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

Download asset Open asset

1. 1. Alvarez-Crespo M
   2. Skibicka KP
   3. Farkas I
   4. Molnár CS
   5. Egecioglu E
   6. Hrabovszky E
   7. Liposits Z
   8. Dickson SL

   (2012) The amygdala as a neurobiological target for ghrelin in rats: neuroanatomical, electrophysiological and behavioral evidence

   PloS One 7:e46321.

   https://doi.org/10.1371/journal.pone.0046321

   • Google Scholar
2. 1. Anand BK
   2. Brobeck JR

   (1951)

   Hypothalamic control of food intake in rats and cats

   The Yale Journal of Biology and Medicine 24:123–140.

   • Google Scholar
3. 1. Benoit SC
   2. Davis JF
   3. Davidson TL

   (2010) Learned and cognitive controls of food intake

   Brain Research 1350:71–76.

   https://doi.org/10.1016/j.brainres.2010.06.009

   • Google Scholar
4. 1. Berthoud HR
   2. Münzberg H

   (2011) The lateral hypothalamus as integrator of metabolic and environmental needs: from electrical self-stimulation to opto-genetics

   Physiology & Behavior 104:29–39.

   https://doi.org/10.1016/j.physbeh.2011.04.051

   • Google Scholar
5. 1. Blum ID
   2. Patterson Z
   3. Khazall R
   4. Lamont EW
   5. Sleeman MW
   6. Horvath TL
   7. Abizaid A

   (2009) Reduced anticipatory locomotor responses to scheduled meals in ghrelin receptor deficient mice

   Neuroscience 164:351–359.

   https://doi.org/10.1016/j.neuroscience.2009.08.009

   • Google Scholar
6. 1. Cacciapaglia F
   2. Wightman RM
   3. Carelli RM

   (2011) Rapid dopamine signaling differentially modulates distinct microcircuits within the nucleus accumbens during sucrose-directed behavior

   The Journal of Neuroscience 31:13860–13869.

   https://doi.org/10.1523/JNEUROSCI.1340-11.2011

   • Google Scholar
7. 1. Cason AM
   2. Aston-Jones G

   (2013) Role of orexin/hypocretin in conditioned sucrose-seeking in rats

   Psychopharmacology 226:155–165.

   https://doi.org/10.1007/s00213-012-2902-y

   • Google Scholar
8. 1. Cenquizca LA
   2. Swanson LW

   (2006) Analysis of direct hippocampal cortical field CA1 axonal projections to diencephalon in the rat

   The Journal of Comparative Neurology 497:101–114.

   https://doi.org/10.1002/cne.20985

   • Google Scholar
9. 1. Cenquizca LA
   2. Swanson LW

   (2007) Spatial organization of direct hippocampal field CA1 axonal projections to the rest of the cerebral cortex

   Brain Research Reviews 56:1–26.

   https://doi.org/10.1016/j.brainresrev.2007.05.002

   • Google Scholar
10. 1. Chemelli RM
    2. Willie JT
    3. Sinton CM
    4. Elmquist JK
    5. Scammell T
    6. Lee C
    7. Richardson JA
    8. Williams SC
    9. Xiong Y
    10. Kisanuki Y
    11. Fitch TE
    12. Nakazato M
    13. Hammer RE
    14. Saper CB
    15. Yanagisawa M

    (1999) Narcolepsy in orexin knockout mice

    Cell 98:437–451.

    https://doi.org/10.1016/S0092-8674(00)81973-X

    • Google Scholar
11. 1. Chen C-T
    2. Dun SL
    3. Kwok EH
    4. Dun NJ
    5. Chang J-K

    (1999) Orexin a-like immunoreactivity in the rat brain

    Neuroscience Letters 260:161–164.

    https://doi.org/10.1016/S0304-3940(98)00977-X

    • Google Scholar
12. 1. Ciriello J
    2. Caverson MM
    3. McMurray JC
    4. Bruckschwaiger EB

    (2013) Co-localization of hypocretin-1 and leucine-enkephalin in hypothalamic neurons projecting to the nucleus of the solitary tract and their effect on arterial pressure

    Neuroscience 250:599–613.

