Preclinical evidence for the addiction potential of highly palatable foods: Current developments related to maternal influence

Accepted Manuscript Preclinical evidence for the addiction potential of highly palatable foods: Current developments related to maternal influence David A. Wiss, Kristen Criscitelli, Mark Gold, Nicole Avena PII:

S0195-6663(16)30935-7

DOI:

10.1016/j.appet.2016.12.019

Reference:

APPET 3264

To appear in:

Appetite

Received Date: 9 September 2016 Revised Date:

14 November 2016

Accepted Date: 14 December 2016

Please cite this article as: Wiss D.A., Criscitelli K., Gold M. & Avena N., Preclinical evidence for the addiction potential of highly palatable foods: Current developments related to maternal influence, Appetite (2017), doi: 10.1016/j.appet.2016.12.019. 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.

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Preclinical Evidence for the Addiction Potential of Highly Palatable Foods: Current Developments Related to Maternal Influence

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Icahn School of Medicine at Mount Sinai

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Washington University in St. Louis

Correspondence should be sent to: Nicole Avena, PhD

Assistant Professor of Pharmacological Science

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Icahn School of Medicine at Mount Sinai 1111 Amsterdam Ave., 12th Floor

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New York, NY 10025

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Nutrition in Recovery LLC

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David A. Wiss1, Kristen Criscitelli2, Mark Gold3, Nicole Avena2

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Abstract It is well established that obesity has reached pandemic proportions. Over the last four decades the prevalence of obesity and morbid obesity have risen

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substantially in both men and women worldwide. Although there are many causative factors leading to excessive weight gain including genetics and sedentary lifestyle, the transformation of the food environment has undoubtedly

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contributed to the dangerously high rates of obesity. The current food landscape is inundated with food engineered to contain artificially high levels of sugar and

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fat. Overconsumption of these types of food overrides the homeostatic mechanisms, which under normal circumstances regulate appetite and body mass, leading to hedonic eating. Evidence from the animal literature has illustrated nutrition-influenced perturbations that occur within the mesolimbic

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dopamine pathway, as well as maladaptive behavioral responses that result from chronic ingestion of highly palatable foods. These neurobehavioral adaptations are similar to what is observed in drugs of abuse. Recent evidence also supports

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that maternal exposure to these foods is capable of provoking neurobehavioral alterations in offspring. Therefore the purpose of this review is to summarize the

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current developments on the addictive potential of highly palatable foods, as well as illuminate the impact of maternal hyperphagia and obesity on the rewardrelated neurocircuitry and addiction-like behaviors in the offspring.

Keywords: Sugar, addiction, maternal, reward, highly palatable, obesity

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Introduction Obesity remains a major public health problem in the United States, with growing prevalence in children (Ng et al., 2014; Swinburn et al., 2011). Several established

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mechanisms contributing to the increased rates of obesity include changes in dietary patterns (Chaput, Klingenberg, Astrup, & Sodjin, 2011; Mozaffarian, Hao, Rimm, Willett, & Hu, 2011; Popkin, Adair, & Ng, 2012), sedentary lifestyles (Myers, Gibbons,

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Finlayson, & Blundell, 2016), genetic susceptibility (Farooqi & O'Rahiliy, 2006; Llewellyn & Wardie, 2015), and gene-environment interactions resulting in epigenetic

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modifications (Rooney & Ozanne, 2011; Skinner, 2011). It is undeniable that the current food environment encourages excessive consumption of highly processed foods due to exaggerated levels of sugar and fat in these foods. The chronic consumption of highly palatable foods results in neuroadaptations within the mesolimbic dopamine (DA)

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reward pathways (Avena, Rada, & Hoebel, 2008; Rada, Avena, & Hoebel, 2005; Willuhn, Burgeno, Groblewski, & Phillips, 2014), leading to neurochemical and behavioral alterations mirroring those seen in drug addiction (Murray, Tulloch, Gold, &

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Avena, 2014). Given the alarmingly high rates of pediatric obesity, researchers have begun to postulate that prenatal or intrauterine influences may contribute to obesity risk

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later in life. Preclinical evidence suggests appetite regulation begins in the prenatal and perinatal period (Ashino et al., 2012; Muhlhausler, Adam, Findlay, Duffield, & McMillen, 2006; Shalev et al., 2010; Sun, Purcell, Terrillion, Yan, & Moran, 2012), when homeostatic and hedonic appetite centers within the brain are sensitive to the maternal nutritional environment. Indeed, maternal drug abuse can predispose offspring to future drug addiction (Pinheiro et al., 2015) as well as impaired behavior (Richardson, Hamel,

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Goldschmidt, & Day, 1996). This has led to the exploration of underlying mechanisms of addictive-like eating observed in offspring that may occur in response to maternal ingestion of a highly palatable diet during gestation and lactation. Therefore, the focus

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of this paper is to provide an update on intrauterine nutritional experiments in animal models and to review preclinical data on nutritional programming. We focus on the

impact of maternal hyperphagia and obesity on the neurohormonal circuitry related to

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addiction-like behaviors in the offspring. "Junk food" and "highly palatable" are terms used to describe highly processed combinations of fat, sugar, and salt, resembling

Hypothalamus & Hormones

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contemporary Westernized convenience foods.

