Orexin System
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The lateral hypothalamus (LH), also called the lateral hypothalamic area (LHA), contains the primary
orexinergic Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. It exists in the forms of orexin-A and orexin-B. The most common form of narcolepsy, type 1, in which the individual experiences brief loss ...
nucleus within the
hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...
that widely projects throughout the
nervous system In biology, the nervous system is the complex system, highly complex part of an animal that coordinates its behavior, actions and sense, sensory information by transmitting action potential, signals to and from different parts of its body. Th ...
; this system of neurons mediates an array of cognitive and physical processes, such as promoting feeding behavior and arousal, reducing
pain perception In physiology, nociception , also nocioception; ) is the Somatosensory system, sensory nervous system's process of encoding Noxious stimulus, noxious stimuli. It deals with a series of events and processes required for an organism to receive a pai ...
, and regulating body temperature, digestive functions, and blood pressure, among many others. Clinically significant disorders that involve dysfunctions of the orexinergic projection system include
narcolepsy Narcolepsy is a chronic neurological disorder that impairs the ability to regulate sleep–wake cycles, and specifically impacts REM (rapid eye movement) sleep. The symptoms of narcolepsy include excessive daytime sleepiness (EDS), sleep-r ...
, motility disorders or
functional gastrointestinal disorder Functional gastrointestinal disorders (FGID), also known as disorders of gut–brain interaction, include a number of separate idiopathic disorders which affect different parts of the human gastrointestinal tract, gastrointestinal tract and involv ...
s involving
visceral hypersensitivity Visceral pain is defined as pain that results from the activation of nociceptors of the thoracic, pelvic, or abdominal viscera (organs) in the human body. Visceral structures are highly sensitive to distension (stretch), ischemia and inflammation, ...
(e.g.,
irritable bowel syndrome Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by a group of symptoms that commonly include abdominal pain, abdominal bloating, and changes in the consistency of bowel movements. These symptoms may ...
), and eating disorders. The
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...
glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...
and the
endocannabinoid Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...
s (e.g.,
anandamide Anandamide (ANA), also referred to as ''N''-arachidonoylethanolamine (AEA) is a fatty acid neurotransmitter belonging to the fatty acid derivative group known as N-acylethanolamine (NAE). Anandamide takes its name from the Sanskrit word ''ananda ...
) and the
orexin Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. It exists in the forms of orexin-A and orexin-B. The most common form of narcolepsy, type 1, in which the individual experiences brief loss ...
neuropeptide Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the ...
s
orexin-A Orexin-A, also known as hypocretin-1, is a naturally occurring neuropeptide and orexin isoform. The orexinergic nucleus in the lateral hypothalamus is the primary orexin projection system in the brain. Structure Orexin-A is a peptide composed of ...
and
orexin-B Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. It exists in the forms of orexin-A and orexin-B. The most common form of narcolepsy, type 1, in which the individual experiences brief losses ...
are the primary signaling neurochemicals in orexin neurons; pathway-specific neurochemicals include
GABA GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...
, melanin-concentrating hormone, nociceptin,
glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
, the
dynorphin Dynorphins (Dyn) are a class of opioid peptides that arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 (PC2), multiple active peptides are released: dynorphin A, dynorphin ...
peptides, and the appetite-regulating peptide hormones
leptin Leptin (from Ancient Greek, Greek λεπτός ''leptos'', "thin" or "light" or "small"), also known as obese protein, is a protein hormone predominantly made by adipocytes (cells of adipose tissue). Its primary role is likely to regulate long ...
and
ghrelin Ghrelin (; or lenomorelin, INN) is a hormone primarily produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a "hunger hormone" because it increases the drive to eat. Blood levels of ghrel ...
, among others. Notably,
cannabinoid receptor 1 Cannabinoid receptor 1 (CB1), is a G protein-coupled cannabinoid receptor that in humans is encoded by the ''CNR1'' gene. And discovered, by determination and characterization in 1988, and cloned in 1990 for the first time. The human CB1 recep ...
(CB1) is colocalized on orexinergic projection neurons in the lateral hypothalamus and many output structures, where the CB1 and
orexin receptor 1 Orexin receptor type 1 (Ox1R or OX1), also known as hypocretin receptor type 1 (HcrtR1), is a protein that in humans is encoded by the HCRTR1 gene. Function The orexin 1 receptor (OX1), is a G-protein coupled receptor that is heavily expresse ...
(OX1) receptors form the CB1–OX1 receptor heterodimer.
Figure 1: Schematic of brain CB1 expression and orexinergic neurons expressing OX1 or OX2
br
Figure 2: Synaptic signaling mechanisms in cannabinoid and orexin systems
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Figure 3: Schematic of brain pathways involved in food intake
/ref>


Inputs

* Medial
prefrontal cortex In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. It is the association cortex in the frontal lobe. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, ...
*
Central nucleus of the amygdala The central nucleus of the amygdala (CeA or aCeN) is a nucleus within the amygdala. It serves as the major output nucleus of the amygdala and participates in receiving and processing pain information. CeA connects with brainstem areas that cont ...


