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High fat diet intake during pre and periadolescence impairs learning of a conditioned place preference in adulthood

High fat diet intake during pre and periadolescence impairs learning of a conditioned place... Background: Brain regions that mediate learning of a conditioned place preference (CPP) undergo significant development in pre and periadolescence. Consuming a high fat (HF) diet during this developmental period and into adulthood can lead to learning impairments in rodents. The present study tested whether HF diet intake, consumed only in pre and periadolescence, would be sufficient to cause impairments using a CPP procedure. Methods: Rats were randomly assigned to consume a HF or a low fat (LF) diet during postnatal days (PD) 21-40 and were then placed back on a standard lab chow diet. A 20-day CPP procedure, using HF Cheetos as the unconditioned stimulus (US), began either the next day (PD 41) or 40 days later (PD 81). A separate group of adult rats were given the HF diet for 20 days beginning on PD 61, and then immediately underwent the 20-day CPP procedure beginning on PD 81. Results: Pre and periadolescent exposure to a LF diet or adult exposure to a HF diet did not interfere with the development of a HF food-induced CPP, as these groups exhibited robust preferences for the HF Cheetos food- paired compartment. However, pre and periadolescent exposure to the HF diet impaired the development of a HF food-induced CPP regardless of whether it was assessed immediately or 40 days after the exposure to the HF diet, and despite showing increased consumption of the HF Cheetos in conditioning. Conclusions: Intake of a HF diet, consumed only in pre and periadolescence, has long-lasting effects on learning that persist into adulthood. Background consumed in a distinct place with a presumably neutral Contextual or environmental cues associated with con- set of environmental cues (the conditioned stimulus, or suming a high fat (HF) food (or an otherwise nutrient CS). Over the course of conditioning, the CS acquires rich diet) can influence learning, cognition, food intake, secondary motivational properties through a Pavlovian and even override physiological sensations of hunger association with the HF food [7,8]. The secondary moti- and fullness [1,2]. In animals, studies using the condi- vational properties of the CS then elicit an approach tioned place preference (CPP) paradigm, a classic animal response, i.e., when allowed to roam freely, the subject model of reward learning, have shown that rats and spends most of its time in the presence of the CS mice prefer and approach environmental cues that are instead of a control place. associated with consumption of a HF food reward. High consumption of HF foods has unfavorable effects Some HF foods successfully used in CPP studies include in humans and animals. In humans, a HF diet is asso- open source HF diet pellets [3], fried potatoes [4], corn ciated with obesity [2], and degrading cognitive opera- oil [5], and Cheetos [6]. In the CPP paradigm, the HF tion and learning deficits [9], particularly in males food serves as an unconditioned stimulus (US) that is [10,11]. Animal studies show impaired learning, spatial memory, memory retention, and hippocampal synaptic * Correspondence: gprivite@sbu.edu plasticity in genetically obese animal models and HF Saint Bonaventure University, Department of Psychology, 3261 West State diet-induced obesity models [12-15]. While many stu- Street, Saint Bonaventure, NY 14778, USA dies with rodents begin the HF diets months after Full list of author information is available at the end of the article © 2011 Privitera et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Privitera et al. Behavioral and Brain Functions 2011, 7:21 Page 2 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/21 weaning [12,16,17], another study began HF diet manip- off at 1130 hours. Both temperature and humidity were ulations immediately following weaning for up to 9 to controlled in the housing facility, and rats were accli- 12 months thereafter [18]. Whether the observed deficits mated to living conditions and handling prior to con- are due to factors at earlier or later stages of develop- ducting experimental procedures. ment has not yet been determined. Of particular interest is the period of adolescence, Apparatus and Diet during which significant brain development occurs The CPP apparatus (26 cm long × 30 cm wide × 32 cm [19,20]. In rodents, a conservative definition of adoles- tall, Model H10-11R-TC) had two end chambers of cence is during postnatal days (PD) 28 to 42 [20,21]; identical size with stainless steel sidewalls and plastic alternative definitions stipulate that adolescence could front and back walls. The two end chambers differed on range from as early as just following weaning to about the type of flooring. The floor of one chamber was wire PD 60 [22,23]. The developmental period from PD 20 to mesh and the floor in the second chamber was alumi- 40 is analogous to preadolescence and adolescence in num sheet metal gauge 9. No bedding was beneath the humans [20]. Adolescence is associated with matura- floor in either chamber. The two end chambers were tional changes that are evident in mesolimbic and meso- connected by a median zone (13 cm long × 23 cm wide cortical brain regions and their terminal regions [24-28]. × 15.25 cm tall, Model H10-37R-NSF-09W), which also This maturation is of particular interest here because had plastic front and back walls. mesolimbic regions are know to mediate the develop- During Phase 1 of the experiment, rats consumed a ment of a CPP for a HF Cheetos food [6,29]. The HF diet (60 kcal % fat; Research Diet, Formula D12492) extent to which a HF diet, consumed only during prea- or LF diet (10 kcal % fat; Research Diet, Formula dolescence and adolescence, leads to CPP learning defi- D12450B) for 20 days prior to CPP procedures. In Phase cits has not been investigated. 2 (CPP Training), rats were given access to Cheetos We hypothesized that HF diet intake during pre and (56 kcal % fat; Frito-Lay, Inc., Plano, TX) inside the CPP periadolescence would produce long-term learning and apparatus. Cheetos were used as a HF US because it is memory impairments, possibly due to the significant an effective HF food used in CPP studies [6]. maturational development that sensitive brain regions undergo during this developmental period. In particular, Procedures we expected that learning and memory impairments Subjects were randomly assigned to one of five groups. would be expressed in the failure to acquire CPP in During Phase 1, two groups consumed a HF diet and adulthood, even if the US were a highly palatable HF two groups consumed a LF diet during PD 21-40 (Adol food itself. We did not expect comparable impairments HF and Adol LF, respectively). Another group of adult in rats consuming a HF diet at an older age for a com- rats consumed the HF diet from PD 61-80 (Adult HF). parableperiodoftimeorin ratsconsuming alow fat The adult rats were used as a control group to deter- (LF) diet. mine whether any observed CPP deficits were specific to intake during PD 21-40. Groups also differed on Methods whether training (Phase 2) began immediately following Subjects Phase 