The arcuate nucleus (ARC) is thought to be the integration site of appetiterelated signals in the hypothalamus. Blood-borne signals including glucose, triglyceride,

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insulin, and leptin contribute information to the ARC (see review by Bauer, Hamr, & Duca, 2015). An individual's metabolic state will profoundly influence the reward system by linking homeostatic mechanisms (governed by the hypothalamus) with reward

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pathways in the midbrain and cortex (see reviews by De Araujo, Ferreira, Tellez, Ren, & Yeckel, 2012; Coll, Farooqi, & O'Rahilly, 2007). In the ARC, orexigenic hormones such

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as neuropeptide Y (NPY) and agouti-related protein (AgRP) are produced to stimulate food intake, while anorexigenic neurons such as proopiomelanocortin (POMC) inhibit food intake (Hahn, Breininger, Baskin, & Schwartz, 1998). It has been established that the appetite-regulating neural network is present before birth in animal models (Muhlhausler et al., 2006). Hormones such as insulin and leptin are implicated in the programmed hyperphagia observed in offspring overfed during pregnancy. A recent

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review summarized the role of various hormones in the hypothalamic appetite-signaling pathway, concluding that the rise in obesity rates could at least in part be explained by early life nutritional imbalances (Ramamoorthy, Begum, Harno, & White, 2015).

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Insulin. Insulin promotes the absorption of glucose from the blood and into both muscles and fat tissue. Insulin can cross the blood brain barrier to influence orexigenic and anorexigenic neurons in the ARC (see reviews by Kleinridders, Ferris, Cai, & Kahn,

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2014; Schwartz, Woods, Porte, Seeley, & Baskin, 2000). Indeed, that excess adipose tissue resulting from chronic intake of a highly palatable diet can cause insulin

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resistance and impaired insulin utilization, leading to diminished insulin secretion (Kahn & Flier, 2000), which impacts both homeostatic and hedonic feeding circuitry. Insulin and DA work together to orchestrate both the motivation to engage in consumptive behavior, and to calibrate the associated reward, particularly related to hedonic feeding

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(Mebel, Wong, Dong, & Borgland, 2012). More specifically, insulin-mediated decreases in DA concentration in the ventral tegmental area (VTA) via increased DA reuptake through DA transporter (DAT) may explain suppressed salience of food, once satiety is

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reached. Insulin can act on the ARC to reduce food intake and body weight, however there is evidence of central insulin resistance in obese patients (see review by Ye,

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2013). Diet induced maternal obesity has a detrimental effect on insulin secretion and metabolic dysfunction, as well as elevated leptin levels in offspring (Zambrano, et al., 2016).

Leptin. Leptin is produced and secreted by adipose tissue to increase metabolic

rate. Leptin signals the individual to reduce energy intake and increase expenditure, generally by inhibiting orexigens such as NPY and stimulating anorexigens such as

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POMC (see reviews by Morton, Meek, & Schwartz, 2014; Shan & Yeo, 2011). Fulton and colleagues (2006) showed that leptin administration to leptin-deficient mice decreased DA activity in the VTA, supporting the hypothesis that that these animals

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compensate for a deficit in NAc DA by increasing food intake. Furthermore, reduced expression of leptin receptors in the VTA and hypothalamus lead to increased food intake via modulation of mesolimbic DA neurons and associated effort-based feeding

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(motivation) (Hommel et al., 2006). Taken together, it appears that leptin-mediated modulation of DA circuits generate an overall behavioral response.

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It has been reported that maternal leptin can cross the placenta and be a significant source of fetal leptin (Smith & Waddell, 2003). Not surprisingly, neonatal overfeeding is associated with elevated juvenile and adult plasma leptin levels in rats (Stefandis & Spencer, 2012). High-fat diets (HFD) can induce leptin resistance and is

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emerging as a cause and consequence of weight gain (Pandit, Mercer, Overduin, La Fleur, & Adan, 2012). The combination of perinatal and post-weaning HFD leads to an elevated fasting plasma glucose and leptin resistance in offspring (Shalev et al., 2010).

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These authors found that increased potential for leptin resistance in the postnatal period can result in abnormal appetite regulation, glucose intolerance, altered reward

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sensitivity, and obesity.

