Social Recognition Deficits Research Articles

Cognitive deficits profiles in the first-episode of schizophrenia, clinical high risk of psychosis, and genetically high-risk of psychosis.

Cognitive deficits are core characteristics of schizophrenia, presenting before the emergence of psychotic symptoms. Individuals with a clinical high-risk for psychosis (CHR) and those with genetically high-risk of psychosis (GHR) also exhibit cognitive impairments. Nonetheless, it remains uncertain in which domains of cognitive impairments in these two groups were more similar to those of schizophrenia patients. Moreover, it is unclear which domains of impairment are caused by quality factors and which are more related to the state of disease. This research initiative aimed to extensively examine the distinct cognitive impairment profiles among the CHR, GHR, and first-episode schizophrenia (FES) cohorts. We compared the cognitive functions of the three groups and a healthy control group (HCs) using the MATRICS Consensus Cognitive Battery (MCCB). The participants for this study were recruited from the Beijing Anding Hospital of Capital Medical University. Our sample consisted of 56 patients with FES, 42 with CHR, 26 with GHR, and 62 HCs. The participants across all groups were matched in terms of gender, age, and level of education. Individuals with FES, GHR, and CHR showed significant impairment across the majority of MCCB domains, with the exception of visual learning, in comparison to HCs. None of the MCCB domains demonstrated a discerning ability to accurately differentiate between individuals with CHR and those with GHR. In the speed of processing and attention/vigilance domains, individuals with GHR and CHR exhibited scores between those of FES and HCs, with all group differences reaching statistical significance. This pattern of results indicates an intermediate level of cognitive function in individuals with GHR and CHR. Conversely, the levels of impairment observed in working memory and verbal learning were relatively consistent across all three groups: FES, CHR, and GHR. Notably, individuals in the CHR group exhibited performance akin to that of the HCs in the reasoning/problem-solving domain, while showing significant differences from the FES group, with the CHR individuals demonstrating better performance. Additionally, individuals with GHR displayed performance in social cognition similar to that of the HCs, while also demonstrating significant distinctions from the FES group, with the GHR individuals demonstrating better performance. Significant cognitive deficits exist in individuals with CHR, GHR, and FES, and these deficits vary across domains. Processing speed and attention/vigilance could potentially serve as robust biomarkers for identifying individuals at a risk of psychosis. The impairment observed in reasoning/problem-solving abilities might signify a qualitative trait, whereas deficits in social recognition could indicate a state characteristic specific to schizophrenia.

Probiotic Therapy with Lactobacillus reuteri Rescues Social and Emotional Recognition Behavior in an Environmental Mouse Model of Autism

Introduction: Polybrominated diphenyl ethers (PBDEs) are neuroendocrine disrupting chemicals with adverse neurodevelopmental effects in children. Our group has previously shown that PBDEs produce autistic-like traits in developmentally exposed mice offspring (Kozlova et al. 2022 Arch Tox; PMID: 34687351). Our pilot data suggests that PBDEs reduce hypothalamic oxytocin expression. Moreover, PBDEs are well established disruptors of thyroid hormones. Lactobacillus reuteri (LR) is a beneficial probiotic that can increase oxytocin and thyroid hormones in other ASD mouse models. Therefore, we hypothesized that LR can restore PBDE-induced deficits in social behavior. Methods: C57BL/6N dams were dosed with a commercial mixture of PBDE congeners, DE-71, at 0.1 mg/kg/d (DE-71), or corn oil vehicle control (VEH/CON) for 10 wk (preconception: 4 wk; gestation: 3 wk; lactation: 3 wk). Dams were gavaged with L. reuteri (LR) ATCC 6475 (gift of Biogaia, Sweeden) at 10 8 CFU/mL. Cohort 1 pups (C1-LR) received LR via dam until weaning (PND 21). Cohort 2 pups (C2-LR) continued to receive gavage of LR post-weaning, daily, through 6 mo of age. Results: PCR analysis showed increased gene expression of fecal LR 6475 in feces collected from LR offspring and dams confirming efficacy of maternal LR supplementation. Compared to VEH/CON neither DE-71 nor LR disrupted normal maternal behavior. In offspring, DE-71 produced deficient short- (SRT, 30 min retention) and long-term social recognition memory (SRMT, 24 h retention) in adult females (short- and long-term) and adult males (short-term). LR normalized these deficits. The social recognition deficit was not present at PND 11 as measured on a maternal attachment homing test. On an emotional recognition test DE-71 exposed male and female offspring did not prefer investigation of stimulus mice subjected to 15 min restraint stress vs neutral conditions (normalized with LR). In a marble burying test, compared to VEH/CON, DE-71 exposed offspring showed abnormally elevated scores, which were normalized by LR treatment only in females. Developmental benchmarks that are likely affected by the TH-disruptive effects of DE-71 showed complex interactions between DE-71 and LR. LR normalized delayed (vs VEH/CON) incisor eruption in DE-71 females and improved latency of righting reflex in DE-71 males. LR normalized DE-71-induced hyperactivity on an open field test in females. Ongoing studies are focused on exploring possible mechanisms underlying the normalization provided by LR. However, our early data suggest a potential role of 1) OXT confirmed by increased plasma OXT in DE-71 male (C1-LR) mice and normalized with LR, and 2) maternal THs since LR supplementation elevated plasma T4 in DE-71 pregnant dams. Conclusions: These results suggest that maternal LR treatment during developmental PBDE exposure provides normalization of autistic-like features in a sex-dependent manner. This work is supported by a Danone North America Gut Microbiome, Yogurt and Probiotics Fellowship Grant and a University of California President's Pre-Professoriate Fellowship to E.V.K. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Age-associated deficits in social behaviour are microbiota-dependent