1 (Immediate), or 40 days following Phase 1 Subjects were 30 experimentally naïve, male Sprague- (Delayed). Delayed groups were used to determine Dawley rats from Charles River Laboratories, Kingston, whether HF diet manipulations induce long-term defi- New York. Male rats were used as they have previously cits in CPP performance. The timeline for each group been shown to exhibit a CPP to Cheetos [6]. Rat pups following weaning is given in Table 1, and each phase is were housed with their dam and were approximately summarized here. one-week old upon arrival to the lab. Rats were 21 days Phase 1 (Diet Manipulation) old at the start of the study, during which they were Rats in Groups Adol HF-Immediate and Adol HF- separated from the dam and were housed individually in Delayedconsumedthe HF dietad lib in their home clear plastic cages (43 cm deep × 21 cm wide × 20 cm cages for 20 days beginning on PD 21. Groups Adol LF- high). The plastic cages had solid bottoms that were Immediate and Adol LF-Delayed consumed the LF diet covered with bedding (Sani-Chips, P.J. Murphy Forest ad lib in their home cages for 20 days beginning on PD Products, Montville, NJ), and the cage tops were stain- 21. Rats in Group Adult HF-Immediate received the HF less steel wire lids. Rats had continuous access to water diet ad lib in their home cages for 20 days beginning on and lab chow (Harlan Teklad: 2018), except during the PD 61. Thereafter, all rats consumed a standard lab 20-day period indicated in the procedures section. chow (Harlan Teklad: 2018; 18 kcal % fat) ad lib in their Lights were on a 10:14 hour dark:light cycle with lights home cages for the duration of the study Privitera et al. Behavioral and Brain Functions 2011, 7:21 Page 3 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/21 Table 1 Timeline for the age of rats in each phase by similar for different groups of rats. Because this was also group the case in this study, the meaning of times spent in the Groups Phase median zone was not interpreted. Data were recorded using a videocamera located above 12 3 each chamber. The time in each end chamber started (Diet (CPP (CPP Manipulation) Training) Testing) when the full body of the rat, excluding the tail, entered Adol LF-Immediate PD 21-40 PD 41-60 PD 61-62 the end chamber. Time was stopped when the full body (n = 6) of the rat, excluding the tail, left the end chamber. The Adol HF-Immediate amount of time spent in each chamber and number of (n = 6) chamber entrances were recorded. It is important to Adol LF-Delayed PD 81-100 PD 101-102 note that these two dependent measures do not necessa- (n = 6) rily covary. Each rat was tested for a total of 20 minutes Adol HF-Delayed (10 min each day for two consecutive days). (n = 6) All procedures followed internationally recognized Adult HF - Immediate PD 61-80 PD 81-100 PD 101-102 (n = 6) guidelines for ethical conduct in the care and use of ani- mals. The St. Bonaventure University Institutional Ani- All rats were weaned at Postnatal Day (PD) 20. Experimental procedures followed weaning beginning at PD 21 for the Adol LF and Adol HF groups, mal Care and Use Committee approved all procedures. and beginning at PD 61 for the Adult HF-Immediate group Statistical Analysis Intake of Cheetos and lab chow during training trials Phase 2 (CPP Training) The Adol LF-Immediate and Adol HF-Immediate groups in Phase 2 were recorded in g, converted to kcal, and began Phase 2 on PD 41. The Adol LF-Delayed, Adol analyzed using a mixed-design analysis of variance HF-Delayed, and Adult HF-Immediate groups began (ANOVA). Groups and food-side pairings were the Phase 2 on PD 81. Rats were placed in one side of the between-subjects factors, and days were the within-sub- CPP apparatus for 20 minutes each day for 20 days. Half jects factor. Post hoc tests were conducted using Tukey’s the rats in each group were given ad lib access to Chee- HSD. The dependent variables were amount of Chee- tos in the wire mesh side on one day and lab chow pel- tos and lab chow pellets consumed. lets in the aluminum side on another day; the other half In Phase 3, a CPP was defined as greater time spent in of rats had the reverse pairings. The only HF food con- the chamber associated with the HF Cheetos food ® ® sumed during this phase was Cheetos . Five Cheetos or compared to time spent in the chamber associated with lab chow pellets were placed on the floor in the center of the lab chow pellets. The preference for the side paired with Cheetos was measured as the log ratio of time the chamber. No rat consumed all the Cheetos or lab spent in the side paired with Cheetos to time spent in chow pellets in any one trial. The difference in the weight the side paired with lab chow. The null hypothesis of the Cheetos and pellets from before to after each trial under evaluation in each experimental condition was was recorded and converted to kcal for data analysis. that the log ratio of the population was zero. Ninety-five The side a rat was placed in was counterbalanced on an and 99% confidence intervals (CIs) were drawn around ABBA schedule, where rats were placed in the side asso- the log ratios. A CPP was identified when the log ratio ciated with the HF food on A-days and the side associated was positive and the CI did not envelop zero. Using the with lab chow pellets on B-days. Because the side that rats same analyses as those in Phase 2, the number of received the Cheetos was chosen at random and was entrances in each chamber was also assessed in Phase 3. counterbalanced within groups, any individual differences Subject weights were recorded each week in each with regard to preferences for one side of the apparatus was assumed to be approximately equal between groups. phase. In each phase subject weights were compared Meta analysis studies show that this counterbalancing pro- using an analysis of variance (ANOVA) with groups as cedure increases effect sizes for a CPP [7]. the between-subjects factor and weeks as the within- Phase 3 (CPP Testing) subjects factor. The day after Phase 2 ended, the barrier between each side of the CPP apparatus was removed. No food was Results placed in either chamber during testing. Each rat was Figure 1 shows the mean consumption of Cheetos and placed in a neutral position in the median zone that lab chow across all days for each group in the training separated the two end chambers, and then allowed to phase (Phase 2). The amount of lab chow consumed roam freely for 10 minutes. Previous studies with 3- varied across days, F(9, 225) = 123.42, p < .001, and a chamber CPP systems [30,31] have shown that the significant Groups × Days interaction was also evident, amount of time spent in a median zone is small and F(36, 225) = 2.73, p < .001. As illustrated in Figure 1, Privitera et al. Behavioral and Brain Functions 2011, 7:21 Page 4 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/21 group (p < .001) over the final four days. Both Adol HF Phase 2 (Training) groups consumed significantly more than the Adol LF groups (p < .001); and both LF groups consumed signifi- Cheetos“ cantly less than the Adult HF-Immediate comparison * * group (p < .01). Figure 2 shows the mean time spent in each chamber of the CPP apparatus during testing (Phase 3). Total times spent in the median zone did not differ between 20 groups (p > .30). To test for a CPP, time data were con- verted to log ratios obtained for each rat and 95% and * 99% CIs were drawn for each group. Log ratio data did # * # * not differ significantly over days, p >.17,sothe data were pooled across both days of testing. A significant 0 * CPP for the side of the apparatus associated with the Lab Chow Pre-Exposure Condition Cheetos was evident for Group Adol LF-Immediate Adol LF - Immediate (99% CI 0.326, 2.007), Adol LF-Delayed (99% CI 0.078, Adol LF - Delayed 1.559), and Adult HF-Immediate (99% CI 0.373, 0.968). Adol HF - Immediate A CPP was not observed for Group Adol HF-Immediate Adol HF - Delayed (95% CI -0.463, 0.338), and Adol HF-Delay (95% CI Adult HF - Immediate -0.181, 0.519). Using 95% CIs, no groups showed a side preference for the left or right side of the cage, indicat- 10 ing that a significant CPP was instead specific to whether a chamber was associated with Cheetos in Phase 2. 