demonstrate that social isolation resulted in decreased social interest (the time spent interacting with an unfamiliar rat of the same sex and age decreased from 115.4 ± 13.3 s in group-housed animals to 82.3 ± 11.0 s in isolated, P < 0.05), while social novelty preference was not significantly different between isolated and group-housed rats. We also report that 6-week resocialization was sufficient to restore social interaction levels in isolated rats (time spent with an unfamiliar rat was 117.9 ± 12.6 s in isolated animals and 102.5 ± 10.9 s in group-housed). These findings may be useful for better understanding the impact of social deprivation on human subjects, which has recently become especially relevant due to the restrictions of the COVID-19 pandemic.

Integrin \u03b23 in forebrain Emx1-expressing cells regulates repetitive self-grooming and sociability in mice

BackgroundAutism spectrum disorder (ASD) is characterized by repetitive behaviors, deficits in communication, and overall impaired social interaction. Of all the integrin subunit mutations, mutations in integrin β3 (Itgb3) may be the most closely associated with ASD. Integrin β3 is required for normal structural plasticity of dendrites and synapses specifically in excitatory cortical and hippocampal circuitry. However, the behavioral consequences of Itgb3 function in the forebrain have not been assessed. We tested the hypothesis that behaviors that are typically abnormal in ASD—such as self-grooming and sociability behaviors—are disrupted with conditional Itgb3 loss of function in forebrain circuitry in male and female mice.MethodsWe generated male and female conditional knockouts (cKO) and conditional heterozygotes (cHET) of Itgb3 in excitatory neurons and glia that were derived from Emx1-expressing forebrain cells during development. We used several different assays to determine whether male and female cKO and cHET mice have repetitive self-grooming behaviors, anxiety-like behaviors, abnormal locomotion, compulsive-like behaviors, or abnormal social behaviors, when compared to male and female wildtype (WT) mice.ResultsOur findings indicate that only self-grooming and sociability are altered in cKO, but not cHET or WT mice, suggesting that Itgb3 is specifically required in forebrain Emx1-expressing cells for normal repetitive self-grooming and social behaviors. Furthermore, in cKO (but not cHET or WT), we observed an interaction effect for sex and self-grooming environment and an interaction effect for sex and sociability test chamber.LimitationsWhile this study demonstrated a role for forebrain Itgb3 in specific repetitive and social behaviors, it was unable to determine whether forebrain Itgb3 is required for a preference for social novelty, whether cHET are haploinsufficient with respect to repetitive self-grooming and social behaviors, or the nature of the interaction effect for sex and environment/chamber in affected behaviors of cKO.ConclusionsTogether, these findings strengthen the idea that Itgb3 has a specific role in shaping forebrain circuitry that is relevant to endophenotypes of autism spectrum disorder.

The GABAB receptor agonist STX209 reverses the autism‑like behaviour in an animal model of autism induced by prenatal exposure to valproic acid.

Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition characterized by impaired social interaction, compromised communication, and restrictive or stereotyped behaviours and interests. Due to the complex pathophysiology of ASD, there are currently no available medical therapies for improving the associated social deficits. Consequently, the present study investigated the effects of STX209, a selective γ-aminobutyric acid type B receptor (GABABR2) agonist, on an environmental rodent model of autism. The mouse model of autism induced by prenatal exposure to valproic acid (VPA) was used to assess the therapeutic potential of STX209 on autism-like behaviour in the present study. This study investigated the effects of STX209 on VPA model mice via behavioral testing and revealed a significant reversal of core/associated autism-like behavior, including sociability and preference for social novelty, novelty recognition, locomotion and exploration activity and marble-burying deficit. This may be associated with STX209 correcting dendritic arborization, spine density and GABABR2 expression in hippocampus of VPA model mice. However, expression of glutamic acid decarboxylase 65/67 in the hippocampus were not altered by STX209. The present results demonstrated that STX209 administration ameliorated autism-like symptoms in mice exposed to VPA prenatally, suggesting that autism-like symptoms in children with a history of prenatal VPA exposure may also benefit from treatment with the GABABR2 agonist STX209.