    https://doi.org/10.1016/j.neuroscience.2013.07.054

    • Google Scholar
13. 1. Cone JJ
    2. McCutcheon JE
    3. Roitman MF

    (2014) Ghrelin acts as an interface between physiological state and phasic dopamine signaling

    Journal of Neuroscience 34:4905–4913.

    https://doi.org/10.1523/JNEUROSCI.4404-13.2014

    • Google Scholar
14. 1. Cowley MA
    2. Smith RG
    3. Diano S
    4. Tschöp M
    5. Pronchuk N
    6. Grove KL
    7. Strasburger CJ
    8. Bidlingmaier M
    9. Esterman M
    10. Heiman ML
    11. Garcia-Segura LM
    12. Nillni EA
    13. Mendez P
    14. Low MJ
    15. Sotonyi P
    16. Friedman JM
    17. Liu H
    18. Pinto S
    19. Colmers WF
    20. Cone RD
    21. Horvath TL

    (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis

    Neuron 37:649–661.

    https://doi.org/10.1016/S0896-6273(03)00063-1

    • Google Scholar
15. 1. Cummings DE
    2. Purnell JQ
    3. Frayo RS
    4. Schmidova K
    5. Wisse BE
    6. Weigle DS

    (2001) A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans

    Diabetes 50:1714–1719.

    https://doi.org/10.2337/diabetes.50.8.1714

    • Google Scholar
16. 1. Davidson TL
    2. Kanoski SE
    3. Schier LA
    4. Clegg DJ
    5. Benoit SC

    (2007) A potential role for the hippocampus in energy intake and body weight regulation

    Current Opinion in Pharmacology 7:613–616.

    https://doi.org/10.1016/j.coph.2007.10.008

    • Google Scholar
17. 1. Davis JF
    2. Choi DL
    3. Clegg DJ
    4. Benoit SC

    (2011) Signaling through the ghrelin receptor modulates hippocampal function and meal anticipation in mice

    Physiology & Behavior 103:39–43.

    https://doi.org/10.1016/j.physbeh.2010.10.017

    • Google Scholar
18. 1. de Lartigue G
    2. Lur G
    3. Dimaline R
    4. Varro A
    5. Raybould H
    6. Dockray GJ

    (2010) EGR1 is a target for cooperative interactions between cholecystokinin and leptin, and inhibition by ghrelin, in vagal afferent neurons

    Endocrinology 151:3589–3599.

    https://doi.org/10.1210/en.2010-0106

    • Google Scholar
19. 1. Delgado JM
    2. Anand BK

    (1953)

    Increase of food intake induced by electrical stimulation of the lateral hypothalamus

    The American Journal of Physiology 172:162–168.

    • Google Scholar
20. 1. Drazen DL
    2. Vahl TP
    3. D'Alessio DA
    4. Seeley RJ
    5. Woods SC

    (2006) Effects of a fixed meal pattern on ghrelin secretion: evidence for a learned response independent of nutrient status

    Endocrinology 147:23–30.

    https://doi.org/10.1210/en.2005-0973

    • Google Scholar
21. 1. Faulconbridge LF
    2. Cummings DE
    3. Kaplan JM
    4. Grill HJ

    (2003) Hyperphagic effects of brainstem ghrelin administration

    Diabetes 52:2260–2265.

    https://doi.org/10.2337/diabetes.52.9.2260

    • Google Scholar
22. 1. Frecka JM
    2. Mattes RD

    (2008) Possible entrainment of ghrelin to habitual meal patterns in humans

    AJP: Gastrointestinal and Liver Physiology 294:G699–G707.

    https://doi.org/10.1152/ajpgi.00448.2007

    • Google Scholar
23. 1. Goforth PB
    2. Leinninger GM
    3. Patterson CM
    4. Satin LS
    5. Myers MG

    (2014) Leptin acts via lateral hypothalamic area neurotensin neurons to inhibit orexin neurons by multiple GABA-independent mechanisms

    The Journal of Neuroscience 34:11405–11415.

    https://doi.org/10.1523/JNEUROSCI.5167-13.2014

    • Google Scholar
24. 1. Goto M
    2. Canteras NS
    3. Burns G
    4. Swanson LW

