A role for adverse childhood experiences and depression in preeclampsia.

Introduction: Adverse childhood experiences (ACEs) are a measure of childhood adversity and are associated with life-long morbidity. The impacts of ACEs on peripartum health including preeclampsia, a common and dangerous hypertensive disorder of pregnancy, remain unclear, however. Therefore, we aimed to determine ACE association with peripartum psychiatric health and prevalence of preeclampsia using a case-control design. Methods: Clinical data were aggregated and validated using a large, intergenerational knowledgebase developed at our institution. Depression symptoms were measured by standard clinical screeners: the Patient Health Questionnaire-9 (PHQ-9) and the Edinburgh Postnatal Depression Scale (EPDS). ACEs were assessed via survey. Scores were compared between participants with (N = 32) and without (N = 46) prior preeclampsia. Results: Participants with ACE scores ≥4 had significantly greater odds of preeclampsia than those with scores ≤ 3 (adjusted odds ratio = 6.71, 95% confidence interval:1.13-40.00; p = 0.037). Subsequent speculative analyses revealed that increased odds of preeclampsia may be driven by increased childhood abuse and neglect dimensions of the ACE score. PHQ-9 scores (3.73 vs. 1.86, p = 0.03), EPDS scores (6.38 vs. 3.71, p = 0.01), and the incidence of depression (37.5% vs. 23.9%, p = 0.05) were significantly higher in participants with a history of preeclampsia versus controls. Conclusions: Childhood sets the stage for life-long health. Our findings suggest that ACEs may be a risk factor for preeclampsia and depression, uniting the developmental origins of psychiatric and obstetric risk.

The role of the placenta-brain axis in psychoneuroimmune programming.

Gestational exposures have enduring impacts on brain and neuroimmune development and function. Perturbations of pregnancy leading to placental structure/function deficits, cell stress, immune activation, and endocrine changes (metabolic, growth factors, etc.) all increase neuropsychiatric risk in offspring. The existing literature links obstetric diseases with placental involvement to offspring neuroimmune outcomes and neurodevelopmental risk. Psychoneuroimmune outcomes in offspring brain include changes to microglia, cytokine/chemokine production, cell stress, and long-term immunoreactivity. These outcomes are altered by structural, anti-angiogenic/hypoxic, inflammatory, and metabolic diseases of the placenta. This fetal programming occurs via direct placental passage or production of factors which can act directly on fetal brain substrates, or indirectly via action of circulating factors on intermediates in the placenta. Placental neuroendocrine, vascular/angiogenic, immune, and extracellular vesicular mechanisms are detailed. These mechanisms interact within various placental and pregnancy conditions. An increased understanding of the placental origins of psychoneuroimmunology will yield dividends for human health. Identifying maternal and placental biomarkers for fetal neuroimmune health may also revolutionize early diagnosis and precision psychiatry, empowering patients to make the best healthcare decisions for their families. Targeting placental mechanisms may be a valuable approach for the prevention and mitigation of intergenerational, lifelong neuropathology.

Alpha-Synuclein Pre-Formed Fibrils Injected into Prefrontal Cortex Primarily Spread to Cortical and Subcortical Structures.

BACKGROUND: Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are characterized by diffuse spread of alpha-synuclein (α-syn) throughout the brain. Patients with PDD and DLB have a neuropsychological pattern of deficits that include executive dysfunction, such as abnormalities in planning, timing, working memory, and behavioral flexibility. The prefrontal cortex (PFC) plays a major role in normal executive function and often develops α-syn aggregates in DLB and PDD. OBJECTIVE: To investigate the long-term behavioral and cognitive consequences of α-syn pathology in the cortex and characterize pathological spread of α-syn. METHODS: We injected human α-syn pre-formed fibrils into the PFC of wild-type male mice. We then assessed the behavioral and cognitive effects between 12- and 21-months post-injection and characterized the spread of pathological α-syn in cortical, subcortical, and brainstem regions. RESULTS: We report that PFC PFFs: 1) induced α-syn aggregation in multiple cortical and subcortical regions with sparse aggregation in midbrain and brainstem nuclei; 2) did not affect interval timing or spatial learning acquisition but did mildly alter behavioral flexibility as measured by intraday reversal learning; and 3) increased open field exploration. CONCLUSIONS: This model of cortical-dominant pathology aids in our understanding of how local α-syn aggregation might impact some symptoms in PDD and DLB.

