Eating can occur for many different reasons. We often eat not simply because we are hungry, but because we have learned to eat at specific times of day or in response to factors in our environments (for example, an advert that reminds of us of something tasty). Despite this, few researchers have investigated how biological signals from the gut communicate with the brain to enable this type of learned, or “conditioned”, feeding behavior.

Brain cells called neurons communicate with each other in specific circuits that can cross between different brain regions. Hsu et al. have now developed a “disconnection neuropharmacology” approach, which alters whether the neurons in different brain regions can communicate with each other, to investigate the effects signaling molecules have on brain activity and behavior. Using this approach in rats revealed a new circuit in the brain that controls learned feeding behavior through ghrelin, a hormone that is released from the stomach and increases appetite.

Hsu et al. found that the hippocampus, a brain region important for learning and memory control, uses ghrelin as a signal to engage in learned feeding behavior. Neurons in the hippocampus that respond to ghrelin communicate with other neurons in a region of the brain called the lateral hypothalamus (known for its role in feeding) that produce a signaling molecule called orexin. This circuit therefore links memory and feeding behavior.

Future work will investigate the neural circuits between the hippocampus and other brain regions that are important for feeding behavior, and the hormones that are important for triggering activity in these circuits.

Feeding behavior rarely occurs as a direct result of an immediate metabolic or nutrient deficiency. Rather, most animals (including humans) have habitual feeding patterns, consuming a fixed number of meals at approximately the same time each day. Environmental stimuli associated with learned meal anticipation elicit preparatory biological ‘cephalic’ responses (e.g., pancreatic insulin release) that occur prior to food consumption (Woods and Ramsay, 2000; Woods et al., 1970). These types of conditioned biological responses are advantageous when environmental factors place constraints on eating (e.g., predator threat, limited periods of food availability, and social or professional obligations) because they promote consumption of a large quantity of food within a relatively short time period. One important biological signal associated with conditioned appetite and feeding is ghrelin, a hormone derived from P/D1 cells in the stomach that is the only known circulating hormone that increases food intake(Tschöp et al., 2000; Cowley et al., 2003). While often referred to as a ‘hunger’ hormone, ghrelin is perhaps more aptly described as a meal-anticipatory hormone based on findings from both humans and rodents showing that ghrelin levels rise before an anticipated feeding bout independent of energy deprivation levels (Frecka and Mattes, 2008; Cummings et al., 2001; Drazen et al., 2006). Genetic deletion of the ghrelin receptor (growth hormone secretagogue receptor 1A; GHSR) eliminates food anticipatory activity under meal entrainment feeding schedules(Blum et al., 2009; Davis et al., 2011), further supporting the notion that ghrelin acts as a conditioned meal-anticipatory signal.

The mechanisms through which ghrelin communicates with the central nervous system to control learned aspects of food intake regulation are poorly understood. The hippocampus is a brain region historically associated with visuospatial and episodic memory function that has more recently been linked with the control of various feeding-relevant behaviors (Benoit et al., 2010; Davidson et al., 2007; Kanoski, 2012; Parent et al., 2014), including conditioned meal anticipation (Poulin and Timofeeva, 2008; Inglis et al., 1994; Henderson et al., 2013). GHSR is expressed abundantly in hippocampal neurons (Mani et al., 2014), and we recently demonstrated that pharmacological activation of GHSR by ghrelin in ventral/temporal subregions of the hippocampus (vHP) potently stimulates food intake by increasing both meal frequency and meal size (Kanoski et al., 2013). However, the extent to which endogenous vHP GHSR signaling controls conditioned anticipatory feeding behavior has not been investigated.

The lateral hypothalamic area (LHA) is implicated in the control of fundamental motivated behaviors, including food intake (For review see: [Stanley et al., 2011; Leinninger, 2011; Berthoud and Münzberg, 2011]). Classic studies show that LHA electrical ablation results in profound hypophagia (Teitelbaum and Epstein, 1962; Anand and Brobeck, 1951), whereas LHA electrical stimulation robustly increases food intake (Delgado and Anand, 1953). The LHA has direct connections with brain regions involved in the regulation of energy balance, including the hypothalamic arcuate and paraventricular nuclei (Hahn and Swanson, 2015), and the medial nucleus of the solitary tract (Ciriello et al., 2013). In addition, the LHA is also directly connected with several brain regions that regulate ‘higher-order’ cognitive aspects of feeding behavior, including the vHP, amygdala, nucleus accumbens (ACB), and ventral tegmental area (VTA) (Hahn and Swanson, 2015; Hahn and Swanson, 2010; Cenquizca and Swanson, 2006; Hahn and Swanson, 2012; Goto et al., 2005). Of note, vHP pyramidal neurons in field CA1 and the subiculum are a major source of direct and exclusively ipsilateral input to the LHA, especially the dorsal perifornical LHA (dpLHA) (Hahn and Swanson, 2015; Cenquizca and Swanson, 2006; Hahn and Swanson, 2012; Kishi et al., 2000). The dpLHA also has abundant expression of the neuropeptide orexin (ORX/hypocretin) (Swanson et al., 2005; Hahn, 2010), which in addition to an established role in behavioral arousal (Hagan et al., 1999; Chemelli et al., 1999), also has a central orexigenic role in the control of ingestive behavior (Willie et al., 2001; Rodgers et al., 2002; Sakurai, 2014; Thorpe et al., 2005; Sweet et al., 2004; Olszewski et al., 2009). We hypothesize that LHA ORX neurons are a critical downstream substrate of vHP ghrelinergic appetitive neural responding, because [1] orexin receptor 1 (Ox1R) signaling is required for ventricular ghrelin-induced hyperphagia (Cone et al., 2014), and [2] LHA ORX neurons are activated in anticipation of feeding under meal entrainment schedules (Jiménez et al., 2013).

