When do we eat? Ingestive behavior, survival, and ...

Hormones and Behavior 64 (2013) 702–728

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Review

When do we eat? Ingestive behavior, survival, and reproductive success☆ Jill E. Schneider a,⁎, Justina D. Wise a, Noah A. Benton a, Jeremy M. Brozek a, Erin Keen-Rhinehart b a b

Department of Biological Sciences, Lehigh University, 111 Research Drive, Bethlehem, PA 18015, USA Department of Biology, Susquehanna University, Selinsgrove, PA 17870, USA

a r t i c l e

i n f o

Article history: Received 18 February 2013 Revised 21 July 2013 Accepted 22 July 2013 Available online 30 July 2013 Keywords: Appetitive behavior Consummatory behavior Food intake Food hoarding Hunting Prey catching Metabolic fuels Reproductive behavior Sex behavior Vaginal scent marking

a b s t r a c t The neuroendocrinology of ingestive behavior is a topic central to human health, particularly in light of the prevalence of obesity, eating disorders, and diabetes. The study of food intake in laboratory rats and mice has yielded some useful hypotheses, but there are still many gaps in our knowledge. Ingestive behavior is more complex than the consummatory act of eating, and decisions about when and how much to eat usually take place in the context of potential mating partners, competitors, predators, and environmental fluctuations that are not present in the laboratory. We emphasize appetitive behaviors, actions that bring animals in contact with a goal object, precede consummatory behaviors, and provide a window into motivation. Appetitive ingestive behaviors are under the control of neural circuits and neuropeptide systems that control appetitive sex behaviors and differ from those that control consummatory ingestive behaviors. Decreases in the availability of oxidizable metabolic fuels enhance the stimulatory effects of peripheral hormones on appetitive ingestive behavior and the inhibitory effects on appetitive sex behavior, putting a new twist on the notion of leptin, insulin, and ghrelin “resistance.” The ratio of hormone concentrations to the availability of oxidizable metabolic fuels may generate a critical signal that schedules conflicting behaviors, e.g., mate searching vs. foraging, food hoarding vs. courtship, and fat accumulation vs. parental care. In species representing every vertebrate taxa and even in some invertebrates, many putative “satiety” or “hunger” hormones function to schedule ingestive behavior in order to optimize reproductive success in environments where energy availability fluctuates. © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . Neuroendocrinology of food intake in laboratory rats and mice . . . A distributed neural network controls food intake . . . . . . . The arcuate perspective . . . . . . . . . . . . . . . . . . . Evidence that deemphasizes the arcuate in control of food intake Appetitive ingestive behavior . . . . . . . . . . . . . . . . . . . Historical perspective on appetitive behavior and motivation . . Food hoarding . . . . . . . . . . . . . . . . . . . . . . . Hunting and prey catching . . . . . . . . . . . . . . . . . Summary of appetitive behaviors . . . . . . . . . . . . . . . Reasons to stop eating . . . . . . . . . . . . . . . . . . . . . . The choice between eating and mating . . . . . . . . . . . . Preference for food or males in Syrian hamsters . . . . . . . . The choice between food and sex in other species . . . . . . . Courtship and eating in semelparous species . . . . . . . . . Energy availability and the HPG system . . . . . . . . . . . . . . Summary and conclusions . . . . . . . . . . . . . . . . . . . .

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☆ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited. ⁎ Corresponding authors at: Department of Biological Sciences, 111 Research Drive, Bethlehem, PA 18015, USA. Fax: +1 610 758 4004. 0018-506X/$ – see front matter © 2013 The Authors. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yhbeh.2013.07.005

J.E. Schneider et al. / Hormones and Behavior 64 (2013) 702–728

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Introduction A clinical perspective on human obesity suggests that we are eating ourselves “to death” (Shelton and Miller, 2010). According to this perspective, some combination of genes, diet, and lifestyle promotes overeating and/or low energy expenditure, which leads to a putative disease known as obesity and its myriad adverse health consequences (Vetter et al., 2010). A biological perspective, however, suggests that many phenotypes we see today have been molded by natural selection; they were maintained in populations over generations because they were adaptive, i.e., they increased reproductive success. If natural selection was a primary architect of the mechanisms that control ingestive behavior, we might gain key insights by studying their link to reproductive success. In other words, we need to know how we eat ourselves to life. We need to determine how putative orexigenic and anorectic hormones schedule ingestive behavior in order to optimize reproductive success. Most often, controls of food intake are assumed to function primarily to maintain homeostasis. As noted by Friedman (2008), homeostasis is from the Latin words for staying “similar to,” not “the same as,” and thus it implies both fluctuation and maintenance. The variable that must be maintained in equilibrium is metabolic fuel availability, not body weight, adiposity, or food intake. Food intake, body fat storage, and energy expenditure often fluctuate wildly in order to maintain energy homeostasis, i.e., homeostasis in the availability and flux of oxidizable metabolic fuels (Friedman, 2008). Energy for cellular processes and organismal activity comes from eating food. In typical laboratory environments, animal subjects have ad libitum access to readily available food. In most natural habitats, however, food supplies fluctuate, and animals must expend energy to find and procure food (Bronson, 1989). In the wild, both survival and reproduction require anticipatory overeating, food storage, and metabolic adaptations to fasting. It is not surprising then that most vertebrate species show metabolic transformations that allow the breakdown of bodily tissue in order to fuel activity during fasting and starvation (Wang et al., 2006). Reproductive processes, including gametogenesis, vitellogenesis, fetal and embryonic development, lactation (in mammals), and parental care are energetically expensive, and these processes can be delayed to conserve energy for survival under harsh energetic conditions (Cooke et al., 2006; Gittleman and Thompson, 1988; Sibly et al., 2012; Van Dyke and Beaupre, 2011). Behavioral phenotypes that were molded by natural selection, including the controls of ingestive behavior, likely increased reproductive success or helped individuals survive to realize their reproductive potential (Darwin, 1859). Behaviors, including sex and ingestive behaviors, are critical in energy homeostasis. Experiments designed to measure the metabolic costs of reproductive processes revealed that the most important adaptation to fluctuating energy availability is behavioral compensation (reviewed by Gittleman and Thompson, 1988). Examples include those species that overeat and store energy on the body as adipose tissue prior to mating so as to meet the future energetic demands of gestation; species in which pregnant females conserve energy for their growing conceptus by reducing flight, locomotion and/or general activity; species of birds that relax their homeothermy during incubation; and species in which lactating female mammals increase food intake or draw upon a food cache or their own adipose tissue (reviewed by Gittleman and Thompson, 1988). Thus, behavioral flexibility allows adaptation to a labile energetic environment, and this idea is central to the behavioral neuroendocrinology of ingestive behavior. We suggest that a primary role of hormones is to orchestrate these changes in behavioral priorities. Anorectic, catabolic hormones often stimulate or permit reproductive

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behaviors and orexigenic, anabolic hormones inhibit reproductive behaviors. The idea that so-called hunger and satiety hormones function to maintain a particular level of body weight or adiposity is incomplete without the understanding that reproductive success depends upon fluctuations in adiposity and the ability to gain access to stored energy in adipose tissue (Schneider and Watts, 2002, 2009; Wade and Schneider, 1992). We begin with a brief overview of chemical messengers that influence food intake in laboratory rats and mice studied in isolation from opposite-sex conspecifics and without behavioral options. Next, we consider the perspective developed from experiments using other mammalian species and a few from other vertebrate taxa. We emphasize a small number of experiments in which energetic variables are manipulated, thereby calling attention to the need for more such experiments. Specifically, it would be instructive to examine ingestive and reproductive processes under conditions in which the following variables are manipulated: food availability, ambient temperature, the amount of energy expended on exercise, and the presence or absence of competitors and potential mating partners. In addition, we emphasize the need to consider appetitive as well as consummatory behaviors. These behaviors provide a window into motivation, and, in many cases, motivation is under the control of neural circuits and neuropeptide systems that differ from those that control performance. So-called anorectic peptides enhance sexual motivation whereas orexigenic peptides inhibit sexual motivation, often with no effect on sexual performance. Chemical messengers control momentto-moment decisions about whether to engage in courtship, parental behavior, ingestive behavior, migration, territoriality, and/or aggression. Furthermore, the effects of these chemical messengers on behavior differ according to subtle changes in food availability, body fat content, and the availability of oxidizable metabolic fuels. When energetic demands are low, there is ample food available to eat, and animals can access metabolic fuels from their adipose tissue stores, there is a pool of oxidizable metabolic fuels that can support cellular process, activity, immune function and reproduction. This is depicted by the full tank in Fig. 1A. Frank starvation (e.g., total food deprivation in lean animals or in fattened animals deprived for prolonged periods) inhibits the hypothalamic–pituitary–gonadal (HPG) system, leaving enough metabolic fuels for survival (depicted by the drained liquid in Fig. 1B and reviewed by I'Anson et al., 1991; Schneider, 2004; Wade and Jones, 2004; Wade and Schneider, 1992). In contrast to severe energetic challenges, mild energetic challenges (e.g., less than 25% food restriction in fattened animals) interact with hormone and neuropeptide action to produce fluctuations in the motivation to engage in sex and ingestive behavior, depicted in Fig. 1C. Effects of mild restriction can change sensitivity to sex hormones without impact on steroid secretion (Klingerman et al., 2010, 2011a, 2011b; Schneider, 2006; Schneider et al., 2007, 2012). If most of these chemical messengers evolved to orchestrate conflicting appetites on a moment-to-moment basis, it is not surprising that any one of these alone fails to prevent or reverse obesity. Understanding neuroendocrine control of behavior in a dynamic energetic environment will be crucial as we face the problems of global climate change, endocrine disruptors in the environment, and rising obesity in human beings, pets, and wildlife (Humphries et al., 2004; Wingfield, 2008). Neuroendocrinology of food intake in laboratory rats and mice In the vast majority of experiments on ingestive behavior, the model system is either laboratory rats or mice (Rattus norvegicus and Mus musculus), and the behavioral end point is food intake, the amount of

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peripheral hormones, leptin from the adipocyte, ghrelin from the stomach, cholecystokinin (CCK) and glucagon-like peptide-I (GLP-I) from the gut, and their targets in the hypothalamus have garnered a great deal of interest. More recently, attention has turned back toward the HPG, HPA, and HPI axes (hypothalamic–pituitary–adrenal in mammals, birds, and reptiles, and the hypothalamic–pituitary–interrenal in fish and amphibians). These so-called sex and stress hormones have major influences on ingestive behavior. Estradiol, secreted primarily from the ovary but also the adrenals, decreases food intake and body weight (Gray and Wade, 1981; Wade and Gray, 1979; Wade et al., 1985), and genetic knock out of estrogen receptor results in obesity (Geary et al., 2001; Heinen et al., 2000; Musatov et al., 2007; Ohlsson et al., 2000). Gonadotropin-releasing hormone-II (GnRH-II) and gonadotropininhibiting hormone (GnIH) influence both sex and ingestive behavior (Clarke et al., 2012; Hoskins et al., 2008; Kauffman et al., 2005, 2006; Klingerman et al., 2011b; Tachibana et al., 2005). The obesity caused by lesions, diet, neuropeptide Y (NPY) treatment, or mutations in the gene for leptin can be reversed by adrenalectomy or simultaneous knock out of genes that inhibit glucocorticoid secretion (Wang et al., 2012 and reviewed by Heinrichs and Richard, 1999). Furthermore, glucocorticoids and gonadal steroids alter the development of the neural circuits that govern metabolism, adipose tissue distribution, and ingestive behavior (Gao et al., 2007). The importance of adrenal and gonadal steroids is magnified because these hormones play a major role in coordinating ingestive behavior with the environment. Future research should focus on the interactions among hormones, environmental energy, and cues from potential mating partners. Food intake in laboratory rodents is most often measured as the size and frequency of meals. In animals housed in isolation with unlimited food, food intake is affected by at least three important interacting factors 1) sensory signals generated by the interaction of food with the gastrointestinal tract, 2) metabolic consequences of digestion, absorption, and the breakdown of macronutrients (fats, carbohydrates, and proteins) into oxidizable metabolic substrates (mainly glucose and free fatty acids), and 3) hormonal signals that vary with 1 and 2, and some that vary with lipogenesis and adipose tissue cell size. A distributed neural network controls food intake

Fig. 1. The pool of oxidizable metabolic fuels is depicted as the liquid panels A, B, and C. These fuels can be chemically transformed to be stored as glycogen in muscle or lipids in adipose tissue (the tank on the left), and used for maintenance of the reproductive system, all behaviors, and cellular processes (the tree on the right). When energy demands are low and energy intake and storage are high, sufficient levels of oxidizable fuels are available for both survival and reproduction (A). When food is not available, animals hydrolyze and mobilize fuels from their fat stores, and when the availability of fuels is low, the hunger for food is urgent, and the reproductive and immune system can be inhibited to conserve fuels necessary for survival (symbolized by the roots) (B). Mild energetic challenges can inhibit sexual motivation and appetitive sex behavior (symbolized by the leaves), increase hunger, and the response to anorectic or orexigenic hormones without inhibition of the hypothalamic–pituitary–gonadal (HPG) system (symbolized by the tree trunk) (C).

food consumed per unit time by animals housed in isolation. Early endocrinologists discovered that food intake is influenced by stressors, adrenalectomy, and treatment with adrenal steroids (Stevenson and Franklin, 1970). In addition, food intake is influenced by the ovulatory cycle, gonadectomy, and treatment with gonadal steroids (Wade and Zucker, 1970). Since that time, the list has grown to over 40 different chemical messengers that either increase or decrease food intake when administered to rats or mice (Table 1, reviewed by Schneider et al., 2012; Schneider and Watts, 2002). In the last decade, the

Signals from the periphery influence food intake via the ascending visceral afferent pathway (Fig. 2), which projects from many peripheral sensory organs via the vagus nerve to a distributed neural network throughout the brain (reviewed by Grill, 2006, 2010). The process of meal termination begins with sensations generated by gut distension and also by increases in the supply of oxidizable fuels. Some of these sensations are carried to the brain by the vagus nerve. These sensations generate neural and hormonal signals in the gut, liver, or other peripheral organs. Examples of metabolic sensory stimuli include the decrease in hepatic energy status brought about by treatments that block fuel oxidation, deplete adenosine triphosphate (ATP), or decrease its phosphorylation potential. These metabolic manipulations increase food intake, and the increases are blocked by surgical transection of the vagus nerve, a procedure that cuts the neural connections between many peripheral organs (but not from brown or white adipose tissue) and the brain (Friedman et al., 2003; Horn et al., 2004; Ji et al., 2000; la Fleur et al., 2003; Rawson et al., 2003). In addition, the interaction of food with the gut stimulates the secretion of gastrointestinal hormones, including CCK, GLP-I, and peptide YY3-36. Post-ingestive increases in hormones stimulate receptors on vagal afferent neurons in the vagal nodose ganglion. The activated cells in the nodose ganglion send afferent signals to the nucleus tractus solitarius, a.k.a., the nucleus of the solitary tract (NTS), which has reciprocal connections to the area postrema (AP) (e.g., Huo et al., 2007; Powley, 2000). NTS cells send information about peripheral fuel availability and gut distension to many regions in the brain, including the lateral parabrachial nucleus


