Animals coexist in commensal, pathogenic or mutualistic relationships with complex communities of diverse organisms including microbes 1 . Some bacteria produce bioactive neurotransmitters which have been proposed to modulate host nervous system activity and behaviors 2 . However, the mechanistic basis of this microbiota-brain modulation and its physiological relevance is largely unknown. Here we show that in C. elegans, the neuromodulator tyramine (TA) produced by gut-colonizing commensal Providencia bacteria can bypass the requirement for host TA biosynthesis to manipulate a host sensory decision. Bacteriallyproduced TA is likely converted to octopamine (OA) by the host tyramine beta-hydroxylase enzyme. OA, in turn, targets the OCTR-1 receptor on the ASH/ASI sensory neurons to modulate an aversive olfactory response. We identify genes required for TA biosynthesis in Providencia, and show that these genes are necessary for modulation of host behavior. We further find that C. elegans colonized by Providencia preferentially select these bacteria in food choice assays, and that this selection bias requires bacterially-produced TA. Our results demonstrate that a neurotransmitter produced by gut microbiota mimics the functions of the cognate host molecule to override host control of a sensory decision, thereby promoting fitness of both host and microbe.

Maternal immune activation (MIA) disrupts the central innate immune system during a critical neurodevelopmental period. Microglia are primary innate immune cells in the brain although their direct influence on the MIA phenotype is largely unknown. Here we show that MIA alters microglial gene expression with upregulation of cellular protrusion/neuritogenic pathways, concurrently causing repetitive behavior, social deficits, and synaptic dysfunction to layer V intrinsically bursting pyramidal neurons in the prefrontal cortex of mice. MIA increases plastic dendritic spines of the intrinsically bursting neurons and their interaction with hyper-ramified microglia. Treating MIA offspring by colony stimulating factor 1 receptor inhibitors induces depletion and repopulation of microglia, and corrects protein expression of the newly identified MIAassociated neuritogenic molecules in microglia, which coalesces with correction of MIA-associated synaptic, neurophysiological, and behavioral abnormalities. Our study demonstrates that maternal immune insults perturb microglial phenotypes and influence neuronal functions throughout adulthood, and reveals a potent effect of colony stimulating factor 1 receptor inhibitors on the correction of MIA-associated microglial, synaptic, and neurobehavioral dysfunctions.

Animals integrate external cues with information about internal conditions such as metabolic state to execute the appropriate behavioral and developmental decisions. Information about food quality and quantity is assessed by the intestine and transmitted to modulate neuronal functions via mechanisms that are not fully understood. The conserved Target of Rapamycin complex 2 (TORC2) controls multiple processes in response to cellular stressors and growth factors. Here we show that TORC2 coordinates larval development and adult behaviors in response to environmental cues and feeding state in the bacterivorous nematode C. elegans. During development, pheromone, bacterial food, and temperature regulate expression of the daf-7 TGF-β and daf-28 insulin-like peptide in sensory neurons to promote a binary decision between reproductive growth and entry into the alternate dauer larval stage. We find that TORC2 acts in the intestine to regulate neuronal expression of both daf-7 and daf-28, which together reflect bacterial-diet dependent feeding status, thus providing a mechanism for integration of food signals with external cues in the regulation of neuroendocrine gene expression. In the adult, TORC2 similarly acts in the intestine to modulate food-regulated foraging behaviors via a PDF-2/PDFR-1 neuropeptide signaling-dependent pathway. We also demonstrate that genetic variation affects food-dependent larval and adult phenotypes, and identify quantitative trait loci (QTL) associated with these traits. Together, these results suggest that TORC2 acts as a hub for communication of feeding state information from the gut to the brain, thereby contributing to modulation of neuronal function by internal state.

1Animals integrate external cues with information about internal conditions such as 2 metabolic state to execute the appropriate behavioral and developmental decisions. 3Information about food quality and quantity is assessed by the intestine and transmitted to 4 modulate neuronal functions via mechanisms that are not fully understood. The 5 conserved Target of Rapamycin complex 2 (TORC2) controls multiple processes in 6 response to cellular stressors and growth factors. Here we show that TORC2 coordinates 7 larval development and adult behaviors in response to environmental cues and feeding 8 state in the bacterivorous nematode C. elegans. During development, pheromone, 9 bacterial food, and temperature regulate expression of the daf-7 TGF-β and daf-28 10 insulin-like peptide in sensory neurons to promote a binary decision between 11 reproductive growth and entry into the alternate dauer larval stage. We find that TORC2 12 acts in the intestine to regulate neuronal expression of both daf-7 and daf-28, which 13 together reflect bacterial-diet dependent feeding status, thus providing a mechanism for 14 integration of food signals with external cues in the regulation of neuroendocrine gene 15 expression. In the adult, TORC2 similarly acts in the intestine to modulate food-regulated 16 foraging behaviors via the PDFR-1 neuropeptide receptor. We also demonstrate that 17 genetic variation affects food-dependent larval and adult phenotypes, and identify 18 quantitative trait loci (QTL) associated with these traits. Together, these results suggest 19 that TORC2 acts as a hub for communication of feeding state information from the gut to 20 the brain, thereby contributing to modulation of neuronal function by internal state. 21

The valence and salience of individual odorants are modulated by an animal’s innate preferences, learned associations, and internal state, as well as by the context of odorant presentation. The mechanisms underlying context-dependent flexibility in odor valence are not fully understood. Here, we show that the behavioral response of Caenorhabditis elegans to bacterially produced medium-chain alcohols switches from attraction to avoidance when presented in the background of a subset of additional attractive chemicals. This context-dependent reversal of odorant preference is driven by cell-autonomous inversion of the response to these alcohols in the single AWC olfactory neuron pair. We find that while medium-chain alcohols inhibit the AWC olfactory neurons to drive attraction, these alcohols instead activate AWC to promote avoidance when presented in the background of a second AWC-sensed odorant. We show that these opposing responses are driven via engagement of distinct odorant-directed signal transduction pathways within AWC. Our results indicate that context-dependent recruitment of alternative intracellular signaling pathways within a single sensory neuron type conveys opposite hedonic valences, thereby providing a robust mechanism for odorant encoding and discrimination at the periphery.