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Integration of sensory and molecular inputs from the environment shapes animal behaviour. A major site of exposure to environmental molecules is the gastrointestinal tract, in which dietary components are chemically transformed by the microbiota 1 and gut-derived metabolites are disseminated to all organs, including the brain 2 . In mice, the gut microbiota impacts behaviour 3 , modulates neurotransmitter production in the gut and brain 4 , 5 , and influences brain development and myelination patterns 6 , 7 . The mechanisms that mediate the gut–brain interactions remain poorly defined, although they broadly involve humoral or neuronal connections. We previously reported that the levels of the microbial metabolite 4-ethylphenyl sulfate (4EPS) were increased in a mouse model of atypical neurodevelopment 8 . Here we identified biosynthetic genes from the gut microbiome that mediate the conversion of dietary tyrosine to 4-ethylphenol (4EP), and bioengineered gut bacteria to selectively produce 4EPS in mice. 4EPS entered the brain and was associated with changes in region-specific activity and functional connectivity. Gene expression signatures revealed altered oligodendrocyte function in the brain, and 4EPS impaired oligodendrocyte maturation in mice and decreased oligodendrocyte–neuron interactions in ex vivo brain cultures. Mice colonized with 4EP-producing bacteria exhibited reduced myelination of neuronal axons. Altered myelination dynamics in the brain have been associated with behavioural outcomes 7 , 9 – 14 . Accordingly, we observed that mice exposed to 4EPS displayed anxiety-like behaviours, and pharmacological treatments that promote oligodendrocyte differentiation prevented the behavioural effects of 4EPS. These findings reveal that a gut-derived molecule influences complex behaviours in mice through effects on oligodendrocyte function and myelin patterning in the brain. The gut-derived molecule 4-ethylphenol influences complex behaviours in mice through effects on oligodendrocyte function and myelin patterning in the brain.

Social interactions among animals mediate essential behaviours, including mating, nurturing, and defence 1 , 2 . The gut microbiota contribute to social activity in mice 3 , 4 , but the gut–brain connections that regulate this complex behaviour and its underlying neural basis are unclear 5 , 6 . Here we show that the microbiome modulates neuronal activity in specific brain regions of male mice to regulate canonical stress responses and social behaviours. Social deviation in germ-free and antibiotic-treated mice is associated with elevated levels of the stress hormone corticosterone, which is primarily produced by activation of the hypothalamus–pituitary–adrenal (HPA) axis. Adrenalectomy, antagonism of glucocorticoid receptors, or pharmacological inhibition of corticosterone synthesis effectively corrects social deficits following microbiome depletion. Genetic ablation of glucocorticoid receptors in specific brain regions or chemogenetic inactivation of neurons in the paraventricular nucleus of the hypothalamus that produce corticotrophin-releasing hormone (CRH) reverse social impairments in antibiotic-treated mice. Conversely, specific activation of CRH-expressing neurons in the paraventricular nucleus induces social deficits in mice with a normal microbiome. Via microbiome profiling and in vivo selection, we identify a bacterial species, Enterococcus faecalis , that promotes social activity and reduces corticosterone levels in mice following social stress. These studies suggest that specific gut bacteria can restrain the activation of the HPA axis, and show that the microbiome can affect social behaviours through discrete neuronal circuits that mediate stress responses in the brain. The gut microbiota in mice can modulate social behaviour by influencing activity in stress-related brain areas.

Epidemiological evidence implicates severe maternal infections as risk factors for neurodevelopmental disorders, such as ASD and schizophrenia. Accordingly, animal models mimicking infection during pregnancy, including the maternal immune activation (MIA) model, result in offspring with neurobiological, behavioral, and metabolic phenotypes relevant to human neurodevelopmental disorders. Most of these studies have been performed in rodents. We sought to better understand the molecular signatures characterizing the MIA model in an organism more closely related to humans, rhesus monkeys (Macaca mulatta), by evaluating changes in global metabolic profiles in MIA-exposed offspring. Herein, we present the global metabolome in six peripheral tissues (plasma, cerebrospinal fluid, three regions of intestinal mucosa scrapings, and feces) from 13 MIA and 10 control offspring that were confirmed to display atypical neurodevelopment, elevated immune profiles, and neuropathology. Differences in lipid, amino acid, and nucleotide metabolism discriminated these MIA and control samples, with correlations of specific metabolites to behavior scores as well as to cytokine levels in plasma, intestinal, and brain tissues. We also observed modest changes in fecal and intestinal microbial profiles, and identify differential metabolomic profiles within males and females. These findings support a connection between maternal immune activation and the metabolism, microbiota, and behavioral traits of offspring, and may further the translational applications of the MIA model and the advancement of biomarkers for neurodevelopmental disorders such as ASD or schizophrenia.

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition with hallmark behavioral manifestations including impaired social communication and restricted repetitive behavior. In addition, many affected individuals display metabolic imbalances, immune dysregulation, gastrointestinal (GI) dysfunction, and altered gut microbiome compositions. We sought to better understand non-behavioral features of ASD by determining molecular signatures in peripheral tissues. Herein, we present the untargeted metabolome of 231 plasma and 97 fecal samples from a large cohort of children with ASD and typically developing (TD) controls. Differences in lipid, amino acid, and xenobiotic metabolism discriminate ASD and TD samples. We reveal correlations between specific metabolite profiles and clinical behavior scores, and identify metabolites particularly associated with GI dysfunction in ASD. These findings support a connection between GI physiology, metabolism, and complex behavioral traits, and may advance discovery and development of molecular biomarkers for ASD. Competing Interest Statement A.S.C., D.H.D. and S.K.M. have financial interest in Axial Biotherapeutics. A.F. has financial interest in Alba Therapeutics. G.M.P. and M.C.C. are employed by Axial Biotherapeutics. B.D.N., M.D.A., G.S., D.R.R., and P.A. report no financial conflicts of interest. Footnotes * This version of the manuscript has been updated to accurately reflect the correct middle initial of the final author.