Aging is associated with remodelling of immune and central nervous system responses resulting in behavioural impairments including social deficits. Growing evidence suggests that the gut microbiome is also impacted by aging, and we propose that strategies to reshape the aged gut microbiome may ameliorate some age-related effects on host physiology. Thus, we assessed the impact of gut microbiota depletion, using an antibiotic cocktail, on aging and its impact on social behavior and the immune system.Indeed, microbiota depletion in aged mice eliminated the age-dependent deficits in social recognition. We further demonstrate that although age and gut microbiota depletion differently shape the peripheral immune response, aging induces an accumulation of T cells in the choroid plexus, that is partially blunted following microbiota depletion. Moreover, an untargeted metabolomic analysis revealed age-dependent alterations of cecal metabolites that are reshaped by gut microbiota depletion. Together, our results suggest that the aged gut microbiota can be specifically targeted to affect social deficits. These studies propel the need for future investigations of other non-antibiotic microbiota targeted interventions on age-related social deficits both in animal models and humans.

Oral Supplementation with Maca Improves Social Recognition Deficits in the Valproic Acid Animal Model of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a congenital, lifelong neurodevelopmental disorder whose main symptom is impaired social communication and interaction. However, no drug can treat social deficits in patients with ASD, and treatments to alleviate social behavioral deficits are sorely needed. Here, we examined the effect of oral supplementation of maca (Lepidium meyenii) on social deficits of in utero-exposed valproic acid (VPA) mice, widely used as an ASD model. Although maca is widely consumed as a fertility enhancer and aphrodisiac, it possesses multiple beneficial activities. Additionally, it benefits learning and memory in experimental animal models. Therefore, the effect of maca supplementation on the social behavioral deficit of VPA mice was assessed using a social interaction test, a three-stage open field test, and a five-trial social memory test. The oral supplementation of maca attenuated social interaction behavior deficit and social memory impairment. The number of c-Fos-positive cells and the percentage of c-Fos-positive oxytocin neurons increased in supraoptic and paraventricular neurons of maca-treated VPA mice. These results reveal for the first time that maca is beneficial to social memory and that it restores social recognition impairments by augmenting the oxytocinergic neuronal pathways, which play an essential role in diverse social behaviors.

Preadolescent exposure to a sexually mature, unrelated male rat reduces postadolescent social recognition memory and CA2 c-Fos labeling.

