Abstract
The maternal environment during pregnancy is critical for fetal development and perinatal perturbations can prime offspring disease risk. Here, we briefly review evidence linking two well-characterized maternal stressors – psychosocial stress and infection – to increased neuropsychiatric risk in offspring. In the current climate of increasing obesity and globalization of the Western-style diet, maternal overnutrition emerges as a pressing public health concern. We focus our attention on recent epidemiological and animal model evidence showing that, like psychosocial stress and infection, maternal overnutrition can also increase offspring neuropsychiatric risk. Using lessons learned from the psychosocial stress and infection literature, we discuss how altered maternal and placental physiology in the setting of overnutrition may contribute to abnormal fetal development and resulting neuropsychiatric outcomes. A better understanding of converging pathophysiological pathways shared between stressors may enable development of interventions against neuropsychiatric illnesses that may be beneficial across stressors.
Keywords: Developmental origins of health and disease, Maternal stress, Maternal diet, Maternal obesity, Maternal immune activation, Inflammation, Allostatic load, Neuropsychiatric risk, Autism spectrum disorders, Schizophrenia, Anxiety, Depression
1. Introduction
The focus of this review is on neuropsychiatric risk associated with in utero exposure to maternal environmental stressors. The field of stress research has largely focused on the health effects of psychosocial or physiological stressors on hypothalamic–pituitary–adrenal (HPA) axis function in adult humans and animal model systems. Yet it has become increasingly clear that the HPA axis is not the only regulatory system sensitive to the effects of stress, and that these effects not only act on adults, but also occur throughout the lifespan. The emergence of the concepts of “allostasis” and “allostatic overload” has broadened the definition of environmental stressors and study of pathophysiological mechanisms across a range of regulatory systems. In parallel, the developmental origins of health and disease (DOHaD) hypothesis has provided a developmental context.
The DOHaD, which emerged as a broadening of the “Barker hypothesis” and was named for epidemiologist David Barker, posits that early life environmental exposures can pattern risk for and severity of later life disease. Since Barker’s initial studies on the cardiovascular and metabolic effects of low birth weight (Barker, 2007; Barker and Osmond, 1986), epidemiological studies have associated exposure to under- and overnutrition (Armitage et al., 2008; Calkins and Devaskar, 2011), psychosocial stress and trauma (King et al., 2012; Van den Bergh et al., 2017; Vaiserman, 2015), infection (Bilbo and Schwarz, 2012; Izvolskaia et al., 2018), and toxins (Young et al., 2018; Drwal et al., 2019) during development with adverse effects on offspring across the lifespan and across a range of organ systems. To understand this mechanistically, we consider the concept of allostatic load. Pregnancy can be considered a state of allostasis, where the maternal-fetal dyad must balance dual goals of maternal and fetal stability across all organ systems, and across the developmental trajectory (Power and Schulkin, 2012). Additional environmental challenges during this time could result in allostatic overload that not only affects the health of the mother, but also impacts the health and resilience of the developing fetus.
It is clear that the developing brain, like other organ systems, is vulnerable to the effects of an adverse early environment (Giussani, 2011). Maternal adversity has been linked to a spectrum of neuropsychiatric problems – from neurodevelopmental diseases to psychiatric disorders to late life neurodegenerative disease – and some suggest that many brain diseases should be considered at least partially neurodevelopmental in origin (Levitt and Veenstra-VanderWeele, 2015; Heindel and Vandenberg, 2015). Here, we begin with an overview of the epidemiological and animal model evidence for two maternal stressors, psychosocial stress and infection, in priming offspring neuropsychiatric risk. In the current climate of increasing obesity and globalization of the Western-style diet model, maternal overnutrition is an emerging and pressing public health issue. We spend the majority of the review discussing the epidemiological and animal model evidence linking maternal overnutrition with increased neuropsychiatric risk in offspring. The overlapping neuropsychiatric consequences for offspring associated with these three maternal stressors suggests pathophysiological convergence, in line with our current understanding of allostatic overload. We discuss putative mechanisms linking maternal overnutrition and offspring neuropsychiatric risk, highlighting potential converging pathways and lessons learned from the infection and stress fields, and how existing model systems and current technologies may lead to better understanding of the multifactorial etiologies of neuropsychiatric illnesses. Finally, identification of common pathophysiological pathways shared between stressors opens the door to potential interventions that may be beneficial across stressors. We conclude with a brief discussion of potential future directions for the field and implications for intervention.
2. Maternal psychosocial stress & immune activation
The contributions of perinatal stress (Van den Bergh et al., 2017; Bale, 2005; Bale et al., 2010; Boersma et al., 2014; Entringer et al., 2015; Chan et al., 2018) and maternal immune activation (Bilbo and Schwarz, 2012; Meyer et al., 2009; Solek et al., 2018; Meyer, 2014; Estes and McAllister, 2016) to offspring neuropsychiatric risk have been extensively reviewed. As such, we will touch on these topics only briefly as a framework to approach the less well-studied role of maternal overnutrition in neuropsychiatric vulnerability.
While it was long established that exposure to stress in adulthood negatively affects mental health, few studies evaluated risks of stress during gestation. Studies of children exposed in utero to disasters, like the 1986 Chernobyl accident or the 1988 Quebec ice storm, provided some of the first associations between perinatal stress exposure and neuropsychiatric outcomes (Boersma et al., 2014; Kolominsky et al., 1999; Laplante et al., 2008). Numerous other epidemiological studies have since expanded this association to prenatal psychosocial stressors of various type, duration, gestational timing, and severity, as well as a range of outcomes. However, recurring limitations in human studies include the difficulty in dissociating prenatal from early postnatal stress and reliance on retrospective self-report of stress experience, which may not adequately account for additional moderating variables.
In recent decades, a large number of studies using animal model systems have allowed for more controlled evaluation of the association between prenatal stress (PNS), timing and severity of stress exposure (Weinstock, 2017; Boersma and Tamashiro, 2015), and neuropsychiatric impairment in offspring. Broadly, offspring exposed to PNS demonstrate behavioral changes relevant to neuropsychiatric disease including but not limited to depression-like behavior (Morley-Fletcher et al., 2003; Morley-Fletcher et al., 2004), anxiety-like behavior (Vallee et al., 1997), alterations in stress coping style (Boersma et al., 2014), cognitive impairment (Vallee et al., 1999), decreased social interaction (Lee et al., 2007), and increased aggression (de Souza et al., 2013). While behavioral changes are consistently reported, phenotype appears highly dependent on type, degree, and timing of maternal stress, as well as sex and age of offspring at evaluation (Boersma et al., 2014). This variance highlights the importance of considering type and severity of stressor when interpreting offspring outcomes from PNS (Lesage et al., 2001), while also pointing to potential critical windows of exposure and thresholds of risk. Among the first investigations of time- and sex-dependent effects of PNS used mild chronic variable stress (CVS) applied to pregnant mice during early, mid, or late gestation (Mueller and Bale, 2006; Mueller and Bale, 2007; Mueller and Bale, 2008). For male offspring, only those exposed to early gestational PNS demonstrated neurobehavioral impairments as adults (Mueller and Bale, 2007; Mueller and Bale, 2008), which were accompanied by increased HPA axis responsivity (Mueller and Bale, 2008). Similarly, only those female offspring exposed to early gestational stress showed changes in behavior, but they exhibited improved learning performance, the opposite outcome compared to their male littermates (Mueller and Bale, 2007; Mueller and Bale, 2008). A growing body of work supports these findings suggesting that females may be less sensitive to the effects of PNS (Bale and Epperson, 2015). That is not to say that female offspring are completely resistant to stress. Instead, gestational stress, particularly in early development, seems to promote a more insidious risk for affective disorders in females compared to risk of autism spectrum disorders (ASDs), behavioral, and intellectual disability in males (Bronson and Bale, 2016; Davis and Pfaff, 2014; Sandman et al., 2013). This dovetails with the sexual dimorphism in neuropsychiatric presentation: among males, the prevalence rates of neurodevelopmental disorders such as ASDs, attention deficit hyperactivity disorder (ADHD), and earlier-onset schizophrenia tend to be higher, whereas females have an increased prevalence of affective disorders (Davis and Pfaff, 2014; McLean et al., 2011; Hantsoo and Epperson, 2017; Fombonne, 2009; Bauermeister et al., 2007; Loomes et al., 2017; Zhang et al., 2012; Froehlich et al., 2007). Moving forward, understanding sexual dimorphism in the developing brain and further elucidating the effects of gestational timing and sex on offspring exposed to maternal stress remains an important direction for the field.
Several mechanisms have been proposed to underlie the relationship between maternal stress and offspring neuropsychiatric phenotypes. The most widely studied are alterations of the HPA axis, including potentially sex-specific changes in the circadian cycle of corticosterone (CORT), HPA axis responsivity, and impaired HPA axis negative feedback (Henry et al., 1994; Barbazanges et al., 1996; Maccari et al., 1995; Koehl et al., 1999). Within the brain, PNS is associated with decreased glucocorticoid and mineralocorticoid receptor binding capacities (Maccari et al., 1995; Koehl et al., 1999), which may alter hippocampal neurogenesis (Gould et al., 1992; Rodriguez et al., 1998; Montaron et al., 1999) and neuronal proliferation (Lemaire et al., 2000; Fujioka et al., 2006; Kawamura et al., 2006). Other mechanisms proposed to mediate the relationship between PNS and brain function include, but are not limited to, alterations in immune regulation and cytokines (Hantsoo et al., 2019), metabolic signaling (Tamashiro et al., 2009), placental function (Bronson and Bale, 2016), neurotrophic signaling (Ruf and Preissner, 2017), microbiome composition (Jasarevic et al., 2015), and epigenetic regulation (Boersma and Tamashiro, 2015), highlighting the diverse and complex actions of early life stress.