In the present study we investigate the neural substrates through which ghrelin communicates conditioned appetite and feeding behavior to and within the brain. We hypothesize the existence of a neural pathway whereby peripherally-derived ghrelin (secreted in anticipation of feeding) activates GHSR-expressing vHP glutamatergic (pyramidal) neurons, which in turn activate orexin-expressing dpLHA neurons to stimulate appetite and feeding via CNS Ox1R signaling. We employed a combination of methods to facilitate a correlative approach, including neural pathway-tracing, immunohistochemistry, behavioral neuropharmacology, meal entrainment conditioning, and excitotoxic unilateral lesion-mediated neural ‘disconnection’ between pharmacological vHP GHSR activation and the dpLHA. The results of these experiments suggest novel mechanisms linking mnemonic processes with gut-brain communication to control feeding behavior.

Ghrelin levels rise in anticipation of feeding (Frecka and Mattes, 2008; Cummings et al., 2001; Drazen et al., 2006) and ghrelin receptor null mice show blunted meal anticipatory responding under meal entrainment feeding schedules (Blum et al., 2009; Davis et al., 2011). Compared to equivalent levels of food restriction, the anticipation of eating in meal entrained rats had a greater stimulatory effect on ghrelin release (Drazen et al., 2006), indicating that ghrelin acts as a meal anticipation hormonal signal that facilitates the consumption of large quantities of food. This notion is also consistent with data showing a role for ghrelin in stimulating gastric motility (Masuda et al., 2000; Peeters, 2003) and increasing meal size (Kanoski et al., 2013; Lee et al., 2011; Swartz et al., 2014; de Lartigue et al., 2010; Faulconbridge et al., 2003). Here we identify and characterize a novel neural substrate extending these previous findings by demonstrating that vHP ghrelin signaling is physiologically relevant for conditioned feeding behavior. After exposure to a meal entrainment schedule in which rats were restricted to 4 hr food access each day, pharmacological blockade of vHP GHSR signaling prior to food access significantly reduced 4 hr chow consumption. Comparatively, vHP GHSR blockade had no effect on a 4 hr chow intake in equally food-restricted rats that had not undergone the meal entrainment learning. Moreover, the intake reduction appears to be specific to conditioned feeding behavior as opposed to being based on higher baseline kcal consumption in meal entrained vs. control rats. This is supported by results showing that vHP JMV2959 administration did not reduce Western diet intake in non-food deprived, non-meal entrained animals under conditions where baseline kcal intake of the Western diet was actually higher than in meal-entrained rats consuming chow. However, another study showed that peripheral GHSR antagonist (Compound 26) delivery failed to suppress feeding in meal-entrained mice (Perello et al., 2010), yet we note that this previous study utilized a different GHSR antagonist, a different species, and a different route of administration (peripheral). Collectively, these findings build on previous work showing that pharmacological vHP GHSR activation increases meal frequency and size (Kanoski et al., 2013). Here we establish the endogenous relevance of vHP GHSR signaling to a specific component of feeding – conditioned feeding. We hypothesize that pharmacologically induced hyperphagia following vHP ghrelin injections occurs, at least in part, by augmenting the saliency of conditioned food-relevant interoceptive stimuli and/or external cues that are present in the environment.

To investigate neural pathways downstream to vHP ghrelin-mediated feeding behavior, we focused on the dpLHA region that contains abundant ORX-expressing neurons (Swanson et al., 2005; Hahn, 2010), and provide evidence of an input to dpLHA ORX-expressing from GHSR-expressing neurons in the vHP (field CA1). Our data confirm the existence of an exclusively ipsilateral direct input to the dpLHA from the vHP field CA1, and further demonstrate that ~85% of vHP field CA1 neurons retrogradely labeled from the dpLHA are immunoreactive for GHSR. These findings suggest that vCA1 ghrelin-responsive neurons send a direct input to the dpLHA, thereby highlighting the dpLHA as a downstream target for vHP ghrelin-mediated feeding.

