Deficits In Social Behavior Research Articles

Resting-state fMRI activation is associated with parent-reported phenotypic features of autism in early adolescence

IntroductionAutism Spectrum Disorder (ASD) is characterized by deficits in social cognition, self-referential processing, and restricted repetitive behaviors. Despite the established clinical symptoms and neurofunctional alterations in ASD, definitive biomarkers for ASD features during neurodevelopment remain unknown. In this study, we aimed to explore if activation in brain regions of the default mode network (DMN), specifically the medial prefrontal cortex (MPC), posterior cingulate cortex (PCC), superior temporal sulcus (STS), inferior frontal gyrus (IFG), angular gyrus (AG), and the temporoparietal junction (TPJ), during resting-state functional magnetic resonance imaging (rs-fMRI) is associated with possible phenotypic features of autism (PPFA) in a large, diverse youth cohort.MethodsWe used cross-sectional parent-reported PPFA data and youth rs-fMRI brain data as part of the two-year follow-up of the Adolescent Brain Cognitive Development (ABCD) study. Our sample consisted of 7,106 (53% male) adolescents aged 10-13. We conducted confirmatory factor analyses (CFAs) to establish the viability of our latent measurements: features of autism and regional brain activation. Structural regression analyses were used to investigate the associations between the six brain regions and the PPFA.ResultsWe found that activation in the MPC (β = .16, p < .05) and the STS (β = .08, p < .05), and being male (β = .13, p < .05), was positively associated with PPFA. In contrast, activation in the IFG (β = −.08, p < .05) was negatively associated.DiscussionOur findings suggest that regions of the “social brain” are associated with PPFA during early adolescence. Future research should characterize the developmental trajectory of social brain regions in relation to features of ASD, specifically brain regions known to mature relatively later during development.

Disrupted Hippocampal-Prefrontal Networks in a Rat Model of Fragile X Syndrome: A Study Linking Neural Dynamics to Autism-Like Behavioral Impairments.

FMR-KO and control rats underwent a battery of behavioral tests assessing sociability, memory, and anxiety. Single-unit electrophysiology recordings were then conducted to measure patterns of neural activity in H-PFC circuit. Advanced mathematical models were used to characterize the patterns that were then compared between groups using generalized linear mixed models. FMR-KO rats demonstrated significant behavioral deficits in sociability, spatial learning, and anxiety, aligning with symptoms of ASD. At the neural level, these rats exhibited abnormal firing patterns in the H-PFC circuit that is critical for learning, memory, and social behavior. The neural networks in FMR-KO rats were also less densely connected and more fragmented, particularly in hippocampal-PFC correlated firing. These findings suggest that disruptions in neural network dynamics underlie the observed behavioral impairments in FMR-KO rats. FMR-KO significantly disrupts several characteristics of action potential firing in the H-PFC network, leading to deficits in social behavior, memory, and anxiety, as seen in FXS. This disruption is characterized by less organized and less resilient hippocampal-PFC networks. These findings suggest that therapeutic strategies aimed at normalizing neural dynamics, such as with brain stimulation, could potentially improve behavior and cognitive functions in autistic individuals. Fragile X Syndrome is associated with autism, cognitive challenges and anxietyThe loss of Fmr1 protein disrupts processes involved in building neural networksThe consequence is abnormal neural dynamics in hippocampal-prefrontal cortex networksNormalization of dynamics could improve outcomes in FXS and ASD.

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

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

The Zebrafish Cerebellar Neural Circuits Are Involved in Orienting Behavior.

Deficits in social behavior are found in neurodevelopmental disorders, including autism spectrum disorders (ASDs). Since abnormalities in cerebellar morphology and function are observed in ASD patients, the cerebellum is thought to play a role in social behavior. However, it remains unknown whether the cerebellum is involved in social behavior in other animals and how cerebellar circuits control social behavior. To address this issue, we employed zebrafish stereotyped orienting behavior as a model of social behaviors, in which a pair of adult zebrafish in two separate tanks approach each other, with one swimming at synchronized angles (orienting angles) with the other. We harnessed transgenic zebrafish that express botulinum toxin, which inhibits the release of neurotransmitters, in either granule cells or Purkinje cells (PCs), and zebrafish mutants of reelin, which is involved in the positioning of cerebellar neurons, including PCs. These zebrafish, deficient in the function or formation of cerebellar neural circuits, showed a significantly shorter period of orienting behavior compared with their control siblings. We found an increase in c-fos and egr1 expression in the cerebellum after the orienting behavior. These results suggest that zebrafish cerebellar circuits play an important role in social orienting behavior.