While many have focused on effects of PNS, others have studied another common early-life exposure, maternal immune activation (MIA), and there is now abundant evidence of overlapping neuropsychiatric risks between these two “stressors.” Though much of the early epidemiological work focused on links between maternal infection and schizophrenia (Mednick et al., 1988; Patterson, 2009; Meyer, 2014; Patterson, 2009) additional associations have been identified with ASDs (Patterson, 2011), developmental delay (Zerbo et al., 2013), cognitive impairment (Richetto and Riva, 2014; Knuesel et al., 2014), and affective disorders (Simanek and Meier, 2015; Murphy et al., 2017; Parboosing et al., 2013). Again similar to PNS, both clinical epidemiology and translational studies suggest that neuropsychiatric phenotypes associated with maternal infection appear to be influenced by gestational timing, duration, and severity of infectious stressor, as well as age and sex of the offspring (Brown and Meyer, 2018; Estes and McAllister, 2016; Schwartzer et al., 2013; Murray et al., 2019; de Souza et al., 2015; Giovanoli et al., 2015; Vernon et al., 2015). Overall, it appears that early immune stress leads to more extensive neuropsychological consequences, but that late gestation remains another critical and specific window for the effects of exposure (Meyer et al., 2007).
Mechanistically, recent evidence suggests that it is immune system activation, and not a specific pathogen, that is primarily responsible for negative effects on developing offspring (Estes and McAllister, 2016). This observation has been leveraged in pre-clinical studies that bypass specific pathogenic infection and instead directly activate the immune response with the viral mimetic polyinosinic:polycytidylic (poly[I:C]), the bacterial endotoxin lipopolysaccharide (LPS), or specific immune components such as cytokines. Doing so allows for study of generalizable and direct effects of MIA while tightly controlling the type, timing, duration, and intensity of the immune activation (Meyer et al., 2009; Brown and Meyer, 2018; Meyer et al., 2009). Offspring in these studies exhibit deficits in sensorimotor gating, attention, learning and memory, and social behavior, in addition to increased repetitive, anhedonic, and anxiety-like behaviors (Meyer, 2014; Estes and McAllister, 2016; Patterson, 2009; Knuesel et al., 2014). These changes have been linked to aberrations in brain structure and function including decreased cortical thickness, increased ventricular volume, and decreased regional volumes in the hippocampus, amygdala, and striatum (Estes and McAllister, 2016; Patterson, 2009; Piontkewitz et al., 2011). Emerging evidence suggests altered circuit connectivity and altered serotonergic, dopaminergic, and GABAergic signaling in some of these regions (Meyer et al., 2009; Estes and McAllister, 2016; Dickerson and Bilkey, 2013; Missault et al., 2019). At the synaptic level, reported changes include decreased dendritic spine density, shortened dendritic length, reductions in pre- and post-synaptic proteins, and deficits in synaptic transmission and long-term potentiation (Giovanoli et al., 2015; Choi et al., 2016; Coiro et al., 2015; Zhang and van Praag, 2015; Patrich et al., 2016). At the cellular level, there is evidence for altered neurogenesis and neuronal migration, as well as alterations in microglia and astroglia (Solek et al., 2018; de Souza et al., 2015; Zhang et al., 2018; Smolders et al., 2018; Prins et al., 2018; Liu et al., 2013; Oskvig et al., 2012).
While individual application of single immune factors has been shown to be sufficient to induce neuropsychiatric alterations (Smith et al., 2007; Ponzio et al., 2007), the immune system is in constant interplay with other biological systems including the placenta, HPA axis, gut microbiome, metabolism, oxidation, neurotrophic signaling, and epigenetic regulation, and changes within each of these systems are implicated in MIA (Estes and McAllister, 2016; Oskvig et al., 2012; Hsiao and Patterson, 2011; Udagawa and Hino, 2016; Gilmore et al., 2005; Babri et al., 2014; Reisinger et al., 2015; Simoes et al., 2018; Lammert et al., 2018). This reflects the complex nature of the etiology of neuropsychiatric risk, but it also points to commonalities between MIA and PNS in producing similar behavioral phenotypes – a concept we will return to at the end of this review.
3. Maternal overnutrition
3.1. Background and summarized clinical findings
While psychosocial stress and infection are among the most widely studied stressors experienced during pregnancy, another major stressor has emerged in the current climate of a global obesity epidemic: maternal overnutrition. Nearly two-thirds of women of reproductive age in the United States are overweight or obese, and rapidly climbing obesity rates in developing countries indicate that this is a worldwide public health problem (Flegal et al., 2010; Hillemeier et al., 2011; Chen et al., 2018). Obesity and overweight are associated with a range of metabolic and cardiovascular comorbidities which, in pregnant women, increase risk for additional complications including pre-eclampsia and gestational diabetes mellitus (GDM) (Sohlberg et al., 2012; Mission et al., 2015; Stang and Huffman, 2016). Exposure to maternal obesity, high-energy diet, and associated metabolic consequences are consistently associated with a multitude of adverse health outcomes in offspring (Nguyen et al., 2015; Rivera et al., 2015; Maftei et al., 2015; Olson et al., 2009; Brekke et al., 2007), including neuropsychiatric disease (Rivera et al., 2015; Olfson et al., 2014; Boyle et al., 2011). Here we review epidemiological and animal model evidence for the association between these maternal conditions and offspring neuropsychiatric risk.
Epidemiological studies suggest a relationship between maternal overnutrition and both risk for and severity of several neurodevelopmental and psychiatric illnesses, including but not limited to ASDs, ADHD, affective disorders, and schizophrenia (Rivera et al., 2015) (Table 1). Maternal overnutrition is additionally associated with cognitive impairments in children and adolescents, and has been suggested to predispose the development of later-life cognitive dementias (Contu and Hawkes, 2017). However, it is important to acknowledge that across these studies there exists no consensus on how to determine or quantify “maternal overnutrition.” The most common determinations are based on body mass index (BMI, both pre- or post-pregnancy), weight gain during pregnancy (gestational weight gain, GWG), prepregnancy type 2 diabetes mellitus (T2DM), and the presence of gestational metabolic disorders including GDM (Rivera et al., 2015; Edlow, 2017). Given the high comorbidity and significant interplay between these conditions – and the resulting overlap in animal model systems used to investigate associated neuropsychiatric outcomes in offspring – we have grouped this discussion under “maternal overnutrition” as an umbrella terminology.
Table 1.
Summarized clinical studies associating maternal overnutrition with neuropsychiatric risk to offspring. Studies referenced are limited to the present review.
| Offspring outcome | Measure of maternal overnutrition | Ref # | Concluded association | Study design | Notes |
|---|---|---|---|---|---|
| ↑ Risk and Severity of ASDs | ↑ Pre-pregnancy BMI | (Reynolds et al, 2014) | Yes | Cohort | |
| (Moss and Chugani, 2014) | Yes | Cohort | |||
| (Krakowiak et al, 2012) | Yes | Case-Control | |||
| (Dodds et al., 2011) | Yes | Cohort | |||
| (Getz et al., 2016) | Yes | Case-Control | |||
| (Gardner et al., 2015) | Inconclusive | Cohort | Population-based association disappears in matched sibling analysis | ||
| (Li et al., 2016) | Inconclusive | Case-Control | Association in combination with maternal diabetes | ||
| (Bilder et al., 2013) | No | Cohort, Case-Control | |||
| ↑ Gestational weight gain (GWG) | (Dodds et al., 2011) | Yes | Cohort | ||
| (Gardner et al., 2015) | Yes | Cohort | |||
| (Bilder et al., 2013) | Yes | Cohort, Case-Control | |||
| (Reynolds et al., 2014) | No | Cohort | |||
| Metabolic Complications (Diabetes, | (Krakowiak et al., 2012) | Yes | Case-Control | ||
| Hypertension, Pre-Eclampsia) | (Dodds et al., 2011) | Yes | Cohort | ||
| (Wallace et al., 2008) | Yes | Cohort | |||
| (Li et al., 2016) | Yes | Case-Control | |||
| (Reynolds et al., 2014) | No | Cohort | |||
| ↑ Risk of Cognitive | ↑ Pre-pregnancy BMI | (Basatemur et al., 2013) | Yes | Cohort | |
| Impairment | (Bliddal et al., 2014) | Yes | Cohort | ||
| (Casas et al., 2013) | Yes | Cohort | |||
| (Craig et al., 2013) | Yes | Case-Control | |||
| (Eriksen et al., 2013) | Yes | Cohort | |||
| (Hinkle et al., 2012) | Yes | Cohort | |||
| (Huang et al., 2014) | Yes | Cohort | |||
| (Neggers et al., 2003) | Yes | Cohort | |||
| (Brion et al., 2011) | Inconclusive | Cohort | Inconsistent between cohorts; potential confounder effect | ||
| (Li et al., 2016) | Inconclusive | Case-Control | Association in combination with maternal diabetes | ||
| (Krzeczkowski et al., 2018) | Inconclusive | Cohort | Association disappears when accounting for maternal diet | ||
| Metabolic Complications (Diabetes, Hypertension, Pre-Eclampsia) | (Li et al., 2016) | Yes | Case-Control | ||
| (Krzeczkowski et al., 2018) | Inconclusive | Cohort | Association disappears when accounting for maternal diet | ||
| ↑ Risk of Anxiety or Depression | ↑ Pre-pregnancy BMI | (Van Lieshout et al., 2013) | Yes | Cohort | |
| (Mina et al., 2017) | Yes | Cohort | |||
| (Rodriguez, 2010) | Yes | Cohort | |||
| (Robinson et al., 2013) | Yes | Cohort | |||
| ↑ Risk of Schizophrenia | ↑ Pre-pregnancy BMI | (Jones et al., 1966) | Yes | Cohort | |
| (Schaefer et al., 2000) | Yes | Cohort | |||
| ↑ GWG | (Kawai et al., 2004) | Yes | Case-Control | ||
| Metabolic Complications (Diabetes, Hypertension, Pre-Eclampsia) | (Cannon et al., 2002) | Yes | Meta-analysis |
Despite a growing body of clinical evidence for a correlation between many of these markers of maternal metabolic state and adverse neuropsychiatric outcomes, not all studies support this. As an example, while several studies have linked high pre-pregnancy BMI with risk for ASD (Reynolds et al., 2014; Moss and Chugani, 2014; Krakowiak et al., 2012; Dodds et al., 2011; Getz et al., 2016), one study suggested that this association is due to residual confounds from familial risk factors (Gardner et al., 2015), and other studies found no association between BMI proximal to pregnancy onset and ASD (Bilder et al., 2013). GWG, while less studied, is consistently associated with ASD in all but one study (Reynolds et al., 2014), and numerous studies have identified metabolic complications prior to and during pregnancy, such as pre-existing diabetes, GDM, or hypertension, with ASD (Krakowiak et al., 2012; Dodds et al., 2011; Gardner et al., 2015; Bilder et al., 2013; Wallace et al., 2008). At least in part, these discrepancies likely arise from the fact that clinical studies are often difficult to control and confounders often difficult to identify. Animal models on the other hand, while less directly translatable, have allowed for more controlled studies aimed at disentangling the potential mechanistic players and pathways.
