Eating ‘Junk-Food’ Produces Rapid and Long-Lasting Increases in NAc CP-AMPA Receptors; Implications for Enhanced Cue-Induced Motivation and Food Addiction (2016)

Introduction

Although urges to eat are regulated by hunger, satiety, and energy demand, they are also strongly influenced by stimuli in the environment that are associated with food (food cues). For example, in non-obese people, exposure to food cues increases food craving and the amount of food consumed (Fedoroff et al, 1997; Soussignan et al, 2012). Obese people are more sensitive to these motivational properties of food cues, reporting stronger cue-triggered food craving and consuming larger portions after food cue exposure (Rogers and Hill, 1989; Yokum et al, 2011). These behavioral similarities between food- and drug-induced craving have led to the concept that ‘food addiction’ induced by the consumption of foods high in sugar and fat may contribute to the obesity epidemic (Carr et al, 2011; Epstein and Shaham, 2010; Kenny, 2011; Rogers and Hill, 1989; Volkow et al, 2013).

Evidence predominantly from human studies suggest that cue-triggered food craving in obese individuals involves alterations in function of the nucleus accumbens (NAc), a region that has long been known to mediate motivation for food and drug rewards, but that is increasingly implicated in obesity. For example, human fMRI studies show that activations in the NAc triggered by food cues are stronger in obese people (Stice et al, 2012; Volkow et al, 2013; Small, 2009). In addition, enhanced responsivity in the NAc to food cues predicts future weight gain and difficulty in losing weight in humans (Demos et al, 2012; Murdaugh et al, 2012). In rats, diet-induced obesity produces enhanced motivational responses to food cues, particularly in obesity-susceptible populations (Brown et al, 2015; Robinson et al, 2015). Together these data suggest that consumption of fatty, sugary foods produce neuroadaptations in NAc function that may enhance motivational processes.

In both rats and humans, susceptibility to obesity may have an important role in the effects of palatable, high-calorie ‘junk-foods’ on neural function and behavior (Albuquerque et al, 2015; Geiger et al, 2008; Robinson et al, 2015; Stice and Dagher, 2010). Although it is difficult to address the role of susceptibility in humans, studies in rats have shown that diet-induced alterations in mesolimbic systems and motivation are more pronounced in obesity-susceptible vs –resistant rats (Geiger et al, 2008; Vollbrecht et al, 2016; Robinson et al, 2015; Valenza et al, 2015; Oginsky et al, 2016). Thus recent data suggest that consumption of ‘junk-foods’ may produce distinct neural alterations in susceptible vs resistant populations.

AMPA-type glutamate receptors (AMPARs) provide the main source of excitation to the NAc, and the ability of food cues to trigger food-seeking relies in part on activation of AMPARs in the NAc core (Di Ciano et al, 2001). Furthermore, consumption of sugary, fatty foods and obesity can alter excitatory transmission in the NAc (Tukey et al, 2013; Brown et al, 2015). In addition, recent work from our laboratory and others has shown that cue-triggered motivation is enhanced in obesity-susceptible populations (Robinson et al, 2015; Brown et al, 2015). The goal of the current study was to determine how junk-food consumption in obesity-susceptible and -resistant rats affects AMPAR expression and transmission in NAc core, as NAc AMPARs mediated cue-triggered drug-seeking but have not been examined in diet-induced obesity models. In addition, cocaine-induced locomotor activity was used as a general ‘read out’ of mesolimbic function, as enhanced responsivity of mesolimbic circuits increases the motivational impact of food cues (Wyvell and Berridge, 2000, 2001).

Two complementary rodent models were used in order to determine the role of susceptibility in ‘junk-food’-induced alterations in NAc AMPARs. First, outbred Sprague-Dawley rats given ‘junk-food’ were identified as ‘Gainers’ and ‘Non-Gainers’ (as in Robinson et al, 2015), after which behavioral and neural differences were measured. Although informative, this model requires the induction of weight gain and diet manipulation in order to identify susceptible populations. Thus we also examined the effects of junk-food in rats selectively bred for their propensity or resistance to diet-induced obesity (Levin et al, 1997; Vollbrecht et al, 2015, 2016).