Investigating brain–gut microbiota dynamics and inflammatory processes in an autistic-like rat model using MRI biomarkers during childhood and adolescence

Autism spectrum disorder (ASD) is characterized by social interaction deficits and repetitive behaviors. Recent research has linked that gut dysbiosis may contribute to ASD-like behaviors. However, the exact developmental time point at which gut microbiota alterations affect brain function and behavior in patients with ASD remains unclear. We hypothesized that ASD-related brain microstructural changes and gut dysbiosis induce metabolic dysregulation and proinflammatory responses, which collectively contribute to the social behavioral deficits observed in early childhood. We used an autistic-like rat model that was generated via prenatal valproic acid exposure. We analyzed brain microstructural changes using diffusion tensor imaging (DTI) and examined microbiota, blood, and fecal samples for inflammation biomarkers. The ASD model rats exhibited significant brain microstructural changes in the anterior cingulate cortex, hippocampus, striatum, and thalamus; reduced microbiota diversity (Prevotellaceae and Peptostreptococcaceae); and altered metabolic signatures. The shift in microbiota diversity and density observed at postnatal day (PND) 35, which is a critical developmental period, underscored the importance of early ASD interventions. We identified a unique metabolic signature in the ASD model, with elevated formate and reduced acetate and butyrate levels, indicating a dysregulation in short-chain fatty acid (SCFA) metabolism. Furthermore, increased astrocytic and microglial activation and elevated proinflammatory cytokines—interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α)—were observed, indicating immune dysregulation. This study provided insights into the complex interplay between the brain and the gut, and indicated DTI metrics as potential imaging-based biomarkers in ASD, thus emphasizing the need for early childhood interventions.

Alleviation of Autophagic Deficits and Neuroinflammation by Histamine H3 Receptor Antagonist E159 Ameliorates Autism-Related Behaviors in BTBR Mice

Background/Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental condition marked by social interaction difficulties, repetitive behaviors, and immune dysregulation with elevated pro-inflammatory markers. Autophagic deficiency also contributes to social behavior deficits in ASD. Histamine H3 receptor (H3R) antagonism is a potential treatment strategy for brain disorders with features overlapping ASD, such as schizophrenia and Alzheimer’s disease. Methods: This study investigated the effects of sub-chronic systemic treatment with the H3R antagonist E159 on social deficits, repetitive behaviors, neuroinflammation, and autophagic disruption in male BTBR mice. Results: E159 (2.5, 5, and 10 mg/kg, i.p.) improved stereotypic repetitive behavior by reducing self-grooming time and enhancing spontaneous alternation in addition to attenuating social deficits. It also decreased pro-inflammatory cytokines in the cerebellum and hippocampus of treated BTBR mice. In BTBR mice, reduced expression of autophagy-related proteins LC3A/B and Beclin 1 was observed, which was elevated following treatment with E159, attenuating the disruption in autophagy. The co-administration with the H3R agonist MHA (10 mg/kg, i.p.) reversed these effects, highlighting the role of histaminergic neurotransmission in observed behavioral improvements. Conclusions: These preliminary findings suggest the therapeutic potential of H3R antagonists in targeting neuroinflammation and autophagic disruption to improve ASD-like behaviors.

Social deficits mirror delayed cerebrovascular dysfunction after traumatic brain injury

Traumatic brain injury (TBI) survivors face debilitating long-term psychosocial consequences, including social isolation and depression. TBI modifies neurovascular physiology and behavior but the chronic physiological implications of altered brain perfusion on social interactions are unknown. Adult C57/BL6 male mice received a moderate cortical TBI, and social behaviors were assessed at baseline, 3-, 7-, 14-, 30-, and 60-days post injury (dpi). Magnetic resonance imaging (MRI, 9.4T) using dynamic susceptibility contrast perfusion weighted MRI were acquired. At 60dpi mice underwent histological angioarchitectural mapping. Analysis utilized standardized protocols followed by cross-correlation metrics. Social behavior deficits at 60dpi emerged as reduced interactions with a familiar cage-mate (partner) that mirrored significant reductions in cerebral blood flow (CBF) at 60dpi. CBF perturbations were dynamic temporally and across brain regions including regions known to regulate social behavior such as hippocampus, hypothalamus, and rhinal cortex. Social isolation in TBI-mice emerged with a significant decline in preference to spend time with a cage mate. Cortical vascular density was also reduced corroborating the decline in brain perfusion and social interactions. Thus, the late emergence of social interaction deficits mirrored the reduced vascular density and CBF in regions known to be involved in social behaviors. Vascular morphology and function improved prior to the late decrements in social function and our correlations strongly implicate a linkage between vascular density, cerebral perfusion, and social interactions. Our study provides a clinically relevant timeline of alterations in social deficits alongside functional vascular recovery that can guide future therapeutics.