A circuit from dorsal hippocampal CA3 to parvafox nucleus mediates chronic social defeat stress-induced deficits in preference for social novelty.

The preference for social novelty is crucial to the social life of humans and rodents. However, the neural mechanisms underlying social novelty preference are poorly understood. Here, we found that chronic social defeat stress (CSDS) reduced the preference for social novelty in mice by impairing the response of CaMKIIα+ neurons in the CA3 region of dorsal hippocampus (dCA3) during approach to an unfamiliar mouse. The deficits of social novelty preference in CSDS-treated mice were reversed by activating the output from dCA3 to the GABAergic neurons in the lateral septum (LS). The activation of GABAergic projection from LS recruited a circuit that inhibited the Foxb1+ neurons in the parvafox nucleus (PFN), which drove social avoidance by projecting to the lateral periaqueductal gray (lPAG). These results suggest that a previously unidentified circuit of dCA3CaMKIIα+→LSGABA+→PFNFoxb1+→lPAG mediates the deficits of social novelty preference induced by CSDS.

Neonatal exposure to sevoflurane impairs preference for social novelty in C57BL/6 female mice at early-adulthood

Social interaction deficit is core symptom of children with autism, owing to interaction of genetic predisposition and environmental toxins. Sevoflurane could induce neurotoxicity in developing brain in rodent models. This study aims to investigate whether sevoflurane anesthesia in neonatal period could impair social behaviors in male and female mice. Twenty-eight male and thirty-one female mice were randomly assigned to receive 3.0% sevoflurane or 60% oxygen on postnatal day 6. They were tested for social interaction behaviors at one- and two-month-old. In addition, the cortex and hippocampus of neonatal mice undergoing sevoflurane anesthesia were harvested for immunoblotting analysis. As a result, both male and female mice undergoing sevoflurane anesthesia showed strong sociability and weak preference for social novelty at juvenile age. In addition, the male mice developed normal preference for social novelty at early-adulthood; However, the female mice remained weak preference for social novelty. Furthurmore, sevoflurane anesthesia could decrease the levels of PSD95 but not Neuroligin-1 in the hippocampus but not cortex of neonatal mice. In conclusion, sevoflurane anesthesia in neonatal period could disturb development of social memory and impair preference for social novelty in female mice at early-adulthood, with the potential mechanism of decreasing PSD95 expression in the hippocampus of C57BL/6 mice.

Oxytocin receptor disruption in Avil-expressing cells results in blunted sociability and increased inter-male aggression.

Social behaviors are foundational to society and quality of life while social behavior extremes are core symptoms in a variety of psychopathologies and developmental disabilities. Oxytocin (OXT) is a neuroactive hormone that regulates social behaviors through its receptor (OXTR), with all previously identified social behavior effects attributed to the central nervous system, which has developmental origins in the neural tube. However, OXTR are also present in neural crest-derived tissue including sensory ganglia of the peripheral nervous system. Avil encodes for the actin-binding protein ADVILLIN, is expressed in neural crest-derived cells, and was therefore used as a target in this study to knock out OXTR expression in neural-crest derived cells. Here, we tested if OXTRs specifically expressed in Avil positive neural crest-derived cells are necessary for species-typical adult social behaviors using a Cre-LoxP strategy. Genetically modified male and female mice lacking OXTR in Avil expressing cells (OXTRAvil KO) were tested for sociability and preference for social novelty. Males were also tested for resident intruder aggression. OXTRAvil KO males and females had reduced sociability compared to OXTRAvil WT controls. Additionally, OXTRAvil KO males had increased aggressive behaviors compared to controls. These data indicate that OXTRs in cells of neural crest origin are important regulators of typical social behaviors in C57BL/6J adult male and female mice and point to needed directions of future research.