    (2005) Projections from the subfornical region of the lateral hypothalamic area

    The Journal of Comparative Neurology 493:412–438.

    https://doi.org/10.1002/cne.20764

    • Google Scholar
25. 1. Hagan JJ
    2. Leslie RA
    3. Patel S
    4. Evans ML
    5. Wattam TA
    6. Holmes S
    7. Benham CD
    8. Taylor SG
    9. Routledge C
    10. Hemmati P
    11. Munton RP
    12. Ashmeade TE
    13. Shah AS
    14. Hatcher JP
    15. Hatcher PD
    16. Jones DNC
    17. Smith MI
    18. Piper DC
    19. Hunter AJ
    20. Porter RA
    21. Upton N

    (1999) Orexin a activates locus coeruleus cell firing and increases arousal in the rat

    Proceedings of the National Academy of Sciences of the United States of America 96:10911–10916.

    https://doi.org/10.1073/pnas.96.19.10911

    • Google Scholar
26. 1. Hahn JD
    2. Swanson LW

    (2010) Distinct patterns of neuronal inputs and outputs of the juxtaparaventricular and suprafornical regions of the lateral hypothalamic area in the male rat

    Brain Research Reviews 64:14–103.

    https://doi.org/10.1016/j.brainresrev.2010.02.002

    • Google Scholar
27. 1. Hahn JD
    2. Swanson LW

    (2012) Connections of the lateral hypothalamic area juxtadorsomedial region in the male rat

    The Journal of Comparative Neurology 520:1831–1890.

    https://doi.org/10.1002/cne.23064

    • Google Scholar
28. 1. Hahn JD
    2. Swanson LW

    (2015) Connections of the juxtaventromedial region of the lateral hypothalamic area in the male rat

    Frontiers in Systems Neuroscience 9:66.

    https://doi.org/10.3389/fnsys.2015.00066

    • Google Scholar
29. 1. Hahn JD

    (2010) Comparison of melanin-concentrating hormone and hypocretin/orexin peptide expression patterns in a current parceling scheme of the lateral hypothalamic zone

    Neuroscience Letters 468:12–17.

    https://doi.org/10.1016/j.neulet.2009.10.047

    • Google Scholar
30. 1. Harris GC
    2. Wimmer M
    3. Aston-Jones G

    (2005) A role for lateral hypothalamic orexin neurons in reward seeking

    Nature 437:556–559.

    https://doi.org/10.1038/nature04071

    • Google Scholar
31. 1. Haynes AC
    2. Jackson B
    3. Chapman H
    4. Tadayyon M
    5. Johns A
    6. Porter RA
    7. Arch JRS

    (2000) A selective orexin-1 receptor antagonist reduces food consumption in male and female rats

    Regulatory Peptides 96:45–51.

    https://doi.org/10.1016/S0167-0115(00)00199-3

    • Google Scholar
32. 1. Henderson YO
    2. Smith GP
    3. Parent MB

    (2013) Hippocampal neurons inhibit meal onset

    Hippocampus 23:100–107.

    https://doi.org/10.1002/hipo.22062

    • Google Scholar
33. 1. Hervieu GJ
    2. Cluderay JE
    3. Harrison DC
    4. Roberts JC
    5. Leslie RA

    (2001) Gene expression and protein distribution of the orexin-1 receptor in the rat brain and spinal cord

    Neuroscience 103:777–797.

    https://doi.org/10.1016/S0306-4522(01)00033-1

    • Google Scholar
34. 1. Inglis FM
    2. Day JC
    3. Fibiger HC

    (1994) Enhanced acetylcholine release in hippocampus and cortex during the anticipation and consumption of a palatable meal

    Neuroscience 62:1049–1056.

    https://doi.org/10.1016/0306-4522(94)90342-5

    • Google Scholar
35. 1. Ishikawa A
    2. Nakamura S

    (2006) Ventral hippocampal neurons project axons simultaneously to the medial prefrontal cortex and amygdala in the rat

    Journal of Neurophysiology 96:2134–2138.