Microglial type I interferon signaling mediates chronic stress-induced synapse loss and social behavior deficits.

Inflammation and synapse loss have been associated with deficits in social behavior and are involved in pathophysiology of many neuropsychiatric disorders. Synapse loss, characterized by reduction in dendritic spines can significantly disrupt synaptic connectivity and neural circuitry underlying social behavior. Chronic stress is known to induce loss of spines and dendrites in the prefrontal cortex (PFC), a brain region implicated in social behavior. However, the underlying mechanisms are not well understood. In the present study, we investigated the role of type I Interferon (IFN-I) signaling in chronic unpredictable stress (CUS)-induced synapse loss and behavior deficits in mice. We found increased expression of type I IFN receptor (IFNAR) in microglia following CUS. Conditional knockout of microglial IFNAR in adult mice rescued CUS-induced social behavior deficits and synapse loss. Bulk RNA sequencing data show that microglial IFNAR deletion attenuated CUS-mediated changes in the expression of genes such as Keratin 20 (Krt20), Claudin-5 (Cldn5) and Nuclear Receptor Subfamily 4 Group A Member 1 (Nr4a1) in the PFC. Cldn5 and Nr4a1 are known for their roles in synaptic plasticity. Krt20 is an intermediate filament protein responsible for the structural integrity of epithelial cells. The reduction in Krt20 following CUS presents a novel insight into the potential contribution of cytokeratin in stress-induced alterations in neuroplasticity. Overall, these results suggest that microglial IFNAR plays a critical role in regulating synaptic plasticity and social behavior deficits associated with chronic stress conditions.

Early postnatal whisker deprivation cross-modally modulates prefrontal cortex myelination and leads to social novelty deficit

Sensory experience affects not only the corresponding primary sensory cortex, but also synaptic and neural circuit functions in other brain regions in a cross-modal manner. However, it remains unclear whether oligodendrocyte (OL) generation and myelination can also undergo cross-modal modulation. Here, we report that while early life short-term whisker deprivation from birth significantly reduces in the number of mature of OLs and the degree of myelination in the primary somatosensory cortex(S1) at postnatal day 14 (P14), it also simultaneously affects the primary visual cortex (V1), but not the medial prefrontal cortex (mPFC) with a similar reduction. Interestingly, when mice were subjected to long-term early whisker deprivation from birth (P0) to P35, they exhibited dramatically impaired myelination and a deduced number of differentiated OLs in regions including the S1, V1, and mPFC, as detected at P60. Meanwhile, the process complexity of OL precursor cells (OPCs) was also rduced, as detected in the mPFC. However, when whisker deprivation occurred during the mid-late postnatal period (P35 to P50), myelination was unaffected in both V1 and mPFC brain regions at P60. In addition to impaired OL and myelin development in the mPFC, long-term early whisker-deprived mice also showed deficits in social novelty, accompanied by abnormal activation of c-Fos in the mPFC. Thus, our results reveal a novel form of cross-modal modulation of myelination by sensory experience that can lead to abnormalities in social behavioral, suggesting a possible similar mechanism underlying brain pathological conditions that suffer from both sensory and social behavioral deficits, such as autism spectrum disorders.

Examining the Role of Oxytocinergic Signaling and Neuroinflammatory Markers in the Therapeutic Effects of MDMA in a Rat Model for PTSD.

