Download Local network regulation of orexin neurons in the lateral hypothalamus

Am J Physiol Regul Integr Comp Physiol 301: R572–R580, 2011.
First published June 22, 2011; doi:10.1152/ajpregu.00674.2010.
Review
Local network regulation of orexin neurons in the lateral hypothalamus
Julia Burt, Christian O. Alberto, Matthew P. Parsons, and Michiru Hirasawa
Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John’s, Newfoundland, Canada
Submitted 12 October 2010; accepted in final form 16 June 2011
food intake; MCH neuron; sleep
THE LATERAL HYPOTHALAMUS (LH) is the most extensively interconnected area of the hypothalamus, allowing it to control and
convey a variety of essential autonomic and somatomotor
functions. Neuroanatomical studies have demonstrated direct
projections from the LH to other hypothalamic areas, cortical/
limbic areas, and the autonomic and motor system of the
brainstem (101, 102, 104). Such extensive connectivity is
thought to represent the anatomical underpinning that supports
sleep-wake regulation (10, 90, 106), energy homeostasis, as
well as cognitive, reward-related, and emotion-related functions (8, 24, 103).
There are a number of neuronal populations that have been
identified within this hypothalamic region. To a significant
degree, the function of the LH can be attributed to orexin
neurons that synthesize orexin A and B (also called hypocretin-1 and -2), 33 and 28 amino acid peptides, respectively,
cleaved from the precursor protein prepro-orexin (22, 96).
Orexin effects are mediated by two subtypes of orexin receptors, OX1R and OX2R, which have extensive, yet distinct,
expression patterns in the brain (118). Orexin neurons are
almost exclusively localized in the LH and adjacent periforni-
Address for reprint requests and other correspondence: M. Hirasawa, Division
of BioMedical Sciences, Faculty of Medicine, Memorial Univ., 300 Prince Philip
Dr., St. John’s, NL, A1B 3V6, Canada (e-mail: [email protected]).
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cal area (PFA) in animal and human brains and have wideranging projections (14, 30, 90, 121), including the LH/PFA
itself, where these neurons make synaptic contacts onto one
another (41). Physiological functions of the orexin peptides
include stabilization of wakefulness (97, 105), energy homeostasis (83, 96, 112), behavioral responses to food reward and
addictive drugs (7, 38), neuroendocrine and autonomic outflow
(99), and analgesia (17).
Many of orexin’s known behavioral effects, such as stimulation of food intake, wheel running, and spontaneous physical
activity can be induced by local injection of orexins into the
LH/PFA (27, 60, 61, 79, 111, 113, 116, 125). An orexin
injection into the LH/PFA also results in Fos expression, a
marker for neuronal activation (79), suggesting that endogenous orexin release within this area has an excitatory effect,
which may lead to an amplification of excitation by further
activating other orexin neurons. The idea of orexin neurons
working in concert explains how a relatively small population
of neurons (90) can coordinate diverse physiological functions.
Furthermore, many previous studies, mainly using in vitro
electrophysiological and histological approaches, collectively
suggest complex interactions that take place among orexin
neurons and other cells types within the LH/PFA. These
interactions can ultimately determine the sensitivity to and
integration of incoming signals and the levels of outgoing
signals.
