Ghrelin: a Link Between Memory and Ingestive Behavior
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PHB-11276; No of Pages 8 Physiology & Behavior xxx (2016) xxx–xxx Contents lists available at ScienceDirect Physiology & Behavior journal homepage: www.elsevier.com/locate/phb Review Ghrelin: A link between memory and ingestive behavior Ted M. Hsu a,b, Andrea N. Suarez a, Scott E. Kanoski a,b,⁎ a Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA b Neuroscience Program, University of Southern California, Los Angeles, CA, USA HIGHLIGHTS • Learning and memory processes strongly influence feeding behavior. • Learned, cephalic endocrine responses are a physiological substrate for conditioned feeding. • The cephalic ghrelin response is a learned, anticipatory signal for feeding. • Ghrelin acts in hippocampus-lateral hypothalamic neural circuitry to express learned feeding. article info abstract Article history: Feeding is a highly complex behavior that is influenced by learned associations between external and internal Received 13 January 2016 cues. The type of excessive feeding behavior contributing to obesity onset and metabolic deficit may be based, Received in revised form 29 March 2016 in part, on conditioned appetitive and ingestive behaviors that occur in response to environmental and/or inter- Accepted 31 March 2016 oceptive cues associated with palatable food. Therefore, there is a critical need to understand the neurobiology Available online xxxx underlying learned aspects of feeding behavior. The stomach-derived “hunger” hormone, ghrelin, stimulates appetite and food intake and may function as an important biological substrate linking mnemonic processes Keywords: Appetite with feeding control. The current review highlights data supporting a role for ghrelin in mediating the cognitive Learning and neurobiological mechanisms that underlie conditioned feeding behavior. We discuss the role of learning and Obesity memory on food intake control (with a particular focus on hippocampal-dependent memory processes) and pro- Hippocampus vide an overview of conditioned cephalic endocrine responses. A neurobiological framework is provided through GHSR which conditioned cephalic ghrelin secretion signals in neurons in the hippocampus, which then engage Cephalic orexigenic neural circuitry in the lateral hypothalamus to express learned feeding behavior. © 2016 Elsevier Inc. All rights reserved. Contents 1. Introduction............................................................... 0 2. Mnemoniccontroloffoodintake...................................................... 0 3. Learnedcephalic-phasebiologicalresponsesandfeedingbehavior....................................... 0 4. Ghrelin:acephalicsignalfortheanticipationoffeeding........................................... 0 5. CNSregulation:hippocampalcontrolofghrelin-mediatedconditionedfoodintake............................. 0 6. Conclusions............................................................... 0 Acknowledgements.............................................................. 0 References.................................................................. 0 1. Introduction of feeding behavior, in particular the type of excessive food intake that contributes to weight gain and metabolic disorders. Food seeking and In light of the current obesity pandemic, there is a recent surge of ingestion rarely occur as passive behaviors in response to energy deficit. interest in investigating the biological and psychological antecedents Rather, for humans, food intake is more often initiated as a result of either habitual feeding patterns (e.g., meals consumed at approximately ⁎ Corresponding author at: University of Southern California, 3616 Trousdale Parkway, AHF-252, Los Angeles, CA 90089-0372, USA. the same time each day) or in response to environmental stimuli asso- E-mail address: [email protected] (S.E. Kanoski). ciated with food consumption, including cues associated with palatable http://dx.doi.org/10.1016/j.physbeh.2016.03.039 0031-9384/© 2016 Elsevier Inc. All rights reserved. Please cite this article as: T.M. Hsu, et al., Ghrelin: A link between memory and ingestive behavior, Physiol Behav (2016), http://dx.doi.org/ 10.1016/j.physbeh.2016.03.039 2 T.M. Hsu et al. / Physiology & Behavior xxx (2016) xxx–xxx foods such as fast food billboards and TV commercials. Indeed, learned recollection of factual information (semantic memory) and autobiograph- associations between food and interoceptive or external cues have the ical memories (episodic memory), requires neural processing in the hip- capability to drive or alter feeding behavior [1–5]. However, despite pocampus [22,23]. Declarative memories of previous meals or eating the robust influence of mnemonic processes on food intake, very little