Ghrelin. Ghrelin is stomach-derived hormone, which decreases after eating and

contributes to satiety. Ghrelin has been shown to increase the intake of high-calorie food including sugar and fat (King, Isaacs, O'Farrel, & Abizaid, 2011; MacKay et al., 2016). Similar to the hormones leptin and insulin, ghrelin is also implicated in homeostatic appetite regulation, and data suggest its implication in hedonic eating

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(Abizaid et al., 2006; Naleid, Grace, Cummings, & Levine, 2005). In addition to its action on orexigenic neurons in the hypothalamus, ghrelin receptors have also been identified in the VTA, hippocampus, and amygdala (Abizaid et al., 2006; Zigman et al., 2006). The

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ghrelin system increases the motivation to eat by altering the set point of dopaminergic neurons in the VTA thereby enhancing the ability of rewarding substances to activate the midbrain DA system (Dickson et al., 2011; Skibicka, Alvarez-Crespo, Friberg, &

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Dickson, 2011). Perello et al. (2010) found that ghrelin is involved in certain rewarding aspects of eating (HFD) and requires the presence of intact orexin signaling, distinct

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from homeostatic mechanisms that promote food intake in response to reduced energy stores. It has been suggested that the mesoaccumbal DA pathway (designed to promote survival in times of food scarcity) is targeted by the ghrelin/growth hormone secretagogue receptor type 1A (GHSR-1A) system and is a driver in the

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overconsumption of palatable foods beyond metabolic need (see Perello & Dickson, 2015). Recently it has been shown that GHSR knockout rats eat less of palatable dessert following a meal (MacKay et al., 2016).

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Just as maternal diet influences leptin levels in offspring, a maternal HFD during prenatal and lactation increases ghrelin levels in offspring when compared to offspring

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from dams fed standard chow (Slupecka, Romanowicz, & Wolinski, 2016). Thus, observable neurobehavioral adaptations in the HFD offspring are not surprising given that the central ghrelin signaling system interfaces with neurobiological circuits involved in reward from both food (Veneliene, 2013) and chemical drugs including cocaine (David, Wellman, & Clifford, 2005) and alcohol (Jerlhag et al., 2009; Leggio et al., 2011). Some investigators have concluded that ghrelin primarily exerts motivational

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effects on feeding, rather than hedonic or opioid-related effects (Overduin, Figlewicz, Bennet-Jay, Kittleson, & Cummings, 2012) while others have identified the mu or kappa opioid system (in the VTA) as being modulated by ghrelin (Kawahara et al., 2013). The

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precise role of ghrelin in the neuroendocrine regulation of feeding behavior is not yet established, but some authors believe it may be involved in disordered eating (Valdivia, Cornejo, Reynaldo, Francesco, & Perello, 2015; King et al., 2016) and addiction

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(Dagher, 2012; Jerlhag, Egecioglu, Dickson, & Engel, 2010).

Summary. Neurodevelopment in utero is influenced by maternal feeding patterns

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via perturbations in insulin, leptin, and ghrelin signaling. These hormones interact with the development of reward system, particularly in the VTA, impacting the homeostatic and hedonic mechanisms that govern feeding behavior. Nutritional imbalances during pregnancy have the potential to stimulate reward-based eating in the offspring.

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Maternal Under and Overfeeding

There is evidence to suggest that the appetite regulating neural network is influenced more by decreases in nutrient supply, rather than increases (see review by

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Ramamoorthy et al., 2015). Fetal under-nutrition or nutrient imbalance which determines adult adiposity has been shown to be intergenerational (Jimenez-Chillaron

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et al., 2009) and may stem from remodeling of hypothalamic structures that govern feeding behavior and altered gene expression related to satiety hormones (see LangleyEvans, Bellinger, & McMullen, 2005) as well as alteration of the hypothalamic-pituitaryadrenocortical (HPA) axis (Zhang et al., 2013). It appears that the exposure to famine during early gestation (associated with an increase in obesity potential) differs from exposure to famine later in pregnancy (associated with lower birth weights) (see

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Ramamoorthy et al., 2015). This "predictive adaptive response" in early gestation may provide a survival advantage for the fetus in anticipation of the long-term environment.

previously overfed mothers (Giraudo et al., 2010).

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Meanwhile, a mild food restriction (25%) appears to be protective against obesity from

While the underfeeding model originally received more attention, there is also evidence that suggests maternal overfeeding increases obesity prevalence as well.

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Overfeeding during perinatal life has been shown to lead to an overweight phenotype, with a more pronounced impact the closer to birth (Ashino et al., 2012; Muhlhauser et

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al., 2006). This concept has been referred to as "metabolic imprinting" (Sullivan, Smith, & Grove, 2011). Research by Stefanidis and Spencer (2012) suggests that rats overfed as newborns do not exhibit hyperphagia but maintain reduced energy expenditure into their juvenile phase, which is a major contributing factor to their greater size, weight,

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and fat mass. Notwithstanding, it has been established that both underweight and overweight offspring are at higher risk for obesity and metabolic disorder, and recent evidence implicates both the DA and opioid systems (Grissom & Reyes, 2013).