1 2 3 4 5 6 7 8 9 10 Table 2 shows the means and standard deviations for the number of chamber entrances in each chamber in Conditioning Day ® Phase 3. No significant differences in the number of Figure 1 Mean intake ± SEM of Cheetos (Top) or Lab chow chamber entrances in Phase 3 were evident across days (Bottom) in kcal consumed during daily 20-min sessions by rats with a history of low fat (LF) or high fat (HF) diet during (p > .32) or between groups (p > .28). pre and periadolescence or adulthood. Access to Cheetos or Figure 3 shows the mean body weights by group in lab chow was counterbalanced on an ABBA schedule across 20 each phase. In Phase 1, rats in the Adol Immediate and days of training (Phase 2). *Significantly different from all other Adol Delayed groups were the same age, so weights in groups (p < .05). Significantly different from all HF groups (p < .05). Significantly different from all LF groups (p < .05). Phase 3 (Testing) Tukey’s HSD tests showed that the Adol HF-immediate Cheetos“ -paired group consumed significantly more lab chow on Days LabChow-paired 3 and 4 of conditioning compared to the LF groups (p < .05). Consumption of Cheetos in Phase 2 significantly var- ied across days, F(9, 225) = 309.08, p < .001, and between groups, F(4, 25) = 51.49, p < .001. A significant Groups × Days interaction was also evident, F(36, 225) = 7.35, p < .001. As illustrated in Figure 1, Tukey’s HSD tests showed that group differences in mean consump- tion of Cheetos were significant on virtually every day Adol LF Adol LF Adol HF Adol HF Adult HF of conditioning (p < .05). Because differences were Immediate Delayed Immediate Delayed Immediate greatest in the final four days of Phase 2, intake was averaged across the final four Cheetos days and differ- Pre-Exposure Condition ences between groups were compared. A one-way Figure 2 Mean time ± SEM spent in each chamber during CPP between-subjects ANOVA showed a significant main testing (Phase 3) in rats with a history of LF or HF diet during pre and periadolescence or adulthood, and conditioned effect of groups, F(4, 25) = 61.84, p < .001. Tukey’s HSD immediately or after 40 days (delayed) with Cheetos .An post hoc tests showed that Group Adol HF-Immediate asterisk (*) indicates significance at a 99% CI. consumed significantly more Cheetos than any other Amount consumed (kcal) Time (s) Privitera et al. Behavioral and Brain Functions 2011, 7:21 Page 5 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/21 Table 2 The mean and standard deviation for the Body Weights number of entrances in each side of the CPP apparatus Phase 1 Phase 2 Phase 3 ® Group Cheetos -Paired Side Lab Chow-Paired Side Mean St. Dev. Mean St. Dev. Adol LF-Immediate 8.5 3.6 7.4 3.3 Adol HF-Immediate 7.9 2.9 7.4 3.1 Adol LF-Delayed 8.5 3.5 7.0 3.3 Adol HF-Delayed 8.7 2.2 8.3 2.9 Adult HF-Immediate 8.6 3.8 7.9 2.3 Adol LF - Immediate 100 Adol HF - Immediate LF-Immediate group each week in Phase 2 (Tukey’s HSD, p < .001). In Phase 2, rats in the two Delayed 21 30 40 41 50 60 62 groups and the Adult HF-Immediate group were the same age, so weights in these groups were compared. Only a significant main effect of days was evident, F(2, 30) = 116.211, p < .001. Overall, weights increased over days (Tukey’sHSD, p < .001), but did not vary by group in this phase for the Delayed groups and the Adult HF- 200 Immediate group. In Phase 3, rats in the two Immediate groups were the Adol LF - Delayed same age, so weights in these groups were compared. A 100 Adol HF - Delayed significant main effect of groups was evident, F(1, 10) = 21 30 40 81 90 100 102 15.290, p < .004, with Group Adol HF-Immediate being significantly heavier than Group Adol LF-Immediate. In Phase 3, rats in the two Delayed groups and Adult HF- Immediate group were the same age, so weights in these groups were compared. The main effect of groups was not significant (p > .80), indicating the weights did not vary substantially between the two Delayed groups and the Adult HF-Immediate group in Phase 3. Adult HF - Immediate Discussion and Conclusions 61 70 80 81 90 100 102 Thepresent studytestedwhether intakeof aHFdiet during the developmental period analogous to preado- Postnatal Day (PD) lescence and adolescence in humans [20] would be suffi- Figure 3 Mean body weights ± SEM by group during each cient to interfere with a CPP using a HF Cheetos food phase. Data are separated to make clear that the age of rats was as a US. When rats were fed a HF diet during this not always the same in each phase. An asterisk (*) indicates significance at p < .05. developmental period (PD 21-40), they consumed the most HF Cheetos in a subsequent CPP training phase (Phase 2) compared to all other groups. However, these these groups were compared. An ANOVA showed a sig- rats did not express a place preference in the CPP test- nificant main effect of days, F(2, 40) = 185.473, p < .001, ing phase (Phase 3). Moreover, consuming a HF diet for with weights increasing over days. A Groups × Days 20 days prior to CPP training in Phase 2 was not suffi- interaction was also evident, F(6, 40) = 18.292, p <.001. cient to interfere with a CPP because a CPP was Simple main effect tests showed that rats in the Adol observed in the Adult HF-Immediate group. Thus, only HF groups were significantly heavier than rats in the when the HF diet was consumed during PD 21-40 was a Adol LF groups (p < .001) in Phase 1. CPP no longer evident in Phase 3. In Phase 2, rats in the two Immediate groups were the One possible explanation for the results is a negative same age, so weights in these groups were compared. contrast effect [32] in that the HF diet was so high in An ANOVA showed a significant main effect of days, fat that, in contrast, the Cheetos were perceived as F(2, 20) = 64.937, p < .001, and groups, F(2, 20) = being relatively low fat. This possibility is unlikely 15.573, p < .004. Post hoc tests showed that rats in the because the HF diet and the Cheetos were actually Adol HF-Immediate group were heavier than the Adol comparable in kcal % fat content: 60 compared to 56 Weight (g) Privitera et al. Behavioral and Brain Functions 2011, 7:21 Page 6 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/21 kcal % fat, respectively. In addition, the HF groups con- periadolescence period, 20 days of consuming a HF diet sumed