Orexin/Hypocretin System

196 Pages·2012·4.851 MB·2-196\196

by  Anantha Shekhar (Eds.)

SERIES EDITORS
STEPHEN G. WAXMAN
BridgetMarieFlahertyProfessorofNeurology
Neurobiology,andPharmacology;
Director,CenterforNeuroscience&Regeneration/NeurorehabilitationResearch
YaleUniversitySchoolofMedicine
NewHaven,Connecticut
USA
DONALD G. STEIN
AsaG.CandlerProfessor
DepartmentofEmergencyMedicine
EmoryUniversity
Atlanta,Georgia
USA
DICK F. SWAAB
ProfessorofNeurobiology
MedicalFaculty,UniversityofAmsterdam;
LeaderResearchTeamNeuropsychiatricDisorders
NetherlandsInstituteforNeuroscience
Amsterdam
TheNetherlands
HOWARD L. FIELDS
ProfessorofNeurology
EndowedChairinPharmacologyofAddiction
Director,WheelerCenterfortheNeurobiologyofAddiction
UniversityofCalifornia
SanFrancisco,California
USA
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List of Contributors
G. Aston-Jones, Department of Neurosciences, Medical University of South Carolina, Charleston, SC,
USA
C. Baimel, Department of Anesthesiology, Pharmacology and Therapeutics, University of British
Columbia, Vancouver, BC, Canada
S.L. Borgland, Department of Anesthesiology, Pharmacology and Therapeutics, University of British
Columbia, Vancouver, BC, Canada
P.J.Coleman,DepartmentofMedicinalChemistry,MerckResearchLaboratories,WestPoint,PA,USA
L.M.Coolen,DepartmentofMolecularandIntegrativePhysiology,UniversityofMichigan,AnnArbor,
MI, USA, and Department of Anatomy and Cell Biology, University of Western Ontario, London,
Ontario, Canada
L.deLecea,DepartmentofPsychiatryandBehavioralSciences,StanfordUniversitySchoolofMedicine,
Palo Alto, CA, USA
A.R. Di Sebastiano, Department of Molecular and Integrative Physiology, University of Michigan, Ann
Arbor, MI, USA, and Department of Anatomy and Cell Biology, University of Western Ontario,
London, Ontario, Canada
S.D. Fitz, Department of Psychiatry, Institute of Psychiatric Research, Indiana University School
of Medicine, Indianapolis, IN, USA
E. Fliers, Department of Endocrinology and Metabolism, Academic Medical Center, University of
Amsterdam, Amsterdam, The Netherlands
E.M.Girault,HypothalamicIntegrationMechanisms,NetherlandsInstituteforNeuroscience(NIN),An
Institute of the Royal Netherlands Academy of Arts and Science, Amsterdam, The Netherlands
A.L. Gotter, Department of Neuroscience, Merck Research Laboratories, West Point, PA, USA
R. Hargreaves, Department of Neuroscience, Merck Research Laboratories, West Point, PA, USA
P.L.Johnson,DepartmentofPsychiatry,InstituteofPsychiatricResearch;StarkNeurosciencesResearch
Institute, and Department of Anatomy and Cell Biology, Indiana University School of Medicine,
Indianapolis, IN, USA
A. Kalsbeek, Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience (NIN), An
Institute of the Royal Netherlands Academy of Arts and Science, and Department of Endocrinology
andMetabolism,AcademicMedicalCenter,UniversityofAmsterdam,Amsterdam,TheNetherlands
A. Li, Department of Physiology and Neurobiology, The Geisel School of Medicine at Dartmouth,
Lebanon, NH, USA
S.V.Mahler,DepartmentofNeurosciences,MedicalUniversityofSouthCarolina,Charleston,SC,USA
M. Mieda, Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine,
Kanazawa University, Kanazawa, Ishikawa, Japan
A. Molosh, Department of Psychiatry, Institute of Psychiatric Research, and Stark Neurosciences
Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
v
vi
D.E. Moorman, Department of Neurosciences, Medical University of South Carolina, Charleston, SC,
USA
E. Nattie, Department of Physiology and Neurobiology, The Geisel School of Medicine at Dartmouth,
Lebanon, NH, USA
J.J. Renger, Department of Neuroscience, Merck Research Laboratories, West Point, PA, USA
A.J.Roecker,DepartmentofMedicinalChemistry,MerckResearchLaboratories,WestPoint,PA,USA
T. Sakurai, Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine,
Kanazawa University, Kanazawa, Ishikawa, Japan
G.C. Sartor, Department of Neurosciences, MedicalUniversity of South Carolina, Charleston, SC,USA
A. Shekhar, Department of Psychiatry, Institute of Psychiatric Research; Stark Neurosciences Research
Institute,andIndianaClinicalandTranslationalSciencesInstitute,IndianaUniversitySchoolofMed-
