The impact of obesity and hypercaloric diet consumption on anxiety and emotional behavior across the lifespan

Accepted Manuscript Title: The impact of obesity and hypercaloric diet consumption on anxiety and emotional behavior across the lifespan Authors: Kathryn D. Baker, Amy Loughman, Sarah J. Spencer, Amy C. Reichelt PII: DOI: Reference:

S0149-7634(17)30429-3 https://doi.org/10.1016/j.neubiorev.2017.10.014 NBR 2975

To appear in: Received date: Revised date: Accepted date:

10-6-2017 14-10-2017 15-10-2017

Please cite this article as: Baker, Kathryn D., Loughman, Amy, Spencer, Sarah J., Reichelt, Amy C., The impact of obesity and hypercaloric diet consumption on anxiety and emotional behavior across the lifespan.Neuroscience and Biobehavioral Reviews https://doi.org/10.1016/j.neubiorev.2017.10.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

The impact of obesity and hypercaloric diet consumption on anxiety and emotional behavior across the lifespan Kathryn D. Baker 1, Amy Loughman 2, Sarah J. Spencer 2 Amy C. Reichelt 2* 1 2

School of Psychology, UNSW Sydney, NSW, 2052, Australia

School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC, 3083, Australia

* Corresponding author Amy Claire Reichelt School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC 3083, Australia Email: [email protected] Highlights    

High incidence of anxiety disorders in people with obesity Common neurobiological mechanisms link obesity and mood disorders We describe effects of hypercaloric diets during various neurodevelopmental periods Increased rates of obesity in young people may promote anxiety disorder development

Abstract Obesity is an increasing problem in young people. Childhood obesity and overweight have increased rapidly on a global scale, and have tripled in the past 30 years, to affect approximately one in five children. Diets high in refined fats and sugar are a major contributor to the development of obesity, and the effects of such obesity-inducing hypercaloric diets on brain function may contribute to the high prevalence of anxiety disorders in people with obesity. Anxiety disorders typically emerge in childhood and adolescence, and symptoms often continue into adulthood. Based on this symptomology, we consider anxiety-related behavioral consequences of hypercaloric diets across development. We review research on the effects of hypercaloric dietary manipulations across the lifespan on emotion regulation and the neurobiological mechanisms that underpin these processes. Cumulatively, the findings reveal that gestation and the juvenile/adolescent developmental periods may be early-life windows of vulnerability for developing anxiety in later life due to the augmented effects of these diets on neuroendocrine stress systems and the maturation of neural circuitry supporting emotion regulation.

1

Keywords: Obesity; anxiety; high fat diet; adolescence; neurodevelopment; stress

2

3

1. Introduction – Anxiety, high energy diets and diet-induced obesity There is growing recognition that poor diet quality is associated with a high prevalence of mood and anxiety disorders not only in adults (Akbaraly et al., 2009; Jacka et al., 2010b; Sanchez-Villegas et al., 2009; Sanchez-Villegas et al., 2012), but, perhaps more alarmingly, in children (Kohlboeck et al., 2012) and adolescents (Jacka et al., 2011; Jacka et al., 2010a; Weng et al., 2012). Poor quality food and excessive consumption of fats and sugars is, not surprisingly, associated with the development of obesity, a problem which is becoming increasingly prevalent amongst young people. In 2013, 23% children and adolescents were overweight or obese in developed countries (Vogt et al., 2014), and within the United States the prevalence rate was as high as 31% of children and adolescents (Ogden et al., 2014). However in terms of absolute numbers, there are more overweight and obese children living in low- and middle-income countries than high-income countries (Vogt et al., 2014), highlighting that overweight and obesity in childhood is a global problem. Obesity has both immediate and enduring impacts on the physical, social, and emotional health of an individual (Dreber et al., 2017; Haslam and James, 2005; Kasen et al., 2008). There is growing recognition for a reciprocal, bidirectional link between obesity and affective disorders including anxiety (Faith et al., 2011; Mansur et al., 2015; Stunkard et al., 2003). Anxiety disorders are one of the most common mental conditions, with current prevalence rates around 7% (Baxter et al., 2013) and lifetime prevalence rates of around 2030% (Slade et al., 2009). Furthermore, obesity is associated with an approximately 25% increase in the odds of developing mood and anxiety disorders (Scott et al., 2008) and the prevalence of depressive symptoms is much higher in obese people than in the normal-weight age-matched population (Luppino et al., 2010; Pan et al., 2012; Roberts et al., 2003). The increased risk of mental illness in those that are obese is concerning not only for adults, but particularly for young people. Adolescence and young adulthood is a peak period of mental illness onset, especially for affective disorders (Kessler et al., 2012; Lee et al., 2014). Anxiety disorders are the most common form of mental illness in adolescence, and these disorders commonly emerge during late childhood and adolescence (Kessler et al., 2012; KimCohen et al., 2003). The complex interaction of obesity and mental illness in young people is illustrated by findings that anxiety or mood disorders in adolescence increases the risk of individuals subsequently becoming overweight or obese (Roberts and Duong, 2013, 2016). However, social factors also contribute to obesity-related affective disorders. Children with obesity have increased incidences of being bullied and teased compared with their normal-

4

weight peers (Griffiths et al., 2010; Puhl et al., 2013; van Geel et al., 2014) and are more likely to suffer from social isolation, depression, and lower self-esteem (Puhl and Luedicke, 2012), all of which may predispose anxiety and mood disorders. These findings are consistent with the increased risk of depression, anxiety disorders, and post-traumatic stress disorder (PTSD) in obese youth compared to non-obese youth (Britz et al., 2000; Perkonigg et al., 2009). Adolescents and young adults with severe obesity also report experiencing more emotional suffering due to psychosocial problems than due to obesity-associated physical health problems such as type-2 diabetes and metabolic syndrome (Dreber et al., 2017; Freedman et al., 2007; Han et al., 2010; Rees et al., 2014). Nevertheless, social factors alone are insufficient to explain the high incidence of anxiety among those with obesity, with genetic, epigenetic, and developmental factors contributing to both anxiety and obesity, as well as a proximate effect of central nervous system alterations resulting from either obesity or anxiety having reciprocal effects. This complexity illustrates the need to understand how obesity during development affects emotional regulation and mood. 2. Obesity, hypercaloric diets, and animal models. Obesity in humans is typically defined as a body mass index (BMI) >25 with additional literature suggesting excess visceral fat, even in the absence of high BMI, is metabolically damaging (Bergman et al., 2006). In animal models, obesity is less well defined, as rats and mice can develop extremes of body weight and adiposity without necessarily displaying insulin resistance or glucose intolerance indicative of metabolic syndrome that is associated with obesity. Diet-induced obesity in animal models is produced by manipulations of macronutrient content, particularly with respect to fat and/or sugar. However, when considering effects across studies, variability in dietary fat and/or sugar composition, whether the diet is available intermittently or continually, and duration of diet exposure typically evokes observable differences in metabolic and behavioral outcomes. Variations in macronutrient content is particularly important to consider for studies that utilize “junk food” or “cafeteria” diets where highly processed convenience foods such as cookies, cakes, and potato chips are used to manipulate macronutrient parameters (e.g. (Reichelt et al., 2015b; Robinson et al., 2015; Vollbrecht et al., 2015)). These diets are potentially more reflective of a varied “Western” diet consumed by people both in daily life and in experimental studies (Attuquayefio et al., 2017) than pelleted formulations, however, the exact dietary conditions are difficult to replicate across laboratories, and consumption can vary across animals depending on individual preferences. More so, the composition of high-fat diets should also be taken into consideration,

5

with many “high-fat” pelleted diets having high levels of sucrose, yet are reported simply as high-fat, or elsewhere as “Western Style”. In these cases, high-fat and high-sugar may be a more accurate description of the macronutrient content. High-sugar diets are typically mimicked through the addition of liquid sucrose to standard laboratory chow diets (sucrose concentrations vary between 5% - 30%; e.g. (Harris and Apolzan, 2012; Reichelt et al., 2015a; Reichelt et al., 2016; Vendruscolo et al., 2010)). The addition of liquid sucrose can result in weight gain and increased adiposity between experimental groups, but even in absence of weight differences, behavioral and metabolic alterations are typically observed with this manipulation. Thus, the range of macronutrient profiles in experimental diets, and also the varied diets consumed by people worldwide, is important to consider. Despite these variations, the functional outcomes of hypercaloric diets is of great importance for mental health and wellbeing, as will be discussed in this review. An advantage of laboratory studies using rodents (typically rats and mice) is that the controlled manipulation of diet consumption during specific periods of neurodevelopment is possible. Such studies have allowed the examination of the immediate and long-term metabolic, physiological, and behavioral consequences of hypercaloric diets for the individual as well as the effects of parental obesity on offspring. In this review, we discuss the impact of obesity and hypercaloric diet consumption during the early-life period from conception through to late adolescence / early adulthood on anxiety and anxiety-like behaviors, addressing both clinical data from humans and corresponding findings in animal models. Drawing developmental stage comparisons between rodent models and humans is complex, the first two weeks of postnatal (P) life (i.e. P0-P14) in rat/mouse models can be regarded as approximately equivalent to the third trimester in humans. Many studies examining cognition and behaviour define rat/mouse models as infants (e.g. P15 – P18), juveniles (e.g. P20-P26), and adolescents (P28-P50) (Campbell and Spear, 1972; Rudy and Morledge, 1994). Moreover, we discuss evidence from a variety of dietary manipulations in animal models, as well as from humans with differing degrees of overweight, obesity, and metabolic dysfunction. 3. The effects of parental obesity on offspring neurodevelopment and anxiety-like behavior The gestational environment is critical for the optimal growth and development of the offspring, and obesity in pregnancy is associated with multiple metabolic changes to the mother that can potentially adversely affect the development of her offspring. This programming effect is described in the fetal programming hypothesis (Gluckman et al., 2005), which proposes that