Effects of a 33-ion sequential beam galactic cosmic ray analog on male mouse behavior and evaluation of CDDO-EA as a radiation countermeasure

In long-term spaceflight, astronauts will face unique cognitive loads and social challenges which will be complicated by communication delays with Earth. It is important to understand the central nervous system (CNS) effects of deep spaceflight and the associated unavoidable exposure to galactic cosmic radiation (GCR). Rodent studies show single- or simple-particle combination exposure alters CNS endpoints, including hippocampal-dependent behavior. An even better Earth-based simulation of GCR is now available, consisting of a 33-beam (33-GCR) exposure. However, the effect of whole-body 33-GCR exposure on rodent behavior is unknown, and no 33-GCR CNS countermeasures have been tested. Here astronaut-age-equivalent (6mo-old) C57BL/6J male mice were exposed to 33-GCR (75cGy, a Mars mission dose). Pre-/during/post-Sham or 33-GCR exposure, mice received a diet containing a 'vehicle' formulation alone or with the antioxidant/anti-inflammatory compound CDDO-EA as a potential countermeasure. Behavioral testing beginning 4mo post-irradiation suggested radiation and diet did not affect measures of exploration/anxiety-like behaviors (open field, elevated plus maze) or recognition of a novel object. However, in 3-Chamber Social Interaction (3-CSI), CDDO-EA/33-GCR mice failed to spend more time exploring a holder containing a novel mouse vs. a novel object (empty holder), suggesting sociability deficits. Also, Vehicle/33-GCR and CDDO-EA/Sham mice failed to discriminate between a novel stranger vs. familiarized stranger mouse, suggesting blunted preference for social novelty. CDDO-EA given pre-/during/post-irradiation did not attenuate the 33-GCR-induced blunting of preference for social novelty. Future elucidation of the mechanisms underlying 33-GCR-induced blunting of preference for social novelty will improve risk analysis for astronauts which may in-turn improve countermeasures.

Early Life Stress Alters Gene Expression and Cytoarchitecture in the Prefrontal Cortex Leading to Social Impairment and Increased Anxiety.

Early life stress (ELS), such as abuse, neglect, and maltreatment, exhibits a strong impact on the brain and mental development of children. However, it is not fully understood how ELS affects social behaviors and social-associated behaviors as well as developing prefrontal cortex (PFC). In this study, we performed social isolation on weaned pre-adolescent mice until adolescence and investigated these behaviors and PFC characteristics in adolescent mice. We found the ELS induced social impairments in social novelty, social interaction, and social preference in adolescent mice. We also observed increases of anxiety-like behaviors in ELS mice. In histological analysis, we found a reduced number of neurons and an increased number of microglia in the PFC of ELS mice. To identify the gene associated with behavioral and histological features, we analyzed transcriptome in the PFC of ELS mice and identified 15 differentially expressed genes involved in transcriptional regulation, stress, and synaptic signaling. Our study demonstrates that ELS influences social behaviors, anxiety-like behaviors through cytoarchitectural and transcriptomic alterations in the PFC of adolescent mice.

Persistent autism-relevant behavioral phenotype and social neuropeptide alterations in female mice offspring induced by maternal transfer of PBDE congeners in the commercial mixture DE-71

Polybrominated diphenyl ethers (PBDEs) are ubiquitous persistent organic pollutants (POPs) that are known neuroendocrine disrupting chemicals with adverse neurodevelopmental effects. PBDEs may act as risk factors for autism spectrum disorders (ASD), characterized by abnormal psychosocial functioning, although direct evidence is currently lacking. Using a translational exposure model, we tested the hypothesis that maternal transfer of a commercial mixture of PBDEs, DE-71, produces ASD-relevant behavioral and neurochemical deficits in female offspring. C57Bl6/N mouse dams (F0) were exposed to DE-71 via oral administration of 0 (VEH/CON), 0.1 (L-DE-71) or 0.4 (H-DE-71) mg/kg bw/d from 3 wk prior to gestation through end of lactation. Mass spectrometry analysis indicated in utero and lactational transfer of PBDEs (in ppb) to F1 female offspring brain tissue at postnatal day (PND) 15 which was reduced by PND 110. Neurobehavioral testing of social novelty preference (SNP) and social recognition memory (SRM) revealed that adult L-DE-71 F1 offspring display deficient short- and long-term SRM, in the absence of reduced sociability, and increased repetitive behavior. These effects were concomitant with reduced olfactory discrimination of social odors. Additionally, L-DE-71 exposure also altered short-term novel object recognition memory but not anxiety or depressive-like behavior. Moreover, F1 L-DE-71 displayed downregulated mRNA transcripts for oxytocin (Oxt) in the bed nucleus of the stria terminalis (BNST) and supraoptic nucleus, and vasopressin (Avp) in the BNST and upregulated Avp1ar in BNST, and Oxtr in the paraventricular nucleus. Our work demonstrates that developmental PBDE exposure produces ASD-relevant neurochemical, olfactory processing and behavioral phenotypes that may result from early neurodevelopmental reprogramming within central social and memory networks.

