Early life exposure to obesogenic diets and learning and memory dysfunction

Abstract

Obesogenic dietary factors, such as simple sugars and saturated fatty acids, have been linked to memory impairments and hippocampal dysfunction. Recent evidence suggests that the brain may be particularly vulnerable to the effects of obesogenic diets during early life periods of rapid growth, maturation, and brain development. Investigations utilizing rodent models indicate that early life exposure to “high fat diets” (40-65% kcal derived from fat) or simple sugars (sucrose or high fructose corn syrup) can impair hippocampus-dependent learning and memory processes. In some cases, these deficits occur independent of obesity and metabolic derangement and can persist into adulthood despite dietary intervention. Various neurobiological mechanisms have been identified that may link early life consumption of obesogenic dietary factors with hippocampal dysfunction, including increased neuroinflammation and reduced neurotrophin mediated regulation of neurogenesis and synaptic plasticity. Age, duration of exposure, and dietary composition are key variables contributing to the interaction between early life diet and cognitive dysfunction, however, more research is needed to unravel the precise critical windows of development and causal dietary factors.

Introduction

A bourgeoning body of research highlights the negative impact of “obesogenic diets” on the brain and cognitive function. The hippocampus, a brain region most famously associated with learning and memory function and more recently with food intake control [1-5], is highly susceptible to the deleterious effects of consuming foods high in saturated fatty acids and simple sugars [6, 7]. While previous reviews have discussed the impact of consuming obesogenic diets on hippocampal dysfunction and memory ability more generally [8-15], these reviews did not highlight age or period of life as a critical variable. Herein we review literature, primarily from animal models, suggesting that the negative impact of obesogenic dietary factors on cognitive function is exacerbated during critical periods of development (prenatal, juvenile, and adolescence) (Tables 1 & 2). We also highlight various neurobiological mechanisms linking early life dietary factors with hippocampal dysfunction.

Table 1. Effects of perinatal obesogenic diet consumption on hippocampal-dependent learning and memory.

Only articles containing hippocampal-dependent cognitive tasks were included. M: male, F: female, SD: Sprague Dawley, RD: Research Diets, PND: post-natal day, MWM: Morris Water Maze, HFD: high-fat diet, TFD: trans-fat diet, CD: control diet, TBI: traumatic brain injury

Study	Subjects	Diets	Exposure	Test design	Task	Outcome
Bilbo et al., 2010 [25]	M and F SD rats	RD D12492 60% kcal fat, RD D06061202 60% kcal TFD or RD D12450B 10% kcal fat (control)	Gestation-weaning (PND 21)	Behavior at PND 85-95	MWM	Early life consumption of HFD or TFD caused spatial learning impairments during adulthood despite switching to chow at weaning.
Can et al., 2012 [28]	M SD rats	65% kcal from fat vs 10% kcal from fat (control)	Gestation-(PND119)	Behavior measured in adulthood	MWM	HFD impaired spatial learning
Kuang et al., 2014 [27]	M SD rats	20% sucrose solution + chow or water + chow (control)	Gestational day 1-21	Behavior at 1 and 2 mo. old	MWM	Impaired spatial learning in offspring of high sucrose-fed dams, especially at 1 mo.
Lepinay et al., 2015 [23]	M Wistar rats	HFD (39% kcal from fat) with omega 6:omega 3 fatty acid ratio of 39 or control diet (12% kcal from fat) with omega 6:omega 3 ratio of 5.	Gestation-weaning (PND 21) or Gestation- 5 mo. old	Behavior at 5 months	MWM	Perinatal HFD or exposure from weaning through adulthood had no effect on memory, however animals fed HFD during the perinatal period and post weaning had impaired spatial memory.
Mychasiuk et al., 2015 [30]	M and F SD rats	HFD (60% kcal from fat) + 20% sucrose solution, standard chow and water (control) or caloric restriction on standard chow	Dams exposed 3 wks prior to mating Gestation-PND 47	At PND 30 animals were given mild TBI or sham injury. Behavioral testing PND 35-45.	MWM, Novel Context Mismatch	F offspring on HFD were impaired in novel context mismatch. TBI impaired performance in the novel context mismatch in both standard chow ad libitum and HFD groups, but not in calorically restricted animals.
Page et al., 2014 [26]	M SD rats	RD D12451 45% kcal from fat vs control chow 10 % kcal from fat D12451B	Dams exposed 4 wks prior to mating Gestation-PND 21 or Gestation-PND 118	Behavioral testing during adulthood (PND 110-118)	MWM	Both HFD-HFD and HFD-CD animals were impared in spatial learning compared with CD-CD and CD-HFD.
Peleg-Raibstein et al., 2012 [24]	M and F C57BL/6N mice	HFD (60% kcal from fat) vs standard chow (control).	Dams exposed 3 wks prior to mating Gestation-weaning (PND 21)	Behavioral testing after PND 90	Pavlovian Fear Conditioning	There were no differences in fear conditioning between offspring from HFD-fed and offspring from chow-fed dams.
Tozuka et al., 2010 [21]	M C57BL/6N mice	HFD Clea Japan (57% kcal from fat) vs CE-2 Clea Japan chow (control)	Gestation-lactation d16	Behavioral testing at PND 28 and PND 77	Barnes Maze	Impaired spatial learning in adolescent but not adult mice.
White et al., 2009 [22]	M Long Evans rats	RD D12492 60% kcal fat or RD D12450B 10% kcal fat control.	Dams exposed 4 wks prior to mating Gestation-weaning (PND 21) At 8 wks old, put back on one of the perinatal diets for 9 wks	Behavioral analyses were performed during adulthood (19.5 wks old)	MWM	HFD-HFD animals were impaired in spatial memory retention, but HFD-CD, CD-CD and CD-HFD showed no difference in performance.