6

changes in neonatal development as a consequence of the intrauterine environment increases the risks of offspring developing obesity (Lawlor et al., 2007) and mood disorders (Rice et al., 2007). With 64% of women of reproductive age in the United States being overweight, and 35% obese (Flegal et al., 2012), the prevalence of maternal overweight and obesity is a serious concern. Obesity among pregnant women in the United States is common, with estimates ranging from 20 to 38% (Yogev and Catalano, 2009), and this trend is also observed worldwide. Antenatal anxiety combined with maternal obesity may be one of the relevant pathways of risk of neurodevelopmental problems, as an estimated 15% of the burden of behavioral problems in early childhood is attributable to antenatal mental health problems (Talge et al., 2007), and it is known that consumption of unhealthy, hypercaloric Western-style diets before, and during, pregnancy increases the risk of mood disorders in the mother (Okubo et al., 2011). However, associations between antenatal anxiety symptoms and obesity are mixed, with only some studies reporting increased odds of antenatal anxiety in obese women (Claesson et al., 2010; Molyneaux et al., 2014; Van den Bergh et al., 2005). Nonetheless, it could be proposed that even if the associations between obesity and risk of anxiety disorders in pregnancy are comparable to those in the non-pregnant population, the public health consequences of maternal obesity are noteworthy for their intergenerational effects (Gariepy et al., 2010; Luppino et al., 2010). Maternal obesity is a particular risk factor for adverse offspring neurodevelopment and later mental health (see Kingston and Tough (2014) for systematic review). For example, a cohort study of Australian adolescents by (Allen et al., 2009) found that each increase of one unit in maternal BMI increased the odds of a diagnosed mood or anxiety disorder in offspring by 7%, demonstrating an intergenerational link between elevated maternal weight and increased risk for psychiatric disturbance. Animal model studies have demonstrated behavioral, emotional, and cognitive alterations to offspring following perinatal exposure to maternal obesity from the consumption of hypercaloric diets (Bilbo and Tsang, 2010; Sullivan et al., 2010). The timing of high-fat feeding in rats during the perinatal period appears critical for the neurodevelopment of offspring. Adult rats weaned on standard chow, but whose dams were fed high-fat diets during gestation, show increased anxiety-like behavior measured by reduced time spent in the open arms of an elevated plus maze (EPM) compared with those fed standard-chow in gestation, demonstrating the intergenerational impact of this diet (Bilbo and Tsang, 2010). Although exposure to high-fat diet during gestation increases offspring anxiety, high-fat diet during

7

lactation is associated with reduced levels of anxiety in male offspring (Wright et al., 2011). These studies together indicate that perinatal exposure to high-fat diets during gestation, but not during the early life suckling period (typically from birth to postnatal day 21 in the rat), increases the risk of anxiety-like behaviors in offspring during adulthood. Increased anxiety-like behavior in the offspring of mothers fed high-energy diets is evident very early in life in non-human primates (Japanese macaques, Macaca fuscata). Infant macaques exposed to maternal high-fat diet and maintained on this diet are more anxious when confronted with threatening novel objects, and display more anxious and/or aggressive behavior towards an unfamiliar human intruder, than infants exposed to a control diet (Sullivan et al., 2010; Sullivan et al., 2011). A further recent study from this group demonstrated that the anxiogenic effects of maternal high-fat diet endured into the juvenile period. Accompanying these behavioral changes were alterations in central serotonin synthesis and stress responsiveness through cortisol signaling pathways, suggesting that maternal high-fat diet influences both brain circuitry and endocrine functions in offspring. Moreover, the increased anxiety effect was not ameliorated by switching to the standard control diet at weaning, suggesting an early nutritional intervention was not sufficient to attenuate the effects of maternal high-fat diet (Thompson et al., 2017). However, nutritional interventions during lactation, as opposed to those delivered from weaning, can reverse enduring effects on anxietylike behavior of adolescent mice offspring of dams fed high-fat diet in the prenatal period (Kang et al., 2014), suggesting that nutritional interventions earlier in life, perhaps not surprisingly, are more effective in ameliorating anxiety than those later on. Rat studies have noted that the offspring of perinatal high-fat diet-exposed dams have an age-dependent anxiety-like phenotype when tested as adolescents (Sasaki et al., 2014) as compared to adults (Sasaki et al., 2013). Specifically, Sasaki and colleagues demonstrated that the offspring of high-fat diet fed dams had reduced anxiety behaviors measured by the EPM and open field in adolescence (Sasaki et al., 2014) but higher levels of anxiety-like behavior as adults (Sasaki et al., 2013). When taken together with findings in primates (Sullivan et al., 2010; Sullivan et al., 2011; Thompson et al., 2017), perinatal high-fat diet may induce anxietylike responses early in life during infancy, the juvenile period, and also in adulthood, but not in adolescence. One potential explanation for the later emergence of anxiogenic behavior is that maternal obesity induces long-term alterations to endocrine systems regulating response to stressors, as reviewed in the following section.

8

--- FIGURE 1 HERE --3.1. Maternal obesity-induced changes to stress response systems One mechanism by which maternal obesity induces behavioral changes in offspring is through long-term alterations in the activity of the hypothalamic–pituitary–adrenal (HPA) axis, the system which controls hormonal responses to stress (see Figure 1). Evidence from several animal models demonstrates that environmental factors, such as hypercaloric diets, during perinatal development program the long-term function of the HPA axis. During infancy and childhood there is a period of stress hyporesponsivity in rodents, primates, and humans (Gunnar and Quevedo, 2007). However, the offspring of female primates fed a high-fat diet have increased hair cortisol, a measure of long-term exposure to cortisol, at weaning (Thompson et al., 2017). This finding indicates that maternal high-fat diet induces early chronic stress and may program increased HPA axis activity throughout the lifespan. The transition to adolescence in humans is accompanied by increased cortisol responses to stressors (Gunnar et al., 2009) and studies in rodents reveal that adolescents show prolonged glucocorticoid responses to acute stressors compared to adults (see (Romeo, 2013; Romeo et al., 2016)). Adult rats exposed to high-fat diets during gestation have protracted corticosterone levels following an acute restraint stress challenge compared with normal chow-fed rats (Sasaki et al., 2013), indicating less efficient HPA axis feedback that may indicate a delayed maturation of the stress response system. The increased corticosterone-mediated response to stress may occur because of increased expression of glucocorticoid receptors that control the response to acute stressors in the amygdala of offspring exposed to perinatal high-fat diet (Sasaki et al., 2013). Whilst it is unclear whether perinatal high-fat diet has direct effects on the HPA axis, indirect effects through inflammatory pathways are also possible as there is evidence of the increased expression of several pro-inflammatory genes in adult offspring exposed to perinatal high-fat diet (Sasaki et al., 2013). Thus, the impact of maternal hypercaloric diets on anxiety-like responses may arise through an increase in HPA axis activity early in life, and as a consequence of delayed maturation of the stress response systems from the adolescent phenotype into that of adults.

3.2. Maternal obesity alters reward systems and serotonin signaling in offspring In addition to dysregulation of the HPA axis, alterations to the function of central reward systems, including dopaminergic, serotonergic and opioid signaling, has been observed 9

in offspring of maternal obesity and/or maternal consumption of a high-fat diet during pregnancy (Grissom et al., 2014; Naef et al., 2011; Ong and Muhlhausler, 2011; Teegarden et al., 2009; Vucetic et al., 2010). The offspring of dams exposed to high-fat or high-sugar diets during pregnancy and/or lactation show an increased preference for high-fat or high-sugar foods as adults, and alterations in monoamine signaling in reward systems in offspring may be an underpinning mechanism (Bayol et al., 2007; Ong and Muhlhausler, 2011; Teegarden et al., 2009; Vucetic et al., 2010). Importantly, these observations suggest that offspring that are exposed to maternal obesity and/or hypercaloric diets during gestation are at an increased risk of developing diet-induced obesity, and potentially affective disorders, as a consequence of this dysregulation of reward signaling (Figure 1). Maternal high-fat diet consumption has been shown to cause perturbations in the central serotonergic (or 5-hydroxytryptamine, 5-HT) system of the offspring (Levin and DunnMeynell, 2002; Sullivan et al., 2010), which is a likely mechanism contributing to changes in emotion regulation in offspring. Serotonin is intrinsically linked to both the regulation of mood and appetite (Lam et al., 2010), and anxiety has been linked to reduced serotonergic tone (Gordon and Hen, 2004). Animal studies find that low serotonin levels that induce alterations to mood regulation are associated with increased food intake due to the actions of serotonin within the hypothalamus. Serotonin in this region inhibits the expression of neuropeptide-Y (NPY), which reduces hunger and leads to decreased food intake (Blundell et al., 1995; Lawton et al., 1995). However, under low hypothalamic serotonin conditions, NPY promotes hyperphagia and weight gain (Neary et al., 2004). Whilst the actions of serotonin in the brain are related to mood regulation and weight gain, this is not the only route by which alterations to serotonin levels induced by obesity might affect behavior of an individual as well as their offspring. Up to 90% of serotonin synthesis, from its precursor tryptophan, and storage occurs in the enterochromaffin cells in the gastrointestinal epithelium, a process which is mediated both directly and indirectly by gut microbiota (Keszthelyi et al., 2009). The gut microbiota provide a bidirectional route of communication between the CNS and gastrointestinal tract via mechanisms such as the synthesis of serotonin, stimulation of the vagus nerve, the production of neuroactive metabolites such as butyrate, and modulation of the HPA axis (Dinan and Cryan, 2017). The role of gut microbiota in anxiety has been demonstrated by animal and human studies alike. Anxiety-like behavior is observed in mice with disruptions to gut microbiota via infections and gut inflammation (Foster and McVey Neufeld, 2013), and such behavioral phenotypes can be

10

‘transferred’ to germ-free rodents from either anxious-type BALB/c mice or human patients with anxiety via faecal microbiota transplant (Bercik et al., 2011; Kelly et al., 2016). The gut microbiota are significantly impacted by diet and are bidirectionally implicated in obesity (David et al., 2014; Turnbaugh et al., 2006). Indeed, maternal obesity has been shown to alter the gut microbiome of their offspring, suggesting a further intergenerational mechanism by which offspring behavior may be affected by maternal diet (Gohir et al., 2015; Wallace et al., 2016). Whilst the concept of a placental microbiome (Aagaard et al., 2014) is controversial (Kim et al., 2017; Perez-Munoz et al., 2017), there is growing evidence regarding the relevance of the maternal diet and gut microbiota for offspring neurodevelopment and behavior (Foster and McVey Neufeld, 2013; Galley et al., 2014; Hsiao et al., 2013; Jacka et al., 2013; Ma et al., 2014). In support of the proposal that early life gut microbiota impacts on neurodevelopment, Heijtz and colleagues demonstrated that behavioral abnormalities observed in germ-free mice in adulthood could be prevented by colonisation of the dam 30 days prior to mating (Diaz Heijtz et al., 2011). Experimental data have suggested that social behavioral deficits that are indicative of anxiety in mouse offspring that had high-fat diet fed mothers were reversed with treatment with Lactobacillus reuteri, a bacterial species that was found to be reduced in the maternal high-fat diet group relative to the control diet group (Buffington et al., 2016). Evidence points towards several possible mechanisms underpinning the impact of maternal obesity on the affective behavior of offspring, spanning prenatal programming of central reward systems, microbiome alterations, increased neuroinflammation, and modulation of glucocorticoid signaling pathways. However, it is not yet known whether there are specific windows of increased vulnerability to hypercaloric diet-evoked alterations during pregnancy itself and whether offspring outcomes differ when an early dietary intervention is applied. Rodent studies have modelled this to an extent through dietary switches at lactation (Kang et al., 2014), however, the effects of switches during gestation are yet to be examined. 4. The impact of neonatal and early life overfeeding on anxiety-like behavior Metabolism and mood in children can be influenced not only by maternal diet, but by postnatal diet consumption. Factors such as duration of breast-feeding, consumption of formulas, age and type of solid food introduction, can have significant long-term impact on the developing infant (Durmus et al., 2012; Koletzko et al., 2009; Seach et al., 2010). In rodent models, changes to the neonatal nutritional environment can be mimicked by changing the litter size in which the animal is raised to evoke overfeeding (for example, pups are suckled in litters

