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J Appl Physiol 115: 954 –971, 2013.
First published May 2, 2013; doi:10.1152/japplphysiol.00700.2012.
Review
A unified survival theory of the functioning of the hypocretinergic system
Michael H. Chase
WebSciences International, Veterans Affairs-Greater Los Angeles Healthcare System, University of California, Los Angeles
School of Medicine, Los Angeles, California
Submitted 5 June 2012; accepted in final form 30 April 2013
hypocretin; orexin; behaviors; survival
THE HYPOCRETINERGIC (also called orexinergic) system, which
consists of hypocretinergic neurons and their receptors, has
been researched extensively since its discovery in 1998 (43,
141). During this period, numerous processes, mechanisms,
and behaviors have been shown to be subjected to hypocretinergic control, including, but not limited to, sleep, wakefulness,
stress, motor activity, food consumption, thermogenesis, reproduction, development, aging, locomotion, energy metabolism,
and the secretion of hormones (112, 119, 139, 140, 143).
Although there have been major findings, no integrative concept of the functioning of the hypocretinergic system has been
proposed that accounts for the vast number of responses that
occur following activation of this system, many of which
appear to be contradictory and/or paradoxical.
This article advances a Unified Survival Theory of the
Functioning of the Hypocretinergic System (i.e., the Unified
Hypocretinergic Survival Theory) that the principal function of
the hypocretinergic system is to orchestrate the coordinated
patterns of central nervous system (CNS) and peripheral organ
activities that comprise survival behaviors and related processes (Fig. 1). It is the intent to present sufficient data to
justify the Unified Hypocretinergic Survival Theory as a credible, formal unifying description of the functioning of the
Address for reprint requests and other correspondence: M. H. Chase,
WebSciences International, University of California, Los Angeles, VA-Greater
Los Angeles Healthcare System, 1251 Westwood Blvd., Los Angeles, CA
90024 (e-mail: [email protected]).
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hypocretinergic system. Data are reviewed that reveal that the
hypocretinergic system is capable of initiating, coordinating,
and maintaining survival behaviors and related processes, and
that other behaviors and processes are not directly impacted by
its actions (see Control of Survival Behaviors by the Hypocretinergic System). Data are also presented demonstrating
that, when hypocretinergic directives are not present, survival
behaviors and related processes are selectively compromised
(9, 14, 86, 119, 140).
Elements of the Unified Hypocretinergic Survival Theory
have been proposed by a number of other investigators, such as
those who are quoted in Fig. 2. Although they have concluded
that the hypocretinergic system plays a key role in certain
aspects of survival behaviors, the data have not been organized
in a manner that allows one to examine the comprehensive
theory presented in this review that the hypocretinergic system
functions primarily to generate survival behaviors and related
processes.
To substantiate the executive role of hypocretinergic neurons and their receptors in the control of survival behaviors, it
is necessary to demonstrate that survival and related behaviors
are not only dependent on the hypocretinergic system for their
successful enactment but that they are also independent of the
forebrain. In this regard, decades of research have confirmed
that neurons in the lateral hypothalamus are capable of controlling all of the critical components of survival behaviors (3,
17, 26, 30, 60, 62, 128). For example, as early as 1951, Anand
and Brobeck (5, 6) reported that a group of cells (which were
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Chase MH. A unified survival theory of the functioning of the hypocretinergic
system. J Appl Physiol 115: 954 –971, 2013. First published May 2, 2013;
doi:10.1152/japplphysiol.00700.2012.—This article advances the theory that the
hypocretinergic (orexinergic) system initiates, coordinates, and maintains survival
behaviors and survival-related processes (i.e., the Unified Survival Theory of the
Functioning of the Hypocretinergic System or “Unified Hypocretinergic Survival
Theory”). A priori presumptive support for the Unified Hypocretinergic Survival
Theory emanates from the fact that neurons that contain hypocretin are located in
the key executive central nervous system (CNS) site, the lateral hypothalamus, that
for decades has been well-documented to govern core survival behaviors such as
fight, flight, and food consumption. In addition, the hypocretinergic system exhibits
the requisite morphological and electrophysiological capabilities to control survival
behaviors and related processes. Complementary behavioral data demonstrate that
all facets of “survival” are coordinated by the hypocretinergic system and that
hypocretinergic directives are not promulgated except during survival behaviors.
Importantly, it has been shown that survival behaviors are selectively impacted
when the hypocretinergic system is impaired or rendered nonfunctional, whereas
other behaviors are relatively unaffected. The Unified Hypocretinergic Survival
Theory resolves the disparate, perplexing, and often paradoxical-appearing results
of previous studies; it also provides a foundation for future hypothesis-driven basic
science and clinical explorations of the hypocretinergic system.
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The Unified Survival Theory of the Functioning of the
Hypocretinergic System
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2
3
4
The hypocretinergic system controls survival behaviors and survival-related processes.
1)
The hypocretinergic system
“The hypocretinergic system” consists of hypocretinergic neurons
and hypocretinergic receptors.
Hypocretinergic neurons – A small phenotypically distinct group of
neurons, approximately 80,000 in humans and 20,000 in rats
(158), that are located exclusively in the lateral hypothalamus,
whose axonal projections release the neurotransmitters
hypocretin-1 and/or -2.
Hypocretinergic receptors – Receptors for hypocretin-1 and
hypocretin-2 that are expressed by neurons in the CNS and by
cells of peripheral organs..
Controls
“Controls” refers to the “direct” effects or actions of the
hypocretinergic system in modulating the activity of particular
behaviors, processes, mechanisms, etc.
3)
Survival Behaviors
“Survival behaviors” refer to behaviors that occur in response to
exteroreceptive or interoceptive stimuli or inputs that are essential
in maintaining the life of an organism and/or the species.
Behavioral responses encompass changes in somatomotor,
visceromotor, hormonal and other processes at all levels including
subcellular, cellular and systems.
4) Survival-related processes
“Survival-related processes” prevent the death of the organism or
strengthen its ability to survive, such as angiogenesis and
neurogenesis; they also include numerous cellular directives
including those that reduce or prevent neurodegeneration and
inflammatory reactions.
Fig. 1.
later identified as hypocretinergic) within the lateral hypothalamus function as a comprehensive “feeding center”; bilateral
lesions of these neurons result in the complete cessation of
food consumption [see Nishino and Sakurai (119) and Adequate Survival Stimuli Activate the Hypocretinergic System].
There are also a plethora of recent studies, cited in the present
text, that confirm that the responsible neurons in the lateral
hypothalamus are hypocretinergic (30, 60, 62, 119). Thus,
during survival behaviors, there are hypocretinergically induced increases in arterial pressure, heart rate, and ventilation
as well as a shift in blood flow from visceral to skeletal muscles
in conjunction with cortical arousal; all of these survivalrelated responses are significantly lacking in preprohypocretin
knockout and hypocretin neuron-ablated animals (14, 83). It is
also well established that hypocretinergic neurons in the lateral
hypothalamus promote not only the individual components of
survival behaviors, but that they also coordinate the complex
patterns that constitute these behaviors, as discussed in Adequate Survival Stimuli Activate the Hypocretinergic System.
Although the full complement of survival behaviors is dependent upon a functioning hypocretinergic system, other areas
of the CNS are capable of influencing, to a limited extent,
portions of these behaviors. Consequently, if hypothalamiclesioned animals, which are initially anorexic, are kept alive by
the intragastric intubation of liquid nutrients, eventually they
are able to maintain some aspects of food consumption, which
occur because other sites are able to promote certain uncoor-
dinated feeding processes (128). Similarly, although integrated
survival-related stress responses to external inputs are dependent upon hypocretinergic actions, localized stressors may
require only brain stem centers for the generation of a response
(128). Accordingly, Furlong et al. (56) found that “Stress
responses to inputs coming from lower CNS levels may not
require more than brain stem centres (medulla pons and midbrain) to orchestrate the appropriate cardiovascular and behavioural responses,” whereas “Hcrt neurons are preferentially
driven by inputs originating high in the nervous system (forebrain) rather than inputs originating from lower levels.” These
and related findings led Zhang et al. (196) to conclude that
hypocretinergic neurons “in the lateral hypothalamus play a
role as a master switch to activate multiple efferent pathways
of the defense response.”