Based on research showing an extensive population of orexin producing neurons in the dpLHA (Swanson et al., 2005; Hahn, 2010; Sakurai et al., 1998; Chen et al., 1999), as well as functional and neuroanatomical interactions between ghrelin and Ox1R signaling (Cone et al., 2014; Olszewski et al., 2003; Perello et al., 2010; Solomon et al., 2007; Toshinai et al., 2003), we next investigated the relationship between vCA1 and dpLHA orexin neurons. A direct connection from the vHP to dpLHA neurons was confirmed by the presence of PHAL-immunoreactive axons in the dpLHA following vHP field CA1 PHAL injections. Several instances of PHAL-labeled axons with varicosities and terminal boutons were recorded in close apposition to dpLHA ORX-expressing neurons. Triple-labeling for PHAL, ORX and the presynaptic marker synaptophysin indicated that some of these close appositions were putative sites of synaptic input. Next, we tested whether vHP GHSR activation engages dpLHA orexin neurons. Immunohistochemical analysis of Fos and orexin expression in the dpLHA in rats treated with vHP ghrelin or vehicle injections revealed Fos expression in approximately 70% of dpLHA orexin-expressing neurons. Taken together, these findings indicate a functional pathway involving GHSR-expressing vHP field CA1 neurons and their downstream communication to dpLHA orexin neurons.

To investigate the functional relevance of a putative vHP field CA1 ghrelin to LHA orexin connection further, we combined behavioral neuropharmacology (vHP ghrelin injection) with an excitotoxic unilateral LHA lesion-mediated neural disconnection approach (adapted after [Petrovich et al., 2002]). This approach takes advantage of an exclusively ipsilateral connection between the vHP and the LHA. Results show that vHP ghrelin administration ipsilateral to unilateral LHA lesions (vHP GHSR to LHA communication eliminated) blocks vHP ghrelin-activated hyperphagia that occurs in rats with sham lesions, and that also occurs when vHP ghrelin injections are given contralateral to the unilateral dpLHA lesion (vHP GHSR to LHA communication intact). These data indicate that vHP to dpLHA communication is critical for vHP ghrelin-mediated feeding effects.

A limitation in interpreting these findings with regard to the control of conditioned feeding behavior is that these experiments utilized pharmacological activation of vHP ghrelin receptors during free feeding conditions, and therefore the endogenous relevance of this neural circuitry during conditioned or entrained feeding requires further research. However, our data from Exp. 1 provide strong support for the endogenous relevance of vHP ghrelin signaling system for conditioned food intake. We hypothesize that the robust hyperphagic response following vHP GHSR activation during free feeding conditions is based, at least in part, on pharmacologically activating conditioned feeding behavior in the presence of food-associated cues. In other words, pharmacological vHP GHSR activation is potentially bolstering the saliency of internal (e.g., circadian, metabolic) or external cues within the animal’s environment (e.g., food hopper) that have the capacity to promote feeding behavior based on learned associations with feeding. Consistent with this framework, vHP GHSR activation increases meal frequency in response to external environmental stimuli (auditory, visual) that were associated with palatable food access, whereas vHP ghrelin signaling does not augment feeding in response to control stimuli with no prior food association (Kanoski et al., 2013). However, because present data do not directly assess the functional importance of vHP ghrelin to LHA orexin neural circuitry in conditioned feeding, we acknowledge that this pathway might also mediate aspects of non-conditioned appetite and feeding behavior. Indeed, ghrelin signaling in other brains regions appears to stimulate non-conditioned appetitive responding (Skibicka et al., 2011; Skibicka et al., 2013). For example, ICV or intra-amydala administration of the same GHSR antagonist used in this study (JMV2959) reduces free feeding in fasted (non-entrained) animals (Salomé et al., 2009; Alvarez-Crespo et al., 2012).

Neurons in the LHA also express GHSR, and LHA orexin-producing neurons are activated by external food-related cues as well as by direct LHA ghrelin administration (Olszewski et al., 2003; Petrovich et al., 2012). These findings suggest that in addition to the vHP, the LHA might also be a target for ghrelinergic conditioned feeding responses. However, our present data reveal that intra-LHA JMV2959 (including a dose that was effective in the vHP) had no effect on food intake in meal-entrained and non-meal-entrained animals, suggesting that while ghrelin signaling in various brain regions stimulates non-conditioned feeding behavior, vHP ghrelin signaling is a potentially unique neural substrate for learned aspects of feeding behavior. We note that it is also possible that vHP ghrelin to LHA orexin neural circuitry mediates non-conditioned aspects of feeding, however, this notion requires further investigation.