11

of four, in the case of rats, instead of the usual 12). This manipulation gives the pups free and easy access to the dams’ milk resulting in increased consumption of milk, fat, and other nutrients (Fiorotto et al., 1991). This overfeeding can increase body weight into adulthood, and has been shown to evoke enduring changes in anxiety-like behaviors and stress responsiveness (Spencer and Tilbrook, 2009). For example, postnatal overfeeding in female rats has been demonstrated to decrease anxiety-like behavior measured on the EPM as adults (Spencer and Tilbrook, 2009). However, in response to acute restraint stress, female offspring that become overweight as a result of early life overfeeding also have enhanced neuronal activation measured by c-Fos expression in the paraventricular nucleus of the hypothalamus (PVN), a brain region involved in the physiological regulation of stress and energy intake, indicating that these offspring may have a greater physiological response to acute stressors (Spencer and Tilbrook, 2009). Although the reduced anxiety-like behaviors evoked by a novel EPM environment in neonatally overfed females may be due to the increased degree of maternal attention they received during the neonatal period, this suggestion does not explain why HPA axis responses to stress are not also attenuated (Caldji et al., 1998; Francis and Meaney, 1999; Liu et al., 1997; Weaver et al., 2004). Nonetheless, these findings indicate that the neonatal dietary environment can play a crucial role in programming the adult phenotype including behavioral and central responses to novel and stressful stimuli, an effect particularly pronounced in females in the case of psychological stress. 5. The effects of hypercaloric diets on affective regulation during adolescence and adulthood Epidemiological studies indicate that adolescents and young adults are high consumers of hypercaloric “junk” foods (Braithwaite et al., 2014; Paeratakul et al., 2003), placing young people at substantial risk of negative outcomes for the development of obesity and associated mental health issues. Indeed, deteriorating diet quality in adolescence is linked to a decline in psychological functioning (Jacka et al., 2011; O'Neil et al., 2014), and even before obesity develops, a higher BMI is associated with anxiety in adolescents (Rofey et al., 2009). Some anxiety disorders are characterized by heightened, persistent fear responses (e.g., panic disorder, social and specific phobias) whereas others are predominantly characterized by more diffuse worry of a number of events or activities that significantly interferes with daily functioning (e.g., Generalized Anxiety Disorder) (Craske and Stein, 2016). Preclinical studies examining both alterations to fear regulation as well as anxiety-like behavior following hypercaloric diet exposure may offer some insight as to whether hypercaloric diets are risk 12

factors for anxiety disorders where impaired fear regulation and/or generalized anxiety may be present. In rats, adolescence begins around postnatal day (P) 28 and ends at approximately P5055 when rats are reproductively mature, signaling the transition into adulthood (Schneider, 2013; Spear, 2000). However, in mice, adolescent dietary manipulations typically occur from 3 weeks of age when animals are late juveniles and have just been weaned. 5.1. Anxiety and fear regulation during adolescence Although there is evidence that long-term exposures to hypercaloric diets beginning in adolescence impair fear regulation and induce anxiety-like behavior in adulthood, as detailed in Section 5.2 below, very little is known about the effects of these diets on fear and emotion regulation within adolescence. Relatively short exposures of 10 days or 4 weeks to hypercaloric diets (e.g., high-fat, high-sucrose, high-fructose corn syrup, or high-fat and high-sugar), do not evoke changes in anxiety-like behavior when animals are tested in adolescence or in the transition to adulthood (Del Rio et al., 2016; Hsu et al., 2015; Rabasa et al., 2016). However, it is possible that fear regulation is adversely affected by hypercaloric diet exposures within adolescence because adolescent rats and mice fed on standard diets already have deficits of extinction compared to adult animals (McCallum et al., 2010; Pattwell et al., 2012), indicating a pre-existing vulnerability in this developmental period. Preliminary evidence suggests that 3 weeks of intermittent consumption of a high-fat and high-sugar diet within adolescence exacerbates extinction retention deficits in adolescent rats (Williams-Spooner et al., 2017). An equivalent diet in adulthood did not induce extinction deficits, suggesting that adolescence may be a sensitive developmental period for hypercaloric diet-induced impairments of fear inhibition. In terms of clinical implications, it may be that exposure to hypercaloric diets in adolescence predisposes individuals to pronounced emotional reactivity to traumatic events, as noted by studies detailing the increased incidence of PTSD in obese adolescents (Britz et al., 2000; Perkonigg et al., 2009). 5.2. Anxiety and fear regulation in adulthood Obesity as a child is predictive of obesity as an adult, with a recent meta-analysis indicating that 55% of obese children continue to be obese in adolescence, and that ~80% of obese adolescents will still be obese as adults (Simmonds et al., 2016). There is a growing number of studies examining the long-term consequences of hypercaloric diets on fear regulation, and anxiety-like behavior in animal models. In such studies, adult rodents have been exposed to hypercaloric diets for several weeks or months, with some of these diets commencing in the juvenile and adolescent developmental periods, and others being given only

13

in adulthood. Such work reveals that animals exposed to high-fat and/or high-sugar diets in adolescence exhibit increased anxiety-like behavior in adulthood, but these behaviors are typically observed after long duration exposures to the diets extending into adulthood (i.e., >12 weeks; (Andre et al., 2014; Boitard et al., 2015; Rabasa et al., 2016; Vinuesa et al., 2016); but see Gainey et al. (2016)) or after an acute stressor (i.e., restraint stress or predator odor). For example, male mice exposed to 9 weeks of a high-fat / high-sugar cafeteria diet did not display increased anxiety-like behavior in the EPM but these changes were evident after 18 weeks of exposure (Andre et al., 2014). Similar effects of increased anxiety-like behavior are observed in rats fed a high refined carbohydrate-containing diet for 12 weeks when the animals were subjected to restraint stress the day before being tested in the EPM, without effects in nonstressed animals (Santos et al., 2016). Other work confirms that exposure to an acute stressor prior to behavioral testing precipitates increased anxiety-like behavior in rodents exposed to dietary manipulations. Kalyan-Masih et al. (2016) reported that young adult rats exposed to 8 weeks of high-fat diet (from P28) only exhibited increased anxiety-like behavior in the openfield test and EPM after exposure to predator (cat) odor stress one week before testing. These findings indicate that hypercaloric diet consumption may confer a vulnerability to anxiety following exposure to acute stressors, potentially through a two-hit effect of a physiological alteration such as an increased baseline in HPA axis / glucocorticoid response that then precipitates a heightened emotional response to stressors. Adults are not immune to deleterious effects of hypercaloric diets on anxiety-like behavior when chronically exposed. Although very brief 10 min daily access to a sweet-fat diet for 2-3 weeks beginning in adulthood did not lead to increased anxiety-like behavior tested in the EPM in rats (Parylak et al., 2012), chronic exposure (i.e., for > 16 weeks) to high-energy diets can induce anxiogenic effects in the EPM, open-field, and/or elevated zero maze in adult male mice and rats (Almeida-Suhett et al., 2017; Dutheil et al., 2016; Heyward et al., 2012). Similar findings were seen after 8 weeks in adult female rats (Sivanathan et al., 2015). In contrast, comparatively shorter exposures (between 4 weeks to 3 months) to high-fat or highsucrose/glucose/fructose diets in adult male rats are insufficient to induce anxiogenic effects (Boitard et al., 2015; Chen et al., 2017; Hsu et al., 2015), unless animals are tested 24 hours after the last exposure (i.e., when deprived, or withdrawn from the palatable diet) (Avena et al., 2008; Colantuoni et al., 2002). Thus, it appears that hypercaloric diets, regardless of whether the diet commences during adolescence or adulthood, typically only induce increased

14

anxiety-like behavior after longer than 12-16 weeks’ exposure in rodents unless there is an acute stress experience before testing. Recent work using rodent models has demonstrated that hypercaloric diets commencing in adolescence enhance the acquisition of conditioned fear and impair fear inhibition in adulthood, indicating that that impaired fear regulation may be a mechanism by which such diets increase the risk of adult anxiety. For example, male rats fed a high-fat diet for 3 months from adolescence (i.e., from weaning to adulthood) displayed enhanced cued fear learning. In contrast, rats that commenced this dietary manipulation as adults did not show these fear learning deficits (Boitard et al., 2015). Similarly, a highly refined carbohydrate diet (for 3 months) from late adolescence also enhanced contextual fear learning in male mice as adults (Santos et al., 2016). These findings of enhanced fear responses contrast with the effects of dietary manipulations beginning in adulthood. Adult female and male mice chronically (i.e., >4 months) exposed to a high-fat diet have impaired retention, but not acquisition, of cued and context fear (Johnson et al., 2016). Taken together, these findings suggest that chronic overconsumption of hypercaloric diets specifically from adolescence, but not adulthood, heightens fear responses, but with more work examining diet comparisons within adolescence compared to adulthood in the same study needed to confirm these effects. Hypercaloric diets consumed in adolescence and into adulthood also impair the inhibition of learned fear in adulthood. This is particularly important for considering potential interference of hypercaloric diets with interventions to reduce anxiety given that extinction of learned fear is a key process underlying exposure-based therapies, the gold-standard treatment for anxiety disorders. For example, extended exposure (7 weeks of 2 hours daily access) to a high-fat high-sugar diet from early adolescence (at P28) impairs extinction retention in adulthood in male rats (Baker and Reichelt, 2016). The impaired retention of extinction in adulthood is due to impairments in both the acquisition and consolidation of extinction, suggesting that hypercaloric diets could potentially prolong fear responses both within, and after, exposure sessions. A similar finding of impaired retention of extinction was also reported in male mice fed a high-fat diet from adolescence to adulthood (Labouesse et al., 2016). Importantly, the same diet in adulthood did not induce the same impairments in fear inhibition, providing evidence that adolescence is indeed a sensitive developmental period to hypercaloric diets. Adolescence may also be an especially vulnerable period to hypercaloric diets for impaired fear regulation compared to exposure during earlier stages of development, such as perinatal exposure. Specifically, adult offspring of maternally obese rodents exhibit increased