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Table 1 A partial list of chemical messengers with effects on ingestive behavior and reproductive behavior in representative species from the vertebrate taxa. Central “Orexigenic” Agents

Ingestive Effects

Reproductive Effects

Agouti-related protein (AgRP), HS04, SHU9119 (MCR antagonists)

Increases food intake in fish (Schjolden et al., 2009), birds (Strader et al., 2003), and mammals (Rossi et al., 1998; Stark, 1998), and food hoarding in hamsters (Day and Bartness, 2004)

Inhibits gonadotropin secretion in fish (Zhang et al., 2012), inhibits LH in the presence of estradiol in female rats (Schioth et al., 2001; Watanobe et al., 1999), stimulates LH in male mammals (Stanley et al., 1999), ablation of AgRP gene restores fertility in ob/ob mice (Wu et al., 2012)

Alarin

Increases food intake in male rats (Van Der Kolk et al., 2010)

Stimulates LH secretion in castrated male rats (Van Der Kolk et al., 2010)

β-Endorphin

Increases food intake in fish (de Pedro et al., 1995b) (reviewed in Lin et al., 2000), birds (Deviche and Schepers, 1984; Maney and Wingfield, 1998; Yanagita et al., 2008), and rats (Grandison and Guidotti, 1977; McKay et al., 1981)

Mediates stress-induced suppression of LH in fish (Ganesh and Chabbi, 2013), birds (Sakurai et al., 1986), inhibits LH secretion and sexual performance (Hughes et al., 1987, 1990; Sirinathsinghji et al., 1983), but might also increase sexual motivation in rats (Mitchell and Stewart, 1990; Torii et al., 1999)

Galanin

Increases food intake in fish (De Pedro et al., 1995a; Lin et al., 2000; Nelson and Sheridan, 2006; Volkoff et al., 2005) and rats (Kyrkouli et al., 1990)

Stimulates LH secretion in birds (Hall and Cheung, 1991), steroid-primed rats (Sahu et al., 1987)

Galanin-like peptide (GALP)

Increases food intake in rats (Matsumoto et al., 2002), also decreases food intake in mice (Krasnow et al., 2003)

Stimulates LH secretion in male mice and rats and in estradiol-treated female rats (Krasnow et al., 2003; Matsumoto et al., 2001; Uenoyama et al., 2008)

Gamma aminobutyric acid (GABA)

Might not mediate hyperphagic effects of orexin in fish (Facciolo et al., 2011); increases food intake in rats (Basso and Kelley, 1999)

Increases gonadotropin release in fish (Kah et al., 1992); GABA-BR decreases excitability of mouse GnRH-I neurons (Zhang et al., 2009); GABA-AR excitatory for mouse GnRH-I neurons (DeFazio et al., 2002; Moenter and DeFazio, 2005)

Melanin-concentrating hormone (MCH)

Increases food intake in rats (Presse et al., 1996), but decreases food intake in fish (Shimakura et al., 2008)

Inhibits LH secretion in rats (Tsukamura et al., 2000a)

Neuropeptide Y (NPY)

Increases food intake in fish (de Pedro et al., 2000; Lopez-Patino et al., 1999), frogs (Crespi et al., 2004), snakes (Morris and Crews, 1990), birds (Strader and Buntin, 2001), rats (Stanley and Leibowitz, 1984) and food hoarding in hamsters (Dailey and Bartness, 2009)

Increases gonadotropin release in fish (Peng et al., 1993), inhibits steroid biosynthesis in frogs (Beaujean et al., 2002), inhibits sex behavior in snakes (Morris and Crews, 1990), inhibits LH in the absence of estradiol, stimulates LH in the presence of estradiol in rats (Crowley et al., 1985; Sahu et al., 1987) (Sahu et al., 1987), inhibits sex behavior in rats (Ammar et al., 2000)

Orexin/hypocretin

Increases food intake in fish (Lin et al., 2000; Volkoff et al., 1999; Volkoff et al., 2005), and rats (Sakurai et al., 1998), but not in birds (da Silva et al., 2008)

Inhibits spawning in fish (Hoskins et al., 2008), inhibits LH in rats with little or no estradiol (Furuta et al., 2002), stimulates LH in rats with high levels of estradiol (Pu et al., 1998)

Gonadotropin inhibiting hormone (GnIH)

Increases food intake in birds (Tachibana et al., 2005), mice, sheep, and monkeys (Clarke et al., 2012; Johnson et al., 2007; Tachibana et al., 2005)

Inhibits GnRH and LH secretion and sex behavior in fish (Moussavi et al., 2012), birds (Bentley et al., 2006; Satake et al., 2001) and blocks the LH surge in sheep and inhibits LH secretion in rats and female hamsters (Bentley et al., 2006; Johnson et al., 2007; Kriegsfeld et al., 2006; Smith et al., 2008)

Peripheral “Orexigenic” Hormones

Ingestive Effects


Corticosteroids

Chronically elevated levels increase food intake in fish (Bernier et al., 2004), amphibians (Crespi et al., 2004), birds (Astheimer et al., 1992), and rats (Hamelink et al., 1994; McLaughlin et al., 1987; Stevenson and Franklin, 1970)

Inhibits a wide array of reproductive parameters in fish including parental behavior (Carragher et al., 1989; O'Connor et al., 2009) reviewed by (Milla et al., 2009), inhibits steroid synthesis and spermatogenesis in amphibians (Moore and Zoeller, 1985; Moore and Jessop, 2003), inhibits sex behavior in snakes (Lutterschmidt et al., 2004; Moore and Jessop, 2003), stimulates gonadotropin secretion at low doses in birds (Etches and Cunningham, 1976), inhibits HPG function at chronically high doses in birds (Etches et al., 1984), and mammals (Vreeburg et al., 1988)

Ghrelin (gut)

Increases food intake in fish (goldfish and tilapia), but decreases food intake in rainbow trout (Jonsson, 2013; Jonsson et al., 2010), decreases food intake in birds (Kaiya et al., 2009), increases food intake in rats and mice (Tschop et al., 2000; Wren et al., 2000) and food hoarding in Siberian hamsters (Keen-Rhinehart and Bartness, 2005)

Stimulates LH release from fish (Grey et al., 2010), inhibits GnRH, LH secretion and sex behavior in rats and mice (Fernandez-Fernandez et al., 2004; Furuta et al., 2001; Shah and Nyby, 2010)

Insulin (pancreas)

Chronically elevated levels increase body weight, adiposity, and food intake in birds (Nir and Levy, 1973), rats (Booth and Brookover, 1968; Friedman, 1977; Friedman et al., 1982; Houpt, 1974)

Systemic treatment inhibits LH secretion at doses that increase food intake in hamsters not allowed to overeat (Wade et al., 1991), inhibits LH secretion in sheep treated peripherally with saline but not with glucose (Clarke et al., 1990)

Motilin (gut)

Increases food intake in fasted rats (Garthwaite, 1985)

Inhibits LH secretion in rats (Tsukamura et al., 2000b)

Progesterone (gonads, adrenals)

Reverses the weight reducing effects of estradiol on body weight and food intake in rodents (Hervey and Hervey, 1966, 1969; Zucker et al., 1972)

Synergizes with estradiol to stimulate female sexual performance in rats (Dempsey et al., 1936), enhances estradiol feedback on LH in female rats (Chappell and Levine, 2000), mimics testosterone in male rats (Witt et al., 1995) (continued on next page)

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Table 1 (continued) Peripheral “Orexigenic” Hormones Central “Orexigenic” Agents

Ingestive Effects


Testosterone (gonads, adrenals)

Increases food intake and growth in rats (Siegel et al., 1981)

Stimulates sexual motivation in females (de Jonge et al., 1986; Everitt and Herbert, 1970) and sexual performance in male rats (Davidson, 1966; Davidson and Bloch, 1969)

Central “Anorectic” Agents

Ingestive Effects


α-Melanocyte stimulating hormone (a-MSH), melanotan-II (MT-II), PT-141

Decreases food intake in fish (Kang et al., 2011; Schjolden et al., 2009), amphibians (Carpenter and Carr, 1996), birds (Kawakami et al., 2000; Tachibana et al., 2007), and rats (Vergoni et al., 1986), and food hoarding in Siberian hamsters (Keen-Rhinehart and Bartness, 2007a; Shimizu et al., 1989)

Enhances electric organ discharge in electric fish (Markham et al., 2009), stimulates LH secretion and sex behavior in rats (Alde and Celis, 1980; Thody et al., 1981)

Cocaine and amphetamine-regulated transcript (CART)

Decreases food intake in fish (Volkoff et al., 2005), birds (Tachibana et al., 2003), rats (Kristensen et al., 1998)

Stimulates GnRH secretion in rats (Lebrethon et al., 2000; Parent et al., 2000)

Cholecystokinin (CCK)

Decreases food intake in fish (Himick and Peter, 1994; Volkoff et al., 2005), birds (Tachibana et al., 2012), rats (Gibbs et al., 1973) and food hoarding in Siberian hamsters (Bailey and Dela-Fera, 1995; Figlewicz et al., 1989; Teubner and Bartness, 2010)

Stimulates GnRH and LH secretion in rats (Ichimaru et al., 2003; Kimura et al., 1983) CCK in the medial preoptic areas is required for estradiolinduced lordosis in rats (Dornan et al., 1989; Holland et al., 1997)

Corticotropin releasing hormone (CRH)

Decreases food intake in fish (De Pedro et al., 1993; Matsuda et al., 2008), amphibians (Crespi et al., 2004), birds (Denbow et al., 1999; Furuse et al., 1997), rats (Heinrichs and Richard, 1999; Levine et al., 1983; Morley and Levine, 1982; Negri et al., 1985) and food hoarding in rats (Cabanac and Richard, 1995) reviewed by (Carr, 2002)

Inhibits spawning in fish (Mousa and Mousa, 2006), inhibits LH secretion and lordosis in rats (Olster and Ferin, 1987) and sex behavior in Syrian hamsters (Jones et al., 2002)

Dopamine (DA)

Decreases food intake in fish (Leal et al., 2013), rats (Heffner et al., 1977), increases food hoarding in rats (Borker and Mascarenhas, 1991; Kelley and Stinus, 1985), and reward (Wise, 2004)

Inhibits gonadotropin secretion in fish (Omeljaniuk et al., 1989), stimulates sexual arousal, motivation and reward in birds (Cornil et al., 2005), rats and hamsters (Agmo and Picker, 1990; Meisel and Mullins, 2006)

Glucagon-like peptide (GLP-I)

Decreases food intake in fish (Silverstein et al., 2001), birds (Tachibana et al., 2006), rats (Turton et al., 1996)

Stimulates LH secretion (Beak et al., 1998)

Gonadotropin releasing hormone (GnRH I or II)

Decreases food intake in fish (Hoskins et al., 2008; Nishiguchi et al., 2012), and female musk shrews (Kauffman and Rissman, 2004b)

Stimulates LH secretion in fish (Moussavi et al., 2012), birds (Chowdhury and Yoshimura, 2004), stimulates LH secretion and sex behavior in amphibians and reptiles (Alderete et al., 1980; Licht et al., 1984), rats and sheep and sex behavior in shrews and mice (Kauffman and Rissman, 2004a; Kauffman et al., 2005) (Temple et al., 2003) (Moss and McCann, 1975) (Clarke and Cummins, 1982)

Insulin-like Growth Factor-1 (IGF-I in CNS)

ICV treatment decreases food intake in diabetic, but not normal rats (Lu et al., 2001), required for post-fast hyperphagia in rats (Todd et al., 2007)

Restores LH surge amplitude in middle-aged rats (Todd et al., 2010), required for the LH surge, estrous behavior, estrous cycles in rats (Etgen and Acosta-Martinez, 2003; Quesada and Etgen, 2002; Todd et al., 2007), and for sex behavior in rats (Etgen and Acosta-Martinez, 2003)

Kisspeptin

Decreases food intake in mice (Stengel et al., 2011)

Stimulates GnRH and LH secretion in fish (Moussavi et al., 2012; Tena-Sempere et al., 2012), stimulates testicular expression of ER-a in frogs (Chianese et al., 2013), rats (Gottsch et al., 2004; Irwig et al., 2004)

Norepinephrine

Decreases food intake in birds (Denbow, 1983) and stimulates food intake in rats (Ritter and Epstein, 1975)

Inhibits LH secretion in rats (Iwata et al., 2011), stimulates sex behavior in birds (Cornil et al., 2005) and rats (Nock and Feder, 1979)

Oxytocin

Decreases food intake in birds (Jonaidi et al., 2003), rats (Olson et al., 1991)

Stimulates GnRH and LH secretion sex behavior in rats (Rettori et al., 1997; Whitman and Albers, 1995)

Secretin (move to VIP)

Decreases food intake in rats (Cheng et al., 2011a)

Stimulates LH secretion in rats (Babu and Vijayan, 1983)

Serotonin (5HT)

Decreases food intake in birds (Denbow et al., 1982), rats (Blundell, 1977)

Stimulates LH in the presence of estradiol in rats (Coen and MacKinnon, 1979) inhibits LH secretion in the absence of estradiol in rats (Coen et al., 1980) (Koh et al., 1984)

Thyrotropin releasing hormone

Decreases food intake in rats (Vijayan and McCann, 1977) and Siberian hamsters (Steward et al., 2003)

Stimulates LH secretion in pituitary in vitro not in vivo in rats (Fujihara and Shiino, 1983), and indirectly by effects on thyroid hormones in rats (Barrett et al., 2007)

Urocortin

Decreases food intake in fish, amphibians, birds, and rats (Spina et al., 1996)

Stimulates LH secretion in ewes (Holmberg et al., 2001), inhibits LH secretion in rats (Li et al., 2005; Nemoto et al., 2010), directly inhibits Leydig cell function in rats (Rivier, 2008)

Peripheral “Anorectic” Hormones

Ingestive Effects


Adiponectin (adipocytes)

Decreases food intake in rats (Bassi et al., 2012), increases food intake in mice (Kubota et al., 2007), decreases body weight and increases energy expenditure, insulin sensitivity, and ffa oxidation without effect on food intake in rats (Fruebis et al., 2001; Qi et al., 2004)