Social memory involves social recognition: the ability to discriminate between two or more conspecifics when one has been previously encountered. The CA2 region of the hippocampus has been implicated in social memory, as lesions and dysfunction to this area lead to social memory impairments. A variety of psychogenic manipulations during postnatal sensitive developmental periods are associated with social memory impairments later in life. In this study, we exposed preadolescent rats to a sexually, mature unrelated male and examined whether this was associated with changes in postadolescent social memory and c-Fos labeling in the CA2 region. Male and female Long-Evans rats were exposed to a male, adult rat on postnatal days 19-21 (P19-21). Social memory was measured during the postadolescent period and defined as increased interactions towards a novel age-matched rat in contrast to a previously-encountered age-matched rat. After the test, rats were euthanized and brain tissue was then collected to quantify c-Fos labeling within the CA2 region. Compared to home cage controls and controls not exposed to the adult male, male and female rats exposed to the unrelated adult during preadolescence were unable to discriminate between a novel and previously encountered conspecific during the postadolescent test showing social memory deficits. The groups that showed social recognition deficits also had significantly fewer c-Fos-positive cells within the CA2 region compared to the control groups. These findings indicate that threatening psychogenic encounters during preadolescence can have detrimental long-term effects on social memory potentially via disrupted activity in the CA2 hippocampal region.

The α2C-adrenoceptor antagonist JP-1302 controls behavioral parameters, tyrosine hydroxylase activity and receptor expression in a rat model of ketamine-induced schizophrenia-like deficits

Schizophrenia is a chronic disabling disease affecting 1 % of the population. Current antipsychotics have limited efficacy in mitigating the severity of the symptoms of the disease. Therefore, searching for new therapeutic targets is essential. Previous studies have shown that α2C-adrenoceptor antagonists may have antipsychotic and pro-cognitive effects. Therefore, the current study evaluates the behavioral and neurochemical effects of JP-1302, a selective α2C-adrenoceptor antagonist, in a model of schizophrenia-like deficits induced by sub-chronic ketamine (KET) administration.Here, we administered ketamine (25 mg/kg, i.p.) to male and female Wistar rats for eight consecutive days. On the last two days of ketamine administration, rats were pretreated with either JP-1302 (1-3-10 μmol/kg, i.p.), chlorpromazine (0.1 mg/kg, i.p.), or saline, and the behavioral tests were performed. Behaviors related to positive (locomotor activity), negative (social interaction), and cognitive (novel object recognition) symptoms of schizophrenia were assessed. Glutamate, glutamine, GABA levels, and α2C-adrenoceptor expression were measured in the frontal cortex and the hippocampus. Tyrosine hydroxylase immunocytochemical reactivity was also shown in the midbrain regions.Sub-chronic ketamine administration increased locomotor activity and produced robust social interaction and object recognition deficits, and JP-1302 significantly ameliorated ketamine-induced cognitive deficits. Ketamine induced a hyperdopaminergic activity in the striatum, which was reversed by the treatment with JP-1302. Also, the α2C-adrenoceptor expression was higher in the frontal cortex and hippocampus in the ketamine-treated rats.Our findings confirm that α2C-adrenoceptor antagonism may be a potential drug target for treating cognitive disorders related to schizophrenia.

Swimming exercise is a promising early intervention for autism-like behavior in Shank3 deletion rats.

SHANK3 is an important excitatory postsynaptic scaffold protein, and its mutations lead to genetic cause of neurodevelopmental diseases including autism spectrum disorders (ASD), Philan McDermid syndrome (PMS), and intellectual disability (ID). Early prevention and treatment are important for Shank3 gene mutation disease. Swimming has been proven to have a positive effect on neurodegenerative diseases. Shank3 gene exon 11-21 knockout rats were intervened by a 40 min/day, 5day/week for 8-week protocol. After the intervention, the rats were tested to behavioral measures such as learning and memory, and the volume and H-spectrum of the brain were measured using MRI; hippocampal dendritic spines were measured using Golgi staining and laser confocal. The results showed that Shank3-deficient rats had significant deficits in social memory, object recognition, and water maze learning decreased hippocampal volume and number of neurons, and lower levels of related scaffold proteins and receptor proteins were found in Shank3-deficient rats. It is suggested that early swimming exercise has a positive effect on Shank3 gene-deficient rats, which provides a new therapeutic strategy for the prevention and recovery of neurodevelopmental disorders.