Table 2. Effects of juvenile/adolescent obesogenic diet consumption on hippocampal-dependent learning and memory.

Only articles containing hippocampal-dependent cognitive tasks were included. M: male, F: female, SD: Sprague Dawley, RD: Research Diets, PND: post-natal day, MWM: Morris Water Maze, HFD: high-fat diet, TFD: trans-fat diet, CD: control diet, HFCS-55: High Fructose Corn Syrup 55, SFA: high saturated fatty acid diet.

Study	Subjects	Diets	Exposure/age	Test design	Task	Outcome
Hsu et al., 2015 [43]	M SD rats	Low-fat chow + either 11% sucrose solution of 11% high fructose corn syrup (HFCS-55) or water (control)	Adolescents: PND 30-60 Adults: PND 60-90 Diet exposure continued through behavioral testing	Behavioral testing beginning at PND 60 (adolescents) or PND 90 (adults)	Barnes Maze	HFCS-55 significantly impaired spatial learning and memory when consumed during juvenile/adolescence but not during adulthood.
Kendig et al., 2013 [44]	M Wistar rats	Standard chow + either 10% sucrose solution or saccharin solution (control)	Adolescents: PND 28-56 Adults: PND 63-91 Intermittent access to sweet solutions (2h/day)	Behavioral testing on PND 61 (adolescents) or PND 96 (adults)	MWM	Intermittent sucrose consumption spatial learning and memory in both adult and adolescent groups
Reichelt et al., 2015 [45]	M SD rats	Standard chow + either 10% sucrose solution or water (control)	PND 28-56 Intermittent access to sweet solutions (2h/day)	Behavioral testing from PND 62-92	Object in Place test	Sucrose exposed rats had impaired performance
Boitard et al., 2012 [41]	M C57BL6/J mice	RD D12451 HFD (45% kcal from fat) vs A04 SAFE chow (10% kcal from fat)	Juvenile-adult: PND 21-98 Adult: PND 84-161	Behavioral testing at PND 98 (juvenile/adult) or PND 161 (adult)	Two-stage Radial Maze	HFD abolished relational memory flexibility in juveniles but not adults
Boitard et al., 2014 [40]	M Wistar rats	Research diets D12451 HFD (45% kcal from fat) vs A04 SAFE chow (10% kcal from fat)	Juvenile: PND 21-133 Adult: PND 84-196	Behavioral testing after 1,2 and 3 mo. diet exposure	MWM	Juvenile HFD consumption impaired spatial memory
Kaczmarczyk et al., 2013 [46]	M C57BL/6J mice	RD D12492 60% kcal fat or RD D12450B 10% kcal fat control.	PND 21-28 or PND 21-42	Behavioral testing at PND 28 or PND 42	Y Maze	One week of HFD impaired spontaneous alternation. At 3 wks. there was no effect of diet on task performance
Valladolid-Acebes et al., 2013 [42]	M C57BL/6J mice	RD D12451 (45% kcal from fat) vs standard chow	Adolescent: PND 35-91 or Adult: PND 56-112	Either 8 wks. of diet or 8 wks. of diet followed by 5 wks. of food restriction prior to behavioral testing	Novel Object Location Recognition	Adolescents, but not adults, on HFD had impaired learning performance, which persisted after 5 wks. of caloric restriction
Nyaradi et al., 2014 [38]	Humans	“Western” vs “Healthy” dietary pattern	Adolescence (14-17 years old)	FFQ 14 years of age, cognitive testing at 17. Data adjusted for energy intake, gender, income, maternal education, paternal presence	Groton Maze Learning Task, Detection Task	“Western” diet consumption was associated with more errors in Groton Maze and longer detection time
Baym et al. 2014 [39]	Humans	Saturated fat (SFA), refined sugar, omega 3 fatty acids	7-9 years old	cross-sectional	Relational memory and item memory tasks	SFA intake associated with impaired performance in both tasks