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Lactation. Gestation and lactation in mice are typically three weeks each. The early postnatal period (first two weeks in mice) is also a critical period for the

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programming of appetite and body fat mass. Maternal diets high in fat during suckling have shown a greater influence in determining metabolic phenotype (i.e. leptin resistance) than prenatal high fat exposure (Sun et al., 2012), suggesting that the composition of the milk may be a key regulator in the development and maturation of central and peripheral appetite control (Bayol, Farrington, & Stickland, 2007). A highly palatable diet during lactation in rodents caused alterations of behavioral feeding

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patterns and higher concentration of hypothalamic DA (Wright, Fone, Langley-Evans, & Voigt, 2011). Further, satiety was delayed in these female offspring, which may negatively impact weight status later in life.

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Summary. Both fetal under- and over-nutrition have potential to impact the

appetite-regulating neural network in the hypothalamus, implicating both the DA and opioid systems in the intergenerational risk for obesity and other metabolic disorders.

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Additionally, the early postnatal period (influenced by quality of milk during lactation) has also been shown to create neuroendocrine imbalances, which can delay feelings of

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satiety and lead to hyperphagia in the offspring. High Fat Diets (HFD)

More research has been conducted with HFDs than high sugar diets (HSDs) but the evidence suggests that excessive excessive intake of either macronutrient during

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pregnancy can have a pronounced neurohormonal and behavioral impact on offspring. Rats maintained on HFD displayed more impulsivity than HSD (Adams et al., 2015). It appears that earlier (closer to birth) exposures to HFDs increase the likelihood that

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mesocorticolimbic DA system adaptations will lead to overconsumption later in life. Adolescent-onset HFD lead to a significant increase in binge behavior in female mice,

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compared to adult-onset HFD (Carlin et al., 2016). Adolescent exposure to HFD decreased expression of DAD1 and D2 receptors, which was absent in adult exposed models. These mice displayed a decrease in sucrose preference, consistent with hyporeward responses (reduced striatal responsivity) associated with obesity and the "feedforward" model (Stice, Yokum, Blum, & Bohon, 2010). In this adolescent-onset group, decreased expression of DAD1 and DAD2 normalized after removal of HFD, but

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less so than the adult-onset group. Carlin et al. (2016) acknowledge that a better understanding of how the DA system responds to the removal of a highly palatable diet is clearly needed.

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Other research has demonstrated that even brief early life (4th week of life in mice) exposures to high fat, calorically dense palatable diets will alter long-term

programming of central mechanisms critical for dietary preferences and associated

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reward (Teegarden, Scott, & Bale, 2009). For example, peference for HFD was

significantly greater in mice that had been exposed to the HFD early in life. However,

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mice exposed to a high carbohydrate diet in early life did not display higher preference for carbohydrate, suggesting that findings for the HFD mice are not simply a result of prior experience with the food. Teegarden and colleagues (2009) suggest that since the circuitry of the ARC is already formed by the fourth week, hypothalamic development is

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unlikely to be the causal mechanism since it is mostly developed by that time. Rather, authors suggest that alterations in reward signaling in the ventral striatum resulting from exposure to the HFD were contributing factors. Higher levels of transcription factor Δ

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FosB and other biochemical measures suggest a reduction in striatal DA signaling that may trigger compensatory maladaptive substance-seeking behaviors, in attempt to

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normalize dopaminergic tone. An intervention study using HFDs in the post-weaning period (3 weeks of age) found increases in fat pad weights, serum glucose, and leptin levels, in addition to final body weight (Odaka et al., 2010). Furthermore, these investigators found that HFD during the fetal environment also induces increased triglyceride, and immune-regulatory dysfunction (assessed by splenic lymphocytes, thickness of thymic cortex, antigen-specific antibody levels, and tumor necrosis factor

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alpha (TNF-α) production). TNF-α is considered a pro-inflammatory cytokine, suggesting that inflammation may be evoked more easily in the fetal HFD group, although authors speculate that it may be due to their use of lard as fat. Interestingly,

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inflammatory markers have been associated with increased obesity risk, and may

promote addictive behaviors leading to a self-perpetuating cycle of overconsumption (Heber & Carpenter, 2011).

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It remains unclear if the insult stems from the HFD exposure itself, or from the type of fat (saturated or unsaturated) exposure, given the different inflammatory

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properties of each type of fat. For example, a diet-induced reduction of brain docosahexaenoic acid (omega-3 fatty acid) can cause decreased density of ventral striatal DAD2 receptors, with a greater (although not significant) magnitude in parous dams than in virgin females (Davis et al., 2010). Therefore, discerning between the type

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of fat (omega-3 vs. saturated fat) appears to be important when critically examining the impact of gestational HFDs (see review by Sullivan, Smith, & Grove, 2011). High Sugar Diets (HSD)

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A recent review summarized the interaction between homeostatic and hedonic neural systems related to the intake of sweeteners (Murray, Tulloch, Criscitelli, & Avena,

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2016). Caloric sweeteners impact the homeostatic and hedonic mechanisms, favoring the hedonic system by activating the mesolimbic dopaminergic reward system. Sweetness is sufficient to motivate feeding by inducing cravings, and caloric sweeteners remain more reinforcing than non-caloric sweeteners (De Araujo et al., 2011; Murray et al., 2016). It has been demonstrated that leptin reduces the reward value of sucrose via reduction in DA signaling (De Araujo et al., 2011). Hormonal regulation of food reward

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may partially explain why sucrose is preferred over artificial sweeteners. However, peripheral ghrelin administration enhances intake and preference for sweetness, for both sugar (Skibicka et al., 2011) as well as artificial sweetener (Disse et al., 2010).