Outputs

The orexinergic projections from the lateral hypothalamus innervate the entirety of the remainder of the
hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...
, with robust projections to the posterior hypothalamus, tuberomammillary nucleus (the
histamine Histamine is an organic nitrogenous compound involved in local immune responses communication, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Discovered in 19 ...
projection nucleus), the
arcuate nucleus The arcuate nucleus of the hypothalamus (ARH), or ARC, is also known as the infundibular nucleus to distinguish it from the arcuate nucleus of the medulla oblongata in the brainstem. The arcuate nucleus is an aggregation of neurons in the medio ...
, and the
paraventricular hypothalamic nucleus The paraventricular nucleus (PVN) is a nucleus in the hypothalamus, located next to the third ventricle. Many of its neurons project to the posterior pituitary where they secrete oxytocin, and a smaller amount of vasopressin. Other secretions a ...
. In addition to the histaminergic nucleus, the orexin system also projects onto the
ventral tegmental area The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is th ...
dopamine nucleus,
locus ceruleus The locus coeruleus () (LC), also spelled locus caeruleus or locus ceruleus, is a nucleus in the pons of the brainstem involved with physiological responses to stress and panic. It is a part of the reticular activating system in the reticular ...
noradrenergic nucleus, the serotonergic
raphe nuclei The raphe nuclei (, "seam") are a moderate-size cluster of nuclei found in the brain stem. They have 5-HT1 receptors which are coupled with Gi/Go-protein-inhibiting adenyl cyclase. They function as autoreceptors in the brain and decrease the ...
, and cholinergic
pedunculopontine nucleus The pedunculopontine nucleus (PPN) or pedunculopontine tegmental nucleus (PPT or PPTg) is a collection of neurons located in the upper pons in the brainstem. It is involved in voluntary movements, arousal, and provides sensory feedback to the cere ...
and
laterodorsal tegmental nucleus The laterodorsal tegmental nucleus (or lateroposterior tegmental nucleus) is a nucleus situated in the brainstem, spanning the midbrain tegmentum and the pontine tegmentum. Its location is one-third of the way from the pedunculopontine nucleus to t ...
. The histaminergic, dopaminergic, serotonergic, noradrenergic, and cholinergic nuclei which the lateral hypothalamic orexin neurons project onto constitute the primary components of the
ascending reticular activating system The reticular formation is a set of interconnected nuclei in the brainstem that spans from the lower end of the medulla oblongata to the upper end of the midbrain. The neurons of the reticular formation make up a complex set of neural networks ...
. Other output regions include: the ventromedial hypothalamus, medial and lateral
septal nuclei The septal area (medial olfactory area), consisting of the lateral septum and medial septum, is an area in the lower, posterior part of the medial surface of the frontal lobe, and refers to the nearby septum pellucidum. The septal nuclei are loca ...
, central medial amygdala,
zona incerta The zona incerta (ZI) is a horizontally elongated small Nucleus (neuroanatomy), nucleus that separates the larger subthalamic nucleus from the thalamus. Its connections project extensively over the brain from the cerebral cortex down into the spin ...
, periaqueductal gray matter,
lateral habenula The habenula (diminutive of Latin meaning rein) is a small bilateral neuronal structure in the brain of vertebrates, that has also been called a microstructure since it is no bigger than a pea. The naming as little rein describes its elongated ...
, diagonal band,
substantia innominata The substantia innominata, also innominate substance or substantia innominata of Meynert (Latin for unnamed substance), is a series of layers in the human brain consisting partly of gray and partly of white matter, which lies below the anterior par ...
(contains the
