Sense of Smell as the Central Driver of Pavlovian Appetite Behavior in Mammals

Abstract

The seminal experiments of Ivan Petrovich Pavlov set the stage for an understanding of the physiological concomitants of appetite and feeding behavior. His findings, from careful and creative experimentation, have been uncontested for over a century. One of Pavlov’s most fundamental observations was that activation of salivary, gastric and pancreatic secretions during feeding and sham-feeding, precedes entry of food into the mouth, generating signals to the brain from various sensory pathways. Pavlov referred to this as the “psychic” phase of digestion. However, quite surprisingly, he did not attempt to isolate any single sensory system as the main driver of this phenomenon. Herein we revisit Pavlov’s findings and hypothesize that the evolutionarily-important sense of smell is the pathway most-likely determinant of feeding behavior in mammals. Substantial understandings of olfactory receptors and their neural pathways in the central nervous system have emerged over the past decade. Neurogenic signals, working in concert with hormonal inputs are described, illustrating the ways in which sense of smell determines food-seeking and food-preference. Additionally, we describe how sense of smell affects metabolic pathways relevant to energy metabolism, hunger and satiety as well as a broad range of human behaviors, thereby reinforcing its central biological role in mammals. Intriguing possibilities for future research, based upon this hypothesis, are raised.

Full text

fphys-10-01151 September 18, 2019 Time: 8:47 # 1
HYPOTHESIS AND THEORY
published: 18 September 2019
doi: 10.3389/fphys.2019.01151
Edited by:
Stephen O’Keefe,
University of Pittsburgh, United States
Reviewed by:
Hélène Volkoff,
Memorial University of Newfoundland,
Canada
Ivan Manzini,
University of Giessen, Germany
Hongxiang Hui,
Southern Medical University, China
*Correspondence:
Leon G. Fine
leon.fine@cshs.org
Celine E. Riera
celine.riera@cshs.org
Specialty section:
This article was submitted to
Gastrointestinal Sciences,
a section of the journal
Frontiers in Physiology
Received: 25 February 2019
Accepted: 26 August 2019
Published: 18 September 2019
Citation:
Fine LG and Riera CE (2019)
Sense of Smell as the Central Driver
of Pavlovian Appetite Behavior
in Mammals. Front. Physiol. 10:1151.
doi: 10.3389/fphys.2019.01151
Sense of Smell as the Central Driver
of Pavlovian Appetite Behavior in
Mammals
Leon G. Fine1,2*and Celine E. Riera1,3,4*
1Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States, 2Program in the
History of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States, 3Center for Neural Science and
Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States, 4Board of Governors Regenerative Medicine
Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
The seminal experiments of Ivan Petrovich Pavlov set the stage for an understanding
of the physiological concomitants of appetite and feeding behavior. His findings, from
careful and creative experimentation, have been uncontested for over a century. One
of Pavlov’s most fundamental observations was that activation of salivary, gastric and
pancreatic secretions during feeding and sham-feeding, precedes entry of food into the
mouth, generating signals to the brain from various sensory pathways. Pavlov referred to
this as the “psychic” phase of digestion. However, quite surprisingly, he did not attempt
to isolate any single sensory system as the main driver of this phenomenon. Herein we
revisit Pavlov’s findings and hypothesize that the evolutionarily-important sense of smell
is the pathway most-likely determinant of feeding behavior in mammals. Substantial
understandings of olfactory receptors and their neural pathways in the central nervous
system have emerged over the past decade. Neurogenic signals, working in concert
with hormonal inputs are described, illustrating the ways in which sense of smell
determines food-seeking and food-preference. Additionally, we describe how sense of
smell affects metabolic pathways relevant to energy metabolism, hunger and satiety
as well as a broad range of human behaviors, thereby reinforcing its central biological
role in mammals. Intriguing possibilities for future research, based upon this hypothesis,
are raised.
Keywords: appetite and energy expenditure, food perception, palatability, hypothalamus, ghrelin
INTRODUCTION
In the context of food, appetite surely means “a desire for eating.” Expressed in a more exaggerated
way, it could be “a passionate longing for food.” Both descriptive phrases were used by Ivan
Petrovitch Pavlov (1849–1936) in his “Lectures on the work of the digestive glands” published in
1897, which was translated into English by Pavlov and Thompson (1902) and re-issued in Russian
and English in Pavlov and Thompson (1982).
We examine herein the seminal discoveries of Pavlov related to appetite and feeding and explore
new interpretations of some of his findings in the light of recent insights into the science of
olfaction. We argue that there was a void in his exploration of the phenomenon of appetite, with
specific regard to the sense of smell, and that this void was not filled by experimentation for over
a century. We hypothesize that sense of smell is a central driver of appetite, food-seeking, food
preference in vertebrates, including humans. We further argue that, if sense of smell is indeed
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central to these functions, from an evolutionary standpoint, it
is likely that it also participates in other, wider physiological
functions. We provide evidence from the literature for the
existence of a number of pathways via which smell influences
behavior and metabolism.
