Hormones and Behavior 66 (2014) 7485

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Hormones and Behavior

journal homepage: www.elsevier.com/locate/yhbeh

Review

Development of food intake controls: Neuroendocrine and

environmental regulation of food intake during early life
Erica J. Crespi , Margaret K. Unkefer
School of Biological Sciences, Washington State University, Pullman, WA 99164, USA

a r t i c l e i n f o a b s t r a c t

Available online 12 April 2014 This article is part of a Special Issue "Energy Balance".

Keywords:
The development of neuroendocrine regulation of food intake during early life has been shaped by natural selection
Appetite regulation
to allow for optimal growth and development rates needed for survival. In vertebrates, neonates or early larval forms
Glucocorticoids
Testosterone typically exhibit feeding drive, characterized by a developmental delay in 1) responsiveness of the hypothalamus
Leptin to satiety signals (e.g., leptin, melanocortins) and 2) sensitivity to environmental cues that suppress food intake. Ho-
Hypothalamus meostatic regulation of food intake develops once offspring transition to later life history stages when growth is
Developmental plasticity slower, neuroendocrine systems are more mature, and appetite becomes more sensitive to environmental or social
Epigenetics cues. Across vertebrate groups, there is a tremendous amount of developmental plasticity in both food intake regu-
Maternal effects lation and stress responsiveness depending on the environmental conditions experienced during early life history
stages or by pregnant/brooding mothers. This plasticity is mediated through the organizing effects of hormones act-
ing on the food intake centers of the hypothalamus during development, which alter epigenetic expression of genes
associated with ingestive behaviors. Research is still needed to reveal the mechanisms through which environmen-
tal conditions during development generate and maintain these epigenetic modications within the lifespan or
across generations. Furthermore, more research is needed to determine whether observed patterns of plasticity
are adaptive or pathological. It is clear, however, that developmental programming of food intake has important ef-
fects on tness, and therefore, has ecological and evolutionary implications.
2014 Elsevier Inc. All rights reserved.

Contents

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Development of food intake controls in mammalian models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Development of food intake controls in amphibians, sh, and birds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Birds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Amphibians . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Fishes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Effects of the environment during development of food intake controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
Endocrine mediators of developmental plasticity in food intake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
Epigenetic modications and developmental plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Future research directions: integration of development, behavior, ecology and evolution. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

Introduction animals that are dependent on parental provisioning of food such as

For most vertebrates, the diet and food intake patterns at the earliest
developmental stages vary greatly from those of adults, especially in
Corresponding author at: P.O. Box 644236, Pullman, WA 99164-4236, USA.
E-mail address: erica.crespi@wsu.edu (E.J. Crespi).
mammals and birds. This is also the case for frogs or sh that have larval
or juvenile forms that inhabit a completely different environment from
those inhabited by adults. In all of these situations, the regulation of
food intake follows a developmental progression that is geared toward
obtaining resources while optimizing growth and survival through
these early life history stages.

http://dx.doi.org/10.1016/j.yhbeh.2014.04.004
0018-506X/ 2014 Elsevier Inc. All rights reserved.
 E.J. Crespi, M.K. Unkefer / Hormones and Behavior 66 (2014) 7485
In this review we take a comparative approach to synthesize
what is known about the development of neuroendocrine regulation
of food intake across vertebrate groups. We do not extensively re-
view all aspects of food intake regulation in each group, although
we provide references of reviews and key papers for each; rather,
we aim to highlight the developmental processes that affect food in-
take behaviors across groups. Food intake strategies also vary within
the adult lifespan due to changes in activity across seasons, e.g., sea-
sonal breeders, migratory species, or hibernators (Cornelius et al.,
2013; Janos et al., 2011). While these transitions offer unique oppor-
tunities to explore how changes in food intake regulation is adapted
to allow for successful life history transitions, here we focus on early
life history stages and how the development of food intake controls
can be altered by the environment. Because the brain is still devel-
oping during early stages, the environment experienced during
this time can inuence food intake regulation throughout the life
of the animal (see reviews Grayson et al., 2010; Grove et al., 2005;
Spencer, 2013). Therefore, we also review what is known develop-
mental plasticity in food intake regulation across vertebrates, and
the endocrine and epigenetic modications that mediate this plas-
ticity. We conclude by highlighting the ecological and evolutionary
signicance of developmental plasticity in food intake regulation
and by providing a prospectus of future research directions in this
eld.
Development of food intake controls in mammalian models
Our understanding of the ontogeny of neuroendocrine mechanisms
regulating food intake largely comes from studies of rodents, which
serve as models to which developmental processes of other organisms
can be compared. Neonatal rat and mice pups are born highly depen-
dent on maternal care and resource provisioning, as many physiological,
morphological and sensory systems are still developing and the accu-
mulation of fat reserves is needed to survive. Not surprisingly, food in-
take regulation during the rst few weeks of this neonatal period is
characterized by an overriding drive to eat (Melnick et al., 2007). In-
stead of the adult homeostatic neuroendocrine model of food intake
regulation, in which post-meal satiety signals regulate meal size and fre-
quency (Schwartz et al., 2000), oral-sensory reexes stimulate food in-
take right after birth (Grove et al., 2005; Smith, 2006). Signals reecting
hydration status are primarily used to determine the volume of milk to
consume, as eating and drinking regulation is the same at this stage
(Smith, 2006). The primary negative feedback that is associated with
the cessation of suckling is driven by the extension of the stomach,
which stimulates peripheral neurological and hormonal signals from
the gastrointestinal tract to the hindbrain (Eisen et al., 2001). There is
no evidence to suggest that nutrition-related cues are used to regulate
food intake within the rst weeks of post-natal life; it appears that it
is all about volume (Smith, 2006).
During this neonatal period in rodents, neural circuits between the
brainstem, the gut, and the hypothalamus are critical to the regulation
of food intake behaviors. The brainstem is thought to be the integrator
of hunger and satiety signals, as the hypothalamic feeding centers
(e.g., arcuate nucleus, ARC, paraventricular nucleus, PVN, ventromedial
and lateral hypothalamus) are not yet involved to a great extent in the
regulation of food intake (Grove et al., 2003, 2005). Studies have
shown that ARC neurons are not yet responsive to circulating hormones
in the periphery, nor are they neurologically connected to other hypo-
thalamic feeding centers (Grove et al., 2003, 2005). For example, exper-
imental administration of neuropeptide Y (NPY), one of the most potent
orexigenic neuropeptides involved in hypothalamic regulation of appe-
tite during later life stages, increases suckling behavior as early as post-
natal day 2 (Capuano et al., 1993). However, endogenous NPY may not
be a signal that promotes food intake at this time, because it is expressed
in very low levels in the ARC, and efferent projections of NPY neurons do
not extend from the ARC to other hypothalamic nuclei until later in the
75
post-natal period (Grove et al., 2003; Smith, 2006). In addition, three of
the primary anorexigenic or satiety signals in adults, the hypothalamic
neuropeptide -melanocyte-stimulating hormone (-MSH), the fat-
secreted hormone leptin, and the gut-secreted hormone cholecystoki-
nin, do not exert their inhibitory effects on food intake until after this
3-week period (Grove et al., 2003; Proulx et al., 2002; Rinaman et al.,
2003). The switch between hindbrain-driven food intake regulation to
hypothalamic-driven regulation occurs during the weaning period
when NPY and MSH neurons in the ARC 1) become sensitive to
orexigenic (e.g., stomach-secreted ghrelin) and anorexigenic signals
(e.g., leptin) coming to the hypothalamus from the periphery, and 2)
form connections to the PVN and other food intake centers of the
brain (e.g., leptin; Melnick et al., 2007).
In addition to the immaturity of the hypothalamic homeostatic
regulatory system, the feeding drive of the early neonatal period is
also established due to the lack of physiological responsiveness to
environmental perturbations displayed by rodent pups. The rst
two weeks after birth is often called the stress hypo-responsive pe-
riod, and is characterized in part by a reduction in stress-induced in-
hibition of food intake relative to responses exhibited by older pups
(Levine, 2002; Sapolsky and Meaney, 1986). During this period, the
hypothalamo-pituitary-adrenal (HPA) axis has not fully developed;
thus the responsiveness of corticotropin-releasing factor (CRF) neu-
rons in the PVN to environmental stimuli is reduced, which also pre-
vents the secretion of glucocorticoids in these conditions (Levine,
2002). Although this hypo-responsive period is thought to be an ad-
aptation to minimize the negative effects of elevated glucocorticoids
on neurogenesis, cell proliferation of developing organ systems, and
immune function (Levine, 2002), the suppression in secretion of CRF,
a potent anorexigenic neuropeptide, also allows for the maximiza-
tion of food intake and growth during the suckling period
(Heinrichs and Richard, 1999). As pups are weaned, the HPA axis ma-
tures and rat pups display a greater sensitivity to social or environ-
mental conditions that prevent foraging in potentially adverse
conditions (Sapolsky and Meaney, 1986). The mechanisms that
modulate the timing of maturation of hypothalamic CRF neurons
and expression of CRF receptors, or lack of sensitivity of various sen-
sory systems that detect potential stressors is an excellent point of
focus for future research.
By contrast to rodents, hypothalamic regulation of food intake
develops in utero in precocial animals with longer gestation periods.
In non-human primates and sheep, bers containing both NPY and
agouti-related protein (AgRP), another orexigenic neuropeptide, are
found throughout the hypothalamus in the late second-trimester, and
density of these projections increases in the third trimester as birth ap-
proaches (Grayson et al., 2006; Muhlhausler et al., 2004, 2006). In addi-
tion, neuronal connections between the brainstem and hypothalamic
feeding centers are established in utero. For example, during late gesta-
tion in nonhuman primates, NPY neurons extend from the brainstem to
the ARC during the late third trimester (these neurons extend to PVN in
post-natal rodents), and there is an increase in NPY neurons extending
from the ARC to the PVN during late gestation (Grayson et al., 2006).
Connectivity of hypothalamic feeding centers also matures during late
gestation in sheep, when experimental administration of NPY stimu-
lates swallowing behavior in late gestation fetuses (El-Haddad et al.,
2004a). Feeding drive (i.e., lack of response to satiety signals) appears
to begin before birth in sheep, as leptin administration does not inhibit
these in utero swallowing behaviors (El-Haddad et al., 2004b; Ross
et al., 2003). Leptin levels are positively correlated with fat mass and
growth in human infants during the rst 90 days after birth (Akcurin
et al., 2005; Karakosta et al., 2011), but to our knowledge there is no ev-
idence to suggest that leptin acts as a physiological regulator of meal
size at this life stage in humans, primates or sheep. These ndings sug-
gest that like rodents, there is a delay in the development of neuroendo-
crine satiety signals during the earliest, rapid-growth life stages of
mammals with extended gestation (Fig. 1).
76 E.J. Crespi, M.K. Unkefer / Hormones and Behavior 66 (2014) 7485