Implicated in embryo implantation and fetal development in pigs and women (Palin et al., 2012), inhibits ovarian steroidogenesis in cows (Lagaly et al., 2008), inhibits GnRH and LH in rats and in GnRH cell cultures (Cheng et al., 2011b; Lu et al., 2008)


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Table 1 (continued) Peripheral “Anorectic” Hormones Central “Orexigenic” Agents

Ingestive Effects


Adrenocorticotropic hormone (ACTH)

Decreases food intake in rats (Vergoni et al., 1986)

Stimulated LH secretion in female rats inhibits LH secretion in male rats (indirect via adrenals) (Mann et al., 1985; Putnam et al., 1991)

Bombesin (gut)

Decreases food intake in fish (Volkoff et al., 2005), birds (Savory and Hodgkiss, 1984; Tachibana et al., 2010), and rats (Gibbs et al., 1979)

Stimulates LH secretion in rats (Babu and Vijayan, 1983)

Cholecystokinin (gut)

Decreases food intake in fish (Volkoff et al., 2005), birds (Savory and Hodgkiss, 1984), and hoarding in Siberian hamsters (Gibbs et al., 1973; Qian et al., 1999; Teubner and Bartness, 2010)

Stimulates LH secretion in rats (Perera et al., 1993); inhibits lordosis duration in rats (Mendelson and Gorzalka, 1984), but see central effects in Table 1.1

Estradiol (gonads, adrenals, adipocytes, brain)

Decreases body weight and food intake in fish (Leal et al., 2009), lizards (Shanbhag and Prasad, 1992), obese but not lean hens (Jaccoby et al., 1995; Jaccoby et al., 1996), rats (Nunez et al., 1980; Roepke et al., 2010; Roy and Wade, 1977; Zucker, 1969) and food hoarding in Syrian hamsters (Klingerman et al., 2010)

Stimulates sexual receptivity and vitellogenesis and has negative feedback on LH in fish, frogs, lizards and birds (Chakraborty and Burmeister, 2009; Cheng, 1973; Crews, 1975; Gavaud, 1986; Gibbins and Robinson, 1982a,1982b; Licht et al., 1985; Liley, 1972; Mason and Adkins, 1976; McCreery and Licht, 1984; Redshaw et al., 1969; Shanbhag and Prasad, 1992; Yu et al., 1981), and stimulates LH surges in female rats (Chazal et al., 1974) and female sex behavior in rats (Dempsey et al., 1936; Powers, 1970), increases courtship and sexual behaviors in hamsters (Ciaccio and Lisk, 1973; Ciaccio et al., 1979; Takahashi et al., 1985)

Insulin (ICV treatment)

Decreases food intake in rats and baboons (Chavez et al., 1995; Woods et al., 1979)

Stimulates LH pulses in rats, pigs, and diabetic sheep and non diabetic ovariectomized sheep (Bucholtz et al., 2000; Cox et al., 1987; Daniel et al., 2000; Kovacs et al., 2003; Miller et al., 1995), inhibits LH in ad libitum-fed ovariectomized lambs (Hileman et al., 1993)

Insulin-like growth factor

Increases body weight gain at superphysiological concentrations (Gruaz et al., 1997)

Does not accelerate reproductive development in female rats (Gruaz et al., 1997)

Leptin (adipocytes, liver)

Decreases body weight, adiposity, and food intake in fish (Crespi and Denver, 2006; Murashita et al., 2008), and mice (Campfield et al., 1995; Halaas et al., 1995; Pelleymounter et al., 1995) and food hoarding in Syrian hamsters (Buckley and Schneider, 2003) while increasing energy expenditure

Mammalian leptin increases gonadotropin secretion in fish (Peyon et al., 2003; Peyon et al., 2001), delays the summertime regression of the testes in lizards (Putti et al., 2009), delays fasting-induced cessation of egg laying, follicular regression, and follicle wall apoptosis in chickens (Paczoska-Eliasiewicz et al., 2003), reverses the effects of metabolic challenges on gonadotropin secretion in mice (Ahima et al., 1996; Barash et al., 1996), estrous cycles, and steroid-induced sex behavior (the latter only in ad libitum fed female hamsters) (Schneider et al., 2007; Schneider et al., 1997; Wade et al., 1997)

Resistin

Transient decreases in food intake in rats (Tovar et al., 2005)

Promotes ovarian steroid secretion in rats (Maillard et al., 2011)

(PBN), the hypothalamus, and the basal forebrain (Fig. 2) (Huo et al., 2007; Powley, 2000). The arcuate perspective In addition, other peripheral signals such as insulin, leptin, and ghrelin can influence food intake by action on receptors in the hypothalamus as well as other brain areas. In terms of the number of articles published, most work in laboratory rodents has emphasized the arcuate nucleus of the hypothalamus (Arc) as a primary controller of ingestive behavior in response to insulin, leptin, and ghrelin (depicted in Fig. 3; reviewed by Barsh and Schwartz, 2002; Crowley et al., 2001; Schwartz and Porte, 2005; Zigman and Elmquist, 2003). Keeping in mind that the number of papers published on a nucleus is a poor judge of its importance, within the Arc, two well-studied orexigenic peptides are found, often within the same cell body: NPY and agouti-related protein (AgRP). Orexigenic effects of NPY and AgRP are thought to be counterbalanced by the anorectic peptides of the Arc: cocaine and amphetamine-regulated transcript (CART) and α-melanocyte stimulating hormone (α-MSH), the latter being a cleavage product of the proopiomelanocortin (POMC) gene (reviewed by Schwartz and Porte, 2005; Zigman and Elmquist, 2003). Both α-MSH and AgRP act via melanocortin receptors (especially melanocortin receptor 4 (MCR4)); the anorectic peptide α-MSH is an agonist and the orexigenic peptide

AgRP is an antagonist. A relatively simple hypothesis holds that NPY/ AgRP and POMC/CART peptides are responsive to gastric signals mediated by peripheral hormones. There are receptors for peripheral hormones such as leptin, insulin, and ghrelin on Arc cells, including NPY/ AgRP and POMC/CART cells. Effects of these peripheral hormones on NPY/AgRP and POMC/CART gene transcription are consistent with their effects on food intake (Coppari et al., 2005; Perello et al., 2012; Williams et al., 2010). For example, leptin treatment decreases meal size, binds to leptin receptor (LepR) on both NPY/AgRP and POMC/ CART cells, increases cellular activation and gene transcription of POMC precursor peptide, and the effects of leptin are blocked by treatment with antagonists to the MC4 receptor. Peripheral hormones affect not only the release of neuropeptides but also the synaptic input into NPY/AgRP and POMC/CART cells (reviewed by Briggs and Andrews, 2011; Eckel, 2011; Gao et al., 2007; Gyengesi et al., 2010; Zigman and Elmquist, 2003). Recent evidence suggests that AgRP cells are uniquely positioned so as to receive signals from peripheral hormones that reflect energy flux. During the development of obesity and high-fat diet-induced leptin resistance, AgRP cells might act as sentinels that monitor decreases in plasma leptin concentrations. AgRP neurons are the predominant cell type situated outside the blood–brain barrier, and they are the first to respond to low levels of circulating leptin. Furthermore, they are the first to develop leptin resistance in response to a small increase in

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LH

PVN PBN

LH

DVM NTS

Arc

Vagus nerve Adipose tissue Leptin

ATP

3V

rv i

Pancreas

LH

LH

PVH

Ce

CCK GLA I Ghrelin

Arc

ca l

Fuels

Insulin

NTS OC

sp i n e C NS afferents

OC

PVH

3V Arc

Distension

Liver Stomach and intestines

3V

LH 3V

PVH

Arc

MCR YR

Fig. 2. A diagram of the distributed neural control of ingestive behavior, which involves peripheral detection of signals that come from ingestion of food and the overall disposition of metabolic fuels in the liver, muscle, and adipose tissue. These signals are sent neurally and hormonally via the caudal hindbrain to relay stations in the mid- and forebrain. Modified from Schwartz et al., 2000.

MCR

POMC CART

YR

NPY AgRP

blood leptin concentrations (Olofsson et al., 2013). Changes in ingestive behavior in response to deletion of the gene that encodes NPY, POMC, or AgRP suggests that the most critical neuropeptide for adult appetite and food intake is AgRP. NPY knockout mice show no effect on body weight or mild obesity, POMC or MCR knockout mice develop obesity, but mice with ablation of the AgRP gene in adulthood starve to death (Cansell et al., 2012; Gropp et al., 2005; Luquet et al., 2005; Segal-Lieberman et al., 2003; Zemel and Shi, 2000). It would be very instructive to know whether these sentinel AgRP cells respond to changes in the availability of oxidizable metabolic fuels. Evidence that deemphasizes the arcuate in control of food intake Despite the pervasive “arcuate perspective,” the Arc is neither necessary nor sufficient for control of consummatory ingestive behavior and energy balance (Grill, 2010). Neonatal ablation of NPY/AgRP Arc cells in mice fails to disrupt food intake and energy balance at any time during development, and does not prevent hyperphagia that occurs in response to inhibition of glucose oxidation (Luquet et al., 2005, 2007). Neonatal Arc ablation fails to block seasonal changes in food intake and body weight in Siberian hamsters (Ebling et al., 1998). Selective destruction of AgRP cells in the Arc in adulthood fails to disrupt food intake when the lesioned animals are treated with gamma-aminobutyric acid (GABA) agonists infused directly into the PBN (Wu et al., 2009). Thus, various other peptide networks can modulate food intake, and these are sufficient to compensate for absence of the Arc when the ablation occurs early in development or when other peptides are replaced in extra-Arc brain areas. Furthermore, a multitude of hormones affect food intake via actions outside the Arc or even outside the hypothalamus. Deletion of LepR, estrogen receptor, or treatment with various orexigenic peptides increases food intake when applied to various extra-Arc regions, to name just a few examples (Dhillon et al., 2006;

Fuels

Fig. 3. A diagram of the “arcuate perspective” of control of food intake. The arcuate nucleus of the hypothalamus contains cells that synthesize and secrete orexigenic, anabolic peptides neuropeptide Y (NPY) and agouti-related protein (AgRP) as well as anorectic, catabolic peptides, cocaine and amphetamine-regulated transcript (CART) and alphamelanocyte-stimulating hormone (α-MSH), the latter being a cleavage product of the proopiomelanocortin (POMC) gene. According to the arcuate perspective, body weight is regulated because NPY/AgRP and POMC/CART peptides are responsive to gastric signals mediated by peripheral hormones such as leptin, ghrelin and/or insulin. Modified from Schwartz et al., 2000.

Faulconbridge et al., 2005; Musatov et al., 2007). Metabolic and hormonal control of consummatory ingestive behavior occurs in chronic decerebrate animals, animals in which the communication between the caudal hindbrain and the hypothalamus has been completely severed by surgical transection of the brain at the border of the posterior diencephalon and the anterior mesencephalon (reviewed by Grill and Hayes, 2009). Decerebrate and neurologically-intact rats do not differ significantly in their responses to taste stimuli and hormonal inhibitors of ingestive behavior. These experiments provide unequivocal evidence that control of consummatory ingestive behavior can occur without descending projections from the hypothalamus, including the Arc (reviewed by Grill and Hayes, 2009).


The neural architecture that provides visceral input to the caudal hindbrain has been identified, and this network controls food intake without input from the forebrain. To be more specific, there is a direct neural connection between vagal afferent NTS neurons and the preoral motor neurons of the parvocellular and intermediate reticular formation of the hindbrain (Kinzeler and Travers, 2008; Nasse et al., 2008; Travers and Hu, 2000; Travers and Travers, 2007; Travers et al., 2010). This pathway is necessary and sufficient for consummatory ingestive behavior, i.e., food intake (reviewed by Grill, 2010). By contrast, the neural architecture connecting the Arc to the motor program for chewing and swallowing is still unknown to the best of our knowledge. One major challenge lies in understanding the integration of the peripheral signals with the caudal hindbrain, Arc, and the seemingly endless list of chemical messengers known to affect food intake in laboratory rats housed separately with ad libitum access to food. To add to this complexity, functional populations of NPY and melanocortin receptors reside in extra-hypothalamic and extra-Arc brain areas, and these areas have reciprocal connections to the Arc (Faulconbridge et al., 2005; Grill et al., 1998). From the Arc, NPY/AgRP neurons project to the paraventricular nucleus of the hypothalamus (PVH), ventromedial nucleus of the hypothalamus (VMH), dorsomedial nucleus of the hypothalamus (DMH), and the lateral hypothalamic area (LHA). From there cells project to the PBN, NTS, and the dorsomotor nucleus of the vagus (DMV), areas that control the motor movements of ingestion (reviewed by Zheng et al., 2010). Further complexity is afforded by the dopamine and opiate systems of the nucleus accumbens, ventral tegmental area (VTA), and parts of the amygdala. These areas are implicated in control of hunger motivation, learning, reward, reinforcement, and the willingness to expend effort to gain access to calorically dense foods (reviewed by Abizaid, 2009). These areas contain receptors for and detect levels of ghrelin, leptin, and other peripheral hormones (reviewed by Abizaid, 2009). In summary, ingestive behavior is influenced by a distributed neural network that encompasses most of the brain and periphery. The mind boggling array of chemical messengers that influence food intake (Table 1) might suggest multiple, redundant neuroendocrine mechanisms, all designed to keep body weight at some optimum level. As illustrated in Table 1, however, all of these chemical messengers have documented effects on reproductive physiology and/or behavior and other processes not covered by this review. An evolutionary perspective suggests that these neuropeptide systems were not designed, but rather molded by their link to survival and reproductive success in environments where energy supply and demand fluctuated. It might be more productive to focus on how these mechanisms influence multiple behaviors, not just food intake, but other aspects of ingestion and reproduction. Experiments that include observations of appetitive behaviors suggest that the systems depicted in Figs. 2 and 3 rank behavioral priorities that optimize reproductive success in energetically labile environments. Appetitive ingestive behavior Historical perspective on appetitive behavior and motivation Ingestive behavior is more complex than the amount of food eaten, just as reproductive behavior is more complex than the act of copulation. Swallowing food is one final step in a longer sequence of behaviors that determine not only whether an animal will maintain an attractive physique, but whether it will survive to reproduce. Appetitive behaviors deserve attention because they provide an outward expression of internal motivation. We can ask our experimental subjects what they desire and how much they desire it; but human subjects often lie or exaggerate, and nonhuman animals often lack the means to describe their motivations to us. Furthermore, appetitive behaviors provide insight into mechanisms that alter behavioral priorities.