It is evident that, although the forebrain (e.g., the cerebral
cortex) assists in directing survival behaviors and in assuring
that they are appropriate to changes in the external environment, the basic circuitry for these behaviors resides within
pools of hypocretinergic neurons in the lateral hypothalamus
(37, 67). For example, in the absence of the forebrain, multiple
studies, including the seminal work of Hess (67), have shown
that fight, flight, and other survival behaviors are “undirected”
and can be easily evoked by a variety of stimuli that normally
would not induce these kinds of behavioral reactions, as in
sham rage. The preceding effects are consistent with extensively documented patterns of brain functioning, wherein be-
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2)
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Support for the Unified Survival Theory
of the Functioning of the Hypocretinergic System
A number of researchers, such as those who are quoted below, have proposed
that the hypocretinergic system controls key elements of survival behaviors and
processes. However, they have not presented a unified framework that accounts
for the totality of the actions of the hypocretinergic system. Their conclusions,
which link the hypocretinergic system with survival behaviors, lend credence to
the Unified Hypocretinergic Survival Theory, presented in this article, that the
function of the hypocretinergic system is to command and coordinate survival
and related behaviors and processes.
“The hypocretin system is one of the most critical systems for
regulating vigilance, linking fundamental hypothalamic functions
required for survival.” Nishino and Sakurai (119)
“In our view, therefore, the LH orexin system is very well placed to
orchestrate the diverse subsystems involved in foraging under
potentially dangerous circumstances, i.e., finding and ingesting food
without oneself becoming a meal for someone else.” Rodgers et al.
(137)
“The synaptic organization of the hypocretinergic system provides the
foundation for easy arousal (from sleep), an ability that, for most
species, is paramount to survival.” De Lecea and Sutcliffe (45)
“This unique wiring and acute stress-induced plasticity of the
hypocretin neurons correlates well with their being involved in the
control of arousal and alertness that are so vital to survival.” Horvath
and Gao (71)
“. . . hypocretin neurons may act as an ‘energy gauge’ in the brain,
which integrates nutritional, energetic and behavioral signals critical
for the survival of animals.” Liu et al. (94)
“Orexin-mediated maintenance of consolidated wakefulness states” ...
is important .. “because proper maintenance of arousal during food
searching and intake is essential for an animal’s survival.” Ohno and
Sakurai (122)
Fig. 2.
haviors and processes that are normally controlled by a specific
“executive” brain site may be present, but are not expressed to
their full extent, when the primary executive area is not
exerting its directives (26, 39, 59, 116, 155, 168). Thus, in the
absence of hypocretinergic control, due to plasticity of brain
function, redundancy, denervation supersensitivity, etc., nonhypocretinergic neuronal groups are able to promote, to a
limited extent, certain aspects of feeding, fight, flight, and other
survival behaviors (5, 37, 46, 47, 75).
Given the limitations in space, the role of hypocretinergic
neurons and their receptors as a command and control system
for survival behaviors will be examined principally in relation
to the prototypical survival behaviors of food consumption,
fight, and flight. In addition, those related processes that directly or
indirectly enhance the success of behaviors that are promulgated by hypocretinergic directives will be described within the
context of the Unified Hypocretinergic Survival Theory.
Evolutionary and Phylogenetic Analysis of the
Hypocretinergic System
The role of the hypocretins in mediating survival behaviors
and related processes is supported by the fact that the hypocretin gene arose ⬃650 million years ago, early in chordate
evolution (4, 66, 120). In addition, the hypocretins (hypocretin-1 and hypocretin-2) are extraordinarily well-conserved neu-
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“Orexin systems are involved in sensing the body’s external and
internal environments as well as regulating the states of sleep and
wakefulness, which are beneficial for survival.” Tsujino and Sakurai
(164)
Review
The Hypocretins: a Command System for Survival Behaviors
Hypocretinergic Neurons and Receptors Constitute a
Command System for Survival Behaviors
The term “command neuron,” which was first presented in
1964, was initially used to describe single cells in the crayfish
that control “tail flips,” which this species employs to escape
predators (125, 170). The key characteristics of these and other
command neurons are their receipt of a multitude of sensory
inputs and their output to a multifarious group of effecter cells
(122). Gradually, the concept of a command neuron was
expanded to that of a “command system,” which was defined
as a small group of integrated neurons that controls specific,
naturally occurring behaviors (51, 91).
It is clear that hypocretinergic neurons exhibit unique characteristics that provide them with the capability of serving as
the key component of a command system for survival behaviors. Hypocretinergic neurons are few in number and all are
located in a discrete region of the lateral hypothalamus (102,
131, 143, 194). Many hypocretinergic somata are small to
medium in size (35) and are therefore relatively easy to excite
by afferents that emanate from all sensory systems (see Hypocretinergic Actions in Response to Survival Stimuli) and sites
throughout the CNS; they are also activated by recurrent
collaterals that arise from their own cell bodies. In turn,
hypocretinergic neurons have long projecting axons with a
multiplicity of bifurcations that allow them to innervate, bilaterally, cells throughout the entire neuraxis (119, 132, 139, 140,
143).
The majority of the synapses on hypocretinergic somata and
dendrites are asymmetric with small, round, clear vesicles
(type 1) that reflect excitatory neural transmission (193). In
fact, hypocretinergic neurons are dominated by excitatory
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inputs; the ratio of excitatory to inhibitory synaptic contacts is
⬃10:1, which is unprecedented in the CNS (71). This pattern
of synaptic organization, which results in noise assuming the
characteristics of signal, allows hypocretinergic neurons to be
easily activated, leading to rapid arousal (71). In addition,
within the terminals of hypocretinergic axons are large dense
core vesicles that contain hypocretin as well as other excitatory
neuropeptides. Therefore, hypocretinergic neurons are activated not only by excitatory neurotransmitters such as glutamate that are released from other axonal projections but also by
the actions of their own recurrent collaterals (71, 72, 194).
The presynaptic control of, and by, hypocretinergic neurons
is novel and very extensive. For example, there is a strategic
positioning of presynaptic hypocretinergic boutons on postsynaptic targets. The extensive interaction of hypocretinergic presynaptic boutons with other axonal terminals further amplifies
the impact of the release of hypocretin from their axon terminals (165). As noted above, hypocretin is also expressed in the
presynaptic boutons of recurrent collaterals from hypocretinergic axons that make excitatory synaptic connections with
hypocretin-containing neurons in the lateral hypothalamus
(165, 191). In addition, there is a superior hierarchical positioning of presynaptic hypocretinergic inputs on the somas and
proximal dendrites of the bodies of neurons that they innervate;
consequently, hypocretinergic neurons are able to exercise
predominate excitatory control of their postsynaptic targets,
which is the basis for the robust effects that hypocretinergic
directives are able to exert (166, 194).
Another important aspect of the synaptic control of hypocretinergic neurons was discovered by Horvath and Gao (71),
who found that the activity of hypocretinergic neurons is
governed to a large extent by local excitatory interneurons
(132). These data are complemented by the fact that hypocretinergic neurons exhibit infoldings in their nuclear envelopes, which is a characteristic that is typical of high-activity
neurons that are responsible for promoting complex behaviors
(134).
The synaptic organization of the hypocretinergic system is
also unusual in that not all inputs that control the excitability of
hypocretinergic neurons are hard-wired; a large number of
hypocretinergic neurons contain specialized organelles, called
nematosomes or botrysomes, that function to enhance synaptic
plasticity (135). These findings led Horvath and Gao to conclude that “this unique wiring and acute stress-induced plasticity of the hypocretin neurons correlates well with their being
involved in the control of arousal and alertness that are so vital
to survival” (71). Hypocretinergic synapses in adult animals
also exhibit immature characteristics, such as incomplete postsynaptic densities, which provide these neurons with the ability
to react in an adaptive manner to changing circumstances, such
as those that arise in conjunction with the execution of survival
behaviors (68). For example, in animals that are fasted, hypocretinergic perikarya, which are already dominated by excitatory inputs, recruit even more excitatory synapses, which
enhance their activation, resulting in increased directives to
promote food consumption (71).
The preceding patterns of presynaptic and postsynaptic control provide hypocretinergic neurons with the ability to react,
rapidly and powerfully, when excited (71, 132, 134, 135). In
addition, when activated, long periods of sustained firing occur, which is the requisite response of a system that controls
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ropeptides: from a phylogenetic perspective, they have been
retained in all vertebrate classes, including fish, amphibians,
reptiles, birds, and mammals (66). Survival behaviors are
similarly “well-conserved”; they are also parallel across species in their form, function, and the factors that initiate their
onset as well as the brain circuitry that controls them (27, 49,
88, 98, 106, 123, 175). For example, homologous sites in the
lateral hypothalamus of rats, mice, cats, primates, and humans
are responsible for each species’ idiosyncratic patterns of
survival behaviors, such as fight-flight (predator-prey) interactions, the foraging for food and its consumption, as well as
reproduction (37). It is therefore parsimonious to conclude, a
priori, that since hypocretinergic neurons are exclusively located in the lateral hypothalamus, they function to fulfill the
well-documented survival directives of this site (6, 37, 70).
