Sex specific effects of "junk-food" diet on calcium permeable AMPA receptors and silent synapses in the nucleus accumbens core

Abstract

CP-AMPARs in the nucleus accumbens (NAc) mediate cue-triggered motivation for food and cocaine. In addition, increases in NAc CP-AMPAR expression and function can be induced by cocaine or sugary, fatty junk-foods. However, the precise nature of these alterations and the degree to which they rely on the same underlying mechanisms is not well understood. This has important implications for understanding adaptive vs. maladaptive plasticity that drives food- and drug-seeking behaviors. Furthermore, effects of junk-foods on glutamatergic plasticity in females are unknown. Here, we use a combination of protein biochemistry and whole-cell patch clamping to determine effects of diet manipulation on glutamatergic plasticity within the NAc of males and females. We found that junk-food consumption increases silent synapses and subsequently increases CP-AMPAR levels in males in the NAc of male rats. In addition, a brief period of junk-food deprivation is needed for the synaptic insertion of CP-AMPARs and the maturation of silent synapses in males. In contrast, junk-food did not induce AMPAR plasticity in females but may instead alter NMDAR-mediated transmission. Thus, these studies reveal sex differences in the effects of junk-food on NAc synaptic plasticity. In addition, they provide novel insights into how essential food rewards alter NAc function.

Fig. 1. Junk-food increases NAc GluA1 surface expression only in obesity-prone male rats.

a Experimental timeline. b Average GluA1 surface expression in obesity-prone (OP) and obesity-resistant (OR) rats. GluA1 surface expression increased following 2 weeks of junk-food deprivation in obesity-prone, but not obesity-resistant rats. c Average GluA2 surface expression in obesity-prone and obesity-resistant rats. GluA2 surface expression was not altered by junk-food in either group. All data shown as mean ± SEM unless otherwise noted. *p < 0.05 obesity-prone chow vs. p < 0.05 junk- food.

Fig. 2. Junk-food increases GluA1 surface expression in obesity-prone males regardless of deprivation.

a Experimental timeline. b Average surface expression of GluA1 in obesity-prone (OP) male rats. Similar increases in GluA1 surface expression were found following 10 days of junk-food consumption with and without junk-food deprivation. c Average surface expression of GluA2 in obesity-prone male rats. GluA2 surface expression was not altered by junk-food or junk-food deprivation. d Average surface expression of GluA1 in obesity-resistant (OR) male rats. No effects of junk-food or junk-food deprivation were found. e Average surface expression of GluA2 in obesity-resistant male rats. No effects of junk-food or junk-food deprivation were found. *p < 0.05 compared with chow.

Fig. 3. Effects of junk-food on CP-AMPAR-mediated transmission and generation of silent synapses in obesity-prone male rats.

a Experimental timeline. CP-AMPAR-mediated transmission and measures of silent synapses were determined following 10 days of junk-food with and without 24–48 h deprivation. b Normalized eEPSC amplitude before and after Naspm (200 µM). Naspm produced similar decreases in eEPSC amplitude in obesity-prone (OP) chow and junk-food groups. However, junk-food deprivation enhanced Naspm sensitivity. The inset shows example traces from chow and junk-food groups before (black) and after bath application of Naspm (red). c Average reduction in eEPSC amplitude in chow and junk-food groups. Junk-food deprivation resulted in enhanced Naspm sensitivity. d Raw eEPSC amplitudes for chow, junk-food, and junk-food deprivation groups. Range of baseline amplitudes does not differ across groups. e The percent of silent synapses in obesity-prone (OP) chow, junk-food, and junk-food deprivation groups. f Representative traces of eEPSCs at +45 (NMDAR mediated) and −70 mV (AMPAR mediated) for junk-food and chow groups. *p < 0.05 chow vs. junk-food, ^#p < 0.05 junk-food vs. junk-food deprivation. g Depiction of recording area within the NAc core.

Fig. 4. Basal differences in GluA1 surface expression and AMPA/NMDA ratio in obesity-prone vs. obesity-resistant male rats.

a Experimental timeline. b Average GluA1 surface expression in chow fed obesity-prone (OP) and obesity-resistant (OR) male rats. Obesity-prone rats have lower GluA1 surface expression in the NAc compared with obesity-resistant rats. c Average GluA2 surface expression in chow fed obesity-prone and obesity-resistant male rats. GluA2 surface expression was similar between obesity-prone and obesity-resistant groups. d Average AMPA/NMDA ratio was smaller in obesity-prone vs. obesity-resistant male rats. e AMPAR amplitude was similar between obesity-prone and obesity-resistant male rats. f NMDAR amplitude was similar between obesity-prone and obesity-resistant male rats. g Representative traces of AMPAR-mediated (black) and NMDAR-mediated (red) currents. *p < 0.05 OP vs. OR.

Fig. 5. Junk-food does not alter CP-AMPARs expression or function in female rats.

a Experiment timeline. b Average GluA1 surface expression was not affected by junk-food in obesity-prone (OP) or obesity-resistant (OR) female rats. c Average GluA2 surface expression was not affected by junk-food in obesity-prone or obesity-resistant female rats. d Normalized amplitude before and after Naspm (200 µM): Naspm decreases relative amplitude in both obesity-prone female rats fed a chow and junk-food groups. Inset: example eEPSC from chow and junk-food obesity-prone female groups before (black) and after Naspm (red). e No differences in Naspm sensitivity were found between obesity-prone chow vs. junk-food groups. g Average AMPA/NMDA ratio was enhanced in obesity-prone females fed a junk-food diet compared with obesity-prone females fed a chow diet. h NMDAR amplitude was similar between obesity-prone females fed a chow diet and a junk-food diet. i AMPAR amplitude was similar between obesity-prone females fed a chow diet and a junk-food diet. j Representative traces of AMPAR-mediated (black) and NMDAR-mediated (red) currents.