Low indoleamine 2, 3 dioxygenase (IDO) activity is associated with psycho-obstetric risk.

OBJECTIVES: Preeclampsia and depression in pregnancy are among the most prevalent obstetric disorders with no known cures. While depression and preeclampsia each increase risk for the other, shared mechansisms are unclear. One possibility is low levels of Indoleamine 2,3 dioxygenase (IDO), which links immune dysregulation and oxidative arterial damage resulting in poor vascular function in both preeclampsia and depression. We hypothesized low circulating IDO activity levels in pregnancy would correspond to poor vascular function and depression symptoms. STUDY DESIGN: In this nested case-control study, clinical, demographic, and biologic data from a cohort of pregnant women recruited to longitudinal studies measuring noninvasive vascular function and circulating factors were analyzed. MAIN OUTCOME MEASURE: IDO activity across all three trimesters of pregnancy was measured using a colorimetric assay. Carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, was also assessed throughout gestation by non-invasive applanation tonometry. Depression symptoms were assessed in pregnancy via the validated patient health questionnaire 9 (PHQ9). RESULTS: Participants with low second and third trimester IDO activity had significantly decreased cfPWV. This association remained statistically significant when controlled for confounders such as BMI and chronic hypertension in the third but not second trimester. While PHQ9 scores were not associated with cfPWV differences, IDO activity was lower in moderate and severely depressed relative to non-depressed pregnant individuals. CONCLUSION: These results implicate IDO in arterial stiffness and depression symptoms, suggesting that decreased IDO may be a central target for improved psycho-obstetric health.

Anti-angiogenic mechanisms and serotonergic dysfunction in the Rgs2 knockout model for the study of psycho-obstetric risk.

Psychiatric and obstetric diseases are growing threats to public health and share high rates of co-morbidity. G protein-coupled receptor signaling (e.g., vasopressin, serotonin) may be a convergent psycho-obstetric risk mechanism. Regulator of G Protein Signaling 2 (RGS2) mutations increase risk for both the gestational disease preeclampsia and for depression. We previously found preeclampsia-like, anti-angiogenic obstetric phenotypes with reduced placental Rgs2 expression in mice. Here, we extend this to test whether conserved cerebrovascular and serotonergic mechanisms are also associated with risk for neurobiological phenotypes in the Rgs2 KO mouse. Rgs2 KO exhibited anxiety-, depression-, and hedonic-like behaviors. Cortical vascular density and vessel length decreased in Rgs2 KO; cortical and white matter thickness and cell densities were unchanged. In Rgs2 KO, serotonergic gene expression was sex-specifically changed (e.g., cortical Htr2a, Maoa increased in females but all serotonin targets unchanged or decreased in males); redox-related expression increased in paraventricular nucleus and aorta; and angiogenic gene expression was changed in male but not female cortex. Whole-cell recordings from dorsal raphe serotonin neurons revealed altered 5-HT1A receptor-dependent inhibitory postsynaptic currents (5-HT1A-IPSCs) in female but not male KO neurons. Additionally, serotonin transporter blockade by the SSRI sertraline increased the amplitude and time-to-peak of 5-HT1A-IPSCs in KO neurons to a greater extent than in WT neurons in females only. These results demonstrate behavioral, cerebrovascular, and sertraline hypersensitivity phenotypes in Rgs2 KOs, some of which are sex-specific. Disruptions may be driven by vascular and cell stress mechanisms linking the shared pathogenesis of psychiatric and obstetric disease to reveal future targets.