Materials and methods

Subjects

Rats were pair-housed on a reverse light–dark schedule (12/12) with free access to food and water throughout and were aged 60–70 days at the start of the experiment. Male Sprague-Dawley rats were purchased from Harlan. Obesity-prone and -resistant rats were bred in house. These lines were originally established by Levin et al (1997); breeders were purchased from Taconic. The inclusion of outbred rats enables comparisons to the broader existing literature, while selectively bred rats enable us to differentiate alterations owing to obesity vs diet manipulation. Weight was measured 1–2 times per week. All procedures were approved by The UM Committee on the Use and Care of Animals.

Junk-Food Diet and Identification of Obesity-Susceptible and -Resistant Outbred Rats

The ‘junk-food’ is a mash of: Ruffles original potato chips (40 g), Chips Ahoy original chocolate chip cookies (130 g), Jif smooth peanut butter (130 g), Nesquik powdered chocolate flavoring (130 g), powdered Lab Diet 5001 (200 g; % of calories: 19.6% fat, 14% protein, 58% carbohydrates; 4.5 kcal/g), and water (180 ml) combined in a food processor. Diet composition is based on previous studies establishing subpopulations (Levin et al, 1997; Robinson et al, 2015). K-means clustering based on weight gain after 1 month of junk-food was used to identify obesity-susceptible (Junk-Food-Gainer) and obesity-resistant (Junk-Food-Non-Gainer) groups. This statistical method provides an unbiased separation that can be applied uniformly across studies (MacQueen, 1967). In addition, we have determined that this is an optimal time point for reliably identifying subpopulations (Robinson et al, 2015; Oginsky et al, 2016; unpublished observations).

Cocaine-Induced Locomotion

Locomotor activity was measured in chambers (41cm × 25.4cm × 20.3 cm) equipped with photocell beams. Rats were placed in chambers for a 40 min habituation period prior to receiving an injection of saline (1 ml/kg, i.p.), followed 1 h later by cocaine (15 mg/kg, i.p.). This dose was chosen based on previous dose–response studies (Oginsky et al, 2016; Ferrario et al, 2005).

Surface vs Intracellular Protein Expression

Tissue from the NAc (core/shell) and dorsal medial striatum (DMS) were collected and processed using established BS³ crosslinking approaches (Boudreau et al, 2012) that enables the detection of cell surface vs intracellular protein expression. DMS samples were included to determine whether differences were selective to the NAc. For each rat, tissue was isolated, chopped (McIllwain chopper; 400 μm slices; St Louis, MO), and incubated in aCSF containing 2 mM BS³ (30 min, 4 °C). Crosslinking was terminated with glycine (100 mM; 10 min), slices were homogenized in lysis buffer (400 μl; in mM: 25 HEPES; 500 NaCl, 2 EDTA, 1 DTT, 1 phenylmethyl sulfonyl fluoride, 20 NaF, 1 : 100 protease inhibitor cocktail set I (Calbiochem, San Diego, CA), and 0.1% Nonidet P-40 [v/v]; pH 7.4), and stored at −80 °C. Protein concentration was determined by BCA assay. See Boudreau et al (2012) for full methodological details.

BS³ crosslinked samples were heated in Laemmli sample treatment buffer with 5% β-mercaptoethanol (70 °C, 10 min), loaded (20 μg protein), and electrophoresed on 4–15% Bis-Tris gradient gels under reducing conditions. Proteins were transferred onto PVDF membranes (Amersham Biosciences, Piscataway, NJ). Membranes were rinsed, blocked (1 h, RT, 5% (w/v) with nonfat dry milk in TBS-Tween 20 (TBS-T; 0.05% Tween 20, v/v)), and incubated overnight (4 °C) with primary antibodies (1 : 1000 in TBS) to GluA1 (Thermo Scientific; PA1-37776) or GluA2 (NeuroMab, UCDavis/NIH: 75-002). Membranes were washed in TBS-T, incubated with HRP-conjugated secondary (Invitrogen, Carlsbad, CA; 1 h, RT), washed, and immersed in chemiluminescence-detecting substrate (GE Healthcare, Piscataway, NJ). Images were acquired on film, and Ponceau S (Sigma-Aldrich) was used to determine total protein. Bands of interest were quantified using Image J (NIH).