significantly more Cheetos during conditioning is not sufficient to induce CPP deficits. in Phase 2 compared to the other three groups. This A CPP for a place associated with a HF Cheetos food pattern of responding is not consistent with a negative is known to be mediated by opioids in mesolimbic brain contrast explanation. An explanation based on motor- regions [6]. Mesolimbic brain structures and their term- related deficits is also unlikely. Groups showed no sig- inal regions, such as the hippocampus, undergo signifi- nificant differences in the number of entrances into cant maturation and shifts in midbrain opioid release each side of the CPP apparatus in Phase 3, which sug- during pre and periadolescence [33,35-39] and are sus- gests comparable locomotion across groups. ceptible to manipulations of fat content in diet [9,40]. Another possible explanation may invoke differ- Thesebrain structures maymediateaCPP,however ences in body weight between groups. Rats in the HF further research is needed to test this hypothesis groups were significantly heavier than the LF rats because many other biochemical and neurobiological during CPP training and testing. But this was only factors related to changes in body weight and appetite true for the Immediate groups. After Phase 1, the regulation may also mediate a CPP using a HF US. Delayed groups were placed back on lab chow for 40 Thesefactors includepossibleHF-diet inducedchanges days before CPP training and testing began. During in leptin [41,42], ghrelin [3,43], neuropeptide Y [44,45], this 40-day period, weights normalized. Hence, there agouti-related protein (AGRP) [46], and proopiomelano- were no significant differences in body weight cortin (POMC) [47]–none of which were measured in between the Adol HF-Delayed and the Adult HF- this study. Immediate groups at the time of testing, but differ- The behavioral pattern observed in the present study ences in CPP testing were evident between these is similar to that for human infants with salt. Studies groups. These differences in CPP testing make it unli- show that 16-week-old human infants of mothers who kely that body weight differences explain the results reported frequent or severe vomiting expressed stronger observed in this experiment. preferences for salty solutions compared to 16-week-old It maybe possiblethattheresultsreflect aHFdiet- infants from mothers reporting little to no vomiting induced motivational deficit where, relative to other [48]. This difference in salt preferences appears to per- rats, Adol HF rats “liked” HF food more (i.e., it was sist at least until adolescence [49]. Hence, when the more palatable), but “wanted” it less (i.e., sought it less) amnion is deplete of salt, mechanisms that control liking [33,34]. Rats in the Adol HF groups, however, moved for salt are enhanced, thereby ensuring that this pre- throughout the CPP apparatus in Phase 3 at comparable sumably scarce nutrient is consumed when it is found. rates to rats that showed a CPP. It would have been Similarly, in this study LF rats showed significant learn- expected that rats that were less motivated to seek HF ing for a place associated with a HF food, whereas HF- food would display reduced locomotor activity in the Adol rats did not. During development, fat was a plenti- CPP chamber. It is possible, nonetheless, that other fac- ful nutrient for the HF-Adol rats and it was a scare tors such as the unconditional locomotor activity eli- nutrient for the LF rats. Hence, it would be advanta- cited by the CPP chamber may have dwarfed the geous for the LF rats to show a place preference for the expression of reduced wanting of HF food as locomotor “scarce” fatnutrient,butnot forthe HF-Adolrats activity. Therefore, selective motivational effects of HF because fat was a presumably “abundant” nutrient. The exposure cannot be completely ruled out. fact that CPP learning was not expressed even in the It is also possible that the HF diet consumed during HF-Delayed group that had 40 days of a lab chow diet, pre and periadolescence may induce a learning deficit. suggests that whatever mechanisms of learning were Previous studies have reported learning deficits after affected, the deficits may be long-lasting. This interpre- intake of a HF diet [12,14,15]. The present study adds tation of the results, however, suggests that HF food- to these data by showing that intake of a HF diet for 20 induced CPP learning deficits may be specific to HF days during the pre and periadolescent period is suffi- USs. Whether these deficits generalize to other USs is cient to disrupt a CPP using a HF food as a US. Pre- yet to be established. vious studies began the HF diet at least 6 to 8 weeks Asidefromonlyconsidering onetypeofUSduring following weaning and continued the diet for months CPP–Cheetos–the present study is also limited to one [12,13,16,17]. This prolonged treatment is similar to the sex (male), a limited duration of exposure (20 days dur- treatment of rats in the Adult HF-Immediate group, ing adolescence), and to a particular HF diet (60 kcal % except this group consumed a HF diet beginning about fat). Although it is yet unknown whether the present 6 weeks post-weaning for 20 days, and not for months. results generalize to female rats, the differential impact A CPP was evident in this group in Phase 3, indicating of a HF diet on cognition and learning across sexes that when a HF diet begins after the pre and [10,11] suggests that such generalization should not be Privitera et al. 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Staszkiewicz J, Horswell R, Argyropoulos G: Chronic consumption of a low- fat diet leads to increased hypothalamic agouti-related protein and reduced leptin. Nutrition 2007, 23:665-671. 47. Horvath TL, Sarman B, Garcia-Caceres C, Enriori PJ, Sotonyi P, Shanabrough M, Borok E, Argente J, Chowen JA, Perez-Tilve D, Pfluger PT, Bronneke HS, Levin BE, Diano S, Cowley MA, Tschop MH: Synaptic input organization of the melanocortin system predicts diet-induced Submit your next manuscript to BioMed Central hypothalamic reactive gliosis and obesity. Proceedings of the National and take full advantage of: Academy of Sciences of the United States of America 2010, 107:14875-80. 48. Crystal SR, Bernstein IL: Infant salt preference and mother’s morning • Convenient online submission sickness. Appetite 1998, 30:297-307. 49. Leshem M: Salt preference in adolescence is predicted by common • Thorough peer review prenatal and infantile mineralofluid loss. Physiology & Behavior 1998, • No space constraints or color figure charges 63:699-704. • Immediate publication on acceptance doi:10.1186/1744-9081-7-21 • Inclusion in PubMed, CAS, Scopus and Google Scholar Cite this article as: Privitera et al.: High fat diet intake during pre and • Research which is freely available for redistribution periadolescence impairs learning of a conditioned place preference in adulthood. Behavioral and Brain Functions 2011 7:21. Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Behavioral and Brain Functions Springer Journals

High fat diet intake during pre and periadolescence impairs learning of a conditioned place preference in adulthood

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Copyright © 2011 by Privitera et al; licensee BioMed Central Ltd.