Fig. 1. Schematic representation of the two generalized stages of food intake during early development in vertebrates. During early life stages (e.g., neonatal mammals, premetamorphic
tadpoles), growth is maximized to rapidly attain a critical body size for survival, thus this stage is characterized by a feeding drive. During the switch to homeostatic regulation of food
intake (e.g., weaning, prometmorphic stage of anuran tadpoles), growth rate tapers off as hypothalamic satiety and hunger centers mature and food intake is more highly inuenced
by environmental or social cues during later developmental stages. (Illustrations by M.K. Unkefer).

Development of food intake controls in amphibians, sh, and birds
Comparative studies have shown that the major neuropeptides and
peripheral hormones known to affect food intake in mammals have
similar roles in other vertebrate groups, such as sh, amphibians, and
birds (Carr et al., 2002; Crespi et al., 2004; Hoskins and Volkoff, 2012;
Kuenzel, 1994; Volkoff et al., 2005). In addition, the hypothalamus and
hindbrain are important regulatory centers of food intake in the central
nervous system of these vertebrates as in mammals, although other
brain regions are studied in this context as well (e.g., pre-tectum/optic
tectum in amphibians, Carr et al., 2013). Given the evolutionary conser-
vation of food intake mechanisms and central nervous systems despite
very different life histories, there are interesting parallels as well as
novel contexts in the development of hypothalamic food intake controls
between pre- and post-weaning rodents and those early life history
stages of other vertebrates. Here we highlight the neuroendocrine
regulation of food intake during early life history stages of birds, am-
phibians and sh and make comparisons to the developmental patterns
in mammals described above.
Birds
In precocial birds, the neonatal chicken has been the model in which
the neuroendocrine controls of food intake have been studied. Experi-
mental administration of orexigenic (e.g., NPY Jonaidi and Noori, 2012)
and anorexigenic neuropeptides (-MSH, Honda et al., 2012; CRF,
Ohgushi et al., 2001) stimulated and inhibited food intake in neonatal
chicks and adults, respectively. Hypothalamic NPY mRNA expression is
low at hatching and increases with age, suggesting that endogenous
NPY may not be playing a signicant role in regulating food intake in
the rst days post-hatching (Cassy et al., 2004). Leptin administration in-
hibits food intake in adult chickens (Cassy et al., 2004; Denbow et al.,
2000), but in neonatal chicks leptin treatment has been shown to cause
a weaker reduction or no effect, depending on the study (Bungo et al.,
1999; Cassy et al., 2004). Like rodents, the expression of leptin receptor
in the hypothalamus of avian neonates is lower than that of 35-day old
chicks (Cassy et al., 2004), which may explain the reduced actions of lep-
tin during earlier life stages in chicks as seen in neonatal rodents. These
results suggest that at least one possible mechanism that mediates the
similarities between post-hatching birds and neonatal rodents is their
relative resistance to the action of satiety signals. However, little is
known about the developmental expression patterns of hypothalamic
neuropeptides involved in food intake during early stages of develop-
ment beyond chickens. Comparative studies in other precocial birds or
in altricial birds are needed to establish whether actions of hypothalam-
ic satiety signals are generally delayed in early life stages of birds.
In both precocial and altricial birds, there is evidence that hatchlings
experience a hypo-responsive period associated with feeding drive as de-
scribed in neonatal rats. In the broiler chicken, a strain selected for rapid
growth and body size, neonatal chicks eat more (Cassy et al., 2004), ex-
hibit less fearful behavior, and lower glucocorticoid responses to stressors
 E.J. Crespi, M.K. Unkefer / Hormones and Behavior 66 (2014) 7485
and standardized CRF injections than chicks from slower growing strains
(e.g., layers; Furuse, 2007). Broiler chicks also have higher amounts of
other factors that suppress HPA axis responsiveness (e.g., melatonin,
lipids, creatine) than other bird strains (Furuse, 2007). In altricial birds,
a neonatal hypo-responsive period also has been proposed, as many spe-
cies show a reduced stress-responsiveness to handling or other stressors
during the early part of the nestling period (Lynn et al., 2013; Wada and
Breuner, 2010). In white-crowned sparrows, the responsiveness of gluco-
corticoids to acute stressors is low right after hatching, but corticosteroid-
binding globulins keep free levels of glucocorticoids low through 79
days of the nestling period (Wada et al., 2007).
Regulation of feeding behavior in the nestling stage also involves
corticosterone and testosterone signaling in altricial birds, although
the direction of the effects of these hormones is not consistent across
species or contexts (reviewed in Henriksen et al., 2011). The level of
competition for food is intense among siblings within the nestling
stage, and factors that increase begging behaviors or vocalizations typi-
cally yield greater amounts of food obtained from parents. Transient in-
creases in glucocorticoids during the nestling stage have been shown to
inhibit begging behaviors and reduced growth in white-crowned spar-
rows (Wada and Breuner, 2008). By contrast, in the context of increased
glucocorticoids in times of food shortages, Kitaysky et al. (2001) showed
that experimentally increasing corticosterone in black legged kittiwake
nestlings increased begging behavior, although it did not stimulate in-
creased feeding rates from parents. Several studies also showed that
circulating testosterone levels in nestlings correlate positively with beg-
ging behaviors, growth, and edgling success of offspring within and
between nests (Goodship and Buchanan, 2006; Groothuis et al., 2005).
Variation in corticosterone and testosterone levels in offspring has
been associated with environmental conditions of the parents, such as
higher population densities (Bentz et al., 2013) or low food availability
(Kitaysky et al., 2001). Elevated circulating concentrations of these hor-
mones in maternal circulation allows for excess allocation of corticoste-
rone and/or testosterone into egg yolks and developing embryos
(corticosterone: Hayward and Wingeld, 2004; Hayward et al., 2005;
testosterone: Groothuis et al., 2005; Schwabl, 1996). Although the fre-
quency of begging behaviors resulting from elevated corticosterone or
testosterone increases tness in some studies, there also can be negative
effects on growth and development rates (Kilner, 2001; Kitaysky et al.,
2003; Wada and Breuner, 2008). Together these ndings show that glu-
cocorticoids and testosterone inuence growth and ingestive behaviors
in newly hatched birds, but there is much work to do to distinguish be-
tween correlation and causation.
Amphibians
In anuran amphibians, there have been several studies examining
the roles of NPY, CRF, and -MSH, glucocorticoids (corticosterone),
and leptin in the regulation of food intake in larval and post-
metamorphic frogs (see Table 1). Early in larval development (i.e.,
premetamorphic stage), elevations in corticosterone (experimental or
stress-induced) inhibit growth in several species (e.g., Glennemeier
and Denver, 2002; Ledon-Rettig et al., 2009), although food intake per
se was not observed. Administration of CRF in the tadpole brain inhibits
food intake in all stages of development, which suggests that elevations
in CRF secretion causes stress-induced anorexia in tadpoles that have
been observed throughout the larval period (Crespi and Denver,
2004). These results are consistent with those in many species suggest-
ing that stress-induced CRF is accompanied by the inhibition of food in-
take; however, we do not know if orexigenic neuropeptides are needed
to stimulate food intake at this stage.
More complex hypothalamic regulation of food intake by inhibitory
factors develops during prometamorphic larval stage (see Table 1),
which is a time when other neuroendocrine systems mature prior to
metamorphosis. Crespi and Denver (2004) showed that icv injection
of a general CRF receptor antagonist had no effect on food intake during
premetamorphic stages, but it caused a dramatic elevation in food
77
intake in prometamorphic tadpoles and juveniles. Therefore, only dur-
ing later tadpole stages does CRF regulate food intake by tonic inhibition
(in non-stressed animals). These ndings also show that CRF as a dual
role in amphibians as seen in other animals. It can inhibit food intake
in stressful and non-stressful situations, an effect with can be reversed
by treatment with a CRF antagonist.
Leptin also inhibits ingestive behaviors in amphibian tadpoles,
but there is a similar developmental shift in its action as seen with
CRF. During premetamorphic stages icv leptin injection does not affect
food intake behaviors, but after the prometamorphic transition leptin
inhibits food intake in a dose-dependent manner as it does in post-
metamorphic frogs (Crespi and Denver, 2006). Given that leptin exerts
its anorexic effect partially via CRF stimulation in mammals (Uehara
et al., 1998), it is possible that these developmental shifts in CRF and lep-
tin actions are functionally linked. This greater regulation of food intake
by inhibitory signals during later tadpole stages is associated with an
overall greater sensitivity to environmental conditions as metamorpho-
sis approaches. Many anuran frogs exhibit plasticity in growth and
developmental timing according to environmental conditions in the
pond; when conditions become adverse, the timing of metamorphosis
can be accelerated in many anuran species by activation of the
hypothalamo-pituitary-interrenal (HPI, analog to HPA in amphibians
and sh) axis (Denver, 1997). Once metamorphic climax is attained
rapid morphological changes ensue, including a reformation of the gut;
anorexia is associated with this process (Crespi and Denver, 2004;
Matsuda et al., 2010). An increase in the actions of anorexigenic factors
in the hypothalamus at this time would allow for this cessation of feeding.
Another developmental shift in the actions of neuropeptides related
to food intake occurs as metamorphosis approaches. In contrast to the
effects of NPY in other vertebrates and in post-metamorphic frog, icv in-
jection of NPY inhibits food intake in prometamorphic tadpoles (Crespi
and Denver, 2012, in spadefoot toads, Spea hammondii; Crespi and
Kucera in Xenopus, unpublished data). This developmental reversal in
the effect of NPY may be due to differential expression of NPY receptors
during this life history transition, with the inhibitory actions mediated
through the Y2 receptor in tadpoles. Alternatively, NPY may stimulate
CRF neurons to cause anorexia and elevations in NPY may serve as a cue
for HPI activation of metamorphosis. NPY also increases with cortisol
levels during late gestation in sheep, and this connection has been pro-
posed to precipitate birth in response to high energy demand as would
be indicated by high fetal NPY levels (Warnes et al., 1998). Developmental
reversals in neuropeptide actions also have been observed in mammals
(Melnick et al., 2007), and future research on NPY regulation of food in-
take through the tadpole-metamorph transition in spadefoot toads will
add to our understanding of the molecular mechanisms that underlie
the differences in ingestive behaviors over the life history of animals.
In contrast to the inhibitory effects of NPY in spadefoot toad tad-
poles, Shimizu et al. (2013) found that NPY injections stimulated food
intake in bullfrog tadpoles (Rana catesbeiana), and this effect was
blocked by the Y1 receptor antagonist. These ndings are similar to
those of Crespi and Denver (unpublished data) that showed that a gen-
eral NPY receptor antagonist reduced food intake in prometamorphic
bullfrog tadpoles (although icv NPY injections did not increase food in-
take). Given that bullfrogs are in a different genus and remain in the
tadpole stage for 23 years, while spadefoot toad tadpoles metamor-
phose within weeksmonths, it is possible that the development of
food intake controls vary phylogenetically and/or with life history with-
in amphibians as they do across different mammals groups with differ-
ent gestation times (see above).
After metamorphosis, most frogs transition from a grazing or lter-
feeding strategy as tadpoles to a predatory, sit-and-wait feeding strategy,
and this shift is associated with differences in their neuroendocrine regu-
lation of food intake. The earliest studies of the regulation of food intake in
frogs showed that stomach distention is a primary signal for short-term
satiety after a meal, as shown by reductions in food intake on subsequent
days after frogs were fed a big meal or given glass beads (reviewed in
78 E.J. Crespi, M.K. Unkefer / Hormones and Behavior 66 (2014) 7485