Thus, the Unified Hypocretinergic Survival Theory accords
with the dictum of Occam’s Razor, which states that the
simplest theory proposed as an explanation of phenomena is
more likely to be the true one than is any other available theory
(157).
The preceding evolutionary and phylogenetic data establish
the bases for the Unified Survival Theory of the Functioning
of the Hypocretinergic System. These data are also complemented by the results of studies, reviewed in the following
section, that reveal that the structure (morphology) and synaptic actions of the hypocretinergic system are necessary and
sufficient for it to command and control survival behaviors and
related processes.
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“ADEQUATE” SURVIVAL STIMULI
Exteroceptive Interoceptive
1
2
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LATERAL HYPOTHALAMUS
Fight
Flight
3
3
Feeding
Reproduction
Reward
Other
3
3
3
3
HYPOCRETINERGIC NEURONS
SITES
+
+
+
+
Sensory
5
Somatomotor
6
Visceromotor
7
Other
8
+
+
+
+
Cerebellum
Thalamus
9
10
Cortex
11
Other
12
Fig. 3. Hypocretinergic circuitry mediating survival behaviors. The proposed hypocretinergic command and control circuitry that initiates and maintains survival
behaviors in response to adequate survival stimuli is presented in this figure. Multiple functions of the hypocretinergic system are combined since it not known
whether the same or different hypocretinergic neurons promote individual or multiple actions, although there appear to be some regional differences in the
functions that are subserved by pools of hypocretinergic neurons (171). When an “adequate” exteroceptive survival stimulus (1), such as a highly rewarding
foodstuff is presented to a food-deprived animal, or an “adequate” interoceptive stimulus (2) arises, such as a decrease in blood glucose, hypocretinergic neurons
begin to discharge at high frequencies (3). The initial response to these stimuli is arousal (4), which occurs due to hypocretinergic activation of arousal-producing
systems such as the locus coeruleus and the raphe nuclei. Transmission via sensory pathways that relay information that is specifically survival-related is
enhanced (5); however, pain sensations are reduced by hypocretinergic directives, which is essential for the successful enactment of survival behaviors.
Simultaneously, projections of hypocretinergic neurons activate, bilaterally, a variety of somatomotor (6), visceromotor (7), and other systems (hormonal,
endocrine, etc.) and peripheral organs (8) that provide the basic physiological foundations for survival behaviors. The hypocretinergic system also controls
circuitry in the flocculonondular lobe of the cerebellum (9), which coordinates survival-related interactions between the visual, vestibular, and somatomotor
systems, such as pursuit eye movements, that allow animals to perform successfully in fight and flight situations. Sustained arousal is also assured by virtue of
direct monosynaptic hypocretinergic excitatory projections to the nonspecific arousal-producing nuclei in the thalamus (10). In addition, global activation of the
cerebral cortex (11) occurs due to the hypocretinergic innervation, selectively, of cortical layer 6b, which produces a general increase in cortical excitability.
Reward and stress-related sites are also activated as are other subcortical areas (12), such as the amygdala, basal ganglia, and hippocampus, which receive
hypocretinergic projections and provide background support for survival behaviors. As discussed in Hypocretinergic Actions in Response to Survival Stimuli, the
preceding circuitry is selectively activated during survival situations, whereas survival-related behaviors are selectively compromised when this circuitry does
not function.
and coordinates complicated survival behaviors (71). Thus,
hypocretinergic neurons possess the critical synaptic processes
and morphological characteristics as well as the necessary
afferent inputs and efferent projections (see below) to serve as
a command system that is capable of controlling all aspects of
survival behaviors.
The following section describes the manner in which the
hypocretinergic system produces coherent organized responses
of CNS sites and peripheral organs to afferent inputs that
comprise “adequate stimuli” for survival behaviors and related
processes.
Adequate Survival Stimuli Activate the Hypocretinergic
System
Prototypical survival behaviors that are controlled by the
lateral hypothalamus, such as fight, flight, and food consumption, are triggered by adequate stimuli, which are defined as a
single form of stimulus energy to which they are specifically
adapted and are most sensitive. For example, light is the
adequate stimulus for rods in the retina, even though pressure
may also activate them under abnormal curcumstances (Fig. 3).
In the wild, animals exhibit reactionary prey behaviors when
hypocretinergic neurons in the lateral hypothalamus of prey
animals are activated by adequate exteroceptive inputs (Fig. 3)
detailing the presence of a hungry predator. Similarly, an
initiating “adequate” interoceptive stimulus for the generation
of food consumption is a decrease in blood glucose (Fig. 3),
which results in the discharge of glucose-sensing hypocretinergic neurons in the lateral hypothalamus.
Interoceptive survival stimuli activate the hypocretinergic
system. Approximately fifty years ago, a specialized set of
neurons in the lateral hypothalamus was discovered whose
discharge rate increased, pari passu, with a decrease in the
concentration of blood glucose (5, 6, 93). Fast forward to the
discovery of the hypocretins in 1998 (43, 141) and the subsequent revelation that ⬃20% of hypocretinergic cells use glucose as a signaling molecule to alter their action potential
frequency (44, 93). Thus, a decrease in glucose concentration
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SYSTEMS
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Arousal
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employed to generate idiosyncratic behavioral responses that
are threat-specific. Wistar rats produce unique alarm calls that
inform the colony that a predator is approaching, whereas
“shrieking” is a piercing, high-pitched squeak that guinea pigs
use as an alarm call (24). Thus, hypocretinergic drives that
selectively enhance the transmission of information within
high-frequency receptive areas of the inferior colliculus are an
essential component of alarm calls that initiate survival behaviors. When the acoustic processing of alarm calls is not enhanced by the hypocretinergic system, deficits in survival
behaviors in animals arise and, in humans, various pathologies
occur (40, 145). For example, individuals with cataplexy who
lack a functioning hypocretinergic system exhibit auditory
hallucinations, deficits in the cognitive processing of auditory
information, etc. (142).
Other sensory systems exhibit similar survival-centric patterns of hypocretinergic control. For example, the entire olfactory pathway is intensively innervated by hypocretinergic neurons, and its activity is modulated by the hypocretins in a
specific manner that supports a variety of survival behaviors (7,
64). In hungry animals there is an increased release of hypocretin in the olfactory bulb, resulting in a decrease in the
threshold for the detection of olfactory information (64, 80).
On the other hand, the complete elimination of olfactory
sensations following destruction of the olfactory bulbs leads
to profound disruptions in sexual and territorial activities,
including a dramatic decrease in predatory behaviors (3).
Cataplectic individuals also exhibit numerous olfactoryrelated pathologies that occur because of the absence of
hypocretinergic directives (10).
Unique survival processes that involve the transmission of
visual information, which begins in the retina and extends to
the central processing of visual data, are also dependent on the
functioning of the hypocretinergic system (146). For example,
the guidance of body movements toward visually detected
objects is promoted by hypocretinergic directives (149). In the
natural environment, when a prey animal suddenly changes its
direction of movement in response to a predator’s actions,
hypocretinergic neurons in the predator activate “smooth eye
pursuit mechanisms” that control eye movements so that the
image of the moving target on the fovea is continuously
maintained (149). There are other intimate relationships between the visual system and somatomotor processes during
survival behaviors, especially those that involve visual-somatic
interactions that are controlled by the cerebellum (which are
described in the following section) that depend on hypocretinergic patterns of control.
The hypocretinergic system’s ability to enhance the transmission of a variety of auditory, olfactory, visual, and other
sensory information is crucial since it enables animals to
respond in an efficacious manner during survival situations. In
this regard, it is instructive to recognize the contributions of
Fred Merkel with respect to our understanding of the functioning of the hypocretinergic system. Fred Merkel, in 1875,
described a unique type of sensory mechanoreceptor (that later
bore his name) that is present throughout the entire epidermis;
these receptors are also located in hair follicles as well as in the
oral mucosa (13). Merkel mechanoreceptors are activated during survival behaviors when animals (such as the rat) sweep
their whiskers across objects, at rates approaching 1,500 Hz,
before making a behavioral decision (13, 101). In 2004, Merkel
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in the blood, and hence in the extracellular fluid that bathes
hypocretinergic neurons, induces depolarization and an increase in the generation of action potentials (93). Conversely,
an increase in the extracellular concentration of glucose results
in hyperpolarization and a cessation or a reduction in neuronal
discharge (93). Therefore, for this subset of hypocretinergic
neurons, their adequate stimulus is a physiologically low level
of blood glucose; it is also important to note that these
glucose-sensing hypocretinergic neurons are sufficiently sensitive to encode variations in blood glucose levels reflecting
those that occur between normal meals (57).