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It has recently been shown that when mice are given short term unlimited access to sweet palatable food, there is an increase in synaptic density within the VTA (Liu et al., 2016). Further, after unlimited access to sweet palatable food, mice subsequently

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increase their future food consumption. After being exposed to cocaine and

subsequently being forced into abstinence, rats (8 weeks old) displayed a persistent

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increase in their motivation to consume sucrose under conditions of intermittent access (12 hours every 12 hours) suggesting that exposure to cocaine cross-sensitizes to the rewarding effects of sucrose (Nicolas, Lafay-Chebassier, & Solinas, 2016). In mice, preference for sugar-sweetened water (SSW) increases over time consumed (Soto et

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al., 2015). These researchers found that mice on HFDs (starting at 7 weeks postnatal) display an even higher preference for SSW than mice fed a normal fat diet. Reductions in striatal DA signaling resulting from HFD and associated compensatory behavior (in

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this case sugar-seeking) are likely mechanisms. Follow-up research demonstrated that combined HFD/HSD with SSW given at intermittent access leads to insulin resistance

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and fatty liver in obesity-prone mice (aged 5 weeks) (Soto et al., 2016). Results show that being obesity-prone (determined by rate of weight gain during first 3 weeks of feeding) increases susceptibility to the obesogenic effects of SSW. Metabolic consequences of SSW in obesity-prone mice were reversible once SSW access was removed. Mice given intermittent access (at two hour intervals) to SSW had a metabolic profile more resistant to reversibility, and authors speculate that a decreased expression

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of anorexigenic neuropeptides (i.e. POMC) may partially explain the hyperphagia observable in the obesity-prone mice (Soto et al., 2016). Rats exposed to SSW between postnatal days 30-46 (adolescence) reached

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adulthood (postnatal day 70) and then showed a lower intake of sweetened beverages (saccharin solution, sugar solution) compared to rats not exposed to SSW during

adolescence (Naneix, Darlot, Coutureau, & Cador, 2016). These results suggest a

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decreased sensitivity to the rewarding properties of sugar, attributing the hedonic deficit to lower c-Fos expression levels found in the NAc. Researchers acknowledge that the

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voluntary consumption of the sweetened beverages in adulthood may be decreased related to the motivational aspect of food intake rather than solely by deficit in hedonic processing. Naneix and colleagues (2016) conclude that consumption of sweet drinks in adolescence may contribute to reward-related disorders in adulthood. Longer-term SSW

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consumption (12 weeks) with binge-like eating patterns has been shown to decrease total dendritic length of NAc shell medium spiny neurons resulting from reduced distal dendritic complexity (Klenowski et al., 2016). Interestingly, these investigators found

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that short-term SSW consumption (4 weeks) did not lead to these changes in the NAc shell region. These findings highlight how a transition to dependence and addiction is a

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progressive process often characterized by repeated cycles of binge intakes and abstinence, and that duration of exposure to SSW is a significant influencer of NAc morphology.

Intrauterine Programming Some of the consequences of maternal exposure to highly palatable foods during the developmental stages of life can impact reward processing well into adulthood.

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Maternal exposure to drugs or highly palatable foods during the pre- and postnatal period alter behavior via the DA reward system (Kendig, Ekayanti, Stewart, Boakes, & Rooney, 2015; Naef et al., 2011) and mu-opioid receptor (MOR) (Carlin, George, &

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Reyes, 2013) in the offspring. Diet-induced obesity has been shown to lead to a state of insulin resistance in male offspring, which can increase food intake and lead to obesity (Nivoit et al., 2009). Term fetuses of HFD rodents exhibit hyperleptinemia and

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hyperinsulinemia (Gupta, Srinivasan, Thamadilok, & Patel, 2009; Mitra, Alvers, Crump, & Rowland, 2009). Furthermore, a highly palatable diet during the prenatal period may

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predispose offspring to exhibit increased impulsivity, a known risk factor for drug abuse and overeating (Adams et al., 2015; Grissom, Herdt, Desilets, Lidsky-Everson, & Reyes, 2015; Koob & Volkow, 2010; Liu et al., 2013). HSD during pregnancy has been shown to induce ADHD-like behavior (hyperactivity, inattention, and impulsivity) in offspring

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(Choi et al., 2015).