3.2. Animal models
The majority of animal studies in this field use dietary manipulations that result in metabolic disturbances in the dam prior to and/or during pregnancy that can affect the developing fetus. These diets vary in their macronutrient content, but in general they are palatable, energy-dense, high in fat, and, in some cases, high in sugar (Winther et al., 2018; Zambrano and Nathanielsz, 2017; Musial et al., 2017; Mucellini et al., 2014; Bolton et al., 2017; Sun et al., 2012; Niculescu and Lupu, 2009; Tozuka et al., 2010; Wright et al., 2011). Diet exposure is usually continued until the end of gestation or lactation, at which point offspring are most commonly weaned onto a control diet. There is strong evidence that maternal overnutrition changes both behavior and brain physiology in offspring (Table 2). In the next several sections, behavioral and brain changes will be discussed as they relate to features of human neurodevelopmental and psychiatric disease.
Table 2.
Findings from animal models of maternal overnutrition. Models of maternal overnutrition are presented with resulting changes to offspring behavior, brain, and peripheral outcomes; maternal physiology; and placental physiology. Studies referenced are limited to the present review.
| Ref | Species (Strain) | Model | Offspring Behavioral Phenotype | Offspring Physiology, Central | Offspring Physiology, Peripheral | Maternal Physiology | Placental Physiology | Notes |
|---|---|---|---|---|---|---|---|---|
| (Winther et al., 2018) | Rat [Sprague- Dawley (SD)] | 60% High-Fat Diet (HFD), 8 w pre-conception (PC) through gestation (G) and lactation (L) | Anxiety-like behaviour | Hippocampus
|
Pre- / at weaning
|
|
_ | |
| (Musial et al., 2017) | Mouse (C57) | 30% kcal fat, 36% kcal sugar (HFHS diet), through G Dam sacrifice G16 or G19 |
- | - | Fetal, G16
|
G16
|
|
|
| (Sun et al., 2012) | Rat(SD) | 60% HFD, through G and L; Offspring cross-fostered to same- or opposite-diet dam at PI
|
- | Hypothalamus, pre- /atweaning
|
Pre- /at weaning, L HFD
|
|
- | Differential effects by exposure window: ↑ impact on offspring metabolic phenotype with L HFD |
| (Niculescu and Lupu, 2009) | Mouse (C57) | 60% HFD, 10 w PC through G Dam sacrifice G17 |
- | Hippocampus, fetal
|
Fetal
|
|
- | |
| (Tozuka et al., 2010) | Mouse (C57) | 57.5% HFD, 6 w PC through G and L until P16 | Cognitive impairment (adolescent) | Hippocampus, adolescent
|
- |
|
- | Cognitive phenotype normalized by adulthood |
| (Wright et al., 2011) | Rat (Wistar) | Cafeteria diet, 11 w PC through G and L 8 experimental groups limiting HFD to PC, G, L, or a combination of exposure windows (e.g. PC & L only) | Decreased anxiety-like behavior (L exposure, ♂) | - |
|
|
- | Differential effects by exposure window |
| (Cordner et al., 2019) | Rat (SD) | 60% HFD, through G and L | Cognitive impairment | Hippocampus, weaning
|
|
- | - | |
| (White et al., 2009) | Rat (Long Evans) | 60% HFD, 4 w PC through G and L Offspring placed as adults onto HFD or Con | Cognitive impairment (HFD offspring exposed to adult HFD) | With maternal HFD
|
|
|
- | Maternal + offspring diet exposure |
| (Can et al., 2012) | Rat(SD) | 65% HFD, through G and L Offspring weaned onto respective dam diet | Anxiety-like behavior Depression-like behavior Cognitive impairment | Hippocampus
|
|
- | - | Maternal + offspring diet exposure |
| (Robb et al., 2017) | Rat (SD) | 45% HFD, 10 w PC through G and L | Cognitive impairment (adolescent ♂, trend in adult ♂) | - |
|
|
Cognitive phenotype normalized by adulthood; Sex differences: ↑ effect ♂ | |
| (Moser et al., 2017) | Rat (Long Evans) | 60% HFD, 6 w PC through G and L | Cognitive impairment | - | Pre- /at weaning
|
|
- | |
| (Page et al., 2014) | Rat (SD) | 45% HFD, 1 m PC through G and L Offspring weaned onto HFD or Con |
Cognitive impairment (maternal HFD exposure) | Hippocampus, maternal HFD exposure
|
Maternal HFD exposure
|
- | - | |
| (Bilbo and Tsang, 2010) | Rat (SD) | 60% high saturated fat HFD (SFD) or 60% high trans fat HFD (TFD), 4 w PC through G and L | Anxiety-like behavior (SFD or TFD ♂) Improved cognitive performance (SFD or TFD ♂) | Hippocampus, neonate
|
Pre- /at weaning
|
|
||
| (Graf et al., 2016) | Mouse (C57) | 60% HFD, 8 w PC through G and L | Cognitive impairment (♂) | Pre- /at weaing
|
Pre- /at weaning
|
|
- | Sex differences: ↑ effect ♂ |
| (Kang et al., 2014) | Mouse (C57) | 60% HFD,
|
Anxiety-like behavior (♀; HFD-HFD, HFD-Con) Social interaction deficits (♀; HFD-HFD only) Hyperactivity (♂; HFD-HFD, HFD-Con) |
Adult
|
|
|
- | Timing of exposure: ↑ impact PC/G v L HFD, partial mitigation with L switch |
| (Buffington et al., 2016) | Mouse (C57) | 60% HFD, 8 w PC through G and L | Social interaction deficits |
|
|
|
- | |
| (Sasaki et al., 2013) | Rat (Long Evans) | 60% HFD, 4 w PC through G and L | Anxiety-like behavior | Amygdala
|
Pre- /at weaning
|
|
- | Timing of offspring effect: altered phenotype in adolescent (Sasaki et al., 2014) v adult animals |
| (Sasaki et al., 2014) | Rat (Long Evans) | 60% HFD, 4 w PC through G and L | Decreased anxiety-like behavior (adolescent) | Amygdala, adolescent
|
Pre- /at weaning
|
|
- | Timing of offspring effect: altered phenotype in adolescent v adult (Sasaki et al., 2013) animals |
| (Giriko et al., 2013) | Rat (Wistar) | 52% HFD, through L | Delayed reflex development (early life) Depression-like behavior (adult) |
- | Pre- / at weaning
|
|
- | |
| (Lin et al., 2015) | Rat (SD) | 45% HFD, 10 d PC through G and L Adult offspring subjected to chronic unpredictable mild stress (CUMS) | Sensitization to stress-induced depression-like behavior |
|
|
Maternal HFD ↑ sensitization to stress | ||
| (Zieba et al., 2019) | Mouse (C57) | 43% HFD, 5 w PC through G and L | Facilitation of PPI | - |
|
|
- | |
| (Wolfrum and Peleg-Raibstein, 2018) | Mouse (C57) | 60% HFD, 3 w PC through G and L | Cognitive impairment (adult, ↑ severity in aged adult)Facilitation of PPI (adult, aged adult) | Ventral hippocampus, adult
|
- | - | - | |
| (Song et al., 2017) | Rat(SD) | 60% HFD, through G | - | - | - |
|
|
|
| (Sun et al., 2014) | Rat(SD) | 60% HFD, through G and L | - | Hypothalamus, pre- /at weaning
|
Pre- / at weaning
|
|
- | |
| (Schmitz et al., 2018) | Mouse (C57) | 60% HFD, 9–11 w PC through G and L | - | Hippocampus, adult
|
Pre- /at weaning
|
|
- | |
| (Ford et al., 2009) | Sheep | 150% of recommended intake sheep diet by body weight, 60 d PC through G Dam sacrifice mid-gestation (G75 of 150 d G course) | - | - | Fetal
|
|
||
| Mouse (C57) | 60% HFD, through G | - | - | Fetal |
|
|
||
| (Qiao et al., 2015) |
|
|
|
|||||
| (Sanders et al., 2014) | Mouse (C57) | 45% HFD, 8 w PC through G | - | Hypothalamus, fetal
|
Fetal
|
|
- | |
| (Edlow et al., 2018) | Mouse (C57) | 60% HFD, 12–14 w PC through G | - | Fetal
|
Fetal
|
|
|
|
| (Kim et al., 2016) | Mouse (C57) | 45% HFD, 8 w PC through G | - | Hypothalamus, fetal
|
- | - | - | |
| (D’Asti et al., 2010) | Rat(SD) | 30%* by weight high n-6 fat HFD OR 30% by weight high n-3 fat HFD, GD 14 through L;* By % weight; % kcal fat not reported | - | Hypothalamus, pre-weaning
|
Pre- / at weaning
|
|
- | |
| (Abuaish et al., 2018) | Rat (Long Evans) | 60% HFD, 3 w PC through G and L | Anxiety-like behavior (neonate) | PVN, pre- /at weaning
|
Pre- /at weaning
|
|
- | |
| (Walker et al, 2008) | Rat (SD) | 30%* by weight HFD, GD 14 through L; * By % weight; % kcal fat not reported | - | - | Pre- /at weaning
|
- | - | |