Hypocretinergic neurons not only function as glucose sensors for the entire brain and body, but they are also capable of
initiating and maintaining the survival behavior of food consumption by activating arousal, sensory, somatomotor, visceromotor, hormonal, and other systems, which results in the
restoration of a homeostatic level of blood glucose (17, 142).
Physiologically, this makes a great deal of sense. Hypocretinergic neurons first detect a deficit in energy resources, i.e.,
glucose, which is the primary metabolic “fuel” for neural and
nonneural cells; they then promote the survival behavior of
food consumption, which eliminates the deficit. These findings
led Yamanaka et al. (179) to conclude that the maintenance of
a homeostatic level of blood glucose, i.e., sufficient energy
resources, is among the prime directives of the hypocretinergic
system.
Exteroceptive survival stimuli activate the hypocretinergic
system. Successful survival behaviors require that animals
maximize the functioning of their sensory systems to critically
evaluate their external environment. Thus, it was not unexpected to find that specific survival-related information from
sensory receptors for vision, olfaction, audition, taste, etc., are
transmitted via high-priority “fast tracks” directly and indirectly to hypocretinergic neurons (3, 10, 24, 36, 58, 64, 71, 80,
119, 130, 147, 149, 184). There are also direct (i.e., monosynaptic) projections to all sensory systems from hypocretinergic
neurons that enhance the receipt of survival-related sensory
information (55, 61, 116, 127, 144, 146).
It is clear that the hypocretinergic system functions to
maximize sensory inputs that are of paramount importance in
promoting survival behaviors. For example, hypocretinergic
neurons innervate, selectively, specific receptive areas for
high-frequency sounds in the inferior colliculus, which is the
key CNS site that processes acoustic information and determines the form in which this information is conveyed to
cephalic sites (48, 96, 133, 161, 173). The question then arises:
why does the hypocretinergic system selectively enhance the
receipt of high-frequency auditory information? The answer is
provided by an analysis of the characteristics of high-frequency
sounds and the manner in which they are employed during
survival behaviors. High-frequency auditory waves, which are
capable of being rapidly transmitted over considerable distances, contain a great amount of data but are difficult to
localize by predators. Therefore, it was not unexpected to find
that most vertebrates respond when threatened by a predator by
generating “alarm signals” (after the Old Italian all’arme, i.e.,
‘to arms’), which are high-frequency acoustic waves that
encode information about the type of predator, the urgency of
the response, etc. For example, specific alarm calls of Vervet
monkeys communicate the presence of different predators such
as eagles, leopards, and pythons; this information is then
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The Hypocretins: a Command System for Survival Behaviors
Hypocretinergic Actions in Response to Survival Stimuli
Hypocretinergic generation of arousal. Survival behaviors
such as food consumption, reproduction, as well as fight and
flight take place during periods of arousal, i.e., heightened
alertness. In this regard, the hypocretins have been shown to
function as critical regulators of arousal.1 For example, Horvath and Gao (71) concluded that “it is essential to an animal’s
1
“Arousal” is utilized in the present text when referring to an activated
waking state that is induced by interoceptive and/or exteroceptive stimuli.
“Aroused” states occur in conjunction with survival and certain other behaviors and processes, including information processing, attention, etc. “Wakefulness” is employed when referring to a motorically quiescient baseline state
of awareness of the environment.
Chase MH
survival that it possesses the ability to adequately respond
[during aroused wakefulness] to threats such as a predator or
other life-threatening circumstances (i.e., food deprivation).”
Therefore, to mediate survival behaviors, hypocretinergic directives must first produce a highly aroused animal, which it
does by directing potent executive monosynaptic excitatory
drives to neurons in practically all of the major sites and
systems involved in the induction of arousal, such as the locus
coeruleus, the raphe nuclei, and the laterodorsal tegmental and
pedunculopontine tegmental nuclei, among others (132, 165).
During periods of arousal, hypocretin neurons discharge at
high frequencies; they are relatively inactive during quiet
wakefulness (104, 139). The administration of hypocretin promotes arousal; when there is a deficiency in hypocretin, there
is a corresponding decrease in wakefulness and the ability of
animals to respond to alerting stimuli (118, 132). Importantly,
it has been shown that hypocretinergic neurons are selectively
activated during arousal that is associated with the enactment
of survival behaviors; however, arousal that occurs in the
absence of such behaviors is not correlated with an increase in
the discharge of hypocretinergic neurons (160, 163).
The maintenance of consolidated periods of alert wakefulness or arousal is an essential aspect of survival behaviors such
as food searching and consumption. When faced with reduced
food availability, animals adapt with longer periods of arousal,
even at the expense of normal circadian patterns of activity
(140). Thus, the arousal imperatives of hypocretinergic origin
trump circadian directives! The importance of hypocretinmediated arousal as a prerequisite for food consumption and
other survival behaviors is highlighted by the fact that, when
hypocretinergic neurons are ablated, animals fail to respond to
a low level of blood glucose with increased wakefulness, motor
activation, or food consumption (36, 122, 139). Complementary data also reveal that hypocretinergic neurons play a critical
role in the maintenance of arousal during fasting (119, 136).
However, it is important to note that these actions of the
hypocretinergic system are not directed simply to sustain or
promote arousal, per se. For example, Torterolo et al. (160,
163) found that hypocretinergic neurons are activated during
arousal that is associated with different survival behaviors,
including food consumption; in contrast, there is minimal
hypocretinergic activation in the absence of these survival
behaviors, even though the animals are equivalently aroused
(160). In addition, hypocretinergic neurons project selectively
to cortical layer 6b and layer 2/3 of the prefrontal cortex, which
results in the activation of widespread areas of the cerebral
cortex, and arousal (12, 183). Direct monosynaptic hypocretinergic excitatory projections to the nonspecific arousal-producing nuclei in the thalamus as well as various subcortical sites,
including the amygdala, basal ganglia, and hippocampus, also
provide background support for survival behaviors (12, 45,
176).
Although the hypocretinergic system initiates arousal specifically in conjunction with the execution of survival behaviors, it does not receive synaptic feedback from arousal systems (152, 184). De Lecea and Sutcliffe (45) suggest that this
pattern of synaptic control allows animals to rapidly awaken
from sleep, which is a critical ability that is necessary for
survival. Similarly, Berthoud et al. (18) suggest that hypocretinergic directives evolved as a mechanism to stay alert
while foraging, which is one of the prime components of
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cells were discovered to contain hypocretin as well as receptors
for hypocretin. When these hypocretinergic receptors are activated, they increase the sensitivity and lower the threshold for
the discharge of Merkel mechanoreceptors (13). Because touch
sensations of the nature conveyed by Merkel cells play an
essential role in behaviors such as fight, flight, feeding, and
reproduction, the expression of hypocretin receptors by Merkel
cells provides unique justification for the Unified Hypocretinergic Survival Theory. In addition, it would be difficult to
integrate or rationalize the control of Merkel cells by the
hypocretins within other concepts of the integrated functioning
of the hypocretinergic system.
Although there are hypocretinergically mediated increases in
the transmission of a vast amount of diverse sensory information that is specifically important in initiating and controlling
survival behaviors, could the suppression of certain sensory
inputs also enhance these behaviors? It was, at first, rather
surprising to discover that the hypocretinergic system functions
to reduce the transmission of painful (nociceptive) neural
impulses, which is opposite to its effects on other sensory
modalities. The antinociceptive effects of the hypocretins are
exceedingly potent since they involve both presynaptic and
postsynaptic processes at all levels of the neuraxis (19, 36,
165). Hypocretinergic reductions in pain also occur at the same
time that transmission in other sensory pathways is enhanced
and arousal mechanisms are activated by hypocretinergic directives (19).
The preceding unique patterns of sensory control occur
because it is essential to be relatively “pain free,” highly alert,
but also acutely aware of the environment (both internal and
external) during survival situations. It would be counterproductive for animals or humans to be incapacitated by pain
when fighting for their lives or procuring food. Soldiers in
battle, professional football and basketball players, as well as
individuals with grievous injuries are nevertheless able to
continue to function and are pain free while engaged in
survival-type activities that take place during aroused wakefulness (see following section). Most other systems or drugs
that consistently reduce or eliminate pain do not produce
arousal, but instead promote sedation, such as the opioids and
similar antinociceptive substances. Thus, hypocretinergically
mandated reductions in pain that are accompanied by the
generation of arousal and heightened sensory “awareness”
makes perfect sense based on the clear need to promote these
processes and behaviors, concurrently, during survival situations.
