br Neural circuits that control hunger br Ghrelin cognitive

Neural circuits that control hunger
Ghrelin & cognitive control of feeding Ghrelin is a 28 amino Pleuromutilin orexigenic peptide that stimulates food intake in rodents and patients (Andrews, 2011, Cummings, 2006, Horvath et al., 2001, Müller et al., 2015, Nakazato et al., 2001, Tschöp et al., 2000, Wren et al., 2001a, Wren et al., 2001b). Ghrelin is produced and released by X/A-like oxytinic cells of the stomach, the predominant source of circulating ghrelin (Müller et al., 2015, Toshinai et al., 2001) and is passively transported into the CNS (Banks et al., 2002). Exogenous application of ghrelin increases food intake, body weight, and appetite in both humans and rodents (Nakazato et al., 2001, Tschöp et al., 2000, Wren et al., 2001a, Wren et al., 2001b). Once released, ghrelin targets the ghrelin-receptor (GHSR-1a) at peripheral and multiple CNS locations to stimulate feeding behavior (Müller et al., 2015). Ghrelin targets the ventral tegmental area (VTA) to stimulate food-seeking behavior and palatable food intake (Dickson et al., 2011, Skibicka et al., 2011, Skibicka et al., 2012, Skibicka et al., 2013). Once released, ghrelin requires acylation on the third serine residue to become maximally active at GHSR-1a (Kirchner et al., 2009). Data from our lab indicate that acylation of ghrelin is required to promote operant responding for sucrose following caloric restriction and hedonic intake of palatable food in sated mice (Davis et al., 2012). These examples suggest that peripheral ghrelin signaling participates in both homeostatic re-feeding and hedonic feeding behaviors. Functional imaging studies indicate that exogenous application of ghrelin in sated patients leads to increases in the subjective ratings for appetite and enhances activation of the mPFC, AMG and striatum (Malik et al., 2008). Notably, circulating levels of ghrelin peak prior to scheduled meals in patients and in rodents (Drazen et al., 2006, Frecka and Mattes, 2008), indicating that peripherally released ghrelin may serve as an “anticipation signal” thereby regulating the ability to predict meals. GI secreted ghrelin reaches the hippocampus (Hp) (Diano et al., 2006), a cognitive CNS region that regulates memory consolidation, and in particular consolidation of food-related memories (Davidson et al., 2009, Davidson and Jarrard, 1993). When applied directly to the Hp, ghrelin initiates cue-based feeding behavior (Kanoski et al., 2013). Moreover, ghrelin-induced feeding via the Hp requires communication with and activation of LH neurons (Hsu et al., 2015). In combination these observations indicate that peripheral ghrelin targets cognitive regions to stimulate cue-based feeding and that this phenomenon requires communication with homeostatic control points to ultimately stimulate food intake. In this context, conditioned exposure to chocolate in NR rats or expectation of rodent chow following RFS leads to increased neuronal activation of the mPFC and LH prior to meal delivery (Choi et al., 2010). Notably this conditioned neuronal activation correlates temporally with conditioned ghrelin release (Drazen et al., 2006). More recently we discovered that conditioned expectation of a nutritionally complete high fat diet (HFD) leads to behavioral anticipation, conditioned ghrelin release, and binge-like intake of HFD. Importantly, blockade of peripheral ghrelin release attenuates binge intake of HFD, suggesting that pre-meal conditioned ghrelin release promotes binge-eating behavior (Sirohi et al., 2016). Notably, conditioned ghrelin release is present in obese patients prior to meal expectation (Frecka and Mattes, 2008), indicating that anticipatory surges in plasma ghrelin may act to maintain excess food intake in the context of obesity. These observations indicate that conditioned release of ghrelin is a powerful process capable of stimulating food intake in the absence of caloric need. Germane to this topic, central blockade of GHSR signaling attenuates behavioral anticipation of chocolate in NR rats (Merkestein et al., 2012). Additional work on this topic indicates that functional deletion of GHSR attenuates food anticipatory behavior in CR mice and spatial learning in the Morris water maze, suggesting that deficiencies in learning may attenuate food anticipatory responses (Davis et al., 2011). This collection of data highlight conditioned ghrelin release as a key event that initiates cognitive processes capable of stimulating feeding in the absence of caloric need.