Perinatal period: obesogenic diets and memory function

The theory that adult susceptibility to disease states is programmed during early development, also termed “fetal programming” [16], has given momentum to investigations of how the perinatal environment, in particular maternal nutrition, affects the cognitive health of the offspring. Human epidemiological studies have reported an association between maternal obesity and poor performance of the child on cognitive tasks [17-20]. However, few studies dissociate the effects of obesity and metabolic dysfunction from the effects of maternal obesogenic diets per se on cognitive outcomes in human children. Several carefully controlled rodent studies discussed below, however, have attempted to bridge this gap.

Consuming a “high fat diet” (HFD) containing 40-65% kcal from fat and abundant simple sugars to enhance palatability (typically half of the total carbohydrate source derived from sucrose), is a commonly used obesity model in rodents. Evidence suggests that maternal consumption of such a HFD beginning prior to mating and ending just prior to weaning caused hippocampal-dependent spatial learning deficits in offspring at 4 weeks of age, however, these deficits were no longer present when animals were tested later during adulthood [21-23]. Similarly, perinatal HFD exposure had no effect on fear conditioning performance when animals were tested during adulthood after having been fed a standard chow diet post-weaning [24]. Thus, the detrimental effects of maternal HFD on cognitive performance are seemingly more pronounced during early life, at least when offspring are weaned on a healthy diet. In fact, one study reported that spatial learning and memory function are improved in the adult male progeny of dams that were fed a 60% HFD [25]. Collectively these data suggest that under some conditions pre- and perinatal exposure to a HFD does not impair hippocampal-dependent learning and memory, whereas in other cases HFD-induced memory deficits may be overcome by switching the pups to standard chow at weaning.

In contrast to these findings, other reports indicate that pre-weaning HFD exposure confers cognitive deficits that persist into adulthood, even when the animals were fed a standard chow diet post-weaning. For example, progeny born from dams that were fed a HFD (45% kcal from fat) performed worse in the hippocampal-dependent Morris Water Maze (MWM) spatial learning task during adulthood relative to offspring born from dams on standard chow. Moreover, animals that were switched to standard chow at weaning were equally impaired in learning the learning task compared to animals weaned on the HFD [26]. One possible explanation for the discrepancies between this study and those discussed above is the percentage of fat and sugar in the diet. The study reporting MWM deficits despite the animals being weaned on chow (Page et al., [26]) utilized a HFD with 45% kcal from fat, whereas others reporting conflicting “recovery of function” results (e.g., [21, 22, 24, 25] utilized a 60% HFD. Notably, these diets not only differ in the % kcal from fat, but also in the % kcal from sugar. The 45% HFD used by Page et al. contains a considerably higher proportion of kcal from sugar compared with the 60% HFD used by others (17% vs 7%) [22, 25]. Thus, it is possible that the combined impact of high sugar and fat in the diet is greater than the impact of fat alone. Alternatively, perinatal exposure to sugar may have a more detrimental effect on adult memory function than perinatal exposure to fat. Consistent with this notion, one study demonstrated that maternal consumption of a 20% sucrose sweetened solution from gestational day 1 to day 21 produced impairments in spatial learning performance of juvenile and adolescent offspring [27], however, the effects of perinatal sucrose exposure in adult offspring was not tested.