| (Niu et al, 2019) | Rat (SD) | 27.5%* by weight HFD, 10 d PC through G and L; *By % weight; % kcal fat not reported | - | Hypothalamus
|
|
- | - | |
| (Frias et al., 2011) | Non-Human Primate (Japanese macaque) | 32% HFD, ≤ 4y PC through G | - | - | Fetal, sensitive/obese
|
Sensitive/obese dams
|
Sensitive/obese dams
|
|
| (Thompson etal., 2017) | Non-Human Primate (Japanese macaque) | 32% HFD + calorically dense treats, ≥ 1 y PC through G and L; Offspring weaned to HFD or Con | Anxiety-like behavior (juvenile, with maternal HFD) Increased stereotypic behaviors (juvenile, postweaning HFD) | Dorsal raphe, juvenile
|
Pre- /at weaning
|
|
- | Differential effects of maternal and postweaning HFD |
| (Hayes et al., 2014) | Rat (SD) | 45% HFD, 16 w PC through G | - | - | - |
|
|
|
| (Mark et al., 2011) | Rat (Wistar) | 45% HFD, through G | - | - | Fetal
|
|
|
|
| (Sullivan et al., 2010) | Non-Human Primate (Japanese macaque) | 32% HFD + calorically dense treats, ≤ 4 y PC through G | Anxiety-like behavior (♀, infant) | Dorsal raphe, fetal
|
- | - | - | |
| (Peleg-Raibstein et al., 2012) | Mouse (C57) | 60% HFD, 3 w PC through G and L | Anxiety-like behavior |
Dorsal hippocampus
|
- | - | - | |
| (Mao et al., 2010) | Mouse (NIH Swiss) | 60% HFD, 30–35 w PC through G (sacrifice at mid-gestation) | - | - | - |
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| (Thompson et al., 2018) | Non-Human Primate (Japanese macaque) | 32% HFD + calorically dense treats, ≥ 1 y PC through G and L | Anxiety-like behavior (juvenile) | - |
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3.2.1. Cognitive impairment
Cognitive impairment is a common feature of several neuropsychiatric and neurodevelopmental diseases, and in some cases is predictive of both severity and trajectory of disease course (Liu-Seifert et al., 2015; Pitteri et al., 2017; Treuer and Tohen, 2010; Stirling et al., 2003).
We have shown that as adults, male rat offspring from dams that were fed a 60% HFD during gestation and lactation are cognitively impaired. Male offspring exhibit slower learning acquisition and impaired memory retention in the Barnes maze as well as decreased novel object preference in the novel object recognition test in comparison to control offspring (Cordner et al., 2019). These behavioral changes were accompanied by decreased hippocampal brain-derived neurotrophic factor (BDNF), insulin receptor, and leptin receptor mRNA at weaning, and persistent downregulation of insulin receptor and leptin receptor in adulthood (Cordner et al., 2019). While BDNF is widely known for its neurotrophic properties, insulin and leptin signaling within the hippocampus are also key regulators of both neural development and function, and have been implicated in impaired cognition associated with adult consumption of HFDs (Van Doorn et al., 2017; Ferrario and Reagan, 2018; Cordner and Tamashiro, 2015). Evidence suggests that maternal overnutrition may additionally sensitize offspring to cognitive impairment associated with adult HFD exposure. Two studies have demonstrated impaired spatial cognition in maternal HFD rats that were also weaned onto HFD (White et al., 2009; Can et al., 2012). In one of these studies, White and colleagues found no significant deficit in maternal HFD rats who were weaned onto standard chow or in offspring of chow-fed dams weaned onto HFD, illustrating the potentially additive effects of both maternal and offspring exposure (White et al., 2009). Given the known comorbidity between obesity and cognitive impairment (Dye et al., 2017), it is critical for investigators to consider whether phenotypic outcomes are a direct consequence of developmental exposure to an insult (e.g. maternal overnutrition causes cognitive deficit) or indirectly related through a different, co-existing phenotype (e.g. maternal overnutrition causes offspring obesity which in turn results in cognitive deficits) (Tamashiro et al., 2009; Trandafir and Temneanu, 2016).
The lack of cognitive impairment seen from maternal HFD alone in White et al., in contrast to our findings, also highlights some inconsistency in the literature. Several studies have now examined aspects of learning and memory in maternal HFD offspring with somewhat conflicting results. Like in the PNS and MIA literature, these discrepancies suggest how differences in experimental design – type, timing, and duration of maternal diet, species and strain differences, and how and when offspring are evaluated – can alter phenotypic outcomes. To the latter point, two studies thus far have found impaired spatial cognitive performance in adolescent but not adult offspring of HFD-fed dams. In one, adolescent offspring also exhibit increased peroxidized lipid accumulation, decreased BDNF, and impaired dendritic arborization within the hippocampus that is normalized by adulthood, suggesting a transient effect of maternal HFD (Tozuka et al., 2010). In the second study, while adult offspring from HFD-fed dams did not meet statistical criteria for cognitive impairment, the authors note that male offspring trend towards impaired performance (Robb et al., 2017). Given the findings by White and others, the question remains whether adult offspring from either study would demonstrate cognitive impairment if challenged with HFD themselves.
Other discrepancies include the nature of cognitive deficit, revealing nuances to seemingly similar outcomes. Two studies demonstrating impaired Morris water maze performance in adult offspring exposed to maternal HFD illustrate subtle variations in outcomes both classified as cognitive impairment (Moser et al., 2017; Page et al., 2014). In Page et al., offspring exhibited impaired retention but intact acquisition of learning, whereas Moser and colleagues found impaired acquisition with no deficits in retention upon acquisition. Other discrepancies in the literature are more striking, with at least one study finding improved spatial learning in adult offspring from HFD-fed dams (Bilbo and Tsang, 2010). Fewer studies have evaluated recognition memory, but with similarly inconsistent results, again perhaps reflecting differences in model and design. Consistent with our findings, in one study of mice exposed to maternal HFD, adult males exhibited impaired recognition memory, though this effect was absent in females (Graf et al., 2016). However, other studies of maternal overnutrition have found no deficits in offspring recognition memory (Winther et al., 2018; Moser et al., 2017).
The variation in the animal literature is reflected in the epidemiological literature. While several studies thus far have found an association between maternal overnutrition and cognitive problems in children, effect size and quality of cognitive deficit vary between studies (Basatemur et al., 2013; Bliddal et al., 2014; Brion et al., 2011; Casas et al., 2013; Craig et al., 2013; Eriksen et al., 2013; Hinkle et al., 2012; Huang et al., 2014; Li et al., 2016; Neggers et al., 2003; Krzeczkowski et al., 2018). Overnutrition in children is independently associated with reduced IQ, and while many of these studies adjusted for child BMI, BMI is only one index of metabolic dysregulation (Wraw et al., 2018). Given the known comorbidity between metabolic and cognitive impairment and the demonstrated influence of maternal metabolic dysregulation on the programming and regulation of offspring metabolism, dissociating direct and indirect maternal effects remains a priority.