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In the broadest sense, appetitive behaviors are defined as those that bring animals in close contact with a goal, such as food or a potential mating partner (Craig, 1917; Everitt, 1990; Lorenz, 1950; Sherrington, 1906). Appetitive sex behaviors bring animals in contact with opposite-sex conspecifics, and some appetitive sex behaviors induce arousal in the potential mating partner (Everitt, 1990; Johnston, 1974, 1977; Lisk et al., 1983). Appetitive ingestive behaviors bring animals in close contact with food, and some appetitive ingestive behaviors ensure that energy might be available in the form of a food cache to be eaten during future energetic challenges (Bartness et al., 2011; Vander Wall, 1990). Appetitive behaviors are partially separable in time and space from consummatory behaviors, and those most useful for scientific study are those that occur hours or days ahead of eating food or copulating. Appetitive behaviors precede or follow the final act of consummation. Many of these behaviors are easily quantified. In order to gauge hunger motivation, investigators have made use of the fact that hungrier animals are apt to initiate meals sooner, consume an unpalatable substance, make more effort to gain access to food, and hoard food in their home or burrow. The importance of the appetitive-consummatory (motivationperformance) dichotomy lies in the fact that different aspects of ingestive behavior are controlled by different chemical messengers, acting on different neural substrates, and stimulated by different environmental stimuli (reviewed by Ball and Balthazart, 2008 with emphasis on sex behavior). With regard to ingestive behavior, the most obvious example is that consummatory, but not appetitive ingestive behavior is controlled in the caudal hindbrain (Grill and Kaplan, 1990; Travers et al., 2010). Hormonal and metabolic control of intra-oral food intake remains intact in chronic decerebrate animals, though these animals do not approach a food source or engage in operant responding for a food reward (Grill and Hayes, 2009; Grill and Kaplan, 1990, 1992, 2001, 2002). Another example is that the brain areas that control predatory hunting differ from those that control food intake per unit time. Behaviors such as stalking prey, and approach to food and water, differ from those involved in the final killing attack (Waldbillig, 1975). Treatment with the central peptide orexin stimulates predatory hunting. Projections from the periaqueductal gray to lateral hypothalamic orexin cells are critical for predatory hunting, although these cells are not necessary for normal locomotion or food intake (Mota-Ortiz et al., 2012). Another example of the appetitive-consummatory dichotomy occurs with regard to estradiol-induced female sex behavior. In female mice and rats, the final, consummatory act of mating, lordosis, is stimulated by sensory cues from the males and high endogenous levels of estradiol followed by progesterone. Lordosis requires classical estradiol action, i.e., estradiol binding to intracellular estrogen receptor-alpha (ER-α), and binding of the steroid-receptor complex to the estrogen response element (ERE) on target genes, which in turn leads to changes in transcription. Nonclassical estradiol action can potentiate this effect without ERE signaling, but nonclassical estradiol action is not sufficient for the occurrence of lordosis (Kow and Pfaff, 2004). Appetitive sex behavior, by contrast, is stimulated by estradiol even in animals that are genetically engineered to lack classical estrogen receptor action. Nonclassical, ERE-independent steroid signaling is sufficient for estradiol-induced appetitive sex behavior whereas classical, ERE-dependent steroid action is required for estradiol-induced consummatory sex behavior (McDevitt et al., 2008). Similar dissociation between opioidergic mechanisms controlling appetitive and consummatory aspects of sex behavior are seen in quail (Riters et al., 1999). Yet another example of different mechanisms controlling different aspects of behavior is illustrated by dopaminergic control of incentive vs. the opioidergic control of palatability. The amount of effort an individual will expend to gain access to food is affected by treatments that deplete dopamine in relatively large areas of the nucleus accumbens (Mahler and Berridge, 2009; Salamone et al., 2009). Affective facial expressions that occur in response to sweet tastes are stimulated by treatments only in very small hedonic “hot spots” in the nucleus

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accumbens shell and other brain areas (Grill and Norgren, 1978; Pfaffmann et al., 1977; Steiner et al., 2001). In nature, incentive, palatability, appetite, and consumption covary, but in the laboratory, they can be dissociated because they are controlled by different neuropeptides and by separate but sometimes overlapping neural circuits. Together all of the above studies emphasize different chemical messengers and different brain areas involved in appetitive and consummatory behaviors. Some of the more entrenched ideas in the history of ingestive behavior research are difficult to demonstrate. For example, treatments that modify meal frequency have been thought to control “hunger” and have been labeled as “appetitive.” Those that influence the size of meals were thought to control “satiety” and labeled as “consummatory” (Baird et al., 2006; Blundell, 1986; DiBattista and Sitzer, 1994; Foltin, 2005; Kowalski et al., 2004; Leibowitz and Alexander, 1991). In rats, consummatory behavior is measured as intraoral intake (voluntary swallowing of a solution that is directly infused into the oral cavity at an experimenter-determined rate and time of onset). Appetitive behavior is measured as the number of approaches to food. Unfortunately, in these types of experiments, it is impossible to know where the appetitive behavior ends and the consummatory behavior begins. It is therefore difficult to say whether a particular peptide influence motivation, performance, or both. Early investigators argued that NPY affects appetitive not consummatory ingestion because intracerebroventricular (ICV) treatment with NPY fails to increase intraoral intake of 0.1 M sucrose, although NPY treatment significantly increases the intake of this same solution when offered to those rats from a bottle spout (Seeley et al., 1995). A reasonable interpretation is that NPY's primary effects are on the appetitive aspects of ingestion, the motivation to go and seek food (Ammar et al., 2000, 2005). By contrast, other results show that NPY can decrease or increase intraoral intake. After many years of studying this phenomenon, and accounting for repeated experience, dose of NPY, age, sex, and species, it appears that NPY increases both appetitive and consummatory aspects of ingestion (Benoit et al., 2005), and that intraoral intake and approaches to a bottle of sucrose are of limited value in distinguishing between motivation and performance. If we wish to study the separate neuroendocrine mechanisms for appetitive and ingestive behaviors, we need to examine behaviors other than those directly involved with food or fluid intake. Paradoxically, studying behavior in the more complex natural environment can simplify and clarify the functional significance of the underlying mechanisms. Food hoarding If we look beyond the consummatory act of eating food, we find empirical tests of appetitive behavior that are not confounded by the ability to perform the consummatory behavior. Food hoarding is an appetitive behavior characterized by foraging for food and carrying it from the source to a home or burrow where it is stored for a period of time before it is consumed (Vander Wall, 1990). In rats, food hoarding is utilized as a proxy for hunger motivation. In these experiments, rats are limited in the time and amount of food they eat per day, which induces body weight loss. The experimenter determines the body weight at which the rats increase their food hoarding. Using this method, it has been demonstrated that hunger motivation is decreased by adrenalectomy and corticotropin-releasing hormone (CRH) treatment, and increased by food deprivation, housing at cold ambient temperatures, and peripheral treatment with low doses of glucocorticoids (Cabanac and Richard, 1995; Fantino and Cabanac, 1984; Gosselin and Cabanac, 1997; Michel and Cabanac, 1999). Food hoarding in rats is not influenced by NPY treatment or treatment with high doses of glucocorticoids (Cabanac et al., 1997; Michel and Cabanac, 1999). In response to energetic challenges, hamsters increase food hoarding without increases in food intake. In this regard, human beings (Homo sapiens) share more in common with hamsters than they do with rats or mice. After a period of fasting or food restriction, rats and mice

typically increase their food intake above their normal ad libitum-fed baseline level, and these increases in food intake are as large or larger than increases in food hoarding (Hill et al., 1984; Kavaliers and Hirst, 1986; Zhao and Cao, 2009). Hamsters, voles, and humans, by contrast, respond to energetic challenges with reliable increases in food hoarding accompanied by little or no increase in food intake. Contrary to popular belief, human beings, unlike laboratory rats and mice, do not reliably overeat after a period of fasting (reviewed by Bartness et al., 2011). Some investigators reported no post-fast increases in food intake (AlHourani and Atoum, 2007; Hetherington et al., 2000; Khatib and Shafagoj, 2004), whereas others reported only slight increases (20% or less over baseline). People do, however, increase grocery shopping; the longer the time since the last meal, the more groceries are purchased (Beneke and Davis, 1985; Beneke et al., 1988; Dodd et al., 1977; Mela et al., 1996). In humans and hamsters, appetitive aspects of ingestion, such as food hoarding, are highly sensitive to energetic challenges and can increase independent of the “consummatory” act of eating. After a period of food deprivation, when food becomes freely available, Syrian, Turkish, and Chinese hamsters fail to increase food intake, and Siberian hamsters and Brandt's voles show little or no increases in food intake (Bartness and Clein, 1994; Bartness et al., 1995; Billington et al., 1984; Rowland, 1982; Silverman and Zucker, 1976). Rather than compensate for the energy deficits by overeating, these species show massive increases in food hoarding. Of these experimental models for the study of appetitive behaviors, most progress has been made in the study of food hoarding in Siberian hamsters, a species with large cheek pouches adapted for carrying food (reviewed by Bartness et al., 2011). Increases in food hoarding in Siberian hamsters are far greater than increases in food intake in response to food deprivation, diet dilution, lipectomy, treatment with orexigenic hormones, and neuropeptides including NPY, neuropeptide Y receptor 1 (Y1R) agonists, AgRP, and ghrelin (Bartness, 1997; Bartness and Clein, 1994; Dailey and Bartness, 2008, 2009; Day and Bartness, 2004; Day et al., 1999, 2005; Keen-Rhinehart and Bartness, 2005, 2007b; Wood and Bartness, 1996, 1997). Food hoarding in Siberian hamsters is decreased by treatment with leptin, CCK, antagonists to the Y1R, and melanotan II (MT-II), a synthetic analog of α-MSH (Keen-Rhinehart and Bartness, 2007a, 2008; Teubner and Bartness, 2010). Food hoarding is controlled by neural circuits that differ from those that control food intake. Lesions of the Arc attenuate NPY-induced increases in food intake but do not attenuate NPY-induced increases in food hoarding in Siberian hamsters (Dailey and Bartness, 2010). Food intake is increased by treatment with Y5R but not Y1R agonists, whereas food hoarding is increased by treatment with Y1R but not Y5R agonists (Day et al., 2005). In addition, circuits that control food intake are activated more rapidly than those that influence food hoarding. Teubner et al. (2012) elegantly exploited this finding to determine which brain areas are activated concomitant with rapid increases in consummatory behavior and which were activated concomitant with the slower increases in appetitive behavior. Food hoarding in Siberian hamsters is significantly increased after ICV co-injection of NPY and AgRP at doses that are not effective when administered separately. This suggests that NPY and AgRP interact to control food hoarding, possibly at the intercellular level. Combined treatment with NPY + AgRP stimulates increases in food intake as early as 1 h after injection, whereas the same treatment does not increase food hoarding until 4–14 h after injection. At the early time point when food intake is elevated, increases in cellular activation occur in the PVH and perifornical area (PFA). At the later time point when hoarding is elevated, increases in cellular activation occur in these same areas plus in the central nucleus of the amygdala (CeA) and the subzona incerta (SZI). Despite the dogma that all changes in ingestive behavior involve the Arc, there is no increase in cellular activation in the Arc with co-infusion of subthreshold doses of NPY + AgRP that significantly increases food intake and hoarding in Siberian hamsters. There are no significant increases in cellular activation in the VMH, Arc, AP, or NTS at either time point. These


data provide correlational evidence for discrete locations in control of appetitive and consummatory behavior. Specifically, AgRP might have synergistic effects on NPY-induced hoarding in the CeA and SZI (Teubner et al., 2012), brain areas with Y1R as well as MC4R receptors (Lyons and Thiele, 2010; Vaughan et al., 2011). These data reveal two new brain areas (CeA and SZI) that might be particularly important for hunger motivation and their expression via appetitive behaviors. It will be interesting to determine the roll of CRH as well as other chemical messengers that are found in these two brain areas. Food hoarding is an appetitive behavior that might elucidate mechanisms involved in the incentive, drive, or motivation to shop for groceries. Some Mongolian gerbils (Meriones unguiculatus) for instance hoard food whereas others never hoard food (nonhoarders), and there are interesting differences among these two groups in brain areas involved in motivation (Yang et al., 2011). The act of hoarding in ad libitum-fed gerbils is accompanied by increased cellular activation in the nucleus accumbens, VTA, and LHA, particularly in tyrosine hydroxylase (TH)containing cells. TH is the rate-limiting enzyme for dopamine conversion (Yang et al., 2011). Food deprivation increases food hoarding in high-hoarding gerbils, and also in some of the gerbils that were previously classified as nonhoarders. In this latter group of former nonhoarders, food deprivation-induced increases in hoarding do not increase cellular activation in the VTA (Yang et al., 2011). Food-deprived Brandt's voles (Lasiopodomys brandtii) also increase food hoarding when provided the opportunity (Zhang et al., 2011). Both increased food hoarding and intake are associated with increases in cellular activation in TH-containing and orexin cells in brain areas including the nucleus accumbens and VTA (Zhang et al., 2011). The association between VTA cellular activation in dopaminergic cells and spontaneous, but not food deprivation-induced food hoarding, suggests that the VTA might play a causal role in the motivation or incentive to hoard food. Animals with the propensity to hoard food or previous experience with food hoarding might be more prone to work for a valued reward, whereas the nonhoarders might be more willing to eat low value food in close proximity. This has obvious relevance to our own species making choices in an environment of food abundance.

Hunting and prey catching Dopamine, NPY, and the melanocortins influence hunting and prey catching, two appetitive behaviors that are separated in time and space from chewing and swallowing. Investigators studying prey catching in anurans have gone so far as to speculate that melanocortins and the HPA (or HPI) system are more important as “antipredator” than as anorectic peptides. In the common toad (Bufo bufo), for instance, the dopamine agonist, apomorphine, blocks locomotion and turning toward prey while it promotes snapping in a stationary, sit-and-wait position. These two aspects of ingestion occur concomitant with increased cellular activation in different brain areas. In response to apomorphine treatment, decreased cellular activation occurs in brain areas involved in locomotion and turning toward prey (medial tectum and ventral striatum), whereas increased cellular activation occurs in those brain areas involved in snapping (medial reticular formation and hypoglossal nucleus). Increases are also found in brain areas related to hunger motivation including the nucleus accumbens, ventral tegmentum, ventromedial pallidum, and septum. These structures are thought to influence motivation and reinforcing aspects of snapping in anurans (Ewert et al., 1999, 2001; Glagow and Ewert, 1994, 1996, 1997a, 1997b, 1999). This amphibian example illustrates the adaptive import of appetitive behavior. Food deprived toads are more likely to remain active even in the presence of predators, and thus, they are less likely to survive predation than toads that are well fed (Heinen, 1994). These studies suggest that the degree of satiety is critical for individual survival in habitats where there may be predators (from Carr, 2002).