Table 1
Development of evolutionarily conserved neuroendocrine regulators of food intake in anurans, with neuroanatomical and behaviors associated with each factor across early life history
stages. NPY = neuropeptide Y, MSH = alpha melanocyte-stimulating hormone, CRF = corticotropin-releasing factor, CORT = corticosterone.

Premetamorphic
Detritivore/omnivore Prometamorphic
Detritivore/omnivore
Post-metamorphic
Predator

NPY
Location Various nuclei in diencephalon including preoptic Higher levels in diencephalon including preoptic area, Pre-tectal thalamus, ventral hypothalamus, optic tectumd
area, dorsal & ventral thalamus dorsal & ventral thalamus
Xenopus laevisa, Rana esculentab, R. arenarumc X. laevisa, R. esculentab, R. arenarumc
Activity Stimulates food intake Regulates food intake Stimulates food intake
R. catesbeianae Spea hammondiif, X. laevisg S. hammondiif, X. laevisg
Inhibits food intake Inhibits visuomotor circuits in optic tectum
S. hammondiif Bombina orientalish,i
Stimulates food intake
R. catesbeianae
MSH
Location Posterior telencephalon Anterior pre-optic area Pre-optic area, pre-tectum, optic tectum & ventral
R. esculentaj R. esculentaj telecephalonk
Activity Reduced orienting behavior Bufo cognitusl, B speciosusm
CRF
Location Fibers in median eminence Increased ber density in median eminence Pre-optic area, ventral hypothalamus, optic tectum
R. catesbeiana R. catesbeianan
Activity Stress-induced anorexian Regulation of food intake Inhibits food intake
S. hammondiio S. hammondiiq, X. laevisf, R. catesbeianap, B. speciosusm
Stress-induced anorexia Inhibits visual prey cues
S. hammondiio, R. catesbeianap B. speciosus
Stress-induced anorexia
X. laevisg, S. hammondiio, R. perezir
CORT
Activity Stress-induced reduction of growth rate Regulates food intake Exposure increased meal size
R. pipienss, Scaphiopus S. hammondiio X. laevisg
Couchiit, S. bombifronst Increases foraging behavior Reduced orienting behavior
S. hammondiio B. marinusl
Leptin
Activity No effect on foraging behavior Inhibits foraging behavior Inhibits foraging behavioru
S. hammondiiu S. hammondiio
Repeated injections lead to weight loss
X. laevisv
a
Tuinhof et al. (1994).
b
D'Aniello et al. (1996).
c
Heer et al. (2009).
d
Andersen et al. (1992).
e
Shimizu et al. (2013).
f
Crespi and Denver (2012).
g
Crespi et al. (2004).
h
Ewert et al. (2001).
i
Funke and Ewert (2006).
j
D'Aniello et al. (1994).
k
Carr et al. (2002).
l
Carpenter and Carr (1996).
m
Olsen et al. (1999).
n
Carr and Norris (1990).
o
Crespi and Denver (2004).
p
Matsuda et al. (2010).
q
Crespi and Denver (2005).
r
Gancedo et al. (1992).
s
Glennemeier and Denver (2002).
t
Ledon-Rettig et al. (2009).
u
Crespi and Denver (2006).
v
Crespi and McKee, unpublished.

Larsen, 1992). However, neuroendocrine factors are likely involved in
driving the motivation to eat (Table 1). As in tadpoles, experiments
have shown that CRF has inhibitory actions on food intake in frogs both
in stressed and non-stressed conditions (Crespi and Denver, 2004,
2005); however, unlike its effect in tadpoles, NPY stimulates food intake,
striking, and increases visual sensitivity to prey in frogs (Crespi and
Denver, 2012). Carr and colleagues showed that CRF, as well as -MSH,
increase habituation to an articial prey stimulus, another dimension of
food intake behavior (see references in Table 1). Because frogs rely on vi-
sual cues to stimulate striking at prey, stimulation of visual circuits is di-
rectly tied to the regulation of ingestive behaviors, and both CRF and
NPY are important factors that regulate excitation of optic tectum via
pre-tectal circuits (Carr et al., 2013; Ewert et al., 2001; Funke and Ewert,
2006). The actions of neuropeptides involved in the regulation of food in-
take behaviors are rarely studied in optic circuits in other groups of ani-
mals, but future research of the actions of orexigenic or anorexigenic
 E.J. Crespi, M.K. Unkefer / Hormones and Behavior 66 (2014) 7485 79