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plexy, but those behavioral and other responses that occur in
both conditions can be accounted for by the Unified Hypocretinergic Survival Theory of the role of the hypocretinergic
system in promoting survival behaviors.
Hypocretinergic neurons not only generate aroused wakefulness as a prime component of their control of survival
behaviors, they also discharge, in bursts, during the phasic
periods of rapid eye movement (REM) sleep (52, 92, 102, 162,
163). However, the effects of hypocretinergic actions during
REM sleep are quite different from those produced during
wakefulness. For example, whereas somatomotor activation
occurs when hypocretinergic neurons discharge during wakefulness (see Control of Survival Behaviors by the Hypocretinergic System), motor inhibition takes place when the hypocretinergic system is activated during REM sleep (Fig. 4) (180,
181). Thus, the hypocretinergic system functions during REM
sleep in a manner similar to that of other systems that initiate
arousal and somatomotor activity in accordance with the phenomenon of Reticular Response-Reversal (Fig. 4) (33, 34, 85,
180 –182). This phenomenon is one wherein motor excitatory
drives that occur during wakefulness are transformed to motor
inhibitory directives when they arise during REM sleep. In
addition to other functions that the hypocretinergic system may
express during REM sleep, it also acts to preserve the integrity
of REM sleep by preventing the expression of motor activity at
a time when the organism is incapable of responding to
external threats, which is a pattern of motor control that has a
high survival value (23). The hypocretinergic system not only
acts to maintain and enhance the occurrence of REM sleep but,
conversely, also promotes rapid arousal at the termination of
this state when animals awaken (169, 177). Consequently, the
Unified Hypocretinergic Survival Theory accounts not only for
the totality of hypocretinergic directives that take place during
wakefulness, but also during sleep, and provides a rational
explanation for the consequences of the discharge of hypocretinergic neurons during sleep as well as waking states.
Hypocretinergic activation of the somatomotor and visceromotor systems. Coordinated patterns of striated (somatomotor) and smooth (visceromotor) muscle activity constitute the
foundation for the expression of survival behaviors. Therefore,
support for the Unified Hypocretinergic Survival Theory must
include data demonstrating that the hypocretinergic system is
capable not only of directly controlling somatomotor and
visceromotor processes but that this control is bound exclusively to situations related to survival.
There are a wealth of reports that demonstrate that the
hypocretinergic system is capable, via direct monosynaptic
projections, of coordinating and maintaining somatomotor activity. Excitatory monosynaptic projections from hypocretinergic neurons initiate the discharge of motoneurons at all levels
of the neuraxis (Fig. 4); they also activate motor-coordinating
sites such as the locomotor center in the brain stem (43, 112,
129, 140, 165, 180 –182, 188). In addition, the direct application of hypocretin on intracellularly recorded motoneurons
results in depolarization of their membrane potential, a decrease in input resistance, and sustained periods of action
potential generation (165, 181, 182). Unit recordings of hypocretinergic neurons also highlight the positive relationship
between their discharge and motor activity (104). Moreover,
when hypocretin is microinjected intraventricularly, there is an
increase in locomotor and muscle activity (63, 73, 112, 129).
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survival behaviors. Thus, for hypocretinergic neurons, arousal
is the necessary initial response to adequate survival stimuli.
To promote “survival” behaviors that occur during waking
states, hypocretinergic neurons interact with diverse functional
components of the CNS, one of the most important being the
noradrenergic arousal-promoting system (15, 16). A key noradrenergic structure, the locus coeruleus, receives extraordinarily dense projections from hypocretinergic neurons (72,
132) and “serves as a necessary downstream effector for Hcrt
function in promoting arousal” (30). It has also been proposed
that the actions of the hypocretinergic system and the locus
coeruleus that result in arousal are promulgated selectively in
conjunction with “stimulus-elicited primitive and goal-directed
behaviors” and “that the distinguishing feature of arousal with
Hcrt involvement is a high level of vigilance and attention to
the surrounding environment” (21, 56). In addition, Rodgers et
al. (137) point out “that arousal cannot be an end in itself but,
rather, is the means whereby animals engage in certain adaptive behaviors–such as foraging while simultaneously maintaining the level of vigilance necessary to avoid becoming a
meal for someone else.” Consequently, hypocretinergic-noradrenergic interactions that initiate and maintain arousal are not
only complex, but are also strongly state- and behavior-dependent.
In addition to arousal, the noradrenergic system, under
specific conditions, may promote antinociception as well as
prociception (130). Although peripheral norepinephrine has
little effect on pain in healthy tissue, following injury or
inflammation, the central and peripheral noradrenergic systems
exert antinociceptive actions that are subject to a number of
variables such as the type of receptor excited, the duration of
pain, the pathophysiological condition, etc. (130). In contrast,
arousal following activation of the hypocretinergic system is
consistently associated with antinociception (see Control of
Survival Behaviors by the Hypocretinergic System). An analysis of these complicated issues is beyond the scope of the
present article; however, they are addressed in Refs. 15, 30, 68,
79, 130, and 139.
The hypocretinergic system also plays an important role in
stabilizing transitions between sleep and wakefulness (15, 30,
68, 79, 119, 130, 139, 140). Thus, Sakurai and coworkers have
suggested that the hypocretinergic system regulates the states
of sleep and wakefulness in relation to its control of survivaltype behaviors that include reward and energy homeostasis
(139, 140, 142). They also propose that reciprocal feedback
loops exist between the hypocretinergic and monoaminergic
systems that act to stabilize wakefulness (142). Other researchers have also supported the concept that the hypocretinergic
system promotes and stabilizes wakefulness as well as controlling motor processes during waking states, specifically during
survival-type situations (30, 119, 142). The consequences that
arise, e.g., cataplexy, when there are deficient hypocretinergic
actions have also been examined (30, 136, 148). An exploration of the basic mechanisms that result in the abnormal control
of motoneurons during cataplexy are beyond the scope of the
present discussion. However, it is important to note that the
adequate stimuli for the induction of cataplectic attacks during
wakefulness are the same as those that initiate survival behaviors, such as the presentation of food during food deprivation
(see Refs. 32 and 122). As discussed above, not only is there a
homology of stimuli that initiate survival behaviors and cata-
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The Hypocretins: a Command System for Survival Behaviors
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The hypocretinergic system not only is capable of directly
activating final common pathway motoneurons and somatomotor systems, but it also exercises this control exclusively during
survival behaviors. For example, hypocretinergic neurons are
activated in conjunction with locomotor activity that occurs
when animals are pursuing a food reward. However, when a
food reward is not present, even though the same level of
motor output is maintained, hypocretinergic neurons are relatively silent (160, 163).
The control of sensorimotor activities that form the foundation for survival behaviors is dependent to a significant
extent on functions that are controlled by the cerebellum.
Therefore, there initially appeared to be a significant problem vis-à-vis the Unified Hypocretinergic Survival Theory,
since early studies reported that, although almost all areas of
the CNS were innervated by hypocretinergic axons, there
was a major exception, which was the cerebellum (132,
139). However, close inspection of these data and subsequent reports revealed that one area of the cerebellum, the
flocculonodular lobe, not only receives projections from
hypocretinergic neurons, but that its constituent neurons
also contain hypocretinergic receptors (97). The flocculonodular lobe, which constitutes the phylogenetically “ancient” archicerebellum, participates in the execution of critical survival functions (53). In this regard, hypocretinergic
neurons have been shown to activate pursuit-related cells in
the flocculonodular lobe, which initiate short-latency eye
movements that allow animals to track the trajectory of a
predator or prey, during walking or running, even if they
momentarily disappear behind an object (97, 186). It is also
important to note that pursuit-related cerebellar (flocculonodular) neurons are activated by hypocretinergic inputs
when external forces, such as prey movements, are the basis
for image instability (53, 97). The hypocretinergic system
also participates in motor control by modulating the activity
of the interpositus nucleus, which is one of the final outputs
of the cerebellum (186). Yu et al. (186) have shown that
hypocretinergic inputs from the hypothalamus to the nucleus
interpositus modulate cerebellar motor functions. Thus,
hypocretinergic/cerebellar systems integrate and coordinate
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Fig. 4. The hypocretin system and Reticular Response-Reversal. Stimulation of the lateral hypothalamus in the area of the greatest concentration of
hypocretinergic neurons (A) promotes motoneuron (B) excitation or inhibition according to the animal’s ongoing behavioral state (1). During wakefulness (2,
C), intracellular recordings reveal that excitatory postsynaptic potentials (upward cross-hatched deflection, C) are induced in lumbar motoneurons following
stimulation of the lateral hypothalamus, wherein hypocretinergic neurons are located. During carbachol-induced rapid eye movement (REM) sleep (3), the
identical stimulus produces large-amplitude inhibitory responses (downward cross-hatched deflection, D). Note, however, that short-latency depolarizing
(excitatory) potentials are still present during REM sleep, which is typical of Reticular Response-Reversal (180 –182). Therefore, these data, together with those
presented in Refs. 162, 163, 176, 177, and 180, indicate that the hypocretinergic system acts to sustain REM sleep by promoting motor inhibition during this
state. However, the hypocretins are also capable, via the circuitry of Reticular Response-Reversal, of inducing rapid arousal from REM sleep, which is a highly
vulnerable state for prey animals. In the absence of hypocretinergic directives and the effects of Reticular Response-Reversal (32, 136), there is a decrease in
motor activity during wakefulness (i.e., cataplexy) and a relative increase during REM sleep (41, 99, 105). N, nucleus. The vertical calibration bar in D indicates
1 mV, and the horizontal bar indicates 50 ms.