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Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
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Abstract

Background: Brain regions that mediate learning of a conditioned place preference (CPP) undergo significant development in pre and periadolescence. Consuming a high fat (HF) diet during this developmental period and into adulthood can lead to learning impairments in rodents. The present study tested whether HF diet intake, consumed only in pre and periadolescence, would be sufficient to cause impairments using a CPP procedure. Methods: Rats were randomly assigned to consume a HF or a low fat (LF) diet during postnatal days (PD) 21-40 and were then placed back on a standard lab chow diet. A 20-day CPP procedure, using HF Cheetos as the unconditioned stimulus (US), began either the next day (PD 41) or 40 days later (PD 81). A separate group of adult rats were given the HF diet for 20 days beginning on PD 61, and then immediately underwent the 20-day CPP procedure beginning on PD 81. Results: Pre and periadolescent exposure to a LF diet or adult exposure to a HF diet did not interfere with the development of a HF food-induced CPP, as these groups exhibited robust preferences for the HF Cheetos food- paired compartment. However, pre and periadolescent exposure to the HF diet impaired the development of a HF food-induced CPP regardless of whether it was assessed immediately or 40 days after the exposure to the HF diet, and despite showing increased consumption of the HF Cheetos in conditioning. Conclusions: Intake of a HF diet, consumed only in pre and periadolescence, has long-lasting effects on learning that persist into adulthood. Background consumed in a distinct place with a presumably neutral Contextual or environmental cues associated with con- set of environmental cues (the conditioned stimulus, or suming a high fat (HF) food (or an otherwise nutrient CS). Over the course of conditioning, the CS acquires rich diet) can influence learning, cognition, food intake, secondary motivational properties through a Pavlovian and even override physiological sensations of hunger association with the HF food [7,8]. The secondary moti- and fullness [1,2]. In animals, studies using the condi- vational properties of the CS then elicit an approach tioned place preference (CPP) paradigm, a classic animal response, i.e., when allowed to roam freely, the subject model of reward learning, have shown that rats and spends most of its time in the presence of the CS mice prefer and approach environmental cues that are instead of a control place. associated with consumption of a HF food reward. High consumption of HF foods has unfavorable effects Some HF foods successfully used in CPP studies include in humans and animals. In humans, a HF diet is asso- open source HF diet pellets [3], fried potatoes [4], corn ciated with obesity [2], and degrading cognitive opera- oil [5], and Cheetos [6]. In the CPP paradigm, the HF tion and learning deficits [9], particularly in males food serves as an unconditioned stimulus (US) that is [10,11]. Animal studies show impaired learning, spatial memory, memory retention, and hippocampal synaptic * Correspondence: gprivite@sbu.edu plasticity in genetically obese animal models and HF Saint Bonaventure University, Department of Psychology, 3261 West State diet-induced obesity models [12-15]. While many stu- Street, Saint Bonaventure, NY 14778, USA dies with rodents begin the HF diets months after Full list of author information is available at the end of the article © 2011 Privitera et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Privitera et al. Behavioral and Brain Functions 2011, 7:21 Page 2 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/21 weaning [12,16,17], another study began HF diet manip- off at 1130 hours. Both temperature and humidity were ulations immediately following weaning for up to 9 to controlled in the housing facility, and rats were accli- 12 months thereafter [18]. Whether the observed deficits mated to living conditions and handling prior to con- are due to factors at earlier or later stages of develop- ducting experimental procedures. ment has not yet been determined. Of particular interest is the period of adolescence, Apparatus and Diet during which significant brain development occurs The CPP apparatus (26 cm long × 30 cm wide × 32 cm [19,20]. In rodents, a conservative definition of adoles- tall, Model H10-11R-TC) had two end chambers of cence is during postnatal days (PD) 28 to 42 [20,21]; identical size with stainless steel sidewalls and plastic alternative definitions stipulate that adolescence could front and back walls. The two end chambers differed on range from as early as just following weaning to about the type of flooring. The floor of one chamber was wire PD 60 [22,23]. The developmental period from PD 20 to mesh and the floor in the second chamber was alumi- 40 is analogous to preadolescence and adolescence in num sheet metal gauge 9. No bedding was beneath the humans [20]. Adolescence is associated with matura- floor in either chamber. The two end chambers were tional changes that are evident in mesolimbic and meso- connected by a median zone (13 cm long × 23 cm wide cortical brain regions and their terminal regions [24-28]. × 15.25 cm tall, Model H10-37R-NSF-09W), which also This maturation is of particular interest here because had plastic front and back walls. mesolimbic regions are know to mediate the develop- During Phase 1 of the experiment, rats consumed a ment of a CPP for a HF Cheetos food [6,29]. The HF diet (60 kcal % fat; Research Diet, Formula D12492) extent to which a HF diet, consumed only during prea- or LF diet (10 kcal % fat; Research Diet, Formula dolescence and adolescence, leads to CPP learning defi- D12450B) for 20 days prior to CPP procedures. In Phase cits has not been investigated. 