'I 161

-13. Chronobiologv

hood: lmplicatiols fc gmsis o[ aurism md rhizophrenia' Cell tlol Neurohiol' activity{est cycle is the most apParent of all circadiao rllvthms-
2N2;2?:25. Daytime and dghttime temporal niches are different" each off€ring
G;.;'R, Kiecot_Glasa lK. yaruchr pT. }.,laccallum RC. Laskowskj BF- \talarlie.v distinct challenges and oppo(unities- Hence, aniruals have evolved
-Wg, in proinflammatory cltokine production h t'ouds"-lrch
S*.*..tuted changc
Ga P I chiatry I 999;56:4j0' to restriclthe ac'Live poition of &e actiYity-rest cycle to a panicular
md- rumor necrmis l-rror
cJ*i il,Jr-1, rtiiirt PJ, Iru'in MR. Ziegler lr'tG: Interleukin-6
-irpl, projt"m" phasewith respect to the tmnsition betwee:] daf 11d nigl.it' Accord-
afta acute psychoiogical strss. exercjse',ard infused isopnonrremi: diur-
ingly, noeturnat animals b"come activ€ as night falls, whereas
Oiferenrial effects aad ;nrhways- Psrrftas om ltled' X)AJ;62:591 ' -rniqats In reality' more
f--rUr f, Irlugtia U, Brc D, Hilderbrand H' Majzoub JA: CRH md the itmffi become active around daybreak'
sls- nai
wr* J N itroimw 1997;72 I 3 l. compl,ex phase relationships benveen aclivity cycles and the astro-
alm-
f"fi"i s, Sa,r"ifoS-l' LiottlAs' Bmd RN, Fafiood]'N' Stsio M: Stress-in&rced
atlons of immunity iu hypophyrctomized .fts ?roc NatI Acorl
Sci U S n' nomical day exist in nature In fact'many mammals are crePuscular'
1988;85:929?-' only .trecoming active at twilighL-
WB' Glarr R:
rc"coti-Clo.t fX,'Prcacber KJ' MacCallum RC Atkinson C Malarkey
--Ch"ori" A &.fining feature of circadian fiyr}ms is that they persist in the
md age-related increases in the Pmintammtory cFokine U'4' Prcc
"*ta absence oftirne cues and are not simply driven by the 24-hour
en\'iron-
Natl Acod Sci U S A- ?003;100:9090'
Xru"eo jlnt, Otrel FJ, Fmg J' Kubora Tl Taishi P: The mle of cytokifles in physiologi- housed for set'eral rnonllrs under
mental cyc19- Experimental anirnals
cal lleeo regulariE a- Acod !t:i- 20Ol;933:21l '
fuu N Y
continue to exhibit robust
tempel:tture, and humidity
r-
- Na- SJ**d nH, Ch.*iot sympatheiromy alters cyrohxic T lymphm-lre constant darlrness,
regonse to herP6 simpler rirus inltcri ot Atn N Y Acad Sci' 2000;9
17:923- ckcadianftythms.Maintenanceofrhythmicityina..timeless',ellviroo-
fr."'rd Xf-, S*idi, Sg, p"pai*mc autoinmme neuropsychiaEic disordes asffiated meot points to the existence of an internal biologicd tiniing system
that
-rridr
stt"ptoc*.sl infectioa {PANDAS)- Iru ! Naropsychophamol N{ll:4:l9l'
.fr{ao Sf, \Valkilrs I-R: Cylokires for psychologists:'krylicalions of bidirectional is responsible for generating these endogenous rhythms-
-
immun"lt*t uio pomsursication for underetanding behavior' rrod' md ognitim' Ttre site of the primary circadian osillator in mammais' includ-
I'sciol rta: .1 998; 1 05:83-
imune sysm and ing humars, is the suprachiasniatic nucl€us (!CN), located in the
Uutis N Riedet l'{' Griber R Ackenheil M' Schwarz MJ: The
schizophreoia:Ar integrarirc .\'ieu A m N Y Aca4 ScL 2cf{J,;9L7 :456' anlerior hypothalamus (Fig- l.t3-l)- The mean circadian period
.f*r."ufri*r DI- I:vrson DIl, Gmick lF, Manaarag AX. Penna S. Goodkin RS' generaled by tte human SCN is approximately 24'18 hours' Like
a