Our neuroanatomical data are consistent with previous research showing that vHP output to the LHA primarily targets the dpLHA region (Hahn and Swanson, 2010; Hahn and Swanson, 2012; Kishi et al., 2000) that was targeted with our unilateral NMDA lesions. While the anatomical and behavioral data in the current study suggest that vHP neurons communicate ghrelinergic signaling to the dpLHA directly, we recognize that multisynaptic pathways are also likely be involved. In addition to providing an input to the LHA, vHP field CA1 neurons also provide an input to several other feeding-related brain regions, including the amygdala and medial prefrontal cortex (mPFC) (Ishikawa and Nakamura, 2006; Cenquizca and Swanson, 2007). These regions also provide a topographically organized input to the LHA (Hahn and Swanson, 2015; Hahn and Swanson, 2012), and neural connectivity between the amygdala-LHA and mPFC-LHA has been shown to be critical for conditioned cue-potentiated feeding (Petrovich et al., 2002; Petrovich et al., 2005). Additional studies are required to determine the functional relevance of these other pathways to vHP ghrelin-mediated appetite.

We examined the requirement of downstream Ox1R signaling for vHP ghrelin-mediated feeding effects, demonstrating that central Ox1R blockade (via LV injections of an Ox1R antagonist) attenuated the hyperphagic effects of vHP ghrelin signaling. However, because ventricular injections spread throughout the CNS and Ox1R s are expressed throughout the brain, (Hervieu et al., 2001; Marcus et al., 2001), we can only speculate as to the mediating sites of Ox1R activation. Recent research has shown that blockade of Ox1Rs in the VTA attenuates food intake induced by LV ghrelin (Cone et al., 2014). Given these findings, and the role of VTA dopaminergic signaling in various aspects of feeding behavior (Cone et al., 2014; Skibicka et al., 2013; Nieh et al., 2015; Liu and Borgland, 2015; Narayanan et al., 2010; Cacciapaglia et al., 2011), we hypothesize that VTA Ox1R signaling is a critical downstream target of vHP ghrelin to dpLHA orexin signaling, however, this remains to be tested. Previous literature has also shown that central orexin signaling has roles in sleep/wake and arousal in addition to regulating feeding behavior (Hagan et al., 1999; Chemelli et al., 1999). The current study did not directly assess the relationship between vHP ghrelin signaling and orexin mediated arousal. It is possible that the enhanced saliency of external food-related cues following vHP ghrelin signaling is mediated by increased arousal, as well as potential changes to circadian activity, from downstream activation of central Ox1R's (possibly in the locus coeruleus). Further studies are required to test these possibilities, as well as the role of downstream Ox1R signaling in other aspects of feeding behavior (Zhu et al., 2002; Goforth et al., 2014; Zheng et al., 2007; Parise et al., 2011; Harris et al., 2005; Cason and Aston-Jones, 2013; Thorpe and Kotz, 2005; Thorpe et al., 2006).

Based on the present results and the findings of related previous research, we propose the following model in which vHP ghrelin signaling engages conditioned feeding behavior (Figure 9): [1] Ghrelin is secreted from the stomach in response to cues (internal or external) related to meal anticipation, [2] Ghrelin crosses the blood brain barrier and enters the central nervous system, [3] vHP GHSR-expressing neurons are activated by ghrelin, [4] These vHP ghrelin-activated neurons engage downstream dpLHA orexin-expressing neurons, [5] Activation of this neural pathway increases appetite and feeding behavior. Together, our data highlight novel neurobiological mechanisms by which ghrelin engages higher-order brain circuitry, that in turn controls hypothalamic systems necessary for the regulation of appetite.

Figure 9

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Author details

1. Ted M Hsu

   1. Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, United States
   2. Neuroscience Program, University of Southern California, Los Angeles, United States

   Contribution

   TMH, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

2. Joel D Hahn

   Neurobiology Section, Department of Biological Sciences, University of Southern California, Los Angeles, United States

   Contribution

   JDH, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

3. Vaibhav R Konanur

   Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, United States

   Contribution

   VRK, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

4. Emily E Noble

   Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, United States

   Contribution

   EEN, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

5. Andrea N Suarez

   Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, United States

   Contribution

   ANS, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

6. Jessica Thai

   Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, United States

   Contribution

   JT, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

7. Emily M Nakamoto

   Neuroscience Program, University of Southern California, Los Angeles, United States

   Contribution

   EMN, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

8. Scott E Kanoski

   1. Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, United States
   2. Neuroscience Program, University of Southern California, Los Angeles, United States

   Contribution

   SEK, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   kanoski@usc.edu

   Competing interests

   The authors declare that no competing interests exist.

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