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Summary of appetitive behaviors The above results in Mongolian gerbils, Brandt's voles, and toads are consistent with Salamone's ideas derived from studying dopaminergic control of effort in laboratory rats. Salamone explains that dopamine, acting in the nucleus accumbens, is critical for incentive motivation as measured by the specific appetitive behaviors that reflect the cost an individual will pay to gain access to a calorically dense, highly palatable food (Salamone et al., 2009). In voles, gerbils, and toads, dopamine comes into play when the behaviors involve hoarding, hunting, and catching prey: all three appetitive ingestive behaviors that involve significant effort to gain access to a highly valued food. Activation of dopamine circuitry is associated with choosing to work harder and longer for a highly valued goal, rather than to settle for an easily obtained, immediately available, less valued goal. By the same line of thinking, dopamine depletion is expected to be associated with immediate consumption of a less valued stimulus, as long as little or no effort is required to obtain that stimulus. A growing body of evidence documents integration of circuits involved in drug addiction, i.e., the mesolimbic dopamine system, with those involved in the incentive for, and rewarding or reinforcing properties of food and sex. The medial preoptic area of the hypothalamus (mPOA), which is a brain area critical for sex behavior, also innervates the mesolimbic dopamine areas (Tobiansky et al., 2013). Furthermore, lesions of the mPOA augment cocaine-induced conditioned place preference and cellular activation in the mesolimbic dopamine circuit. More than half of the mPOA-VTA efferents are sensitive to dopamine (Tobiansky et al., 2013). These results illustrate one of many possible interactions among neural systems that mediate the naturally-rewarding effects of natural stimuli and the systems that mediate the addictive effects of drugs. It will be interesting to determine whether food hoarding in Syrian and Siberian hamsters is also associated with the dopaminergic system, particularly since NPY infused into the PFA increases food hoarding (Dailey and Bartness, 2009), and natural increases in food hoarding are associated with increases in cellular activation in the SZI and CeA (Teubner et al., 2012). In Syrian hamsters, food restriction decreases appetitive sex behavior and increases food hoarding, but the same levels of food restriction does not decrease the rewarding aspects of mating (the ability to condition a place preference with mating as a reinforcer) (Lazzarini et al., 1988; Schneider et al., 1988). Food restriction does not reverse the mating-induced increases in cellular activation in the mesolimbic dopamine system, but it is not known whether vaginal scent marking itself is rewarding (without it leading to vagino-cervical stimulation by the male), and, if so, whether food restriction decreases the rewarding aspects of appetitive behavior, or whether food restriction simply increases the reward value of food (Klingerman et al., 2011a). Another gap in our understanding is related to the effects of deficits in metabolic energy availability on food hoarding. In Siberian and Syrian hamsters, as well as the Mongolian gerbils, food hoarding is increased by food deprivation. How is the deficit in energy availability detected, what exactly is detected, and where are these detectors? Food intake in rats is highly responsive to treatments that deplete the availability of specific metabolic fuels, whereas food hoarding in hamsters, and other measures of hunger motivation do not appear to be sensitive to inhibition of the oxidation of those particular fuels. In rats, food intake is increased by treatments that block either glucose or fatty acid oxidation, and there is a synergistic stimulatory effect when the oxidation of both fuels are blocked simultaneously (Friedman, 1992; Ritter, 1986). These same treatments fail to influence food hoarding in Siberian hamsters, at least at the range of doses tried so far (Bartness and Clein, 1994). This raises the interesting possibility that some appetitive behaviors are controlled by hormones, such as ghrelin and leptin, whereas food intake is directly affected by the availability of oxidizable metabolic fuels (Lazzarini et al., 1988; Schneider et al., 1988).

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Do the hormones that influence appetitive ingestive behaviors act directly on brain mechanisms that control these behaviors or indirectly by changing the disposition of metabolic fuels? Is there an interaction between fuel availability and the central peptides that control appetitive behavior? There is precedence for this type of interaction; the resistance to the action of leptin, insulin and ghrelin on food intake increases with adiposity (Caro et al., 1996; Cusin et al., 1996; Schwartz et al., 1996; Ur et al., 1996). Treatment with orexin A increases food intake in ad libitum-fed but not food restricted female rats, and treatment with orexin A inhibits pulsatile LH secretion in food-deprived but not in ad libitum-fed or food-deprived, glucose-treated female rats (Furuta et al., 2010). In common lizards (Zootoca vivipara), glucocorticoids increased activity and thermoregulatory behaviors in well-fed but not in food-deprived males (Cote et al., 2010). In house sparrows (Passer domesticus), glucocorticoid treatment inhibits feeding responses and coloration in energetically stressed but not in unstressed chicks (Loiseau et al., 2008). In black-legged kittiwakes (Rissa tridactyla), glucocorticoid-induced foraging is stimulated in birds with high levels of body weight but inhibited in those in poor condition (low body weight) (Kitaysky et al., 2001). Given the importance of glucocorticoids and gonadal sex steroids and their interactions with energy availability, what are their effects on food hoarding? Given the fact that glucocorticoids control fuel metabolism and storage, it will be important to examine the behavioral effects when both hormone level and the availability of metabolic fuels are manipulated simultaneously. Reasons to stop eating The choice between eating and mating It is often assumed that food intake “regulation” functions solely to prevent body weight gain, insulin resistance, and obesity. There are, however, many other good reasons to stop eating. In many species, foraging and eating are incompatible with courtship, mating, migration, and hibernation/torpor, the latter being a regulated drop in body temperature that decreases the energy expenditure required for survival during periods of low ambient temperature and food availability. The focus of this review is the conflict between ingestive behavior and reproduction, but several excellent reviews indicate that similar mechanisms are at work when ingestive behavior is inhibited during torpor and hibernation (Dark, 2005; Florant and Healy, 2012; Humphries et al., 2003). Energy acquisition and storage is an important prerequisite for reproductive success (Bronson, 1989). Thus, in most species, behavioral sequences are organized so that a period of eating and fattening often proceeds mating and caring for offspring. This is particularly important in habitats where food availability fluctuates or is unpredictable. Bull elephant seals (Miriounga angustirostris) spend several months at sea doing little else but fishing, eating, and accumulating massive stores of blubber. The blubber is critical for reproductive success, because the bulls fast for several weeks while they compete for territories. The fast continues while the winners of the territorial competitions impregnate multiple females (Le Boeuf and Laws, 1994). Fatty acids mobilized from the triglycerides stored in blubber allow them to make a radical switch in behavioral priorities: from aquatic foraging to terrestrial territorial defense on beaches miles from their food source. Male fur seals (Callorhinus ursinus) also fast for several weeks during the breeding season (Baker et al., 1994; Osgood et al., 1914). Not all examples are as extreme, however. Red deer stags (Cervus elaphus) reduce food intake and body fat during the rut, even though food is readily available and their female mating partners continue to eat normally (Mitchell et al., 1976). Female Syrian hamsters (Mesocricetus auratus) engage in intense foraging, hoarding, and eating for the three infertile days of their ovulatory cycle and then neglect their foraging duties for the few short hours that they engage in sex behavior on the eve of the fourth day (Figs. 4 and 5). Examples like these are not confined to mammals. In sea birds, such

as king penguins (Aptenodytes patagonicus) and emperor penguins (Aptenodytes forsteri), long-term fasting during the breeding season can lead to reproductive success, but if internal lipid stores are depleted and parents are forced to dip into their lean mass for gluconeogenesis, the parents abandon their eggs or chicks (Dewasmes et al., 1980; Robin et al., 1998; Warham, 1996). Similarly, in equatorial birds such as jungle fowl (Gallus gallus) the mothers eat little or nothing while sitting on their nests full of eggs, losing 20% of their body weight during the 20-day incubation (Sherry et al., 1980). In fish, the tradeoff between foraging and courtship is the foundation of many behavioral ecology studies (Abrahams, 1993; Fernald and Hirata, 1977; Griffiths, 1996; Lindstrom et al., 2009). African cichlids (e.g., Sarotherodon melanotheron) are normally voracious carnivores, with fish eggs topping their list of favorite foods. After mating, however, males and females (depending on the species) display remarkable restraint by incubating fertilized eggs in their mouths (Goldstein, 1973). Mechanisms that inhibit eating are necessary, but the duration of inhibition is only long enough to allow the individual to get busy with reproductive activities, i.e., courtship, copulation, or offspring care. It is well established that severe metabolic challenges (e.g., food deprivation in lean animals) inhibit the HPG system, but new insights show that mild energetic challenges (less than 25% restriction in fattened animals) influence moment-to-moment decisions about whether to engage in reproductive or ingestive behaviors. Severe energetic challenges inhibit the HPG system in almost every species in which it has been studied (reviewed by Bronson, 1989; Fernandez-Fernandez et al., 2006; Hill et al., 2008; Schneider et al., 2012; Wade and Jones, 2004; Wade and Schneider, 1992). Mild energetic challenges can inhibit sexual motivation, without significant effects on circulating concentrations of gonadal steroids (Klingerman et al., 2010, 2011a, 2011b; Schneider, 2006; Schneider et al., 2007). This has not impressed many laboratory scientists, but it is important in nature, to promote vigilant foraging and eating prior to engaging in the energetically costly process of reproduction, and to avoid wasted efforts on courtship during the infertile phases of the reproductive cycle. Furthermore, it is important to characterize effects of mild energetic challenges on behavior because they are mediated by so-called anorectic and orexigenic peptides and hormones. It follows that one critical role of ‘satiety’ hormones is to set behavioral priorities in order to optimize reproductive success in natural habitats where food availability varies unpredictably. This hypothesis is useful because it predicts that the effects of said hormones on ingestive/reproductive behaviors will differ according to 1) the availability of metabolic fuels (energy that can be derived from food), and 2) the availability of potential mating partners. Preference for food or males in Syrian hamsters Work with Syrian hamsters shows that ovarian steroids and GnIH are likely to be involved in orchestrating behavioral motivation, i.e., the disposition of energy availability, GnIH, and ovarian steroids dictate the choice between courtship and food hoarding. Prior to the experiments on Syrian hamsters, it was well known that food intake fluctuates over the menstrual cycle in primates, including women (reviewed by Buffenstein et al., 1995; Fessler, 2003), and over the estrous cycle in nonprimates housed in the absence of conspecific males (reviewed by Asarian and Geary, 2006; Wade, 1972; Wade and Gray, 1979). The decrease in food intake coincides with the periovulatory peak in plasma estradiol concentrations and the increase in sexual motivation and/or behavior. Ovariectomy-induced hyperphagia is reversed by estradiol but not progesterone treatment (reviewed by Asarian and Geary, 2006; Wade, 1972). In women, fluctuations in food intake over the menstrual cycle are found in some but not all studies, but in women that restrict their food intake, binge-eating is less likely during the periovulatory phase of the menstrual cycle (Klump et al., 2006). In addition to effects on food intake and energy balance, estradiol is critical for sexual motivation and behavior in


females of most laboratory species (Drewett, 1973; McDonald and Meyerson, 1973; Meyerson and Lindstrom, 1973; Myerson et al., 1973). Estradiol is also important for sexual libido in women. Although women can and do have sexual intercourse over the entire menstrual cycle, there are documented increases in sexual motivation, sexual fantasy, masturbation, and other aspects of sexuality during the periovulatory period (Bullivant et al., 2004; Durante and Li, 2009; Gangestad, 2001; Gangestad and Thornhill, 2008; Tarin and GomezPiquer, 2002). In primates, estradiol is implicated in female sexual desire by both menstrual cycle correlations (Roney and Simmons, 2013) and experiments that manipulate plasma estradiol concentrations (Wallen, 2001). Even in male mice, classical genotropic action, which involves binding of estradiol to estradiol receptor (ER), is necessary for male sex behavior, even in the presence of high circulating testosterone concentrations (McDevitt et al., 2007). The entangled mechanisms controlling energy balance and reproduction are illustrated by animals with mutations that lead to a nonfunctional ER-α. ER-α knockout mice lack a functional ER-α, lack estradiol-negative feedback on luteinizing hormone (LH) secretion, and develop obesity, increased adiposity, decreased energy expenditure, hyperinsulinemia, and hyperleptinemia (Heine et al., 2000; Musatov et al., 2007; Ohlsson et al., 2000; Rissman et al., 1997). Estradiol-negative feedback, appetitive sex behaviors, and all metabolic parameters are rescued by a mutation that restores nonclassical estradiol signaling while simultaneously eliminating all classical estradiol action (McDevitt et al., 2008; Park et al., 2011). Other mutations are designed to eliminate functional ER-α specifically in neural cells that synthesize POMC. These mice lack estradiol-negative feedback on LH secretion and are hyperphagic but show normal body weight and adiposity. Mutations that eliminate ERα in neurons that synthesize SF-1 result in normal estradiol-negative feedback, normal food intake, infertility, and abdominal obesity (Xu et al., 2011). Together, these data show reproduction and energy balance remain tightly coupled even when point mutations dissect aspects of energy balance from one another (e.g., hyperphagia is dissociated from adiposity). We hypothesize that in natural habitats where animals work hard to forage for their food, this system functions primarily to decrease the appetite for food and increase the desire for sex in order to optimize reproductive success. None of the above experiments directly test the idea that the effects of estradiol on appetitive behaviors have been adaptive in environments where energy availability fluctuates. In order to test this hypothesis, environmental energy availability must be manipulated and experimental subjects must show quantifiable appetitive behaviors. Thus, we measure both appetitive and consummatory behaviors in female Syrian hamsters that have been either well-fed or food-restricted prior to behavioral testing. Some experiments examine gonadally-intact females over the estrous cycle and some examine ovariectomized females treated with either gonadal hormones or vehicle. Several considerations suggest that attention to the choice between food and sex in female Syrian hamsters will provide insight into the mechanisms that orchestrate behavior during energetic challenges. Some aspects of hamster behavior (activity, wheel running) are nocturnal in the laboratory, but laboratory-housed Syrian hamsters eat almost as much in the light as in the dark phase of the photoperiod (Klingerman et al., 2010). In contrast to the laboratory, in their natural habitat near the border of Syria and Turkey, hamsters live separately in underground burrows and are found to be active only for brief periods at dawn and dusk (Gattermann et al., 2008). Hamsters store massive amounts of food in their burrows, but the sparse distribution of the burrow and their large surrounding territories suggests that competition for burrows is stiff. Hamsters spend only about 90 min per day above ground, and virtually every minute of this time is spent hoarding food or standing vigilantly at the burrow entrance (Gattermann et al., 2008). This suggests that their nocturnal active period might be constricted in the wild by predators or other unknown factors, and that the burrow provides protection from predators and fluctuations