Rats fed a junk food diet during pregnancy had offspring with birth weights lower than those fed with standard chow (Bayol, Farrington, & Stickland, 2007; Ong &

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Muhlhauser, 2011). These authors propose that this may be attributed to a reduction in maternal protein intake, caused by displacement with junk food. Low protein pregnancy

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diets have been associated with increased food intakes by the offspring (Whitaker, Totoki, & Reyes, 2012) as well as increased anxiety (Ramirez-Lopez et al., 2016). Offspring from maternal low-protein diets displayed increased attention to rewardpredicting cues, a hallmark of addiction (Grissom et al., 2015). Mothers who consumed approximately one-third less protein than controls had offspring with higher preference for foods rich in fat, sugar, and salt (Bayol, Farrington, & Stickland, 2007). Furthermore,

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rats given standard chow were heavier at weaning yet significantly lighter at week ten, indicating that a balanced diet during gestation and lactation is protective against dietinduced obesity in the offspring. Other research has demonstrated that pups born from

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obese dams were heavier than those from lean dams (Ashino et al., 2012; Chen & Morris, 2009). In one study mothers had been obese over the long-term, implying

different long-term metabolic implications compared to simply introducing of junk food

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during pregnancy (Bayol, Farrington, & Stickland, 2007). Specifically, elevated plasma leptin in pups from obese mothers implicates a state of leptin resistance, where leptin

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fails to successfully inhibit both NPY and AgRP. Compared to the offspring of lean dams, offspring from pre-existing obese mothers had greater increases in these hypothalamic orexigenic regulators, directly contributed to hyperphagia and weight gain (Chen & Morris, 2009).

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When rats were fed highly palatable diets and exposed both post-weaning and during the perinatal period, it led to a significantly more pronounced interaction with amphetamine, showing higher sensitivity to the locomotor activating effects of the drug

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(Naef et al., 2008; Shalev et al., 2010). Similar alterations in locomotor effects have also been observed with cocaine (Collins et al., 2015; Oginsky, Goforth, Nobile, Lopez-

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Santiago, & Ferrario, 2016). The sensitized response to amphetamine/cocaine suggests an increase in DA transmission in the mesocorticolimbic DA system, which serves as an indicator of adaptations in hedonic feeding mechanisms (incentive salience and motivation), likely related to changes in the sensitivity of synaptic receptor balance in NAc (Naef et al., 2008). Other data suggest that prenatal and pre-weaning exposure to HFD/HSD affects responses to drugs of abuse including alcohol (Bocarsly et al., 2012).

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Rats exposed to HFD in utero drank more alcohol as adults, while rats exposed to HSD in utero displayed increased amphetamine-induced locomotor activity. Taken together, these findings suggest that food exposure during critical periods of offspring

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neurodevelopment impact consumption behavior and thus may be a contributing factor to the rising rates of obesity and addictive disorders (Bocarsly et al., 2012).

Naef et al. (2011) found that maternal HFD from the last week of gestation until

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weaning led to a decreased expression of presynaptic D2 autoreceptors in projection areas such as the NAc. As adults, rats fed with HFD differed from controls in their

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sensitivity to the reinforcing properties of fat-enriched food rewards. Maternal dietinduced effects were observed more than two months after offspring had been weaned and returned to control diet, suggesting that early life nutritional programming can have a lasting impact of mesolimbic DA neurons (Naef et al., 2011). This effect was not

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observed with HSD. These authors speculate that the changes in circulating levels of insulin, leptin, and ghrelin, and their interaction with DA neurons may explain the altered operant response for fat-rich rewards.

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Maternal junk food diet can cause a significant increase in MOR and a decrease in dopamine active transporter (DAT) in the offspring at six weeks of age (Ong &

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Muhlhauser, 2011). These changes are consistent with heightened activation of opioid and dopaminergic signaling within the central reward pathway, and may be the driving force behind the early preference for HFD in the junk food offspring. Authors propose that the significantly higher concentrations of leptin in the junk food offspring may play a role in the altered development of central reward circuitry. Interestingly, MOR expression and DAT differences were reversed at 3 months following chronic exposure

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to HFD, with MOR being lower, and DAT being higher, than controls. Recent research has shown that HSD mice offspring had increased DAT mRNA expression in the striatum (Choi et al., 2015). Moreover, administration of the opioid antagonist naloxone

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for ten days after weaning alters gene expression of opioid and DA signaling pathways in the mesolimbic reward system, however was not sufficient to predict changes in

eating behavior in adulthood (Gugusheff, Ong, & Muhlhausler, 2014). Collectively the

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data indicate reduced opioid and DA signaling, both pathways that are involved in the development of addiction.

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Genetics. Weaver et al. (2004) demonstrated that an epigenomic state is established through maternal behavior and environmental programming. Nutritional insults during pregnancy can be passed to a second and third generation (Ponzio, Carvahlo, Fortes, & Franco, 2012). In humans, epigenetic gene promoter methylation at

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birth has been associated with offspring adiposity, suggesting a possible utility in identifying individual vulnerability to the onset of obesity and metabolic disease (Godfrey et al., 2011). Mechanisms behind increased preference for junk food in offspring from

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maternal HFD appear related to DNA methylation and altered expression of DA and opioid-related genes (Vucetic, Kimmel, Totoki, Hollenbeck, & Reyes, 2010).