    https://doi.org/10.1152/jn.00069.2006

    • Google Scholar
36. 1. Jiménez A
    2. Caba M
    3. Escobar C

    (2013) Food-entrained patterns in orexin cells reveal subregion differential activation

    Brain Research 1513:41–50.

    https://doi.org/10.1016/j.brainres.2013.03.031

    • Google Scholar
37. 1. Kanoski SE
    2. Fortin SM
    3. Ricks KM
    4. Grill HJ

    (2013) Ghrelin signaling in the ventral hippocampus stimulates learned and motivational aspects of feeding via PI3K-akt signaling

    Biological Psychiatry 73:915–923.

    https://doi.org/10.1016/j.biopsych.2012.07.002

    • Google Scholar
38. 1. Kanoski SE

    (2012) Cognitive and neuronal systems underlying obesity

    Physiology & Behavior 106:337–344.

    https://doi.org/10.1016/j.physbeh.2012.01.007

    • Google Scholar
39. 1. Kishi T
    2. Tsumori T
    3. Ono K
    4. Yokota S
    5. Ishino H
    6. Yasui Y

    (2000) Topographical organization of projections from the subiculum to the hypothalamus in the rat

    The Journal of Comparative Neurology 419:205–222.

    https://doi.org/10.1002/(SICI)1096-9861(20000403)419:2<205::AID-CNE5>3.0.CO;2-0

    • Google Scholar
40. 1. Lee J
    2. Martin E
    3. Paulino G
    4. de Lartigue G
    5. Raybould HE

    (2011) Effect of ghrelin receptor antagonist on meal patterns in cholecystokinin type 1 receptor null mice

    Physiology & Behavior 103:181–187.

    https://doi.org/10.1016/j.physbeh.2011.01.018

    • Google Scholar
41. 1. Leinninger GM

    (2011) Lateral thinking about leptin: a review of leptin action via the lateral hypothalamus

    Physiology & Behavior 104:572–581.

    https://doi.org/10.1016/j.physbeh.2011.04.060

    • Google Scholar
42. 1. Liu S
    2. Borgland SL

    (2015) Regulation of the mesolimbic dopamine circuit by feeding peptides

    Neuroscience 289:19–42.

    https://doi.org/10.1016/j.neuroscience.2014.12.046

    • Google Scholar
43. 1. Mani BK
    2. Walker AK
    3. Lopez Soto EJ
    4. Raingo J
    5. Lee CE
    6. Perelló M
    7. Andrews ZB
    8. Zigman JM

    (2014) Neuroanatomical characterization of a growth hormone secretagogue receptor-green fluorescent protein reporter mouse

    The Journal of Comparative Neurology 522:3644–3666.

    https://doi.org/10.1002/cne.23627

    • Google Scholar
44. 1. Marcus JN
    2. Aschkenasi CJ
    3. Lee CE
    4. Chemelli RM
    5. Saper CB
    6. Yanagisawa M
    7. Elmquist JK

    (2001) Differential expression of orexin receptors 1 and 2 in the rat brain

    The Journal of Comparative Neurology 435:6–25.

    https://doi.org/10.1002/cne.1190

    • Google Scholar
45. 1. Masuda Y
    2. Tanaka T
    3. Inomata N
    4. Ohnuma N
    5. Tanaka S
    6. Itoh Z
    7. Hosoda H
    8. Kojima M
    9. Kangawa K

    (2000) Ghrelin stimulates gastric acid secretion and motility in rats

    Biochemical and Biophysical Research Communications 276:905–908.

    https://doi.org/10.1006/bbrc.2000.3568

    • Google Scholar
46. 1. Narayanan NS
    2. Guarnieri DJ
    3. DiLeone RJ

    (2010) Metabolic hormones, dopamine circuits, and feeding

    Frontiers in Neuroendocrinology 31:104–112.

    https://doi.org/10.1016/j.yfrne.2009.10.004

    • Google Scholar
47. 1. Nieh EH
    2. Matthews GA
    3. Allsop SA
    4. Presbrey KN
    5. Leppla CA
    6. Wichmann R
    7. Neve R
    8. Wildes CP
    9. Tye KM

