scholarly journals EphB6 regulates social behavior through gut microbiota-mediated vitamin B6 metabolism and excitation/inhibition balance of medial prefrontal cortex in mice

2019 ◽  
Author(s):  
Ying Li ◽  
Zheng-Yi Luo ◽  
Yu-Ying Hu ◽  
Yue-Wei Bi ◽  
Jian-Ming Yang ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Social Behavior ◽  
Gut Microbiota ◽  
Medial Prefrontal Cortex ◽  
Vitamin B6 ◽  
Fecal Microbiota ◽  
Autism Spectrum ◽  
Dopamine Synthesis ◽  
New Strategy ◽  
Deficient Mice

AbstractAutism spectrum disorder (ASD) is a developmental disorder with no effective pharmacological treatments so far. Gut microbiota has been suggested to contribute to autistic symptoms. However, the key genes and the mechanisms linking gut microbiota and brain dysfunctions in ASD are still unclear. Here, we found deletion of EphB6, an ASD-associated candidate gene, induced dysregulated gut microbiota and autism-like behavior in mice. More importantly, transplanting fecal microbiota from EphB6-deficient mice resulted in disturbed gut microbiota and autism-like behavior in antibiotics-treated C57BL/6J mice. Meanwhile, transplanting fecal microbiota from wild-type mice ameliorated disturbed gut microbiota and autism-like behavior in mice with deletion of EphB6. At the metabolic levels, dysregulated gut microbiota led to vitamin B6 and dopamine defects in EphB6-deficient mice. At the cellular levels, excitation/inhibition (E/I) imbalance in medial prefrontal cortex was induced by gut microbiota-mediated defects of vitamin B6 metabolism in EphB6-deficient mice. Our study uncovers a key role for EphB6 in regulation of social behavior by gut microbiota-mediated vitamin B6 metabolism, dopamine synthesis and E/I balance, suggesting a new strategy for treatment of ASD patients.

scholarly journals Gut microbiota regulates autism-like behavior by mediating vitamin B6 metabolism in EphB6-deficient mice

2020 ◽  
Author(s):  
Jian-Ming Li ◽  
Ying Li ◽  
Zheng-Yi Luo ◽  
Yu-Ying Hu ◽  
Yue-Wei Bi ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Vitamin B6 ◽  
Fecal Microbiota ◽  
Autism Spectrum ◽  
Dopamine Synthesis ◽  
Functional Link ◽  
Regulated Expression ◽  
Autistic Symptoms ◽  
Deficient Mice ◽  
New Strategies

Abstract Background Autism spectrum disorder (ASD) is a developmental disorder with limited effective pharmacological treatments for the core autistic symptoms so far. Increasing evidences, especially the clinical studies in ASD patients, suggest a functional link between gut microbiota and development of ASD. However, the mechanisms linking gut microbiota and brain dysfunctions (gut-brain axis) in ASD are still not well-established. With genetic mutations and down-regulated expression in patients with ASD, EPHB6, which is also important in homeostasis of gut, has been generally considered to be a candidate gene for ASD. Nonetheless, the role and mechanism of EPHB6 involved in regulating gut microbiota and development of ASD have been unclear. Results Here, we found deletion of EphB6 induced autism-like behavior and disturbed gut microbiota in mice. More importantly, transplanting fecal microbiota from EphB6-deficient mice resulted in autism-like behavior in antibiotics-treated C57BL/6J mice. Meanwhile, transplanting fecal microbiota from wild-type mice ameliorated autism-like behavior in EphB6-deficient mice. At the metabolic levels, disturbed gut microbiota led to vitamin B6 and dopamine defects in EphB6-deficient mice. At the cellular levels, excitation/inhibition (E/I) imbalance in medial prefrontal cortex was induced by gut microbiota-mediated defects of vitamin B6 metabolism in EphB6-deficient mice. Conclusions Our study uncovers a key role for gut microbiota in regulation of autism-like social behavior by mediating vitamin B6 metabolism, dopamine synthesis and E/I balance in EphB6-deficient mice, suggesting new strategies for understanding and treatment of ASD.

scholarly journals Gut microbiota regulates autism-like behavior by mediating vitamin B6 metabolism in EphB6-deficient mice

2020 ◽  
Author(s):  
Jian-Ming Li ◽  
Ying Li ◽  
Zheng-Yi Luo ◽  
Yu-Ying Hu ◽  
Yue-Wei Bi ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Vitamin B6 ◽  
Fecal Microbiota ◽  
Autism Spectrum ◽  
Dopamine Synthesis ◽  
Functional Link ◽  
Regulated Expression ◽  
Autistic Symptoms ◽  
Deficient Mice ◽  
New Strategies