peptides in these brain regions could yield interesting insights into the
neurological basis of visual-stimulation of ingestive behaviors.
Fishes
The most information about the development of food intake regula-
tion across early life stages in shes can be found in salmonid shes. In
Atlantic salmon, which has an anadromous life cycle, food intake regu-
lation varies across early life history stages in association with differ-
ences in stress responsiveness and growth. A study by Pankhurst et al.
(2007) demonstrated that food intake is not interrupted by handling
stress during the parr stage just prior to smoltication (the switch
from freshwater to salt water). By contrast, sh in the smolt stage
show a modest inhibition to food intake, and sh in the post-smolts
showed the greatest inhibition of food intake (Pankhurst et al., 2007).
These changes in food intake paralleled the responsiveness of the HPI
axis, as post-smolt sh show the greatest increase in cortisol after 1 h
acute connement stress and parr sh exibit the least. Cortisol response
to acute stressors also was blunted during the rst few weeks of larval
development in rainbow trout (Oncorhynchus mykiss, Barry et al.,
1995). This lack of sensitivity to environmental stress is similar to the
post-natal non-responsive period associated with the rodent pups dur-
ing the suckling stage and immediate post-hatching period in birds (as
described above), and may be an adaptation allowing for maximal
growth during this life history stage and survival during the subsequent
transition from fresh to salt water during smoltication.
Similar to the anorexia exhibited by anuran tadpoles as they reach
metamorphic climax, anadromous sh undergo a period of anorexia
prior to smoltication. Depending on the species, food intake is reduced
for up to 30 days upon exposure to salt water (e.g., Arctic charr, steelhead
trout, Atlantic salmon; Pankhurst et al., 2007; Pirhonen et al., 2003). This
reduction in food intake could be specically associated with the physi-
ological changes that occur in response to the increase in salinity experi-
enced during this life history stage (Pankhurst et al., 2007). As sh
go into smoltication, endocrine factors, such as growth hormone,
insulin-like growth factor and cortisol, are elevated to stimulate the pre-
paratory development of seawater tolerance in osmoregulatory tissues
(McCormick et al., 1998). It seems that an activation of the neuroendo-
crine stress axis is often associated with morphological and physiological
changes involved in early life history transitions (see Crespi et al., 2013),
which through elevated CRF secretion or chronic glucocorticoid secretion
causes reduced food intake during these transitions.
Summary
Although there is great variation in life histories among the
animal groups described above, we see a generalized pattern in the de-
velopment of neuroendocrine regulators of food intake (Fig. 1). In each
of these animal groups, there is a period after birth in which growth rate
is maximized by delays in both the expression or reception of inhibitory
neuropeptides and the formation of food intake circuits in the hypothal-
amus and brainstem. During this feeding drive stage, gastric lling ap-
pears to be the dominant regulator of meal size and frequency
overriding a drive to eat. In addition, animals maximize growth rate
during this time via a reduction in sensitivity to environmental stimuli
that would normally inhibit food intake in other life history stages
(e.g., non-responsive neonatal period in rats, parr stage in salmon,
premetamorphic period in anuran tadpoles).