Some studies have extended feeding of an obesogenic diet beyond the perinatal period to study the impact of perinatal through childhood and/or early adulthood consumption of an obesogenic diet on learning and memory function. For example, progeny of dams maintained on a HFD (60-65% kcal from fat) who were also fed the HFD for over 2 months post-weaning exhibited impaired performance in the MWM [22, 28]. Another study comparing the effects of a HFD (39% kcal from fat) reported that when the diet was confined exclusively to either the prenatal or postnatal phase, HFD-feeding had no effect on spatial memory in the MWM during adulthood relative to controls. However, when the HFD was fed throughout both pre- and postnatal development, as well as post-weaning, the offspring had deficits in spatial learning capabilities during adulthood [23]. Similar findings were reported using the Novel Context Mismatch task, which is a hippocampus-dependent memory task that presumably measures contextual episodic memory [29]. Juvenile rats born of dams that had been exposed to a combined HFD/high sucrose diet (60% kcal from fat/ 20% sucrose in the drinking water) that were maintained on the diet post-weaning had impaired performance in the Novel Context Mismatch task [30]. Overall the literature suggests that consumption of obesogenic diets during the perinatal period and throughout juvenile/adolescent phase of development impairs hippocampal dependent learning and memory. There are various unresolved discrepancies, however, regarding the long-term impact to the offspring following maternal consumption of obesogenic dietary factors during the perinatal period. For example, the extent that maternal obesity plays a role independent of prenatal offspring diet exposure is an important unresolved question. One additional area for further study is to investigate the importance of the fat:sugar ratio in the diet, as in some cases it appears that a higher % kcal from sugar may preclude the benefits of being weaned on a healthy diet.

Juvenile and adolescent period

It is critical to understand how consumption of obesogenic foods impacts the brain during childhood, as the juvenile/adolescent period of development is one of rapid growth and maturation and is a particularly critical period for hippocampal development [31-35]. While little is known thus far on the impact of childhood metabolic and dietary factors on cognition in human populations, a link between childhood obesity and impaired performance on tasks involving executive function and attention has been identified [36, 37]. Notably, a recent prospective epidemiological study showed that consumption of a “Western” dietary pattern during early adolescence is associated with poor cognitive performance during late adolescence, specifically on visual spatial learning and long-term memory tasks [38]. In addition, saturated fatty acid intake in children is associated with reduced performance in hippocampal-dependent relational and item memory tasks independent of body mass index [39].

Several recent studies using highly controlled animal models have revealed that juvenile and adolescent obesogenic dietary factors negatively impact hippocampal function. Boitard et al., observed that in juvenile but not adult rats, HFD (45% kcal from fat) consumption impaired spatial memory retention and spatial reversal learning [40]. The same group reported that mice fed HFD for 11 weeks post weaning (a period spanning the entire juvenile adolescent period and ~7 weeks into young adulthood) demonstrated impaired relational memory flexibility assessed in a two-stage radial arm maze concurrent spatial discrimination task, whereas adults exposed to the diet beginning at 12 weeks and for a similar amount of time were not impaired [41]. On a similar diet, juvenile/adolescent mice (5 weeks old) were impaired in the hippocampal dependent Novel Location Recognition task, whereas mice that were given the diet at 8 weeks old were not impaired [42]. Collectively these studies strongly suggest that the juvenile/adolescent brain is particularly vulnerable to the effects of obesogenic dietary factors.

Consistent with perinatal and adult exposure studies, the hippocampus appears to be a particularly susceptible brain region to the negative effects of dietary sugars consumed during the juvenile and adolescent period, even in the absence of elevated fat intake. For example, Hsu, Kanoski and colleagues recently reported in rats that juvenile and adolescent, but not adult, ad libitum consumption of an 11% high fructose corn syrup (HFCS-55) solution for 30 days impaired hippocampal-dependent spatial learning and memory retention [43]. Kendig et al. utilized an intermittent access model of 10% sucrose solution for 28 days and observed that both juvenile/adolescent and young adult exposure to the intermittent sucrose impaired learning and memory in the MWM [44]. Using a similar paradigm of intermittent sucrose access, a recent study exposed rats to 10% sucrose for 2 hours a day during the juvenile and adolescent period. Results revealed sucrose-associated deficits in object-in-place task, which tests hippocampal-dependent episodic contextual memory. In this study access to the diet ended at the end of the adolescent period and the testing was performed during adulthood 5-weeks after the last sucrose treatment [45].