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963
activity, this control appears to be dependent upon the animal’s
behavioral state and/or condition (82, 89, 171, 185). During
survival situations, the hypocretinergic system exercises adaptive control of respiration, as evidenced by the fact that it
suppresses or resets the baroreceptor reflex to a higher pressure
range to provide for an increase in arterial blood pressure in the
brain (82, 89). During nonsurvival conditions, such as nonrapid
eye movement sleep, hypocretinergic control of central chemoreception is absent (113, 115). Studies of the influence of the
hypocretinergic system on central chemoreception also indicate that the hypocretins participate in the “wakefulness drive”
of breathing (113, 114). In contrast, basal ventilation is similar
in hypocretin knockout and wild-type mice, irrespective of
whether the animals are awake or asleep (82, 89, 171). In
addition, in hypocretin knockout animals, the loss of hypocretin neurons does not affect the circadian or sleep/wake regulation of core body or tail temperature, heart rate, or pulse
pressure, even though blood pressure is significantly lower
during all states of sleep and wakefulness in these animals
(150). These conflicting data may be resolved by studies that
examine the effects of the hypocretins during sleep and waking
states in conjunction with specific survival-related behaviors.
Hypocretinergic neurons are also capable of enhancing other
peripheral organ and related visceromotor functions that are
critical for survival, such as stress-induced increases in body
temperature and energy balance (151). Therefore, it was not
surprising to find that neurons that contain hypocretin in the
lateral hypothalamus, a site traditionally associated with the
promotion of feeding, are also involved in the control of brown
fat thermogenesis, which contributes to cold defense (151).
These and related data led Oldfield et al. (124) to suggest that
“single command neurons in the lateral hypothalamus project
to sites responsible for the initiation of feeding behaviors,” thus
providing a “substrate whereby information relating to both
thermogenesis and food intake may be locally integrated.”
It has been well documented that, when the hypocretinergic
system is activated, a panoply of coordinated peripheral organ
and hormonal responses arise that provide foundational support
for survival behaviors. In this regard, it is of significance to
note that almost all peripheral organs contain receptors for
hypocretin (77, 78), even though axons of hypocretinergic
neurons do not exit the CNS (142). Therefore, peripheral
hypocretinergic receptors, most of which are expressed by
nonneural cells, must be activated by nonsynaptic mechanisms.
For example, circulating hypocretin activates adrenocortical
cells without any direct axonal input from the CNS (77, 78,
100). Hypocretin receptor expression is strongly upregulated in
the ovaries during proestrus; these data, together with the
effects of hypocretin in the testes, indicate an important role for
hypocretin in the reproductive process that is mediated by
nonsynaptic mechanisms (78). The activity of peripheral organs and their visceromotor functions during survival behaviors are also enhanced by hypocretinergic control of the sympathetic and parasympathetic divisions of the autonomic nervous system (82, 89).
In addition to the indirect modulation of the activity of
peripheral organs by hypocretinergic activation of CNS sites,
there are substantive data that reveal that peripheral hypocretinergic receptors are excited by hypocretin that originates
from neurons in the lateral hypothalamus, which is subsequently released into the CSF, and hence into the circulatory
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somatic and visceral responses so that they are appropriate
to survival-related challenges (36, 37, 97).
The role of the hypocretinergic system in controlling survival behaviors is supported by data involving its pattern of
innervation of the cerebellum and the functioning of the flocculondular lobe and interpositus nucleus, as well as by its lack
of innervation of cerebellar sites that are not directly involved
with the execution of survival behaviors. In this regard, Zhang
et al. (190) concluded that, “Our results demonstrate that
endogenous orexin is critical for motor control for animals
facing a major motor challenge. Therefore, the modulation of
the central orexinergic system on motor control may be not
readily noticeable when internal and external environments are
relatively stable, as during rest or routine movements.” Clearly,
any credible theory regarding the functions of the hypocretinergic system must place its activities in context and account for
all of its many and varied actions in a state-dependent fashion.
The hypocretinergic system also activates visceromotor processes and coordinates the output of the autonomic nervous
system with respect to the control of heart rate, blood pressure,
hormonal secretions, etc., in a manner that enhances survival
behaviors (84). It is suggested that this pattern of hypocretinergic signaling is unique and that it evolved to assure that
foraging behavior in a potentially dangerous environment is
accompanied by appropriate activation of visceromotor processes (84). For example, there are numerous reports that
demonstrate that the hypocretins are capable of controlling
cardiovascular functions and that this control is expressed
selectively during survival situations. In this regard, the following question was posed by Samson et al. (144): “Is the
action of orexin needed for an appropriate cardiovascular
response to stress?” It was answered in the affirmative by
Kayaba et al. (82) who found, under survival-related conditions, that cardiovascular responses to a resident-intruder stress
were compromised in hypocretin knockout mice, but not in
intact animals. Complementary data were obtained by Nattie
and Li (114), who concluded that the hypocretins play a critical
role in the defense response from the perspective of its control
of central chemoreception; thus, the control of chemoreceptive
processes by the hypocretins is not exercised indiscriminately
during sleep or even waking states. Luong and Carrive (95)
also highlight a hypocretin-raphe relay that contributes to
cardiovascular changes evoked by arousal and survival-related
stressors. In addition, Silvani et al. (154) report that the
hypocretinergic system plays a subtle role in maintaining
alterations in heart rate during certain spontaneous survivaltype behaviors but that it is not necessary for the occurrence of
physiological sleep-dependent changes in systolic blood pressure variability. Hypocretin deficiency in humans, together
with altered blood pressure regulation, also increases cardiovascular risk, according to Grimaldi et al. (61). However, the
data are somewhat inconsistent, since there is evidence that
hypocretin deficiency in animals and humans may not always
be associated with reduced sympathetic tone, but may also
occur in conjunction with sympathetic activation (47, 60, 61,
95, 152, 196). Additional cardiorespiratory effects elicited by
the hypocretins during normal and pathological states are
reviewed in Shahid el al. (152).
There are other unique aspects of the control of the visceromotor system by the hypocretins. For example, although the
hypocretins are capable of modulating visceromotor receptor
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The Hypocretins: a Command System for Survival Behaviors
Control of Survival Behaviors by the Hypocretinergic System
Prior sections of this article include datasets that describe the
manner in which the hypocretinergic system controls synaptic,
sensory, somatomotor, visceromotor, hormonal, and other processes and mechanisms in a very specific manner that promotes
successful survival behaviors. Also presented are data that
demonstrate that these hypocretinergic directives are not activated in the absence of survival or survival-related processes or
behaviors. In this section, the integrative functioning of the
hypocretinergic system is described with respect to the manner
in which it “commands” and “coordinates” the vast panoply of
CNS and peripheral organ responses that arise as a result of the
presence of adequate survival stimuli (Figs. 1 and 3).
Martinez et al. (98) found that, when prey animals are
exposed to a predator, there is an increase in the discharge of
hypocretinergic neurons. In a related study, Canteras et al. (28)
reported that defensive behaviors in prey that are being attacked by predators are significantly reduced after the lateral
hypothalamus is lesioned (28). Complementary studies reveal
significantly greater immediate-early gene expression in the
hypothalamus of cat-exposed rats compared with confined or
handled rats (98). Environmental imperatives of a survival
nature that involve explorations of a potentially threatening
environment are also accompanied by the discharge of hypocretinergic neurons (160). However, the hypocretinergic system is not engaged during restraint or cold exposure when
Chase MH
animals are unable to respond physically and the environment
is “reduced,” e.g., to the insides of a refrigerator, even though
the animals are highly aroused (56). Thus, the hypocretinergic
system is activated and contributes to cold defense when an
animal is actively engaged with its environment and is able to
react with a variety of somatic and visceral responses (56). On
the other hand, when no response is possible in these situations,
the hypocretinergic system is not activated (56). Therefore, the
critical determinant for hypocretinergic activation is the expression of survival behaviors and/or related processes.