Fig. 2. Environmental conditions experienced during early development can alter food intake behaviors throughout life. Animals have different critical windows of exposure, depending on
when maturation of hypothalamic and brainstem food intake centers occurs, but it is clear that environmental conditions experienced by individuals during these early life stages can alter
levels of organizing hormones, which in turn can alter the development of neuroanatomy to produce permanent food intake phenotypes and predispositions throughout life. Neuropeptide
Y (NPY), agouti-related peptide (AgRP), -melanocyte-stimulating hormone (MSH), corticotropin-releasing factor (CRF). (Illustrations by M.K. Unkefer).
80 E.J. Crespi, M.K. Unkefer / Hormones and Behavior 66 (2014) 7485
Effects of the environment during development of food intake controls
While there are phylogenetically determined differences in the
development of food intake behaviors across vertebrate groups,
likely the result of selection on growth rates at different stages of de-
velopment within the life history of the animal (see Kingsolver and
Gomulkiewicz, 2003), the environment experienced during early
life stages can alter the development of food intake controls
(Fig. 2). Both correlative and experimental studies in humans, ani-
mal models, and wildlife have shown that variation in environment
conditions experienced during oocyte development or during early
post-natal/hatching development can predispose individuals to-
ward different patterns in food intake during later life stages. Varia-
tion in factors such as food availability, hypoxia, clutch size, density,
and maternal care during early developmental stages across species
has been shown to affect food intake, as well as anxiety-related be-
haviors, growth, glucose regulation, and predispositions to late-
onset diseases such as type II diabetes and obesity (reviewed in
Crespi and Warne, 2013; Khulan and Drake, 2012; Koletzko et al.,
2011; Krause et al., 2009; Spencer, 2013).
Developmental plasticity in food intake behaviors has been shown
to result from environmentally induced alterations in the development
of hypothalamic circuitry, such that homeostatic regulation of food
intake functions differently throughout life (Grayson et al., 2006) But
because the timing of hypothalamic maturation varies across species,
the critical periods during which the environment will have the greatest
effects on food intake also vary across species (see Fig. 2). In rodents,
conditions in utero and during the neonatal period are important, as
variation in nutrition, parental care and sibling interactions have
been shown to affect food intake behaviors later in life (Jones and
Friedman, 1982; Levine, 2002; Meaney, 2001; Page et al., 2009; Shin
et al., 2012). For example, offspring of diabetic and hyperglycemic
mothers often show hyperphagia and increased weight gain associated
with more neurons expressing orexigenic neuropeptides such as NPY
and ArGP in the ventromedial hypothalamus and ARC that suppress an-
orexigenic -MSH neurons (Franke et al., 2005), although maternal
food restriction during pregnancy could also cause hyperphagia in off-
spring (Jones and Friedman, 1982).
In animals with long gestation periods, environmental conditions
experienced during late gestation can have signicant effects on the
development of food intake control centers in the brain. In humans
and sheep, babies experiencing intrauterine growth retardation
(IUGR) or that were small for gestational age (which can be caused
by either maternal obesity or undernutrition) are more likely to be-
come obese later in life, in part due to hyperphagia (resulting in
catch-up growth) during the neonatal period (Cianfarani et al.,
2002; Edwards and McMillen, 2002; Li et al., 2013; Soto et al.,
2003). There is still debate as to whether IUGR or the post-natal
catch-up growth is more important in establishing a hyperphagic pheno-
type throughout life; but in general, these trajectories of nutrient intake
and growth are thought to enhance survival during early life history
stages at the cost of a higher probability of the onset of later-life obesity
and metabolic disease (Hales and Barker, 1992).
In amphibians, environmental conditions during the larval stage
(e.g., high conspecic density, low food resources) have been shown
to affect post-metamorphic food intake behaviors associated with
compensatory growth (Hu et al., 2008; Morey and Reznick, 2001).
In birds, the environmental conditions of parents prior to egg laying
and during nesting have been shown to affect food intake displayed
by hatchlings (Hayward and Wingeld, 2004; Henriksen et al.,
2011). For example, high conspecic density (Bentz et al., 2013)
and reduced food availability (Kitaysky et al., 2001). It is clear that
across such phylogenetic diversity, the developmental plasticity in
food intake behaviors is a common feature in vertebrates that has
important physiological, ecological and evolutionary implications
(Monaghan, 2008).
Endocrine mediators of developmental plasticity in food intake
The organizing effects of hormones, both on developing offspring
and on mothers, have been linked to the plasticity of food intake pheno-
types that vary across environmental conditions. Studies initially
conducted in mammals have shown that elevated levels of glucocorti-
coids in response to adverse environmental conditions during early de-
velopmental stages mediate these long-term effects on phenotype
(Khulan and Drake, 2012; Seckl and Meaney, 2004; Spencer, 2013).
Glucocorticoid-mediated developmental programming is also seen in
birds and frogs, suggesting that this form of programming is an evolu-
tionarily conserved mechanism of phenotypic plasticity across verte-
brates (Hayward and Wingeld, 2004; Hu et al., 2008; Spencer and
Verhulst, 2007; Spencer et al., 2009).
An example of how exposure to corticosteroids during early devel-
opment can affect later-life behavior and health is illustrated by the in-
uence of reduced resources (i.e., maternal malnutrition) during fetal/
larval stages on food intake behavior. In mammals, maternal nutritional
restriction causes increases in basal CRF content in the PVN and circulat-
ing glucocorticoid concentration of the fetus/neonate, reduced gluco-
corticoid receptor-mediated negative feedback, and is often associated
with hyperphagia and catch-up growth (Cianfarani et al., 2002;
Vickers et al., 2000). Although there are many factors associated with
catch-up growth, if pre- or neonatal stress programs basal plasma glu-
cocorticoid concentration to a higher homeostatic set point, then daily
food intake is expected to be higher in these individuals given the
orexigenic actions of glucocorticoids (Dallman et al., 2004). Interesting-
ly, the same long-term effects of nutrient restriction during early life can
be seen in diverse taxa including amphibians: reduced food availability
or high conspecic density in the tadpole stage is associated with in-
creased food intake, compensatory growth, and elevated circulating
glucocorticoid levels in juvenile frogs, particularly when in high food
conditions (Hu et al., 2008; Morey and Reznick, 2001).
By contrast, several studies have shown that elevations in glucocor-
ticoids experienced during embryonic development reduce food intake
and growth later in life. In yellow-legged gulls, Rubolinia et al. (2005)
showed that offspring hatching from eggs that were treated with corti-
costerone showed reduced begging and calling behavior of nestlings, al-
though body sizes did not vary between treated and the control groups.