15

anxiety-like behavior but they do not have any deficits of fear learning or extinction (PelegRaibstein et al., 2012), which differs to the marked impairments of rats exposed to high-energy diets in adolescence to adulthood (Baker and Reichelt, 2016; Labouesse et al., 2016). As exposure-therapy is based on extinction, a question for future research is whether individuals consuming poor quality Western or high-fat diets during adolescence have reduced treatment efficacy when receiving exposure-based therapies for anxiety disorders. 5.3. Potential neuronal mechanisms One reason that adolescent hypercaloric diets may particularly impair fear regulation is by evoking enduring alterations to the function of the prefrontal cortex, amygdala, and hippocampus (Figure 1), regions which form an essential circuit regulating the expression and inhibition of fear (Giustino and Maren, 2015; Milad and Quirk, 2012). The hippocampus is particularly sensitive to alterations in response to high-fat and/or high-sugar diets from adolescence. Both structural and functional changes are noted when the animals reach adulthood, including hippocampal atrophy (Kalyan-Masih et al., 2016), decreased blood vessel density (Kalyan-Masih et al., 2016), reduced neurogenesis (Boitard et al., 2012), increased stress biomarker FKBP51 protein expression (Kalyan-Masih et al., 2016), and reduced synaptic plasticity (indicated by both long-term potentiation and long-term depression in the CA1 region) (Hwang et al., 2010). Increased levels of pro-inflammatory cytokines (e.g., IL-1β and IL-6), especially after an immune challenge, are found in the hippocampus of animals fed highfat and/or high-sugar diets from adolescence (Boitard et al., 2014; Hsu et al., 2015). These findings have been interpreted to reflect high levels of inflammation in this region after highfat or Western diets in adolescence. However, exposure to the same diets in adulthood did not induce the same inflammatory responses at baseline or after an immune challenge (Boitard et al., 2014; Hsu et al., 2015), suggesting that adolescents may be more susceptible to inflammation in the hippocampus than adults, and that this inflammation endures through adolescence into adulthood. Future research may uncover whether these hippocampal changes contribute to changes in contextual fear learning in animals consuming hypercaloric diets. The prefrontal cortex and amygdala are also sensitive to the consumption of hypercaloric diets (Francis and Stevenson, 2013; Guillemot-Legris and Muccioli, 2017). The prefrontal cortex undergoes substantial maturation during adolescence (Caballero et al., 2016; Mills et al., 2014) and, due to its relative immaturity at this stage, this region may be particularly vulnerable to the deleterious effects of high energy diets (Reichelt, 2016). As

16

evidence for this idea, postweaning high-fat diet reduced serotonergic immunoreactivity in the medial prefrontal cortex in the juvenile non-human primate (Thompson et al., 2017), suggesting that decreased serotonergic innervation of this region, and/or differences in serotonin release and reuptake, could underlie the increased behavioral inhibition of high-fat fed juveniles. Similarly, a high-fat / high-sugar diet from adolescence alters prefrontal cortical function in rats, inducing a loss of GABAergic parvalbumin neurons and increased expression of the stable transcription factor FosB/ΔFosB in the infralimbic cortex (Baker and Reichelt, 2016), a region critical for both fear inhibition (Milad and Quirk, 2012) and the regulation of stress responses (Spencer et al., 2005). These findings suggest that a high-fat / high-sugar diet may cause prefrontal cortex dysregulation or hyperactivation, however, studies have not yet compared these effects directly with rats commencing the same diet protocol during adulthood. Nevertheless, there is other more direct evidence that hypercaloric diet exposure from adolescence, but not adulthood, impairs synaptic plasticity in the prefrontal cortex. High-fat diet exposure from adolescence in mice impairs long-term depression in the medial prefrontal cortex and reduces the expression of the synaptic modulator and glycoprotein reelin in the infralimbic, prelimbic, and anterior cingulate subregions (Labouesse et al., 2016). The same diet exposure in adulthood had no effect on reelin in the medial prefrontal cortex but instead reduced its expression in the dentate gyrus of the hippocampus. Moreover, animals fed highfat diet from adolescence exhibited impaired extinction retention in adulthood and this deficit was absent in transgenic mice that overexpressed reelin (Labouesse et al., 2016). The findings of these studies suggest that deficits consolidating fear extinction in animals consuming hypercaloric diets from adolescence, but not adulthood, may be associated with altered inhibitory neurotransmission function and synaptic plasticity of the prefrontal cortex, with a key role of the glycoprotein reelin in this process. Reelin signaling is particularly important during early neurodevelopment where it regulates neuronal migration and positioning in the cortex, thus further investigation into the involvement of reelin during later sensitive neurodevelopmental windows, such as adolescence, should be undertaken. The functional development of the amygdala is tightly linked to HPA axis function (Moriceau et al., 2006). Rats that consumed a high-fat diet from adolescence have a protracted corticosterone stress response after an aversive stimulus and greater neuronal activation and synaptic plasticity within the basolateral nucleus (Boitard et al., 2015). These effects may relate to the enhanced fear learning noted in animals fed a high-fat diet. Thus, neurobiological functional changes to the prefrontal cortex and amygdala after chronic exposure to hypercaloric

17

diets in adolescence may shift a balance in fear regulation towards impaired fear inhibition and enhanced fear expression. One possible mechanism by which this could occur is through alterations to the maturation of amygdala-prefrontal functional connectivity, which is notably sensitive to stress during early life (VanTieghem and Tottenham, 2017). This may then manifest as an anxiogenic phenotype in adulthood, with increased anxiety and fear responses to threat-related stimuli. 6. Conclusions, future directions, and implications Anxiety disorders and obesity are multisystem disorders marked by alterations in the fronto-limbic circuit and the dysregulation of interacting inflammatory, metabolic, and endocrine systems. Empirical evidence points towards sensitive windows of increased sensitivity to poor quality diets, including hypercaloric diets during developmental periods. In particular, the intrauterine environment during gestation and the early life periods through to adolescence have been demonstrated to be sensitive stages of development during which hypercaloric diets can evoke enduring and pronounced behavioral changes in emotional reactivity. These effects have been measured by anxiety-like responses in animal models as well as molecular and neurochemical changes to central and peripheral systems involved in behavioral control and emotion regulation. The outcomes of experimental studies in preclinical settings that examine the effects of hypercaloric diets during postnatal development highlight the increased vulnerability to the development of anxiety and mood disorders of children and youth consuming similar diets. These findings indicate a cumulative risk profile for those consuming hypercaloric diets over extended periods for the development of anxiety disorders. However, not all those with such diets will go on to develop alterations in emotion regulation. It appears that the duration and / or timing of the diet exposure is an important factor as to whether an anxiety-like phenotype is observed. The combined effect of an adverse experience and the severity of these events also plays a role in the development of anxiety in those with a history of poor diet. A further issue to consider is that maternal obesity may place offspring at risk of anxiety through epigenetic modifications affecting neurodevelopment. Epigenetic modifications to the genome can arise from a variety of paternal and maternal lifestyle factors including obesity, nutrition, physical activity, stress, and toxins, and these changes can be intergenerationally transmitted leading to alterations in the physical and mental health of offspring. Epigenetic modifications in pregnancy may alter aspects of offspring neurodevelopment, particularly

18

those arising from obesity and mental health problems (Teh et al., 2014). In particular, DNA methylation has been postulated as a mechanism for enduring effects of the prenatal environment particularly in reward processing (Vucetic et al., 2010; Weaver et al., 2004). Moreover, maternal or paternal exposure to a high-fat diet has been shown to lead to insulin resistance, a key pathogenic alteration observed in obesity, in subsequent generations (Dunn and Bale, 2009; Ng et al., 2010), potentially through epigenetic changes to sperm (Fullston et al., 2013). A fruitful direction of future research might be to investigate whether epigenetic alterations after perinatal obesity modulate the emergence of anxiety-like behaviors in offspring. Moreover, examining anxiety-like responses in selectively bred rats with a tendency to develop obesity (obesity prone) and dietary obesity resistant rats (Levin et al., 2004; Levin et al., 2003)provides unique observations to separate diet effects from obesity with respect to anxiety-like behaviour. This has been shown by a recent paper by Vogel et al. (2017), which demonstrated that obesity prone rats exhibited a higher level of anxiety-like behaviour in the open field and EPM when compared to obesity resistant rats, when maintained on standard diets. An additional avenue for future research is to investigate whether improvements to diet and/or exercise levels can reverse adolescent diet-induced anxiety and impaired fear regulation. There is some evidence that diet modifications can reverse altered neural and endocrine responses to aversive events. For example, switching rats that consumed a high fat diet across adolescence to a standard diet for three months normalizes HPA axis reactivity and basolateral amygdala activation after an aversive stimulus (Boitard et al., 2016). Therefore, dietary-based strategies to reduce HPA axis reactivity may provide therapeutic methods to attenuate anxiety. In addition, concurrent treadmill exercise can reverse adolescent hypercaloric diet-induced impairments in active avoidance tasks in adult female rats (Cigarroa et al., 2016), suggesting exercise may be a useful supplement for interventions aimed at reducing emotional reactivity. Prospective studies in humans demonstrate that improving diet quality improves mental health in adolescence (Jacka et al., 2011; Lana et al., 2015). Pediatric inpatient weight management programs involving medical nutritional therapy, exercise programs, and behavioral therapies can also improve anxiety symptoms in clinically obese children and adolescents (Taylor et al., 2017). Thus, dietary or physical activity-based interventions may have significant potential in reducing anxiety symptoms. Moreover, there is evidence that the gut microbiome is able to modulate limbic system function (Mu et al., 2016; Vuong et al., 2017). Further understanding of the microbiome-brain axis and harnessing its potential through the utilization of

19

psychobiotics to modify emotional behavior may provide a therapeutic method to address anxiety disorders (Dinan et al., 2013). In conclusion, the identification of vulnerable developmental windows to hypercaloric diets may help to encourage the formation of targeted dietary interventions and health recommendations aimed at specific periods of development, both gestational and across life, and the behavioral and neurobiological consequences of poor quality diets. Moreover, the physiological response to dietary, behavioral, or environmental interventions may be augmented if applied during sensitive periods of development and may help to prevent subsequent detrimental neurodevelopmental and psychological outcomes. Nevertheless, as improving diet quality has been shown to promote better mental health in all ages (Jacka et al., 2011; Jacka et al., 2017; Opie et al., 2017a; Opie et al., 2017b), dietary modifications either alone or in combination with psychological and/or pharmacological therapies for anxiety and its treatment, could present an opportunity to improve mental health across the lifespan. 7. Acknowledgements ACR is the recipient of an Australian Research Council Discovery Early Career Research Award (DE140101071). KDB is the recipient of an Australian Research Council Discovery Early Career Research Award (DE170100392) and a grant from the National Health and Medical Research Council (APP1086855). SJS is the recipient of a National Health and Medical Research Council Career Development Fellowship (APP1128646), a Club Melbourne Fellowship and a Brain Foundation Research Gift. 8. References Aagaard, K., Ma, J., Antony, K.M., Ganu, R., Petrosino, J., Versalovic, J., 2014. The placenta harbors a unique microbiome. Science translational medicine 6, 237ra265. Akbaraly, T.N., Brunner, E.J., Ferrie, J.E., Marmot, M.G., Kivimaki, M., Singh-Manoux, A., 2009. Dietary pattern and depressive symptoms in middle age. The British journal of psychiatry : the journal of mental science 195, 408-413. Allen, K.L., Byrne, S.M., Forbes, D., Oddy, W.H., 2009. Risk factors for full- and partialsyndrome early adolescent eating disorders: a population-based pregnancy cohort study. Journal of the American Academy of Child and Adolescent Psychiatry 48, 800-809. Almeida-Suhett, C.P., Graham, A., Chen, Y., Deuster, P., 2017. Behavioral changes in male mice fed a high-fat diet are associated with IL-1beta expression in specific brain regions. Physiology & behavior 169, 130-140.