The question as to whether obesity as a consequence of the obesogenic diet, or rather, components of the diet itself are driving the deficits in hippocampal dependent cognitive function is a critical one that is not easily addressed with many experimental designs. In one of the aforementioned studies, however, Valladolid Acebes and colleagues conclude that caloric intake was not driving the impairment, since the controls and HFD animals consumed similar total kcal amounts. Rather, the authors argue that the effect is likely due to dietary composition [42]. In support of this notion, they found that cognitive performance remained impaired after a 5-week dietary restriction (restricted to 70% of their ad libitum total kcal of the HFD) period following 8 weeks of ad libitum HFD (45% kcal from fat) consumption. In further support of the idea that dietary factors rather than obesity or excess adipose tissue is causing the effects, short-term (1 week) HFD feeding (60% kcal from fat) significantly impaired spatial memory in the spatial-cued Y-maze prior to the onset of weight gain or impaired glucose metabolism in juvenile mice [46]. Moreover, Hsu et al., found that despite similar caloric intake and levels of body weight gain, animals that consumed an 11% HFCS-55 solution during the juvenile and adolescent period performed worse in the spatial Barnes Maze task relative to controls [43], however, the HFCS group was showed moderate glucose intolerance relative to controls. Taken together these data strongly suggest that dietary factors contribute to the memory impairments rather than excessive caloric intake, weight gain, or full-blown metabolic derangements. Future studies are warranted to understand which specific dietary factors (e.g., monosaccharide ratios, fatty acid profiles, fat to sugar ratio) are causally related to early life obesogenic diet-induced cognitive deficits.

Neurobiological mechanisms

Inflammation/cytokines

Obesity promotes a form of chronic low-grade inflammation (for review see [47]). Elevated levels of proinflammatory cytokines in the brain are directly linked with impaired hippocampal-dependent memory [48, 49] and the offspring hippocampus is particularly susceptible to maternal inflammation [50]. Perinatal and juvenile exposure to a chow diet supplemented with saturated fat, cholesterol, and sugar, produced elevations in expression of the cytokines TNF-alpha and IL-6, with concurrent morphological changes in the hippocampal CA-1 region [51]. Similar to effects observed following prenatal LPS injections which promote acute inflammation [52], hippocampal pyramidal cells were smaller in pups born from dams fed the fat, cholesterol, and sugar-enriched diet [51]. Maternal saturated fat consumption is also associated with increased expression of the proinflammatory cytokine, IL-1β at P20 and during adulthood, as well as increased microglia expression in the CA1, CA3 and dentate gyrus of the hippocampus [25]. Hsu et al. reported elevated levels of IL-1β and IL-6 in the dorsal hippocampus of rats fed 11% HFCS-55 solution during the juvenile and adolescent period, however, no significant cytokine elevations were observed either in adult rats fed 11% sucrose or HFCS-55 solutions, or in juvenile/adolescent animals fed the sucrose solution. These findings are notable with regard to the relationship between neuroinflammation and hippocampal function, as only the juvenile/adolescent rats fed HFCS-55 had pronounced spatial memory deficits [43]. Conversely, in a study showing impairments in long-term memory after juvenile HFD consumption, no differences were observed in expression of the inflammatory cytokines TNFα and IL-1β in untreated animals; however, there was an exaggerated increase in expression of both of these two cytokines following an LPS immune challenge [40], suggesting that the dietary manipulation did indeed increase neuroinflammatory signaling pathways relative to controls.

Neurotrophic factors: neurogenesis and synaptic plasticity

Neurogenesis and synaptic plasticity are purported to be essential for hippocampal-dependent learning and memory, and these functions rely on neurotrophic factors such as brain derived neurotrophic factor (BDNF) (for review see [15]). Tozuka et al. observed that hippocampal BDNF was reduced and dendritic arborization was impaired during the juvenile/adolescent phase in offspring born from dams fed a HFD (57% kcal from fat). BDNF levels were not different from controls in adulthood, however, which is consistent with previously discussed behavioral outcomes showing HFD-associated impaired spatial learning during adolescence, but not adulthood [21]. Page and colleagues reported that hippocampal BDNF and activity-regulated cytoskeleton associated protein (ARC), whose expression is necessary for late phase learning and memory consolidation [53, 54], were significantly reduced in the adult offspring of HFD-fed dams compared with those of chow-fed dams, irrespective of whether they were weaned on chow or HFD (45% kcal from fat). These findings corresponded to impaired spatial memory performance during adulthood in the offspring of HFD-fed dams [26]. Together these data suggest that HFD consumption during the perinatal period reduces hippocampal BDNF expression in the offspring (particularly when HDF is maintained post weaning), which may negatively impact neurogenesis and synaptic plasticity in hippocampal neurons.