Hayward and Wingeld (2004) showed that maternal implantation
with corticosterone resulted in eggs with higher circulating corticoste-
rone levels, which was associated with slower growth of hatchlings
(although food intake behavior was not measured in this study).
In wood frogs, Crespi and Warne (2013) showed that the post-
metamorphic effects of precocial elevations in corticosteorne at the
end of the larval period depended on food resources available to tad-
poles. When tadpoles are reared in high food environments, early
pond drying caused animals to metamorphose at a smaller size, but
they caught-up in body size to those not experiencing pond drying by
10 weeks after metamorphosis. By contrast, when tadpoles were reared
in low food environments, early pond drying also caused a reduction in
body size, but animals had slower growth after metamorphosis, and a
blunted glucocorticoid response to handling stress at 10 weeks. This re-
sult and others suggest that glucocorticoid-mediated long-term effects
of early life stress depend on the severity of the stressor in context
with the overall condition of the animal.
Another hormone that more recently has been hypothesized to have
organizational effects during development is leptin, although much less
is known about the developmental effects of leptin during early life
(reviewed in Granado et al., 2012; Vickers and Sloboda, 2012). In rodent
and sheep models, energy balance homeostasis and metabolism disor-
ders associated with intrauterine growth retardation (IUGR), or other
causes of leptin deciency during early life, can be at least partially re-
versed with leptin treatment during the neonatal period, but not at
any other period (Attig et al., 2010; Bouret et al., 2004). There is evi-
dence that the rise in leptin levels during late-gestation or towards
the end of the suckling period allows for proper development of
 E.J. Crespi, M.K. Unkefer / Hormones and Behavior 66 (2014) 7485
neuronal projections from the ARC to other hypothalamic nuclei in-
volved in the regulation of food intake, including NPY, ArRP, and
proopiomelanocortin neurons (Simerly, 2005). In addition, the timing
and size of this leptin surge can vary with maternal nutrition, and this
variance has been associated with differential onset of leptin resistance
later in life (Yura et al., 2005). Much of this work has been done in ro-
dent models, so much more research is needed to clarify leptin's specic
roles in developmental programming, including whether it mediates
epigenetic changes in gene transcription (e.g., changes are DNA methyl-
ation and histone modication) that could affect later life physiological
function (see Gluckman et al., 2007).
Interestingly, glucocorticoids and leptin may have opposing actions
during early development (Spencer, 2013). For example, elevation in glu-
cocorticoids caused by prenatally experienced stressors, such as undernu-
trition or hypoxia, induces apoptosis in the brain, reduces synaptic
connectivity and transmission of neurons (Fuxe et al., 1996; Khulan and
Drake, 2012; Levy and Tasker, 2012), and alters epigenetic regulation of
gene expression (Harris and Seckl, 2011; Szyf et al., 2005; Weaver,
2009). Leptin, which circulates at greater concentrations when animals
are in good nutritional condition, has been shown to rescue cells from ap-
optosis (Folch et al., 2012; Shin et al., 2009; Takahashi et al., 1999; Zhang
et al., 2012) and enhance dendritic morphology or synapse formation
(Harvey et al., 2006) in the face of stress. The antagonism between leptin
and glucocorticoids appears to be driven by indirect interactions of down-
stream signaling effects of these hormones on target cells, although there
are studies that show inhibitory effects of leptin on the HPA axis at the
level of brain (Heiman et al., 1997) and adrenal gland (Pralong et al.,
1998). Although much more research is needed to understand the inter-
actions between leptin and glucocorticoids, these ndings support the hy-
pothesis that variation in circulating leptin levels during stressful events
could mediate condition-dependent effects of early life stress.
Variation in sex steroid hormone exposure during early develop-
ment may also affect food intake patterns in offspring by altering the
composition, morphology and function of neural networks in the brain
(e.g., Culbert et al., 2013; Klump et al., 2006; Nohara et al., 2011;
Sheppard et al., 2011). Just as these hormones organize developmental
processes in the brain that lead to post-natally expressed sex-specic
behaviors, variation in the exposure of these hormones during critical
windows of development can cause permanent changes in the limbic-
hypothalamic circuits associated with food intake within and between
sexes (Simerly, 2005). Similar to the effects of excess in utero exposure
to glucocorticoids and leptin described above, elevations in testosterone
exposure during fetal development results in IUGR and post-natal
catch-up growth, which is associated with altered insulin and insulin-
like growth factor physiology (Crespi et al., 2006); however, increased
food intake during the catch-up growth stage has not been reported.
In altricial birds, elevations in testosterone during embryonic devel-
opment, resulting from elevated testosterone concentrations in eggs
(either from maternal transfer or experimental manipulations) increase
food intake by enhancing the competitive ability of nestlings to acquire
resources from parents in birds. Schwabl (1996) was the rst to show
that variation in maternal allocation of testosterone in the yolk of eggs
enhances growth in canary hatchlings primarily by enhancing the fre-
quency of begging behaviors relative to other hatchlings in the nest,
and this enhanced post-natal growth through edging. Subsequent
studies in several species have shown similar effects of elevated in ovo
maternal transfer of testosterone on nestling behavior, growth, and sur-
vival (reviewed in Boncoraglio et al., 2006; Goodship and Buchanan,
2006; Groothuis et al., 2005). Furthermore, increased maternal transfer
of testosterone to eggs is associated with elevations in circulating
testosterone levels in nestlings displaying increased begging and
growth (Bentz et al., 2013; Hinde et al., 2009). Given that these high-T
nestlings attain larger body sizes and greater probability of survival
through edging, the maternal transfer of testosterone to offspring is
considered to be adaptive, although tness trade-offs have been report-
ed (Groothuis et al., 2005; Kilner, 2001). Relevant to the topic of
81
this paper, however, the long-term effects of elevated testosterone on
feeding behaviors per se are not known, although increases in aggres-
sion, territoriality and social dominance have been shown to persist
(reviewed in Bentz et al., 2013).
Epigenetic modications and developmental plasticity
Studies primarily in rodents have shown that developmental plastic-
ity in feeding behavior phenotypes results from epigenetic modica-
tions (primarily DNA methylation) in gene expression. Early work in
this area showed that differences in maternal behaviors (e.g., licking,
grooming of young) could affect methylation patterns of offspring in
rats (Weaver et al., 2004), thus environmental conditions during early
development could alter behaviors and physiology throughout life via
epigenetic mechanisms. These maternally induced epigenetic effects
in offspring are mediated by elevations in glucocorticoids caused by re-
duced maternal behaviors (Weaver, 2009).
Subsequently, other factors such as maternal diet during pregnancy
have been shown to signicantly alter the epigenome of the fetus, creat-