3.2.2. Autism spectrum disorder (ASD)-like phenotypes
ASD in human patients has a considerably heterogeneous presentation largely characterized by impaired social interaction and patterns of restricted, repetitive behaviors (Ha et al., 2015). Female mice exposed to maternal HFD until weaning have decreased sociability compared to controls, though this difference was not seen in male siblings or in females whose mothers were switched to a control diet upon delivery (Kang et al., 2014). Decreased sociability in female offspring was associated with increased microglial activation and levels of pro-inflammatory cytokines IL-1β and TNF-α within the brain, reminiscent of ASD-like behavior and associated cytokine changes in models of maternal immune activation (Estes and McAllister, 2016). In a similar model of murine HFD-induced maternal obesity, male offspring (females were not tested) display increased repetitive behavior and a complement of socially deficient behavior including fewer reciprocal interactions, decreased sociability, and no preference for social novelty (Buffington et al., 2016). Mechanistically, a synergistic interaction between oxytocin and dopamine is implicated in the processing of social cues (Modi and Young, 2012). These mice also demonstrated reduced oxytocin immunoreactivity in the paraventricular nucleus (PVN) of the hypothalamus and an absence of social interaction-induced long-term potentiation in ventral tegmental dopamine neurons, known projection targets for oxytocin-expressing PVN neurons (Melis et al., 2007). Taken together, these findings support the growing body of epidemiological evidence associating maternal overnutrition to ASD risk (Reynolds et al., 2014; Moss and Chugani, 2014; Krakowiak et al., 2012; Dodds et al., 2011; Getz et al., 2016; Gardner et al., 2015; Bilder et al., 2013; Wallace et al., 2008) and begin to link this risk to inflammatory and neuroendocrine mediated changes
3.2.3. Anxiety- and depression-like phenotypes
Several studies have associated maternal overnutrition with increased anxiety-like behavior in offspring (Wright et al., 2011; Bilbo and Tsang, 2010; Kang et al., 2014; Sasaki et al., 2013; Sasaki et al., 2014). Bilbo and Tsang found that adult male rat offspring exposed to maternal HFD swim faster within the MWM, suggesting an anxiety-like motivation to escape (Bilbo and Tsang, 2010). These animals also spent less time in the open arms of the EPM, supporting an anxiety-like phenotype. Female rats in this model did not exhibit anxiety-like behavior, and in fact several studies have demonstrated sexual dimorphism in the anxiety phenotype. These differences suggest sex effects in brain programming and its behavioral consequences, an assertion that appears to be true in other behavioral phenotypes associated with maternal overnutrition such as locomotor hyperactivity, but may also be indicative of variations in study design (Rivera et al., 2015; Kang et al., 2014; Sasaki et al., 2013). Few studies have evaluated females, and in studies that have, the female estrous cycle, which is known to affect behavior, is often not accounted for (Frye et al., 2000; D’Souza and Sadananda, 2017). There is also the possibility that some behavioral measures used to assess anxiety have different sensitivities in male versus female offspring. For example, Sasaki et al. found increased anxiety-like behavior in both male and female offspring of HFD dams, but this was specific to the elevated plus maze in females and the open field in males (Sasaki et al., 2013). In both males and females, increased anxiety-like behavior was accompanied by decreased baseline corticosterone, slower returns to baseline levels following an acute stress (restraint) challenge, increased gene expression of the glucocorticoid receptor within the amygdala, and altered gene expression of cytokines within limbic areas of the brain, suggesting a similar underlying physiology to sexually dimorphic anxiety-like behavioral phenotypes. In a follow up study, the same group found that as adolescents, male and female offspring of maternal HFD dams have decreased anxiety-like behavior, suggesting that maternal overnutrition may have age-dependent influences on anxiety-like behavior (Sasaki et al., 2014). Fewer studies have evaluated depression-like behavior in offspring exposed to maternal overnutrition, though existing data suggest that maternal overnutrition may have a role in programming this set of behaviors as well. Two studies have found that as adults, rats exposed to maternal HFD exhibit depression-like behavior in the FST (Can et al., 2012; Giriko et al., 2013). Another study evaluating mild CVS in adult offspring exposed to maternal HFD found that maternal HFD sensitized offspring to stress-induced depression-like behavior, with stressed HFD offspring demonstrating reduced sucrose preference, decreased locomotor activity, and increased FST immobility in comparison to stressed offspring from dams fed a standard diet (Lin et al., 2015). In contrast, another group found that maternal HFD may actually mitigate stress-induced behavioral alterations in offspring exposed to early life stress, suggesting a potentially divergent interaction between discrete stressors across the course of development (Rincel et al., 2016).
Epidemiological studies suggest a link between maternal overnutrition and affective problems in children. To date multiple cohort studies have associated maternal overnutrition with increased internalizing pathology, including anxiety and depression symptomatology (Van Lieshout et al., 2013; Mina et al., 2017; Rodriguez, 2010; Robinson et al., 2013). Increasing maternal pre-pregnancy BMI attenuates the normal decline of internalizing symptoms across childhood and adolescence (Van Lieshout et al., 2013). While a positive association between maternal BMI and internalizing psychopathology emerged at age 8, this association increased in strength across childhood through age 17. These results suggest the continued potential for increased anxiety and depression in adults exposed to maternal HFD, but long-term prospective epidemiological studies on adult offspring remain to be conducted.
3.2.4. Schizophrenia-like phenotypes
Despite epidemiological evidence for increased schizophrenia risk in the offspring of obese mothers, few studies have examined models of maternal overnutrition in the context of schizophrenia-like behavior. Contrary to epidemiological data, one study in mouse dams fed HFD found facilitation of prepulse inhibition (PPI) in adult offspring, and no changes in cognition, social behavior, or locomotor behavior (Zieba et al., 2019). Another murine study also found improved PPI in adult offspring, however this was accompanied by cognitive impairment (Wolfrum and Peleg-Raibstein, 2018). It is possible that altered maternal care behavior during the lactation period may partially play into these results. In both studies, HFD exposure was continued until the end of lactation. We have previously shown in rats that dams fed HFD during gestation and lactation exhibit altered maternal care behavior, spending more time nursing their pups and doing so in a more optimal nursing posture (Purcell et al., 2011). In turn, while studies are limited, early-life maternal care appears to influence later-life sensorimotor gating. For example, one study in mice found that adult offspring of dams who spent less time engaged in pup-licking behavior during lactation exhibited impaired PPI compared to offspring of high pup-licking dams (Pedersen et al., 2011). While the limited evidence available creates a largely speculative discussion, it further highlights the importance of distinguishing between the prenatal and early postnatal environments.
In addition, the discrepancy between epidemiological work associating maternal overnutrition and schizophrenia and the limited animal literature suggests a gap that remains to be filled. Two cohort studies have associated elevated maternal BMI with multifold increased risk for schizophrenia in offspring (Jones et al., 1966; Schaefer et al., 2000), and one meta-analysis calculated that children of mothers with diabetes were over 7 times more likely to develop schizophrenia (Cannon et al., 2002). Kawai and colleagues report that schizophrenia risk increases by 24% for every maternal BMI unit increase in early pregnancy and 19% per unit in late pregnancy (Kawai et al., 2004). Considerable work remains to be done to evaluate schizophrenia-relevant phenotypes in animal models of overnutrition.
3.2.5. Summary and future directions
Maternal overnutrition has a significant long-term influence on brain function and behavior in offspring. Existing data suggest that maternal overnutrition is a risk factor for development of behavioral deficits consistent with a number of neuropsychiatric disorders. As with stress and infection, variation in outcomes could stem from differences in type and length of maternal exposure. As an example, obesity or HFD consumption during the pre-conception period alone has been shown to affect oocyte metabolism and morphology (Reynolds et al., 2015). In addition, the comorbidity between metabolic dysregulation and behavioral aberration calls to question whether behavioral phenotypes in offspring are due directly to maternal exposure or indirect, secondary to maternal programming of metabolic dysregulation in offspring. Future studies may be focused on sex differences, determining the degree of interdependence between cognitive and metabolic phenotypes, and determining critical periods of neuropsychiatric risk and resilience in response to maternal overnutrition. Despite these remaining questions, it is apparent that, like stress and infection, maternal overnutrition potentiates offspring neuropsychiatric risk. In the next sections, we examine putative mechanisms underlying this relationship.
4. Potential mechanisms linking maternal overnutrition and offspring neuropsychiatric outcomes
A range of mechanisms linking maternal nutrition to neuropsychiatric outcomes in offspring have been proposed. Like in both maternal psychosocial stress and maternal infection, these include changes to the HPA axis and neuroendocrine communication, metabolic hormones, immune regulation, placental structure and function, neurotrophic signaling, microbiome, and epigenetics. Here we will overview the rationale and evidence for some of the more well studied mechanisms and discuss how they may interact with one another (Table 2).
4.1. Metabolic regulation
Maternal overnutrition consistently results in metabolic impairment in the dam. We have shown that rat dams exposed to a HFD (60% kcal fat) during gestation only have increased plasma leptin by G10, lower plasma adiponectin by G14, impaired glucose tolerance and increased plasma insulin in a glucose tolerance test at G15, and increased adiposity at G21 (Song et al., 2017). Offspring in this model also exhibit metabolic impairment despite being weaned onto a standard chow diet (Tamashiro et al., 2009; Sun et al., 2012; Sun et al., 2014; Sun et al., 2013). While overnutrition induced metabolic impairment in dams is likely important in patterning metabolic programming in offspring, evidence from our lab and others suggests it also has a role in patterning brain development and function (Cordner et al., 2019; Sun et al., 2014; Treesukosol et al., 2014). In addition to their role in energy balance and metabolism, metabolic hormones including insulin, leptin, and ghrelin have been shown to cross the blood brain barrier and act as key regulators of neural development and plasticity (Van Doorn et al., 2017; Ferrario and Reagan, 2018; Fadel et al., 2013; Bouret, 2017). Here we will discuss insulin and leptin as potential candidates linking maternal overnutrition and alterations in offspring brain and behavior.