Circulating microparticle proteins predict pregnancies complicated by placenta accreta spectrum.

Placenta accreta spectrum (PAS) is characterized by abnormal attachment of the placenta to the uterus, and attempts at placental delivery can lead to catastrophic maternal hemorrhage and death. Multidisciplinary delivery planning can significantly improve outcomes; however, current diagnostics are lacking as approximately half of pregnancies with PAS are undiagnosed prior to delivery. This is a nested case-control study of 35 cases and 70 controls with the primary objective of identifying circulating microparticle (CMP) protein panels that identify pregnancies complicated by PAS. Size exclusion chromatography and liquid chromatography with tandem mass spectrometry were used for CMP protein isolation and identification, respectively. A two-step iterative workflow was used to establish putative panels. Using plasma sampled at a median of 26 weeks' gestation, five CMP proteins distinguished PAS from controls with a mean area under the curve (AUC) of 0.83. For a separate sample taken at a median of 35 weeks' gestation, the mean AUC was 0.78. In the second trimester, canonical pathway analyses demonstrate over-representation of processes related to iron homeostasis and erythropoietin signaling. In the third trimester, these analyses revealed abnormal immune function. CMP proteins classify PAS well prior to delivery and have potential to significantly reduce maternal morbidity and mortality.

Effects of maternal hypertension on cord blood Arginine vasopressin receptor expression.

Arginine vasopressin (AVP) signaling is altered in preeclampsia and physiologic stress. AVP is implicated in fluid homeostasis and cardiovascular (CV) function, which is disrupted in some progeny from preeclamptic pregnancies. However, whether altered fetal AVP signaling occurs in preeclampsia is unknown. Here, we measured CV-related transcripts (e.g., AVP receptors) in cord blood via quantitative PCR. Chronic hypertension decreased AVPR1b, AVPR2, OXTR, LNPEP, and CUL5. AVPR1a, AVPR1b, and AVPR2 were decreased while OXTR was increased in preeclamptic cord blood. In sum, we found prenatal exposure to hypertension in pregnancy alters fetal AVP signaling and may thereby prime offspring CV disease risk.

Selective serotonin reuptake inhibitors and preeclampsia: A quality assessment and meta-analysis.

Serotonin modulates vascular, immune, and neurophysiology and is dysregulated in preeclampsia. Despite biological plausibility that selective serotonin reuptake inhibitors (SSRIs) prevent preeclampsia pathophysiology, observational studies have indicated increased risk and providers may be hesitant. The objective of this meta-analysis and quality assessment was to evaluate the evidence linking SSRI use in pregnancy to preeclampsia/gestational hypertension. PubMed was searched through June 5, 2020 manually and using combinations of terms: "preeclampsia", "serotonin", and "SSRI". This review followed MOOSE guidelines. Inclusion criteria were: 1) Observational cohort or population study, 2) exposure defined as SSRI use during pregnancy, 3) cases defined as preeclampsia or gestational hypertension, and 4) human participants. Studies were selected that addressed the hypothesis that gestational SSRI use modulates preeclampsia and/or gestational hypertension risk. Review Manager Web was used to synthesize study findings. Articles were read and scored (Newcastle-Ottawa Quality Assessment Scale) for quality by two independent reviewers. Publication bias was assessed using a funnel plot and the Egger test. Of 179 screened studies, nine were included. The pooled risk ratio (random effects model) was 1.43 (95 % CI: 1.15-1.78, P < 0.001; range 0.96-4.86). Two studies were rated as moderate quality (both with total score of 6); others were high quality. Heterogeneity was high (I2 = 88 %) and funnel asymmetry was significant (p < 0.00001). Despite evidence for increased preeclampsia risk with SSRIs, shared risk factors and other variables are poorly controlled. Depression treatment should not be withheld due to perceived gestational hypertension risk. Mechanistic evidence for serotonin modulation in preeclampsia demonstrates a need for future research.