THE EXPERIMENTS AND CONCLUSION
OF PAVLOV
Pavlov the Physiologist
Pavlov, a Nobel Prize-winning physiologist, was born in Russia
and studied at the St Petersburg University and the Medico-
chirurgical Academy, from which he graduated in 1879.
Thereafter, he worked as the laboratory head at the Military
Medical Academy in St. Petersburg, before moving abroad in
1884 to study with Ludwig in Leipzig and Heidenhain in Breslau,
both being physiologists of the highest repute at the time. He
returned to the Military Academy in 1888, where he discovered
the secretory nerves to the pancreas. In the following year, he
began his experiments on sham-feeding.
He ultimately obtained a chair in pharmacology and in 1891
was appointed as Director of the Department of Physiology in
the Institute of Experimental Medicine. He became renowned for
his recognition of the conditioned reflex. Pavlov’s work focussed
mainly on the neural control of organ function, an interest
which was sustained despite the emergence of contemporaneous
discoveries of humoral control of gastrointestinal function at the
time, including the discovery of secretin, a stimulant of pancreatic
secretion, by Starling (Fine, 2014).
Pavlov’s skill as a surgeon was legion, as was his obsessive
attention to experimental detail, his use of antiseptic techniques
and his imaginative surgically created experimental models. The
conclusions he drew from his experiments never exceeded the
realities of the data generated.
Below we review Pavlov’s discovery of the stimulatory effects
of appetite on the initiation of gastrointestinal secretion and his
neuro-physiological explanations for such. We then focus on
current discoveries related to the sense of smell and olfaction as a
driver of food-seeking, appetite-stimulation and taste perception,
to which Pavlov payed specific attention.
Pavlov Revisited: End-Organ Response
Patterns
In his lectures Pavlov posed a series of pointed questions
about gastrointestinal end-organ function, which provided the
direction for his studies (Pavlov and Thompson, 1982). These
related to the quantities and constituents of secreted fluids
in different parts of the gastrointestinal tract, their inter-
relationships and their variations in response to the food ingested.
Here we focus on appetite, which precedes the phase of food
ingestion and which drives the search for food, the preferences
for certain foods and the underlying physiological processes
which govern the phenomenon of appetite. The details are of
importance since they reinforce the care and creativity which
Pavlov brought to his work.
Pavlov proclaimed: “I hope to furnish you with evidence
sufficiently convincing, that the alimentary canal is endowed, not
with mere general excitability, (that is to say, does not respond to
every conceivable form of agency), but only to special conditions
which are different for different portions of its length.”
He continues: “Gastric and pancreatic glands have, what we
may call, an instinct. They pour out their juice in a manner which
exactly corresponds, both qualitatively and quantitatively to the
amount and kind of food partaken of. Moreover, they secrete
precisely that quality of fluid which is most advantageous for the
digestion of the meal. We naturally ask ourselves at once, by what
means is this made possible? On what does this instinct of the
glands depend, and in what does it consist? A probable answer to
this question is easily given and, naturally, an explanation of the
adaptability of the glands is, above all, to be sought for in their
innervation”(Pavlov and Thompson, 1982).
It had been shown previously, in experiments on dogs and
later in a patient with a surgically created gastrotomy, that
gastric secretion was induced prior to any contact of food
with the stomach. Pavlov thus needed to set up experiments
which would allow him to determine the secretory responses
to raw materials to be found in separate portions of the
digestive canal and which would identify the stimuli to
such responses.
Pavlov’s Experimental Models
Pavlov’s experimental animal was the dog. He needed to
be able to measure salivary, gastric and pancreatic secretion
quantitatively as a function of time. Being a highly skilled
surgeon, he was able to exteriorize the salivary ducts and
the pancreatic duct and to create an isolated gastric pouch
(Figure 1) which retained it innervation but was separated
from the main body of the stomach, so that its secretions
could be sampled via an exteriorized opening in the absence of
contact with food. By observing the time courses of secretion
of these individual organs he could determine whether or
not they acted in sequence and whether they responded to
similar signals.
An important experimental model was that of “sham feeding,”
in which the esophagus was sectioned, the proximal portion
being exteriorized and the distal portion closed off. Although
the animal could eat hungrily, all the food swallowed would exit
the body via the esophageal stoma. Dogs could be fed this way
for hours, since satiety was not induced, and secretion of gastric
juice (sampled from the blind pouch) continued for the duration
of the experiment.
The “Psychic Phase” and
Physical-Chemical Stimulation of the
Salivary and Gastric Glands
The phrase “to make one’s mouth water” refers figuratively to the
phenomenon of salivation prior to putting food into one’s mouth.