The brain is densely populated with insulin receptors (Insr) (Abbott et al., 1999; Werther et al., 1987; Kar et al., 1993). Importantly, these receptors are not only found in areas of the brain involved in peripheral metabolic control, such as the hypothalamus, but also in regions relevant to cognition, motivation, and mood regulation (Ferrario and Reagan, 2018; Werther et al., 1987; Kar et al., 1993). These receptors bind peripheral insulin, which crosses the blood brain barrier throughout life (Banks et al., 2012; Banks, 2004). Receptor density is highest during early development, when their activation is postulated to play critical roles in a variety of functions including neurogenesis, neuronal maturation, and synaptogenesis (Kar et al., 1993; Chiu and Cline, 2010). In adulthood, regional insulin signaling is important not only for regulation of energy homeostasis (Schwartz et al., 2000), but also for behavior. Within the hippocampus, insulin signaling regulates structural and functional plasticity via facilitation of glutamatergic and GABAergic activity to promote cognition (Ferrario and Reagan, 2018). Recent evidence suggests that insulin signaling within the hippocampus and amygdala may also coordinate anxiety-like behavior; virally-mediated knockdown of insulin and insulin-like growth factor 1 receptors within either the hippocampus or amygdala increase anxiety-like behavior in adult mice (Soto et al., 2019). Finally, emerging evidence suggests a role for insulin signaling in coordinating neuro-transmitter activity within the nucleus accumbens – ventral tegmental area reward network (Ferrario and Reagan, 2018; Stouffer et al., 2015).
Exposure to overnutrition in adulthood is widely associated with central insulin resistance and resulting cognitive impairment (Fadel and Reagan, 2016). Recent evidence suggests that maternal overnutrition may program similar changes to offspring (Cordner et al., 2019; Schmitz et al., 2018). Insulin does not appear to cross the placental barrier, but glucose does. When glucose is transported in high amounts such as in the context of maternal overnutrition, it has been shown to increase production of insulin by the fetus, thereby exposing the developing fetal brain to a hyperinsulinemic environment (Sullivan et al., 2014; Ford et al., 2009; Oken and Gillman, 2003). Increased insulin action during this period may alter the development of neural circuitry involved in higher order processing (Sullivan et al., 2014). Further, it may prime for future insulin resistance within the offspring brain. A recent study demonstrated that maternal obesity in mice results in hippocampal insulin resistance within adult offspring along with decreased markers of neurogenesis, functional plasticity, and synaptic plasticity (Schmitz et al., 2018). We have shown that cognitive impairment in adult rat offspring exposed to maternal HFD during pregnancy and lactation is preceded by decreased hippocampal expression of Insr and glucose transporter 1 (Slc2a1) at P21, with continued downregulation of Insr in adulthood, though we have not yet evaluated downstream markers of insulin resistance in the brain (Cordner et al., 2019).
Unlike insulin, maternal leptin can directly cross the placenta to act on the developing fetal brain (Luo et al., 2013; Djiane and Attig, 2008). Leptin acts through overlapping signaling cascades with insulin to promote neurodevelopment and cognitive function, and changes to leptin signaling during early life have been shown to alter the development of neural circuitry (Fadel and Reagan, 2016; Djiane and Attig, 2008; Bouret, 2010). We have shown that rat offspring exposed to maternal HFD also exhibit downregulation of hippocampal leptin receptor (Lepr) expression that persists into adulthood (Cordner et al., 2019). These animals additionally exhibit downregulated Lepr in the hypothalamus along with impaired signaling (Sun et al., 2012). It remains to be seen whether hippocampal expression changes in Insr and Lepr within the maternal HF diet model translate to signaling deficits, and the relative contributions of each to altered behavior.
4.2. Immune-related changes
Inflammatory mechanisms have a role in mediating maternal overnutrition-induced changes to brain and behavior. Obesity is considered a state of low-grade inflammation, and increasing adiposity is associated with greater circulating levels of both pro-inflammatory cytokines and markers of systemic inflammation (Hotamisligil, 2006; Howell and Powell, 2017; Segovia et al., 2014; Das, 2001). Overnutrition is additionally associated with inflammation at the level of the placenta, which may be stimulated not only through systemic inflammatory influences but also directly through activation of placental toll-like receptor (TLR)4 (Howell and Powell, 2017; Challier et al., 2008; Lackey and Olefsky, 2016; Basu et al., 2011; Roberts et al., 2011). TLR4, traditionally known to respond to bacterial endotoxin, also binds to and is activated by saturated fatty acids such as those found in HFDs, triggering an inflammatory cascade characterized by production and secretion of pro-inflammatory cytokines (Howell and Powell, 2017; Yang et al., 2016; Yang et al., 2015). In addition, the placenta expresses endogenous lipases, and in obesity possesses increased lipid storage capacity, suggesting that placental TLR4 activation in a state of maternal overnutrition may be induced by increases in both systemically circulating and local fatty acids (Pathmaperuma et al., 2010; Varastehpour et al., 2006; Qiao et al., 2015; Gauster et al., 2011). Obese women have a 3- to 9-fold increase in placental TLR4 expression, which positively correlates with pro-inflammatory interleukin(IL)-6 and IL-8 levels within both systemic circulation and the placenta (Yang et al., 2016). It is unclear to what degree systemic and placental inflammation contribute to fetal inflammation, though it is suggested that both may play a role. Evidence from MIA models suggests that both placental-derived and maternal circulating pro-inflammatory cytokines contribute to cytokine accumulation in the fetal brain (Ponzio et al., 2007; Hsiao and Patterson, 2011; Dahlgren et al., 2006).
While cytokines are well known for their roles in immune system regulation, strong evidence for their functions in neurodevelopment and function suggests that this may be a mechanism through which maternal overnutrition primes neuropsychiatric risk. First, cytokines have pleiotropic roles during normal neurodevelopment, including promotion of neurogenesis, neuronal migration, axon guidance, synapse formation, circuitry refinement, and synaptic plasticity (Deverman and Patterson, 2009). These functions are under tight temporal and spatial regulation over the course of development, and altering the trajectory and magnitude of availability, localization, and balance between different cytokines could disrupt the neurodevelopmental trajectory. Increased pro-inflammatory cytokine levels within fetuses exposed to maternal overnutrition are associated with impaired cognition, increased anxiety-like behavior, and decreased social behavior (Rivera et al., 2015; White et al., 2009; Bilbo and Tsang, 2010; Sullivan et al., 2014; Sanders et al., 2014).
Second, an inflammatory milieu in early life may alter the development and function of astrocytes and microglia, the brain’s resident immunocompetent cells that also perform essential neurodevelopmental functions including support of neuronal proliferation and differentiation, angiogenesis and vascular guidance, apoptosis and debris clearance, synaptogenesis, patterning, and pruning, myelination, and establishment of connectivity. Increased fetal brain inflammation associated with maternal overnutrition may prime microglia towards excessive production of pro-inflammatory cytokines and altered function, which may not only have consequences for the neurodevelopmental trajectory in utero but also persistent consequences, including increased sensitivity to future insult (Bilbo and Schwarz, 2009). For example, Edlow et al. found that maternal obesity in mice primes fetal microglia to overrespond to an immune challenge (Edlow et al., 2018). Bilbo and Tsang demonstrated further that offspring of maternal HFD-fed dams not only have increased microglial activation and Il-1β production within the hippocampus at birth, but also present as adults with increased hippocampal microglial activation at baseline and greater reactivity to an immune challenge, accompanied by increased anxiety-like behavior (Bilbo and Tsang, 2010). Maternal obesity increases proliferation of astrocytes within the hypothalamus, a relationship that is postulated to be mediated by IL-6 (Kim et al., 2016). Emerging evidence also implicates complement proteins and major histocompatibility complex class I molecules in mediating neurodevelopment and these may also be altered in maternal overnutrition (Estes and McAllister, 2015; Hsiao, 2013).
4.3. HPA axis and neuroendocrine hormones
The impact of early life insult on the development and function of the HPA axis has been demonstrated across several maternal stressors, including prenatal stress and immune activation. Neuroendocrine modulation may be a mechanism by which maternal overnutrition promotes neuropsychiatric risk in offspring (Sullivan et al., 2015). In response to stress, the PVN produces corticotropin releasing hormone (CRH) and arginine vasopressin, which stimulate the pituitary to release adrenocorticotropic hormone (ACTH) into systemic circulation. ACTH triggers the release of glucocorticoids from the adrenal cortex, which in turn act on brain regions including the pituitary, hypothalamus, hippocampus, and amygdala to regulate HPA axis activity and stress behavior. Extrahypothalamic populations of CRH in the amygdala and lateral bed nucleus of the stria terminalis are additionally thought to regulate fear and anxiety behavior (Schulkin et al., 1998). In addition to acute stress reactivity, aspects of the HPA axis demonstrate circadian biorhythmicity at baseline (Sage et al., 2001). It is suggested that maternal overnutrition affects both baseline HPA axis activity and stress responsivity in offspring, and that these changes may contribute to altered brain signaling and behavior (Sullivan et al., 2015).