Dataset describing maternal prenatal restraint stress effects on immune factors in mice.

Maternal immune dysregulation, caused by gestational psychological stress, infection, and other perturbations, results in altered offspring neurodevelopment and increases risk for psychiatric disorders. Prior work has found that multiple cytokines play critical roles in shaping offspring neurodevelopment after gestational stress, though how maternal psychological stress impacts maternal, placental, and fetal cytokine levels more broadly remains unclear. The purpose of the present study was to assess changes to IL-1ß, IL-2, IL-4, IL-6, IL-10, IL-17A, IFNγ, and TNFα in a widely-used mouse prenatal restraint stress model. After repetitive restraint stress on gestational days 12-14, stressed dams had increased serum levels of IL-1ß, IL-6, and IL-10. Embryonic day 14 IL-2 and IL-1ß levels were decreased in prenatally stressed male fetal forebrain, while placental IL-2 was decreased by stress regardless of offspring sex. Placental and fetal forebrain IL-2 levels were negatively correlated. These data provide important insights into the immune changes that occur with prenatal restraint stress.

Group B Streptococcus Screening and Treatment Adherence in Pregnancy: A Retrospective Cohort Study and Opportunities for Improvement.

Introduction: Pregnancy is a time of increased healthcare screening, and past adherence to evolving guidelines informs best practices. Although studies of Group B Streptococcus guideline adherence have focused primarily on treatment of Group B Streptococcus carriers, this study broadly evaluated long-term adherence to both Group B Streptococcus screening and treatment guidelines. Adherence was evaluated across provider types (obstetrics and gynecology, certified nurse midwives, and family medicine). Methods: We conducted a retrospective cohort study. Demographic and clinical information were extracted from all prenatal care and delivery patients at a single institution in a single year. Vancomycin prescriptions in pregnancy were tracked for 10 years to determine long-term adherence. Adherence was defined as no deviation from 2010 Group B Streptococcus screening and treatment guidelines. Results: Adherence occurred in 89% (1,610/1,810) of patients. Reasons for deviations from guidelines could not always be determined. There was no significant difference in maternal age, race, prenatal provider type, provider type at delivery, gestational age at delivery, delivery mode, or whether antibiotic sensitivities were performed between compliant and noncompliant groups. Significant differences in adherence were found between obstetric clinics (high-risk obstetrics clinic, maternal‒fetal medicine fellows clinic, continuity of care clinic, and faculty private clinic) (p<0.0001) and between the faculty family medicine clinic and resident family medicine clinic (p=0.001). Vancomycin prescription practice did not change significantly over the10-year period. Conclusions: High rates of adherence to Group B Streptococcus screening and treatment guidelines in pregnancy have positive implications for reducing antibiotic resistance. Given evolving guidelines, there is a need to periodically evaluate adherence and to re-educate providers about standard practices and best documentation practices.

The Serotonin-Immune Axis in Preeclampsia.

PURPOSE OF REVIEW: To review the literature and detail the potential immune mechanisms by which hyperserotonemia may drive pro-inflammation in preeclampsia and to provide insights into potential avenues for therapeutic discovery. RECENT FINDINGS: Preeclampsia is a severe hypertensive complication of pregnancy associated with significant maternal and fetal risk. Though it lacks any effective treatment aside from delivery of the fetus and placenta, recent work suggests that targeting serotonin systems may be one effective therapeutic avenue. Serotonin dysregulation underlies multiple domains of physiologic dysfunction in preeclampsia, including vascular hyporeactivity and excess platelet aggregation. Broadly, serotonin is increased across maternal and placental domains, driven by decreased catabolism and increased availability of tryptophan precursor. Pro-inflammation, another hallmark of the disease, may drive hyperserotonemia in preeclampsia. Interactions between immunologic dysfunction and hyperserotonemia in preeclampsia depend on multiple mechanisms, which we discuss in the present review. These include altered immune cell, kynurenine pathway metabolism, and aberrant cytokine production mechanisms, which we detail. Future work may leverage animal and in vitro models to reveal serotonin targets in the context of preeclampsia's immune biology, and ultimately to mitigate vascular and platelet dysfunction in the disease. Hyperserotonemia in preeclampsia drives pro-inflammation via metabolic, immune cell, and cytokine-based mechanisms. These immune mechanisms may be targeted to treat vascular and platelet endophenotypes in preeclampsia.