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in ambient temperature. Hamsters are expected to have controls that balance their hunger for food with the need to remain safe from predators and harsh environmental conditions. This short, active, aboveground time period is likely to be a critical point of conflict between appetitive sex and ingestive behaviors. Engaging in courtship behavior during this 90-minute period might preclude vigilant food hoarding, thereby compromising the females' ability to survive future energy shortages. On the other hand, engaging in food hoarding during the periovulatory period would likely preclude rendezvous with a potential mating partner at the burrow entrance. Thus, hamsters are an excellent species for testing the hypothesis that so-called “anorectic” or “satiety” hormones orchestrate behavioral motivation in environments where energy availability fluctuates (Klingerman et al., 2010; Schneider et al., 2007). Hunger motivation in Syrian hamsters is reflected by food hoarding; after a period of food deprivation, Syrian hamsters fail to increase food intake (Silverman and Zucker, 1976), but food-deprived hamsters show significant increases in food hoarding, increasing food hoarding ten to a hundred fold (Buckley and Schneider, 2003; Smith and Ross, 1950). Sexual motivation in hamsters is determined by counting the number of vaginal scent marks made in response to adult male hamsters or male hamster odors (Johnson, 1973; Johnston, 1974, 1975, 1977; Tiefer and Johnson, 1971). Another measure of sexual motivation is the females' preference for spending time with either males or food. These appetitive sex and ingestive behaviors are likely to be important to Syrian hamsters in the wild. To examine the role of energy availability on the choice between food and sex, estrous-cycling female hamsters are housed in a burrow system comprised of a home cage, a tunnel leading to a t-shaped intersection, and two more tunnels leading in the opposite directions: one tunnel leads to food and the other leads to a sexually-experience male hamster. Female subjects are either fed ad libitum or mildly food restricted (75% of ad libitum intake) for 8 days and then tested for 90 min at the onset of the dark phase of the light–dark cycle for food hoarding and preference for males vs. food. All behaviors and location are recorded every 5 s. Food-restricted or ad libitum-fed hamsters are tested every day of the estrous cycle to reveal the interaction of gonadal hormones with different energetic and social environments. When females are fed ad libitum and provided the choice between food hoarding and courtship, they prefer courtship over food on every day of the estrous cycle (Klingerman et al., 2010; Schneider et al., 2007). In these well-fed females, food hoarding is consistently low and does not vary much over the estrous cycle. In sharp contrast, when access to a male is coupled with limited energy availability, females show remarkable fluctuations in food hoarding and preference for males over the estrous cycle (Fig. 4). Food-restricted females show a strong preference for food and high levels of hoarding on the days when circulating estradiol is low. Food hoarding falls and vaginal scent marking increases the night before ovulation and ceases altogether on the night of ovulation (Klingerman et al., 2010). Thus, the effects of estrous cycle fluctuations in gonadal steroids on appetitive behaviors are masked in females with unlimited energy availability. Furthermore, there are no effects of this level of food restriction on consummatory behaviors (lordosis duration and food intake). This is a prime example of what we miss by studying food intake in animals housed with unlimited access to food in small cages isolated from conspecifics. Similar results are seen in ovariectomized females treated with physiological levels of ovarian steroids. In ovariectomized females, the fluctuations in appetitive behavior over the estrous cycle are mimicked by treatment with estradiol and progesterone, and the effects of estradiol differ according to energy availability. In unrestricted, estradioltreated females, the preference for males is high, but not that much higher than that of ovariectomized females. Mild food restriction drastically decreases preference for males (but not lordosis duration) and increases food hoarding (but not food intake) in ovariectomized but not in estradiol-treated females. Severe food restriction (12–16 days),

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Fig. 4. Appetitive sex behavior was measured over the estrous cycle in females either fed ad libitum or food restricted. The Y-axis is male preference, that is, the mean preference for spending time with a male calculated as the time spent with a male divided by (the time spent with a male + the time spent with food) in a 15 min test. Male preference was measured at the onset of the dark period on every day of the estrous cycle in females that were either fed ad libitum or previously food restricted to 75% of their ad libitum intake. In the figures above the graphs, energy availability is symbolized as water filling the large reservoir that provides fuels for all physiological process. Food intake is symbolized as a faucet, and body fat stores are symbolized as the small container on the left of the large reservoir. When energy in the environment is unlimited and energy expenditure requirements are low, there is sufficient energy for sexual motivation, the HPG system, as well as for all of the energy-using processes necessary for survival (top left). However, processes necessary for survival have the first priority. When there are severe metabolic challenges, and females deplete their body fat reserves, there is not enough energy available for the HPG system and sex behavior (not shown). As shown in the picture and graph on the right, after mild energetic challenges that do not inhibit the HPG system, sexual motivation is low on most days of the estrous cycle, however, there is a significant increase in sexual motivation in the periovulatory period when plasma estradiol concentrations are high. As shown in the graph and figure on the left, this estrous cycle fluctuation is masked in hamsters that are housed with food available ad libitum. Modified from Klingerman et al., 2010.

Fig. 5. Appetitive ingestive behavior was measured over the estrous cycle in females fed ad libitum or food restricted. The Y axis is grams of food hoarded in a 90 min test at the onset of the dark period on every day of the estrous cycle in females that were either fed ad libitum (solid line, filled circles) or previously food restricted to 75% of their ad libitum intake (dashed line, open triangles). After this mild energetic challenge, which did not inhibit the HPG system, food hoarding was high on most days of the estrous cycle, but decreased as ovulation approached and was at its nadir on the day of estrus (dashed line, open triangles). This estrous cycle fluctuation in appetitive ingestive behavior is masked in hamsters that are housed with food available ad libitum (solid line, filled circles). Above the time points for mean food hoarded, hamster appetitive sex behaviors are depicted. On days 1 and 2, the post-ovulatory day, and the early follicular phase, hamsters show very few appetitive sex behaviors. On the third day of the estrous cycle, the day before ovulation, females show peak levels of vaginal scent marking. On the fourth day, the day of ovulation, females show lordosis in response to a sexually-experienced, adult male hamster. Modified from Klingerman et al., 2010.

unlike mild food restriction, inhibits the preference for males as well as lordosis duration even in females treated with estrous-inducing doses of estradiol and progesterone (Klingerman et al., 2010). These experiments also examine the relative importance of time constraints vs. energy constraints. In the 8 days prior to testing for the choice between food and sex, one group of female hamsters had unlimited time to forage for and hoard food, but overnight food supply was limited to 75% of ad libitum intake. Another group had only limited time each day to forage for and hoard food, but had unlimited energy availability. This latter group did not differ significantly from ad libitum-fed, ad libitum-time controls in their appetitive sex and ingestive behavior, whereas those with limited energy availability showed remarkable fluctuations in food hoarding, vaginal scent marking, and preference for males over the estrous cycle (Klingerman et al., 2010). These results suggest that the hamsters' behavioral priorities are profoundly affected by their experience with limited energy availability but not by their experience with limited time for foraging and hoarding. These results are consistent with the idea that the hormones of the estrous cycle modulate appetitive ingestive and sex behaviors according to the availability of energy and potential mates. Appetitive behaviors are affected at low levels of food restriction that have no effect on consummatory behaviors. This role of estradiol is obscured in most laboratories because appetitive behaviors are ignored, food intake is measured in females isolated from males and under conditions of artificial energy abundance and minimal energy demands. In environments where energy availability fluctuates or is unpredictable, an important function of anorectic gonadal hormones is to promote vigilant food hoarding and prevent sexual adventures during the nonfertile phases of the estrous


cycle. Under conditions of constant energy abundance, however, sexual motivation remains high despite fluctuations in gonadal hormones (Figs. 4 and 5). GnIH, NPY, leptin, and their interaction with ovarian steroid receptors are implicated in energetic control of appetitive behaviors. First, ICV treatment with GnIH mimics the effect of mild food restriction by inhibiting appetitive, but not consummatory aspects of sex behavior in female Syrian hamsters (Piekarski et al., 2012). In an experiment designed to discriminate among GnIH effects on appetitive behavior, consummatory behavior, or the HPG system, GnIH is implicated in only appetitive behavior. Cellular activation in GnIH cells in fooddeprived, lean, anestrous hamsters was compared to that in fooddeprived, fat, estrous-cycling hamsters. Cellular activation in GnIH cells was elevated in both food-deprived groups, and did not differ between food-deprived, anestrous compared to food-deprived, estrous cycling hamsters. In hamsters subjected to mild food restriction, cellular activation in GnIH cells was closely associated with fluctuations in vaginal scent marking, the preference for spending time with males, and food hoarding (Klingerman et al., 2011b). Together, the above results illustrate that the effects of hormones and neuropeptides vary with energy availability. GnIH function is more closely related to behavioral motivation than to control of consummatory behavior and the HPG system. Furthermore, vaginal scent marking is inhibited by 24 h of food deprivation and the effects of food deprivation are reversed by treatment with leptin (Schneider et al., 2007), known to inhibit effects of NPY (Kotz et al., 1998). The effects of leptin on vaginal scent marking (an appetitive sex behavior) was greater in fattened, fasted females (that continued to show estrous cycles and high levels of ovarian steroids) than in ad libitum-fed females. In another experiment by W. P. Williams in the Kriegsfeld laboratory, fibers that contain NPY are found in close apposition to GnIH cells in the Syrian hamster DMH (Klingerman et al., 2011b). It is important to note that effects of mild food restriction occur without effects on circulating gonadal steroids. In support of the idea that energetic challenges influence sensitivity to ovarian steroids, energetic challenges decrease levels of estrogen receptor-alpha (ER-α) in the VMH (implicated in sex behavior) and increase levels of ER-α in the PVH (Li et al., 1994). In support of a role for both NPY and CRH in hamster motivation, central treatment with either a Y2/5 R agonist or a CRH receptor antagonist reverses the effects of severe food deprivation on lordosis duration (Jones et al., 2002, 2004; Keene et al., 2003; Seymour et al., 2005). Although this latter study focused on lordosis duration, not the appetitive behavior vaginal scent marking, the results are consistent with a role for NPY and CRH on the underlying sexual motivation. Consistent with these studies on appetitive behavior, other investigators have suggested that GnIH is important for consummatory aspects of ingestive behavior and for control of the HPG system. Clarke et al., have noted that central GnIH treatment increases food intake while it inhibits the HPG system in mice, rats, sheep, and monkeys (Clarke et al., 2012). These results are not in conflict with GnIH effects on motivation; these investigators did not attempt to differentiate between appetitive and consummatory behavior. Our studies in Syrian hamsters indicate that GnIH is more closely associated with appetitive than consummatory sex and ingestive behavior (Klingerman et al., 2011b). This line of research suggests that when animals are mildly energetically challenged, sexual motivation is inhibited by orexigenic peptides that promote vigilant foraging and hoarding during the infertile part of the estrous cycle. As ovulation nears, however, the effects of these orexigenic peptides are inhibited by rising levels of estradiol. Estradiol dampens the urge to forage and turns attention toward sex; perhaps via effects on anorectic peptides. This idea is supported by data showing the expected interaction between estradiol and other hormones, including corticosteroids, ghrelin, the melanocortins, and CCK (Asarian and Geary, 2007; Clegg et al., 2007; Gao et al., 2007). Thus, future work should be aimed at understanding the role of other neuropeptide systems, such as the CRH system, in setting behavioral priorities.

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The choice between food and sex in other species This phenomenon, energetic control of appetitive sex and ingestive behavior, is echoed in other vertebrate species. We have already noted that in Siberian hamsters, appetitive ingestive behaviors are more sensitive than consummatory behaviors to NPY, leptin, ghrelin, melanocortins, and CCK (reviewed by Bartness et al., 2011). Even in rats, NPY treatment increases the number of approaches to a bottle of sucrose, an empty bottle, or a bottle of water at doses that do not increase (and might sometimes decrease) consummatory behavior (Ammar et al., 2000). The lack of NPY effects on consummatory behavior in some experiments can be explained by the effects of repeated testing or other confounds (Benoit et al., 2005). More robust, however, are the effects of NPY and leptin in the presence of opposite-sex conspecifics. Increases in response to NPY and decreases in response to leptin in appetitive ingestive behaviors are consistent with their role in orchestrating the appetites for food and sex (Ammar et al., 2005; Bartness et al., 2011; Schneider et al., 2007; Sederholm et al., 2002; Seeley et al., 1995). Well-fed male rats offered a choice between an estrous female and a bottle of sucrose will choose the female every time. By contrast, NPY-treated males offered a choice between an estrous female and a bottle of sucrose show a bias toward the sucrose solution. Leptin-treated males offered a choice between sugar solution and sex with an estrous female decrease their frequency of approaches to a bottle of sucrose and consume fewer calories overall, but they also increase the frequency of ejaculations relative to vehicle-treated control males (Ammar et al., 2000). These results concur with our hamster studies demonstrating that NPY and leptin are more than simply orexigenic and anorectic; they direct attention toward or away from sexual stimuli. The results of Klingerman et al. (2010, 2012) in Syrian hamsters demonstrate that appetitive behaviors respond to gonadal steroids differently, depending on the energetic status of the female (prior food restriction or ad libitum feeding). A similar interaction between prior energetic status and behavioral response to hormones is seen in at least three other independent laboratories studying food-restricted male rats. In male hooded Wistar rats, the latency to intromission was significantly longer in those food restricted by 50% compared to those restricted by 25% or 0%, and females preferred ad libitum-fed males over the 50% food-restricted males, even though there was no significant difference among the two levels of restriction in plasma testosterone concentrations (Govic et al., 2008). In another study using male Wister rats, food restriction significantly decreased mount and intromission latency without significant effect on plasma testosterone (Alvarenga et al., 2009). In yet another study of male laboratory rats, food restriction accelerated the disappearance of copulatory behavior that normally accompanies castration (Broere et al., 1985). All of these studies are consistent with the idea that male copulatory motivation and performance are inhibited by energetic challenges. They are all consistent with the idea that this occurs via decreases in behavioral responsiveness to gonadal steroids. Similarly, in male mice, appetitive sex behavior can be measured as rapid, short latency courtship ultrasounds in response to female mice and their odors, and this appetitive behavior is prevented by pretreatment with ghrelin (Shah and Nyby, 2010), an orexigenic gut hormone that acts via AgRP/NPY. Male mouse ultrasounds are testosteronedependent (Sipos and Nyby, 1998), but the effects of ghrelin occur within 20 min, more rapid than would be expected if they occurred via inhibition of the HPG system and via inhibition of testosterone secretion (Shah and Nyby, 2010). Together, these results are consistent with the hypothesis that one important function of putative “body weightregulating” hormones is to orchestrate the motivation for foraging and courting on a moment-to-moment basis. The effects of food deprivation or restriction was not examined, but ghrelin is known to increase in food-deprived rodents (Gualillo et al., 2002), and thus, these experiment implicate ghrelin in energetic effects on male appetitive sex behavior.