    (2015) Decoding neural circuits that control compulsive sucrose seeking

    Cell 160:528–541.

    https://doi.org/10.1016/j.cell.2015.01.003

    • Google Scholar
48. 1. Olszewski PK
    2. Li D
    3. Grace MK
    4. Billington CJ
    5. Kotz CM
    6. Levine AS

    (2003) Neural basis of orexigenic effects of ghrelin acting within lateral hypothalamus

    Peptides 24:597–602.

    https://doi.org/10.1016/S0196-9781(03)00105-0

    • Google Scholar
49. 1. Olszewski PK
    2. Shaw TJ
    3. Grace MK
    4. Höglund CE
    5. Fredriksson R
    6. Schiöth HB
    7. Levine AS

    (2009) Complexity of neural mechanisms underlying overconsumption of sugar in scheduled feeding: involvement of opioids, orexin, oxytocin and NPY

    Peptides 30:226–233.

    https://doi.org/10.1016/j.peptides.2008.10.011

    • Google Scholar
50. 1. Parent MB
    2. Darling JN
    3. Henderson YO

    (2014) Remembering to eat: hippocampal regulation of meal onset

    AJP: Regulatory, Integrative and Comparative Physiology 306:R701–R713.

    https://doi.org/10.1152/ajpregu.00496.2013

    • Google Scholar
51. 1. Parise EM
    2. Lilly N
    3. Kay K
    4. Dossat AM
    5. Seth R
    6. Overton JM
    7. Williams DL

    (2011) Evidence for the role of hindbrain orexin-1 receptors in the control of meal size

    American Journal of Physiology 301:R1692–R1699.

    https://doi.org/10.1152/ajpregu.00044.2011

    • Google Scholar
52. Book

    1. Paxinos G
    2. Watson C

    (2007)

    The Rat Brain in Stereotaxic Coordinates (6th ed.)

    Amsterdam; Boston: Academic Press/Elsevier.

    • Google Scholar
53. 1. Peeters TL

    (2003)

    Central and peripheral mechanisms by which ghrelin regulates gut motility

    Journal of Physiology and Pharmacology 54:95–103.

    • Google Scholar
54. 1. Perello M
    2. Sakata I
    3. Birnbaum S
    4. Chuang JC
    5. Osborne-Lawrence S
    6. Rovinsky SA
    7. Woloszyn J
    8. Yanagisawa M
    9. Lutter M
    10. Zigman JM

    (2010) Ghrelin increases the rewarding value of high-fat diet in an orexin-dependent manner

    Biological Psychiatry 67:880–886.

    https://doi.org/10.1016/j.biopsych.2009.10.030

    • Google Scholar
55. 1. Petrovich GD
    2. Hobin MP
    3. Reppucci CJ

    (2012) Selective fos induction in hypothalamic orexin/hypocretin, but not melanin-concentrating hormone neurons, by a learned food-cue that stimulates feeding in sated rats

    Neuroscience 224:70–80.

    https://doi.org/10.1016/j.neuroscience.2012.08.036

    • Google Scholar
56. 1. Petrovich GD
    2. Holland PC
    3. Gallagher M

    (2005) Amygdalar and prefrontal pathways to the lateral hypothalamus are activated by a learned cue that stimulates eating

    The Journal of Neuroscience 25:8295–8302.

    https://doi.org/10.1523/JNEUROSCI.2480-05.2005

    • Google Scholar
57. 1. Petrovich GD
    2. Setlow B
    3. Holland PC
    4. Gallagher M

    (2002)

    Amygdalo-hypothalamic circuit allows learned cues to override satiety and promote eating

    The Journal of Neuroscience 22:8748–8753.