nucleus basalis In the human brain, the nucleus basalis, also known as the nucleus basalis of Meynert or nucleus basalis magnocellularis, is a group of neurons located mainly in the substantia innominata of the basal forebrain. Most neurons of the nucleus basa ...
),
stria terminalis The stria terminalis (or terminal stria) is a structure in the brain consisting of a band of fibers running along the lateral margin of the ventricular surface of the thalamus. Serving as a major output pathway of the amygdala, the stria termina ...
,
prefrontal cortex In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. It is the association cortex in the frontal lobe. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, ...
, various
brain stem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is co ...
substructures, including the rostral ventromedial medulla,
rostral ventrolateral medulla The rostral ventrolateral medulla (RVLM), also known as the pressor area of the medulla, is a part of the ventrolateral medulla in the brainstem responsible for basal and reflex control of sympathetic activity associated with cardiovascular fun ...
,
nucleus ambiguus The nucleus ambiguus ("ambiguous nucleus" in English) is a group of large motor neurons, situated deep in the medullary part of the reticular formation named by Jacob Clarke. The nucleus ambiguus contains the cell bodies of neurons that innerva ...
,
solitary nucleus The solitary nucleus (SN) (nucleus of the solitary tract, nucleus solitarius, or nucleus tractus solitarii) is a series of neurons whose cell bodies form a roughly vertical column of grey matter in the medulla oblongata of the brainstem. Their a ...
,
spinal trigeminal nucleus The spinal trigeminal nucleus is a nucleus in the medulla that receives information about deep/crude touch, pain, and temperature from the ipsilateral face. In addition to the trigeminal nerve (CN V), the facial (CN VII), glossopharyngeal (CN ...
,
pontine micturition center In neuroanatomy, the pontine micturition center (PMC, also known as Barrington's nucleus) is a collection of neuronal cell bodies located in the rostral pons in the brainstem involved in the supraspinal regulation of micturition (urination). When ...
,
ventral respiratory group Standard anatomical terms of location are used to describe unambiguously the anatomy of humans and other animals. The terms, typically derived from Latin or Greek roots, describe something in its standard anatomical position. This position provi ...
, and pontine respiratory group),
area postrema The area postrema, a paired structure in the medulla oblongata of the brainstem, is a circumventricular organ having permeable capillaries and sensory neurons that enable its role to detect circulating chemical messengers in the blood and tra ...
, and
dorsal nucleus of vagus nerve The dorsal nucleus of vagus nerve (or posterior nucleus of vagus nerve or dorsal vagal nucleus or nucleus dorsalis nervi vagi or nucleus posterior nervi vagi) is a cranial nerve nucleus of the vagus nerve (CN X) situated in the medulla oblongata ...
.
Cannabinoid receptor 1 Cannabinoid receptor 1 (CB1), is a G protein-coupled cannabinoid receptor that in humans is encoded by the ''CNR1'' gene. And discovered, by determination and characterization in 1988, and cloned in 1990 for the first time. The human CB1 recep ...
(CB1) is colocalized on orexinergic projection neurons in the lateral hypothalamus and many output structures, where the CB1 and
orexin receptor 1 Orexin receptor type 1 (Ox1R or OX1), also known as hypocretin receptor type 1 (HcrtR1), is a protein that in humans is encoded by the HCRTR1 gene. Function The orexin 1 receptor (OX1), is a G-protein coupled receptor that is heavily expresse ...
(OX1) receptors physically and functionally join to form the CB1–OX1 receptor heterodimer. There is substantial anatomical and functional overlap and systemic cross-talk between the
endocannabinoid system The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the central nervous system ( ...
and orexin system within the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
.