0363-6119/11 Copyright © 2011 the American Physiological Society
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Burt J, Alberto CO, Parsons MP, Hirasawa M. Local network regulation
of orexin neurons in the lateral hypothalamus. Am J Physiol Regul Integr Comp
Physiol 301: R572–R580, 2011. First published June 22, 2011;
doi:10.1152/ajpregu.00674.2010.—Obesity and inadequate sleep are among the
most common causes of health problems in modern society. Thus, the discovery
that orexin (hypocretin) neurons play a pivotal role in sleep/wake regulation, energy
balance, and consummatory behaviors has sparked immense interest in understanding the regulatory mechanisms of these neurons. The local network consisting of
neurons and astrocytes within the lateral hypothalamus and perifornical area
(LH/PFA), where orexin neurons reside, shapes the output of orexin neurons and
the LH/PFA. Orexin neurons not only send projections to remote brain areas but
also contribute to the local network where they release multiple neurotransmitters
to modulate its activity. These neurotransmitters have opposing actions, whose
balance is determined by the amount released and postsynaptic receptor desensitization. Modulation and negative feedback regulation of excitatory glutamatergic
inputs as well as release of astrocyte-derived factors, such as lactate and ATP, can
also affect the excitability of orexin neurons. Furthermore, distinct populations of
LH/PFA neurons express neurotransmitters with known electrophysiological actions on orexin neurons, such as melanin-concentrating hormone, corticotropinreleasing factor, thyrotropin-releasing hormone, neurotensin, and GABA. These
LH/PFA-specific mechanisms may be important for fine tuning the firing activity of
orexin neurons to maintain optimal levels of prolonged output to sustain wakefulness and stimulate consummatory behaviors. Building on these exciting findings
should shed further light onto the cellular mechanisms of energy balance and
sleep-wake regulation.
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NEUROTRANSMITTER INTERACTIONS IN THE LATERAL HYPOTHALAMUS
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Fig. 1. Regulation of orexin neurons by local neurotransmitters. The activity of
orexin neurons is controlled by positive and negative feedback mechanisms
mediated by neurotransmitters released by lateral hypothalamus/perifornical
area (LH/PFA) neurons. Orexin neurons corelease excitatory neurotransmitters
orexin (Orx) and glutamate (Glut), and inhibitory transmitters dynorphin (Dyn)
and nociceptin/orphanin FQ (N/OFQ), all of which can directly affect postsynaptic orexin neurons (A) or indirectly by modulating glutamate release at
excitatory synapses (B). The balance between the excitatory and inhibitory
effects determines the activity levels of the postsynaptic cell. C: at excitatory
synapses, glutamate acts on presynaptic autoreceptors to inhibit glutamate
release, completing a short, negative feedback loop. In addition, depolarization
of orexin neurons induces release of endocannabinoids (eCB), which in turn
act as retrograde messengers to inhibit excitatory inputs (D). Reciprocal
communications between orexin neurons and MCH/GABA neurons (E) as well
as GABAergic interneurons (F) also represent local feedback mechanisms.
Excitation of Orexin Neurons
Orexin neurons have intrinsic features and the local environment that can promote a long-lasting firing activity. This
may be because neuropeptide release from dense core vesicles
needs prolonged depolarization (21) and/or because of its
primary role in the maintenance of wakefulness and homeostasis etc., where sustained output may be more relevant than
precise timing.
Orexin neurons are intrinsically in a depolarized state (28),
largely due to a constitutively active nonselective cation current mediated by transcient receptor potential C channels (20).
Furthermore, the local network of orexin neurons allows them
to sustain an active state and/or to recruit a larger number of
orexin neurons, utilizing excitatory neurotransmitters, such as
orexins and glutamate (1, 94, 117). Orexin A or B activate
OX2Rs, which in turn open nonselective cation channels to
depolarize orexin neurons (137) (Fig. 1A) and increase presynaptic glutamate release without affecting GABA transmission
(66, 137) (Fig. 1B). Notably, orexin perikarya receive numerous excitatory inputs that greatly outnumber inhibitory synAJP-Regul Integr Comp Physiol • VOL
Fig. 2. Regulation of orexin (Orx) neurons by astrocytes. Activated astrocytes
release lactate (Lac) and protons (H⫹) through monocarboxylate transporters
(MCT). Orexin neurons metabolize astrocyte-derived lactate, not glucose
itself, as an energy substrate to sustain firing activity. In addition, a pH drop,
resulting from the MCT activity, stimulates these neurons. ATP can also be
released into the extracellular space by astrocytes or neurons, which has a
direct excitatory effect on orexin neurons. Adenosine can be hydrolyzed from
ATP or released from neurons, which has a direct and indirect (synaptic) effect
leading to inhibition of orexin neurons. Glut, glutamate.
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apses as shown by ultrastructural and electrophysiological
studies (56), which provide the structural basis for fast glutamatergic transmission that supplies a major excitatory drive
mediated by ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA), but not
kainate receptors (4, 66, 92).