Pavlov referred to saliva as the “host to every substance taken
in, preparing the food for further passage if the mouth deems it
acceptable for ingestion.” He saw this as a specific physiological
“sense” independent of the stimulation of buccal nerve endings.
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FIGURE 1 | Illustration of Pavlov’s gastric pouch. A copy of the illustration
published in the 1902 English translation of Pavlov’s “Work of the digestive
glands” (Pavlov and Thompson, 1902, 1982). (The figure was originally
created by Pavlov for the 1897 publication in Russian, the wording having
been converted into English). (A) Anatomy of stomach showing anterior and
posterior plexuses of the vagus nerve. AB shows line of incision through
anterior and posterior walls of the stomach to form a triangular flap (not
shown) in area C. An incision was made at the base of the flap only through
the mucous membrane, the muscular and peritoneal coats remaining intact.
Out of a piece of the flap a cupola was formed (not shown) to create an
innervated pouch separate from the main body of the stomach. (B) Gastric
pouch (S) with intact mucous membrane opening onto the surface of the
abdominal wall (AA) and separated from the main body of the innervated
stomach (V) Nerve endings are not shown. Sampling of gastric fluid was
performed through the open end of the pouch.
Regardless of what foodstuffs Pavlov tested, the salivary
and gastric responses to food placed into the mouth of his
experimental animals, without it entering the stomach (sham
feeding), elicited little or no immediate secretory responses. On
the other hand, tempting the dogs with food for only 5 min,
did induce secretion. The more eager the dogs were to eat, the
greater was the volume of the secretions. He further observed
that dogs demonstrated food preferences which he ascribed to
the sense organs collectively. For instance, in contrast to that
observed with meat or bread, his dogs showed little interest in
milk and very little gastric secretion accompanied its ingestion.
On the other hand, the parotid response to introduction of
flesh into the mouth was absent, but when powdered dry
flesh was introduced an abundant secretion followed. This
occurred despite the fact that the desire to eat was clearly
stronger for flesh than for dry food as assessed by salivation
prior to eating.
From an experimental standpoint, Pavlov says: “It is only
necessary that some food be near the dog or that the
hands of the attendant who has prepared the food should
smell of it or that some other similar circumstance should
come into play, which would incorrectly attribute gastric
secretion to a physical stimulus.” However, he did not conduct
experiments to isolate sense of smell as a driver of this
response (Pavlov and Thompson, 1982).
Quoting Pavlov: “To restore appetite to a man means to
secure him a large stock of gastric juice wherewith to begin
digestion of the meal.” The act of feeding, stimulated by appetite,
is transmitted to the stomach by nervous channels to the gastric
glands and does not require physical contact with food. Pavlov
referred to this as “psychic” stimulation. He made no attempt to
separate the various sensory stimuli which constituted the pre-
ingestion phase, i.e., sight, sound, smell, tactile senses, to which
he referred only collectively.
Pavlov on the Enjoyment of Eating
The satisfaction derived from eating is a combination of
anticipatory preparation of secretion and tactile and taste
sensation in the mouth, followed by “impulses awakened
by the passage of food along deeper portions of the
esophagus and by entry into the stomach.” The craving
for food and the impulse to seek it, is thus the first
and strongest exciter of several gastrointestinal organs.
Processing of food serially along the alimentary tract,
prepares each subsequent section to “harmonize” with that
which it receives.
Given the primacy of expression of the pre-ingestion phase
of eating, “perhaps the old and empirical requirement that
food should be eaten with interest and enjoyment, is the
most imperatively emphasized and strengthened of all” says
Pavlov. Regarding a meal, he talks of the time of day, the
company present, the special features of the room and the
lack of urgency, as a means to “take away the thoughts
from the cares of daily life and to concentrate on the
repast.” He alludes to alcoholic beverages in helping this
distraction. It is not obvious to him why bitters are used as
therapeutic secretagogues, but he suggests that they perhaps
stimulate appetite by first eliciting an unpleasant impulse
which “awakens the idea of a pleasant one.” Meat extract
and acidic foods he sees as the most effective agents to
stimulate appetite.
Awakening of curiosity and interest, augments the desire for
food. Quoting Pavlov: “It is only necessary to give an impulse
to the organs of taste, that is, to excite them, in order that their
activity may be later maintained by less powerful excitants. Even
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a hungry dog will not eat everything with equal pleasure but will
seek out the food which it relishes best.”
GENERAL CONSIDERATIONS OF
FEEDING BEHAVIOR, METABOLISM AND
THE NEUROBIOLOGY OF ENERGY
BALANCE
Beyond Pavlov: Physiology of Food
Reward
Where has Pavlov left us? Over a century has passed since
he published his findings. He made no obvious attempt
to tease out which of the senses to which he referred
collectively (sight, smell, hearing, touch), accounted for
the appetitive behavior patterns which he observed. The
following sections address the neurohumoral pathways
which govern appetite and food seeking and the central
role of sense of smell in this context, arguing that this sense
can probably best account for the rapid response which
Pavlov described.