ing a predisposition for certain metabolic proles in the offspring that
can be further altered by postnatal feeding behavior (Canani et al.,
2011; Drummond and Gibney, 2013; Martnez et al., 2012). In mamma-
lian systems, high-fat/carbohydrate diets have the ability to modify pla-
cental nutrient transfer and gene expression, resulting in differential
phenotypes in the offspring (Sferruzzi-Perri et al., 2013). Rats that
experience a prenatal low-protein diet show reduced food intake be-
havior, but demonstrate dramatic growth in adipose tissue when fed a
postnatal high-fat diet. These changes were associated with increased
methylation of insulin-like growth factor 2 (IGF-2) in adipose tissue
(Claycombe et al., 2013). The fetuses of Japanese macaques fed high-
fat diets demonstrated a three-fold increase in liver triglycerides and sig-
nicant acetylation of H3 histones in hepatic tissue (Aagaard-Tillery et al.,
2008). These ndings are supported in human systems; Drake et al.
(2012) analyzed DNA methylation of key metabolic genes (associated
with glucocorticoid actions) in the adult children of women who were in-
volved in an unbalanced dietary study during pregnancy. Methylation at
specic sites regulating 11-hydroxysteroid dehydrogenase 2, glucocorti-
coid receptor, and IGF-2 were associated with increased adult adiposity
and elevated blood pressure in these offspring (Drake et al., 2012).
While epigenetic regulation of specic food intake behaviors has yet
to be well described, alterations in the chromatin structure of offspring
resulting from variation in adult diet have been documented. The hypo-
thalamus and ventral tegmental area of mice with post-weaning diet-
induced obesity show altered gene expression and methylation patterns
within the dopamine reward pathway, demonstrating the ability of cer-
tain diets to alter food intake behavior (Vucetic et al., 2012). In compar-
isons of obese mice fed either high-fat or high-carbohydrate diets,
subjects receiving higher carbohydrates showed increased methylation
of the stearoyl-CoA gene, which was correlated with increased expres-
sion of leptin levels and decreased levels of ghrelin (Schwenk et al.,
2013). Some diet-induced epigenetic modications appear to be labile,
as the diet in later life stages could reverse such modication. Rats
raised on an obesogenic diet show differential methylation of leptin
promoters, but these effects reverted to normal levels after 10 weeks
of feeding on a standard diet (Uriarte et al., 2013). Supplementation
to poor diets can also alter methylation patterns. For example, rats fed
high-fat-sucrose diets demonstrated differential methylation of fatty
acid synthase promoter in the liver and high levels of triglycerides;
however, supplementation of the same diet with methyl donors (such
as folate) can modify methylation to a more normal state and reduce
hepatic triglyceride accumulation (Cordero et al., 2012).
More recently, the diet of parents, particularly obesogenic diets, have
been shown to alter epigenetic signatures of the parental germ line such
that the effects of diets can persist through generations. A recent study in
rats found metabolic effects in the offspring of obese fathers related to al-
tered methylation and microRNA expression in the F0 offspring's germ
line (Fullston et al., 2013). In addition, transgenerational epigenetic
82 E.J. Crespi, M.K. Unkefer / Hormones and Behavior 66 (2014) 7485
modications in offspring through the F3 generation have been caused
by exposure to endocrine disruptors, such as the pro-estrogenic com-
pounds diethylstilbestrol (DES, reviewed in Rosenfeld, 2010), bisphenol
A (Dolinoy et al., 2007), and genistein (Dolinoy et al., 2006), as well as
the anti-androgenic vinclozolin (Skinner et al., 2012, 2013). In these
studies, maternal or paternal exposure to these compounds increases
risk of reproductive disorders and cancers, altered mating preference
and social recognition (Crews et al., 2007; Wolstenholme et al., 2013),
as well as stress responsiveness and anxiety related behaviors (Crews
et al., 2012; Skinner et al., 2008). Whether these transgenerational effects
can be mediated by exposure to different environmental conditions
across generations is still in question, and in some cases epigenetically
derived phenotypes in offspring have been reversed by dietary supple-
ments of folic acid or genistein (Dolinoy et al., 2007).
An element of complexity associated with studies of developmental
plasticity of food intake behaviors is that there are signicant sex differ-
ences in plastic phenotypes, which seems to be more the rule than the
exception. Sex-specic effects of environmental conditions or expo-
sures to hormones on growth and feeding behaviors have been reported
in mammals (Jones and Friedman, 1982; Schneider et al., 2014; Simerly,
2005; Spencer, 2013) birds (de Coster et al., 2011; Hayward et al., 2006;
Sockman et al., 2008) and amphibians (Morey and Reznick, 2001). The
same holds for studies examining environmental epigenetic modica-
tions (e.g., Culbert et al., 2013; Fullston et al., 2013). Given that there
could be interactive actions between glucocorticoids and leptin with
sex steroids during early developmental periods when sexual differen-
tiation is patterned, it is not surprising that effects of early environmen-
tal conditions on food intake behaviors vary with sex (Schneider et al.,
2014; Spencer, 2013). While epigenetic modication of gene expression
and brain development is associated with sex-specic effects on behav-
ior (e.g., Crews et al., 2007; Wolstenholme et al., 2013), many of the de-
velopmental mechanisms are not understood, and the variance in the
behavioral effects does not seem consistent and cannot be predicted at
this time. Understanding these mechanisms not only will advance our
fundamental knowledge about the ways in which the environment
shapes behaviors, but will also help us to predict signicant effects of
environmental change on population and evolutionary dynamics.
Future research directions: integration of development, behavior, ecology
and evolution
Because the study of the developmental origins of food intake behav-
iors has been studied in multiple vertebrate groups, cross-group compar-
isons of processes add to a greater understanding of the common
features that exist in the development of behaviors in general. Within
many groups, however, the number of taxa studied is limited, and
there is a greater diversity of life histories in which the development of
food intake behaviors could be studied. Furthermore, most of the studies
showing developmental plasticity in food intake controls reviewed thus
far have been conducted within the laboratory or in controlled settings,
which is often necessary a) to minimize variance in environments
when rst identifying developmental mechanisms associated with food
intake behaviors, and b) to conduct experiments testing causal links be-
tween environmental conditions and behavioral phenotypes. However,
we have little understanding about the nature of developmental plastic-
ity in food intake behaviors or their endocrine or epigenetic bases in the
complexity of natural populations (see Ledon-Rettig, 2013).
Studying environmental effects on the development of offspring food
intake behaviors in the natural context allows for complete integration of
ecology, developmental biology, behavior, and evolution. In an extensive
study of red squirrels, which cycle in population density with the uctu-
ation in availability of food resources, offspring produced by females in