Grcios K Nerreroff CB, It{iller AH: Paoxetine.for r}r prevention of depression
induced by high{ose tutaifm alfa A' Ez gl t Med-'2001'344:96r- *atcU rAat ticts l0 minutes and 48 seconds too 'slo{ly per day' an
eance OB: Schizophrenia aod viml lofeetion durug neutdeveloamear: A fm on ind-fu-idual with such a peridgradually eomes' ro.gl:.of slng!rcn)
t'il
nrdchmisms. Mo! P.rychia4'- 200L6:634. .-r: . the asnbnomical da1 In slightly more tlian 3 months' a norinalll'
iRaison CLi Cillmick jF, !"liBer, .\H, Neurendwio+immune inleraclioN: iatplica'
iions for hatth and belia{or. In: Pfaff D'rV, Amtd AB Etgen Alr{. Fahrbach sE diurnal human \i'ould be in antiphase.tc the day-night cycle and thus
Rubin Ri eds. HoruMs, Erain md Behanior tb} 5. San Diego, CA: Aademic would becorne transicntly nocumal- Therefore' a circadian clock
ftess;2002'
must be reset on a regular basis to be effective at maintaining
lhe
Raim CI- Miller AH: When not enough is too muh: The role of inufficient gluc'e
processes
corticoid signaling in Oe pathophlsiology of stress-rctated disorders"{'' J Pi:'r&ia- proper Phase relaiionships of behavioral and physiological
rry ?003;160:15-i{ within ihe context of the l4-hour &y.
Rirlt S, tsoix S, Vallieres L Nadeau S' Z-hang J. tiflamme N: Hos the blood talks
to the bnin parcncbyma aud the paravcnrriolar nucleus of the hlpothalmus duriqg Although factors such. as temperature ind humidity extribit daill''
systenric inflammarory and iafecrious stimuli- Prr Src 'E? Biol Med- 2f{'10:?2-i:ll' fluctuations, the envir.oniirenral parameter that most reiiablv
c'rre-
*Sheridar JF, Start JL, AYirsur R, Parigeu DA: Scial disrupiiorq immunilr'. and su*rp- clrange
sponds'to the period of Earth's rot?.tion arbund.its axis is the
tibilig to riral infection: Role of,slucoconic-oid insensitivity and NGF- '{an r\t t'"I<rrl cycle'
Sci. 2000;9 I 7:894. in itluminance ass()!:iated u'itlr lhe tlal'-night dg:c1'1dlpq!t"
;ts il
Spiegel D: Effecrs of psy-chothenP)- otr cancer su*ival. Nat-Ra' Cmcrr 2003i2:i8-i' organisms have eurlvr-tl to use this daily chan-ee in light [evels
Spielel D, Krremcr HC, Blmrn iR' Cotheil E: Effrca of psychoseial lrestnrnl on (Cemian: i:"t't' time; geber' givetl to reset the
sui'i.'al of patitnrs rvirh metastatic trre asa cancel brcrl' 1989;2:888'
tirle cue or ieitgelvr
endogenous circatlian clock- Regulation of the circatlian
pldctrlaker
tr\'ong N{L. Bongiomo PB. Rertbri V- \{cCann SM. Licinio J: lnterleutin (lL) ! beta ll'
I rJceptor arrtagonisf tFl0. and Ill3 gene e-rpression in the enrral nenous llislcm through the.detection of changes in illulninance requires a photore-
md mterior piroit ry aotiog sysrenlic inflamation; Pathophysiological implica- that cornmunicates rvith the centrdl oscillator' This
tions. Proc NatlAcad.Sci US;i. 1991-91:?2'1- ceptive apparatus
Yolken RH, I(arlsson, H. Ye F' Johnston-\\'ilson NL, Toney, EF: Endogenous rctrovi. apparatus is knortn to resiCe iri the eyes, because su€ical removal
of
rus and Rev- 200031:99-
schiaphreniz BrainRes
,t" renilers an animal incapable o[ resetting its clock in
*2roriila McKay J' Roesnthal R: The ielationship of &pressim and
E fru"*i.y f- "y*
stressos to imunological assls: A met&anal)rtic rstiew' Brait BeluY lmt resPorBe to light.