We have entered the era of exploration of the concept of
“food reward” and its physiological underpinnings. Berridge,
in his classical paper (Berridge, 1996), distinguishes between
“wanting” and “’liking” food. “Wanting” corresponds to appetite
or craving, whereas liking refers to the concept of palatability
and the hedonic consequence of eating pleasurable food. Pavlov’s
dogs “wanted” food when they had been deprived of it for some
time and generated the appropriate secretory responses, which
prepared them to receive it. On the other hand, when offered
some foods for which they had no “liking” (milk was one),
they ignored it.
Berridge contends that fundamental brain processes can be
separated from the subjective experience (Berridge, 1996). His
premise is that palatability, the hedonic component of food
reward, results from an integrative process which melds taste
with the underlying physiological and psychological states and
with individual history and memory. The pleasantness of taste
of a particular food varies according to the physiological state,
accounting for aversion to food in a number of disease states.
He contends that food reward is largely an incentive process
conditioned by its own control system.
Olfactory memory and prior experience with the food, is one
of the factors which act as incentives to eating, the others being
the nature of the food and the state of energy repleteness or
depletion (Spence and Youssef, 2015;Sullivan et al., 2015). These
entities activate neural and humoral pathways which govern
behavioral patterns and are conditioned by the pleasure induced
by the reward. This, in turn, triggers further neural activity.
The pleasure associated with food or its palatability, in
which olfaction is important, is a critical aspect of food
selection and food ingestion, and which also drives meal size
decisions (Harris et al., 2008;McCrickerd and Forde, 2016).
Foods with high positive valence can motivate ingestion without
the requirement of hunger signals (Berthoud et al., 2017).
Opposing homeostatic feeding (food consumption to reload
energy sources), this type of eating behavior is considered
non-homeostatic. Certain brain circuits process information
related to food reward, and are sensitive to the hedonic value
of palatable food, thereby influencing motivation behaviors
to acquire these foods. These neurons respond to metabolic
and hormonal signals released within the body to inform the
brain about current available energy supplies. These reward
circuits have been identified in rodent studies as mesolimbic
dopaminergic neurons in the ventral tegmental area (VTA),
which project to the nucleus accumbens (NAc) and other
forebrain areas (Kelley et al., 2005;Morton et al., 2014).
Multiple hypothalamic neurons send projections into these
reward centers, such as a hypothalamic nucleus termed the lateral
hypothalamic area (LHA) and proposed to integrate reward-
related input with information related to energy homeostasis
(Leinninger et al., 2009). Functional magnetic resonance imaging
in humans have provided confirmation that the human
hypothalamus is sensitive to the satiation state of the individual
(Page et al., 2013;Luo et al., 2017).
Current Views on Feeding and the
Neurobiology of Energy Balance
Research efforts over the past 60 years in rodent models
have considerably extended our knowledge of what goes on
physiologically and at a molecular level before and after the
ingestion of a meal, such as decisions to eat and how energy levels
are maintained between meals. Energy balance is the difference
between energy intake (calories eaten) and energy expenditure
(calories utilized by the body). For humans and other mammals,
this process is regulated by hormonal and neuroendocrine cross-
talk between the brain and peripheral tissues (Figure 2). Weight
gain occurs when energy intake surpasses energy expenditure,
whereas weight loss is a result of energy expenditure exceeding
food intake. Such an intricate balance depends on the coordinated
chemical communication between vital organs and brain regions
such as the hypothalamus (Schneeberger et al., 2014).
The major hormonal players in these circuits include insulin,
leptin, ghrelin, and multiple gut peptides (Besser and Mortimer,
1974;Schneeberger et al., 2014). These circulating hormones
secreted by peripheral tissues inform the brain of available energy
stores and as a results, corrective tunings to food intake are
initiated in the brain. A powerful suppressor of appetite is
the adipose hormone leptin, discovered by Jeffrey Friedman’s
group in 1994 (Zhang et al., 1994). Acute leptin injections
powerfully suppress food intake and promote weight loss in
rodent studies. However, leptin resistance observed in obese
individuals potentially disqualifies leptin therapies as a cure
to the obesity and type 2 diabetes epidemic (Coppari and
Bjørbæk, 2012;Neill, 2013). In addition, other hormonal signals
also moderately influence satiety circuits, notably the pancreatic
hormone insulin, in addition to its well established role of
promoting glucose uptake in peripheral tissues.
Interestingly, meal initiation is influenced by many external
factors such as sensory perception of food, whereas meal
size mostly depends on the release of gut peptides, notably
peptide YY3–36 (PYY3–36), glucagon-like peptide 1 (GLP-1) and
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FIGURE 2 | The hypothalamus regulates energy balance by integrating internal and external feeding signals. Food-based olfactory cues reach the olfactory
epithelium in the nose to stimulate olfactory sensory neurons. Such neurons signal to olfactory processing centers in the brain. Olfactory cues are likely to promote
hunger signals within the brain through the activation of olfactory processing neurons and hypothalamic stimulation of AgRP neurons controlling appetite.
