Integration of sensory and molecular inputs from the environment shapes animal behavior. A major site of exposure to environmental molecules is the gastrointestinal tract, where 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 behavior 3 , modulates neurotransmitter production in the gut and brain 4,5 , and influences brain development and myelination patterns 6,7 . Mechanisms mediating gut-brain interactions remain poorly defined, though broadly involve humoral or neuronal connections. We previously reported that levels of the microbial metabolite 4-ethylphenyl sulfate (4EPS) were elevated in a mouse model of atypical neurodevelopment 8 . Herein, we identified biosynthetic genes from the gut microbiome that mediate 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 as well as 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 behavioral outcomes 7,[9][10][11][12][13][14]13,14 . Accordingly, we observed that mice exposed to 4EPS displayed anxiety-like behaviors, and pharmacologic treatments that promote oligodendrocyte differentiation prevented the behavioral effects of 4EPS. These findings reveal that a gut-derived molecule influences complex behaviors in mice via effects on oligodendrocyte function and myelin patterning in the brain.

A spontaneous monoamine oxidase A (MAO A) mutation (A863T) in exon 8 introduced a premature stop codon, which produced MAO A/B double knock-out (KO) mice in a MAO B KO mouse colony. This mutation caused a nonsense-mediated mRNA decay and resulted in the absence of MAO A transcript, protein, and catalytic activity and abrogates a DraI restriction site. The MAO A/B KO mice showed reduced body weight compared with wild type mice. Brain levels of serotonin, norepinephrine, dopamine, and phenylethylamine increased, and serotonin metabolite 5-hydroxyindoleacetic acid levels decreased, to a much greater degree than in either MAO A or B single KO mice. Observed chase/ escape and anxiety-like behavior in the MAO A/B KO mice, different from MAO A or B single KO mice, suggest that varying monoamine levels result in both a unique biochemical and behavioral phenotype. These mice will be useful models for studying the molecular basis of disorders associated with abnormal monoamine neurotransmitters. (21), indicating that the increase in 5-HT, a preferred substrate for MAO A, and concomitant decrease in 5-HIAA may form the basis for increased aggression, consistent with the association of low 5-HIAA levels in the cerebrospinal fluid of men who exhibit aggressive behavior (22,23). Although increased aggressive behavior has not been observed in MAO B KO mice (21), low platelet MAO B activity in humans is associated with, and considered a marker for, criminal or impulsive behavior (24), although whether this is accompanied in human subjects by a concomitant decrease in MAO A activity or other related genetic or biochemical aberration is not known.MAO A/B KO mice cannot be generated through the breeding of MAO A KO and MAO B KO mice, due to the close proximity of the isoenzyme genes on the X chromosomes, where the two genes are next to each other at their 3Ј tails, organized in opposite orientations with their last exons being less than 24 kb apart (determined by blat analysis of human and mouse MAO A and B

Epidemiological and clinical trials have suggested that exercise is beneficial for patients with Parkinson’s disease (PD). However, the underlying mechanisms and potential for disease modification are currently unknown. This review presents current findings from our laboratories in patients with PD and animal models. The data indicate that alterations in both dopaminergic and glutamatergic neurotransmission, induced by activity-dependent (exercise) processes, may mitigate the cortically driven hyper-excitability in the basal ganglia normally observed in the parkinsonian state. These insights have potential to identify novel therapeutic treatments capable of reversing or delaying disease progression in PD.