Glutamatergic transmission may also stimulate orexin neurons indirectly in an unconventional manner (Fig. 2). Glutamate is known to stimulate lactate production in astrocytes,
which in turn release lactate into the extracellular space
through monocarboxylate transporters (MCTs) (45, 89). Since
MCTs cotransport protons along with lactate, lactate release
accompanies a local decline in extracellular pH (45). A decrease in pH would result in depolarization of orexin neurons
(129). Moreover, orexin neurons utilize astrocyte-derived lactate, but not glucose, as an energy substrate to maintain
spontaneous firing activity (86). In conditions where lactate
supply is insufficient or ATP production is impaired, ATPsensitive K⫹ channels become active and hyperpolarize these
neurons (86). Therefore, the MCT-mediated astrocyte-neuronlactate shuttle can mediate the excitatory action of glutamatergic transmission.
Activation of astrocytes or neurons can also induce release
of ATP, which can, in turn, act as a transmitter molecule (26,
42) (Fig. 2). Extracellular ATP directly depolarizes orexin
neurons via ionotropic P2X receptors expressed on the plasma
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NEUROTRANSMITTER INTERACTIONS IN THE LATERAL HYPOTHALAMUS
Self-Regulatory Mechanisms
Excitatory positive-feedback mechanisms can conceivably
continue until exhaustion without regulatory mechanisms that
keep them in check. Indeed, many negative feedback pathways
exist that regulate orexin neurons upon their excitation, including inhibitory neurotransmitters released by the same neurons.
Dynorphin, a neuropeptide coexpressed by orexin neurons
(18), directly hyperpolarizes these neurons by a ␬-opioid receptor-mediated activation of G protein-dependent inwardly
rectifying potassium channels and suppression of Ca2⫹ currents (67) (Fig. 1A). Interestingly, the dynorphin effect desensitizes faster than that of orexins, which results in a timedependent shift in the balance between inhibitory (dynorphin)
and excitatory (orexin) influence over the neurons (67). Another neuropeptide recently identified to be coexpressed by
orexin neurons is nociceptin/orphanin FQ (N/OFQ) (73).
N/OFQ inhibits orexin neurons through activation of K⫹ currents and inhibition of Ca2⫹ currents via N/OFQ peptide
receptors (135). This, unlike dynorphin, is a long-lasting effect
that can last for over an hour (M. P. Parsons, unpublished
observation).
Glutamate, a classical neurotransmitter, can be expected to
be released with less intense activity compared with peptide
transmitters (21). Thus, it is tempting to speculate that the
intensity and duration of firing activity dictate the release and
postsynaptic response to the four coneurotransmitters of orexin
neurons. At low-to-moderate activity levels, orexin neurons
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will preferentially release glutamate and increase the excitability of postsynaptic orexin neurons. With higher firing frequencies, glutamate release becomes depressed (133), while peptide
release would be favored. This will initially induce an inhibitory postsynaptic response due to the inhibitory actions of
dynorphin and N/OFQ, masking the excitatory orexin effect.
However, during a prolonged firing activity, ␬-receptors will
be desensitized and the excitatory orexin effect will eventually
prevail. Nonetheless, the excitability will be kept in check due
to the nondesensitizing N/OFQ effect. It has been postulated
that the dynamic balance of orexin neuron’s excitatory and
inhibitory neurotransmitters underlie the apparent lag between
the electrophysiological activity and functional outcome (128).
Specifically, on one hand, the timing of orexin neuron’s spiking activity precedes wakefulness (64, 75), which suggests that
orexins should affect every wake bout. On the other hand,
orexins are only effective at maintaining sustained wake bouts
and not brief wake bouts of ⬍ 1 min (25). Perhaps the initial
glutamate release is not sufficient to fully recruit and maintain
the activity of a large number of orexin neurons, and the orexin
effect needs to be unmasked from the inhibitory dynorphin for
the maintenance of wakefulness.