Conversely, after meal ingestion, satiety is driven by gastro-intestinal inputs and central stimulation of POMC neurons. Reward circuits play an important role in food
ingestion, by influencing both hypothalamic and olfactory activity. MOB, main olfactory bulb; Hypo, hypothalamus.
cholecystokinin (CCK) (Druce et al., 2004). Feeding as observed
first by Pavlov is stimulated by gastric juices arising from the
stomach, which have now been attributed by the hormone ghrelin
discovered in Kojima et al. (1999). Ghrelin is secreted before meal
onset and drives appetite in rodents and other mammals through
hypothalamic activation of arcuate nucleus neurons (Abizaid and
Horvath, 2012). Ghrelin’s action on feeding works through its
activation on neuropeptide Y (NPY) and Agouti-related protein
(AgRP) neurons and inhibitory effect on proopiomelanocortin
(POMC) neurons (Cowley et al., 2003). The NPY/AgRP and
POMC neurons ability to be modulated by opposing hormonal
feedback mechanisms represents a fundamental neurocircuit to
control appetite and satiety (Morton et al., 2014).
Intergration of Signals Which Govern
Feeding Behavior
In the brain, the hypothalamus is the critical modulator of
homeostasis therefore controlling many vital functions such
as feeding, reproduction or thermal regulation (Timper and
Brüning, 2017). This is achieved via the integration of a wide
range of endocrine, neural and metabolic signals, into effector
responses of behavioral, autonomic, and endocrine nature.
Other brain areas in the cerebral cortex and the brainstem
(Schneeberger et al., 2014;Nectow et al., 2017) are also able
to influence appetite and satiety, however, it is unclear if they
achieve these functions independently of hypothalamic activity.
Rodent studies have evidenced that leptin action depends
on specific receptors expressed in two distinct subsets of
neurons in the arcuate nucleus (Cowley et al., 2001;Gropp
et al., 2005;Luquet et al., 2005;Dietrich and Horvath, 2013).
The orexigenic group of neurons (feeding-inducing) contains
neuropeptides NPY and AgRP, with leptin suppressing their
activity. The other group expresses anorexigenic peptides,
cocaine and amphetamine related transcript (CART) and α-MSH
(derived from POMC), with leptin inducing firing of these
neurons and peptides release. Remarkably, AgRP and α-MSH
are considered antagonistic ligands of a common receptor, the
melanocortin 4 receptor (MC4R) (Dietrich and Horvath, 2013).
MC4R is found exclusively in the brain (Balthasar et al., 2005).
Activation of MC4R-expressing neurons decreases food intake,
while their inhibition increases feeding and impairs leptin satiety
responses in the brain.
In humans, functional magnetic resonance imaging
studies have shown reduced hypothalamic responses upon
glucose administration, and increased responses in limbic
regions including the thalamus after overnight fasting
(Smeets et al., 2005;Page et al., 2013).
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OLFACTION AS AN INDEPENDENT
INFLUENCE IN DRIVING APPETITE,
RESPONSE TO FOOD AVAILABILTY AND
ENERGY BALANCE
Olfaction as an Important Driver of
Appetite and Food-Seeking Behavior
Darwin provided evidence that a pleasurable or uncomfortable
feeling can be detected in animals across a wide evolutionary
spectrum, by observing their facial expressions. In his book,
The descent of man and selection in relation to sex (Darwin,
1888), he says: “Those who believe in the principle of gradual
evolution, will not readily admit that the sense of smell in
its present state was originally acquired by man, as he now
exists. He inherits the power in an enfeebled, and rudimentary
condition, from some early progenitor, to whom it was highly
serviceable, and by whom it was continually used. In those
animals which have this sense highly developed, such as
dogs and horses, the recollection of persons and of places is
strongly associated with their odor, and we can thus perhaps
understand how it is, as Dr. Maudsley has truly remarked,
that the sense of smell in man is singularly effective in
recalling vividly the ideas and images of forgotten scenes
and places.”
There exits a tacit belief that the olfactory capability of humans
does not match that of animals, which use smell as a warning
and as a feeding signal. Current information does not support
this contention (Mainland et al., 2014a,b) arguing that the human
sense of smell is far more powerful than it was thought to be
and that it plays an important regulatory in a wide range of
human behaviors.
Sense of Smell and Olfactory Processing
as the Link Between Appetite, Food
Reward and Metabolism
The experience of food relies on the timely contribution of visual,
auditory, olfactory, tactile and gustatory inputs. Food-related
visual, olfactory and gustatory information converges on related
areas of the brain, including the orbito-frontal cortex, insula
and amygdala, where inputs from food experience influence
behavior (reviewed in Riera and Dillin, 2016). Sensory inputs
are well known to influence digestive processes (Figure 3). In
the anticipatory or cephalic phase, sensory perception of food
drives the secretion of gastric juices in preparation for food
intake via parasympathetic control through the vagus nerve
(Giduck et al., 1987).