Altered offspring neurodevelopment in an arginine vasopressin preeclampsia model.

Preeclampsia is a severe gestational hypertensive condition linked to child neuropsychiatric disorders, although underlying mechanisms are unclear. We used a recently developed, clinically relevant animal model of preeclampsia to assess offspring. C57BL/6J mouse dams were chronically infused with arginine vasopressin (AVP) or saline (24 ng/h) throughout pregnancy. Adult offspring were behaviorally tested (Y-maze, open field, rotarod, social approach, and elevated plus maze). Offspring brain was assessed histologically and by RNA sequencing. Preeclampsia-exposed adult males exhibited increased anxiety-like behavior and social approach while adult females exhibited impaired procedural learning. Adult AVP-exposed males had reduced total neocortical volume. Adult AVP-exposed females had increased caudate-putamen volume, increased caudate-putamen cell number, and decreased excitatory synapse density in hippocampal dentate gyrus (DG), CA1, and CA3. At postnatal day 7 (P7), AVP-exposed male and female offspring both had smaller neocortex. At P7, AVP-exposed males also had smaller caudate-putamen volume, while females had increased caudate-putamen volume relative to neocortical size. Similar to P7, E18 AVP-exposed offspring had smaller dorsal forebrain, mainly in reduced intermediate, subventricular, and ventricular zone volume, particularly in males. Decreased volume was not accounted for by cell size or cerebrovascular vessel diameter changes. E18 cortical RNAseq revealed 49 differentially-expressed genes in male AVP-exposed offspring, over-representing cytoplasmic translation processes. In females, 31 genes were differentially-expressed, over-representing collagen-related and epithelial regulation pathways. Gene expression changes in E18 AVP-exposed placenta indicated potential underlying mechanisms. Deficits in behavior and forebrain development in this AVP-based preeclampsia model were distinctly different in males and females, implicating different neurobiological bases.

Manipulating CD4+ T Cell Pathways to Prevent Preeclampsia.

Preeclampsia (PreE) is a placental disorder characterized by hypertension (HTN), proteinuria, and oxidative stress. Individuals with PreE and their children are at an increased risk of serious short- and long-term complications, such as cardiovascular disease, end-organ failure, HTN, neurodevelopmental disorders, and more. Currently, delivery is the only cure for PreE, which remains a leading cause of morbidity and mortality among pregnant individuals and neonates. There is evidence that an imbalance favoring a pro-inflammatory CD4+ T cell milieu is associated with the inadequate spiral artery remodeling and subsequent oxidative stress that prime PreE's clinical symptoms. Immunomodulatory therapies targeting CD4+ T cell mechanisms have been investigated for other immune-mediated inflammatory diseases, and the application of these prevention tactics to PreE is promising, as we review here. These immunomodulatory therapies may, among other things, decrease tumor necrosis factor alpha (TNF-α), cytolytic natural killer cells, reduce pro-inflammatory cytokine production [e.g. interleukin (IL)-17 and IL-6], stimulate regulatory T cells (Tregs), inhibit type 1 and 17 T helper cells, prevent inappropriate dendritic cell maturation, and induce anti-inflammatory cytokine action [e.g. IL-10, Interferon gamma (IFN-γ)]. We review therapies including neutralizing monoclonal antibodies against TNF-α, IL-17, IL-6, and CD28; statins; 17-hydroxyprogesterone caproate, a synthetic hormone; adoptive exogenous Treg therapy; and endothelin-1 pathway inhibitors. Rebalancing the maternal inflammatory milieu may allow for proper spiral artery invasion, placentation, and maternal tolerance of foreign fetal/paternal antigens, thereby combatting early PreE pathogenesis.