    • Google Scholar
58. 1. Poulin AM
    2. Timofeeva E

    (2008) The dynamics of neuronal activation during food anticipation and feeding in the brain of food-entrained rats

    Brain Research 1227:128–141.

    https://doi.org/10.1016/j.brainres.2008.06.039

    • Google Scholar
59. 1. Ritter R
    2. Slusser P
    3. Stone S

    (1981) Glucoreceptors controlling feeding and blood glucose: location in the hindbrain

    Science 213:451–452.

    https://doi.org/10.1126/science.6264602

    • Google Scholar
60. 1. Rodgers RJ
    2. Ishii Y
    3. Halford JCG
    4. Blundell JE

    (2002) Orexins and appetite regulation

    Neuropeptides 36:303–325.

    https://doi.org/10.1016/S0143-4179(02)00085-9

    • Google Scholar
61. 1. Sakurai T
    2. Amemiya A
    3. Ishii M
    4. Matsuzaki I
    5. Chemelli RM
    6. Tanaka H
    7. Williams SC
    8. Richardson JA
    9. Kozlowski GP
    10. Wilson S
    11. Arch JRS
    12. Buckingham RE
    13. Haynes AC
    14. Carr SA
    15. Annan RS
    16. McNulty DE
    17. Liu W-S
    18. Terrett JA
    19. Elshourbagy NA
    20. Bergsma DJ
    21. Yanagisawa M

    (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and g protein-coupled receptors that regulate feeding behavior

    Cell 92:573–585.

    https://doi.org/10.1016/S0092-8674(00)80949-6

    • Google Scholar
62. 1. Sakurai T

    (2014) The role of orexin in motivated behaviours

    Nature Reviews Neuroscience 15:719–731.

    https://doi.org/10.1038/nrn3837

    • Google Scholar
63. 1. Salomé N
    2. Haage D
    3. Perrissoud D
    4. Moulin A
    5. Demange L
    6. Egecioglu E
    7. Fehrentz JA
    8. Martinez J
    9. Dickson SL

    (2009) Anorexigenic and electrophysiological actions of novel ghrelin receptor (gHS-R1A) antagonists in rats

    European Journal of Pharmacology 612:167–173.

    https://doi.org/10.1016/j.ejphar.2009.03.066

    • Google Scholar
64. 1. Skibicka KP
    2. Hansson C
    3. Alvarez-Crespo M
    4. Friberg PA
    5. Dickson SL

    (2011) Ghrelin directly targets the ventral tegmental area to increase food motivation

    Neuroscience 180:129–137.

    https://doi.org/10.1016/j.neuroscience.2011.02.016

    • Google Scholar
65. 1. Skibicka KP
    2. Shirazi RH
    3. Rabasa-Papio C
    4. Alvarez-Crespo M
    5. Neuber C
    6. Vogel H
    7. Dickson SL

    (2013) Divergent circuitry underlying food reward and intake effects of ghrelin: dopaminergic VTA-accumbens projection mediates ghrelin's effect on food reward but not food intake

    Neuropharmacology 73:274–283.

    https://doi.org/10.1016/j.neuropharm.2013.06.004

    • Google Scholar
66. 1. Solomon A
    2. De Fanti BA
    3. Martínez JA

    (2007) Peripheral ghrelin interacts with orexin neurons in glucostatic signalling

    Regulatory Peptides 144:17–24.

    https://doi.org/10.1016/j.regpep.2007.05.006

    • Google Scholar
67. 1. Stanley BG
    2. Urstadt KR
    3. Charles JR
    4. Kee T

    (2011) Glutamate and GABA in lateral hypothalamic mechanisms controlling food intake

    Physiology & Behavior 104:40–46.

    https://doi.org/10.1016/j.physbeh.2011.04.046

    • Google Scholar
68. 1. Swanson LW
    2. Sanchez-Watts G
    3. Watts AG

    (2005) Comparison of melanin-concentrating hormone and hypocretin/orexin mRNA expression patterns in a new parceling scheme of the lateral hypothalamic zone

    Neuroscience Letters 387:80–84.

    https://doi.org/10.1016/j.neulet.2005.06.066

    • Google Scholar
69. 1. Swartz EM
    2. Browning KN
    3. Travagli RA
    4. Holmes GM

    (2014) Ghrelin increases vagally mediated gastric activity by central sites of action

    Neurogastroenterology and Motility 26:272–282.

    https://doi.org/10.1111/nmo.12261

    • Google Scholar
70. 1. Sweet DC
    2. Levine AS
    3. Kotz CM

    (2004) Functional opioid pathways are necessary for hypocretin-1 (orexin-A)-induced feeding

