Preface : Over a short period in the
late 1990s, three groups converged on the
discovery of a neuropeptide system, centred in
the dorsolateral hypothalamus, that regulates
arousal states, influences feeding and is
implicated in the sleep disorder narcolepsy.
Subsequent studies have illuminated many aspects
of the circuitry of the hypocretin (also called
orexin) system, which also influences hormone
secretion and autonomic homeostasis, and have
led to the hypothesis that most human
narcolepsies result from an autoimmune attack
against the hypocretin-producing neurons. The
biochemical, physiological and anatomical
components that regulate the switch between
waking and sleeping are becoming clear. The
rapidity with which the hypocretin story has
emerged is a testament to both the conceptual
and the technical evolution of genomic science
in the past two decades. Schematic
model of neurotransmitter circuits that are
involved in the three states of
vigilance.
Summary : The hypocretins (orexins),
Hcrt1 and Hcrt2, are expressed only in a few
thousand neurons in the dorsolateral
hypothalamus. These secreted peptides are found
in both rat and human brain, and a gene for
their precursor (preprohypocretin) is also found
in pufferfish and frog species. The gene, Hcrt,
seems to have arisen by genetic rearrangement of
the secretin gene. There are two
G-protein-coupled receptors for the hypocretins,
Hcrtr1and Hcrtr2. They have different
distributions within the brain and bind the two
hypocretin peptides with different affinities.
The hypocretin neurons of the hypothalamus
project widely to many areas of the brain,
consistent with the expression of the hypocretin
receptors. The hypocretins are found in
dense-core vesicles at synapses and can be
neuroexcitatory. They can increase the
presynaptic release of neurotransmitters and can
also have a postsynaptic effect by opening Ca2+
channels in the plasma membrane.
Intracerebroventricular administration of
hypocretin in rats increases short-term food
consumption, and food deprivation can lead to
increased concentrations of hypocretin peptides
in the hypothalamus. Although these and other
observations point to a function for the
hypocretins in the control of feeding, it is
unclear whether this is a primary role. Findings
that relate to the feeding-related activities of
the hypocretins have been inconsistent, and it
is possible that their influence on feeding
might be indirect, through their effects on
arousal.
Studies of three colonies of dogs in which
narcolepsy was inherited showed that the
affected gene in each case was the Hcrtr2 gene.
Mice in which the Hcrt gene is inactivated show
a marked narcoleptic-like phenotype, whereas
knocking out either of the hypocretin receptor
genes produces a milder phenotype. Knocking out
both receptor genes reproduces the severe Hcrt
knockout phenotype. In humans with narcolepsy,
concentrations of hypocretins are severely
reduced and hypocretin neurons are reduced in
number or missing altogether, indicating that
human narcolepsy results from degeneration of
these neurons, possibly as a result of an
autoimmune process.
It is clear that the hypocretins are central
to the control of sleep and arousal. The
hypocretin neurons project to areas involved in
these processes, including the ascending
reticular activating system, and hypocretin
levels fluctuate across the sleepÐwake cycle
and increase with sleep deprivation. Hypocretin
neurons activate brainstem 'REM-off' neurons
(which are active during wakefulness but not
during rapid eye movement (REM) sleep) during
arousal to maintain the awake state, and reduce
the activity of 'REM-on' neurons (active during
both wakefulness and REM sleep), acting as a
gate to entry into REM sleep. A fuller
understanding of the functions of the
hypocretins and the control of sleep and arousal
will aid the treatment of narcolepsy and other
sleep disorders. Patients with narcolepsy and
animals with mutations in the hypocretin system
also show reduced feeding together with
increased weight. It is proposed that the effect
of the hypocretins on feeding behaviour comes
from a 'resetting' of the metabolic 'set point'
in patients and animal models in which
hypocretin signalling is perturbed. In this
model, the hypocretins provide a means by which
metabolic needs can influence arousal, rather
than being orexigenic or anorexigenic per
se.
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