Correction: Chronic maternal interleukin-17 and autism-related cortical gene expression, neurobiology, and behavior.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Neurodevelopmental Outcomes of Prenatal Preeclampsia Exposure.

Preeclampsia is a dangerous hypertensive disorder of pregnancy with known links to negative child health outcomes. Here, we review epidemiological and basic neuroscience work from the past several decades linking prenatal preeclampsia to altered neurodevelopment. This work demonstrates increased rates of neuropsychiatric disorders [e.g., increased autism spectrum disorder, attention deficit hyperactivity disorder (ADHD)] in children of preeclamptic pregnancies, as well as increased rates of cognitive impairments [e.g., decreased intelligence quotient (IQ), academic performance] and neurological disease (e.g., stroke and epilepsy). We also review findings from multiple animal models of preeclampsia. Manipulation of key clinical preeclampsia processes in these models (e.g., placental hypoxia, immune dysfunction, angiogenesis, oxidative stress) causes various disruptions in offspring, including ones in white matter/glia, glucocorticoid receptors, neuroimmune outcomes, cerebrovascular structure, and cognition/behavior. This animal work implicates potentially high-yield targets that may be leveraged in the future for clinical application.

Chronic maternal interleukin-17 and autism-related cortical gene expression, neurobiology, and behavior.

Chronic inflammation during pregnancy (e.g., preeclampsia, diabetes) is linked to increased risk for offspring neurodevelopmental disorders such as autism spectrum disorder (ASD). However, mediators of such exposures that could be targeted with maternal intervention are unclear, as few chronic gestational inflammation models have been tested. One potential mediator is interleukin-17 (IL-17), a pro-inflammatory cytokine implicated in neurodevelopmental disorders and gestational disease. To test chronic maternal IL-17 impacts on offspring, C57BL/6J dams were administered IL-17A continuously throughout pregnancy. Offspring were assessed for body weight; cortical volume, gene expression, and cellular composition; and adult behavior. IL-17A-condition offspring exhibited decreased somatic and cortical size at embryonic day 18 (E18) and as adults. mRNA sequencing of E18 cortex revealed 320 differentially expressed genes in males, but none in females. These were significantly enriched for ASD (Simons Foundation Autism Research Initiative), synaptic, and cell cycle genes. By adulthood, neocortical glial cell density and gene expression were decreased, while GABAergic synaptic gene expression was increased in males. Furthermore, IL-17A-condition male but not female offspring exhibited reduced anxiety-like behavior. Social approach deficits in males were negatively correlated with neocortical GABAergic synaptic gene expression. Chronic gestational IL-17A was sufficient to cause ASD-like phenotypes early and persistently in male offspring. This echoes the male bias, altered cortical development, and behavioral findings in ASD, suggesting that chronic maternal IL-17 contributes to offspring ASD pathogenesis. Furthermore, the trajectory from embryonically dysregulated synaptic and cell cycle genes to disrupted adult glia, inhibitory synapses, and behavior suggests a mechanism for chronic maternal IL-17 effects on offspring.

Maternal Nicotinamide Riboside Enhances Postpartum Weight Loss, Juvenile Offspring Development, and Neurogenesis of Adult Offspring.