Sex-specific involvement of the Notch\u2013JAG pathway in social recognition

Under the hypothesis that olfactory neural epithelium gene expression profiles may be useful to look for disease-relevant neuronal signatures, we examined microarray gene expression in olfactory neuronal cells and underscored Notch–JAG pathway molecules in association with schizophrenia (SZ). The microarray profiling study underscored JAG1 as the most promising candidate. Combined with further validation with real-time PCR, downregulation of NOTCH1 was statistically significant. Accordingly, we reverse-translated the significant finding from a surrogate tissue for neurons, and studied the behavioral profile of Notch1+/− mice. We found a specific impairment in social novelty recognition, whereas other behaviors, such as sociability, novel object recognition and olfaction of social odors, were normal. This social novelty recognition deficit was male-specific and was rescued by rapamycin treatment. Based on the results from the animal model, we next tested whether patients with psychosis might have male-specific alterations in social cognition in association with the expression of NOTCH1 or JAG1. In our first episode psychosis cohort, we observed a specific correlation between the expression of JAG1 and a face processing measure only in male patients. The expression of JAG1 was not correlated with any other cognitive and symptomatic scales in all subjects. Together, although we acknowledge the pioneering and exploratory nature, the present work that combines both human and animal studies in a reciprocal manner suggests a novel role for the Notch–JAG pathway in a behavioral dimension(s) related to social cognition in psychotic disorders in a male-specific manner.

Auts2 deletion involves in DG hypoplasia and social recognition deficit: The developmental and neural circuit mechanisms.

The involvement of genetic risk and the underlying developmental and neural circuit mechanisms in autism-related social deficit are largely unclear. Here, we report that deletion of AUTS2, a high-susceptibility gene of ASDs, caused postnatal dentate gyrus (DG) hypoplasia, which was closely relevant to social recognition deficit. Furthermore, a previously unknown mechanism for neural cell migration in postnatal DG development was identified, in which Auts2-related signaling played a vital role as the transcription repressor. Moreover, the supramammillary nucleus (SuM)–DG-CA3 neural circuit was found to be involved in social recognition and affected in Auts2-deleted mice due to DG hypoplasia. Correction of DG-CA3 synaptic transmission by using a pharmacological approach or chemo/optogenetic activation of the SuM-DG circuit restored the social recognition deficit in Auts2-deleted mice. Our findings demonstrated the vital role of Auts2 in postnatal DG development, and this role was critical for SuM-DG-CA3 neural circuit-mediated social recognition behavior.

Oral Supplementation with L-Carnosine Attenuates Social Recognition Deficits in CD157KO Mice via Oxytocin Release.

The outcomes of supplementation with L-carnosine have been investigated in clinical trials in children with autism spectrum disorder (ASD). However, reports on the effects of L-carnosine in humans have been inconsistent, and the efficacy of L-carnosine supplementation for improving ASD symptoms has yet to be investigated in animal studies. Here, we examined the effects of oral supplementation with L-carnosine on social deficits in CD157KO mice, a murine model of ASD. Social deficits in CD157KO mice were assessed using a three-chamber social approach test. Oral supplementation with L-carnosine attenuated social behavioral deficits. The number of c-Fos-positive oxytocin neurons in the supraoptic nucleus and paraventricular nucleus was increased with L-carnosine supplementation in CD157KO mice after the three-chamber social approach test. We observed an increase in the number of c-Fos-positive neurons in the basolateral amygdala, a brain region involved in social behavior. Although the expression of oxytocin and oxytocin receptors in the hypothalamus was not altered by L-carnosine supplementation, the concentration of oxytocin in cerebrospinal fluid was increased in CD157KO mice by L-carnosine supplementation. These results suggest that L-carnosine supplementation restores social recognition impairments by augmenting the level of released oxytocin. Thus, we could imply the possibility of a safe nutritional intervention for at least some types of ASD in the human population.

Social cue recognition and attributional bias in remitted bipolar disorder: Impact on social functioning

The role of social cue recognition and attributional bias on social functioning has been sparsely studied in remitted bipolar disorder (BD). In view of this, we evaluated thirty subjects with BD (without a history of psychotic symptoms) who were in remission and thirty age and, gender-matched healthy controls for social cue recognition [using SoCueReTI (Social Cue Recognition Test- Indian Setting)], and attributional bias (using an Attributional style questionnaire). Social functioning was assessed in subjects with BD using the Functional assessment short test (FAST) - Interpersonal relationships. Subjects with BD had significant deficits in recognizing social cues in low-intensity and high-intensity vignettes when compared to healthy controls. Deficits in recognizing social cues in low-intensity vignettes were significantly correlated with the FAST scores, even after controlling for the number of episodes and duration of illness. Further replication studies are needed to ascertain the association between social cue recognition deficits and social functioning in BD.