Abstract Background Autism spectrum disorder (ASD) is a developmental disorder with limited effective pharmacological treatments for the core autistic symptoms so far. Increasing evidences, especially the clinical studies in ASD patients, suggest a functional link between gut microbiota and development of ASD. However, the mechanisms linking gut microbiota and brain dysfunctions (gut-brain axis) in ASD are still not well-established. With genetic mutations and down-regulated expression in patients with ASD, EPHB6 , which is also important in homeostasis of gut, has been generally considered to be a candidate gene for ASD. Nonetheless, the role and mechanism of EPHB6 involved in regulating gut microbiota and development of ASD have been unclear. Results Here, we found deletion of EphB6 induced autism-like behavior and disturbed gut microbiota in mice. More importantly, transplanting fecal microbiota from EphB6-deficient mice resulted in autism-like behavior in antibiotics-treated C57BL/6J mice. Meanwhile, transplanting fecal microbiota from wild-type mice ameliorated autism-like behavior in EphB6-deficient mice. At the metabolic levels, disturbed gut microbiota led to vitamin B6 and dopamine defects in EphB6-deficient mice. At the cellular levels, excitation/inhibition (E/I) imbalance in medial prefrontal cortex was induced by gut microbiota-mediated defects of vitamin B6 metabolism in EphB6-deficient mice. Conclusions Our study uncovers a key role for gut microbiota in regulation of autism-like social behavior by mediating vitamin B6 metabolism, dopamine synthesis and E/I balance in EphB6-deficient mice, suggesting new strategies for understanding and treatment of ASD.

scholarly journals The gut microbiota regulates autism-like behavior by mediating vitamin B6 homeostasis in EphB6-deficient mice

2020 ◽  
Author(s):  
Jian-Ming Li ◽  
Ying Li ◽  
Zheng-Yi Luo ◽  
Yu-Ying Hu ◽  
Yue-Wei Bi ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Vitamin B6 ◽  
Fecal Microbiota ◽  
Autism Spectrum ◽  
Cellular Level ◽  
Functional Link ◽  
Gut Homeostasis ◽  
Autistic Symptoms ◽  
Deficient Mice ◽  
New Strategies

Abstract Background Autism spectrum disorder (ASD) is a developmental disorder, and the effective pharmacological treatments for the core autistic symptoms are currently limited. Increasing evidence, particularly that from clinical studies on ASD patients, suggests a functional link between the gut microbiota and the development of ASD. However, the mechanisms linking the gut microbiota with brain dysfunctions (gut-brain axis) in ASD have not yet been full elucidated. Due to its genetic mutations and downregulated expression in patients with ASD, EPHB6, which also plays important roles in gut homeostasis, is generally considered a candidate gene for ASD. Nonetheless, the role and mechanism of EPHB6 in regulating the gut microbiota and the development of ASD are unclear.Results Here, we found that the deletion of EphB6 induced autism-like behavior and disturbed the gut microbiota in mice. More importantly, transplantation of the fecal microbiota from EphB6-deficient mice resulted in autism-like behavior in antibiotic-treated C57BL/6J mice, and transplantation of the fecal microbiota from wild-type mice ameliorated the autism-like behavior in EphB6-deficient mice. At the metabolic level, the disturbed gut microbiota in EphB6-deficient mice led to vitamin B6 and dopamine defects. At the cellular level, the excitation/inhibition (E/I) balance in the medial prefrontal cortex was regulated by gut microbiota-mediated vitamin B6 in EphB6-deficient mice.Conclusions Our study uncovers a key role for the gut microbiota in the regulation of autism-like social behavior by vitamin B6, dopamine and the E/I balance in EphB6-deficient mice, and these findings suggest new strategies for understanding and treating ASD.

scholarly journals Maternal Immune Activation Causes Social Behavior Deficits and Hypomyelination in Male Rat Offspring with an Autism-Like Microbiota Profile

2021 ◽  
Vol 11 (8) ◽  
pp. 1085
Author(s):  
Gilbert Aaron Lee ◽  
Yen-Kuang Lin ◽  
Jing-Huei Lai ◽  
Yu-Chun Lo ◽  
Yu-Chen S. H. Yang ◽  
...  
Keyword(s):  
Social Behavior ◽  
Gut Microbiota ◽  
Immune Activation ◽  
Repetitive Behavior ◽  
Fecal Microbiota ◽  
Autism Spectrum ◽  
Male Rat ◽  
Maternal Immune Activation ◽  
Rat Offspring ◽  
Microbial Dysbiosis