Maternal Gut Dysbiosis Alters Offspring Microbiota and Social Interactions.

Increasing application of antibiotics changes the gut microbiota composition, leading to dysbiosis of the gut microbiota. Although growing evidence suggests the potential role of gut dysbiosis as the cause of neurodevelopmental disorders and behavioral defects, a broad gap of knowledge remains to be narrowed to better understand the exact mechanisms by which maternal gut dysbiosis alters microbiota development and social interactions of offspring. Here, we showed that maternal gut dysbiosis during gestation is a critical determinant of gut microbiota and social interactions off mouse offspring. Gut microbiota of 2-week-old offspring showed significant changes in response to maternal antibiotic treatment. We even detected distinct effects of maternal oral antibiotics on gut microbiota of 14-week-old offspring. Compared to controls, offspring born to antibiotics-treated mothers displayed reduction in sociability and preference for social novelty, suggesting that the altered offspring social behavior was closely linked to dysbiosis of maternal gut microbiota. Our study opens the possibility to better understand the mechanism of how maternal gut microbiota vertically impairs social interactions of offspring in animal models, providing support to the maternal gut microbiota as a potential mediator between offspring microbiota and behaviors.

Signal Transducer and Activator of Transcription 3 Activation in Hippocampal Neural Stem Cells and Cognitive Deficits in Mice Following Short-term Cuprizone Exposure

Recent studies have emphasized that adult hippocampal neurogenesis impairment may be associated with cognitive problems. Because cuprizone (CPZ), a copper-chelating reagent, was shown to decrease the production of new neurons, we aimed to further understand the involvement of adult hippocampal neurogenesis impairment in cognitive function by using a short-term (2-week) CPZ exposure paradigm. The CPZ-fed mice showed cognitive deficits, i.e., impaired sensorimotor gating and reduced social novelty preference, compared to normal-fed mice. Although a long-term (e.g., 5-week) CPZ exposure paradigm was found to cause demyelination, we encountered that the labeling for myelin in the hippocampus was unaffected by 2-week CPZ exposure. The densities of neuronal progenitor cells (NPCs) and newborn granule cells (NGCs) were lower in CPZ-fed mice than in normal-fed mice, while those of neural stem cells (NSCs) were comparable between groups. We then examined whether short-term CPZ exposure might induce activation of signal transducer and activator of transcription 3 (STAT3), which plays a major role in cytokine receptor signaling. The densities of phosphorylated STAT3-positive (pSTAT3+) NSCs were higher in CPZ-fed mice than in normal-fed mice, while those of pSTAT3+ NPCs/NGCs were very low in both groups. Interestingly, the densities of bromodeoxyuridine-positive (BrdU+) NSCs were higher in CPZ-fed mice than in normal-fed mice 2 weeks after BrdU injection, while those of BrdU+ NPCs/NGCs were lower in CPZ-fed mice than in normal-fed mice. These findings suggest that short-term CPZ exposure inhibits differentiation of NSCs into NPCs via activation of STAT3, which may in part underlie cognitive deficits.