Electrophysiology

The BS³ crosslinking procedure described above provides information about surface expression (synaptic and extra synaptic) of individual AMPAR subunits, whereas electrophysiological data provide information about functional synaptic AMPARs (tetramers). Whole-cell patch-clamp recordings of medium spiny neurons (MSNs) in the NAc core were conducted after junk-food exposure in outbred and selectively bred rats. Prior to slice preparation, rats were anesthetized with chloral hydrate (400 mg/kg, i.p.), brains were rapidly removed and placed in ice-cold oxygenated (95% O₂–5% CO₂) aCSF containing (in mM): 125 NaCl, 25 NaHCO₃, 12.5 glucose, 1.25 NaH₂PO₄, 3.5 KCl, 1 L-ascorbic acid, 0.5 CaCl₂, 3 MgCl₂, and 305 mOsm, pH 7.4. Coronal slices (300 μm) containing the NAc were made using a vibratory microtome (Leica Biosystems, Buffalo Grove, IL, USA) and allowed to rest in oxygenated aCSF (40 min). For the recording aCSF (2 ml/min), CaCl₂ was increased to 2.5 mM and MgCl₂ was decreased to 1 mM. Patch pipettes were pulled from 1.5 mm borosilicate glass capillaries (WPI, Sarasota, FL; 3–7 MΩ resistance) and filled with a solution containing (in mM): 140 CsCl, 10 HEPES, 2 MgCl₂, 5 Na⁺-ATP, 0.6 Na⁺-GTP, 2 QX314, pH 7.3, and 285 mOsm. Recordings were conducted in the presence of picrotoxin (50 μM). Evoked EPSCs (eEPSCs) were elicited by local stimulation (0.05–0.30 mA square pulses, 0.3 ms, delivered every 20 s) using a bipolar electrode placed ~300 μm lateral to recorded neurons. The minimum amount of current needed to elicit a synaptic response with <15% variability in amplitude was used. If >0.30 mA was required, the neuron was discarded. AMPAR-mediated eEPSCs were recorded at −70 mV before and after application of the CP-AMPAR selective antagonist naspm (200 μM; as in Conrad et al, 2008; Ferrario et al, 2011).

Statistics

Two-tailed t-tests, one-way or two-way repeated-measures ANOVAs, Sidak’s post-hoc multiple comparisons tests, and planned comparisons between obesity-susceptible and -resistant groups were used (Prism 6, GraphPad, San Diego, CA).

Results

Experiment 1

Sprague Dawley rats were given junk-food using an approach that leads to obesity in some rats (Junk-Food Gainers) but not others (Junk-Food Non-Gainers; Robinson et al, 2015; Oginsky et al, 2016). We then measured the response to a single cocaine injection (a general readout of mesolimbic function), surface vs intracellular expression of AMPAR subunits, and AMPAR-mediated transmission in the NAc core using whole-cell patch clamping approaches in these two populations.

Greater cocaine-induced locomotion in Junk-Food-Gainers

As expected, when given junk-food some rats gained a substantial amount of weight (Junk-Food-Gainers, N=6) while others did not (Junk-Food-Non-Gainers, N=4; Figure 1a; two-way RM ANOVA: main effect of group: F_(1,9)=11.85, p=0.007; group × time interaction: F_(18,162)=6.85, p<0.001). These rats had access to junk-food for 5 months total to allow for maximal separation between groups. They were then returned to standard laboratory chow (Lab Diet 5001: 4 kcal/g; 4.5% fat, 23% protein, 48.7% carbohydrates; percentage of caloric content) for a 2 week junk-food deprivation period to evaluate differences that persist after junk-food removal. Next rats were given a single cocaine injection and locomotor activity was monitored; the purpose of this was to obtain a general readout of mesolimbic function. The response to cocaine was greater in Junk-Food-Gainers vs Junk-Food-Non-Gainers (Figure 1b; two-way RM ANOVA: group × time interaction: F_(21,168)=2.31, p=0.0018; Sidak’s test, *p<0.05). In addition, while Junk-Food-Gainers showed a significantly stronger locomotor response to cocaine than saline (two-way RM ANOVA, time × injection interaction: F_(6,30)=2.39, p<0.05), Junk-Food-Non-Gainers did not. Locomotion during habituation and after saline did not differ between groups (Figure 1b inset), consistent with previous reports (Oginsky et al, 2016; Robinson et al, 2015).