A Temporal Activity of CA1 Neurons Underlying Short-Term Memory for Social Recognition Altered in PTEN Mouse Models of Autism Spectrum Disorder.

Memory-guided social recognition identifies someone from previous encounters or experiences, but the mechanisms of social memory remain unclear. Here, we find that a short-term memory from experiencing a stranger mouse lasting under 30 min interval is essential for subsequent social recognition in mice, but that interval prolonged to hours by replacing the stranger mouse with a familiar littermate. Optogenetic silencing of dorsal CA1 neuronal activity during trials or inter-trial intervals disrupted short-term memory-guided social recognition, without affecting the ability of being sociable or long-term memory-guided social recognition. Postnatal knockdown or knockout of autism spectrum disorder (ASD)-associated phosphatase and tensin homolog (PTEN) gene in dorsal hippocampal CA1 similarly impaired neuronal firing rate in vitro and altered firing pattern during social recognition. These PTEN mice showed deficits in social recognition with stranger mouse rather than littermate and exhibited impairment in T-maze spontaneous alternation task for testing short-term spatial memory. Thus, we suggest that a temporal activity of dorsal CA1 neurons may underlie formation of short-term memory to be critical for organizing subsequent social recognition but that is possibly disrupted in ASD.

Intranasal Administration of Oxytocin Attenuates Social Recognition Deficits and Increases Prefrontal Cortex Inhibitory Postsynaptic Currents following Traumatic Brain Injury.

Pediatric traumatic brain injury (TBI) results in heightened risk for social deficits that can emerge during adolescence and adulthood. A moderate TBI in male and female rats on postnatal day 11 (equivalent to children below the age of 4) resulted in impairments in social novelty recognition, defined as the preference for interacting with a novel rat compared with a familiar rat, but not sociability, defined as the preference for interacting with a rat compared with an object in the three-chamber test when tested at four weeks (adolescence) and eight weeks (adulthood) postinjury. The deficits in social recognition were not accompanied by deficits in novel object recognition memory and were associated with a decrease in the frequency of spontaneous inhibitory postsynaptic currents (IPSCs) recorded from pyramidal neurons within Layer II/III of the medial prefrontal cortex (mPFC). Whereas TBI did not affect the expression of oxytocin (OXT) or the OXT receptor (OXTR) mRNAs in the hypothalamus and mPFC, respectively, intranasal administration of OXT before behavioral testing was found to reduce impairments in social novelty recognition and increase IPSC frequency in the mPFC in brain-injured animals. These results suggest that TBI-induced deficits in social behavior may be linked to increased excitability of neurons in the mPFC and suggests that the regulation of GABAergic neurotransmission in this region as a potential mechanism underlying these deficits.

Social isolation impairs the prefrontal-nucleus accumbens circuit subserving social recognition in mice.

Although medial prefrontal cortex (mPFC) is known to play important roles in social behaviors, how early social experiences affect the mPFC and its subcortical circuit remains unclear. We report that mice singly housed (SH) for 8weeks after weaning show a social recognition deficit, even after 4weeks of resocialization. In SH mice, prefrontal infralimbic (IL) neurons projecting to the shell region of nucleus accumbens (NAcSh) show decreased excitability compared with group-housed (GH) mice. NAcSh-projecting IL neurons are activated when GH mice encounter a familiar conspecific, which is not observed in SH mice. Chemogenetic inhibition of NAcSh-projecting IL neurons in normal mice impairs social recognition without affecting social preference, whereas activation of these neurons reverses social recognition deficit in SH mice. Our findings demonstrate that early social experience critically affects mPFC IL-NAcSh projection, the activation of which is required for social recognition by encoding information for social familiarity.

Maternal antibiotic administration during a critical developmental window has enduring neurobehavioural effects in offspring mice

Rates of perinatal maternal antibiotic use have increased in recent years linked to prophylactic antibiotic use following Caesarean section delivery. This antibiotic use is necessary and beneficial in the short-term; however, long-term consequences on brain and behaviour have not been studied in detail. Here, we endeavoured to determine whether maternal administration of antibiotics during a critical window of development in early life has lasting effects on brain and behaviour in offspring mice. To this end we studied two different antibiotic preparations (single administration of Phenoxymethylpenicillin at 31 mg/kg/day; and a cocktail consisting of, ampicillin 1 mg/mL; vancomycin 0.5 mg/mL; metronidazole 1 mg/mL; ciprofloxacin 0.2 mg/mL and imipenem 0.25 mg/mL). It was observed that early life exposure to maternal antibiotics led to persistent alterations in anxiety, sociability and cognitive behaviours. These effects in general were greater in animals treated with the broad-spectrum antibiotic cocktail compared to a single antibiotic with the exception of deficits in social recognition which were more robustly observed in Penicillin V exposed animals. Given the prevalence of maternal antibiotic use, our findings have potentially significant translational relevance, particularly considering the implications on infant health during this critical period and into later life.

