Microglial-serotonin interactions in the developing brain.

Summary of Work Decades of research have strongly linked disruptions in the serotonin (5HT) system to mental health disorders such as depression, and social and communication difficulties. Despite this link a gap remains in understanding the etiologies of many of these disorders. Beyond its role in neurotransmission, 5HT is a critical morphogenic

signal during neurodevelopment, with known roles in cell proliferation, migration and differentiation, and in programmed cell death. We have recently determined that a maternal high saturated-fat diet (mHFD) throughout pregnancy in mice causes bacterial endotoxin accumulation in fetal placenta and brain, driving a central immune

response and leading to sex-specific behavioral abnormalities in offspring. Measurement of 5HT levels in mHFD offspring revealed a male-specific decrease in fetal brain that persisted into adulthood. Maternal dietary intervention with tryptophan (the precursor to 5HT) rescued normal brain 5HT levels and behavior only in mHFD

males. Microglia colonize the developing dorsal raphe nucleus (DRN) where 5HT cell bodies are localized starting as early as embryonic day (E)10 and thus are likely to shape this brain region as it develops. Strikingly, in male offspring only, we found that mHFD increased microglial phagocytosis of 5HT neurons in the E14.5 DRN,

whereas either restoring normal 5HT levels via tryptophan supplementation of the dam's diet or conditional knockout (cKO) of the innate immune receptor toll-like-receptor 4 (TLR4) in microglia prevents this overeating response in male microglia and restores normal behavior. These data point to microglia as a critical effector cell

between maternal inflammatory signals and subsequent neural development. Our goal is to determine the mechanisms by which microglia target 5HT cells for removal in males but not females in mHFD conditions, and to determine if maternal diet alters specific DRN circuits in males vs females underlying the different behavioral

abnormalities.