MDMA-assisted psychotherapy has shown potential as an effective treatment for post-traumatic stress disorder (PTSD). Preclinical studies involving rodents have demonstrated that MDMA can facilitate the extinction of fear memories. It has been noted that MDMA impacts oxytocin neurons and pro-inflammatory cytokines. Thus, the aim of this study was to explore the role of oxytocinergic signaling and neuroinflammatory markers in the therapeutic effects of MDMA. To achieve this, male rats were subjected to a model of PTSD involving exposure to shock and situational reminders. MDMA was microinjected into the medial prefrontal cortex (mPFC) before extinction training, followed by behavioral tests assessing activity levels, anxiety, and social function. Our findings indicate that MDMA treatment facilitated fear extinction and mitigated the shock-induced increase in freezing, as well as deficits in social behavior. Shock exposure led to altered expression of the gene coding for OXT-R and neuroinflammation in the mPFC and basolateral amygdala (BLA), which were restored by MDMA treatment. Importantly, the OXT-R antagonist L-368,899 prevented MDMA's therapeutic effects on extinction and freezing behavior. In conclusion, MDMA's therapeutic effects in the PTSD model are associated with alterations in OXT-R expression and neuroinflammation, and MDMA's effects on extinction and anxiety may be mediated by oxytocinergic signaling.

Chronic ingestion of soy peptide supplementation reduces aggressive behavior and abnormal fear memory caused by juvenile social isolation

Juvenile loneliness is a risk factor for psychopathology in later life. Deprivation of early social experience due to peer rejection has a detrimental impact on emotional and cognitive brain function in adulthood. Accumulating evidence indicates that soy peptides have many positive effects on higher brain function in rodents and humans. However, the effects of soy peptide use on juvenile social isolation are unknown. Here, we demonstrated that soy peptides reduced the deterioration of behavioral and cellular functions resulting from juvenile socially-isolated rearing. We found that prolonged social isolation post-weaning in male C57BL/6J mice resulted in higher aggression and impulsivity and fear memory deficits at 7 weeks of age, and that these behavioral abnormalities, except impulsivity, were mitigated by ingestion of soy peptides. Furthermore, we found that daily intake of soy peptides caused upregulation of postsynaptic density 95 in the medial prefrontal cortex and phosphorylation of the cyclic adenosine monophosphate response element binding protein in the hippocampus of socially isolated mice, increased phosphorylation of the adenosine monophosphate-activated protein kinase in the hippocampus, and altered the microbiota composition. These results suggest that soy peptides have protective effects against juvenile social isolation-induced behavioral deficits via synaptic maturation and cellular functionalization.

Maternal Limosilactobacillus reuteri rescues social and emotional recognition behavior in an environmental mouse model of autism

Introduction: Polybrominated diphenyl ethers (PBDEs) are thyroid disrupting chemicals with adverse neurodevelopmental effects in children. Our group has previously shown that PBDEs produce autism (ASD)-like traits (Kozlova et al. 2022 Arch Tox; PMID: 34687351) in combination with reduced hypothalamic oxytocin expression in developmentally exposed female mice offspring. Limosilactobacillus reuteri (LR) is a beneficial probiotic that can increase oxytocin and thyroid hormones (THs) in other ASD mouse models. Therefore, we hypothesized that LR would ameliorate PBDE-induced deficits in social behavior, oxytocin and thyroid status. Methods: C57BL/6N dams (n=8/group) 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) during preconception, gestation and lactation). Dams were gavaged with L. reuteri (LR) ATCC-PTA-6475 at 107-108 CFU/mL (gift of Biogaia, Sweden). Cohort 1 pups (C1) received LR via dam until weaning (PND 21). Cohort 2 pups (C2) continued to receive gavage of LR post-weaning, daily, through 6 mo of age. Results: Fecal microbiome analysis confirmed colonization of LR in dams after 25 doses and their offspring at postnatal day 22 and 40. Beta diversity PCoA using unweighted Unifrac revealed differences in microbial communities in 6 month old female (p<.05-.01) and male offspring (apparent) between DE-71 and VEH/CON (C2). LR treatment normalized DE-71-induced abnormal social novelty preference (30 min retention) in adult male (p<.01) and females (p<.05) and long-term social recognition memory (24 h retention) in adult C2 females (p<.001). Using an emotional recognition task DE-71-exposed C2 male and female offspring were unable to distinguish between emotional state of stimulus mice but LR supplementation normalized the DE-71-induced deficits in C2 males (p<.01) and females (p<.05). On a marble burying test DE-71 exposed offspring showed abnormally elevated scores compared to VEH/CON, which were normalized by LR treatment only in C1 females (p<.05). In females, maternal LR treatment ameliorated DE-71-induced locomotor hyperactivity in C1. Since social behavior involves discrimination between social odors we also investigated the effects of DE-71 and LR treatment on olfactory discrimination ability. LR treatment ameliorated DE-71 effects compared to VEH/CON, i.e., reduced dishabituation from social odor 1 to 2 in males and female (p<.0001). Single molecule in situ hybridization performed on paraventricular hypothalamic nucleus (PVN) sections revealed upregulation of thyroid hormone transporter monocarboxylate transporter 8 (Mct8) and downregulation of iodothyronine deiodinase 3 (Dio3) on oxytocin-positive neurons in DE-71 vs VEH/CON in C2 females. Dio3 expression was normalized in DE-71+LR. Conclusions: These results indicate that early life exposure to PBDEs alters thyroid hormone system genes in PVN neurons that express oxytocin, suggesting that PBDEs may alter ASD-relevant behavior via brain thyroid signaling. In addition, maternal LR supplementation provides normalization 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 and an NIH/NIGMS R35GM124724 to A.H. This is the full abstract presented at the American Physiology Summit 2024 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.