icine, Indianapolis, IN, USA
R.J. Smith, Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA
W.A. Truitt, Department of Psychiatry, Institute of Psychiatric Research; Stark Neurosciences Research
Institute, and Department of Anatomy and Cell Biology, Indiana University School of Medicine,
Indianapolis, IN, USA
C.J. Winrow, Department of Neuroscience, Merck Research Laboratories, West Point, PA, USA
C.-X. Yi, Department of Internal Medicine, Metabolic Diseases Institute, University of Cincinnati,
Cincinnati, OH, USA
Preface
This volume for Progress in Brain Research on the orexin/hypocretin system brings together leading
international experts writing about the role of this neuropeptide in regulating a wide range of normal
biological functions such as sleep, appetite, reward and fear, as well as disease states, ranging from nar-
colepsy, obesity, and addictions to panic disorder. The idea for this volume sprang out of some
discussions with the scientific program group from Elsevier during the Annual Meeting of the Society
for Neuroscience in 2010. Inspired by their interest, I approached several colleagues who are leading
researchersinthisareaandwaspleasedtohearfromthemthatsuchavolumewasindeedtimelyandthat
they would be willing to contribute articles for such a volume. That positive support continued through-
outthedevelopmentofthisbookandisnowrepresentedinthemanyoutstandingchapterswrittenbymy
fellow researchers.
A book like this can only become a reality with the help and support of many people. First, I would
begin by thanking each and every one of the authors for their outstanding efforts in preparing these
chapters and distilling the findings from various published papers into such thoughtful presentations.
In addition to the contributors, I am also grateful to the many of the anonymous reviewers who helped
fine-tune the submissions and helped me enormously in my editorial efforts.
Next,IwouldliketosincerelythankoureditorialprojectmanagerShellieBryantforhertirelesswork
andPaul Milner, ourassociateeditor from Elsevier,formaking this volume possible.Withouttheircon-
stant support, prompting,and sticking to project timeline,this volume would nothave comeout ontime
with such outstanding contributions.
Finally, I would like to thank and dedicate this effort to my wife Dr. Gina Laite for her unwavering
support and suggestions to help me work through the act of editing and writing.
Anantha Shekhar
Indianapolis
March 2012
vii
A.Shekhar(Ed.)
ProgressinBrainResearch,Vol.198
ISSN:0079-6123
Copyright(cid:1)2012ElsevierB.V.Allrightsreserved.
CHAPTER1
Many faces of orexin/hypocretin
Anantha Shekhar*
IndianaUniversitySchool ofMedicine,Indianapolis,IN,USA
Abstract:
Orexin/hypocretin (ORX/Hcrt) is a neuropeptide discovered in 1998 that is produced by a
small group of neurons exclusively localized to the hypothalamus with extensive CNS wide projections.
These neurons appear to regulate a wide range of homeostatic functions. Much innovative research
has emerged in this field over the past decade, and several novel drug candidates targeting the ORX/
Hcrt receptors are being pursued for a variety of disease states. This introduction is a brief overview
of the outstanding research reports by leading experts in the field presented in this collection
specifically compiled to provide comprehensive, most current reviews of the many functions of the
ORX/Hcrt system.
Keywords: sleep; appetite; reward; panic; neuropeptide; hypothalamus.
Orexin/hypocretin (ORX/Hcrt) is a neuropeptide aptly called pre-pro-orexin or pre-pro-hypocretin
that was identified independently by two groups by the two groups, which is broken down into
utilizing different approaches (de LeCea et al., oneofthetwodifferentpeptidesthatarereleased
1998;Sakuraietal.,1998).Bothstudiesidentified asneuromodulators(hypocretin1and2ororexin
that the neurons producing this novel peptide are A and B). This duality in the peptide’s name has
exclusively localized to the perifornical and lat- remained to this day and, in fact, captures the
eral regions of the hypothalamus. Initially, the many complex and at times seemingly opposing
Sakuraigroupidentifiedthispeptideasbeingcrit- functions of the neuropeptide.