2&l;I5:199. Tlre circadian clock drives many rh)rthms, including rhythrns
in
behavior, cor€ body temperarure' sleep, feeding, drinking' and
hor-
monal levels. One such circadian regulated hormone is the
indoleamine, melatonin- Melaronin synthesis is controlled thrcu-qh
a

multis;naptic pathway from the SCN to the pineal gland- Senrm

levels ofmelatonio become elevated at night axd return to
baseline
during the day- The nocturnal rise in melatonin is a convetlicnt
mark;r of circadian phase- Exposure to light elicits ts'o disrinct
IGNACIO PROVENCIO, PH.D. effects on the daily melatcnin profile- Firsl iight acuteli' suppresses
elevaied melalonin levels- imnrediately decreasing them' to baseline
tevels. Second. light shifts the phase of the circadian rh-vthnr
of
melatonin can be assayed easih'' it
melatonin synthesis. Because
rvindow into the st'ate of the circadian pace-
Chrcnobiolog.v- is the study of biological time- A manifeitation of provides a convenient
biological ,;t11ng is biological r-h1'thmicity' Periods of biological maker- Any perturbation of the clock is reflected in the tnelatotrirt
profiie; thus, melatonirl offers an output that cao be used tr studl the
rhythmicity varv widely. ranging fro:n seconds to days aod even
months. For ex;mple, the period ot rcspiratory rhythms is in the regulatior, of the central circad; rln pace,..'rker'
realm of seconds, lvhereas
-oouts
of depression associated with Jen- Taken together, the circad;an axis of mamrhal's can be divrtrcd
sonal affectiv-e disorder (SAIJ) recur wilh a period of approximately into three distinct fttnctional colnporients: (l) a masler pacctn;rker
situated in the SCN. (2) a photoreceptii'e inPut to the SCN
thal ()ris-
1 year. Among biological rhythnls- circadian (Latin: cfrra- about: prt:r'i'le
inates in the eye- and (i ) the myriad of rhythmic Qutputs that
dfes. day) rhythms are the most extensively studied- As the term
insight into the clocks'ork tlf the circadian pacemaker'
implies, these rhlthms have periods of approximatelv 24 h"rurs' The
f
162 L Neural Sciences
FICUR' 1.13-1 The human suprachiasmatic nucleus Top: Nisslt stain
of section through the human hypothalamus. The suprachiasmatic nuclei
are indicated bv arrows and are located clorsal io the optic cfriasm (OO.
Bottonr Autora'diqgnph of same section. Specific bindiog of a radioiodi-
nated analog of rnelatonin is indicated by the darkening of *re suprachias-
matic nuclei. (From Reppert SM, Weaver DR, Rivkees 5A, Stopa EC:
Putative melatonin receptors in a human biological ckv:,k. Science.
1 988;2 42 :7 8, r,vith permission.)
CIRCADIAN PACEMAKERS
Anatomy The mammalian circadian system is organized as a
hierarchy of pacemakers. The SCN is the master oscillator ,hat orches-
trates a multirude of slal'e oscillators. These slave oscillalors are lbund
in a wide range of peripheral tissues including kidney, liver, Iung, and
other sites in the brain. Because most of the cnrrent understarding of
the SCN and its slave oscillators is derived fro,n rodent srudies, the
information presented here is largely based on the-se findings.
The SCN are small, paired, hypothalarnic struclures situated
immeriiately dorsal to the optic chiasm--lhey were recognized as the
site of the prinlary circadian pac€maker. br;ause iesions in the ven-
tral hypoth;rJalnus rhat encompassed the SCN renttered rodents
b;haviorally arrhythmic. Transplantation of SCN tissue Ilom mutant
hamsters that e-tpressed abnormally short circadian periods into the
brains of SCtr--lesioned host harnsrers rvith normal prelesion circa-
diarr periods resulted in a transler of the abnormally shon period.
