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 saline in non-obese 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.
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the Icahn School of Medicine at Mount Sinai (#08-0676, #08-0675; LA10-00398; LA12-00193; LA12-00146).
© 2016, Gacias et al.
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Microbes in the gut influence the social behaviour of mice.
Mental and behavioral disorders are associated with extended period of hot weather as found in heatwaves, but the underlying neural circuit mechanism remains poorly known. The posterior paraventricular thalamus (pPVT) is a hub for emotional processing and receives inputs from the hypothalamic preoptic area (POA), the well-recognized thermoregulation center. The present study was designed to explore whether chronic heat exposure leads to aberrant activities in POA recipient pPVT neurons and subsequent changes in emotional states. By devising an air heating paradigm mimicking the condition of heatwaves and utilizing emotion-related behavioral tests, viral tract tracing, in vivo calcium recordings, optogenetic manipulations, and electrophysiological recordings, we found that chronic heat exposure for 3 weeks led to negative emotional valence and hyperarousal states in mice. The pPVT neurons receive monosynaptic excitatory and inhibitory innervations from the POA. These neurons exhibited a persistent increase in neural activity following chronic heat exposure, which was essential for chronic heat-induced emotional changes. Notably, these neurons were also prone to display stronger neuronal activities associated with anxiety responses to stressful situations. Furthermore, we observed saturated neuroplasticity in the POA-pPVT excitatory pathway after chronic heat exposure that occluded further potentiation. Taken together, long-term aberration in the POA to pPVT pathway offers a neurobiological mechanism of emotional and behavioral changes seen in extended periods of hot weather like heatwaves.