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Food deprivation inhibits some aspects of sex behavior in female meadow voles (Microtus pennsylvanicus), and there are some differences in this species from the examples discussed thus far. The effects of deprivation are limited to attractivity. The scent marks of female meadow voles are attractive to males such that males show a preference for female versus male scent marks, and food deprivation of females decreases the male's preference for those marks (Pierce and Ferkin, 2005; Pierce et al., 2005). Food deprivation also inhibits self grooming in both sexes, an appetitive behavior that releases volatile pheromones into the atmosphere (Hobbs et al., 2012). In contrast the appetitive behaviors, scent marking and scent overmarking, are not affected by food deprivation. Unlike appetitive sex behaviors in Syrian hamsters, attractivity of meadow vole scent marks is associated with significant decreases in plasma estradiol and the effects of food deprivation on attractivity are reversed by estradiol treatment (Pierce et al., 2007). Re-feeding restores attractivity, but it is not necessary for the fooddeprived voles to regain their lost body weight (Pierce and Ferkin, 2005). Together, these results suggest that steroid-dependent pheromone production is sensitive to minute-to-minute changes in circulating metabolic fuels, rather than signals from body fat content or size. This hypothesis was elegantly supported by experiments in which red-sided garter snakes (Thamnophis sirtalis parietalis) were tested in an environment that offered the choice between sexual or foodrelated stimuli (O'Donnell et al., 2004). In northern-most members of this species, males and females must eat enough food to survive an 8 month hibernation period followed by 2–4 weeks of intense courtship and mating, followed by a new cycle of dispersal, foraging and eating (Gregory, 1977). Breeding and eating are thought to be mutually exclusive in the wild because courting males at the dens are found rarely if ever with food in their stomachs (Aleksiuk and Gregory, 1974; Aleksiuk and Stewart, 1971; Crews et al., 1987) and males have been known to refuse food offered by the experimenter during the breeding season (Aleksiuk and Gregory, 1974; Crews et al., 1987). O'Donnell et al. asked whether newly emerged, breeding snakes have a normal appetite and are able to eat, or whether there is an endogenous mechanism that inhibits food intake while courting and mating. In this ingenious design, male red-sided garter snakes are tested in a Y-maze that offers olfactory cues from either a prey item or sexually attractive females (females in which the attractiveness pheromone is present). Red-sided garter snakes use chemical trails to locate prey items such as earthworms (Halpern and Martínez-Marcos, 2003; Halpern et al., 1986; Kubie and Halpern, 1975), and males use chemical trails to locate potential mates (e.g., see LeMaster and Mason, 2001, 2002; Mason et al., 1989, 1990). Thus, in the preference test, the male is placed in the starting position at the outer arm of the Y, and the experimenter records the male's preferences and behaviors when provided with two types of odor trails. After the Y-maze test, courtship and eating are assessed directly, by exposing males to females in the absence of food, or exposing males to prey in the absence of females, and scoring their responses (O'Donnell et al., 2004). Male red-sided garter snakes, captured near the den where they emerge from hibernation, invariably prefer the arm scented with the female pheromone over the arm scented with the food odors, and this preference is gradually reversed over the next 2–4 weeks, until finally, all males reverse their preference. In post-tests with each stimulus alone, the decrease in hunger motivation occurs in the absence of female pheromones. Similarly, the decrease in courtship and mating occurs in the absence of food and in the presence of females. Thus, the changes in motivation and appetitive behaviors are due to endogenous mechanisms that control hunger and sexual motivation. It will be fascinating to find the environmental cues (ambient temperature, photoperiod, energy availability) and endocrine events that determine these preferences (O'Donnell et al., 2004). NPY and glucocorticoids are implicated in these changes in the preference for food or sex. ICV treatment with NPY significantly inhibits red-sided garter snake courtship behaviors 4–5 h after the

start of infusion and stimulates food intake at 4–5 h and returns to baseline at 24 h after infusion (Morris and Crews, 1990). Furthermore, the switch from a preference for sex to a preference for food is associated with fluctuations in plasma glucocorticoids and melatonin. Treatment with corticosterone, melatonin, or serotonergic type 2A receptor antagonist during the breeding season suppresses courtship in male red-sided garter snakes in a dose-dependent manner, whereas treatment with glucocorticoid synthesis inhibitors increases the preference for food over male pheromones in this species (Lutterschmidt et al., 2004, 2011). Corticosterone is inhibitory for reproductive behaviors in many different species, but a number of species that breed in harsh environments appear “resistant” to these effects. This difference might be related to environmental energy availability. Newly emerged male red-sided garter snakes trapped near the dens and are about to embark on frenzied courtship and mating have higher circulating concentrations of corticosterone and a blunted stress response compared to those males that have courted and initiated their dispersal to the feeding grounds. Together, these results suggest that one important role of seasonal fluctuations in the stress response is to increase baseline corticosterone concentrations while inhibiting the flight-or-fight response in order to promote synchronized mass mating in the spring (Cease et al., 2007). Thus, newly emergent snakes might benefit from high baseline corticosterone concentrations (because corticosterone increases lipolysis, decreases lipogenesis, and increases gluconeogenesis resulting in elevated availability of oxidizable fuels). At the same time they would be spared the stress-induced inhibition of sex behavior and the HPG system. It would be interesting to know whether high circulating levels of glucocorticoids would support breeding even in severely undernourished snakes. We speculate that the switch from courtship to foraging behavior might be related to the need to replenish depleted stores of metabolic fuels after two weeks of intense energy expenditure (mating) and/or post-hibernation changes in thermoregulatory function. One hypothesis is that the trigger for increased feeding results from an interaction between high levels of glucocorticoids and a depleted supply of metabolic fuels (glucose, free fatty acids, or ketone bodies) or accompanying low levels of hormones such as leptin and high levels of hormones such as ghrelin. Changes in internally circulating oxidizable fuels might not be reflected in overall body weight or condition. As with the Syrian hamsters discussed above, steroid effects on behavior may differ according to internal metabolic fuel availability. This is a testable hypothesis. The switch from mating to eating has been linked to the HPA system and metabolism in northern sea birds that cope with cold winters. Antarctic king penguins (Aptenodytes patagonicus) fast for up to one month while mating, incubating, and molting (Cherel et al., 1988). During incubation, one parent fasts and incubates, while the other forages for food far out at sea. These shifts in ingestive behavior are accompanied by distinct and quantifiable appetitive behaviors. Just before egg abandonment, the incubating parent begins to increase locomotor behaviors and starts singing; the song calls the other parent to the nest, and these changes in appetitive behavior are correlated with the shift from utilization of lipid-derived to protein-derived fuels (Groscolas et al., 2000). Examination of these appetitive behaviors in the laboratory suggests that the likelihood of abandonment of either an egg or a chick are linked to increased plasma concentrations of corticosterone and decreased plasma prolactin (Groscolas et al., 2008). Similarly, in emperor penguins, during the first two phases of fasting, energy for reproduction is supplied by glycogen and lipid but not protein stores. Glycogenolysis and lipolysis are stimulated in part by steady concentrations of glucocorticoids (corticosterone). When lipids are depleted, elevated corticosterone and glucagon concentrations trigger gluconeogenesis, creating new glucose from amino acids and glycerol, resulting in the breakdown of proteins and muscle wasting. The combination of elevated glucocorticoids and low energy availability can be such a powerful motivational signal that it sometimes causes the birds to abandon the eggs in order to


forage for food. During fasting, body weight and concentrations of uric acid and corticosterone increase, whereas plasma levels of betahydroxybutyrate decreases. Decreases in the ketone body, betahydroxybutyrate, are diagnostic for the depletion of fat fuels because ketone bodies are a byproduct of fatty acid oxidation (Robin et al., 1998). Thus, the switch from reproductive to ingestive behavior is not a simple function of plasma glucocorticoid concentrations, but perhaps a function of the ratio of fuel availability to plasma glucocorticoids. This is a testable hypothesis but requires experimental manipulation of energy availability. This general idea is echoed in at least some species of mammals and birds that hibernate, species that optimize reproductive success in environments where fluctuations in energy supply and demand are extreme. Hibernators prepare for winter by increasing their food intake and body fat storage in the summer and late autumn. In winter they cease their foraging while they undergo a controlled drop in body temperature. Given the geographic location of hibernators, the function of hibernation is to conserve metabolic fuels necessary for survival during harsh winters when food supplies are virtually non-existent and ambient temperatures are low. Fattening over the summer and early autumn are correlated with increases in glucocorticoids (Nunes et al., 2006), but there are very few experiments in which corticosteroids were administered to determine their effects on body temperature, torpor, or hibernation. Other investigators, however, manipulated corticosteroid levels in hibernating birds. Corticosterone treatment increases nocturnal restfulness in captive white-crowned sparrows (Buttemer et al., 1991) and increases the incidence of daily torpor in humming birds (Hiebert et al., 2000). Furthermore there is some evidence that the effects of corticosteroids on activity and body temperature differ according to energetic history and possibly the availability of metabolic fuels (Hiebert et al., 2000). Missing from studies of glucocorticoids and hibernation is simultaneous manipulation of energy stores, food intake, and glucocorticoid levels. It is reasonable to imagine that motivation is a unique characteristic of “higher” organisms, and yet motivational priorities are affected by energy availability even in invertebrates with relatively simple nervous systems. For example, male nematodes of the species Caenorhabditis elegans show appetitive behaviors that indicate their interest in either food or sex, though the nervous system is comprised of only a few hundred cells (Lipton et al., 2004). Much like the male preference test we use to examine sexual motivation in female hamsters, appetitive sex behavior in male C. elegans is quantified by placing males on their preferred food source and then measuring how often they exit in search of mating partners in what the experimenters call a “leaving assay.” Leaving a food source in male C. elegans occurs only in a sexual context, i.e., it occurs only in adult, gonadally intact males, not in juveniles or castrated males. Sexually mature males tend to linger on the food source when dining with a potential mating partner (in C. elegans males mate with hermaphrodites) but leave readily when no hermaphrodites are present at the food source. Instead, they wander off searching for mates, but not just any mate; a hermaphrodite with an abundant food source. These motivated behaviors are sensitive to energy availability. Food-deprived males have a longer latency to leave a food source before finally exiting the food source in search of a mating partner. The longer the food deprivation, the longer the males delay their exit from a food source. These changes in the hunger for food and desire for sex may be mediated by neuropeptides and sex hormones. Serotonin is released in response to eating in C. elegans, and mutations in the genes that encode serotonin receptors create males that 1) are insensitive to serotonin action and 2) act as though they have been food deprived. They fail to leave a food source in search of mating partners. Mutations or other manipulations that inhibit gonadal function also mimic food deprivation, i.e., they prevent males from exiting is search of hermaphrodites. Mutation of the fog-1 gene transformed males that produce sperm into males that produce oocytes, fail to show the “leaving

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response,” but instead remain on the food source as though they are food deprived. The biochemical pathways that determine whether a young nematode develops into an adult male or a hermaphrodite might also determine the appetitive behavior, the “leaving response” to a food source (Lipton et al., 2004). Together these results are consistent with the idea that sex hormones and neuropeptides orchestrate the choice between food and sex in some of the earliest animals. Courtship and eating in semelparous species Not all species curtail reproduction when energy availability is low, but in these cases, the exception proves the rule: Mechanisms that orchestrate the appetites function to optimize reproductive success. In electric fish, (Brachyhypopomus gauderio), males emit an electric organ discharge (EOD) that is testosterone-dependent, energetically expensive, and necessary for successful competition for female mating partners. In the presence of other males, the social competition stimulates androgen and cortisol secretion, which in turn amplifies the EOD (Salazar and Stoddard, 2009). By contrast to other species in which food restriction inhibits sex behavior, in competing electric fish, EOD is amplified by food restriction. Previously food-restricted males that show the strongest EODs will eat more if food is made available, but in the absence of food, they amplify the EODs and rapidly burn through their remaining energy reserves (Gavassa and Stoddard, 2012). The difference between electric fish and species that delay reproduction until energy becomes available is that electric fish are semelparous. They get only one chance to mate in their lifetime. The delay of courtship and mating would be for naught; by that time they will be dead. The same strategy is seen in other species with severely limited mating opportunities. Male Arctic ground squirrels hibernate for 7 winter months, and emerge in the spring, in time for what is likely to be their only chance at becoming a father. Copulation is the prize for surviving the brutal, two-week, male–male competition. At emergence and throughout the two weeks of fighting and mating, the males' plasma cortisol concentrations are at their annual peak and free cortisol is constant. Yet, when challenged by another male, testosterone and aggression levels “rise to the occasion” (Boonstra et al., 2001). Only about one half of the males will survive to the next year, and Boonstra et al. (2001) suggest that this severely limits their lifetime reproductive success. The short breeding season, with only one opportunity to mate immediately after hibernation, may have selected for animals that are buffered from chronic stress incurred by aggression. By contrast, female hamsters and other rodents are likely to have several opportunities to mate, due to their short gestation period (16–18 days) and, in some species, a postpartum estrous. Thus, despite their short life spans, multiple litters per season in most small rodents increase the likelihood that metabolic control of reproduction will have a payoff in terms of overall reproductive success. A similar strategy to the semelparous arctic ground squirrel is seen in other truly semelparous species (Bradley et al., 1980). In those rotifer species that reproduce only once in a lifetime, egg production increases, rather than decreases during starvation (Kirk, 1997). In iteroparous rotifer species, reproduction is delayed by starvation, and these species are able to survive starvation longer than the semelparous rotifer species. In summary, species that will have multiple chances to reproduce in their lifetime, delay reproduction under energetic challenges. In species that will get only one chance to reproduce in their lifetime, energetic challenges stimulate rather than inhibit reproduction. A testable hypothesis is that, in iteroparous species, sensitivity to energetic challenges decreases as animals age and approach reproductive senescence. Energy availability and the HPG system The study of gradual changes in appetitive behavior under mild, temporary energetic challenges on behavioral motivation is relatively new compared to the well-known effects of metabolic fuel availability