Gut microbiome is dispensable for normal respiratory function and respiratory chemoreflex

Increasing evidence indicates that gut microbiota can influence changes in respiratory homeostasis. Alterations to the gut microbiome have been hypothesized to play roles in autoimmune diseases, social behavioral deficits, and metabolic diseases such as diabetes and cardiovascular disease. We therefore aimed to determine if a model of gut dysbiosis, the absence of a gut microbiome, would result in alterations to respiratory homeostasis. After 5 days of habituation inside the Gnotobiotic animal facility, we assayed 8-week-old C57Bl/6J germ-free (GF, n=24) and specific-pathogen-free (SPF, n=24) control mice under normoxic (21% O2,79% N2) conditions, followed by a hypercapnic challenge (5% CO2, 21% O2, 74% N2) and hypoxic challenge (10% O2, 90% N2). Importantly, this germfree model does not involve treatment with high-dose antibiotics, which have been implicated in neurotoxic sequela. Whole-body flow through plethysmography was used to monitor respiratory function and metabolic demand in conscious and unrestrained animals. Recordings were interrogated using our newly published open-source software, Breathe Easy, for breath cycle duration, respiratory rate (Vf), tidal volume (VT), minute ventilation (VE), oxygen consumption (VO2), and minute ventilation normalized by oxygen consumption (VE/VO2) during room air, initial hypoxic and hypercapnic exposures, and steady-state hypoxic and hypercapnic respiratory responses. A linear mixed effects model with a Tukey post-hoc test was performed to test for significant differences wherein respiratory outcomes were dependent variables, and strain and sex were independent variables. In male mice, there was a significant decrease in breath cycle duration during room air in GF compared to SPF controls. We also saw a significant decrease in ventilatory equivalents of oxygen in the initial hypoxic response in GF mice compared to SPF controls in males, but not in the steady-state of hypoxic exposure. Finally, we note a significant increase in oxygen consumption in females during room air measurements. Of note, female mice showed significant irregularity in all respiratory parameters except oxygen consumption whereas males only showed significant irregularity in breath cycle duration during hypoxic steady-state and the hypercapnic steady-state, and tidal volume in the initial hypoxic response. While there are significant changes, it remains to be determined what the underlying mechanisms are and how they may play a contributory role in pathophysiologies co-morbid with gut microbiome dysregulation. Taken together, these results suggest that the gut microbiome is largely dispensable for normal respiratory function and respiratory chemoreflexes in adult mice and that the lack of a gut microbiome, a model of gut dysbiosis, does not result in broad significant changes in respiratory homeostasis. NIH: 1F32HL160073-01A1, R01HL130249 44617-S4. BCM McNair Scholar Program, March of Dimes Basil O'Connor Research Award, Parker B. Francis Fellowship, CJ Foundation for SIDS. This is the full abstract presented at the American Physiology Summit 2024 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.

197. Toll-Like Receptor 9 (TLR9) Inhibition Attenuates Chronic Stress-Induced Social Behavior Deficits

197. Toll-Like Receptor 9 (TLR9) Inhibition Attenuates Chronic Stress-Induced Social Behavior Deficits

Colon impairments and inflammation driven by an altered gut microbiota leads to social behavior deficits rescued by hyaluronic acid and celecoxib.