    Peptides 25:307–314.

    https://doi.org/10.1016/j.peptides.2003.12.014

    • Google Scholar
71. 1. Teitelbaum P
    2. Epstein AN

    (1962) The lateral hypothalamic syndrome: recovery of feeding and drinking after lateral hypothalamic lesions

    Psychological Review 69:74–90.

    https://doi.org/10.1037/h0039285

    • Google Scholar
72. 1. Thorpe AJ
    2. Cleary JP
    3. Levine AS
    4. Kotz CM

    (2005) Centrally administered orexin a increases motivation for sweet pellets in rats

    Psychopharmacology 182:75–83.

    https://doi.org/10.1007/s00213-005-0040-5

    • Google Scholar
73. 1. Thorpe AJ
    2. Doane DF
    3. Sweet DC
    4. Beverly JL
    5. Kotz CM

    (2006) Orexin a in the rostrolateral hypothalamic area induces feeding by modulating GABAergic transmission

    Brain Research 1125:60–66.

    https://doi.org/10.1016/j.brainres.2006.09.075

    • Google Scholar
74. 1. Thorpe AJ
    2. Kotz CM

    (2005) Orexin a in the nucleus accumbens stimulates feeding and locomotor activity

    Brain Research 1050:156–162.

    https://doi.org/10.1016/j.brainres.2005.05.045

    • Google Scholar
75. 1. Toshinai K
    2. Date Y
    3. Murakami N
    4. Shimada M
    5. Mondal MS
    6. Shimbara T
    7. Guan JL
    8. Wang QP
    9. Funahashi H
    10. Sakurai T
    11. Shioda S
    12. Matsukura S
    13. Kangawa K
    14. Nakazato M

    (2003) Ghrelin-induced food intake is mediated via the orexin pathway

    Endocrinology 144:1506–1512.

    https://doi.org/10.1210/en.2002-220788

    • Google Scholar
76. 1. Tschöp M
    2. Smiley DL
    3. Heiman ML

    (2000) Ghrelin induces adiposity in rodents

    Nature 407:908–913.

    https://doi.org/10.1038/35038090

    • Google Scholar
77. 1. Willie JT
    2. Chemelli RM
    3. Sinton CM
    4. Yanagisawa M

    (2001) To eat or to sleep? Orexin in the regulation of feeding and wakefulness

    Annual Review of Neuroscience 24:429–458.

    https://doi.org/10.1146/annurev.neuro.24.1.429

    • Google Scholar
78. 1. Woods SC
    2. Hutton RA
    3. Makous W

    (1970) Conditioned insulin secretion in the albino rat

    Experimental Biology and Medicine 133:964–968.

    https://doi.org/10.3181/00379727-133-34605

    • Google Scholar
79. 1. Woods SC
    2. Ramsay DS

    (2000) Pavlovian influences over food and drug intake

    Behavioural Brain Research 110:175–182.

    https://doi.org/10.1016/S0166-4328(99)00194-1

    • Google Scholar
80. 1. Zheng H
    2. Patterson LM
    3. Berthoud HR

    (2007) Orexin signaling in the ventral tegmental area is required for high-fat appetite induced by opioid stimulation of the nucleus accumbens

    The Journal of Neuroscience 27:11075–11082.

    https://doi.org/10.1523/JNEUROSCI.3542-07.2007

    • Google Scholar
81. 1. Zhu Y
    2. Yamanaka A
    3. Kunii K
    4. Tsujino N
    5. Goto K
    6. Sakurai T

    (2002) Orexin-mediated feeding behavior involves both leptin-sensitive and -insensitive pathways

    Physiology & Behavior 77:251–257.

    https://doi.org/10.1016/S0031-9384(02)00843-0

    • Google Scholar
82. 1. Zigman JM
    2. Jones JE
    3. Lee CE
    4. Saper CB
    5. Elmquist JK

    (2006) Expression of ghrelin receptor mRNA in the rat and the mouse brain

    The Journal of Comparative Neurology 494:528–548.

    https://doi.org/10.1002/cne.20823

    • Google Scholar

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.

• 3,949

  views

• 675

  downloads

• 92

  citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.