Olfaction in particular, plays a dual role in food recovery
and food perception in humans. In the “first contact” with
food, odorants travel through the air to arouse olfactory sensory
neurons in the nose via sniffing or orthonasal smelling, therefore
leading to the localization and identification of food stimuli
(Bojanowski and Hummel, 2012). In the “second contact” which
occurs during food consumption, a large component of flavor
perception is achieved through retronasal pathways: the olfactory
molecules released during food breakdown through mastication
enter the nasal cavity upon exhalation to stimulate olfactory
sensory neurons (Bojanowski and Hummel, 2012).
It has been observed for several decades, that smell acuity
varies depending on the feeding status. Hunger signals released
during fasting are associated with increased olfactory perception,
most likely to increase appetite for calorie dense foods (Albrecht
et al., 2009;Tong et al., 2011;Cameron et al., 2012;Riera
and Dillin, 2016). Food-related odors have also been shown
to induce pre-oral salivation and cephalic responses such as
gastric acid secretion and insulin release (Yeomans, 2006).
While a meal is being consumed, a process termed sensory
specific satiety is initiated and refers to the reduced pleasantness
of the consumed food compared to new foods (Rolls et al.,
1981;Critchley and Rolls, 1996). This variation in hedonic
value may contribute to satiety and the decision to terminate
the meal, together with post-ingestive signals released by
the gastro-intestinal tract to the brain. Importantly, primate
orbitofrontal cortex neurons stop responding to olfactory
and gustatory cues after feeding to satiation (Critchley and
Rolls, 1996), suggesting that satiety signals dampen olfactory
neuronal activity.
As mentioned above, the hormone leptin, secreted by adipose
tissue, suppresses appetite by inhibiting AgRP/NPY neurons
activity in the hypothalamus. In mice lacking leptin (ob/ob)
or leptin receptors (db/db), a voracious appetite elicited by
high AgRP/NPY activity is associated by marked obesity and
type 2 diabetes. Getchell et al. (2006) reported that in addition
to a strong metabolic impairment, these mice presented a
differential olfactory response to food ingestion. Interestingly,
db/db and ob/ob mean time to smell and find food was
approximately ten times shorter than wild-type. Remarkably,
daily leptin injections are sufficient to suppress this enhanced
olfactory phenotype. These data support a role for leptin in
the regulation of olfactory-mediated pre-ingestive behavior by
controlling olfactory sensitivity through a leptin-receptor (LepR)
based mechanism.
Opposing leptin and its satiety action, the gastric hormone
ghrelin is released in the stomach to stimulate appetite and food
ingestion through its positive action on NPY/AgRP neurons
and inhibitory effect on POMC neurons (Cowley et al., 2003).
Ghrelin acts on olfactory processing centers in the brain of
rats and humans by boosting olfactory acuity, most likely
through direct binding of ghrelin receptors (GHSR) in these
brain regions (Tong et al., 2011). Stereotaxic intracranial
delivery of ghrelin improves olfactory sensitivity in rats and
increased sniffing frequency (Tong et al., 2011). Ghrelin receptors
have been localized in the main olfactory bulb and olfactory
processing centers such as the amygdala and piriform cortex,
both regions being important relays for olfactory information
from the olfactory bulb (Becskei et al., 2007). How these neurons
communicate with the hypothalamus remains to be determined.
A potential excitatory circuit could mediate the enhanced
olfactory acuity observed during fasting, and dependent upon
ghrelin gastric secretion and action in the hypothalamus. In this
scenario, ghrelin and leptin would promote opposite effects on
olfactory sensing in order to adjust food scavenging behavior to
metabolic states.
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FIGURE 3 | Sensory inputs on digestive processes. In the cephalic phase, smelling, seeing or thinking about food (1) drives the secretion of gastric juices in
preparation for food intake via parasympathetic control through the vagus nerve (2). In the gastric phase, food enters the stomach leading to secretion of gastrin,
and other hormones promoting acid secretion in the stomach (3) preceding the intestinal phase when food leaves the stomach. Cholecystokinin (CCK) a major
gastrointestinal hormone responsible for gallbladder contraction and pancreatic enzyme secretion functions in the small intestine to inhibit gastric emptying and allow
digestion to occur.