The exact mechanisms linking the gut microbiota and social behavior are still under investigation. We aimed to explore the role of the gut microbiota in shaping social behavior deficits using selectively bred mice possessing dominant (Dom) or submissive (Sub) behavior features. Sub mice exhibit asocial, depressive- and anxiety-like behaviors, as well as systemic inflammation, all of which are shaped by their impaired gut microbiota composition. An age-dependent comparative analysis of the gut microbiota composition of Dom and Sub mice was performed using 16S rRNA sequencing, from early infancy to adulthood. Dom and Sub gastrointestinal (GI) tract anatomy, function, and immune profiling analyses were performed using histology, RT-PCR, flow cytometry, cytokine array, and dextran-FITC permeability assays. Short chain fatty acids (SCFA) levels in the colons of Dom and Sub mice were quantified using targeted metabolomics. To support our findings, adult Sub mice were orally treatedwith hyaluronic acid (HA) (30 mg/kg) or with the non-steroidal anti-inflammatory agent celecoxib (16 mg/kg). We demonstrate that from early infancy the Sub mouse gut microbiota lacks essential bacteria for immune maturation, including Lactobacillus and Bifidobacterium genera. Furthermore, from birth, Sub mice possess a thicker colon mucin layer, and from early adulthood, they exhibit shorter colonic length, altered colon integrity with increased gut permeability, reduced SCFA levels and decreased regulatory T-cells, compared to Dom mice. Therapeutic intervention in adult Sub mice treated with HA, celecoxib, or both agents, rescued Sub mice phenotypes. HA treatment reduced Sub mouse gut permeability, increased colon length, and improved mouse social behavior deficits. Treatment with celecoxib increased sociability, reduced depressive- and anxiety-like behaviors, and increased colon length, and a combined treatment resulted in similar effects as celecoxib administered as a single agent. Overall, our data suggest that treating colon inflammation and decreasing gut permeability can restore gut physiology and prevent social deficits later in life. These findings provide critical insights into the importance of early life gut microbiota in shaping gut immunity, functionality, and social behavior, and may be beneficial for the development of future therapeutic strategies.

Slitrk4 is required for the development of inhibitory neurons in the fear memory circuit of the lateral amygdala.

The Slitrk family consists of six synaptic adhesion molecules, some of which are associated with neuropsychiatric disorders. In this study, we aimed to investigate the physiological role of Slitrk4 by analyzing Slitrk4 knockout (KO) mice. The Slitrk4 protein was widely detected in the brain and was abundant in the olfactory bulb and amygdala. In a systematic behavioral analysis, male Slitrk4 KO mice exhibited an enhanced fear memory acquisition in a cued test for classical fear conditioning, and social behavior deficits in reciprocal social interaction tests. In an electrophysiological analysis using amygdala slices, Slitrk4 KO mice showed enhanced long-term potentiation in the thalamo-amygdala afferents and reduced feedback inhibition. In the molecular marker analysis of Slitrk4 KO brains, the number of calretinin (CR)-positive interneurons was decreased in the anterior part of the lateral amygdala nuclei at the adult stage. In in vitro experiments for neuronal differentiation, Slitrk4-deficient embryonic stem cells were defective in inducing GABAergic interneurons with an altered response to sonic hedgehog signaling activation that was involved in the generation of GABAergic interneuron subsets. These results indicate that Slitrk4 function is related to the development of inhibitory neurons in the fear memory circuit and would contribute to a better understanding of osttraumatic stress disorder, in which an altered expression of Slitrk4 has been reported.

Effects of fluorene-9-bisphenol exposure on anxiety-like and social behavior in mice and protective potential of exogenous melatonin.

