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  • A central question that arises in this discussion is whether

    2023-03-11

    A central question that arises in this discussion is whether enhanced neurobehavioral responses to food cues emerge as a consequence of weight gain, or whether there are intrinsic differences in the motivational responses to food cues that precede weight gain. In support of pre-existing differences, we recently found that outbred rats subsequently identified as susceptible to diet-induced obesity display greater cue-triggered approach (an indicator of incentive motivation) prior to diet manipulation and weight gain (Robinson et al., 2015). However, identification of susceptible and resistant rats in outbred populations requires the introduction of high-fat diets and weight gain which can themselves alter neural function and behavior (Baladi et al., 2012, Brown et al., 2017, Dingess et al., 2017, Hryhorczuk 17 aag et al., 2016, Oginsky et al., 2016a). This limitation can, however, be overcome by using established rat lines that were selectively bred for their propensity or resistance to diet-induced obesity (Levin et al., 1997, Vollbrecht et al., 2015). Thus, by using these obesity-prone and obesity-resistant rats in the current study we can know a priori who is susceptible and resistant to obesity without introducing a high-fat diet or weight gain. This allows us to examine intrinsic neurobehavioral differences that precede obesity. Recent studies from our group have shown that NAc function is enhanced in these selectively-bred obesity-prone vs. obesity-resistant rats. For example, basal intrinsic excitability of medium spiny neurons within the NAc is enhanced in adult obesity-prone vs. obesity-resistant rats, in the absence of any diet manipulation (Oginsky et al., 2016b). Furthermore, consumption of a sugary, fatty “junk-food” diet increases the 17 aag and function of NAc calcium-permeable AMPA receptors (CP-AMPARs) in obesity-prone, but not obesity-resistant rats (Oginsky et al., 2016a). This up-regulation of CP-AMPARs is interesting in part because these receptors mediate the “incubation of cocaine-seeking” (Wolf, 2016, Wolf and Ferrario, 2010), consistent with the role of the NAc in incentive motivational processes (Berridge et al., 2009, Berridge et al., 2010, Cartoni et al., 2016). However, whether cue-triggered food-seeking (i.e., Pavlovian-to-instrumental transfer; PIT) is stronger in obesity-prone vs. obesity-resistant rats prior to obesity is unknown. Moreover, while NAc AMPAR-mediated transmission has been indirectly implicated in the expression of PIT (Corbit and Balleine, 2011, Crombag et al., 2008), to date no studies have directly examined the role of endogenous NAc AMPAR-mediated transmission in this behavior. Therefore here, we used PIT, a well-established measure of incentive motivation, to determine whether cue-triggered food-seeking is stronger in obesity-prone vs. obesity-resistant rats. We then examined whether experience during training leading up to PIT testing alters NAc AMPAR expression. Lastly, we determined the role of NAc AMPARs in the expression this behavior.
    Materials and methods
    Results
    Discussion Studies in humans suggest that in obesity-susceptible individuals, stronger motivational responses elicited by food cues drive over-consumption that lead to and maintain obesity (see introduction) and may share neurobehavioral features with drug addiction (Berridge et al., 2010, Dagher, 2009, Ferrario, 2017). However, to date only one preclinical study has examined potential intrinsic differences in cue-triggered motivation in models of susceptibility to obesity (Robinson et al., 2015), and the underlying mechanisms are poorly understood. Differences in motivational responses to food cues may arise from alterations in NAc function, as cue-triggered food- and drug-seeking require NAc excitatory transmission (Corbit and Balleine, 2011, Di Ciano and Everitt, 2004, Fuchs et al., 2004). Here, we found that obesity-prone rats exhibited robust PIT (i.e., incentive motivation) that was mediated by NAc core CP-AMPARs. Additionally, biochemical data suggest that this is due in part to experience-induced increases in NAc CP-AMPAR surface expression. In contrast, obesity-resistant rats displayed weak and variable PIT that was not associated with CP-AMPAR up-regulation. These data demonstrate that incentive motivational responses to food cues are stronger in obesity-prone rats prior to obesity, and establish a novel role for the up-regulation of NAc CP-AMPARs in this form of incentive motivation. Together these data substantiate the idea that enhanced cue-triggered food “craving” is a feature of susceptibility to obesity that may lead to over-eating and weight gain.