20

Andre, C., Dinel, A.L., Ferreira, G., Laye, S., Castanon, N., 2014. Diet-induced obesity progressively alters cognition, anxiety-like behavior and lipopolysaccharide-induced depressive-like behavior: focus on brain indoleamine 2,3-dioxygenase activation. Brain, behavior, and immunity 41, 10-21. Attuquayefio, T., Stevenson, R.J., Oaten, M.J., Francis, H.M., 2017. A four-day Westernstyle dietary intervention causes reductions in hippocampal-dependent learning and memory and interoceptive sensitivity. PloS one 12, e0172645. Avena, N.M., Rada, P., Hoebel, B.G., 2008. Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake. Neuroscience and biobehavioral reviews 32, 20-39. Baker, K.D., Reichelt, A.C., 2016. Impaired fear extinction retention and increased anxietylike behaviours induced by limited daily access to a high-fat/high-sugar diet in male rats: Implications for diet-induced prefrontal cortex dysregulation. Neurobiol Learn Mem 136, 127-138. Baxter, A.J., Scott, K.M., Vos, T., Whiteford, H.A., 2013. Global prevalence of anxiety disorders: a systematic review and meta-regression. Psychological medicine 43, 897-910. Bayol, S.A., Farrington, S.J., Stickland, N.C., 2007. A maternal 'junk food' diet in pregnancy and lactation promotes an exacerbated taste for 'junk food' and a greater propensity for obesity in rat offspring. Br J Nutr 98, 843-851. Bercik, P., Denou, E., Collins, J., Jackson, W., Lu, J., Jury, J., Deng, Y., Blennerhassett, P., Macri, J., McCoy, K.D., Verdu, E.F., Collins, S.M., 2011. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 141, 599-609, 609 e591-593. Bergman, R.N., Kim, S.P., Catalano, K.J., Hsu, I.R., Chiu, J.D., Kabir, M., Hucking, K., Ader, M., 2006. Why visceral fat is bad: mechanisms of the metabolic syndrome. Obesity 14 Suppl 1, 16S-19S. Bilbo, S.D., Tsang, V., 2010. Enduring consequences of maternal obesity for brain inflammation and behavior of offspring. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24, 2104-2115. Blundell, J.E., Lawton, C.L., Halford, J.C., 1995. Serotonin, eating behavior, and fat intake. Obesity research 3 Suppl 4, 471S-476S. Boitard, C., Cavaroc, A., Sauvant, J., Aubert, A., Castanon, N., Laye, S., Ferreira, G., 2014. Impairment of hippocampal-dependent memory induced by juvenile high-fat diet intake is associated with enhanced hippocampal inflammation in rats. Brain, behavior, and immunity 21

40, 9-17. Boitard, C., Etchamendy, N., Sauvant, J., Aubert, A., Tronel, S., Marighetto, A., Laye, S., Ferreira, G., 2012. Juvenile, but not adult exposure to high-fat diet impairs relational memory and hippocampal neurogenesis in mice. Hippocampus 22, 2095-2100. Boitard, C., Maroun, M., Tantot, F., Cavaroc, A., Sauvant, J., Marchand, A., Laye, S., Capuron, L., Darnaudery, M., Castanon, N., Coutureau, E., Vouimba, R.M., Ferreira, G., 2015. Juvenile obesity enhances emotional memory and amygdala plasticity through glucocorticoids. The Journal of neuroscience : the official journal of the Society for Neuroscience 35, 4092-4103. Boitard, C., Parkes, S.L., Cavaroc, A., Tantot, F., Castanon, N., Laye, S., Tronel, S., PachecoLopez, G., Coutureau, E., Ferreira, G., 2016. Switching Adolescent High-Fat Diet to Adult Control Diet Restores Neurocognitive Alterations. Frontiers in behavioral neuroscience 10, 225. Braithwaite, I., Stewart, A.W., Hancox, R.J., Beasley, R., Murphy, R., Mitchell, E.A., Group, I.P.T.S., Group, I.P.T.S., 2014. Fast-food consumption and body mass index in children and adolescents: an international cross-sectional study. BMJ open 4, e005813. Britz, B., Siegfried, W., Ziegler, A., Lamertz, C., Herpertz-Dahlmann, B.M., Remschmidt, H., Wittchen, H.U., Hebebrand, J., 2000. Rates of psychiatric disorders in a clinical study group of adolescents with extreme obesity and in obese adolescents ascertained via a population based study. International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity 24, 1707-1714. Buffington, S.A., Di Prisco, G.V., Auchtung, T.A., Ajami, N.J., Petrosino, J.F., CostaMattioli, M., 2016. Microbial Reconstitution Reverses Maternal Diet-Induced Social and Synaptic Deficits in Offspring. Cell 165, 1762-1775. Caballero, A., Granberg, R., Tseng, K.Y., 2016. Mechanisms contributing to prefrontal cortex maturation during adolescence. Neuroscience and biobehavioral reviews 70, 4-12. Caldji, C., Tannenbaum, B., Sharma, S., Francis, D., Plotsky, P.M., Meaney, M.J., 1998. Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. Proceedings of the National Academy of Sciences of the United States of America 95, 5335-5340. Campbell, B.A., Spear, N.E., 1972. Ontogeny of memory. Psychol Rev 79, 215-236. Chen, Z., Xu, Y.Y., Wu, R., Han, Y.X., Yu, Y., Ge, J.F., Chen, F.H., 2017. Impaired learning and memory in rats induced by a high-fat diet: involvement with the imbalance of nesfatin-1 abundance and copine 6 expression. J Neuroendocrinol. 22

Cigarroa, I., Lalanza, J.F., Caimari, A., del Bas, J.M., Capdevila, L., Arola, L., Escorihuela, R.M., 2016. Treadmill Intervention Attenuates the Cafeteria Diet-Induced Impairment of Stress-Coping Strategies in Young Adult Female Rats. PloS one 11, e0153687. Claesson, I.M., Josefsson, A., Sydsjo, G., 2010. Prevalence of anxiety and depressive symptoms among obese pregnant and postpartum women: an intervention study. BMC public health 10, 766. Colantuoni, C., Rada, P., McCarthy, J., Patten, C., Avena, N.M., Chadeayne, A., Hoebel, B.G., 2002. Evidence that intermittent, excessive sugar intake causes endogenous opioid dependence. Obesity research 10, 478-488. Craske, M.G., Stein, M.B., 2016. Anxiety. Lancet 388, 3048-3059. David, L.A., Maurice, C.F., Carmody, R.N., Gootenberg, D.B., Button, J.E., Wolfe, B.E., Ling, A.V., Devlin, A.S., Varma, Y., Fischbach, M.A., Biddinger, S.B., Dutton, R.J., Turnbaugh, P.J., 2014. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559-563. Del Rio, D., Morales, L., Ruiz-Gayo, M., Del Olmo, N., 2016. Effect of high-fat diets on mood and learning performance in adolescent mice. Behav Brain Res 311, 167-172. Diaz Heijtz, R., Wang, S., Anuar, F., Qian, Y., Bjorkholm, B., Samuelsson, A., Hibberd, M.L., Forssberg, H., Pettersson, S., 2011. Normal gut microbiota modulates brain development and behavior. Proceedings of the National Academy of Sciences of the United States of America 108, 3047-3052. Dinan, T.G., Cryan, J.F., 2017. Microbes, Immunity, and Behavior: Psychoneuroimmunology Meets the Microbiome. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 42, 178-192. Dinan, T.G., Stanton, C., Cryan, J.F., 2013. Psychobiotics: a novel class of psychotropic. Biological psychiatry 74, 720-726. Dreber, H., Reynisdottir, S., Angelin, B., Tynelius, P., Rasmussen, F., Hemmingsson, E., 2017. Mental distress in treatment seeking young adults (18-25 years) with severe obesity compared with population controls of different body mass index levels: cohort study. Clinical obesity 7, 1-10. Dunn, G.A., Bale, T.L., 2009. Maternal high-fat diet promotes body length increases and insulin insensitivity in second-generation mice. Endocrinology 150, 4999-5009. Durmus, B., Ay, L., Duijts, L., Moll, H.A., Hokken-Koelega, A.C., Raat, H., Hofman, A., Steegers, E.A., Jaddoe, V.W., 2012. Infant diet and subcutaneous fat mass in early childhood: the Generation R Study. European journal of clinical nutrition 66, 253-260. 23

Dutheil, S., Ota, K.T., Wohleb, E.S., Rasmussen, K., Duman, R.S., 2016. High-Fat Diet Induced Anxiety and Anhedonia: Impact on Brain Homeostasis and Inflammation. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 41, 1874-1887. Faith, M.S., Butryn, M., Wadden, T.A., Fabricatore, A., Nguyen, A.M., Heymsfield, S.B., 2011. Evidence for prospective associations among depression and obesity in populationbased studies. Obesity reviews : an official journal of the International Association for the Study of Obesity 12, e438-453. Fiorotto, M.L., Burrin, D.G., Perez, M., Reeds, P.J., 1991. Intake and use of milk nutrients by rat pups suckled in small, medium, or large litters. The American journal of physiology 260, R1104-1113. Flegal, K.M., Carroll, M.D., Kit, B.K., Ogden, C.L., 2012. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010. Jama 307, 491-497. Foster, J.A., McVey Neufeld, K.A., 2013. Gut-brain axis: how the microbiome influences anxiety and depression. Trends in neurosciences 36, 305-312. Francis, D.D., Meaney, M.J., 1999. Maternal care and the development of stress responses. Current opinion in neurobiology 9, 128-134. Francis, H., Stevenson, R., 2013. The longer-term impacts of Western diet on human cognition and the brain. Appetite 63, 119-128. Freedman, D.S., Mei, Z., Srinivasan, S.R., Berenson, G.S., Dietz, W.H., 2007. Cardiovascular risk factors and excess adiposity among overweight children and adolescents: the Bogalusa Heart Study. The Journal of pediatrics 150, 12-17 e12. Fullston, T., Ohlsson Teague, E.M., Palmer, N.O., DeBlasio, M.J., Mitchell, M., Corbett, M., Print, C.G., Owens, J.A., Lane, M., 2013. Paternal obesity initiates metabolic disturbances in two generations of mice with incomplete penetrance to the F2 generation and alters the transcriptional profile of testis and sperm microRNA content. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 27, 4226-4243. Gainey, S.J., Kwakwa, K.A., Bray, J.K., Pillote, M.M., Tir, V.L., Towers, A.E., Freund, G.G., 2016. Short-Term High-Fat Diet (HFD) Induced Anxiety-Like Behaviors and Cognitive Impairment Are Improved with Treatment by Glyburide. Frontiers in behavioral neuroscience 10, 156. Galley, J.D., Bailey, M., Kamp Dush, C., Schoppe-Sullivan, S., Christian, L.M., 2014. Maternal obesity is associated with alterations in the gut microbiome in toddlers. PloS one 9, e113026. 24