2 (CPP Training), rats were given access to Cheetos We hypothesized that HF diet intake during pre and (56 kcal % fat; Frito-Lay, Inc., Plano, TX) inside the CPP periadolescence would produce long-term learning and apparatus. Cheetos were used as a HF US because it is memory impairments, possibly due to the significant an effective HF food used in CPP studies [6]. maturational development that sensitive brain regions undergo during this developmental period. In particular, Procedures we expected that learning and memory impairments Subjects were randomly assigned to one of five groups. would be expressed in the failure to acquire CPP in During Phase 1, two groups consumed a HF diet and adulthood, even if the US were a highly palatable HF two groups consumed a LF diet during PD 21-40 (Adol food itself. We did not expect comparable impairments HF and Adol LF, respectively). Another group of adult in rats consuming a HF diet at an older age for a com- rats consumed the HF diet from PD 61-80 (Adult HF). parableperiodoftimeorin ratsconsuming alow fat The adult rats were used as a control group to deter- (LF) diet. mine whether any observed CPP deficits were specific to intake during PD 21-40. Groups also differed on Methods whether training (Phase 2) began immediately following Subjects Phase 1 (Immediate), or 40 days following Phase 1 Subjects were 30 experimentally naïve, male Sprague- (Delayed). Delayed groups were used to determine Dawley rats from Charles River Laboratories, Kingston, whether HF diet manipulations induce long-term defi- New York. Male rats were used as they have previously cits in CPP performance. The timeline for each group been shown to exhibit a CPP to Cheetos [6]. Rat pups following weaning is given in Table 1, and each phase is were housed with their dam and were approximately summarized here. one-week old upon arrival to the lab. Rats were 21 days Phase 1 (Diet Manipulation) old at the start of the study, during which they were Rats in Groups Adol HF-Immediate and Adol HF- separated from the dam and were housed individually in Delayedconsumedthe HF dietad lib in their home clear plastic cages (43 cm deep × 21 cm wide × 20 cm cages for 20 days beginning on PD 21. Groups Adol LF- high). The plastic cages had solid bottoms that were Immediate and Adol LF-Delayed consumed the LF diet covered with bedding (Sani-Chips, P.J. Murphy Forest ad lib in their home cages for 20 days beginning on PD Products, Montville, NJ), and the cage tops were stain- 21. Rats in Group Adult HF-Immediate received the HF less steel wire lids. Rats had continuous access to water diet ad lib in their home cages for 20 days beginning on and lab chow (Harlan Teklad: 2018), except during the PD 61. Thereafter, all rats consumed a standard lab 20-day period indicated in the procedures section. chow (Harlan Teklad: 2018; 18 kcal % fat) ad lib in their Lights were on a 10:14 hour dark:light cycle with lights home cages for the duration of the study Privitera et al. Behavioral and Brain Functions 2011, 7:21 Page 3 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/21 Table 1 Timeline for the age of rats in each phase by similar for different groups of rats. Because this was also group the case in this study, the meaning of times spent in the Groups Phase median zone was not interpreted. Data were recorded using a videocamera located above 12 3 each chamber. The time in each end chamber started (Diet (CPP (CPP Manipulation) Training) Testing) when the full body of the rat, excluding the tail, entered Adol LF-Immediate PD 21-40 PD 41-60 PD 61-62 the end chamber. Time was stopped when the full body (n = 6) of the rat, excluding the tail, left the end chamber. The Adol HF-Immediate amount of time spent in each chamber and number of (n = 6) chamber entrances were recorded. It is important to Adol LF-Delayed PD 81-100 PD 101-102 note that these two dependent measures do not necessa- (n = 6) rily covary. Each rat was tested for a total of 20 minutes Adol HF-Delayed (10 min each day for two consecutive days). (n = 6) All procedures followed internationally recognized Adult HF - Immediate PD 61-80 PD 81-100 PD 101-102 (n = 6) guidelines for ethical conduct in the care and use of ani- mals. The St. Bonaventure University Institutional Ani- All rats were weaned at Postnatal Day (PD) 20. Experimental procedures followed weaning beginning at PD 21 for the Adol LF and Adol HF groups, mal Care and Use Committee approved all procedures. and beginning at PD 61 for the Adult HF-Immediate group Statistical Analysis Intake of Cheetos and lab chow during training trials Phase 2 (CPP Training) The Adol LF-Immediate and Adol HF-Immediate groups in Phase 2 were recorded in g, converted to kcal, and began Phase 2 on PD 41. The Adol LF-Delayed, Adol analyzed using a mixed-design analysis of variance HF-Delayed, and Adult HF-Immediate groups began (ANOVA). Groups and food-side pairings were the Phase 2 on PD 81. Rats were placed in one side of the between-subjects factors, and days were the within-sub- CPP apparatus for 20 minutes each day for 20 days. Half jects factor. Post hoc tests were conducted using Tukey’s the rats in each group were given ad lib access to Chee- HSD. The dependent variables were amount of Chee- tos in the wire mesh side on one day and lab chow pel- tos and lab chow pellets consumed. lets in the aluminum side on another day; the other half In Phase 3, a CPP was defined as greater time spent in of rats had the reverse pairings. The only HF food con- the chamber associated with the HF Cheetos food ® ® sumed during this phase was Cheetos . Five Cheetos or compared to time spent in the chamber associated with lab chow pellets were placed on the floor in the center of the lab chow pellets. The preference for the side paired with Cheetos was measured as the log ratio of time the chamber. No rat consumed all the Cheetos or lab spent in the side paired with Cheetos to time spent in chow pellets in any one trial. The difference in the weight the side paired with lab chow. The null hypothesis of the Cheetos and pellets from before to after each trial under evaluation in each experimental condition was was recorded and converted to kcal for data analysis. that the log ratio of the population was zero. Ninety-five The side a rat was placed in was counterbalanced on an and 99% confidence intervals (CIs) were drawn around ABBA schedule, where rats were placed in the side asso- the log ratios. A CPP was identified when the log ratio ciated with the HF food on A-days and the side associated was positive and the CI did not envelop zero. Using the with lab chow pellets on B-days. Because the side that rats same analyses as those in Phase 2, the number of received the Cheetos was chosen at random and was entrances in each chamber was also assessed in Phase 3. counterbalanced within groups, any individual differences Subject weights were recorded each week in each with regard to preferences for one side of the apparatus was assumed to be approximately equal between groups. phase. In each phase subject weights were compared Meta analysis studies show that this counterbalancing pro- using an analysis of variance (ANOVA) with groups as cedure increases effect sizes for a CPP [7]. the between-subjects factor and weeks as the within- Phase 3 (CPP Testing) subjects factor. The day after Phase 2 ended, the barrier between each side of the CPP apparatus was removed. No food was Results placed in either chamber during testing. Each rat was Figure 1 shows the mean consumption of Cheetos and placed in a neutral position in the median zone that lab chow across all days for each group in the training separated the two end chambers, and then allowed to phase (Phase 2). The amount of lab chow consumed roam freely for 10 