Excitatory synaptic inputs are also subject to negative regulation (Fig. 1B). Dynorphin acts on presynaptic excitatory
terminals to attenuate glutamate release (67, 135), while
N/OFQ inhibits both excitatory and inhibitory transmission
(135). Furthermore, synaptically released glutamate negatively
regulates the presynaptic release of glutamate and GABA
through group III metabotropic glutamate receptors (mGluRs)
(2) (Fig. 1C). This would primarily be an autoinhibitory mechanism that limits glutamatergic transmission, since the inhibitory mGluRs on excitatory terminals (autoreceptors) are tonically activated by endogenous glutamate, whereas those expressed on GABAergic terminals seem to require more intense
synaptic activation and glutamate spillover to be activated (2).
Endocannabinoids, on the other hand, are typically released by
the postsynaptic neuron upon a strong depolarization and act as
a retrograde messenger (5). In orexin neurons, postsynaptic
depolarization results in an inhibition of glutamatergic transmission (depolarization-induced suppression of excitation) but
not GABAergic transmission, subsequently hyperpolarizing
the postsynaptic cell (58) (Fig. 1D). These processes are
designed not to turn on when the excitatory synapse or the
postsynaptic cell is quiescent, thus providing negative feedback mechanisms to prevent overexcitation.
Intra-LH/PFA Neuronal Network
Several neuronal populations have been identified within the
LH/PFA that are distinct from the orexin-expressing population. There is no doubt that these neurons also play important
roles in the LH/PFA functions, including shaping the output
and/or mediating the functions of orexin neurons (Fig. 3).
Melanin-concentrating hormone neurons. Melanin-concentrating hormone (MCH) neurons are concentrated in the LH/
PFA as well as in the zona incerta, where they are densely
intermingled with orexin neurons but constitute a distinct cell
group (14, 30, 90, 121). These neurons have also been the
subject of intense research because of the crucial roles of MCH
in promoting positive energy balance (91, 95, 108), sleep (3,
51, 123), and anxiety (11, 37). MCH neurons, like orexin
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membrane, while having little effect on synaptic inputs (131).
Adenosine, an inhibitory purine, is released endogenously onto
orexin neurons by stimulation of afferent fibers at a frequency
as low as 10 Hz in vitro (133), and an A1-receptor antagonist
has been shown to increase wakefulness when injected locally
into the LH/PFA in vivo (114). Whether or not neurons are the
source of adenosine in this case remains unresolved, as adenosine is thought to be primarily produced by hydrolysis of
astrocyte-derived ATP in the extracellular space by ectonucleotidases (124, 142) and affect neuronal activity (88). In orexin
neurons, adenosine inhibits voltage-gated Ca2⫹ currents (69)
and suppresses firing activity by A1-receptor-mediated reduction of presynaptic glutamate release (69, 133). The ratio of the
two purines would depend on the rate of ATP release, conversion of ATP to adenosine, and uptake by nucleoside transporters (124) and would determine the polarity of the effect
(excitatory or inhibitory) on orexin neurons. This may have
important functional implications in sleep homeostasis (44,
114) and survival of LH neurons (141).
In summary, there are a number of local mechanisms that
drive orexin neurons to be in a sustained active state. These
include intrinsic ion channels (transcient receptor potential C
channels), paracrine and/or autocrine actions of excitatory
neurotransmitters released by orexin neurons, and neighboring
astrocytes that can amplify excitatory inputs and further stimulate orexin neurons by releasing lactate, protons, and ATP.
Astrocytes may also mediate the propagation of excitatory
signals among neurons that are not physically coupled (85,
140). These mechanisms may be important for orexin neurons
in exerting their physiological functions that require prolonged
output, such as maintaining wakefulness and stimulating consummatory behaviors.
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NEUROTRANSMITTER INTERACTIONS IN THE LATERAL HYPOTHALAMUS
neurons, project widely within the central nervous system (10,
14, 16, 90) and form reciprocal connections with orexin neurons within the LH/PFA (41). MCH neurons are also known to
express GABA (31, 50) as well as anorexic peptides nesfatin-1
(34, 35) and cocaine- and amphetamine-regulated transcript
(13, 29, 49). It remains to be seen whether and how these
peptides, which are functionally opposite to MCH (in terms of
feeding effect), exert electrophysiological effects on LH/PFA
neurons.
