Serotonin (5-hydroxytryptamine; 5-HT) is thought to regulate neurodevelopmental processes through maternal-fetal interactions that have long-term mental health implications. Dogma states that beyond fetal 5-HT neurons, there are significant maternal contributions to fetal 5-HT during pregnancy1,2, but this has not been tested empirically. To examine putative central and peripheral sources of embryonic brain 5-HT, we used the Pet-1−/− mice in which most dorsal raphe (DR) neurons lack 5-HT3. Measures of 5-HT revealed previously unknown differences in accumulation between the fore- and hindbrain during early and late fetal stages, through an exogenous source of 5-HT. We show that this source is not of maternal origin. Using additional genetic strategies, a new technology for studying placental biology ex vivo, and direct manipulation of placental neosynthesis, we investigated the nature of this exogenous source and uncovered a placental 5-HT synthetic pathway from a maternal tryptophan precursor, in both mice and humans. This study reveals a new, direct role for placental metabolic pathways in modulating fetal brain development and implicates novel maternal-placental-fetal interactions that could underlie the pronounced impact of 5-HT on long-lasting mental health outcomes.

The powerful regulation of bone mass exerted by the brain suggests the existence of bone-derived signals modulating this regulation or other functions of the brain. We show here that the osteoblast-derived hormone osteocalcin crosses the blood-brain barrier, binds to neurons of the brainstem, midbrain and hippocampus, enhances the synthesis of monoamine neurotransmitters, inhibits GABA synthesis, prevents anxiety and depression and favors learning and memory independently of its metabolic functions. In addition to these post-natal functions, maternal osteocalcin crosses the placenta during pregnancy and prevents neuronal apoptosis before embryos synthesize this hormone. As a result the severity of the neuro-anatomical defects and learning and memory deficits of Osteocalcin−/− mice is determined by the maternal genotype, and delivering osteocalcin to pregnant Osteocalcin−/− mothers rescues these abnormalities in their Osteocalcin−/− progeny. This study reveals that the skeleton via osteocalcin influences cognition and contributes to the maternal influence on fetal brain development.

Modifying serotonin (5-HT) abundance in the embryonic mouse brain disrupts the precision of sensory maps formed by thalamocortical axons (TCAs), suggesting that 5-HT influences their growth. We investigated the mechanism by which 5-HT influences TCAs during development. 5-HT(1B) and 5-HT(1D) receptor expression in the fetal forebrain overlaps with that of the axon guidance receptors DCC and Unc5c. In coculture assays, axons originating from anterior and posterior halves of the embryonic day 14.5 dorsal thalamus responded differently to netrin-1, reflecting the patterns of DCC and Unc5c expression. 5-HT converts the attraction exerted by netrin-1 on posterior TCAs to repulsion. Pharmacological manipulation of 5-HT(1B/1D) receptors and intracellular cAMP showed the signaling cascade through which this modulation occurs. An in vivo correlate of altered TCA pathfinding was obtained by transient manipulation of 5-HT(1B/1D) receptor expression abundance in the dorsal thalamus by in utero electroporation. These data demonstrate that serotonergic signaling has a previously unrecognized role in the modulation of axonal responsiveness to a classic guidance cue.

Accumulating evidences suggest that serotonin (5-HT) contributes to the developmental programming of childhood- and adult-onset mental illnesses. This is thought to occur through the capacity of 5-HT to modulate developmental processes such as cell proliferation, migration and circuit wiring. For instance, genetic studies in mice show that disruption of 5-HT signaling during a restricted period of pre- and postnatal development results in long-term behavioral abnormalities such as increased anxiety in adulthood (Gaspar et al., 2003, Oberlander et al., 2009). The developmental programming of adult anxiety can be triggered either by a transient knockdown of a single 5-HT receptor [5-HT1A, (Gross et al., 2002)] or by a transient developmental exposure to specific serotonin reuptake inhibitors (SSRIs) (Ansorge et al., 2004, Ansorge et al., 2008). The recent discovery of a role for 5-HT in fetal forebrain wiring in utero (Bonnin et al., 2007, Bonnin et al., 2011) suggests a potential mechanism by which 5-HT signaling disruption can have long-term consequences on brain function. 5-HT signaling through two receptors (htr1b/1d; 5-HT1B/1D) switches the response of thalamic axons to netrin-1 from attraction to repulsion in vitro (Bonnin et al., 2007). Targeted disruption in vivo of 5-HT1B/1D receptors expression in the dorsal thalamus led to abnormal thalamocortical axons (TCAs) pathways in the internal capsule and cortex (Bonnin et al., 2007). Thus, the level 5-HT signaling through the number and/or type of 5-HT receptors activated is critical for normal brain development. The concentration of 5-HT available for receptors activation is likely another important parameter for normal brain development. We recently demonstrated that the fetal forebrain selectively accumulates placenta-derived 5-HT during the initial axon growth period (Bonnin et al., 2011). These data suggest that certain developing circuits in the fetal brain are sensitive to placental 5-HT during their initial ontogeny, which could be impacted by both genetic and environmental disturbances that are known to increase risk for mental illnesses. The role of 5-HT signaling in fetal brain wiring and the potential importance of placental metabolism in 5-HT-mediated fetal programing are discussed below.