minutes. Previous studies with 3- varied across days, F(9, 225) = 123.42, p < .001, and a chamber CPP systems [30,31] have shown that the significant Groups × Days interaction was also evident, amount of time spent in a median zone is small and F(36, 225) = 2.73, p < .001. As illustrated in Figure 1, Privitera et al. Behavioral and Brain Functions 2011, 7:21 Page 4 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/21 group (p < .001) over the final four days. Both Adol HF Phase 2 (Training) groups consumed significantly more than the Adol LF groups (p < .001); and both LF groups consumed signifi- Cheetos“ cantly less than the Adult HF-Immediate comparison * * group (p < .01). Figure 2 shows the mean time spent in each chamber of the CPP apparatus during testing (Phase 3). Total times spent in the median zone did not differ between 20 groups (p > .30). To test for a CPP, time data were con- verted to log ratios obtained for each rat and 95% and * 99% CIs were drawn for each group. Log ratio data did # * # * not differ significantly over days, p >.17,sothe data were pooled across both days of testing. A significant 0 * CPP for the side of the apparatus associated with the Lab Chow Pre-Exposure Condition Cheetos was evident for Group Adol LF-Immediate Adol LF - Immediate (99% CI 0.326, 2.007), Adol LF-Delayed (99% CI 0.078, Adol LF - Delayed 1.559), and Adult HF-Immediate (99% CI 0.373, 0.968). Adol HF - Immediate A CPP was not observed for Group Adol HF-Immediate Adol HF - Delayed (95% CI -0.463, 0.338), and Adol HF-Delay (95% CI Adult HF - Immediate -0.181, 0.519). Using 95% CIs, no groups showed a side preference for the left or right side of the cage, indicat- 10 ing that a significant CPP was instead specific to whether a chamber was associated with Cheetos in Phase 2. 1 2 3 4 5 6 7 8 9 10 Table 2 shows the means and standard deviations for the number of chamber entrances in each chamber in Conditioning Day ® Phase 3. No significant differences in the number of Figure 1 Mean intake ± SEM of Cheetos (Top) or Lab chow chamber entrances in Phase 3 were evident across days (Bottom) in kcal consumed during daily 20-min sessions by rats with a history of low fat (LF) or high fat (HF) diet during (p > .32) or between groups (p > .28). pre and periadolescence or adulthood. Access to Cheetos or Figure 3 shows the mean body weights by group in lab chow was counterbalanced on an ABBA schedule across 20 each phase. In Phase 1, rats in the Adol Immediate and days of training (Phase 2). *Significantly different from all other Adol Delayed groups were the same age, so weights in groups (p < .05). Significantly different from all HF groups (p < .05). Significantly different from all LF groups (p < .05). Phase 3 (Testing) Tukey’s HSD tests showed that the Adol HF-immediate Cheetos“ -paired group consumed significantly more lab chow on Days LabChow-paired 3 and 4 of conditioning compared to the LF groups (p < .05). Consumption of Cheetos in Phase 2 significantly var- ied across days, F(9, 225) = 309.08, p < .001, and between groups, F(4, 25) = 51.49, p < .001. A significant Groups × Days interaction was also evident, F(36, 225) = 7.35, p < .001. As illustrated in Figure 1, Tukey’s HSD tests showed that group differences in mean consump- tion of Cheetos were significant on virtually every day Adol LF Adol LF Adol HF Adol HF Adult HF of conditioning (p < .05). Because differences were Immediate Delayed Immediate Delayed Immediate greatest in the final four days of Phase 2, intake was averaged across the final four Cheetos days and differ- Pre-Exposure Condition ences between groups were compared. A one-way Figure 2 Mean time ± SEM spent in each chamber during CPP between-subjects ANOVA showed a significant main testing (Phase 3) in rats with a history of LF or HF diet during pre and periadolescence or adulthood, and conditioned effect of groups, F(4, 25) = 61.84, p < .001. Tukey’s HSD immediately or after 40 days (delayed) with Cheetos .An post hoc tests showed that Group Adol HF-Immediate asterisk (*) indicates significance at a 99% CI. consumed significantly more Cheetos than any other Amount consumed (kcal) Time (s) Privitera et al. Behavioral and Brain Functions 2011, 7:21 Page 5 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/21 Table 2 The mean and standard deviation for the Body Weights number of entrances in each side of the CPP apparatus Phase 1 Phase 2 Phase 3 ® Group Cheetos -Paired Side Lab Chow-Paired Side Mean St. Dev. Mean St. Dev. Adol LF-Immediate 8.5 3.6 7.4 3.3 Adol HF-Immediate 7.9 2.9 7.4 3.1 Adol LF-Delayed 8.5 3.5 7.0 3.3 Adol HF-Delayed 8.7 2.2 8.3 2.9 Adult HF-Immediate 8.6 3.8 7.9 2.3 Adol LF - Immediate 100 Adol HF - Immediate LF-Immediate group each week in Phase 2 (Tukey’s HSD, p < .001). In Phase 2, rats in the two Delayed 21 30 40 41 50 60 62 groups and the Adult HF-Immediate group were the same age, so weights in these groups were compared. Only a significant main effect of days was evident, F(2, 30) = 116.211, p < .001. Overall, weights increased over days (Tukey’sHSD, p < .001), but did not vary by group in this phase for the Delayed groups and the Adult HF- 200 Immediate group. In Phase 3, rats in the two Immediate groups were the Adol LF - Delayed same age, so weights in these groups were compared. A 100 Adol HF - Delayed significant main effect of groups was evident, F(1, 10) = 21 30 40 81 90 100 102 15.290, p < .004, with Group Adol HF-Immediate being significantly heavier than Group Adol LF-Immediate. In Phase 3, rats in the two Delayed groups and Adult HF- Immediate group were the same age, so weights in these groups were compared. The main effect of groups was not significant (p > .80), indicating the weights did not vary substantially between the two Delayed groups and the Adult HF-Immediate group in Phase 3. Adult HF - Immediate Discussion and Conclusions 61 70 80 81 90 100 102 Thepresent studytestedwhether intakeof aHFdiet during the developmental period analogous to preado- Postnatal Day (PD) lescence and adolescence in humans [20] would be suffi- Figure 3 Mean body weights ± SEM by group during each cient to interfere with a CPP using a HF Cheetos food phase. Data are separated to make clear that the age of rats was as a US. When rats were fed a HF diet during this not always the same in each phase. An asterisk (*) indicates significance at p < .05. developmental period (PD 21-40), they consumed the most HF Cheetos in a subsequent CPP training phase (Phase 2) compared to all other groups. However, these these groups were compared. An ANOVA showed a sig- rats did not express a place preference in the CPP test- nificant main effect of days, F(2, 40) = 185.473, p < .001, ing phase (Phase 3). Moreover, consuming a HF diet for with weights increasing over days. A Groups × Days 20 days prior to CPP training in Phase 2 was not