ically involved in the regulation of feeding Chapter 2 provides an excellent overview of
behaviors (hence the name orexin), while the de their discovery and the emerging complexity of
Lecea group thought the peptide was similar to this system. After a thoughtful consideration
secretin family (hence the name hypocretin). of the evidence, the authors summarize that
Both groups also identified a precursor peptide, “orexin neurons are likely to function as
stabilizers” of sleep or appetitive neuronal
networks.Similarly,Chapter3bydeLeceadetails
the discovery and their recent findings that have
*Correspondingauthor.
enriched the hypocretin story, leading him to con-
Tel.:[phone];Fax:[phone]
E-mail:[email protected] clude that “Hcrt neurons act as integrators that
DOI:10.1016/B978-0-444-59489-1.00019-7 1
2
convey possibly conflicting physiological signals molecular mechanisms associated with the ORX
into a coherent output to other effector systems, system are only now beginning to be delineated
which include norepinephrine neurons for arousal resulting in many ground-breaking research ideas
transitions and dopaminergic neurons of the that have emerged in the field of sleep research,
mesocorticolimbic system to engage in rewarding metabolic syndrome, anxiety and stress,
activities.” Both these pioneering groups have addictions, and respiratory regulation.
studiedthissystemforalongtime,haveintimately Nattie and Li provide an overview of the role
followedtheadvancesinthisfield,andseemtobe of ORX/Hcrt in respiration and autonomic regu-
coming to similar conclusions that this system lation,demonstratingthatorexinactivityisheavily
functions as a complex modulator of opposing influenced by the sleep–wake state. Current data
biological forces. support a role for ORX/Hcrt in respiratory
Soon after the discovery of the ORX/Hcrt chemosensitivity to CO predominantly in wake-
2
neurons in the hypothalamus, it also became fulness, and a much more limited role during the
apparent that these neurons project extensively sleep period (Dias et al., 2010). Similarly, orexin
tomostareasofthecentralnervoussystem.Inthis neurons may participate in the regulation of
respect, the system is very reminiscent of other sympathetic activity, including effects on blood
systemssuchastheserotonergiccellsoftheraphe pressure and temperature regulation, again
nuclei and the noradrenergic cells in the locus influenced by diurnal patterns.
coeruleus, collections of highly localized neurons Kalsbeek and colleagues provide comprehen-
with unique phenotypes with wide distribution sive review of orexin in feeding and energy bal-
of terminals across the brain, and putative roles ance in Chapter 5 and confirm that it has a
that regulate a number of biological functions. central integrative function, with a key role in
Unlike these global modulatory classical neuro- maintaining the body in a balanced and healthy
transmitter systems, by utilizing a neuropeptide, state.Theyfurtherspeculatethatdisruptionofthis
one would expect that ORX/Hcrt may modulate system may have serious consequences, perhaps
homeostaticfunctionsinamorecomplexmanner, representing part of the pathogenesis of diabetes
perhaps at a somewhat slower and long-lasting (Yi et al., 2009) and other metabolic syndromes.
pace, and provide a more nuanced regulation of Inanexceptionallycomprehensivereview,Gary
many biological functions. This complexity of Aston-Jones, Mahler, and colleagues describe the
modulatory function by the ORX/Hcrt system, roles played by ORX/Hcrts in a variety of models
especially affecting such diverse functions as ofdrugaddiction,emphasizingbothcommonalities
wakefulness, sleep, diurnal activity, feeding, vigi- and differences for its involvement in seeking of
lance, reward behaviors, addiction reinstatement, themajorclassesofabuseddrugs.Theyfindacom-
anxiety, and peripheral autonomic responses, is monthemeintheinvolvementofORX/Hcrtindrug
the focus of the many excellent chapters in this seeking triggered by external stimuli (e.g., cues or
volume. stressors).Theyoutlinethewell-delineatedcircuits
At the cellular level, ORX as a neuropeptide that mediate addiction-related behaviors (Harris
appears to act through two distinct subtypes of etal.,2005),withparticularfocusontheroleofthe
G-protein couple receptors, ORX1 and ORX2 neuropeptideandglutamateinteractions.
receptors, which have unique distributions and Along the same lines of ORX/Hcrt-induced
functional properties. Activation of these ORX plasticity and its effects on glutamate synaptic
receptors results intheactivation of unique intra- transmission, Baimel and Borgland, following up
cellular mechanism that results in neuronal firing on their previous studies of synaptic plasticity in
as well changes in long-term plasticity. Such the reward pathways (Borgland et al., 2006),
3
conclude that it modulates synaptic strength in alsoworthmentioningthattheirgroupdeveloped
the reward pathways not only on its own but also the one molecule that is currently the most
for those induced by drugs of abuse. Thus the advanced drug candidate undergoing phase III
mechanism could underlie motivational processes trialsforinsomnia.