Mu-opioid receptor agonism differentially alters social behaviour and immediate early gene expression in male adolescent rats prenatally exposed to valproic acid versus controls

Mu-opioid receptors (MOPs) mediate and modulate social reward and social interaction. However, few studies have examined the functionality of this system in rodent models of social impairment. Deficits in social motivation and cognition are observed in rodents following pre-natal exposure to the anti-epileptic valproic acid (VPA), however it is not known whether MOP functionality is altered in these animals. The present study examined the effects of acute administration of the prototypical MOP agonist morphine (1 mg/kg) on social behavioural responding in the 3-chamber test and immediate early gene expression in adolescent rats (postnatal day 28–43) prenatally exposed to VPA vs saline-exposed controls. Pharmacokinetic analysis of morphine concentration, MOP binding and expression were also examined. The data revealed that sociability and social novelty preference in the 3-chamber test were reduced in rats prenatally exposed to VPA compared to saline-exposed control counterparts. Morphine reduced both sociability and social novelty preference behaviour in saline-, but not VPA-, exposed rats. Analysis of immediate early gene expression revealed that morphine reduced the expression of cfos in the prefrontal cortex of both saline- and VPA-exposed rats and reduced expression of cfos and junb in the hippocampus of VPA-exposed rats only. Pharmacokinetic analysis revealed similar concentrations of morphine in the plasma and brain of both saline- and VPA-exposed rats and similar thalamic MOP occupancy levels. Gene and protein expression of MOP in prefrontal cortex and hippocampus did not differ between saline and VPA-exposed rats. These data indicate differential effects of morphine on social responding and immediate early gene expression in the hippocampus of VPA-exposed rats compared with saline-exposed controls. This study provides support for altered MOP functionality in rats prenatally exposed to VPA, which may underlie the social deficits observed in the model.

Loss of Calretinin in L5a impairs the formation of the barrel cortex leading to abnormal whisker-mediated behaviors

The rodent whisker-barrel cortex system has been established as an ideal model for studying sensory information integration. The barrel cortex consists of barrel and septa columns that receive information input from the lemniscal and paralemniscal pathways, respectively. Layer 5a is involved in both barrel and septa circuits and play a key role in information integration. However, the role of layer 5a in the development of the barrel cortex remains unclear. Previously, we found that calretinin is dynamically expressed in layer 5a. In this study, we analyzed calretinin KO mice and found that the dendritic complexity and length of layer 5a pyramidal neurons were significantly decreased after calretinin ablation. The membrane excitability and excitatory synaptic transmission of layer 5a neurons were increased. Consequently, the organization of the barrels was impaired. Moreover, layer 4 spiny stellate cells were not able to properly gather, leading to abnormal formation of barrel walls as the ratio of barrel/septum size obviously decreased. Calretinin KO mice exhibited deficits in exploratory and whisker-associated tactile behaviors as well as social novelty preference. Our study expands our knowledge of layer 5a pyramidal neurons in the formation of barrel walls and deepens the understanding of the development of the whisker-barrel cortex system.

Lysergic acid diethylamide (LSD) promotes social behaviour through 5-HT2A and ampa in the medial prefrontal cortex (MPFC)

IntroductionAutism Spectrum Disorder and Social Anxiety Disorder are mental illnesses characterized by a dysfunction in social behavior (SB); a phenomenon largely mediated by the medial prefrontal cortex (mPFC). Clinical studies have demonstrated that lysergic acid diethylamide (LSD), a partial agonist of the 5-HT2A receptor, can promote SB. However, its mechanism of action on SB is unknown.ObjectivesTo assess the effects of repeated LSD administration on social behavior in mice and to identify which mPFC receptors mediate LSD’s behavioral effects.MethodsEight-week-old C57BL/6J male mice received vehicle or repeated LSD (30 μg/kg/day i.p. for 7 days) as well the selective 5-HT2A receptor antagonist MDL, or the AMPA receptor antagonist NBQX. Twenty-four hours following the last injection, mice underwent the Direct Social Interaction Test and the Three-Chamber Test (TCT) to assess sociability and preference for social novelty. in vivo electrophysiological recordings were performed in mice treated with vehicle or LSD using multi-barrelled electrodes for microiontophoretic ejections of the selective 5-HT2A receptor agonist DOI or the selective AMPA receptor agonist quisqualate on mPFC pyramidal neurons.ResultsRepeated treatment with low doses of LSD increased the interaction time in the DSI as well as sociability and social novelty indices in the TCT. These pro-social effects were blocked by the intra-PFC administration of both 5-HT2A and AMPA antagonists. LSD also potentiated, in a current-dependent manner, the excitatory response of mPFC neurons to 5-HT2Aand AMPA agonists.ConclusionsRepeated, low doses of LSD increases social behavior via a mechanism of action that is mediated by 5-HT2A and AMPA in the mPFC.