Gariepy, G., Wang, J., Lesage, A.D., Schmitz, N., 2010. The longitudinal association from obesity to depression: results from the 12-year National Population Health Survey. Obesity 18, 1033-1038. Giustino, T.F., Maren, S., 2015. The Role of the Medial Prefrontal Cortex in the Conditioning and Extinction of Fear. Frontiers in behavioral neuroscience 9, 298. Gluckman, P.D., Cutfield, W., Hofman, P., Hanson, M.A., 2005. The fetal, neonatal, and infant environments-the long-term consequences for disease risk. Early human development 81, 51-59. Gohir, W., Whelan, F.J., Surette, M.G., Moore, C., Schertzer, J.D., Sloboda, D.M., 2015. Pregnancy-related changes in the maternal gut microbiota are dependent upon the mother's periconceptional diet. Gut microbes 6, 310-320. Griffiths, L.J., Parsons, T.J., Hill, A.J., 2010. Self-esteem and quality of life in obese children and adolescents: a systematic review. International journal of pediatric obesity : IJPO : an official journal of the International Association for the Study of Obesity 5, 282-304. Grissom, N.M., Lyde, R., Christ, L., Sasson, I.E., Carlin, J., Vitins, A.P., Simmons, R.A., Reyes, T.M., 2014. Obesity at conception programs the opioid system in the offspring brain. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 39, 801-810. Guillemot-Legris, O., Muccioli, G.G., 2017. Obesity-Induced Neuroinflammation: Beyond the Hypothalamus. Trends in neurosciences 40, 237-253. Gunnar, M., Quevedo, K., 2007. The neurobiology of stress and development. Annual review of psychology 58, 145-173. Gunnar, M.R., Wewerka, S., Frenn, K., Long, J.D., Griggs, C., 2009. Developmental changes in hypothalamus-pituitary-adrenal activity over the transition to adolescence: normative changes and associations with puberty. Development and psychopathology 21, 69-85. Han, J.C., Lawlor, D.A., Kimm, S.Y., 2010. Childhood obesity. Lancet 375, 1737-1748. Harris, R.B., Apolzan, J.W., 2012. Changes in glucose tolerance and leptin responsiveness of rats offered a choice of lard, sucrose, and chow. American journal of physiology. Regulatory, integrative and comparative physiology 302, R1327-1339. Haslam, D.W., James, W.P., 2005. Obesity. Lancet 366, 1197-1209. Heyward, F.D., Walton, R.G., Carle, M.S., Coleman, M.A., Garvey, W.T., Sweatt, J.D., 2012. Adult mice maintained on a high-fat diet exhibit object location memory deficits and reduced hippocampal SIRT1 gene expression. Neurobiol Learn Mem 98, 25-32. Hsiao, E.Y., McBride, S.W., Hsien, S., Sharon, G., Hyde, E.R., McCue, T., Codelli, J.A., 25

Chow, J., Reisman, S.E., Petrosino, J.F., Patterson, P.H., Mazmanian, S.K., 2013. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155, 1451-1463. Hsu, T.M., Konanur, V.R., Taing, L., Usui, R., Kayser, B.D., Goran, M.I., Kanoski, S.E., 2015. Effects of sucrose and high fructose corn syrup consumption on spatial memory function and hippocampal neuroinflammation in adolescent rats. Hippocampus 25, 227-239. Hwang, L.L., Wang, C.H., Li, T.L., Chang, S.D., Lin, L.C., Chen, C.P., Chen, C.T., Liang, K.C., Ho, I.K., Yang, W.S., Chiou, L.C., 2010. Sex differences in high-fat diet-induced obesity, metabolic alterations and learning, and synaptic plasticity deficits in mice. Obesity 18, 463-469. Jacka, F.N., Kremer, P.J., Berk, M., de Silva-Sanigorski, A.M., Moodie, M., Leslie, E.R., Pasco, J.A., Swinburn, B.A., 2011. A prospective study of diet quality and mental health in adolescents. PloS one 6, e24805. Jacka, F.N., Kremer, P.J., Leslie, E.R., Berk, M., Patton, G.C., Toumbourou, J.W., Williams, J.W., 2010a. Associations between diet quality and depressed mood in adolescents: results from the Australian Healthy Neighbourhoods Study. The Australian and New Zealand journal of psychiatry 44, 435-442. Jacka, F.N., O'Neil, A., Opie, R., Itsiopoulos, C., Cotton, S., Mohebbi, M., Castle, D., Dash, S., Mihalopoulos, C., Chatterton, M.L., Brazionis, L., Dean, O.M., Hodge, A.M., Berk, M., 2017. A randomised controlled trial of dietary improvement for adults with major depression (the 'SMILES' trial). BMC medicine 15, 23. Jacka, F.N., Pasco, J.A., Mykletun, A., Williams, L.J., Hodge, A.M., O'Reilly, S.L., Nicholson, G.C., Kotowicz, M.A., Berk, M., 2010b. Association of Western and traditional diets with depression and anxiety in women. The American journal of psychiatry 167, 305311. Jacka, F.N., Ystrom, E., Brantsaeter, A.L., Karevold, E., Roth, C., Haugen, M., Meltzer, H.M., Schjolberg, S., Berk, M., 2013. Maternal and early postnatal nutrition and mental health of offspring by age 5 years: a prospective cohort study. Journal of the American Academy of Child and Adolescent Psychiatry 52, 1038-1047. Johnson, L.A., Zuloaga, K.L., Kugelman, T.L., Mader, K.S., Morre, J.T., Zuloaga, D.G., Weber, S., Marzulla, T., Mulford, A., Button, D., Lindner, J.R., Alkayed, N.J., Stevens, J.F., Raber, J., 2016. Amelioration of Metabolic Syndrome-Associated Cognitive Impairments in Mice via a Reduction in Dietary Fat Content or Infusion of Non-Diabetic Plasma. EBioMedicine 3, 26-42. 26

Kalyan-Masih, P., Vega-Torres, J.D., Miles, C., Haddad, E., Rainsbury, S., Baghchechi, M., Obenaus, A., Figueroa, J.D., 2016. Western High-Fat Diet Consumption during Adolescence Increases Susceptibility to Traumatic Stress while Selectively Disrupting Hippocampal and Ventricular Volumes. eNeuro 3. Kang, S.S., Kurti, A., Fair, D.A., Fryer, J.D., 2014. Dietary intervention rescues maternal obesity induced behavior deficits and neuroinflammation in offspring. Journal of neuroinflammation 11, 156. Kasen, S., Cohen, P., Chen, H., Must, A., 2008. Obesity and psychopathology in women: a three decade prospective study. International journal of obesity 32, 558-566. Kelly, J.R., Borre, Y., C, O.B., Patterson, E., El Aidy, S., Deane, J., Kennedy, P.J., Beers, S., Scott, K., Moloney, G., Hoban, A.E., Scott, L., Fitzgerald, P., Ross, P., Stanton, C., Clarke, G., Cryan, J.F., Dinan, T.G., 2016. Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat. Journal of psychiatric research 82, 109-118. Kessler, R.C., Petukhova, M., Sampson, N.A., Zaslavsky, A.M., Wittchen, H.U., 2012. Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. International journal of methods in psychiatric research 21, 169-184. Keszthelyi, D., Troost, F.J., Masclee, A.A., 2009. Understanding the role of tryptophan and serotonin metabolism in gastrointestinal function. Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society 21, 1239-1249. Kim, D., Hofstaedter, C.E., Zhao, C., Mattei, L., Tanes, C., Clarke, E., Lauder, A., SherrillMix, S., Chehoud, C., Kelsen, J., Conrad, M., Collman, R.G., Baldassano, R., Bushman, F.D., Bittinger, K., 2017. Optimizing methods and dodging pitfalls in microbiome research. Microbiome 5, 52. Kim-Cohen, J., Caspi, A., Moffitt, T.E., Harrington, H., Milne, B.J., Poulton, R., 2003. Prior juvenile diagnoses in adults with mental disorder: developmental follow-back of a prospective-longitudinal cohort. Archives of general psychiatry 60, 709-717. Kingston, D., Tough, S., 2014. Prenatal and postnatal maternal mental health and school-age child development: a systematic review. Maternal and child health journal 18, 1728-1741. Kohlboeck, G., Sausenthaler, S., Standl, M., Koletzko, S., Bauer, C.P., von Berg, A., Berdel, D., Kramer, U., Schaaf, B., Lehmann, I., Herbarth, O., Heinrich, J., plus, G., Groups, L.I.p.S., 2012. Food intake, diet quality and behavioral problems in children: results from the GINI-plus/LISA-plus studies. Annals of nutrition & metabolism 60, 247-256. 27

Koletzko, B., von Kries, R., Monasterolo, R.C., Subias, J.E., Scaglioni, S., Giovannini, M., Beyer, J., Demmelmair, H., Anton, B., Gruszfeld, D., Dobrzanska, A., Sengier, A., Langhendries, J.P., Cachera, M.F., Grote, V., European Childhood Obesity Trial Study, G., 2009. Infant feeding and later obesity risk. Advances in experimental medicine and biology 646, 15-29. Labouesse, M.A., Lassalle, O., Richetto, J., Iafrati, J., Weber-Stadlbauer, U., Notter, T., Gschwind, T., Pujadas, L., Soriano, E., Reichelt, A.C., Labouesse, C., Langhans, W., Chavis, P., Meyer, U., 2016. Hypervulnerability of the adolescent prefrontal cortex to nutritional stress via reelin deficiency. Molecular psychiatry. Lam, D.D., Garfield, A.S., Marston, O.J., Shaw, J., Heisler, L.K., 2010. Brain serotonin system in the coordination of food intake and body weight. Pharmacology, biochemistry, and behavior 97, 84-91. Lana, A., Lopez-Garcia, E., Rodriguez-Artalejo, F., 2015. Consumption of soft drinks and health-related quality of life in the adult population. European journal of clinical nutrition 69, 1226-1232. Lawlor, D.A., Smith, G.D., O'Callaghan, M., Alati, R., Mamun, A.A., Williams, G.M., Najman, J.M., 2007. Epidemiologic evidence for the fetal overnutrition hypothesis: findings from the mater-university study of pregnancy and its outcomes. American journal of epidemiology 165, 418-424. Lawton, C.L., Wales, J.K., Hill, A.J., Blundell, J.E., 1995. Serotoninergic manipulation, meal-induced satiety and eating pattern: effect of fluoxetine in obese female subjects. Obesity research 3, 345-356. Lee, F.S., Heimer, H., Giedd, J.N., Lein, E.S., Sestan, N., Weinberger, D.R., Casey, B.J., 2014. Mental health. Adolescent mental health--opportunity and obligation. Science 346, 547-549. Levin, B.E., Dunn-Meynell, A.A., 2002. Maternal obesity alters adiposity and monoamine function in genetically predisposed offspring. American journal of physiology. Regulatory, integrative and comparative physiology 283, R1087-1093. Levin, B.E., Dunn-Meynell, A.A., Banks, W.A., 2004. Obesity-prone rats have normal bloodbrain barrier transport but defective central leptin signaling before obesity onset. American journal of physiology. Regulatory, integrative and comparative physiology 286, R143-150. Levin, B.E., Dunn-Meynell, A.A., McMinn, J.E., Alperovich, M., Cunningham-Bussel, A., Chua, S.C., Jr., 2003. A new obesity-prone, glucose-intolerant rat strain (F.DIO). American journal of physiology. Regulatory, integrative and comparative physiology 285, R1184-1191. 28