Fluorene-9-bisphenol (BHPF) is widely used in the manufacture of plastic products and potentially disrupts several physiological processes, but its biological effects on social behavior remain unknown. In this study, we investigated the effects of BHPF exposure on anxiety-like and social behavior in female mice and the potential mechanisms, thereby proposing a potential therapy strategy. We exposed female Balb/c mice to BHPF by oral gavage at different doses (0.5, 50 mg/kg bw/2-day) for 28 days, which were found BHPF (50 mg/kg) exposure affected motor activity in the open field test (OFT) and elevated cross maze (EPM), resulting in anxiety-like behaviors, as well as abnormal social behavioral deficits in the Social Interaction Test (SIT). Analysis of histopathological staining results showed that BHPF exposure caused damage to hippocampal neurons in the CA1/CA3/DG region and decreased Nissl pyramidal neurons in the CA1/CA3 regions of the hippocampus, as well as a decrease in parvalbumin neuron expression. In addition, BHPF exposure upregulated the expression of excitatory and inhibitory (E/I) vesicle transporter genes (Vglut1, Vglut2, VGAT, GAD67, Gabra) and axon growth gene (Dcc) in the mouse hippocampus. Interestingly, behavioral disturbances and E/I balance could be alleviated by exogenous melatonin (15 mg/kg bw/2-day) therapy. Our findings suggest that exogenous melatonin may be a potential therapy with protective potential for ameliorating or preventing BHPF-induced hippocampal neuronal damage and behavioral disturbances. This study provided new insight into the neurotoxicological effects on organisms exposed to endocrine-disrupting chemicals and aroused our vigilance in current environmental safety about chemical use.

Innate Immune Dysfunction and Neuroinflammation in Autism Spectrum Disorder (ASD).

Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder characterized by communication and social behavior deficits. The presence of restricted and repetitive behaviors often accompanies these deficits, and these characteristics can range from mild to severe. The past several decades have seen a significant rise in the prevalence of ASD. The etiology of ASD remains unknown; however, genetic and environmental risk factors play a role. Multiple hypotheses converge to suggest that neuroinflammation, or at least the interaction between immune and neural systems, may be involved in the etiology of some ASD cases or groups. Repeated evidence of innate immune dysfunction has been seen in ASD, often associated with worsening behaviors. This evidence includes data from circulating myeloid cells and brain resident macrophages/microglia in both human and animal models. This comprehensive review presents recent findings of innate immune dysfunction in ASD, including aberrant innate cellular function, evidence of neuroinflammation, and microglia activation. Appeared originally in Brain Behav Immun 2023; 108:245-254.

Female-specific dysfunction of sensory neocortical circuits in a mouse model of autism mediated by mGluR5 and estrogen receptor α

Little is known of the brain mechanisms that mediate sex-specific autism symptoms. Here, we demonstrate that deletion of the autism spectrum disorder (ASD)-risk gene, Pten, in neocortical pyramidal neurons (NSEPten knockout [KO]) results in robust cortical circuit hyperexcitability selectively in female mice observed as prolonged spontaneous persistent activity states. Circuit hyperexcitability in females is mediated by metabotropic glutamate receptor 5 (mGluR5) and estrogen receptor α (ERα) signaling to mitogen-activated protein kinases (Erk1/2) and de novo protein synthesis. Pten KO layer 5 neurons have a female-specific increase in mGluR5 and mGluR5-dependent protein synthesis. Furthermore, mGluR5-ERα complexes are generally elevated in female cortices, and genetic reduction of ERα rescues enhanced circuit excitability, protein synthesis, and neuron size selectively in NSEPten KO females. Female NSEPten KO mice display deficits in sensory processing and social behaviors as well as mGluR5-dependent seizures. These results reveal mechanisms by which sex and a high-confidence ASD-risk gene interact to affect brain function and behavior.

The prenatal use of agmatine prevents social behavior deficits in VPA-exposed mice by activating the ERK/CREB/BDNF signaling pathway.

According to reports, prenatal exposure to valproic acid can induce autism spectrum disorder (ASD)-like symptoms in both humans and rodents. However, the exact cause and therapeutic method of ASD is not fully understood. Agmatine (AGM) is known for its neuroprotective effects, and this study aims to explore whether giving agmatine hydrochloride before birth can prevent autism-like behaviors in mouse offspring exposed prenatally to valproic acid. In this study, we investigated the effects of AGM prenatally on valproate (VPA)-exposed mice. We established a mouse model of ASD by prenatally administering VPA. From birth to weaning, we evaluated mouse behavior using the marble burying test, open-field test, and three-chamber social interaction test on male offspring. The results showed prenatal use of AGM relieved anxiety and hyperactivity behaviors as well as ameliorated sociability of VPA-exposed mice in the marble burying test, open-field test, and three-chamber social interaction test, and this protective effect might be attributed to the activation of the ERK/CREB/BDNF signaling pathway. Therefore, AGM can effectively reduce the likelihood of offspring developing autism to a certain extent when exposed to VPA during pregnancy, serving as a potential therapeutic drug.