Behavioral Consequences of a Combination of Gad1 Haplodeficiency and Adolescent Exposure to an NMDA Receptor Antagonist in Long-Evans Rats.

Glutamate decarboxylase 67-kDa isoform (GAD67), which is encoded by the GAD1 gene, is one of the key enzymes that produce GABA. The reduced expression of GAD67 has been linked to the pathophysiology of schizophrenia. Additionally, the excitatory glutamatergic system plays an important role in the development of this disorder. Animal model studies have revealed that chronic blockade of NMDA-type glutamate receptors can cause GABAergic dysfunction and long-lasting behavioral abnormalities. Based on these findings, we speculated that Gad1 haplodeficiency combined with chronic NMDA receptor blockade would lead to larger behavioral consequences relevant to schizophrenia in a rat model. In this study, we administered an NMDAR antagonist, MK-801 (0.2 mg/kg), to CRISPR/Cas9-generated Gad1 +/− rats during adolescence to test this hypothesis. The MK-801 treated Gad1 +/− rats showed a shorter duration in each rearing episode in the open field test than the saline-treated Gad1 +/+ rats. In contrast, immobility in the forced swim test was increased and fear extinction was impaired in Gad1 +/− rats irrespective of MK-801 treatment. Interestingly, the time spent in the center region of the elevated plus-maze was significantly affected only in the saline-treated Gad1 +/− rats. Additionally, the MK-801-induced impairment of the social novelty preference was not observed in Gad1 +/− rats. These results suggest that the synergistic and additive effects of Gad1 haplodeficiency and NMDA receptor blockade during adolescence on the pathogenesis of schizophrenia may be more limited than expected. Findings from this study also imply that these two factors mainly affect negative or affective symptoms, rather than positive symptoms.

Maternal anesthesia with sevoflurane during the mid-gestation induces social interaction deficits in offspring C57BL/6 mice

Sevoflurane anesthesia in pregnant mice could induce neurotoxicity in the developing brain and disturb learning and memory in the offspring mice. Whether it could impair social behaviors in the offspring mice is uncertain. Therefore, we assessed the neurobehavioral effect of in-utero exposure to sevoflurane on social interaction behaviors in C57BL/6 mice. The pregnant mice were anesthetized with 2.5% sevoflurane in 100% oxygen for 2 h, and their offspring mice were tested in three-chambered social paradigm, which includes three 10-min sessions of habituation, sociability, and preference for social novelty. At the juvenile age, the offspring mice showed abnormal sociability, as proved by not taking more time sniffing at the stranger 1 mouse compared with the empty enclosure (108.5 ± 25.4 vs. 108.2 ± 44.0 s, P = 0.9876). Meanwhile, these mice showed impaired preference for social novelty, as evidenced by not taking more time sniffing at the stranger 2 compared with the stranger 1 mouse (92.1 ± 52.2 vs. 126.7 ± 50.8 s, P = 0.1502). At the early adulthood, the offspring mice retrieved the normal sociability (145.6 ± 33.2 vs. 76.0 ± 31.8 s, P = 0.0001), but remained the impaired preference for social novelty (100.6 ± 29.3 vs. 118.0 ± 47.9 s, P = 0.3269). Collectively, these results suggested maternal anesthesia with sevoflurane could induce social interaction deficits in their offspring mice. Although the disturbance of sociability could be recoverable, the impairment of preference for social novelty could be long-lasting.