Neuronal Control of the Smell Response
to Food Availability
From the foregoing, it is clear that anticipatory signals provide
rapid information about the availability and hedonic properties of
food. To survive in a steady-state of access to food, two neuronal
cell types play a key role in controlling feeding: NPY/AgRP
and POMC-expressing cells residing in the arcuate nucleus of
the hypothalamus. The elegant studies of Knight and coworkers
(Chen et al., 2015) have shown that chemosensory detection of
food resets the electrical state of these neurons within a very short
time-frame supporting the notion that such behavior is under
neuronal rather than humoral control. Using recent technological
advances, Knight and colleagues performed awake-free behaving
recording of hypothalamic neurons using an optical method
called fiber photometry (Chen et al., 2015). Remarkably, it is the
hedonic property and the energy content of the food, rather than
its availability, that is sensed and processed, likely based upon
smell and other sensory cues retained in memory.
Whereas AgRP and POMC neurons have hitherto been
considered to be sensors of the nutritional state of the organism,
activated by energy deficit to restore energy balance, the studies
by Knight and coworkers show this not to be the case. They
have clearly shown that resetting of the function of these neurons
occurs well in advance of food consumption, by the detection of
food alone. That sense of smell plays a key role in this regard,
was demonstrated in fasted mice which were presented with
food (peanut butter) in a closed container which avoided viewing
by the animal. Rapid modulation of AgRP and POMC neuron
discharges occurred within 1 min, mimicking the response to
food presentation. If acess to the food was prevented following
this response, the neural activity returned to baseline within
8 min. Thus sensory cues elicited by smell can modulate these
neurons in anticipation of access to food, even if such access is
not fulfilled. This insight indicates that foraging, the motivational
search for food, is an instinct of the highest order, which elicits
an immediate response rather than being a downstream event
consequent upon food ingestion.
Do AgRP neurons drive food consumption via a smell-
memory process? Does activation provide a stimulus analogous
to learned hunger pangs? If so, this could drive food-seeking
behavior as a means to avoid such sensations, leading to a
repetitive cycle of appetitive behavior and consumption, with
the hedonic properties of the food determining the magnitude
of the response. The fast regulation of foraging described above
is superimposed upon slow regulation controlled by nutrients,
hormones and feeding/satiety cycles. This latter set of events is
not the subject of the present paper.
Independent Influence of Smell on
Food-Seeking Behavior and Energy
Balance
There is evidence for an independent influence of smell on food-
seeking behavior in humans. One example is the suppression
of appetite induced by smelling dark chocolate, an effect which
correlates with changes in ghrelin levels in young females
(Massolt et al., 2010). Another is the response to appetitive
conditioning (exposure to a pleasant odor like vanilla) and
aversive conditioning (exposure to an unpleasant odor like
fermented yeast). This has been well studied with quantitative
tools such as electromyography, electroencephalography, heart
rate variation, skin conductance and functional magnetic
resonance imaging (De Silva et al., 2012). Although the aversive
response has been relatively easy to recognize (including typical
facial expressions), the appetitive response, through which
rewards and motivation are learned, has received less attention.
Thus, whereas exposure of humans to an unpleasant odor
elicits a measurable response, a pleasant odor fails to do so.
Whether metabolic signals, such as fasting, can suppress neural
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Fine and Riera Olfaction and Pavlovian Appetite Behavior
responses to visual cues, or whether they affect the response to
odors, is not known.
An important question remains. When considering olfaction
and energy balance, can changes in olfactory sensitivity directly
influence weight gain by manipulating neurocircuits converging
to the hypothalamus? This question has been partially addressed
in a mouse study. Riera et al. (2017) engineered mice harboring
either reduced olfactory perception (hyposmia) or increased
smell sensitivity (hyperosmia). Hyposmic mice were resistant to
diet-induced obesity during high fat diet feeding. Chronic loss of
smell perception in adult mice did not impact food intake but
influenced satiety signals toward increased autonomic tone and
higher fat burning mechanisms. Remarkably, in mice engineered
to present increased olfactory sensing, weight gain upon normal
chow was observed without altering food intake, leading over
time to insulin resistance (Riera et al., 2017). These results suggest
that olfactory circuits communicate with central neurons to
regulate energy balance, and the precise nature of these circuits
remains to be determined.
CONSEQUENCES OF LOSS OR
ABNORMALITY OF SENSE OF SMELL
Impact of the Loss of Sense of Smell
It is common experience that loss of smell (like that which
occurs with a common cold) leads to a diminution of food
enjoyment largely due to a loss of the tastefulness of food.
Patients with smell disorders often report “eating disorders.”
Studies which have examined food enjoyment before and after
the onset of such disorders, have recorded appreciable lessening
of enjoyment of food, associated with loss of appetite in many
cases (Croy et al., 2014). Compensation for this is manifested
by over-salting, over-sweetening or over-spicing of the food.