In interpreting the mechanistic role of the HPA axis in behavioral outcomes within offspring exposed to maternal overnutrition, it is important to consider the developmental stage of the offspring at evaluation. In one study by Sasaki et al., adult offspring of rat dams fed a HFD during pregnancy and lactation exhibited decreased baseline corticosterone, increased glucocorticoid receptor expression in the amygdala, and increased anxiety-like behavior (Sasaki et al., 2013). In response to a restraint stress challenge, these offspring demonstrated a heightened corticosterone response followed by a slower return to baseline (Sasaki et al., 2013). Yet in a follow up study, this same group found that adolescent offspring exposed to the same maternal paradigm demonstrate decreased anxiety-like behavior and increased glucocorticoid receptor expression in the hippocampus but not the amygdala (Sasaki et al., 2014). Thus, these changes appear to be age-dependent, likely following the developmental trajectory of the HPA axis and maturation of feedback systems mediating corticosteroid sensitivity (McCormick et al., 2010; Romeo, 2013). Increased glucocorticoid receptor expression in the hippocampus is suggested to inhibit the HPA axis, whereas increased expression in the amygdala potentiates the stress response, demonstrating within this context the developmental and spatial relationship between HPA axis changes and behavior (Groeneweg et al., 2011). Additionally, it appears there may be a relationship between increased exploratory and risk-taking behaviors in adolescence and increased anxiety-like behaviors in adulthood, potentially implicating early stressor-induced alterations in the developmental trajectory of HPA regulation in different abnormal behaviors across development (Jacobson-Pick and Richter-Levin, 2010; Jacobson-Pick et al., 2011; McCormick and Green, 2013). Studies in neonate offspring are limited, but overall it appears that maternal overnutrition increases stress-induced corticosterone release and anxiety-like behavior in pre-weanlings, again reflecting the complexity of the developmental course (D’Asti et al., 2010; Abuaish et al., 2018). In conjunction with age, offspring sex is also of critical consideration as males and females have differential HPA axis responsivity at baseline as well as dimorphic development and maturation of stress circuitry beginning in gestation but continuing throughout life (Bale et al., 2010; Bale and Epperson, 2015).
The complex relationship between maternal overnutrition and neuroendocrine function not only exhibits spatial and temporal sensitivity in terms of developmental trajectory, but may also be highly dependent on type of maternal dietary intervention, diurnal rhythm for baseline measurements, and method of stress challenge. For example, Sasaki et al.’s finding of decreased basal corticosterone in adult offspring was conducted in the middle of the light cycle, whereas Walker and colleagues found increased basal corticosterone during the dark but not light cycle (Sasaki et al., 2013; Walker et al., 2008). Niu et al. sampled basal plasma corticosterone over a 24-h period and found an overall increase secondary to increases in both pulse frequency and amplitude of corticosterone secretion (Niu et al., 2019). Consistent with Sasaki’s group, however, Niu and colleagues went on to demonstrate that offspring have heighted stress responsivity, exhibiting increased corticosterone levels and slower negative feedback following acute restraint stress, and additionally that they exhibit attenuated habituation to repeated restraint stress (Niu et al., 2019). Niu also showed that maternal HFD-induced stress sensitization was dependent on the amygdala (Niu et al., 2019). Overall, while methodological considerations appear to greatly influence findings, maternal HFD appears to change the developmental trajectory and function of the HPA axis in offspring, and these changes may underlie offspring changes to brain and behavior.
5. The placenta as an integrator and propagator of allostatic load
It is important to note that metabolic, immune, and neuroendocrine pathways exhibit significant co-regulation and crosstalk. Pregnancy is a state of normally occurring allostasis, where the body must maintain maternal health while changing physiological set points towards protection and resource allocation for the developing fetus (Power and Schulkin, 2012). These changes occur in temporal sequence across the metabolic, neuroendocrine, and immune systems, and changes within each system may influence one another. Disruption to any of these axes by maternal overnutrition may potentiate disruptions within the other systems towards a multisystem allostatic overload that can only be conveyed to the developing fetus through one organ: the placenta. The placenta serves as both messenger and sentinel between the mother and developing fetus, but its function in that role is adversely impacted by systemic dysregulation. For example, the placental inflammation associated with maternal overnutrition is not only the result of increased cytokine production from adipose tissue and direct effects of fatty acids at the placenta, but also likely impacted by dysregulation of metabolic hormones that can act as adipokine immune mediators. Leptin, high in obese pregnancy, has structural similarity to IL-6 and pro-inflammatory action (Iikuni et al., 2008; Lappas et al., 2005); adiponectin, low in obese pregnancy, has anti-inflammatory action (Ouchi and Walsh, 2007). Leptin and insulin also act through converging pathways with cytokine signaling (Iikuni et al., 2008; Shoelson et al., 2006). Thus, in gestational diabetes for example, inflammation at the placenta can promote both placental insulin resistance and maternal hyperglycemia, potentially increasing the metabolic dysregulation experienced by the fetus (Feng et al., 2016). In another example of placental pathway convergence, placental 11β-hydroxysteroid dehydrogenase type 2, an enzyme that inactivates glucocorticoids and protects the fetus from exposure to excess maternal glucocorticoids, is inhibited by pro-inflammatory cytokines, representing a mechanism by which maternal overnutrition-associated inflammation may increase fetal exposure to glucocorticoids (Kossintseva et al., 2006). Thus, the placenta is itself vulnerable to the effects of overload via alterations in its structure and function thereby amplifying an environment of dysregulation in the fetal compartment. In this section, we will use lessons learned from the stress and infection literature to comment on how maternal overnutrition may increase risk for offspring psychopathology by altering placental structural integrity, nutrient transfer, and neurotrophic communication (Table 2).
5.1. Structural integrity and nutrient transfer
Placental structure and sufficiency are critical for proper growth and development of the fetus. Placental insufficiency as seen in excessive maternal inflammation is associated with spontaneous miscarriage. Yet even mild disruptions of placental architecture can alter the capacity of the placenta to provide oxygen and nutrients to the fetus, changing the trajectory of fetal growth and development and potentially promoting neuropsychiatric risk. This mechanism has been studied more extensively in the context of MIA, where there is loss of placental integrity, decreased blood perfusion to the fetus, and perinatal brain damage. Evidence suggests that maternal overnutrition may also alter placental cytoarchitecture and blood flow. In non-human primates (NHP), exposure to maternal HFD increases placental inflammation and decreases uterine blood flow volume even in lean, metabolically unimpaired mothers. In obese, hyperinsulinemic mothers, HFD exposure additionally reduces fetal compartment blood flow and induces placental infarctions, increasing frequency of stillbirth (Frias et al., 2011). Behaviorally, the offspring of HFD fed NHP mothers display greater anxiety despite weaning onto a low-fat control diet (Thompson et al., 2017). Studies in rodent models are consistent for placental structure changes, but mixed for blood flow capacity. Hayes et al. found that maternal HFD-induced obesity in rats increases placental inflammation, impairs vascular maturation, induces placental hypoxia, and compromises fetal growth and viability (Hayes et al., 2014), whereas Mark et al. showed decreased placental and fetal size and increased inflammation without changes to markers of vascular development (Mark et al., 2011). We have found that in rats provided maternal HFD the thickness of the placental labyrinth layer is reduced, suggesting reduced vascular capacity, but we have not examined hemodynamics in this model (Song et al., 2017). Even without frank changes to blood flow, reductions in placental thickness and integrity may alter the protective capacity of the placenta against systemic dysregulation.
The impact of maternal overnutrition on placental nutrient transfer has been more widely studied. The three major nutrient substrates for the growing fetus are glucose, lipids, and amino acids. Epidemiological and animal model studies suggest that maternal overnutrition may alter fetal exposure to these substrates by altering placental nutrient sensing, metabolism, and levels of nutrient transporters themselves (Song et al., 2017; Gallo et al., 2017). The variable interplay between reduced placental thickness and increased nutrient transporters may account for the range of aberrant birth weights associated with maternal overnutrition, from small for gestational age to macrosomia (Howell and Powell, 2017). This interplay may also reflect on the range of neuropsychiatric phenotypes associated with maternal overnutrition, as these nutrient substrates are also the building blocks for the developing brain.
5.2. Neurotrophic communication
In addition to its role as an arbiter of maternal signaling, the placenta is a significant source of neurotrophic signals to the developing fetal brain. Serotonin (5-HT) is produced by the placenta and is critical for normal brain development (Bonnin et al., 2011). In addition to its action in mood regulation, 5-HT signaling during fetal life has a significant role in promoting neurogenesis, neuronal migration, axon guidance, and synaptogenesis (Bonnin et al., 2011; Velasquez et al., 2013). Since the early fetal brain does not have the capacity to produce 5-HT, it is synthesized in the placenta from maternal l-tryptophan (TRP). Placental 5-HT is necessary for fetal brain development until the arrival of serotonergic projections from the dorsal raphe in mid-gestation (Bonnin et al., 2011). Too much or too little placental 5-HT availability during this early period leads to developmental alterations, including aberrant serotonergic outgrowth and abnormal development of the major thalamocortical axon tract (Goeden et al., 2016). A seminal study by Goeden et al. demonstrated that poly(I:C)-induced inflammation (a moderate immune challenge) in mouse dams increases placental synthesis of 5-HT via a transient increase in substrate availability of maternal TRP to the placenta and subsequent increase in the expression and biosynthetic activity of placental tryptophan hydro-xylase 1 (TPH1). Increased placental output of 5-HT accumulates in the fetal forebrain and blunts serotonergic axon outgrowth from the hind-brain (Goeden et al., 2016). Proinflammatory cytokine treatment has additionally been shown to reduce survival of 5-HT neurons within the dorsal raphe and substantia nigra (Hochstrasser et al., 2011). Impairment of central serotonergic signaling is implicated across several neuropsychiatric illnesses associated with maternal overnutrition including ASD, ADHD, and mood disorders.