Effects of maternal exposure to arsenic on social behavior and related gene expression in F2 male mice

BackgroundArsenic is a developmental neurotoxicant. It means that its neurotoxic effect could occur in offspring by maternal arsenic exposure. Our previous study showed that developmental arsenic exposure impaired social behavior and serotonergic system in C3H adult male mice. These effects might affect the next generation with no direct exposure to arsenic. This study aimed to detect the social behavior and related gene expression changes in F2 male mice born to gestationally arsenite-exposed F1 mice.MethodsPregnant C3H/HeN mice (F0) were given free access to tap water (control mice) or tap water containing 85 ppm sodium arsenite from days 8 to 18 of gestation. Arsenite was not given to F1 or F2 mice. The F2 mice were generated by mating among control F1 males and females, and arsenite-F1 males and females at the age of 10 weeks. At 41 weeks and 74 weeks of age respectively, F2 males were used for the assessment of social behavior by a three-chamber social behavior apparatus. Histological features of the prefrontal cortex were studied by ordinary light microscope. Social behavior-related gene expressions were determined in the prefrontal cortex by real time RT-PCR method.ResultsThe arsenite-F2 male mice showed significantly poor sociability and social novelty preference in both 41-week-old group and 74-week-old group. There was no significant histological difference between the control mice and the arsenite-F2 mice. Regarding gene expression, serotonin receptor 5B (5-HT 5B) mRNA expression was significantly decreased (p < 0.05) in the arsenite-F2 male mice compared to the control F2 male mice in both groups. Brain-derived neurotrophic factor (BDNF) and dopamine receptor D1a (Drd1a) gene expressions were significantly decreased (p < 0.05) only in the arsenite-F2 male mice of the 74-week-old group. Heme oxygenase-1 (HO-1) gene expression was significantly increased (p < 0.001) in the arsenite-F2 male mice of both groups, but plasma 8-hydroxy-2′-deoxyguanosine (8-OHdG) and cyclooxygenase-2 (COX-2) gene expression were not significantly different. Interleukin-1β (IL-1β) mRNA expression was significantly increased only in 41-week-old arsenite-F2 mice.ConclusionsThese findings suggest that maternal arsenic exposure affects social behavior in F2 male mice via serotonergic system in the prefrontal cortex. In this study, COX-2 were not increased although oxidative stress marker (HO-1) was increased significantly in arsnite-F2 male mice.

Effects of the Prenatal Administration of Tetanus Toxoid on the Sociability and Explorative Behaviors of Rat Offspring: A Preliminary Study.

ObjectiveAutism spectrum disorder (ASD) is a severely disabling psychiatric disease characterized by impairments in communication and social skills. Although efforts have been made to explore the etiology of ASD, its pathophysiology remains unclear. This issue is rendered more challenging by confounding data about the effects of vaccination on disease etiology. In this study, therefore, we investigated the neurodevelopmental effects of maternal tetanus toxoid administration on rat offspring. We hypothesized that the vaccine affects the sociability and preference for social novelty of rat offspring as well as the production of immunological and neurotrophic factors, including tumor necrosis factor-alfa (TNF-α), neuregulin-1 (NRG-1), neuron growth factor (NGF), and oxytocin.MethodsThe study involved 12 female and 4 male adult Sprague−Dawley rats (238 ± 10 g), which were assigned to two groups. Group 1 (control group) was given 0.5 ml of normal saline (0.9% NaCl) on the 10th day of pregnancy, whereas Group 2 (experimental group) was administered 0.5 ml of tetanus vaccine (tetanus toxoid, 40 IU).ResultsMaternal tetanus toxoid administration exerted beneficial effects on the sociability and explorative behaviors of the rats. The brain tissue levels of TNF-α, NGF, NRG-1, and oxytocin were higher in the experimental group than those among the controls. All these significant differences were found in both the male and female rats.ConclusionThis study is the first to demonstrate the advantages of tetanus toxoid administration in relation to the sociability and explorative behaviors of rat offspring. The results showed that the vaccine also influences NRG-1, neuregulin, and oxytocin production.