Bilateral amygdala damage linked to impaired ability to predict others' fear but preserved moral judgements about causing others fear.

The amygdala is a subcortical structure implicated in both the expression of conditioned fear and social fear recognition. Social fear recognition deficits following amygdala lesions are often interpreted as reflecting perceptual deficits, or the amygdala's role in coordinating responses to threats. But these explanations fail to capture why amygdala lesions impair both physiological and behavioural responses to multimodal fear cues and the ability to identify them. We hypothesized that social fear recognition deficits following amygdala damage reflect impaired conceptual understanding of fear. Supporting this prediction, we found specific impairments in the ability to predict others' fear (but not other emotions) from written scenarios following bilateral amygdala lesions. This finding is consistent with the suggestion that social fear recognition, much like social recognition of states like pain, relies on shared internal representations. Preserved judgements about the permissibility of causing others fear confirms suggestions that social emotion recognition and morality are dissociable.

Comprehensive Profiling of Gene Expression in the Cerebral Cortex and Striatum of BTBRTF/ArtRbrc Mice Compared to C57BL/6J Mice.

Mouse line BTBR T+ Iptr3tf/J (hereafter referred as to BTBR/J) is a mouse strain that shows lower sociability compared to the C57BL/6J mouse strain (B6) and thus is often utilized as a model for autism spectrum disorder (ASD). In this study, we utilized another subline, BTBRTF/ArtRbrc (hereafter referred as to BTBR/R), and analyzed the associated brain transcriptome compared to B6 mice using microarray analysis, quantitative RT-PCR analysis, various bioinformatics analyses, and in situ hybridization. We focused on the cerebral cortex and the striatum, both of which are thought to be brain circuits associated with ASD symptoms. The transcriptome profiling identified 1,280 differentially expressed genes (DEGs; 974 downregulated and 306 upregulated genes, including 498 non-coding RNAs [ncRNAs]) in BTBR/R mice compared to B6 mice. Among these DEGs, 53 genes were consistent with ASD-related genes already established. Gene Ontology (GO) enrichment analysis highlighted 78 annotations (GO terms) including DNA/chromatin regulation, transcriptional/translational regulation, intercellular signaling, metabolism, immune signaling, and neurotransmitter/synaptic transmission-related terms. RNA interaction analysis revealed novel RNA–RNA networks, including 227 ASD-related genes. Weighted correlation network analysis highlighted 10 enriched modules including DNA/chromatin regulation, neurotransmitter/synaptic transmission, and transcriptional/translational regulation. Finally, the behavioral analyses showed that, compared to B6 mice, BTBR/R mice have mild but significant deficits in social novelty recognition and repetitive behavior. In addition, the BTBR/R data were comprehensively compared with those reported in the previous studies of human subjects with ASD as well as ASD animal models, including BTBR/J mice. Our results allow us to propose potentially important genes, ncRNAs, and RNA interactions. Analysis of the altered brain transcriptome data of the BTBR/R and BTBR/J sublines can contribute to the understanding of the genetic underpinnings of autism susceptibility.

Oxytocin-MCH circuit regulates monosynaptic inputs to MCH neurons and modulates social recognition memory