A review compiles findings from a total of 14 eating disorders
human studies, and demonstrate that firm conclusions on the
association between loss of smell and eating disorders are difficult
to reach (Islam et al., 2015) Partial loss of smell (hyposmia)
or full loss of smell (anosmia) are found to be associated with
anorexia nervosa, but not bulimia nervosa. However, these
associations may be driven by the greater number of studies
on anorexia compared to bulimia. Loss of smell in disease
has been reported abundantly, with conflicting reports. It is
important to distinguish if loss of smell is created by an
acute insult (common cold, head injury, exposure to certain
chemicals such as pesticides or chemotherapy) or developing
progressively with another disturbance (chronic diseases or
aging). Acute loss of smell in otherwise healthy humans is
a documented cause of weight loss, anorexia nervosa, and
depression (Henkin and Smith, 1971).
However, progressive loss of smell is associated with chronic
obesity and inflammatory diseases such as Parkinson’s disease,
Alzheimer’s disease, multiple sclerosis, hypertension, and natural
aging (Graves et al., 1999;Ross et al., 2008;Wilson et al.,
2009;Pinto et al., 2014). This suggests a strong correlation
between early signs of neurodegeneration and olfactory decline
(Riera and Dillin, 2016). Olfaction has been viewed as the
“miner’s canary” of human brain health (Riera and Dillin,
2016), most likely because of its early failure due to high
demand for neuronal regeneration in the olfactory epithelium
and the olfactory bulb. To maintain olfactory function, stem
cells pools constantly need to replace mature olfactory neurons
in the nose where the half-life of these neurons is rather short
(Pignatelli and Belluzzi, 2010). Therefore, olfactory loss may
serve more generally as an indicator of deterioration in age-
related regenerative capacity or as a marker of physiologic
repair function.
Abnormal smell (parosmia), unpleasant smell (cacosmia)
and phantom smells (phantosmia) are disturbances of olfaction
which can lead to weight loss even though the relationship
between weight loss and smell may be driven by psychological
factors such as depression (Henkin and Smith, 1971;Palouzier-
Paulignan et al., 2012;Oral et al., 2013). Of interest is the
fact that congenital loss of sense of smell does not appear to
affect food preferences. Loss of smell leads to loss of recognition
of hazards such as smoke detection, difficulties with cooking,
or accidentally eating rotten or spoiled food (Boesveldt et al.,
2017). In a meta-analysis of studies on subjects with disorders
of smell, the single-most prominent symptom in daily life, was
a decrease in the enjoyment of food (Croy et al., 2014). In
the Dutch Anosmia Association, about 40% of the members
reported reduced appetite, but whether this condition can lead
to alternative eating patterns is overall unclear (Toussaint et al.,
2015). In certain cases, a shift toward healthier food options
is reported among individuals which lost interest in food
palatability (Aschenbrenner et al., 2008).
Here it is worth reflecting on the management of patients
who are fed through a percutaneous endoscopic gastrotomy or a
nasogastric tube, where there is no prior contact with the food
(which, anyway, comes in a form which would not stimulate
the senses), and hence there is no appetite response. Digestion
and absorption would not proceed as would occur normally,
but satiety does occur. Such patients are described as “forgetting
their stomachs” (Pavlov and Thompson, 1982). To promote and
improve digestion, Pavlov recommended restoring appetite, since
“no other excitant can compare with the passionate craving
for food.”
CONCLUSION AND DIRECTIONS FOR
FUTURE EXPLORATION
The importance of the contribution of Pavlov in exposing the
“psychic” phase of digestion, which initiates all of the molecular
events described above, cannot be overestimated (Pavlov and
Thompson, 1902). This phase serves as being anticipatory of a
reward and involves sensory triggers such as sight and smell,
for which memory of prior experience bolsters the drive to seek
food, the ingestion of which amplifies the motivating power of the
preparatory phase.
It is surprising that Pavlov did not home in on smell as a
major component of the “psychic’ phase of feeding. Other than
remarking that the hands of those who fed his experimental
animals should be free of the smell of flesh, he did not seek to
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Fine and Riera Olfaction and Pavlovian Appetite Behavior
isolate this important sensory dimension for experimentation. He
could have blindfolded his dogs or he could have presented foods
in a form which was unidentifiable other than the odor which
it emitted, to isolate smell as a stimulus. Although Pavlov chose
not to focus on specific sensory dimensions and assumed that
neural afferent traffic accounted for all that he had observed, he
was working on the cusp of an era of hormonal discoveries which
soon would serve to embellish and clarify aspects that remained
as open questions to him.
The foundations of the physiology of appetite laid down
by Pavlov, have endured unchanged over the past century
in the face of a vast amount of biological research. Appetite
now involves integration of gastrointestinal physiology,
neuroscience and cognitive and behavioral sciences. We
propose that the multiple roles of sense of smell in the
homeostatic and hedonic aspects of feeding have clearly
entered center stage.
AUTHOR CONTRIBUTIONS
LF wrote the historical perspective. CR wrote the current
knowledge on olfaction component of the hypothesis.
FUNDING
CR was supported by Pathway to Stop Diabetes 1-15-INI-22
from American Diabetes Association, and LLHF Start-Up Grant
2018-A-009-SUP.
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Conflict of Interest Statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
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