Communication between orexin and MCH neurons is bidirectional (Fig. 1E). Orexin A and B directly induce depolarization of MCH neurons (67, 122) and stimulate presynaptic
glutamate release (122), whereas dynorphin and N/OFQ have
direct hyperpolarizing effects, each through activation of
GIRK channels (67, 87). Unlike orexin neurons, not only
dynorphin (67) but also N/OFQ, induce an effect that desensitizes with repeated applications (87), while the orexin effect
does not desensitize (67). Together, the effect of coreleased
excitatory and inhibitory peptides from orexin neurons onto
MCH neurons can be expected to shift toward excitation with
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prolonged activity, because the sustained excitatory orexin
effect outlasts the desensitizing dynorphin and N/OFQ effects.
MCH neurons also receive glutamatergic inputs, some of
which may be from orexin neurons. Fast EPSCs are mediated
by NMDA and non-NMDA receptors (122), whereas postsynaptic group I mGluRs provide another excitatory pathway to
MCH neurons that induces a slow depolarization mediated by
Na⫹/Ca2⫹ exchanger and potentiation of NMDA currents (57).
Thus, somewhat akin to orexin neurons, MCH neurons are
regulated by a balance between excitatory (orexins and glutamate) and inhibitory (dynorphin and N/OFQ) neurotransmitters
originating from orexin neurons, a balance influenced by the
quantity and time course of each transmitter release.
On the other hand, MCH released onto orexin neurons can
act as a gatekeeper to prevent excess excitatory inputs. MCH
does not have any apparent presynaptic effect on its own, but
can attenuate presynaptic glutamate release induced by activation of orexin and D1-like receptors (93). At the postsynaptic
side, MCH downregulates AMPA receptors in orexin neurons
(93). Therefore, in response to the excitatory input from orexin
neurons, MCH neurons send a negative feedback signal via
inhibitory neurotransmitters MCH and GABA. Such mechanisms may be underlying the reciprocal firing activities of
MCH neurons and orexin neurons observed in vivo (51).
MCH neurons can also self-regulate their activity levels. The
MCH peptide does not affect the resting membrane potential of
MCH neurons, but inhibits voltage-gated Ca2⫹ channels (36).
Thus, it is possible that MCH can negatively regulate its own
release via modulation of Ca2⫹ channels expressed at the axon
terminals. GABA also conveys important information to MCH
neurons, because inhibitory inputs are dominant over excitatory inputs, evident from spontaneous EPSCs being relatively
scarce compared with inhibitory postsynaptic currents (58, 68)
in stark contrast to orexin neurons that receive dominant
excitatory inputs (56). In neonate rodents, GABAA currents are
depolarizing until about postnatal days 8 –9, providing the
main excitatory inputs to MCH neurons (68). In mature MCH
neurons, the GABAA current becomes inhibitory and mediates
a tonic inhibitory tone by endogenous GABA (58, 68). In
addition, the GABAB receptor agonist baclofen has been observed to hyperpolarize a subpopulation of MCH neurons (n ⫽
2 out of 6 cells examined; C. O. Alberto, unpublished data).
Endocannabinoids are also released by depolarization of
MCH neurons, which inhibit presynaptic GABA release (depolarization-induced suppression of inhibition). This works as
a positive feedback, since the postsynaptic cell is consequently
disinhibited from a tonic GABAA tone (58, 59). Although
endocannabinoids also inhibit glutamate release to MCH neurons, depolarization-induced suppression of inhibition seems to
have an overwhelming influence (58). Since depolarizationinduced endocannabinoid release is dependent on Ca2⫹ currents (59), a concurrent MCH release (although likely from
different subcellular locations i.e., dendrites vs. terminals respectively), resulting in an inhibition of Ca2⫹ channels may put
a break on the positive feedback by endocannabinoids.
Leptin receptor-expressing GABAergic neurons. Another
distinct neuronal population that exists in the LH/PFA is the
leptin receptor-expressing (LepRb⫹) neurons (65). These neurons are excited by leptin, use GABA as a neurotransmitter
(65), and make synaptic contacts with orexin neurons but not
MCH neurons (70). This suggests that leptin not only inhibits
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Fig. 3. Local network within the lateral hypothalamus/perifornical area (LH/PFA).