suffi- interaction was also evident, F(6, 40) = 18.292, p <.001. cient to interfere with a CPP because a CPP was Simple main effect tests showed that rats in the Adol observed in the Adult HF-Immediate group. Thus, only HF groups were significantly heavier than rats in the when the HF diet was consumed during PD 21-40 was a Adol LF groups (p < .001) in Phase 1. CPP no longer evident in Phase 3. In Phase 2, rats in the two Immediate groups were the One possible explanation for the results is a negative same age, so weights in these groups were compared. contrast effect [32] in that the HF diet was so high in An ANOVA showed a significant main effect of days, fat that, in contrast, the Cheetos were perceived as F(2, 20) = 64.937, p < .001, and groups, F(2, 20) = being relatively low fat. This possibility is unlikely 15.573, p < .004. Post hoc tests showed that rats in the because the HF diet and the Cheetos were actually Adol HF-Immediate group were heavier than the Adol comparable in kcal % fat content: 60 compared to 56 Weight (g) Privitera et al. Behavioral and Brain Functions 2011, 7:21 Page 6 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/21 kcal % fat, respectively. In addition, the HF groups con- periadolescence period, 20 days of consuming a HF diet sumed significantly more Cheetos during conditioning is not sufficient to induce CPP deficits. in Phase 2 compared to the other three groups. This A CPP for a place associated with a HF Cheetos food pattern of responding is not consistent with a negative is known to be mediated by opioids in mesolimbic brain contrast explanation. An explanation based on motor- regions [6]. Mesolimbic brain structures and their term- related deficits is also unlikely. Groups showed no sig- inal regions, such as the hippocampus, undergo signifi- nificant differences in the number of entrances into cant maturation and shifts in midbrain opioid release each side of the CPP apparatus in Phase 3, which sug- during pre and periadolescence [33,35-39] and are sus- gests comparable locomotion across groups. ceptible to manipulations of fat content in diet [9,40]. Another possible explanation may invoke differ- Thesebrain structures maymediateaCPP,however ences in body weight between groups. Rats in the HF further research is needed to test this hypothesis groups were significantly heavier than the LF rats because many other biochemical and neurobiological during CPP training and testing. But this was only factors related to changes in body weight and appetite true for the Immediate groups. After Phase 1, the regulation may also mediate a CPP using a HF US. Delayed groups were placed back on lab chow for 40 Thesefactors includepossibleHF-diet inducedchanges days before CPP training and testing began. During in leptin [41,42], ghrelin [3,43], neuropeptide Y [44,45], this 40-day period, weights normalized. Hence, there agouti-related protein (AGRP) [46], and proopiomelano- were no significant differences in body weight cortin (POMC) [47]–none of which were measured in between the Adol HF-Delayed and the Adult HF- this study. Immediate groups at the time of testing, but differ- The behavioral pattern observed in the present study ences in CPP testing were evident between these is similar to that for human infants with salt. Studies groups. These differences in CPP testing make it unli- show that 16-week-old human infants of mothers who kely that body weight differences explain the results reported frequent or severe vomiting expressed stronger observed in this experiment. preferences for salty solutions compared to 16-week-old It maybe possiblethattheresultsreflect aHFdiet- infants from mothers reporting little to no vomiting induced motivational deficit where, relative to other [48]. This difference in salt preferences appears to per- rats, Adol HF rats “liked” HF food more (i.e., it was sist at least until adolescence [49]. Hence, when the more palatable), but “wanted” it less (i.e., sought it less) amnion is deplete of salt, mechanisms that control liking [33,34]. Rats in the Adol HF groups, however, moved for salt are enhanced, thereby ensuring that this pre- throughout the CPP apparatus in Phase 3 at comparable sumably scarce nutrient is consumed when it is found. rates to rats that showed a CPP. It would have been Similarly, in this study LF rats showed significant learn- expected that rats that were less motivated to seek HF ing for a place associated with a HF food, whereas HF- food would display reduced locomotor activity in the Adol rats did not. During development, fat was a plenti- CPP chamber. It is possible, nonetheless, that other fac- ful nutrient for the HF-Adol rats and it was a scare tors such as the unconditional locomotor activity eli- nutrient for the LF rats. Hence, it would be advanta- cited by the CPP chamber may have dwarfed the geous for the LF rats to show a place preference for the expression of reduced wanting of HF food as locomotor “scarce” fatnutrient,butnot forthe HF-Adolrats activity. Therefore, selective motivational effects of HF because fat was a presumably “abundant” nutrient. The exposure cannot be completely ruled out. fact that CPP learning was not expressed even in the It is also possible that the HF diet consumed during HF-Delayed group that had 40 days of a lab chow diet, pre and periadolescence may induce a learning deficit. suggests that whatever mechanisms of learning were Previous studies have reported learning deficits after affected, the deficits may be long-lasting. This interpre- intake of a HF diet [12,14,15]. The present study adds tation of the results, however, suggests that HF food- to these data by showing that intake of a HF diet for 20 induced CPP learning deficits may be specific to HF days during the pre and periadolescent period is suffi- USs. Whether these deficits generalize to other USs is cient to disrupt a CPP using a HF food as a US. Pre- yet to be established. vious studies began the HF diet at least 6 to 8 weeks Asidefromonlyconsidering onetypeofUSduring following weaning and continued the diet for months CPP–Cheetos–the present study is also limited to one [12,13,16,17]. This prolonged treatment is similar to the sex (male), a limited duration of exposure (20 days dur- treatment of rats in the Adult HF-Immediate group, ing adolescence), and to a particular HF diet (60 kcal % except this group consumed a HF diet beginning about fat). Although it is yet unknown whether the present 6 weeks post-weaning for 20 days, and not for months. results generalize to female rats, the differential impact A CPP was evident in this group in Phase 3, indicating of a HF diet on cognition and learning across sexes that when a HF diet begins after the pre and [10,11] suggests that such generalization should not be Privitera et al. 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