Maternal immune activation (MIA) increases the risk of autism spectrum disorder (ASD) in offspring. Microbial dysbiosis is associated with ASD symptoms. However, the alterations in the brain–gut–microbiota axis in lipopolysaccharide (LPS)-induced MIA offspring remain unclear. Here, we examined the social behavior, anxiety-like and repetitive behavior, microbiota profile, and myelination levels in LPS-induced MIA rat offspring. Compared with control offspring, MIA male rat offspring spent less time in an active social interaction with stranger rats, displayed more anxiety-like and repetitive behavior, and had more hypomyelination in the prefrontal cortex and thalamic nucleus. A fecal microbiota analysis revealed that MIA offspring had a higher abundance of Alistipes, Fusobacterium, and Ruminococcus and a lower abundance of Coprococcus, Erysipelotrichaies, and Actinobacteria than control offspring, which is consistent with that of humans with ASD. The least absolute shrinkage and selection operator (LASSO) method was applied to determine the relative importance of the microbiota, which indicated that the abundance of Alistipes and Actinobacteria was the most relevant for the profile of defective social behavior, whereas Fusobacterium and Coprococcus was associated with anxiety-like and repetitive behavior. In summary, LPS-induced MIA offspring showed an abnormal brain–gut–microbiota axis with social behavior deficits, anxiety-like and repetitive behavior, hypomyelination, and an ASD-like microbiota profile.

scholarly journals Fecal Microbiota Transplantation: A New Therapeutic Attempt from the Gut to the Brain

2021 ◽  
Vol 2021 ◽  
pp. 1-20
Author(s):  
Hao-Ming Xu ◽  
Hong-Li Huang ◽  
You-Lian Zhou ◽  
Hai-Lan Zhao ◽  
Jing Xu ◽  
...  
Keyword(s):  
Nervous System ◽  
Gut Microbiota ◽  
Fecal Microbiota Transplantation ◽  
Fecal Microbiota ◽  
Autism Spectrum ◽  
Recurrent Clostridium Difficile Infection ◽  
New Strategy ◽  
Cerebral Diseases ◽  
The Brain

Gut dysbacteriosis is closely related to various intestinal and extraintestinal diseases. Fecal microbiota transplantation (FMT) is a biological therapy that entails transferring the gut microbiota from healthy individuals to patients in order to reconstruct the intestinal microflora in the latter. It has been proved to be an effective treatment for recurrent Clostridium difficile infection. Studies show that the gut microbiota plays an important role in the pathophysiology of neurological and psychiatric disorders through the microbiota-gut-brain axis. Therefore, reconstruction of the healthy gut microbiota is a promising new strategy for treating cerebral diseases. We have reviewed the latest research on the role of gut microbiota in different nervous system diseases as well as FMT in the context of its application in neurological, psychiatric, and other nervous system-related diseases (Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, epilepsy, autism spectrum disorder, bipolar disorder, hepatic encephalopathy, neuropathic pain, etc.).

scholarly journals The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota

Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Patricia Bermudez-Martin ◽  
Jérôme A. J. Becker ◽  
Nicolas Caramello ◽  
Sebastian P. Fernandez ◽  
Renan Costa-Campos ◽  
...  
Keyword(s):  
Social Behavior ◽  
Fecal Microbiota Transplantation ◽  
Fecal Microbiota ◽  
Autism Spectrum ◽  
Dopamine Neurons ◽  
Therapeutic Interventions ◽  
Microbiota Composition ◽  
Microbial Metabolite ◽  
Central Dopamine Neurons ◽  
Induced Changes

Abstract Background Autism spectrum disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis, changes in microbiota composition as well as in the fecal, serum, and urine levels of microbial metabolites. Yet a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite p-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice. Results Mice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, p-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol excretion, compared to mice transplanted with the microbiota of control mice. In addition, we identified possible p-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability, and fecal p-Cresol levels when transplanted to p-Cresol-treated mice. Conclusions The microbial metabolite p-Cresol induces selectively ASD core behavioral symptoms in mice. Social behavior deficits induced by p-Cresol are dependant on changes in microbiota composition. Our study paves the way for therapeutic interventions targeting the microbiota and p-Cresol production to treat patients with ASD.

The Role of the Medial Prefrontal Cortex in Moderating Neural Representations of Self and Other in Primates

2021 ◽  
Vol 44 (1) ◽  
Author(s):  
Masaki Isoda
Keyword(s):  
Prefrontal Cortex ◽  
Medial Prefrontal Cortex ◽  
Critical Role ◽  
Autism Spectrum ◽  
Annual Review ◽  
Publication Date ◽  
Self And Other ◽  
Neural Representations ◽  
The Social