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Overexpression of δ-opioid receptor resulting from gestation HFD has been associated with poor executive functioning performance (Grissom et al., 2015). It is unknown if DArelated epigenetic modifications and gene expression are simply consequences of intrauterine programming, or if these alterations propagate other epigenetic changes (Grissom & Reyes, 2013).

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DNA methylation has been described as a "biochemical process involving the covalent addition of a methyl group at the 5' position of cytosine in DNA" (Zheng, Xiao, Zhang, & Yu, 2014). Vucetic et al. (2010) showed DNA global hypomethylation in the

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brains of offspring from HFD mothers, which may play a role in the transgenerational perpetuation of addictive symptomatology and subsequent obesity. Maternal cocaine administration during the second and third trimester of gestation has been shown to

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alter DNA methylation (hypomethylation and hypermethylation) and thereby modify gene expression (Novikova et al., 2008). Interestingly, promethylation dietary

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supplements have been shown to mediate alterations in epigenetic mechanisms (Waterland, Travisano, Tahiliani, Rached, & Mirza, 2008). When supplemented with a methyl donor, mRNA changes in DAT and MOR in response to a maternal HFD were normalized suggesting that methyl donor supplementation can affect gene expression of

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reward circuitry (Carlin, George, & Reyes, 2013).

In research conducted by Vucetic et al. (2010), HFD dams had offspring with 3to-10- fold increased expression of DAT within the VTA, NAc, and prefrontal cortex

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(PFC), and a 50% reduction in expression in the hypothalamus. DA D1 and D2 receptors were reduced in the NAc and PFC, while MOR was significantly increased in

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the PFC, NAc, and hypothalamus. Taken together, these findings suggest that altered genetic expression within the mesolimbic and hypothalamic circuitry may be responsible for programming the rewarding properties of food in offspring from HFD mothers (Vucetic et al., 2010). This may prove to be an important factor in the increased motivation for overconsumption of highly palatable foods currently driving rates of obesity.

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Summary. Early life nutritional programming can have a lasting impact on behavior via the reward system (including DAT) and MOR. Elevated blood levels of insulin and leptin in the offspring of overfed mothers can lead to states of resistance and

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subsequent weight gain. Hormonal influence on DA neurons may lead to symptoms of addiction-like eating (impulsivity, attentional bias, incentive salience). Furthermore,

epigenetic modifications stemming from nutritional insults during pregnancy have the

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potential to become transgenerational. Changes in DNA methylation appear to modify genetic expression of DAT and MOR, preprogramming the rewarding properties of

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highly palatable foods. Sex Differences

Parental obesity is one of the several risk factors associated with the development of obesity in offspring. However, it appears as though maternal BMI has a

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greater influence on weight status of offspring when compared to paternal BMI (Linabery, et al., 2013). In humans, associations between maternal and offspring BMI have been found across three generations, but similar associations spanning three

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generations do not exist between paternal and offspring BMI (Murrin, Kelly, Tremblay, & Kelleher, 2012). Thus sex is an important variable in generationally inherited eating

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patterns, which may be related to differences in types and levels of gonadal hormones between males and females, specifically estrogen (Xu, Cao, & Xu, 2015). Recent data suggest that hypothalamic endocannabinoid levels are reduced in male offspring from mothers fed a highly palatable diet during gestation, suggesting a potential role in nutritional programming (Ramirez-Lopez et al., 2016). Moreover, both behavioral and neurobiological differences are observed between sexes in response to drugs of abuse

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(Fattore, Melis, Fadda, & Fratta, 2014), which is consistent with the neurobehavioral differences observed from exposure of a highly palatable diet. Sucrose consumption enhanced the development of locomotor sensitization in

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female but not male mice (Collins et al., 2015). Using naloxone treatment during

maternal junk food diet, females are more susceptible to decreased expression of

certain elements related to the DA pathway (Gugusheff, Ong, & Muhlhausler, 2014).

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Interestingly, female mice exposed to HFD at six weeks of age have increased

likelihood of developing binge behavior compared to males, when given only restricted

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access (one hour per day) to palatable food (Carlin et al., 2016). These authors speculate that binge behavior is attributable to changes in dopaminergic gene expression of DAD1 receptor in the prefrontal cortex (PFC) and an increase in DAD2 receptors in the NAc of the female mice.