Liu, D., Diorio, J., Tannenbaum, B., Caldji, C., Francis, D., Freedman, A., Sharma, S., Pearson, D., Plotsky, P.M., Meaney, M.J., 1997. Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science 277, 1659-1662. Luppino, F.S., de Wit, L.M., Bouvy, P.F., Stijnen, T., Cuijpers, P., Penninx, B.W., Zitman, F.G., 2010. Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies. Archives of general psychiatry 67, 220-229. Ma, J., Prince, A.L., Bader, D., Hu, M., Ganu, R., Baquero, K., Blundell, P., Alan Harris, R., Frias, A.E., Grove, K.L., Aagaard, K.M., 2014. High-fat maternal diet during pregnancy persistently alters the offspring microbiome in a primate model. Nature communications 5, 3889. Mansur, R.B., Brietzke, E., McIntyre, R.S., 2015. Is there a "metabolic-mood syndrome"? A review of the relationship between obesity and mood disorders. Neuroscience and biobehavioral reviews 52, 89-104. McCallum, J., Kim, J.H., Richardson, R., 2010. Impaired extinction retention in adolescent rats: effects of D-cycloserine. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 35, 2134-2142. Milad, M.R., Quirk, G.J., 2012. Fear extinction as a model for translational neuroscience: ten years of progress. Annual review of psychology 63, 129-151. Mills, K.L., Lalonde, F., Clasen, L.S., Giedd, J.N., Blakemore, S.J., 2014. Developmental changes in the structure of the social brain in late childhood and adolescence. Social cognitive and affective neuroscience 9, 123-131. Molyneaux, E., Poston, L., Ashurst-Williams, S., Howard, L.M., 2014. Obesity and mental disorders during pregnancy and postpartum: a systematic review and meta-analysis. Obstetrics and gynecology 123, 857-867. Moriceau, S., Wilson, D.A., Levine, S., Sullivan, R.M., 2006. Dual circuitry for odor-shock conditioning during infancy: corticosterone switches between fear and attraction via amygdala. The Journal of neuroscience : the official journal of the Society for Neuroscience 26, 6737-6748. Mu, C., Yang, Y., Zhu, W., 2016. Gut Microbiota: The Brain Peacekeeper. Front Microbiol 7, 345. Naef, L., Moquin, L., Dal Bo, G., Giros, B., Gratton, A., Walker, C.D., 2011. Maternal highfat intake alters presynaptic regulation of dopamine in the nucleus accumbens and increases motivation for fat rewards in the offspring. Neuroscience 176, 225-236. Neary, N.M., Goldstone, A.P., Bloom, S.R., 2004. Appetite regulation: from the gut to the 29

hypothalamus. Clinical endocrinology 60, 153-160. Ng, S.F., Lin, R.C., Laybutt, D.R., Barres, R., Owens, J.A., Morris, M.J., 2010. Chronic highfat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 467, 963966. O'Neil, A., Quirk, S.E., Housden, S., Brennan, S.L., Williams, L.J., Pasco, J.A., Berk, M., Jacka, F.N., 2014. Relationship between diet and mental health in children and adolescents: a systematic review. American journal of public health 104, e31-42. Ogden, C.L., Carroll, M.D., Kit, B.K., Flegal, K.M., 2014. Prevalence of childhood and adult obesity in the United States, 2011-2012. Jama 311, 806-814. Okubo, H., Miyake, Y., Sasaki, S., Tanaka, K., Murakami, K., Hirota, Y., Osaka, M., Child Health Study, G., 2011. Dietary patterns during pregnancy and the risk of postpartum depression in Japan: the Osaka Maternal and Child Health Study. Br J Nutr 105, 1251-1257. Ong, Z.Y., Muhlhausler, B.S., 2011. Maternal "junk-food" feeding of rat dams alters food choices and development of the mesolimbic reward pathway in the offspring. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 25, 2167-2179. Opie, R.S., Itsiopoulos, C., Parletta, N., Sanchez-Villegas, A., Akbaraly, T.N., Ruusunen, A., Jacka, F.N., 2017a. Dietary recommendations for the prevention of depression. Nutritional neuroscience 20, 161-171. Opie, R.S., O'Neil, A., Jacka, F.N., Pizzinga, J., Itsiopoulos, C., 2017b. A modified Mediterranean dietary intervention for adults with major depression: Dietary protocol and feasibility data from the SMILES trial. Nutritional neuroscience, 1-15. Paeratakul, S., Ferdinand, D.P., Champagne, C.M., Ryan, D.H., Bray, G.A., 2003. Fast-food consumption among US adults and children: dietary and nutrient intake profile. Journal of the American Dietetic Association 103, 1332-1338. Pan, A., Sun, Q., Czernichow, S., Kivimaki, M., Okereke, O.I., Lucas, M., Manson, J.E., Ascherio, A., Hu, F.B., 2012. Bidirectional association between depression and obesity in middle-aged and older women. International journal of obesity 36, 595-602. Parylak, S.L., Cottone, P., Sabino, V., Rice, K.C., Zorrilla, E.P., 2012. Effects of CB1 and CRF1 receptor antagonists on binge-like eating in rats with limited access to a sweet fat diet: lack of withdrawal-like responses. Physiology & behavior 107, 231-242. Pattwell, S.S., Duhoux, S., Hartley, C.A., Johnson, D.C., Jing, D., Elliott, M.D., Ruberry, E.J., Powers, A., Mehta, N., Yang, R.R., Soliman, F., Glatt, C.E., Casey, B.J., Ninan, I., Lee, F.S., 2012. Altered fear learning across development in both mouse and human. Proceedings 30

of the National Academy of Sciences of the United States of America 109, 16318-16323. Peleg-Raibstein, D., Luca, E., Wolfrum, C., 2012. Maternal high-fat diet in mice programs emotional behavior in adulthood. Behav Brain Res 233, 398-404. Perez-Munoz, M.E., Arrieta, M.C., Ramer-Tait, A.E., Walter, J., 2017. A critical assessment of the "sterile womb" and "in utero colonization" hypotheses: implications for research on the pioneer infant microbiome. Microbiome 5, 48. Perkonigg, A., Owashi, T., Stein, M.B., Kirschbaum, C., Wittchen, H.U., 2009. Posttraumatic stress disorder and obesity: evidence for a risk association. American journal of preventive medicine 36, 1-8. Puhl, R.M., Luedicke, J., 2012. Weight-based victimization among adolescents in the school setting: emotional reactions and coping behaviors. Journal of youth and adolescence 41, 2740. Puhl, R.M., Peterson, J.L., Luedicke, J., 2013. Weight-based victimization: bullying experiences of weight loss treatment-seeking youth. Pediatrics 131, e1-9. Rabasa, C., Winsa-Jornulf, J., Vogel, H., Babaei, C.S., Askevik, K., Dickson, S.L., 2016. Behavioral consequences of exposure to a high fat diet during the post-weaning period in rats. Hormones and behavior 85, 56-66. Rees, R.W., Caird, J., Dickson, K., Vigurs, C., Thomas, J., 2014. 'It's on your conscience all the time': a systematic review of qualitative studies examining views on obesity among young people aged 12-18 years in the UK. BMJ open 4, e004404. Reichelt, A.C., 2016. Adolescent Maturational Transitions in the Prefrontal Cortex and Dopamine Signaling as a Risk Factor for the Development of Obesity and High Fat/High Sugar Diet Induced Cognitive Deficits. Frontiers in behavioral neuroscience 10, 189. Reichelt, A.C., Killcross, S., Hambly, L.D., Morris, M.J., Westbrook, R.F., 2015a. Impact of adolescent sucrose access on cognitive control, recognition memory, and parvalbumin immunoreactivity. Learn Mem 22, 215-224. Reichelt, A.C., Maniam, J., Westbrook, R.F., Morris, M.J., 2015b. Dietary-induced obesity disrupts trace fear conditioning and decreases hippocampal reelin expression. Brain, behavior, and immunity 43, 68-75. Reichelt, A.C., Morris, M.J., Westbrook, R.F., 2016. Daily access to sucrose impairs aspects of spatial memory tasks reliant on pattern separation and neural proliferation in rats. Learn Mem 23, 386-390. Rice, F., Lifford, K.J., Thomas, H.V., Thapar, A., 2007. Mental health and functional outcomes of maternal and adolescent reports of adolescent depressive symptoms. Journal of 31

the American Academy of Child and Adolescent Psychiatry 46, 1162-1170. Roberts, R.E., Deleger, S., Strawbridge, W.J., Kaplan, G.A., 2003. Prospective association between obesity and depression: evidence from the Alameda County Study. International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity 27, 514-521. Roberts, R.E., Duong, H.T., 2013. Obese youths are not more likely to become depressed, but depressed youths are more likely to become obese. Psychol Med 43, 2143-2151. Roberts, R.E., Duong, H.T., 2016. Do Anxiety Disorders Play a Role in Adolescent Obesity? Ann Behav Med 50, 613-621. Robinson, M.J., Burghardt, P.R., Patterson, C.M., Nobile, C.W., Akil, H., Watson, S.J., Berridge, K.C., Ferrario, C.R., 2015. Individual Differences in Cue-Induced Motivation and Striatal Systems in Rats Susceptible to Diet-Induced Obesity. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 40, 2113-2123. Rofey, D.L., Kolko, R.P., Iosif, A.M., Silk, J.S., Bost, J.E., Feng, W., Szigethy, E.M., Noll, R.B., Ryan, N.D., Dahl, R.E., 2009. A longitudinal study of childhood depression and anxiety in relation to weight gain. Child psychiatry and human development 40, 517-526. Romeo, R.D., 2013. The Teenage Brain: The Stress Response and the Adolescent Brain. Curr Dir Psychol Sci 22, 140-145. Romeo, R.D., Patel, R., Pham, L., So, V.M., 2016. Adolescence and the ontogeny of the hormonal stress response in male and female rats and mice. Neuroscience and biobehavioral reviews 70, 206-216. Rudy, J.W., Morledge, P., 1994. Ontogeny of contextual fear conditioning in rats: implications for consolidation, infantile amnesia, and hippocampal system function. Behav Neurosci 108, 227-234. Sanchez-Villegas, A., Doreste, J., Schlatter, J., Pla, J., Bes-Rastrollo, M., Martinez-Gonzalez, M.A., 2009. Association between folate, vitamin B(6) and vitamin B(12) intake and depression in the SUN cohort study. Journal of human nutrition and dietetics : the official journal of the British Dietetic Association 22, 122-133. Sanchez-Villegas, A., Toledo, E., de Irala, J., Ruiz-Canela, M., Pla-Vidal, J., MartinezGonzalez, M.A., 2012. Fast-food and commercial baked goods consumption and the risk of depression. Public health nutrition 15, 424-432. Santos, C.J., Ferreira, A.V., Oliveira, A.L., Oliveira, M.C., Gomes, J.S., Aguiar, D.C., 2016. Carbohydrate-enriched diet predispose to anxiety and depression-like behavior after stress in mice. Nutritional neuroscience, 1-7. 32