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on food intake (Friedman, 1989; Ritter, 1986), and the effects of severe metabolic challenges on the HPG system (reviewed extensively Crown et al., 2007; Elias and Purohit, 2013; Schneider, 2004; Schneider and Watts, 2009; Schneider et al., 2012; Wade and Jones, 2004). It has long been known that energy is the most important factor that controls reproduction in all vertebrate taxa (Bronson, 1989; Gittleman and Thompson, 1988; Lack, 1954; Rousseau and Dufour, 2007; Sibly et al., 2012). Both the mechanisms that control the HPG system and those that control food intake are sensitive to fluctuations in the availability of oxidizable metabolic fuels. Food intake is increased by food restriction or deprivation, and by treatments that decrease levels of glucose oxidation, fatty acid oxidation, suppression of hepatic ATP levels, central activation of adenosine monophosphate-activated protein kinase (AMPK), enhanced expression of malonyl coenzyme A decarboxylase, and increases in energy expenditure (Friedman, 1989, 1998, 2008; Friedman et al., 1986, 1999; He et al., 2006; Horn et al., 2004; Ji and Friedman, 1999; Ji et al., 2000; Kohno et al., 2011; Li et al., 2011; Ritter, 1986). Similarly, energetic challenges (e.g., food restriction or deprivation) inhibit the HPG system in representative members of every mammalian order and of every vertebrate class (reviewed by Bronson, 1989). Fertility is constrained by energy availability in birds, reptiles, amphibians, and fish (Rousseau and Dufour, 2007). Energy availability has welldocumented inhibitory effects on the HPG system in birds, affecting sex, parental, and social behaviors (Lack, 1968; Perfito et al., 2008; Scheuerlein and Gwinner, 2002; Sibly et al., 2012; Thomas et al., 2001; Watts and Hahn, 2012). Reproductive success is linked to both food availability and body size in snakes (Shine, 2003; Shine et al., 2000). Energy availability is linked to reproductive success in amphibians. In anurans, reproduction is energetically expensive; females produce several thousand eggs in a season. Egg size and number in bull frogs (Hoplobatrachus tigerinus, formerly known as Rana tigrina) is controlled by the overall availability of fuels from the diet and body fat stores, and the inhibitory effects of lipectomy on fertility are prevented by increasing the frequency of meals (Girish and Saidapur, 2000). Energy availability is an important mediator of reproductive success in fish. Female zebrafish (Danio rerio) spawn daily when supplied with food, but unless they can eat continuously their egg production declines sharply (Wang et al., 2006). Even in invertebrates, energy availability is linked to reproductive success. Male fiddler crab (Uca lactea) courtship displays are linked to environmental energy availability; supplementing the males' food supply increases the number of nights they engage in courtship displays (Kim et al., 2008). In the fruit fly, (Drosophila melanogaster), females match the rate of re-matings to the perceived nutritional environment (Wigby et al., 2011). Even in C. elegans, fooddeprivation inhibits mating and causes retention of eggs, and mating and egg-laying are stimulated by re-feeding (Luedtke et al., 2010). According to parental investment theory (Trivers, 1972), it might be expected that the male HPG system is insensitive to energy availability, since sperm production requires less energetic investment than oogenesis, pregnancy, and laction/incubation. To the contrary, deficits in food availability inhibit GnRH and luteinizing hormone (LH) secretion in both males and females, and there is a similar pattern in both sexes. In both males and females, food restriction is a potent inhibitor of LH secretion even though it has little or no effect on follicle stimulating hormone (FSH) secretion (e.g., Howland, 1975; Meredith et al., 1986; Root et al., 1975; Sisk and Bronson, 1986). Steroidogenesis in both males and females require pulsatile LH secretion of the amplitude and frequency characteristic of the well-fed animal, and thus, in both sexes, steroidogenesis is quite susceptible to food restriction or deprivation. Despite these similarities between males and females, male fertility is less sensitive to energetic challenges than female fertility. The sexual dimorphism in response to energy availability is at the level of ovulation vs. spermatogenesis. Ovulation requires high levels of LH secretion, whereas spermatogenesis does not. During food restriction, when LH secretion is inhibited, the continued secretion of FSH at high levels maintains spermatogenesis for long time periods (Bronson, 1989).

It may be true that some laboratory strains of rodents appear to be buffered from the effects of food restriction or deprivation (Jarmon and Gerall, 1961; Sachs, 1965). This might be due to using animals of a very high initial body fat content, which tends to be true of laboratory vs. wild animals, or it might be an artifact of domestication. In many wild species, the male HPG system is quite sensitive to deficits in energy availability, and these effects are exacerbated in young, lean, peripubertal animals (reviewed by Bronson, 1989). For example, mild food restriction results in profound reductions in spermatogenesis, plasma LH, and testosterone in deer mice (Peromyscus maniculatus), yet the same level of food restriction fails to affect the same parameters in house mice (M. musculus) (Blank and Desjardins, 1985). Male Siberian hamsters are sensitive to very mild food restriction in spring, at the time of the vernal reproductive recrudescence (Dooley and Prendergast, 2012). Ad libitum-fed males decrease their food intake and become gonadally regressed in response to the short day lengths of autumn and increase their food intake and show spontaneous gonadal recrudescence in the spring. By contrast, males limited to their winter food intake remain gonadally-regressed in spring until such time as they are allowed to increase their food intake (Dooley and Prendergast, 2012). In early spring when day lengths are increasing and late summer when day lengths are decreasing, Siberian hamsters experience intermediate day lengths, e.g., 13.5 h of light (10.5 h of dark). In intermediate day lengths, the male reproductive system is more sensitive to food availability than that of males housed in long days. Food restriction rapidly and significantly decreases body weight, epididymal white adipose tissue weight, and testes size in hamsters housed in an intermediate day length (13.5 h of light). The same level of food restriction has no significant effect on these parameters in long day-housed males (16 h of light), and intermediate day length has no effect on these parameters in ad libitum-fed males (Paul et al., 2009a, 2009b). As the above examples illustrate, the male reproductive system is clearly responsive to energy deficits, but the effects can be masked by other environmental variables (stimulatory photoperiods, a high body fat content, strong cues from opposite-sex conspecifics). It is difficult to accurately claim that males of a particular species are less sensitive to energetic deficits than females if that species has been domesticated for many generations, selected for maximum reproductive output rather than for the ability to modulate reproductive output according to energy availability, and tested in only the conditions that are the most stimulatory for the HPG system (i.e., long days, high levels of body fat storage, ad libitum food intake, strong pheromonal cues from opposite-sex conspecifics) (Bronson, 1989; Paul et al., 2009a, 2009b). It might be expected that the sensitivity to energy availability varies with age, prior body fat content, and prior energetic challenges, and therefore these factors confound differences due to sex. Parental investment theory might underestimate the cost of male reproductive activities. In reality, reproductive success in males is linked to many activities that include territorial defense, courtship displays, competition for copulations, copulation itself, and, in some cases, parental care. Each of these individual behaviors is not particularly energetically expensive, but the summation of the energy used in these activities may make up a substantial portion of the energy budget. Furthermore, whereas spermatogenesis is not energetically costly, synthesis and secretion of the ejaculate is more costly, and in some species each ejaculation decreases the sperm count in subsequent ejaculations; thus, energy and lifetime reproductive success are linked in males (Dewsbury, 1982). Almost every hormone and neuropeptide that inhibits the HPG system increases food intake, whereas almost every hormone and neuropeptide that stimulates the HPG system decreases food intake (Table 1) (reviewed by Donato et al., 2011; Elias and Purohit, 2013; Hill et al., 2008; Schneider et al., 2012). A notable exception is CRH, which is released in response to various stressors and is inhibitory for food intake, sex behavior, GnRH secretion, and gonadotropin secretion. The dual action of many of these so-called feeding hormones might


have been conserved, or might have arisen over and over again throughout evolution. From this line of research important principles have emerged, and these are applicable to the study of ingestive behavior and the choice between courtship and foraging. First, the HPG system is primarily responsive to the availability of oxidizable metabolic fuels. The correlations among HPG function, body fat content, and circulating concentrations of leptin are explained by the fact that body fat is a primary source of metabolic fuels, and leptin stimulates fuel oxidation. During food shortages, triglycerides are hydrolyzed and fatty acids are mobilized to tissues where they can be oxidized. Furthermore, plasma leptin is correlated with reproductive function, not only because it is correlated with body fat content, but because leptin stimulates free fatty acid and glucose oxidation (Muoio et al., 1997) and possibly because it inhibits lipogenesis (Buettner et al., 2008). HPG function requires a sufficient supply of metabolic fuels, but does not require plasma leptin concentrations to rise above starvation levels. First, in sheep, the pulsatile secretion of LH is inhibited by food deprivation and rapidly restored by re-feeding, prior to increases in body fat content or plasma leptin concentration (Szymanski et al., 2007). Second, in hamsters, food deprivationinduced anestrous is reversed by re-feeding with no significant increases in plasma leptin concentrations above those of food-deprived females (Schneider et al., 2000; Wade et al., 1997). Third, in birds, seasonal fluctuations in reproduction occur independent of leptin (Sharp et al., 2008; Te Marvelde and Visser, 2012). Rather, the HPG system is controlled by the availability of metabolic fuels, although in some cases, leptin can enhance fuel oxidation. First, in Syrian hamsters, food deprivation-induced anestrous can be reversed by leptin treatment, but not when the availability of oxidizable metabolic fuels is blocked using doses of pharmacological inhibitors of glucose and fatty acid oxidation lower than those that induce anestrous in female hamsters fed ad libitum (Schneider et al., 1997, 1998). Second, in rats, pulsatile LH secretion is inhibited by fasting or treatment with inhibitors of glucose or fatty acid oxidation, but leptin treatments that inhibit the secretion of corticosterone fail to restore LH pulses (Nagatani et al., 2001; True et al., 2011). Third, the infertility of the ob/ob mutant mouse that lacks a functional leptin protein can be fully reversed by the addition of a knockout of the CRH gene, and this is also true with regard to the hyperphagia and obesity of ob/ob mice (Wang et al., 2012). These data on leptin and reproduction have parallels to data on leptin and food intake. Elevated plasma corticosterone concentrations are both necessary and sufficient for the induction of hypothalamic AGRP mRNA with fasting and diabetes (Makimura et al., 2003), two conditions characterized by hyperphagia. This suggests that leptin does not inhibit food intake directly, but rather, leptin influences food intake indirectly by its effects on glucocorticoids, hormones with profound effects on the disposition of metabolic fuels. In a similar vein, leptin is a poor signal for the decreases in food intake that occur during winter hibernation because hibernation requires not only a cessation of eating but a precipitous drop in metabolic rate and fuel oxidation; leptin, by contrast, increases metabolic fuel oxidation (Rossetti et al., 1997). Leptin treatment prevents the onset of daily torpor in both the striped-faced dunnart (Sminthopsis macroura) and the Siberian hamster (Phodopus sungorus) (Freeman et al., 2004; Geiser et al., 1998). Changes in plasma leptin concentration do not explain seasonal changes in food intake in little brown bats (Myotis lucifugus). During prehibernation hyperphagia and body weight gain, plasma leptin concentrations peak well before peaks in body weight and food intake. Thus, high circulating concentrations of leptin do not prevent prehibernation fattening and hyperphagia and do not explain decreases in food intake during entry into hibernation (Kronfeld-Schor et al., 2000). Thus, though there are correlations between plasma leptin concentrations and body weight over the year in some hibernators (Concannon et al., 2001), this correlation is not present in others (Freeman et al., 2004; Geiser et al., 1998), and a causal relationship between plasma leptin and

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hibernation hypophagia has not been documented to the best of our knowledge. In summary, metabolic control of the HPG system and food intake are most proximately related to availability of oxidizable metabolic fuels. Consistent with this idea, effects of leptin, ghrelin, and possibly kisspeptin appear to act on the HPG system and food intake via intracellular detectors of fuel metabolism such as AMPK and mTOR (Minokoshi et al., 2008; Roa et al., 2009; Sajapitak et al., 2008 and reviewed by Woods et al., 2008). Estrous cycles, GnRH, and pituitary LH secretion are influenced directly by central and peripheral availability of oxidizable fuels, including free fatty acids (Garrel et al., 2011; I'Anson et al., 2003; Sajapitak et al., 2008; Schneider and Wade, 1989; Shahab et al., 2006; Szymanski et al., 2011). Summary and conclusions The chemical messengers listed in Table 1 have profound effects on appetitive aspects of both reproduction and ingestion in addition to their well-known effects on food intake. Mechanisms that control the choice between food and sex are ancient and they may have been conserved, since they appear in a wide range of species including invertebrates, amphibians, reptiles, birds, and mammals. Behavioral motivation and the choice between sex and ingestive behavior appear to be important even in the nematode worm, C. elegans. The effects of hormones on appetitive behaviors are masked when energy is abundant and illuminated when energy is scarce, consistent with the idea that they function to orchestrate the appetites for food and sex in the face of fluctuations in energy availability. The study of both appetitive and consummatory behaviors can be instructive because appetitive behaviors are often under the control of neural circuitry and neuropeptide systems that differ from those that control the performance of ingestion and copulation. The idea that motivation is controlled by an interaction between metabolic fuel availability and hormones is echoed in examples from species as diverse as mice, rats, voles, Syrian hamsters, penguins, humming birds, sparrows, kittiwakes, lizards, garter snakes, and toads. Progress will be facilitated by location and characterization of the sensory system that detects metabolic fuel availability. It will be important to understand how fuel availability stimulates hormone secretion and action, as well as how hormones change energy oxidation and storage thereby altering the metabolic stimulus. Ingestive behavior is most often studied in the field, or in laboratory animals housed in isolation in small, confined spaces with few behavioral options. Field and laboratory experiments often yield conflicting results and conclusions. The discrepancies might be resolved by experiments that manipulate metabolic fuel availability and the presence or absence of potential mating partners. The key to a realistic and indepth understanding of the function of neuroendocrine systems might be attention to a wide range of species studied in a context in which critical environmental variables are controlled. Other than the ease of genetic manipulation, there is little reason to confine our attention to laboratory rats and mice. Acknowledgments We extend our heartfelt appreciation to the anonymous reviewers and the editor who provided critical information, insights, and corrections to the original version of this review. We also thank Jay Alexander for his outstanding artistic and technical talents exhibited in Figs. 1–5. For astute comments on drafts of the manuscript we thank Amber Rice, John Nyby, Murray Itzkowitz, Erica Crespi, Deborah Lutterschmidt, Fran Ebling, and Brian Prendergast. Finally, we thank the Schneider laboratory undergraduates for thorough proof reading and grammar advice: Elizabeth Krumm, Ryan Andrews, Brandon Salzman, Joseph Munier, Connor Funsch, Emma Galarza, Jessica Sevetson, Elise Esposito, and Emma Newkirk. Nobody does it gooder.

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