occasions can be consolidated and retrieved at a later time to influence is understood about the neurobiological substrates of learned feeding subsequent feeding behaviors. This is perhaps most powerfully illustrated behavior. In this review we discuss psychological and biological mecha- by research in amnesic patients with bilateral damage to the hippocam- nisms underlying learned feeding behavior, focusing primarily on the pus and surrounding medial temporal lobe. These patients are impaired gut-derived hormone, ghrelin as being a critical interface linking mem- in episodic memory formation, and under some experimental conditions ory and ingestion. they will consume a second or third meal offered only minutes after con- suming a meal [24,25]. Parent and colleagues [26] have elegantly modeled 2. Mnemonic control of food intake this phenomenon in rodent models, demonstrating that reversible inacti- vation of hippocampal neurons immediately following a scheduled, antic- Learning and memory processes have powerful control over appe- ipated sucrose meal reduces meal initiation latency and increases the size tite and food intake. Through experience, food-associated cues (e.g. of the subsequent meal [26]. This group more recently demonstrated that environmental cues or interoceptive cues) become associated with orosensory stimulation through either intake of sucrose or non-caloric rewarding or aversive postingestive consequences, and these learned saccharin robustly increases hippocampal synaptic plasticity in an associations robustly affect future feeding behaviors. An example is experience-dependent manner [27]. Together, these results suggest conditioned flavor avoidance (or aversion) learning, a process through that 1) hippocampal neural processing can regulate the consolidation which animals learn to avoid (or reject) neutral flavors that were previ- of food-related declarative memories, and 2) disrupted hippocampal ously associated with nausea or malaise [6]. Studies have also dem- processing can potentially lead to excessive eating. Indeed, rodents with onstrated appetite promoting effects through learned associations selective bilateral hippocampal lesions are hyperphagic and gain excess between neutral flavor cues and nutritive postingestive consequences. body weight relative to control rats [28]. More specifically, animals can learn to prefer a neutral flavor that was pre- An alternative and complementary framework for the influence of viously paired with gastric or intestinal infusion of nutrients [7].Thus, hippocampal-dependent memory processes on feeding behavior – one even simple associative learning mechanisms have the capacity to power- that does not evoke the use of complex mnemonic constructs like fully modulate feeding either by stimulating appetite or by inducing declarative memory – is provided by Davidson and colleagues (see avoidance/aversive behaviors. This review will focus on the role of ghrel- [3,28–31] for reviews on the role of hippocampal neural processing in, an appetite-promoting hormone released primarily from the gastric P/ in the mnemonic regulation of feeding behavior). In this model, D1 cells, on learned aspects of eating behavior. hippocampal-dependent memory processes influence feeding by In addition to associations between food-relevant stimuli and utilizing interoceptive energy status cues (e.g., different levels of food postingestive consequences, learned relationships between food access restriction) to resolve ambiguous learned relationships between food- and other types of interoceptive cues, including circadian rhythms, also related stimuli and their postingestive consequences [32]. Within this have the capacity to guide and alter feeding behavior. Many humans framework, energy status cues (e.g., hunger, satiety) modulate the and nonhuman animals have habitual feeding patterns in which meals strength of learned associations between food-related stimuli and are consumed at approximately the same time each day (e.g., breakfast, postingestive nutritive reinforcement. These energy status cues are likely lunch, and dinner), and accordingly, conditioned interoceptive circadian communicated to the hippocampus, in part, by ghrelin and other endo- cues can acquire the capacity to elicit preparatory cephalic release of crine signals (e.g., leptin, glucagon-like peptide-1) whose receptors are ghrelin and other endocrine signals that influence appetitive behavior expressed on hippocampal neurons [33]. [8–10] (a phenomenon discussed in more depth below). In some cases Based on the work described above, it is apparent that both simple feeding behavior is entrained, not based on convenient habitual feeding learned associations and more complex hippocampal-dependent mne- patterns, but rather, based on limited