Sasaki, A., de Vega, W., Sivanathan, S., St-Cyr, S., McGowan, P.O., 2014. Maternal high-fat diet alters anxiety behavior and glucocorticoid signaling in adolescent offspring. Neuroscience 272, 92-101. Sasaki, A., de Vega, W.C., St-Cyr, S., Pan, P., McGowan, P.O., 2013. Perinatal high fat diet alters glucocorticoid signaling and anxiety behavior in adulthood. Neuroscience 240, 1-12. Schneider, M., 2013. Adolescence as a vulnerable period to alter rodent behavior. Cell and tissue research 354, 99-106. Scott, K.M., McGee, M.A., Wells, J.E., Oakley Browne, M.A., 2008. Obesity and mental disorders in the adult general population. Journal of psychosomatic research 64, 97-105. Seach, K.A., Dharmage, S.C., Lowe, A.J., Dixon, J.B., 2010. Delayed introduction of solid feeding reduces child overweight and obesity at 10 years. International journal of obesity 34, 1475-1479. Simmonds, M., Llewellyn, A., Owen, C.G., Woolacott, N., 2016. Predicting adult obesity from childhood obesity: a systematic review and meta-analysis. Obesity reviews : an official journal of the International Association for the Study of Obesity 17, 95-107. Sivanathan, S., Thavartnam, K., Arif, S., Elegino, T., McGowan, P.O., 2015. Chronic high fat feeding increases anxiety-like behaviour and reduces transcript abundance of glucocorticoid signalling genes in the hippocampus of female rats. Behavioural Brain Research 286, 265270. Slade, T., Johnston, A., Oakley Browne, M.A., Andrews, G., Whiteford, H., 2009. 2007 National Survey of Mental Health and Wellbeing: methods and key findings. The Australian and New Zealand journal of psychiatry 43, 594-605. Spear, L.P., 2000. The adolescent brain and age-related behavioral manifestations. Neuroscience and biobehavioral reviews 24, 417-463. Spencer, S.J., Buller, K.M., Day, T.A., 2005. Medial prefrontal cortex control of the paraventricular hypothalamic nucleus response to psychological stress: possible role of the bed nucleus of the stria terminalis. The Journal of comparative neurology 481, 363-376. Spencer, S.J., Tilbrook, A., 2009. Neonatal overfeeding alters adult anxiety and stress responsiveness. Psychoneuroendocrinology 34, 1133-1143. Stunkard, A.J., Faith, M.S., Allison, K.C., 2003. Depression and obesity. Biological psychiatry 54, 330-337. Sullivan, E.L., Grayson, B., Takahashi, D., Robertson, N., Maier, A., Bethea, C.L., Smith, M.S., Coleman, K., Grove, K.L., 2010. Chronic consumption of a high-fat diet during pregnancy causes perturbations in the serotonergic system and increased anxiety-like 33

behavior in nonhuman primate offspring. The Journal of neuroscience : the official journal of the Society for Neuroscience 30, 3826-3830. Sullivan, E.L., Smith, M.S., Grove, K.L., 2011. Perinatal exposure to high-fat diet programs energy balance, metabolism and behavior in adulthood. Neuroendocrinology 93, 1-8. Talge, N.M., Neal, C., Glover, V., Early Stress, T.R., Prevention Science Network, F., Neonatal Experience on, C., Adolescent Mental, H., 2007. Antenatal maternal stress and long-term effects on child neurodevelopment: how and why? Journal of child psychology and psychiatry, and allied disciplines 48, 245-261. Taylor, S.J.A., Rennie, K., Jon, C., 2017. Clinical outcomes of an inpatient pediatric obesity treatment program in the USA. Int J Adolesc Med Health. Teegarden, S.L., Scott, A.N., Bale, T.L., 2009. Early life exposure to a high fat diet promotes long-term changes in dietary preferences and central reward signaling. Neuroscience 162, 924-932. Teh, A.L., Pan, H., Chen, L., Ong, M.L., Dogra, S., Wong, J., MacIsaac, J.L., Mah, S.M., McEwen, L.M., Saw, S.M., Godfrey, K.M., Chong, Y.S., Kwek, K., Kwoh, C.K., Soh, S.E., Chong, M.F., Barton, S., Karnani, N., Cheong, C.Y., Buschdorf, J.P., Stunkel, W., Kobor, M.S., Meaney, M.J., Gluckman, P.D., Holbrook, J.D., 2014. The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes. Genome research 24, 1064-1074. Thompson, J.R., Valleau, J.C., Barling, A.N., Franco, J.G., DeCapo, M., Bagley, J.L., Sullivan, E.L., 2017. Exposure to a High-Fat Diet during Early Development Programs Behavior and Impairs the Central Serotonergic System in Juvenile Non-Human Primates. Frontiers in endocrinology 8, 164. Turnbaugh, P.J., Ley, R.E., Mahowald, M.A., Magrini, V., Mardis, E.R., Gordon, J.I., 2006. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027-1031. Van den Bergh, B.R., Mulder, E.J., Mennes, M., Glover, V., 2005. Antenatal maternal anxiety and stress and the neurobehavioural development of the fetus and child: links and possible mechanisms. A review. Neuroscience and biobehavioral reviews 29, 237-258. van Geel, M., Vedder, P., Tanilon, J., 2014. Are overweight and obese youths more often bullied by their peers? A meta-analysis on the correlation between weight status and bullying. International journal of obesity 38, 1263-1267. VanTieghem, M.R., Tottenham, N., 2017. Neurobiological Programming of Early Life Stress: Functional Development of Amygdala-Prefrontal Circuitry and Vulnerability for 34

Stress-Related Psychopathology. Curr Top Behav Neurosci. Vendruscolo, L.F., Gueye, A.B., Darnaudery, M., Ahmed, S.H., Cador, M., 2010. Sugar overconsumption during adolescence selectively alters motivation and reward function in adult rats. PloS one 5, e9296. Vinuesa, A., Pomilio, C., Menafra, M., Bonaventura, M.M., Garay, L., Mercogliano, M.F., Schillaci, R., Lux Lantos, V., Brites, F., Beauquis, J., Saravia, F., 2016. Juvenile exposure to a high fat diet promotes behavioral and limbic alterations in the absence of obesity. Psychoneuroendocrinology 72, 22-33. Vogel, H., Kraemer, M., Rabasa, C., Askevik, K., Adan, R.A.H., Dickson, S.L., 2017. Genetic predisposition to obesity affects behavioural traits including food reward and anxiety-like behaviour in rats. Behav Brain Res 328, 95-104. Vogt, Merly C., Paeger, L., Hess, S., Steculorum, Sophie M., Awazawa, M., Hampel, B., Neupert, S., Nicholls, Hayley T., Mauer, J., Hausen, A.C., Predel, R., Kloppenburg, P., Horvath, Tamas L., Brüning, Jens C., 2014. Neonatal Insulin Action Impairs Hypothalamic Neurocircuit Formation in Response to Maternal High-Fat Feeding. Cell 156, 495-509. Vollbrecht, P.J., Nobile, C.W., Chadderdon, A.M., Jutkiewicz, E.M., Ferrario, C.R., 2015. Pre-existing differences in motivation for food and sensitivity to cocaine-induced locomotion in obesity-prone rats. Physiology & behavior 152, 151-160. Vucetic, Z., Kimmel, J., Totoki, K., Hollenbeck, E., Reyes, T.M., 2010. Maternal high-fat diet alters methylation and gene expression of dopamine and opioid-related genes. Endocrinology 151, 4756-4764. Vuong, H.E., Yano, J.M., Fung, T.C., Hsiao, E.Y., 2017. The Microbiome and Host Behavior. Annual review of neuroscience 40, 21-49. Wallace, J.G., Gohir, W., Sloboda, D.M., 2016. The impact of early life gut colonization on metabolic and obesogenic outcomes: what have animal models shown us? Journal of developmental origins of health and disease 7, 15-24. Weaver, I.C., Cervoni, N., Champagne, F.A., D'Alessio, A.C., Sharma, S., Seckl, J.R., Dymov, S., Szyf, M., Meaney, M.J., 2004. Epigenetic programming by maternal behavior. Nature neuroscience 7, 847-854. Weng, T.T., Hao, J.H., Qian, Q.W., Cao, H., Fu, J.L., Sun, Y., Huang, L., Tao, F.B., 2012. Is there any relationship between dietary patterns and depression and anxiety in Chinese adolescents? Public health nutrition 15, 673-682. Williams-Spooner, M., Richardson, R., Baker, K.D., 2017. A High-Fat High-Sugar DietInduced Impairment of Fear Inhibition and Place-Recognition Memory in Adolescent Rats. 35

Biological Psychiatry, 72nd Annual Scientific Convention and Meeting, S338-S339. Wright, T., Langley-Evans, S.C., Voigt, J.P., 2011. The impact of maternal cafeteria diet on anxiety-related behaviour and exploration in the offspring. Physiology & behavior 103, 164172. Yogev, Y., Catalano, P.M., 2009. Pregnancy and obesity. Obstet Gynecol Clin North Am 36, 285-300, viii.

36

Figure captions Figure 1. A schematic timeline illustrating the physiological and neural mechanisms that may contribute to increased expressions of anxiety in individuals and anxiety-like behaviour in preclinical animal models when hypercaloric diets are consumed at different stages of development. The specific developmental life stages are gestation (prenatal exposure), neonatal / juvenile period (early childhood), adolescence and adulthood. As shown in the figure, differential trajectories of neural system and structure maturation occur across development. Furthermore, HPA axis programming and epigenetic modification influences may occur in very early life and influence behavioural reactivity across the lifespan. Figure 1

37