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  • Resiquimod Despite a robust impact on learned social feeding


    Despite a robust impact on learned, social feeding behaviors, we observed no differences in body weight or food intake when the control or vHP GHSR-1A KD animals were maintained on either a normal chow diet or a Western diet high in fat and sugar. This is interesting in light of our previous work showing that pharmacological vHP GHSR-1A activation has potent hyperphagic effects, whereas vHP GHSR-1A blockade reduces chow intake in rats exposed to a meal entrainment schedule (Hsu et al., 2015, Kanoski et al., 2013). It is unknown whether caloric intake and/or body weight would be impacted with greater vHP GHSR-1A KD magnitude (∼50% KD observed in the current study) or whether compensatory mechanisms arise to occlude potential food intake and/or body weight effects. Indeed, GHSR-1A whole body knockout mice exhibit reduced food intake, body weight, and adiposity when maintained on a high-fat diet compared to wild-type animals (Zigman et al., 2005). More specifically, Zigman et al., 2005 demonstrated that female, but not male, GHSR-1A KO mice exhibited obesity resistant phenotypes (reduced food intake, body weight, and adiposity) when maintained on a standard chow diet, revealing potential sex dimorphism regarding ghrelin mediated feeding behaviors. Recent data has also demonstrated that female rats, but not male rats show decreased food intake, body weight, and food motivated behaviors following acute lateral hypothalamic GHSR-1A blockade (Lopez-Ferreras et al., 2017). Overall future experiments should examine whether vHP GHSR-1A-mediated STFP effects have similar sex dimorphism. Finally, animals with GHSR-1A KO also exhibit impairments in other types of conditioned feeding behaviors (Blum et al., 2009, Davis et al., 2011, Lamont et al., 2014, Walker et al., 2012), while others have demonstrated that ghrelin signaling in the amygdala mediates fear-related memories and circulating ghrelin is increased in response to stress-related stimuli (Meyer et al., 2014). Thus additional experiments should also examine whether vHP GHSR-1A KD might impact different variations of learned feeding behaviors (e.g. feeding driven by environmental or interoceptive contextual cues) and motivated behaviors. GHSR-1As are expressed throughout the Resiquimod (Alvarez-Crespo et al., 2012, King et al., 2011, Mani et al., 2014, Schele et al., 2016, Skibicka et al., 2011, Skibicka et al., 2013, St-Onge et al., 2015, Zigman et al., 2006) and we acknowledge the possibility that other brain regions besides the vHP can regulate learned, socially-driven feeding behaviors. For example, the lateral hypothalamic area (LHA) not only expresses GHSR-1A, but also influences feeding in response to environmental food cues (Olszewski et al., 2003, Petrovich et al., 2012). Our recently published data demonstrated that LHA ghrelin signaling does not mediate feeding in response to learned, circadian cues (Hsu et al., 2015), however whether LHA ghrelin signaling mediates STFP requires further investigation. Other neuropeptides and neurobiological systems also regulate socially-transmitted food preferences, including hypothalamic oxytocin signaling (Olszewski et al., 2014) and hippocampal acetylcholine, CREB, and PDE11A signaling (Countryman and Gold, 2007, Gold et al., 2011, Hegde et al., 2016). In addition, GHSR-1As and 5-HT2C receptors are colocalized in cultured hippocampal rat neurons and 5-HT2C receptor blockade attenuates ghrelin-induced hyperphagia (Schellekens et al., 2015). Whether vHP ghrelin signaling interacts with these systems also requires deeper examination.
    Conclusions Overall, the results presented here provide strong evidence in support of ghrelin's role in promoting learned aspects of feeding behavior and extend previous data demonstrating that the ventral subregion of the hippocampus is a critical brain substrate for mediating these effects. Our results corroborate and expand on our previously proposed model whereby hippocampal neural processing represents a broad, comprehensive integrator of learned associations between learned episodic experiences, external food cues, and interoceptive cues that inform about energy status (Kanoski and Grill, 2017). The latter is likely communicated to hippocampal neurons via endocrine and neuropeptidergic signals (e.g., ghrelin, insulin, leptin, orexin, glucagon-like peptide-1), many of which promote hippocampal-dependent memory function (see (Fadel et al., 2013, Van Doorn et al., 2017) for reviews). Here we extend our model by highlighting social interactions as an important episodic mnemonic experience that links external food cues (olfactory) and interoceptive state cues (GHSR-1A signaling) to influence subsequent food preference in rats.