A number of neuronal populations have been identified within the LH/PFA in
addition to orexin (Orx) neurons, including those expressing melaninconcentrating hormone (MCH), thyrotropin-releasing hormone (TRH), corticotropin-releasing factor (CRF), neurotensin (NT), galanin (Gal) and leptin receptor
(LepRb⫹)-expressing GABAergic neurons. With the exception of galanin, whose
electrophysiological effect remains unknown, these neurotransmitters have been
demonstrated to modulate the excitability of orexin neurons. Therefore, these
neurons, along with astrocytes, constitute a local network that can fine-tune the
activity levels of this brain area through complex interactions. Further investigation is necessary to fully elucidate the intricate mechanisms that control the
functional output of the LH/PFA in physiological and pathological conditions.
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lar level, TRH has been found to directly depolarize orexin
neurons by activating nonselective cation channels (39, 47).
However, TRH also increases the firing activity of presynaptic
GABAergic interneurons, increasing the inhibitory synaptic
influence (47). Therefore, the location of synaptic release of
TRH would likely determine whether TRH excites or inhibits
orexin neurons.
It is interesting that these neuropeptides that excite orexin
neurons are known to promote energy expenditure and inhibit
food intake [CRF (107), TRH (63), and neurotensin (72)].
Some of these effects may indeed be mediated by orexin
neurons; for example the TRH effect on locomotor activity is
reduced in orexin neuron-ablated mice (47). Unlike other
orexigenic neuropeptides that inhibit energy expenditure to
promote positive energy balance, orexins not only induce
feeding but also spontaneous physical activity (61, 81, 110,
115), sympathetic outflow (32, 33, 99, 100, 109), thermogenesis (84, 138, 139), and oxygen consumption (107). In fact, the
role of orexins in energy expenditure may be more substantial
than in food intake, because, in the absence of orexin signaling,
animals become obese despite accompanying hypophagia (46,
48). Thus, it seems plausible that orexin neurons mediate the
effects of catabolic neuropeptides expressed in the LH/PFA.
Likewise, orexins (9, 76, 126, 135), CRF (62), and TRH (12)
have been shown to have antinociceptive properties. Therefore,
orexin neurons could possibly mediate the effects of CRF and
TRH. On the other hand, N/OFQ is known to block opioidmediated stress-induced antinociception (78), which involves
suppression of orexin neurons and the downstream analgesic
effect (135).
Perspectives and Significance
Previous studies have revealed intricate interactions within
the network of neurons and astrocytes that may fine tune the
output of the LH/PFA. A given neuron can release multiple
neurotransmitters to other LH/PFA neurons, some with opposing actions on the postsynaptic cell, and the impact of each
neurotransmitter can change in a time-dependent manner.
What remains largely unknown is whether or not these cotransmitters are regulated in parallel, with respect to synthesis,
storage (are they packaged in the same vesicle?), release
(amount and site of release), and receptor expression (number
and subcellular localization).
Many of the neurotransmitters expressed in the LH/PFA are
not exclusive to this brain area, with the exception of orexins
and MCH that are largely confined. Future studies should
investigate the roles of LH/PFA-specific expression of neurotransmitters to fully elucidate the characteristics of local
neurochemical interactions as well as specific physiological
functions of the LH/PFA. Site-specific knockdown of individual neurotransmitters may prove to be useful in this regard.
Not all LH/PFA neurons make synaptic contacts onto one
another simply because of their proximity, as seen with MCH
neurons not receiving synaptic inputs from the nearby LepRb⫹
neurons (70). Nonetheless, unlike glutamate or GABA, whose
diffusion is restricted, neuropeptides can act as volume transmitters even in the absence of synaptic specialization between
the pre- and postsynaptic cell (143) and can be expected to play
an important role within the local circuitry.
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orexin neurons directly, as demonstrated as a reversible hyperpolarization in isolated orexin neurons (136), but also indirectly by activating these inhibitory LepRb⫹ neurons. Leptin
also increases the transcription factor STAT3 immunoreactivity in orexin neurons (43), and local action of leptin within the
LH results in a robust orexin mRNA expression after 26 h (71).