GluA1, but not GluA2, NAc surface expression is greater in Junk-Food-Gainers

Next, we examined surface and intracellular protein expression of AMPAR subunits in Junk-Food-Gainers and Junk-Food-Non-Gainers. The majority of AMPARs in the NAc are GluA1/GluA2 containing, with some GluA2/3 AMPARs, and a small number of GluA2-lacking, CP-AMPARs (~10%; Reimers et al, 2011; Scheyer et al, 2014). So we focused on GluA1 and GluA2 expression levels, as this provides a good indication of changes in these different AMPAR populations. The abundance of surface and intracellular GluA1 and GluA2 protein was measured 1 week after testing for cocaine-induced locomotor activity (Figure 1c–e). Previous studies have established that a single cocaine injection does not alter AMPARs at this time (Boudreau and Wolf, 2005; Ferrario et al, 2010; Kourrich et al, 2007), enabling us to interpret AMPAR differences as related to the diet (see also below). NAc surface expression of GluA1 was greater in Junk-Food-Gainers vs Junk-Food-Non-Gainers (Figure 1d; t₈=2.7, p=0.03). In contrast, NAc GluA2 expression did not differ between groups (Figure 1e). In addition, GluA1 and GluA2 expression in the DMS of these same rats was similar between groups (data not shown), suggesting that changes in AMPAR expression occur selectively in the NAc. An increase in NAc GluA1 surface expression in the absence of changes in surface GluA2 suggests the presence of CP-AMPARs (GluA1/1- or GluA1/3-containing receptors). However, this must be confirmed using electrophysiological methods. We therefore conducted whole-cell patch clamp recordings after junk-food exposure to determine whether there is an increase in the contribution of CP-AMPARs to synaptic transmission in the NAc of Junk-Food-Gainers.

CP-AMPAR-mediated transmission is increased in Junk-Food-Gainers

For electrophysiological experiments, a separate cohort of rats was given junk-food for 3 months and recordings were made after 3 weeks of junk-food deprivation. This procedure was chosen to minimize overcrowding in cages due to weight gain, and to examine relatively long-lasting effects of junk-food. In this cohort, all junk-food rats were ‘Gainers’, gaining even more weight than Junk-Food-Gainers within cohort 1 (3-month gain: cohort 1, 106.2±9.7 g; cohort 2, ~132±5.4 g). Therefore, comparisons were made between the Chow (N=5 cells, 3 rats) and Junk-Food-Gainer groups (N=10 cells, 7 rats). To assess the contribution of CP-AMPARs to total AMPAR-mediated synaptic transmission, we used the selective CP-AMPAR antagonist naspm (200 μM). Naspm produced a small reduction in eEPSC amplitude in the Chow-fed controls (Figure 2a; Two-way ANOVA: main effect of naspm, F_(1,13)=19.14, p=0.0008), consistent with prior reports that CP-AMPARs contribute 5–10% of the basal AMPAR-mediated eEPSC (eg, Scheyer et al, 2014). However, in the junk-food group, naspm produced a significantly greater reduction (Figure 2b; t₁₃=1.8; p=0.046). These data show that CP-AMPARs are increased in Junk-Food-Gainers compared with Chow-fed rats. Furthermore, as the cohort used for electrophysiology was not given cocaine, these data strongly suggest that the biochemical changes in the previous experiment reflected effects of junk-food, not the single cocaine exposure.

Experiment 2

Data above from outbred rats are consistent with the idea that junk-food preferentially increases CP-AMPARs in obesity-susceptible rats. However, this difference could be due to the development of obesity or to preexisting differences in susceptible rats. To address these possibilities, we conducted similar biochemical and electrophysiological studies in selectively bred obesity-prone and -resistant rats with and without junk-food exposure. Because we know a priori which rats are susceptible to obesity, we can use this model to differentiate preexisting differences vs changes induced by junk-food.

Basal GluA1 levels are similar, but junk-food increases GluA1 expression in obesity-prone rats

First, we examined NAc AMPAR expression in obesity-prone and -resistant rats given chow or junk-food. NAc tissue was collected and crosslinked after 1 month of junk-food followed by 1 month of junk-food deprivation. A shorter junk-food exposure was used here to increase feasibility of experiments, as selectively bred obesity-prone rats tend to gain weight more rapidly than the outbred population. GluA1 expression was similar in obesity-prone and -resistant rats given chow (Figure 3, solid bars; N=6/group), suggesting that baseline levels of GluA1-containing AMPARs are similar in susceptible rats. This is consistent with previous electrophysiological results showing that basal AMPAR-mediated transmission is similar in these rats (Oginsky et al, 2016). In the junk-food fed groups, the abundance of surface to intracellular (S/I) GluA1 expression was increased in obesity-prone, but not obesity-resistant, rats compared with chow-fed controls (Figure 3a: one-way ANOVA, F_{(3, 19)}=2.957, p=0.058; OP-Chow vs OP-JF, p<0.05; OP-JF N=5, OR-JF N=6). This increase in S/I was due to slight increases in GluA1 surface expression (Figure 3b) and slight reductions in intracellular GluA1 (Figure 3c). Again, no differences were found in GluA2 expression (data not shown). Results here are consistent with biochemical results above in outbred rats and show that differences in AMPAR expression in obesity-prone rats are the result of junk-food and not due to basal differences between obesity-prone and -resistant groups.