Conditions of metabolic stress dysregulate the NAD metabolome. By restoring NAD, nicotinamide riboside (NR) provides resistance to such conditions. We tested the hypotheses that postpartum might dysregulate maternal NAD and that increasing systemic NAD with NR might benefit mothers and offspring. In postpartum mothers, the liver NAD metabolome is depressed while blood increases circulation of NAD metabolites to enable a >20-fold increase in mammary NAD+ and NADP+. Lactation and NR synergize in stimulating prolactin synthesis and mammary biosynthetic programs. NR supplementation of new mothers increases lactation and nursing behaviors and stimulates maternal transmission of macronutrients, micronutrients, and BDNF into milk. Pups of NR-supplemented mothers are advantaged in glycemic control, size at weaning, and synaptic pruning. Adult offspring of mothers supplemented during nursing retain advantages in physical performance, anti-anxiety, spatial memory, delayed onset of behavioral immobility, and promotion of adult hippocampal neurogenesis. Thus, postgestational maternal micronutrition confers lasting advantages to offspring.

Maternal Inflammation and Neurodevelopmental Programming: A Review of Preclinical Outcomes and Implications for Translational Psychiatry.

Early disruptions to neurodevelopment are highly relevant to understanding both psychiatric risk and underlying pathophysiology that can be targeted by new treatments. Much convergent evidence from the human literature associates inflammation during pregnancy with later neuropsychiatric disorders in offspring. Preclinical models of prenatal inflammation have been developed to examine the causal maternal physiological and offspring neural mechanisms underlying these findings. Here we review the strengths and limitations of preclinical models used for these purposes and describe selected studies that have shown maternal immune impacts on the brain and behavior of offspring. Maternal immune activation in mice, rats, nonhuman primates, and other mammalian model species have demonstrated convergent outcomes across methodologies. These outcomes include shifts and/or disruptions in the normal developmental trajectory of molecular and cellular processes in the offspring brain. Prenatal developmental origins are critical to a mechanistic understanding of maternal immune activation-induced alterations to microglia and immune molecules, brain growth and development, synaptic morphology and physiology, and anxiety- and depression-like, sensorimotor, and social behaviors. These phenotypes are relevant to brain functioning across domains and to anxiety and mood disorders, schizophrenia, and autism spectrum disorder, in which they have been identified. By turning a neurodevelopmental lens on this body of work, we emphasize the importance of acute changes to the prenatal offspring brain in fostering a better understanding of potential mechanisms for intervention. Collectively, overlapping results across maternal immune activation studies also highlight the need to examine preclinical offspring neurodevelopment alterations in terms of a multifactorial immune milieu, or immunome, to determine potential mechanisms of psychiatric risk.

Prenatal stress and genetic risk: How prenatal stress interacts with genetics to alter risk for psychiatric illness.

Risk for neuropsychiatric disorders is complex and includes an individual's internal genetic endowment and their environmental experiences and exposures. Embryonic development captures a particularly complex period, in which genetic and environmental factors can interact to contribute to risk. These environmental factors are incorporated differently into the embryonic brain than postnatal one. Here, we comprehensively review the human and animal model literature for studies that assess the interaction between genetic risks and one particular environmental exposure with strong and complex associations with neuropsychiatric outcomes-prenatal maternal stress. Gene-environment interaction has been demonstrated for stress occurring during childhood, adolescence, and adulthood. Additional work demonstrates that prenatal stress risk may be similarly complex. Animal model studies have begun to address some underlying mechanisms, including particular maternal or fetal genetic susceptibilities that interact with stress exposure and those that do not. More specifically, the genetic underpinnings of serotonin and dopamine signaling and stress physiology mechanisms have been shown to be particularly relevant to social, attentional, and internalizing behavioral changes, while other genetic factors have not, including some growth factor and hormone-related genes. Interactions have reflected both the diathesis-stress and differential susceptibility models. Maternal genetic factors have received less attention than those in offspring, but strongly modulate impacts of prenatal stress. Priorities for future research are investigating maternal response to distinct forms of stress and developing whole-genome methods to examine the contributions of genetic variants of both mothers and offspring, particularly including genes involved in neurodevelopment. This is a burgeoning field of research that will ultimately contribute not only to a broad understanding of psychiatric pathophysiology but also to efforts for personalized medicine.