The maintenance of genomic integrity is essential for normal cellular functions. However, it is difficult to maintain over a lifetime in postmitotic cells such as neurons, in which DNA damage increases with age and is exacerbated by multiple neurological disorders, including Alzheimer’s disease (AD). Here we used immunohistochemical staining to detect DNA double strand breaks (DSBs), the most severe form of DNA damage, in postmortem brain tissues from patients with mild cognitive impairment (MCI) or AD and from cognitively unimpaired controls. Immunostaining for γH2AX—a post-translational histone modification that is widely used as a marker of DSBs—revealed increased proportions of γH2AX-labeled neurons and astrocytes in the hippocampus and frontal cortex of MCI and AD patients, as compared to age-matched controls. In contrast to the focal pattern associated with DSBs, some neurons and glia in humans and mice showed diffuse pan-nuclear patterns of γH2AX immunoreactivity. In mouse brains and primary neuronal cultures, such pan-nuclear γH2AX labeling could be elicited by increasing neuronal activity. To assess whether pan-nuclear γH2AX represents DSBs, we used a recently developed technology, DNA damage in situ ligation followed by proximity ligation assay, to detect close associations between γH2AX sites and free DSB ends. This assay revealed no evidence of DSBs in neurons or astrocytes with prominent pan-nuclear γH2AX labeling. These findings suggest that focal, but not pan-nuclear, increases in γH2AX immunoreactivity are associated with DSBs in brain tissue and that these distinct patterns of γH2AX formation may have different causes and consequences. We conclude that AD is associated with an accumulation of DSBs in vulnerable neuronal and glial cell populations from early stages onward. Because of the severe adverse effects this type of DNA damage can have on gene expression, chromatin stability and cellular functions, DSBs could be an important causal driver of neurodegeneration and cognitive decline in this disease.

Tidal marshes are threatened coastal ecosystems known for their capacity to store large amounts of carbon in their water-logged soils. Accurate quantification and mapping of global tidal marshes soil organic carbon (SOC) stocks is of considerable value to conservation efforts. Here, we used training data from 3710 unique locations, landscape-level environmental drivers and a global tidal marsh extent map to produce a global, spatially explicit map of SOC storage in tidal marshes at 30 m resolution. Here we show the total global SOC stock to 1 m to be 1.44 Pg C, with a third of this value stored in the United States of America. On average, SOC in tidal marshes’ 0–30 and 30–100 cm soil layers are estimated at 83.1 Mg C ha −1 (average predicted error 44.8 Mg C ha −1 ) and 185.3 Mg C ha −1 (average predicted error 105.7 Mg C ha −1 ), respectively. A new study shows the total global SOC stock of 1 m in the world’s tidal marshes to be 1.44 Pg C. On average, SOC in tidal marshes’ 0–30 cm and 30–100 cm soil layers are estimated at 83.1 Mg C ha −1 and 185.3 Mg C ha −1 , respectively.

Involvement of the nervous system by human immunodeficiency virus (HIV) continues to be a serious problem. Among individuals with HIV who have a history of illicit drug use, those coinfected with hepatitis C virus (HCV) are a fast-growing population. However, few studies have assessed the penetration of HCV into the central nervous system (CNS) and its clinical and neuropathological impacts on HIV-infected individuals. For this purpose, the distribution of HCV was investigated in the brains of patients infected with HIV. The presence of HCV RNA in the CNS as detected by nested polymerase chain reaction was associated with a history of methamphetamine use, considerable antemortem cognitive impairment and abundant astrogliosis, and less-severe HIV encephalitis. HCV antigens were detected by immunoblot analysis, using heparin-purified brain samples, and HCV immunoreactivity was detected in astrocytes and in macrophage-microglial cells. The results support the hypothesis that HCV traffics into the HIV-infected brain, where it might lead to a productive coinfection associated with cognitive impairment.

Tidal marshes are threatened coastal ecosystems known for their capacity to store large amounts of carbon in their water-logged soils. Accurate quantification and mapping of global tidal marshes soil organic carbon (SOC) stocks is of considerable value to conservation efforts. Here, we used training data from 3,710 unique locations, landscape-level environmental drivers and a newly developed global tidal marsh extent map to produce the first global, spatially-explicit map of SOC storage in tidal marshes at 30 m resolution. We estimate the total global SOC stock to 1 m to be 1.44 Pg C, with a third of this value stored in the United States of America. On average, SOC in tidal marshes’ 0-30 and 30-100 cm soil layers are estimated at 83.1 Mg C ha-1 (average predicted error 44.8 Mg C ha-1) and 185.3 Mg C ha-1 (average predicted error 105.7 Mg C ha-1), respectively. Our spatially-explicit model is able to capture 59% of the variability in SOC density, with elevation being the strongest driver aside from soil depth. Our study reveals regions with high prediction uncertainty and therefore highlights the need for more targeted sampling to fully capture SOC spatial variability.