Other studies have shown that the hypocretinergic system
promotes adaptive stress responses of the brain and body when
an animal is confronted with survival imperatives, which are
inherently stressful; however, the hypocretins are not involved
in nonsurvival-related stressful responses. For example, the
hypocretins are a critical component of stress responses that are
activated by corticotropin-releasing factor (CRF) (117). CRFimmunoreactive terminals not only make direct contact with
hypocretin-expressing neurons in the lateral hypothalamus, but
hypocretinergic neurons also express CRF receptors (174).
CRF depolarizes hypocretinergic neurons and increases their
firing rate in paradigms that emulate fight-or-flight behaviors
(174). The hypocretins also promote the discharge of pituitary
corticotrophic cells by CRF, which activates the hypothalamicpituitary-adrenal axis, resulting in the release of glucocorticoids from the adrenal gland (117, 127). In addition, hypocretins
in the CSF are transported via the circulatory system to adrenal
cells that express hypocretinergic receptors (195). Complementary data also reveal that the excitation of hypocretinergic
neurons in response to acute stress is significantly impaired in
CRF knockout mice (i.e., mice that do not have a functioning
CRF system). As pointed out by Furlong et al., “stress itself is
not a critical factor in the activation of the Hcrt system” (56);
these data demonstrate that the hypocretinergic system functions selectively in stressful situations of a survival nature.
Hypocretinergic neurons exhibit a dramatic increase in discharge in conjunction with the presentation of noxious, fearproducing stimuli as animals attempt to escape or avoid these
stimuli (126, 197). Nevertheless, after repeated conditioned
fear trials, when animals learn that they cannot execute a
behavioral (i.e., survival) response to avoid noxious stimuli,
there is no increase in the discharge of hypocretinergic neurons
(197). In fact, there is a reduction in hypocretinergic activation
(197). Thus, activation of the hypocretinergic system only
occurs in conjunction with the presence of specific survivalrelated behavioral responses or the preparation for such responses.
Another data set reveals different, but equally important,
integrative functions of the hypocretinergic system that provide
essential support for survival behaviors. Studies of attentional
performance demonstrate that the hypocretins enhance the
accuracy of signal detection in survival-type situations, such as
when predators and prey interact; however, the hypocretins are
not involved in the detection or evaluation of similar kinds of
signals that are nonsurvival related (20). In addition, the
surprising omission of an expected event enhances attention to
cues that occur at the moment of surprise, which facilitates
subsequent learning regarding the nature and importance of the
relevant cue. Hypocretinergic input is critical for this pattern of
surprise-induced learning, which does not occur in hypocretinlesioned animals (69). Thus, the hypocretinergic system does
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system. For example, the concentration of hypocretin in the
cerebrospinal fluid (CSF) and blood varies in conjunction with
ongoing normal and pathological states and processes (22, 103,
107). Intracerebroventricular injections of hypocretin induce
not only central, but also peripheral, effects (65, 121). Therefore, CNS-derived hypocretin is capable, nonsynaptically, of
activating hypocretinergic receptors that are expressed by peripheral organs. This conclusion has been supported by studies
using supraparamagnetic particles of iron oxide (MNPs) (1, 2),
which are conjugated with molecules of hypocretin and then
injected into the lateral ventricles (195). With histological and
magnetic resonance imaging (MRI) techniques, one can track
the location of identified molecules of hypocretin from the
CNS to peripheral organs, where they activate their cognizant
receptors in a time-dependent manner. Using this novel technology, it was first determined that MNP-“tagged” molecules
of hypocretin are absorbed by epithelial cells of the choroid
plexus of the cerebral ventricles that express hypocretin receptors (195). Hypocretin-conjugated MNPs are then conveyed,
via the circulatory system, to peripheral organs where they
attach to cells that contain receptors for hypocretin, such as
endocrine cells of the pancreas (195). These and related studies
reveal that the CSF-circulatory system transports hypocretins
from the CNS to the periphery, and, by this route, the hypocretinergic system is able to control the functioning of peripheral organs by nonsynaptic processes (195).
The preceding data demonstrate that the hypocretinergic
system activates, selectively, a wide range of visceromotor
processes. Complementary correlated patterns of somatomotor
control are also promulgated by hypocretinergic actions. In
addition, hypocretinergic control of the somatomotor and visceromotor systems is exercised, selectively, only when survivalrelated behaviors and related processes are being expressed.
•
Review
The Hypocretins: a Command System for Survival Behaviors
Chase MH
965
activity when food deprived (86). Thus, hypocretinergically
driven, positively rewarding directives are an essential component of survival behaviors. It would certainly be nonproductive
if animals sought to avoid behaviors that enhanced their ability
to survive!
The preceding studies reveal that the hypocretinergic system
controls the output of numerous systems at all levels of the
neuraxis, as well as the activities of peripheral organs, in the
performance of survival behaviors that are stressful but also
highly rewarding. In addition, as described above, the integrative actions of the hypocretinergic system encompass all of the
command and control directives that comprise the multifaceted
components of survival behaviors.
Control of Survival-Related Processes by the
Hypocretinergic System
Survival-related actions of the hypocretinergic system.
Based upon the established actions of the hypocretins in
promoting arousal, food consumption, motor activity, antinociception, etc., as well as its key role in the control of integrated survival behaviors, one might not necessarily assume
that the hypocretinergic system also functions to mitigate
diseases such as cancer or prevent processes such as neurodegeneration. Nevertheless, from the perspective that the hypocretins act in a multitude of ways to promote the survival of
individual animals as well as the species, such data could have
been anticipated. For example, it has been shown that, in
addition to playing a key role in food consumption, the hypocretins also enhance gastric defense mechanisms and ulcer
healing, especially during stress such as that which occurs in
conjunction with fight-or-flight behaviors (25). In addition, the
hypocretins induce both neurogenesis (31, 74) and angiogenesis (83).
Surprisingly, the hypocretins have also been shown to be
anti-carcinogenic. For example, it is known that cells of the
epithelium of the normal, disease-free colon do not contain
receptors for hypocretin; however, when these epithelial cells
become cancerous, they begin to express, de novo, receptors
for hypocretin (90, 138). Amazingly, when these aberrant
hypocretinergic receptors in the colon are activated by hypocretin, instead of functioning as normal receptors that promote
cellular activity (166), they initiate intracellular processes that
result in cell death by a process of apoptosis (167). Thus,
hypocretinergic receptors that are generated by cancerous cells
in the colon, by acting as “suicide” receptors, have potent
cellular effects that are life-preserving. The hypocretinergic
system has also been found to prevent neurodegeneration that
is induced by hypoxia (110, 187). This finding is especially
significant because almost every known neuroprotective substance acts by suppressing or inhibiting neural activity. Consequently, even though hypocretin is an excitatory neuropeptide, in this case its effects are more closely related to those
produced by inhibitory neurotransmitters (54, 189).
Anticipated survival-related actions of the hypocretinergic
system. As described above, in a multitude of ways the hypocretinergic system provides protection from injury and disease
and promotes survival-related processes at subcellular, cellular,
systems, and behavioral levels. As our knowledge of the
central and peripheral as well as the synaptic and nonsynaptic
actions of the hypocretins increases, based upon concepts that
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not simply enhance general neural performance, rather, it is
essential for the integration of meaningful stimuli of a survival
nature.
The superior colliculus and the periaqueductal gray (PAG)
play well-established roles in the execution of the survival
behavior of predatory hunting: these sites first integrate visual,
auditory, somatosensory, and olfactory cues and then generate
appropriate motor responses of a survival nature (107). For
example, it has been shown that hypocretinergic neurons control cells in the superior colliculus and PAG with respect to the
execution of predatory hunting (107, 108). Both the superior
colliculus and PAG are massively innervated by hypocretinergic neurons and, in turn, send substantive projections to them
(55, 107, 132). Studies of fos expression indicate that cells in
the superior colliculus and PAG as well as hypocretinergic
neurons discharge at accelerated rates during predatory hunting
and related behaviors, but not during nonsurvival motor behaviors (29, 38, 55, 107, 122). On the other hand, animals with
lesions of the superior colliculus and/or PAG are unable to
orient themselves toward moving prey and exhibit significant
deficits in their ability to capture, hold, and kill prey (55, 108).
It is also important to highlight the converse finding that
hypocretin-lesioned animals perform in a manner that is equivalent to intact animals in situations that are not survival-related,
e.g., in open field tests of arousal or locomotion (28, 108).