Insulin and insulin-like growth factor-1 (IGF-1) are important regulators of CNS development. Similar to neurotrophins, IGF-1 and insulin signaling promotes both neurogenesis and synaptogenesis in the dentage gyrus via dendritic sprouting, stem cell activation, cell growth signaling, synaptic maintenance, cell repair and neuroprotection [55-60]. The hippocampus is densely populated with insulin receptor and IGF-1R, and their activity has been linked with hippocampal-dependent memory function [61, 62]. Impaired IR and/or IGF-1R signaling may be one mechanism through which early life consumption of obesogenic dietary factors leads to hippocampal dysfunction. For example, when confined only to the gestational period, maternal consumption of a 20% sucrose sweetened beverage impairs spatial learning concurrent with reduced expression of IGF-1, and downstream signaling molecules phosphoinositide 3 kinase (PI3K), and phosphorylated protein kinase B (pAKT) in the hippocampus of juvenile offspring [27]. Insulin receptor expression was reduced in the hippocampus of adult rats that were exposed to HFD (39% kcal from fat) prior to weaning, both in animals weaned on chow and on HFD. However, only those weaned on HFD demonstrated sustained memory impairments in the MWM [23]. These data indicate that impairments in insulin and IGF-1 receptor signaling pathways represent one potential mechanism through which early life exposure to obesogenic diets impairs hippocampal function.

Like insulin, the adipokine leptin has a role in facilitating synaptic plasticity [63, 64]. For example, in the hippocampal CA1 region leptin increases AMPA receptor trafficking at synapses [65], which is required for synaptic plasticity [66]. Furthermore, rodents who have a deficient leptin receptor function have cognitive deficits [48, 67], and peripheral [63] and intra-hippocampal [68] leptin injections enhance hippocampal-dependent spatial learning and memory performance. Valladolid-Acebes et al. reported that there was a specific resistance of the PI3K/Akt pathway in LepRb-expressing neurons in the hippocampus of juvenile, but not adult rodents fed a HFD (45% kcal from fat), which corresponded to impaired hippocampal-dependent cognitive function [69].

Since the discovery of adult neurogenesis, evidence has mounted to support that adult born neurons contribute significantly to hippocampal-dependent learning and memory function (for review see [70]). Animals fed HFD (65% kcal from fat) during both the perinatal and post-weaning phase have a significantly reduced number of neurons in the pyramidal layer of CA1-3 of the hippocampus [28], which may be related to HFD-induced reductions in neurogenesis. Similarly offspring born from dams that were fed an obesogenic HFD (46% kcal from fat) prior to pregnancy and up until weaning had markers of impaired neurogenesis, Notch 1 (which suppresses neuronal differentiation) and Hes5 (which negatively regulates neurogenesis), at PND 28 [71, 72]. These data are corroborated by a recent study showing that the Notch/Hes5 signaling pathway is significantly increased in neural stem cells of offspring from dams fed a HFD (35% kcal from fat) during and prior to pregnancy [73]. Another study showed that progeny of HFD-fed dams had elevated markers of cell proliferation in hippocampal and cortical subventricular zones, but reduced markers in the dentate gyrus, which the authors hypothesized represents a form of developmental delay [74]. Similar to animals exposed to HFD during the perinatal period, neurogenesis is also impaired in mice fed HFD during the juvenile/adolescent period, but not during adulthood [41]. However, the impact of dietary factors during juvenile/adolescence on neurogenesis is an area that has thus far received little attention.

Conclusions and thoughts on future directions

Perinatal exposure to obesogenic diets may confer deficits in hippocampal-dependent memory that can, in some cases, persist despite switching to a healthy diet at weaning. The juvenile/adolescent period is a particularly vulnerable time for diet-induced impairments in hippocampal function, and recent evidence suggests that sugar may be as potent (or more) as HFD in its deleterious effects on memory. Mechanistic rodent studies suggest that obesogenic dietary factors impair hippocampal function independent of obesity and metabolic derangement, and therefore further research into neurobiological mechanisms of diet, metabolic, and cognitive interactions should carefully consider nuances of the dietary composition. Due to recent reports suggesting that diet alters neurotrophic factors in the hippocampus via epigenetic mechanisms [75], future studies that consider whether dietary interventions impart long-lasting epigenetic changes to genes critical for learning and memory function will be highly relevant.