Function

Through the diverse outputs of the orexin system, the orexin neurons in the lateral hypothalamus mediate an array of functions. Two of the most commonly noted functions of orexin peptides in the lateral hypothalamus are the promotion of feeding behavior and arousal (i.e., wakefulness). More generally, the orexinergic neural projections of the lateral hypothalamus are involved in
thermoregulation Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different. A thermoconforming organism, by contrast, simply adopts the surrounding temperature ...
, regulating
gastrointestinal motility Gastrointestinal physiology is the branch of Human body, human physiology that addresses the physical function of the Human gastrointestinal tract, gastrointestinal (GI) tract. The function of the GI tract is to process ingested food by mechanical ...
and gastrointestinal function by way of the dorsal nucleus of the vagus nerve, reducing pain and
nociception In physiology, nociception , also nocioception; ) is the Somatosensory system, sensory nervous system's process of encoding Noxious stimulus, noxious stimuli. It deals with a series of events and processes required for an organism to receive a pai ...
through several output structures (e.g.,
periaqueductal gray The periaqueductal gray (PAG), also known as the central gray, is a brain region that plays a critical role in autonomic function, motivated behavior and behavioural responses to threatening stimuli. PAG is also the primary control center for ...
matter), modulating the rewarding property of stimuli through the
ventral tegmental area The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is th ...
projections and other outputs in the
reward system The reward system (the mesocorticolimbic circuit) is a group of neural structures responsible for incentive salience (i.e., "wanting"; desire or craving for a reward and motivation), associative learning (primarily positive reinforcement and c ...
, regulating
energy homeostasis In biology, energy homeostasis, or the homeostatic control of energy balance, is a biological process that involves the coordinated homeostatic regulation of food intake (energy inflow) and energy expenditure (energy outflow). The human brain, p ...
and neuroendocrine functions (e.g.,
HPA axis The pascal (symbol: Pa) is the unit of pressure in the International System of Units (SI). It is also used to quantify internal pressure, stress, Young's modulus, and ultimate tensile strength. The unit, named after Blaise Pascal, is an SI ...
,
HPG axis HPG may refer to: * Huppuguda railway station, in Hyderabad, India * Hypothalamic–pituitary–gonadal axis * People's Defence Forces (Kurdish: '), the armed wing of the Kurdistan Workers' Party * Shennongjia Hongping Airport, in Hubei, China ...
, and
HPT axis HPT may refer to: * Harlem Park Three, American trio falsely convicted for murder * Hazard Perception Test, a component of the United Kingdom driving test * Hazleton Public Transit, in Pennsylvania, United States * ''Health Policy and Technology'', ...
) through other hypothalamic outputs, and regulating visceral functions (e.g., respiration, blood pressure, and
urination Urination is the release of urine from the bladder through the urethra in Placentalia, placental mammals, or through the cloaca in other vertebrates. It is the urinary system's form of excretion. It is also known medically as micturition, v ...
) via a group of structures in the brain stem, among other functions. The
endocannabinoid system The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the central nervous system ( ...
and the orexin system mediate many of the same cognitive and physical effects, and a significant overlap in their function and localization has been noted in a 2013 medical review; the receptor heterodimer produces a 100-fold amplification of the potency of the
orexin receptor 1 Orexin receptor type 1 (Ox1R or OX1), also known as hypocretin receptor type 1 (HcrtR1), is a protein that in humans is encoded by the HCRTR1 gene. Function The orexin 1 receptor (OX1), is a G-protein coupled receptor that is heavily expresse ...
-mediated ERK pathway signaling. Unique functional interactions have been noted as well, such as an OX1-induced CB1 pressor response in the
rostral ventrolateral medulla The rostral ventrolateral medulla (RVLM), also known as the pressor area of the medulla, is a part of the ventrolateral medulla in the brainstem responsible for basal and reflex control of sympathetic activity associated with cardiovascular fun ...
.


Clinical significance

Narcolepsy Narcolepsy is a chronic neurological disorder that impairs the ability to regulate sleep–wake cycles, and specifically impacts REM (rapid eye movement) sleep. The symptoms of narcolepsy include excessive daytime sleepiness (EDS), sleep-r ...
is associated with a marked reduction in the number of orexinergic projection neurons from the lateral hypothalamus and very low orexin peptides in
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...
. This has been identified as the mechanism responsible for narcoleptic symptoms. Evidence suggest that OX1 neurons that synapse onto the dorsal nucleus of the vagus nerve and parts of the
brain stem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is co ...
may play a role in the
pathophysiology Pathophysiology (or physiopathology) is a branch of study, at the intersection of pathology and physiology, concerning disordered physiological processes that cause, result from, or are otherwise associated with a disease or injury. Pathology is ...
of
chronic pain Chronic pain is pain that persists or recurs for longer than 3 months.https://icd.who.int/browse/2025-01/mms/en#1581976053 It is also known as gradual burning pain, electrical pain, throbbing pain, and nauseating pain. This type of pain is in cont ...
and
visceral hypersensitivity Visceral pain is defined as pain that results from the activation of nociceptors of the thoracic, pelvic, or abdominal viscera (organs) in the human body. Visceral structures are highly sensitive to distension (stretch), ischemia and inflammation, ...
in
functional gastrointestinal disorder Functional gastrointestinal disorders (FGID), also known as disorders of gut–brain interaction, include a number of separate idiopathic disorders which affect different parts of the human gastrointestinal tract, gastrointestinal tract and involv ...
s.


References


External links


Figure 1: Schematic of brain CB1 expression and orexinergic neurons expressing OX1 or OX2

Figure 2: Synaptic signaling mechanisms in cannabinoid and orexin systems

Figure 3: Schematic of brain pathways involved in food intake
{{Authority control Hypothalamus Limbic system Narcolepsy Sleep disorders