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INTRODUCTION

Recent Advances in and J.C. Gillin, M.D.

The hows and the whys of sleep and chronobiology , two groups published papers in within remain among the leading scientific challenges to a full of each other, linking abnormalities in the hypocretin/ comprehension of the central and its orexin system to narcolepsy. In the first paper, a team . Nearly all but the “lowest” ex- headed by Emmanuel Mignot reported a of hibit daily periods of repose and action. Cycles of rest the hypocretin/orexin receptor 2 (Hcrtr 2) in canine and activity or sleep and wakefulness are carefully reg- narcolepsy (L. Lin et al.); in the second paper, the team ulated by both endogenous circadian “” and ho- headed by M. Yanagisawa reported that hypocretin/or- meostatic processes. The circadian system adjusts the exin knockout mice appeared to have narcolepsy (R.M. timing of sleep or activity over the 24- . Ho- Chemelli et al.). In this issue, Emmanuel Mignot, who meostatic processes reflect both the increased propen- directed for the past 15 the only dedicated re- sity to sleep with extended duration of wakefulness search laboratory on the pathophysiology of narco- and the recovery or recuperative benefits of sleep itself. lepsy, comments on the neurobiology of the hypocre- In most mammals, three important processes regulate tin/orexin system. His paper reviews the diagnosis, states of and : the circadian sys- treatment, , and of tem, the homeostatic system, and of narcolepsy. Finally, he speculates on the role of NonREM and REM sleep. hypocretin/orexin in sleep, sleep deprivation, and The basic and clinical of sleep and chronobi- other physiological issues. Jerry Siegel and colleagues, ology have been the beneficiaries of recent advances in who have studied the of canine nar- , including molecular neurobiology and colepsy for many years, discuss the role of hypocretin/ , cellular , functional imag- orexin in symptom variability, regulation of brainstem ing, computational neuroscience, topographical EEG, motor systems, and control of the locus coeruleus and , and neuropsychopharmacology. The new nucleus magnocellularis. Both groups independently findings and methodologies have important implica- examined autopsied human narcoleptic and re- tions for understanding the pathophysiology and treat- ported low numbers of hypocretin/orexin cells in lat- ment of neuropsychiatric disorders. This special issue eral , but with some differences. In a of Neuropsychopharmacology contains 18 invited papers third paper in this issue, Rafael Salin-Pasqual and col- on recent advances in basic and clinical research, espe- leagues summarize the role of the whole hypothalamus cially in sleep and, to a lesser extent, in chronobiology. in the regulation of sleep and wakefulness. They also One of the most dramatic recent discoveries in neu- venture some conjectures about the role of hypocretin/ roscience is the identification of the hypocretin/orexin orexin in depression, the night eating syndrome, and neuropeptide system and its role in the pathophysiol- obstructive sleep apnea. ogy of narcolepsy. In 1998, two groups (L. De Lecea et A fundamental question has been whether behav- al., T. Sakurai et al.) independently identified this pep- ioral states—sleep, wakefulness, sleep deprivation, Non- system in the lateral hypothalamus. In the next REM sleep, and REM sleep— . Giulio Tononi and Chiara Cirelli have investigated thousands of transcripts in the brains of rats and, more From the Department of , University of California at recently, fruit flies, which appear to sleep according to San Diego (UCSD) Mental Health Clinical Research Center and Vet- accepted behavioral criteria. Their results suggest that erans Affairs San Diego Healthcare System, San Diego, CA. most of the genes upregulated during wakefulness or Address correspondence to: J.C. Gillin, Department of Psychiatry 116A, 3350 La Jolla Village Drive, San Diego, CA 92161, Tel.: (858) sleep deprivation are known; in contrast, most of the 534-2137, Fax: (858) 458-4201, E-mail: [email protected] genes upregulated during sleep are unknown at this .

NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. S5 © 2001 American College of Neuropsychopharmacology Published by Elsevier Inc. 0893-133X/01/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(01)00335-9

NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. S5 Introduction S3

Two papers address the role of Brown review the limited literature on the effects of which may regulate sleep. Wally Mendelson and An- sleep deprivation on performance in normal controls thony Basile review the data on oleamide, an endoge- who undergo functional brain imaging studies. Their fatty acid amide, which is synthesized in the mam- own studies with functional magnetic resonance imag- malian brain, interacts with cannabinergic, serotonergic, ing (FMRI) suggest that sleep deprivation may be asso- and GABAa receptors, and which may be an endoge- ciated with adaptive cerebral responses during some nous sleep-inducing compound. Polly Moore and col- but not all cognitive tasks. Joe Wu and colleagues re- leagues confirm that ipsapirone, a 5HT1A receptor ago- view the functional imaging literature of sleep depriva- nist, inhibits REM sleep in normal volunteers but fails to tion in depression. The studies more or less consistently replicate an earlier paper indicating that rapid trypto- report that metabolic activity in ventral anterior cingu- phan depletion (RTD) with the tryptophan free amino late and medial orbital prefrontal cortex is elevated prior acid drink disinhibits REM sleep. The latter finding to sleep deprivation and normalized in association with may suggest individual different responses to the RTD. the antidepressant effects after sleep deprivation. Camel- Michael Irwin reviews the intriguing relationships lia Clark and colleagues describe a potential FMRI between sleep, sleep deprivation, and immune pro- method for quantitative cerebral perfusion and illustrate cesses and nocturnal of cytokines. Moreover, its usefulness in two depressed patients and one control his data suggest for the first time that alcohol depen- subject before and after sleep deprivation. dence and African-American ethnicity jointly contrib- Erich Seifritz provides a brief overview of the sleep ute to the reduction of Stages 3 and 4 sleep (low fre- disturbances associated with depression and their po- quency, high amplitude EEG measured also by spectral tential contributions to understanding the neurobiology analysis), reduced natural killer (NK) and stimulated of depression and sleep. In a 4-year longitudinal follow- NK activity, reduced pro-inflammatory cytokine IL-6, up survey of 1176 adolescents with notable depressive and increased Th2 IL-10. Since sleep deprivation is symptoms at baseline conducted by Christi Patten and common in our 24-hour society and in many psychiat- colleagues, persistent depressive symptoms were asso- ric, sleep, and medical illnesses, the question arises ciated with female , changes in sleep problems whether sleep disturbance is associated with clinically and cigarette smoking, and other variables. significant impairment in immune functioning. In a more chronobiological perspective, Kurt Kräu- Monte Buchsbaum and colleagues a re- chi and Anna Wirz-Justice present physiological data analysis of their pioneering quantitative study of local supporting their new hypothesis that the onset of sleep cerebral glucose in wakefulness, nonREM depends upon a circadian upregulation of the distal to sleep, and REM sleep in normal volunteers, showing proximal skin temperature gradient, followed by de- dramatic global and regional differences among the creased core body temperature. For many years Ray three different stages of consciousness. Lam and colleagues have studied seasonal affective Applying new methods for topographical EEG (27 disorder (SAD), a disorder which may have a chronobi- EEG derivations) in normal volunteers before and after ological basis. In their current paper, catecholamine de- sleep deprivation for 40 , Luca Finelli and col- pletion induces a clinical relapse during the untreated, leagues demonstrate that the EEG power distribution in summer-remitted, state in these patients. In their re- nonREM sleep has a characteristic pattern (“finger print”) view paper, Barbara Parry and Ruth Newton argue for each individual. Furthermore, power in specific EEG that chronobiological disturbances may occur in pre- frequency bands increased or decreased in different corti- menstrual dysphoric disorder, pregnancy and post-par- cal regions during recovery sleep after sleep deprivation tum depression, and menopause and that all of these compared with normal sleep without prior sleep depriva- disorders respond to sleep deprivation, in some cases tion; this observation suggests that the recuperative func- for long periods of time. tions of sleep may vary between anatomically specific The future of sleep and chronobiology depends upon cortical areas. Hans-Peter Landolt and Lieselotte Post- basic and . Powerful new tools prom- huma de Boer studied three depressed patients with ise historic discoveries in many scientific disciplines. The MAOI-induced near total suppression of REM sleep for recent discovery of orexin/hypocretin has lessons for in- 6–18 , the longest such published study. At a time vestigators in many areas. It illustrates the importance of when several research groups have suggested that mem- the bi-directional perspective in “translational” research: ory consolidation may occur during REM sleep, these ob- communication between the bench and the bedside must servations pose a cautionary note. These patients did not go both ways. Yanagisawa’s group made an orexin/hypo- complain of cognitive impairment. cretin knockout mouse because they hypothesized that One of the paradoxes of experimental sleep depriva- this regulated feeding, but a clinician in that group tion for a night is that it impairs cognitive performance recognized the signs of human narcolepsy in these mutant in normal subjects but improves depressive symptoms mice. At the same time, Mignot’s group, after a long in depressed patients. Sean Drummond and Greg search through the dog genome, found a mutation in the

S4 J.C. Gillin NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. S5

hypocretin/orexin receptor associated with canine narco- ACKNOWLEDGMENTS lepsy which suggested the mechanism but not the exact pathophysiology of human narcolepsy. Whether one at- The papers in this special issue resulted from a Festschrift tributes such success to serendipity or the “prepared for J. Christian Gillin, M.D., on October 28–29, 2000 at the ,” we can hope for more “breakthroughs” in the fu- School of , University of California, San Diego (UCSD) and VA San Diego Healthcare System. The meeting ture. In the field of sleep and chronobiology, we should was proposed and organized by Dr. Lewis Judd, M.D., Chair- anticipate further advances in understanding the molecu- man of Psychiatry, UCSD, and Sonia Ancoli-Israel, PhD, Pro- lar basis of sleep, sleep deprivation, biological rhythms, fessor of Psychiatry, UCSD. The organizers and Dr. Gillin and genetics. Recent studies, for example, have suggested thank the contributors to this special issue; Robert Lenox, MD, the genetic and molecular basis of the advanced phase Editor-in-Chief of Neuropsychopharmacology; Council, the American College of Neuropsychopharmacology (ACNP); sleep syndrome. Indeed, sleep and/or William E. Bunney, Jr, MD, for editorial review and sugges- could be among the first complex behaviors in mam- tions; Sheila Neely, Kathy Stuart, and Jady Psek, for adminis- mals to be well understood at a basic level. Functional trative assistance, and the UCSD General Clinical Research brain imaging, , cellular neurophysiol- Center (Michael Ziegler, MD, Director), the American Acad- ogy, genetics, and computational neuroscience have much emy of , the Sleep Research Society, Bristol- Myers-Squibb, Ely Lilly and Company, ResMed, Wyeth Ay- to contribute to understanding basic and clinical issues. erst Laboratories, and Ambulatory Monitoring Company for Sleep and chronobiology are slowly but surely giving up unrestricted educational grants to support the Festschrift and some of their secrets. this special issue.