The mechanisms linking maternal inflammation during pregnancy with increased risk of neurodevelopmental disorders in the offspring are poorly understood. In this study, we show that maternal inflammation in midpregnancy results in an upregulation of tryptophan conversion to serotonin (5-HT) within the placenta. Remarkably, this leads to exposure of the fetal forebrain to increased concentrations of this biogenic amine and to specific alterations of crucially important 5-HT-dependent neurogenic processes. More specifically, we found altered serotonergic axon growth resulting from increased 5-HT in the fetal forebrain. The data provide a new understanding of placental function playing a key role in fetal brain development and how this process is altered by adverse prenatal events such as maternal inflammation. The results uncover important future directions for understanding the early developmental origins of mental disorders.

The neurotransmitter serotonin (5-HT) plays a central role in brain development, regulation of mood, stress reactivity and risk of psychiatric disorders, and thus alterations in 5-HT signaling early in life have critical implications for behavior and mental health across the life span. Drawing on preclinical and emerging human evidence this narrative review paper will examine three key aspects when considering the consequences of early life changes in 5-HT: (1) developmental origins of variations of 5-HT signaling; (2) influence of genetic and epigenetic factors; and (3) preclinical and clinical consequences of 5-HT-related changes associated with antidepressant exposure (SSRIs). The developmental consequences of altered prenatal 5-HT signaling varies greatly and outcomes depend on an ongoing interplay between biological (genetic/epigenetic variations) and environmental factors, both pre and postnatally. Emerging evidence suggests that variations in 5-HT signaling may increase sensitivity to risky home environments, but may also amplify a positive response to a nurturing environment. In this sense, factors that change central 5-HT levels may act as ‘plasticity’ rather than ‘risk’ factors associated with developmental vulnerability. Understanding the impact of early changes in 5-HT levels offers critical insights that might explain the variations in early typical brain development that underlies behavioral risk.

Blood CD14+ monocytes are the frontline immunomodulators categorized into classical, intermediate or non-classical subsets, subsequently differentiating into M1 pro- or M2 anti-inflammatory macrophages upon stimulation. While Zika virus (ZIKV) rapidly establishes viremia, the target cells and immune responses, particularly during pregnancy, remain elusive. Furthermore, it is unknown whether African- and Asian-lineage ZIKV have different phenotypic impacts on host immune responses. Using human blood infection, we identified CD14+ monocytes as the primary target for African- or Asian-lineage ZIKV infection. When immunoprofiles of human blood infected with ZIKV were compared, a classical/intermediate monocyte-mediated M1-skewed inflammation by African-lineage ZIKV infection was observed, in contrast to a non-classical monocyte-mediated M2-skewed immunosuppression by Asian-lineage ZIKV infection. Importantly, infection of pregnant women’s blood revealed enhanced susceptibility to ZIKV infection. Specifically, Asian-lineage ZIKV infection of pregnant women’s blood led to an exacerbated M2-skewed immunosuppression of non-classical monocytes in conjunction with global suppression of type I interferon-signaling pathway and an aberrant expression of host genes associated with pregnancy complications. 30 ZIKV+ sera from symptomatic pregnant patients also showed elevated levels of M2-skewed immunosuppressive cytokines and pregnancy complication-associated fibronectin-1. This study demonstrates the differential immunomodulatory responses of blood monocytes, particularly during pregnancy, upon infection with different lineages of ZIKV.

The olfactory epithelium of the mouse has many properties that make it an ideal system for studying the molecular regulation of neurogenesis. We have used a combination of in vitro and in vivo approaches to identify three distinct stages of neuronal progenitors in the olfactory receptor neuron lineage. The neuronal stem cell, which is ultimately responsible for continual neuron renewal in this system, gives rise to a transit amplifying progenitor identified by its expression of a transcription factor, MASH1. The MASH1-expressing progenitor gives rise to a second transit amplifying progenitor, the Immediate Neuronal Precursor, which is distinct from the stem cell and MASH1-expressing progenitor, and gives rise quantitatively to olfactory receptor neurons. Regulation of progenitor cell proliferation and differentiation occurs at each of these three cell stages, and growth factors of the fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) families appear to play particularly important roles in these processes. Analyses of the actions of FGFs and BMPs reveal that negative signaling plays at least as important a role as positive signaling in the regulation of olfactory neurogenesis.