beyond drug seeking. Finally, much like the brain itself, more func-
Extending this concept further, and in another tional complexities are being discovered each
very interesting chapter looking at the role of year with the ORX/Hcrt system using novel tec-
ORX/Hcrt in “naturally rewarding” behaviors, hniques such as gene regulation and optical stim-
Di Sebastiano and Coolen demonstrate that ulation (Adamantidis et al., 2007). I am sure that
orexin plays an important role in mediation of in the next 5–10 years there will be much new
naturally rewarding and motivated behaviors. information which will substantially revise our
While more is known about the role of orexin in current understanding of this system. With that
feeding and energy homeostasis, they explore in mind, and knowing that the present reviews
the role of orexin in other natural reward come from the many leadersin this field whowill
behaviors, including maternal and sexual behav- likely be contributing to those future revisions in
ior (Di Sebastiano et al., 2010). our understanding, it has been my pleasure to
Our group came to study the role of ORx/Hcrt read each of these reviews as I compiled this vol-
in anxiety and stress and, in particular, panic ume. I hope the readers will similarly find the
disorder, a severe form of anxiety disorder contributions in this volume valuable to their
characterized by recurrent panic attacks, in a work and their understanding of novel brain
somewhat indirect route. We had shown quite mechanisms.
some time ago that acute activation of
the dorsomedial/perifornical hypothalamus leads
References
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awakening probed with optogenetic control of hypocretin
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not depression symptoms did indeed have high Bonci, A. (2006). Orexin A in the VTA is critical for the
levels of orexin in their CSF, suggesting that loss inductionof synapticplasticityandbehavioral sensitization
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4
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A.Shekhar(Ed.)
ProgressinBrainResearch,Vol.198
ISSN:0079-6123
Copyright(cid:1)2012ElsevierB.V.Allrightsreserved.
CHAPTER2
Overview of orexin/hypocretin system
Michihiro Mieda and Takeshi Sakurai*
DepartmentofMolecularNeuroscience andIntegrativePhysiology,FacultyofMedicine,Kanazawa University,
Kanazawa,Ishikawa,Japan
Abstract: A series of recent studies has established the orexin/hypocretin system as a critical regulator
ofsleep/wakestates.Itsdeficiency resultsinthesleepdisordernarcolepsyinhumans,dogs,androdents.
These findings have brought about the possibility of novel therapies for sleep disorders including
narcolepsy and insomnia. Moreover, accumulating evidence indicates that the orexin/hypocretin system
regulates sleep and wakefulness through interactions with neuronal systems that regulate emotion,
reward, and energy homeostasis. Here, we briefly summarize the progress of orexin/hypocretin studies
and future perspectives.
Keywords: orexin/hypocretin; sleep/wakefulness; narcolepsy; feeding; reward.
Introduction attemptstoapplyorexin/hypocretinbiologytoclin-
ical areas have led to the development of a novel
Since its discovery in 1998, the field of orexin/ anddefinitediagnosisofnarcolepsyandarefurther
hypocretinbiologyiscontinuingtoexpand.Discov- makingprogresstowardnoveltreatmentsforsleep-
eryoforexin/hypocretinpeptidesledtoelucidation relateddisorders.
of an unexpected causal relationship between Because details of every aspect of orexin/
deficiencyoftheorexin/hypocretinsystemand the hypocretinbiologywillbediscussedinthefollowing
human sleep disorder narcolepsy, which brought chapters,wehereoverviewthelinesofresearchon
about a huge impact on the study of sleep and orexin/hypocretinbiologyandfurtherdiscussitsstill
wakefulness.Subsequent studies further expanded unansweredquestionsandfuturedirections.
orexin/hypocretin biology beyond the field of
sleep/wakefulness,sheddinglightontheintegrative
role of the orexin/hypocretin system. In parallel, Discovery of orexin/hypocretin
Completely different approaches taken by two
*Correspondingauthor.
Tel.:þ81-76-265-2173;Fax:þ81-76-234-4224 independent laboratories beautifully converged
E-mail:[email protected] on the identification of orexin/hypocretin peptides
DOI:10.1016/B978-0-444-59489-1.00002-1 5