Thus, leptin induces an acute reversible inhibition as well as a
slow, long-term stimulation of the orexin system.
At inhibitory synapses to orexin neurons, GABAA receptors
mediate fast inhibitory postsynaptic currents (66), whereas
GABAB receptors mediate a slow hyperpolarization (134).
GABAB agonists also inhibit excitatory and inhibitory transmission presynaptically (134). Genetic knockout of GABAB
receptors on orexin neurons indirectly activates inhibitory
interneurons, which in turn increase the membrane conductance of orexin neurons and shunt other synaptic inputs (74).
Therefore, it seems that there is reciprocal communication
between orexin and GABAergic interneurons, where orexin
neurons activate interneurons, which in turn send negative
feedback to orexin neurons (Fig. 1F). Whether or not LepRb⫹
GABAergic neurons play a part in this reciprocal network
remains to be elucidated.
Obviously, local interneurons are not the sole source of
glutamatergic and GABAergic synaptic inputs to orexin neurons; major projections from other brain areas are also mediated by these important neurotransmitters. Sources of glutamatergic afferents, in addition to orexin neurons, include those
originating from energy balance-related arcuate proopiomelanocortin neurons (53), arousal-related basal forebrain (52), and
lateral parabrachial neurons (82), as well as the dorsomedial
hypothalamus that relays circadian rhythms from the suprachiasmatic nucleus to the LH/PFA (19, 23). MCH and LepRb⫹
neurons are one source of GABAergic inputs to LH/PFA
neurons, but other GABAergic sources include the sleep-wakerelated preoptic area (98) and basal forebrain (52), energy
balance-related neuropeptide Y, proopiomelanocortin neurons
of the arcuate nucleus (14, 30, 53–55), and emotion-related
central amygdaloid nucleus (80). Thus, to understand the
cellular mechanisms underlying the essential functions mediated by the LH/PFA, it would be important to determine how
excitatory and inhibitory synaptic inputs from various brain
areas are integrated by orexin neurons.
Other peptidergic neurons. Other neuropeptides have also
been detected in cells within the LH/PFA (Fig. 3). Galaninpositive neurons have relatively small cell bodies and are
separate from the orexin-expressing population (43, 132), although it has been shown that some orexin neurons may
coexpress galanin (43). Galanin has no effect on Ca2⫹ signaling in orexin neurons (119); however, no study has examined
the electrophysiological effect.
Corticotrophin-releasing factor (CRF) neurons located in the
LH/PFA are also distinct from orexin and MCH neurons but
coexpress neurotensin (127). CRF depolarizes a subpopulation
of orexin neurons (25%) via CRF1 receptors. The effect is
reversible but nondesensitizing as long as the ligand is present
(130). Neurotensin has been shown to activate Ca2⫹ signaling
(119).
A significant number of neurons expressing thyrotropinreleasing hormone (TRH) are also found in the LH/PFA
according to the Allen Institute for Brain Science Atlas (http://
mouse.brain-map.org/brain/gene/71016631.html). At the cellu-
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NEUROTRANSMITTER INTERACTIONS IN THE LATERAL HYPOTHALAMUS
These local interactions may also affect the sensitivity of
LH/PFA neurons to incoming projections from other brain
areas (15). The functioning of the LH/PFA circuitry is further
complicated by functional plasticity and dynamic synaptic
remodeling of orexin neurons that occurs in response to changing physiological needs, as seen following sleep (40, 77, 92,
120) and food deprivation (56) and in relation to circadian
rhythm (6). It is highly likely that the intra-LH/PFA network
activity discussed here would be altered as a result. Further
research on neurotransmitter effects and synaptic integration in
various physiological and pathological contexts will help provide a clearer picture of the regulatory mechanisms for orexin
neurons and the LH/PFA.
14.
15.
16.
17.
The authors thank Dr. Jackie Vanderluit for the critical reading of the
manuscript.
18.
GRANTS
19.
This work was supported by funding from the Canadian Institutes of Health
Research.
20.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
21.
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