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Other data suggest that females are more vulnerable to the adverse long-term health consequences of low birth weight (Whitaker, Totoki, & Reyes, 2012). Authors found that a maternal low protein diet during pregnancy led to a lower metabolic rate in

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female offspring compared to males, suggesting an increased sensitivity of the female offspring to in utero insults. Meanwhile, there is evidence to suggest that male offspring

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are more likely to develop metabolic dysfunction when born from overfed mothers (Giraudo et al., 2010; Nivoit et al., 2009). Dunn and Bale (2011) found a paternally transmitted phenotype of obesity to female offspring, supporting a transgenerational mode of inheritance via paternal lineage. A recent review indicated that paternal diet can induce impaired glucose metabolism in offspring (Zheng et al., 2014). Sex differences in the literature remain relevant to intrauterine programming given that only

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females give birth, but more research is needed on how gender interacts with the development of reward-related circuitry. Discussion

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The concept of maternal diet impacting the mental health of the offspring can be traced back to the 1950s (Knobloch & Pasamanick, 1958). Prenatal programming of increased childhood overweight and obesity has been established in humans (Huang,

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Lee, & Lu, 2007) and preclinical evidence reviewed here suggests that addiction

transfer via dysregulation of reward systems begins to develop in utero. It is likely that

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maternal ingestion of foods known to induce addictive-like eating, such as pizza, cake, cookies, etc. (Schulte, Avena, & Gearhardt, 2015) can impact fetal neurodevelopment and subsequent ingestive behavior. The obesity crisis may be in part related to hedonic mechanisms overriding homeostatic mechanisms. Evidence supports the notion that

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maternal exposure to highly palatable foods is capable of engendering neurobehavioral alterations in the offspring, further perpetuating the cycle across generations. Meanwhile, dysregulation of food intake attributed to the complex interplay between

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neurochemistry and endocrine function remains poorly understood. Given the fact that not all individuals who find substances pleasurable become addicted, research will

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continue to elucidate the underlying differences in neural circuitry, genetics, and behavioral traits contributing to the development of addiction. Hormone-influenced neuroplasticity infers behavioral changes that include an

elevated preference for high-fat and high-sugar diets commonly associated with the phenomenon that has been referred to as “food addiction” (Alsio, Olszewski, Levine, & Schioth, 2012). Observable increases in the preference for high-fat and high-sugar

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foods in the offspring from overfed dams are likely due to permanent changes within the central mesolimbic reward system. Grissom and colleagues (2015) demonstrated dissociable deficits in reward processing and executive function in fetuses born from

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maternal malnutrition. Neuroadaptations in NAc function following consumption of highly palatable foods can enhance motivational processes that drive ingestive behavior,

particularly in rats susceptible to obesity (Oginsky et al., 2016). These authors suggest

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that food-induced changes in striatal function may be mechanisms contributing to

addictive-like behaviors. Junk food diets produce metabolic dysregulation that is more

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pronounced in obesity-prone rodents, suggesting that highly palatable foods can interact with striatal DA receptors systems differently across various phenotypes (Vollbrecht, Mabrouk, Nelson, Kennedu, & Ferrario, 2016).

Timing of Nutritional Insult. The most sensitive time windows for

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developmental programming seem to be gestation and lactation. Mitra and colleagues (2009) have identified that HFD introduced before impregnation does not lead to overeating and obesity in offspring, suggesting that HFD during gestation and lactation

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induces changes in metabolic rate or energy efficiency. Findings implicate the perinatal maternal environment in programming metabolic function, stemming from an altered

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development of peptide systems producing neuronal changes that persist postnatally. In rodents, dopaminergic neurons in the brain are detectable at embryonic day

twelve but are not fully developed until the second to third week of postnatal life (see Ong & Muhlhausler, 2011). However, metabolic dysfunction stemming from maternal nutritional exposures can occur independent of postnatal nutrition (Ashino et al., 2012) implying that the exposures during critical times of development can have lasting

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neurodevelopmental consequences, likely related to mechanisms of genetic expression. Specifically, highly palatable diets consumed during pregnancy have lasting effects on offspring body weight, food preference, and drug preference, all of which can persist

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into adulthood (Bocarsly et al., 2012). Conclusion

In summary, recent research supports the assertion that certain foods have the

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potential to become addictive. The neurobehavioral commonalities observed between substances of abuse and highly palatable foods is strong. These neuroadaptations

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within the reward related centers of the brain contribute to hedonic hyperphagia, likely leading to obesity and a myriad of other chronic ailments. With a greater understanding of these neurobiological underpinnings, more effective treatment strategies can be developed to combat the obesity pandemic. Given what we know about food addiction,

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it is likely that a mother who consumes highly palatable food during gestation will consume similar items during lactation. It is also likely that a mother who consumes junk food during gestation will create a post-natal food environment (home) with exposure to

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these foods. The combination of exposure to junk food during gestation, lactation, and in early life is likely to create a composite effect on the development of offspring food

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addiction. Thus monitoring dietary intake during pregnancy can become an important preventative measure against obesity and neurodevelopmental disorders. Intake of macronutrients during the fetal period should be balanced while minimizing exposure to foods with addictive potential. Further, it has been shown that belief in the addictive potential of a substance or behavior creates support for policies intended to curb their use (Moran et al., 2016). Accepting certain foods as addictive hopefully will lead to the

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implementation of obesity-related policies, and educational interventions during

Funded by grants Kildehoj-Santini and DA-03123.

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