Indeed, animal models suggest that maternal overnutrition may impair development of the brain serotonergic system, resulting in lower 5-HT production and signaling. Non-human primates exposed to maternal HFD have reduced gene expression in the 5-HT synthesis pathway in the dorsal raphe and decreased serotonergic immunoreactivity in the prefrontal cortex, with concomitant anxiety and hyperactivity (Sullivan et al., 2015; Sullivan et al., 2010). Rats exposed to maternal HFD have increased expression of the 5HT1A receptor within the ventral hippocampus, maybe a compensatory response to reduced 5-HT availability, leading to increased anxiety-like behavior (Peleg-Raibstein et al., 2012).
In addition to potential consequences from overnutrition-induced placental inflammation, insulin appears to be a regulator of placentally sourced 5-HT by modulating cell surface localization of serotonin transporter (SERT) within the placenta, suggesting a potential convergence of mechanisms by which maternal overnutrition may alter the availability of 5-HT to the fetal brain and subsequent serotonergic system development (Murthi and Vaillancourt, 2019).
Importantly, 5-HT synthesis accounts for less than 5% of normal TRP metabolism, most of which occurs through the kynurenine (KYN) pathway (Gal and Sherman, 1980). Placental KYN pathway components are also upregulated in inflammation, and there is evidence for KYN system alterations within the brains of offspring exposed to maternal HFD, suggesting another possible pathway through which maternal overnutrition may promote neuropsychiatric risk (Winther et al., 2018; Schwarcz et al., 2012; Williams et al., 2017; Campbell et al., 2015; Manuelpillai et al., 2005). In the study by Goeden et al., in addition to augmenting TRP availability and upregulating TPH1 gene expression, maternal poly(I:C) injection also upregulated placental gene expression of indoleamine 2,3-dioxygenase (IDO1), responsible for converting maternal TRP to KYN, and subsequently increased KYN concentrations within the fetal brain (Goeden et al., 2016). In another, more severe model of intrauterine infection and inflammation, Williams et al. report upregulation of the placental KYN pathway and increased fetal brain accumulation of KYN (Williams et al., 2017). Here, the authors found decreased placental TRP and an increased KYN:TRP ratio, suggesting that TRP was shunted away from 5-HT synthesis pathway, potentially (placental 5-HT was not measured) resulting in a decrease in placental 5-HT availability for the developing fetal brain. There has been limited examination of the placental KYN pathway in maternal overnutrition, but one clinical study found a positive correlation between BMI and plasma KYN in pregnant women (Groer et al., 2018). High BMI was also associated with decreased plasma TRP, suggesting a potential reduction in substrate availability as well as possible shunting towards KYN production at the level of the placenta, though exact placental changes remain to be determined (Groer et al., 2018). These examples illustrate that inflammation may have varying effects on placental 5-HT and that the severity of immune challenge or inflammatory response may dictate whether 5-HT production and signaling is decreased or increased. Nevertheless, such immune stressors ultimately lead to similar neuropsychiatric outcomes via an altered 5-HT system.
In addition to 5-HT, the placenta also produces BDNF which facilitates placental development and metabolism. Both maternal and placental BDNF cross the placental barrier into fetal circulation to reach the fetal brain (Kodomari et al., 2009; Antonakopoulos et al., 2018) where it plays a critical role in supporting neuronal survival, synaptic transmission, plasticity, growth, and repair (Reichardt, 2006). Maternal overnutrition decreases BDNF expression within the cortex and hippocampus of offspring, and the decrease in BDNF associates with cognitive impairment (Tozuka et al., 2010; Cordner and Tamashiro, 2015; Page et al., 2014; Arnold et al., 2014; Yamada-Goto et al., 2012). Maternal obesity has been shown to impair placental BDNF signaling (Prince et al., 2017). Additionally, elevated glucocorticoids associated with maternal stress has been shown to alter BDNF within the placenta and offspring brain (Suri and Vaidya, 2013; Kertes et al., 2017) and may thus contribute to maternal overnutrition and maternal stress associated behavioral deficits.
5.3. Sex differences and the placenta
The number of studies in which male and female offspring are both evaluated remain limited, but existing studies suggest sex differences in offspring behavior and physiology across stressors. Recent work has suggested that these differences may emerge in part at the level of the placenta, consistent with its role as an integrator and propagator of maternal stress. The placenta is sexually dimorphic, with differences emerging as early as the trophectoderm stage of embryogenesis (Bale, 2016; O’Connell et al., 2013; Sood et al., 2006). Studies across a variety of maternal insults have revealed sexually dimorphic placental responses to stressors (Bronson and Bale, 2016; Davis and Pfaff, 2014; Sandman et al., 2013; Mao et al., 2010; Howerton et al., 2013; Bronson and Bale, 2014; Dunn et al., 2011; Gabory et al., 2013; Clifton, 2010). In general, the XY placenta appears to be more sensitive to environmental change, whereas the XX placenta is relatively resistant (Bale, 2016), suggesting that such differential responses may, in part, underlie sexually divergent brain development and behavioral outcomes. As an example, Bale and colleagues have found that O-linked N-acetylglucosamine transferase (OGT), an X-linked gene expressed in the placenta, is decreased in response to maternal CVS during early gestation in both male and female offspring. Under normal conditions, OGT expression is lower in the XY placenta compared to XX placenta because OGT escapes X-inactivation and is biallelically expressed in XX placentas. Thus, maternal stress resulted in even lower OGT in stressed XY placentas compared to unstressed placentas from both sexes as well as stressed XX placentas (Howerton et al., 2013; Howerton and Bale, 2014). OGT plays a critical role in chromatin remodeling and reduced OGT was associated with significant transcriptional changes in the placenta and brain that was consistent with behavioral and physiological abnormalities in male, but not female, offspring exposed to maternal stress, as well as in unstressed mice with targeted placental deletion of OGT (Howerton et al., 2013; Howerton and Bale, 2014). The OGT story thus illustrates one way in which the placenta may mediate sex-specific effects of gestational stress on offspring.
6. Final perspectives
It is now clear that diverse maternal stressors including psychosocial stress, infection, and overnutrition result in overlapping neuropsychiatric outcomes for offspring. Considering the shared outcomes across diverse stressors, some have started to investigate common etiologies, and evidence supporting this idea is growing. As has long been recognized in the adult stress literature, it is increasing clear that the concepts of allostatic load and allostatic overload apply to maternal stressors, with aberrant neurodevelopment and neuropsychiatric risks to offspring emerging from stress effects on interacting maternal regulatory systems, the placenta, and the developing fetal brain (Fig. 1).
Fig. 1.
Different maternal environmental stressors lead to common neuropsychiatric risk profiles in offspring. Epidemiological and animal model studies associate maternal stress, infection, and altered nutrition with increased risk for an overlapping range of neuropsychiatric outcomes in offspring, including cognitive impairment, anxiety, depression, schizophrenia, and autism spectrum disorders. Evidence suggests that these stressors act via converging pathophysiological pathways characterized by systemic allostatic overload across regulatory systems including the hypothalamic–pituitary–adrenal (HPA) axis, metabolic signaling, and inflammatory pathways. The placenta acts as an integrator and propagator of allostatic overload, not only communicating the maternal environment to the fetus but also altering its own structural and functional capacity in response. The developing fetus, patterned in an environment of dysregulation, is programmed towards increased neuropsychiatric risk. Created with BioRender.com.
Common risks and mechanisms across various stressors have attracted greater attention and the information gained will be critical in identifying potential interventions that could apply to a wide variety of developmental “stressors”. Collaboration across disciplines and innovations in design and analysis that can better account for the ways in which different stressors overlap and interact with each other will facilitate advancement in the field. Importantly, individuals exposed a particular stressor are often the same individuals at highest risk for facing other stressors, suggesting that successful interventions should also be broad in scale. As such, behavioral interventions may not only be more accessible to those at risk, but may also allow for more widespread mechanistic action, functioning across multiple systems to broadly promote neuropsychiatric resilience.
In the interest of translating findings to humans, pre-clinical studies that incorporate individual differences and experiences rather than simply single-variable group effects are needed. Thompson and colleagues recently utilized multivariate analysis in a non-human primate model of maternal overnutrition, concluding that maternal pre-pregnancy adiposity and gestational HFD consumption exert unique effects on offspring behavior (Thompson et al., 2018). Thompson’s work demonstrates the ability to utilize more sophisticated statistical modeling to go beyond single variable associations towards a more complex, nuanced understanding of underlying etiology. Although resources limit extensive collection of multisystem variables across all studies, more robust collaboration across disciplines and open-source reporting of raw data from individual studies may offer alternatives. Expanding such databases would significantly increase our ability to compare between studies and stressors, identify promising etiological pathways, and design and test interventions.
Acknowledgements
The authors thank Dr. Timothy H. Moran for enlightening conversations and his continual mentoring and guidance. This work was supported by the National Institutes of Health (NIH) HD093338 (S. G. K.), the Greif Family Scholar Fund (Z. A. C.), NIH MH108944 (K. L. T.), and the Dalio Philanthropies.
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