Junk-food increases NAc CP-AMPAR-mediated transmission in obesity-prone rats in the absence of differences in weight or junk-food consumption

Next we determined whether junk-food consumption in the absence of weight gain is sufficient to enhance NAc AMPARs. A separate cohort of selectively bred rats were given chow or junk-food for 9–10 days (to minimize the development of obesity) followed by 2 weeks of junk-food deprivation and measurement of CP-AMPAR-mediated transmission as described above. Naspm reduced the AMPAR-mediated eEPSC amplitude in all groups (Figure 4a; Two-way RM ANOVA: main effect of naspm: F_(1,20)=22.5, p=0.0001; group × drug interaction: F_(3,20)=4.29, p=0.02; OP-JF and OR-JF: N=7 cells, 5 rats; OP-Chow: N=4 cells, 3 rats; OR-Chow N=5 cells, 3 rats). However, the effect of naspm was significantly greater in obesity-prone rats given junk-food compared with all other groups (Figure 4b: two-way RM ANOVA, group × time interaction: F_(18,114)=2.87, p=0.0003; *p<0.05 OP-JF vs all other groups; Figure 4c: one-way ANOVA, F_(3,20)=9.53, p=0.0004; OP-JF vs OR-JF and OP-Chow vs OP-JF, p<0.01). In addition, the effect of naspm was similar in the OP-Chow, OR-Chow, and OR-JF groups and was comparable to that seen in outbred rats (above) and to previously reported basal CP-AMPAR transmission (Conrad et al, 2008; Scheyer et al, 2014). Furthermore, weight gain, weight on recording day, and the amount of junk-food consumed was similar between obesity-prone and -resistant groups (Figure 4d and e). Thus, these data show that consumption of junk-food preferentially increases CP-AMPARs in obesity-prone rats prior to the onset of differential weight gain.

One possibility is that junk-food produces CP-AMPAR upregulation in obesity-resistant rats but that this effect subsides after 2 weeks of junk-food deprivation. To address this, recordings were made after 1 day of junk-food deprivation in another cohort of obesity-prone and -resistant rats given the same junk-food exposure (9–10 days; OR-JF: N=7 cells, 4 rats; OP-JF: N=6 cells, 3 rats). Again, we found that the effect of naspm was much greater in the OP-JF group (Figure 5a; two-way RM ANOVA: main effect of naspm: F_(1,11)=53.94, p<0.0001; group × naspm interaction: F_(1,11)=13.75, p=0.0035; Figure 5b: main effect of naspm: F_(7,77)=13.39, p<0.0001; group × naspm interaction: F_(7,77)=7.57, p<0.0001, post-test *p<0.05; Figure 5c: unpaired t-test: p=0.001). In addition, the magnitude of naspm’s effect in the OR-JF group was comparable to chow controls. Together these data show that junk-food induced increases in CP-AMPARs are absent in obesity-resistant rats after both early and late deprivation periods. Furthermore, weight gain and food intake were again similar in obesity-prone and -resistant rats (Figure 5d and e). Thus junk-food induced increases in CP-AMPARs in obesity-prone rats are not due to weight gain or differences in the amount of junk-food consumed. Finally, no differences were found in baseline eEPSC amplitude across all the groups studied (Figure 5f one-way ANOVA baseline amplitudes: F_(7,44)=1.993, p=0.09). Thus differences in naspm sensitivity above are not due to differences in baseline responding. Raw amplitudes before and after naspm for all data are shown in Figure 5f.

Funding and disclosure

Cocaine was provided by the NIDA drug supply program. This work was supported by NIDDK R01DK106188 to CRF; MFO was supported by NIDA T32DA007268. Research support to PBG was provided by the Michigan Diabetes Research Center (NIH Grant P30 DK020572) and the Michigan Nutrition and Obesity Research Center (P30 DK089503). The authors declare no conflict of interest.

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