From an evolutionary perspective, a rewarding stimulus can
be considered as a directional force with a high survival value
for the species. Therefore, it is of significance that the greatest
concentration of hypocretinergic neurons overlaps precisely
with the area in the lateral hypothalamus that has been identified as the “reward” or “pleasure” zone, which is responsible
for promoting self-stimulation and generating positively rewarding feelings and emotions (37). The importance of the
hypocretinergic system in defense and survival behaviors has
also been proposed by Choi et al. (36) and Benoit et al. (14)
based upon elevated hypocretinergic activity in conjunction
with risk-reward seeking survival-related behaviors (14, 36,
42). It was therefore not surprising to find that the dopaminergic system is a special target of hypocretin projections that
enhance motivated, positively rewarding survival-related activities, including food consumption and reproduction (87). In
addition to predatory hunting, the hypocretinergic system,
together with the superior colliculus and the PAG, also mediates related survival behaviors such as reward seeking (107,
108). The complementary behavioral studies of Muschamp et
al. (109) led them to conclude that “activation of the hcrt/orx
system is an integral component of motivated behaviors” and
that hypocretinergic neurons are activated by natural rewards
such as food and sex (109). Thus, hypocretinergic neurons
constitute the core of the “emotional motor system,” described
by Holstege, which is responsible for promoting the emotional,
somatomotor, and visceromotor components of survival behaviors (70).
In animals wherein there is a deficit in the functioning of the
hypocretinergically regulated reward system, survival and related behaviors are severely compromised (14). In humans
with cataplexy who lack hypocretin, there is also a corresponding reduction in reward-based behaviors, such as drug addiction (9). Hypocretin knockout mice exhibit attenuated morphine dependence and withdrawal; similarly, hypocretin neuron-ablated mice fail to show increased arousal and motor
•
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966
The Hypocretins: a Command System for Survival Behaviors
Potential Limitations of the Unified Survival Theory of the
Functioning of the Hypocretinergic System
Novel theories are based upon a consideration of existing
data that, by their very nature, are insufficient to transform the
theory into established fact. Therefore, in this section, potential
“limitations” of the Unified Hypocretinergic Survival Theory
that are due to a lack of data are examined, and a number of
experiments are proposed that would resolve these limitations.
The Unified Hypocretinergic Survival Theory has not yet
encompassed the manner in which the hypocretinergic system,
as with other primitive systems, developed over time to include
more functions than those subsumed early in its phylogenetic
development. For example, a role in stabilizing the states of
sleep and wakefulness may be an evolved function of the
hypocretinergic system that provides a background for the
“stable” expression of survival behaviors, especially those that
are related to this system’s interactions with forebrain structures involved in the control of arousal as well as other waking
and sleep states. The influence of the hypocretins on circadian
Chase MH
processes may also be complementary to its role in stabilizing
sleep and waking states since there are strong reciprocal
connections between hypocretinergic neurons and various sites
that are involved in the regulation of circadian rhythms (94,
118, 119). These are complex processes as evidenced by the
fact that hypocretins and their receptors are present in the
retina, and photosensitive retinal ganglion cells play a role in
setting the suprachiasmatic circadian clock (146). Stable circadian rhythms, as with the states of sleep and wakefulness,
provide an important foundation for the expression of survival
and related behaviors, which are highlighted by the deficits in
survival-related processes and states that arise in hypocretin
knockout animals (82, 89). Additional studies are required to
determine the precise manner in which survival behaviors are
dependent on hypocretinergic/circadian/sleep/wakefulness interactions; experiments that define the deficits in survival
behaviors that arise when these interactions are not maintained
would therefore be of great value.
The importance of the hypocretinergic system in controlling
respiratory activities is well established in survival situations
that take place during arousal (82, 89). However, the hypocretins also play a critical role in the control of CO2 sensitivity in
a state-dependent manner by preserving ventilatory stability
during sleep (110, 111). These actions of the hypocretins
during sleep may be viewed as supporting the Unified Hypocretinergic Survival Theory insofar as they represent an example of a survival-related function of this system that maintains/
stabilizes sleep, and this assures optimal functioning during
wakefulness/arousal. In this regard, the finding that there is a
high incidence of apneaic episodes during sleep in hypocretin
knockout mice, and the consequences that arise with respect to
survival behaviors that take place during wakefulness, has been
relatively unexplored (152). The Unified Hypocretinergic Survival Theory may also be expanded by conducting clinically
related studies involving an evaluation of the therapeutic potential of hypocretin for the treatment of sleep- and wakingrelated breathing disorders (178).
Other aspects of the Unified Hypocretinergic Survival Theory would benefit from additional srudies dealing with the
various behaviors/reactions of animals that occur when the
hypocretinergic system is rendered nonfunctional either by
ablation of its constituent neurons, the generation of hypocretin
knockout animals, the administration of receptor antagonists,
etc. Data must also be examined over an extended period of
time in behaving animals. In addition, studies of hypocretin
knockout animals should take into account the possible impact
of processes such as neuronal plasticity as well as compensatory actions by alternate sites. Although there is a consensus
that the locus coeruleus-noradrenergic system plays a causal
role in the induction of arousal states, lesions of the noradrenergic system have an inconsistent impact on indexes of arousal,
which is thought to be due to the presence of time-dependent
lesion-induced compensation by other systems (15, 16).
The ontogenetic development of the hypocretinergic system
as well as its response to aging processes have not been
examined to any significant extent from the perspective of the
Unified Hypocretinergic Survival Theory (192, 193). Destruction of the hypocretinergic system in newborn animals and the
aged in conjunction with behavioral survival-related tests could
clarify the role of the hypocretins in promoting survival behaviors across the life span. In addition, the Unified Hypo-
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are inherent in the Unified Hypocretinergic Survival Theory, a
host of other phenomena/processes can logically be anticipated
to be discovered, such as enhanced immune directives, blood
coagulation, recovery from trauma, the prevention or reduction
in Traumatic Brain Injury (11, 172), etc. It has already been
shown that there are surges of hypocretinergic activity that are
correlated with critical periods of infant and adolescent development (8, 159). In addition, hypocretinergic neurons have
been shown to be relatively resistant to the deleterious effects
of the aging process, compared with other neuronal phenotypes
(192, 193).
Many other positive actions of the hypocretins will likely
emerge based upon their role in mediating survival behaviors.
For example, there is a fascinating phenomenon called time
dilation wherein, under certain situations of a life-threatening
nature, such as those that occur in combat or when one loses
control of a speeding automobile, information is processed in a
unique mode (50). When these situations arise, there is a
profound subjective impression that time slows down (i.e., that
it dilates); individuals feel as if they have “all the time in the
world” to make reasoned critical decisions of a life-preserving
nature. Since time dilation occurs exclusively during survivaltype situations, it is likely to be mediated by the hypocretinergic system, which simultaneously promotes arousal, motor
activity, surprise-induced learning, etc. under similar circumstances. For example, CSF and plasma concentrations of hypocretin in combat veterans with posttraumatic stress disorder
(PTSD) are significantly lower than in healthy control subjects
(156). These data may reflect a paucity of effective hypocretinergic control mechanisms that result in an inability of individuals to cope with the wide range of physiological and psychological responses that arise in fight or flight (e.g., combat)
situations (76). It would be interesting to determine if there is
a cause and effect relationship, i.e., do combat veterans that
develop PTSD have low levels of hypocretin before their
engagement in warfare? Clearly, data detailing the actions of
the hypocretinergic system, when presented from the perspective of its role in promoting survival and related behaviors and
processes, have the potential to impact many new and diverse
areas of basic and clinical research.
•
Review
The Hypocretins: a Command System for Survival Behaviors
cretinergic Survival Theory has not addressed, to any significant extent, gender differences vis-à-vis the functioning of the
hypocretinergic system. Although there is a paucity of relevant
behavioral data, it is known, for example, that the expression of
hypocretin receptors in the adrenal cortex is gender specific
and is magnified not only by plasma glucose, but also by
gonadal steroids during conditions that are survival related
(81). Thus, the Unified Hypocretinergic Survival Theory is
currently limited by a lack of data as opposed to existing data
that do not support the Theory.
Summary
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author.
AUTHOR CONTRIBUTIONS
Author contributions: M.H.C. analyzed data; M.H.C. prepared figures;
M.H.C. drafted manuscript; M.H.C. edited and revised manuscript; M.H.C.
approved final version of manuscript.
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peripheral organs to ensure the animal’s survival. In a complementary fashion, the data reveal that, when there is a deficit in
the functioning of the hypocretinergic system, survival behaviors and related processes are compromised, whereas processes
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