As a frontal node in the primate social brain, the medial prefrontal cortex (MPFC) plays a critical role in coordinating one's own behavior with respect to that of others. Current literature demonstrates that single neurons in the MPFC encode behavior-related variables such as intentions, actions, and rewards, specifically for self and other, and that the MPFC comes into play when reflecting upon oneself and others. The social moderator account of MPFC function can explain maladaptive social cognition in people with autism spectrum disorder, which tips the balance in favor of self-centered perspectives rather than taking into consideration the perspective of others. Several strands of evidence suggest a hypothesis that the MPFC represents different other mental models, depending on the context at hand, to better predict others’ emotions and behaviors. This hypothesis also accounts for aberrant MPFC activity in autistic individuals while they are mentalizing others. Expected final online publication date for the Annual Review of Neuroscience, Volume 44 is July 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Mar Gacias ◽  
Sevasti Gaspari ◽  
Patricia-Mae G Santos ◽  
Sabrina Tamburini ◽  
Monica Andrade ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prefrontal Cortex ◽  
Social Behavior ◽  
Gut Microbiota ◽  
Nod Mice ◽  
Mouse Strains ◽  
Social Avoidance ◽  
Nonobese Diabetic ◽  
Gene Environment ◽  
Transcriptional Changes

Gene-environment interactions impact the development of neuropsychiatric disorders, but the relative contributions are unclear. Here, we identify gut microbiota as sufficient to induce depressive-like behaviors in genetically distinct mouse strains. Daily gavage of vehicle (dH2O) in nonobese diabetic (NOD) mice induced a social avoidance behavior that was not observed in C57BL/6 mice. This was not observed in NOD animals with depleted microbiota via oral administration of antibiotics. Transfer of intestinal microbiota, including members of the Clostridiales, Lachnospiraceae and Ruminococcaceae, from vehicle-gavaged NOD donors to microbiota-depleted C57BL/6 recipients was sufficient to induce social avoidance and change gene expression and myelination in the prefrontal cortex. Metabolomic analysis identified increased cresol levels in these mice, and exposure of cultured oligodendrocytes to this metabolite prevented myelin gene expression and differentiation. Our results thus demonstrate that the gut microbiota modifies the synthesis of key metabolites affecting gene expression in the prefrontal cortex, thereby modulating social behavior.

scholarly journals Effects of cross-rearing with social peers on myelination in the medial prefrontal cortex of a mouse model with autism spectrum disorder

Heliyon ◽  
2017 ◽  
Vol 3 (11) ◽  
pp. e00468 ◽  
Author(s):  
Manabu Makinodan ◽  
Kazuki Okumura ◽  
Daisuke Ikawa ◽  
Yasunori Yamashita ◽  
Kazuhiko Yamamuro ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Prefrontal Cortex ◽  
Mouse Model ◽  
Medial Prefrontal Cortex ◽  
Autism Spectrum ◽  
Spectrum Disorder

scholarly journals Maternal Separation Modifies the Activity of Social Processing Brain Nuclei Upon Social Novelty Exposure

2021 ◽  
Vol 15 ◽  
Author(s):  
Sara Mejía-Chávez ◽  
Arturo Venebra-Muñoz ◽  
Fabio García-García ◽  
Aleph Alejandro Corona-Morales ◽  
Arturo Enrique Orozco-Vargas
Keyword(s):  
Prefrontal Cortex ◽  
Nucleus Accumbens ◽  
Social Behavior ◽  
Medial Prefrontal Cortex ◽  
Paraventricular Nucleus ◽  
Maternal Separation ◽  
Lateral Septum ◽  
Medial Amygdala ◽  
Physiological Basis ◽  
Brain Nuclei

Maternal separation has been shown to disrupt proper brain development and maturation, having profound consequences on the neuroendocrine systems in charge of the stress response, and has been shown to induce behavioral and cognitive abnormalities. At the behavioral level, maternal separation has been shown to increase offensive play-fighting in juvenile individuals and reduce social interest in adulthood. Since most of the studies that have evaluated the consequences of maternal separation on social behavior have focused on behavioral analysis, there is a need for a further understanding of the neuronal mechanisms underlying the changes in social behavior induced by maternal separation. Therefore, the aim of the present research was to assess the long-term effects of maternal separation on social interaction behavior and to assess the activity of several brain regions involved in the processing of social cues and reward upon social novelty exposure, using c-Fos immunohistochemistry as a marker of neuronal activity. Male Wistar rats were subjected to 4 h maternal separation during the neonatal period, 9:00 h–13:00 h from postnatal day 1 to 21, and exposed to social novelty during adulthood. After social novelty exposure, brains were fixed and coronal sections of the medial amygdala, lateral septum (LS), paraventricular nucleus of the hypothalamus, nucleus accumbens, and medial prefrontal cortex were obtained for c-Fos immunohistochemistry. Maternally separated rats spent less time investigating the novel peer, suggesting that maternal separation reduces social approach motivation. Furthermore, maternal separation reduced the number of c-Fos positive cells of the medial amygdala, paraventricular nucleus of the hypothalamus, LS, nucleus accumbens, and medial prefrontal cortex upon social novelty exposure. These findings suggest that maternal separation can reduce the plastic capacity of several brain nuclei, which constitute a physiological basis for the emergence of behavioral disorders presented later in life reported to be linked to early life adversity.

Sign in / Sign up

Export Citation Format

Share Document