Project Summary More than 50% of women in the United States are overweight or obese when they become pregnant. Maternal high-fat diet (HFD) and obesity create an environment of chronic inflammation and are associated with a range of detrimental outcomes for offspring, including metabolic dysregulation and increased susceptibility to psychiatric disorders such as autism spectrum disorder, anxiety, and depression. Despite these observations, many studies are correlative and do not propose a mechanism through which maternal HFD or obesity contribute to psychiatric disorder development in the offspring. The placenta acts as a critical interface between the maternal environment and the developing fetal brain, and as such is uniquely poised to translate maternal insults into neural outcomes in offspring. The placenta is the primary source of serotonin for the fetal forebrain during mid-gestation, and decreased serotonin signaling is correlated with increased vulnerability to stress in rodents. Importantly, serotonin levels can be decreased in the context of inflammation, and we hypothesize that placental inflammation induced by maternal HFD may reduce placental serotonin levels thus altering the development of the central serotonin system and causing serotonin circuit-dependent behavior changes in mice. Preliminarily, we see that maternal HFD increases placental inflammation particularly in males. Increased placental inflammation in males is correlated with decreased placental and fetal forebrain serotonin levels. Moreover, male maternal HFD offspring also display behavior alterations consistent with disrupted central serotonin circuit function. Therefore, in Aim 1, I will determine if maternal HFD-induced serotonin deficiency is causal to male-specific behavior changes. Building upon this, I will then use a mouse model incapable of producing a pro-inflammatory response in placental macrophages to asses if maternal HFD-induced perinatal inflammation is causal to (i) male-specific serotonin deficiency and (ii) serotonin-circuit relevant behavior changes. Finally, I will address a possible mechanism through which maternal HFD affects the central serotonin system. Previous studies have suggested that microglia regulate neural development and behavioral outcomes, and that the number and activation state of microglia in utero influences microglia phagocytosis of neuronal progenitors. This has not been explored in the context of serotonergic neuronal progenitors. Therefore, I will assess if microglia phagocytosis of serotonin neurons is increased in maternal HFD offspring, and whether this results in decreased serotonin levels in the forebrain thus influencing maternal HFD-dependent neurological outcomes. I expect this project to result in several novel findings by bridging three bodies of research that are only beginning to collaborate: (i) the contribution of maternal HFD to sex-biased psychiatric disorder development, (ii) the role of the placenta in ne...