high density conditions showed increased growth rates compared with
those of mothers in low densities with no access to additional resources
(Dantzer et al., 2013). This increase in growth rate was associated with el-
evated fecal glucocorticoids in mothers and offspring (increased growth
rate also occured when pups were fed glucocorticoid supplements
(Dantzer et al., 2013)). These authors argue that this environment-
determined maternal programming of offspring growth is an adaptive
adjustment to anticipated conspecic density conditions that typically
cycle with availability of food resources (white spruce seeds).
In populations of snowshoe hares that undergo 10-year episodic cy-
cles that vary with predation threat, maternal and offspring glucocorticoid
levels are elevated in years of higher predation, and offspring experienc-
ing these elevations in glucocorticoids had decreased fecal glucocorticoid
concentrations but greater HPA responsiveness (Sheriff et al., 2010).
These authors suggest that this transgenerational effect on the HPA axis
is associated with reduced reproductive rates observed in these offspring
of mothers from the peak in predation levels that contribute to predator
prey population cycling. Note that the argument for the adaptive nature of
these maternally-transmitted phenotypic effects on offspring is that these
population cycles are predictable, and therefore selection can act to in-
crease patterns in developmental plasticity that optimize tness in
these species. Many more questions exist in both the red squirrel and
snowshoe hare populations, including how this transgenerational plastic-
ity specically relates to offspring behaviors (e.g., do behaviors resulting
from glucocorticoid programming allow offspring to more efciently for-
age for food in high density conditions or show greater abilities to evade
predators). Given the depth of knowledge about the ecology of this sys-
tem, hypotheses about the adaptive nature of developmental plasticity
of behaviors can be tested in these systems.
These systems are ideal to test the basic hypothesis promoted by lab-
oratory studies: diet- or endocrine-mediated epigenetic modications
resulting from environmental stimuli cause developmental plasticity of
offspring physiology and behaviors. We already know that environmen-
tally induced elevations in glucocorticoids or testosterone during preg-
nancy in mammals, during egg formation in birds, and during the larval
period in amphibians, alter offspring behaviors and physiology (as de-
scribed above), but the epigenetic mechanisms associated with these ef-
fects are largely not known. With increased sequencing of genomes in
non-model organisms and molecular approaches to uncovering epige-
netic patterns, future research will likely reveal additional patterns of en-
vironmentally induced epigenetic inheritance of phenotypes, including
ingestive behaviors (see Ledon-Rettig, 2013; Schrey et al., 2013).
A common evolutionary framework within which developmental
plasticity is studied in both biomedical and ecological contexts is the
thrifty phenotype hypothesis, which is an ultimate explanation used
to describe either 1) adaptive effects of maternal diet on offspring
food intake behaviors and resource allocation, or 2) pathological effects
of post-natal patterns of diet and food intake (see Wells, 2009 for re-
view). According to this hypothesis, the fetus should develop a metabol-
ic physiological system that aligns with the amount of resources
forecast by its maternal nutrient supply for its post-natal environment.
In times of low or unpredictable food availability, for example, offspring
should opportunistically acquire as much food as possible, and store ex-
cess resources as fat that can be tapped into when resources are scarce.
The thrifty phenotype hypothesis has been invoked to explain the adap-
tive nature of post-natal catch-up growth after intrauterine nutrient re-
striction. But because the adaptive nature of this phenotype requires a
match between maternal and neonatal environments, it also has been
used to explain the higher probability of obesity and metabolic disor-
ders later in life when IUGR individuals experience an abundance of
food after birth (but see critique in Speakman, 2008; Wells, 2007,
2009). However, other models exist that predict long-term responses
to early life stress and don't require matching of parental and offspring
environments, such as the silver spoon (Monaghan, 2008) or best of
bad lot hypotheses (Whiteman, 1994), which may be more parsimoni-
ous since the correlation between parental and offspring environments
is often loosely applied or other hypotheses are not explicitly tested.
In another perspective, the development of food intake behaviors can
be viewed within the development of personalities (or behavioral syn-
dromes, Sih et al., 2004), dened as suites of correlated behaviors that
 E.J. Crespi, M.K. Unkefer / Hormones and Behavior 66 (2014) 7485
are consistent across time and contexts that develop throughout the life of
the animal depending on experience (Stamps and Groothuis, 2010). In
this view, food intake behaviors are associated with other behavioral phe-
notypes such as aggression, exploratory activity, or anxiousness, all of
which should be considered simultaneously when assessing the adaptive
nature of behavioral plasticity. These authors emphasize that personali-
ties can change through space and time due to variation in experiences,
and the ongoing nature of this developmental process is necessary to con-
sider when examining variation in animal personalities across ecological
and evolutionary time scales (Stamps and Groothuis, 2010). This form
of developmental plasticity can be adaptive, for example, if the variation
created allows individuals in the population to partition space or differen-
tially utilize resources in a way that enhances individual tness.
Whichever the context or the specic mechanisms involved, the accu-
mulation of studies has shown signicant developmental plasticity in
food intake behaviors resulting from environmental variation during
early development when the neuroendocrine controls of food intake
are rst established. The extent to which the neuroendocrine controls
of food intake behavior are ecologically exible may relate to the evolu-
tionary capacity of vertebrates to facilitate adaptive divergence in body
sizes and diet specializations (West-Eberhard, 1989). For example, in
the sexually dimorphic house nch, the larger size of adult males relative
to females is due to faster growth rates in males during the nestling peri-
od; thus, selection on adult body size manifests in adaptations relating to
the regulation of food intake behaviors during early life (Badyaev, 2002;
Badyaev et al., 2001; Isaksson et al., 2010). Similarly, changes in the sen-
sitivity of the hypothalamus to anorexigenic factors (e.g., ,-MSH) dur-
ing the post-hatching stage have been associated with selection for larger
body size between broiler and layer chicken strain (Furuse, 2007; Honda
et al., 2012). Further examination of developmental plasticity, local
adaptation of food intake behaviors, and growth within and between
populations and species will contribute signicantly to an integrated
understanding of the ecology and evolution of behavior in general.
Acknowledgments
We thank Jill Schneider for the invitation to contribute this review
for this special issue, and the suggestions of the anonymous reviewers
who greatly improved the manuscript. Work reported in this review
was funded by NSF IOS 0818212 to E.J. Crespi.
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