Oxytocin regulates social behaviors and has been linked to the etiology of autism and schizophrenia. Oxytocin and another hypothalamic neuropeptide, melanin concentrating hormone (MCH), share several physiological actions such as emotion, social behavior and recognition, maternal care, sexual behavior and stress, which suggests that these two systems may interact, however, how they would do it is not known. Here, we study the interactions between the oxytocin and MCH systems in behaviors related to autism and schizophrenia. Specifically, we examined the synaptic inputs of the oxytocin-to the MCH neurons. We selectively deleted oxytocin receptors (OXTR) from MCH neurons (OXTR-cKO mice) using a Cre/loxP recombinase-technology, and used rabies-mediated circuit mapping technique to reveal the changes in the direct monosynaptic inputs to MCH neurons. We examined the behavioral responses of OXTR-cKO mice. Deletion of OXTR from MCH neurons induced a significant decrease in the primary inputs received by MCH neurons from the paraventricular nucleus and the lateral hypothalamus, and from the nucleus accumbens and ventral tegmental area. While OXTR-cKO mice exhibited similar social interactions as control mice, they displayed significantly impaired social recognition memory and increased stereotypic behavior.Our study identifies a selective role for the oxytocin-MCH pathway in social recognition memory and stereotyped behavior that are relevant to psychiatric disorders such as schizophrenia and autism, and warrant further investigation of this circuit to uncover potential benefit of targeting the oxytocin-MCH circuit as a novel therapeutic target for treatment of social recognition deficits in these two disorders.

Neonatal phencyclidine and social isolation in the rat: effects of clozapine on locomotor activity, social recognition, prepulse inhibition, and executive functions deficits.

There is a need to develop animal models of schizophrenia-like behaviors that have both construct and predictive validity. Recently, a neonatal phencyclidine (PCP) and post-weaning social isolation dual-hit model was developed; however, its face and predictive validities need to be further investigated. The aims of this study were to extend the characterization of the behavioral changes occurring in the neonatal PCP and post-weaning social isolation dual-hit rat model and to evaluate the effects of chronic treatment with clozapine on signs related to schizophrenia. Male Wistar rat pups were treated with PCP (10 mg/kg s.c.) on postnatal days (PND) 7, 9, and 11. Starting from weaning, neonatal PCP-treated rat pups were socially isolated, while control saline-treated rats were group housed. At adulthood, rats were assessed using behavioral tasks evaluating locomotor activity, social recognition, prepulse inhibition, and reversal learning. Clozapine (3 mg/kg i.p.) was administered daily starting from a week before behavioral tests and until the end of the study. Neonatal PCP-treated and post-weaning social isolated (PCP-SI) rats displayed persistent and robust locomotor hyperactivity as well as social recognition impairment. The latter could not be explained by variations in the motivation to interact with a juvenile rat. Weak-to-moderate deficits in prepulse inhibition and reversal learning were also observed. Chronic treatment with clozapine attenuated the observed locomotor hyperactivity and social recognition deficits. The PCP-SI model presents enduring and robust deficits (hyperactivity and social recognition impairment) associated with positive symptoms and cognitive/social deficits of schizophrenia, respectively. These deficits are normalized by chronic treatment with clozapine, thereby confirming the predictive validity of this animal model.

Deep rTMS Mitigates Behavioral and Neuropathologic Anomalies in Cuprizone-Exposed Mice Through Reducing Microglial Proinflammatory Cytokines.

In comparison to conventional repetitive transcranial magnetic stimulation (rTMS), theta burst stimulation is stronger and more effective as a brain stimulation approach within short periods. Although this deep rTMS technique is being applied in treating neuropsychiatric disorders, few animal studies have attempted to clarify the neurobiological mechanisms underlying its beneficial effects. This animal study examined the effects of deep rTMS on the cuprizone-induced neuropathologic and behavioral anomalies and explored the underlying mechanism. Adolescent male C57BL/6 mice were fed a rodent chow without or with cuprizone (CPZ; 0.2% w/w) for 5 weeks. Another two groups of mice were subjected to deep rTMS or sham rTMS once a day during weeks 2–5 of the CPZ-feeding period. The behaviors of all mice were assessed after the withdrawal of CPZ before neuropathological and immunological analyses. Compared to the CNT group, mice in CPZ and CPZ + Sham groups showed deficits in social recognition and spatial working memory as well as anxiety-like behavior, in addition to myelin breakdown and OL loss in the corpus callosum (CC), caudate putamen, cerebral cortex, and hippocampus of the brain. Deep rTMS effectively reduced behavioral anomalies and blocked myelin breakdown and OL loss in CPZ-fed mice. Besides, it also dampened microglia activation at lesion sites and rectified cytokines levels (IL-1β, IL-6, and IL-10) in CPZ-affected regions. The most significant effect was seen in the cerebral cortex where alleviated neuropathology co-existed with less microglia activation and higher IL-10 level. These data provided experimental evidence for the beneficial effects of deep rTMS in CPZ-fed mice and revealed a neurobiological mechanism of the modality.