*1,***
N2
-
o
(U
L
o)
.E1
L
24 48
hours
f
l.o uu
2
"cc
FICURE 1.-13-2 Circadian rhythnr in the firing
rate of an individual
suprachiasmatic nucleus (SCN) neuron. Top: Firing rate of an individual
SCN neuron over J successive da,'-s, lnset shorvs naveform of a single
.lction potential Boilom: Extracellular recording tiitces corresponcling to
the labeled tinres indicated cl-rring clar'2 in the top panel. {Fronr \Velsh DK,
Logothetis DE, tvleister M, Reppert SN1: Ir,clividual nt:unxrs disstriated lronr
rat suprachiasmatic nucleus express inr.lependentlv phasecl circadian iiring
rhrthms. i\leuron. 1995;1 4:697, rvith lrerntissior,.i
This transfer of a distinguishing pararneter of the circadi'an clock
indicated that the SCN is a true biokrgical pacemaker aad not simply
a neural relay for a rhyfhm generator located elsewhere in the brain.
Although long suspected of being the primarl' circadian pacemaker,
these studies firnrly established the central role. of the SCN in dri"ing
circadian rhythmicity in mamnrals.
Metabolically, the SCN sholv peak activity during the subjective
day. This increased level of metabolism is paralleled by increased
elecuophysiological acrivity evident from brain slice recordings-
SCN rieurons that are isolated and inaintained in culture for several
days also continue to shou' approximateiy 24-hour rhyt-hnu in action
potential fiequency (Fig- l.l3-2)
This observation indicates that the rhythnricity oithe SCN is not an
emergent property of the system but ralher an irherent feature of indi-
vidual SCN neurons. Molecular studies have confirmed that the oscilla-
tory machinery cf the SCN is indeed contained ..vithin the individual
neurons. It is likely, however. that tire -sen.rsl rutput of the ,9CN is a
result of coupling behveen individual cellular osr:;llators, rc-,Lrlttng iu a
coordiaated rhythmic signal. The p:cvaiiin-u vieq' of SCN oscillat.,r
organizarion is that the in.lividualll' osci.llatin:i neurons are largeh'syn-
chronized and the composite ouil:rut rrl the SCl.\ reflects the mean phase
of these oscillators. Rec-ent sl-;dies. holr'evcr have- sltorvn that discrete
phase grouplrgs ofcscillator: ':xjst. The relative contributions oi these
"phase ensenrbles" to the overali rttythrrtic output of the SCN are likely
to be nrodulared by enti"ining aqcnLs such ar light. In addition to the

variable contributions of the ensembles to the global outp-ut of ik SCN'
rhe arnplitude and relaur= phase of the ensembles may also be rafilifi.d
b1, enu:abrng agents. Thelntential to manipulate so nrany pararnae,r-s ol
rhese sets cf oscillatory nanrons affords a tremendous degree of flexibil-
ity rvith respect to cltrk-rcsetting rnechanisms. Furthermora the relatite
phasing of heterogenerxsoscillator gr-oups provides a saa4gy by rvhici
seasonality can be trans&red into a biological signal-
The neurons of the SCN are among the smallest neurons in ttle
entire brain- Thei, pos*rss short dendrites that are not exlensively
branched. A consequerc of these cellular dimensions is fle high
packing density of the srcleus- Virnrally every neuron in the SCN is
ilr:nrunopositir'e ftlr tlre inhibirory nertrotralrsmitter lamin'otrutl'ric
acid (GABA)- The subdivisions of tbe SCN have also been defined
according to irhmunohisrochemical and neural tract tracing criteria.
Perhaps the most obviors anatoniical subdivision is the care of tbe
SCN, defined by the presence of calbindin-positive neurom. The
remainder of the SCN rtrn surrounds fhe core is considered the shcll-
Discrete ftrnctioh.s have fix been firml.v assigned to subdivisirolrs of the
SCN, but the afferent ard efferent projections to and from these subdi-
visions are beginning to lmvide- insights into theAputative fturctions,
Afferent Projectiom Thb retinohy,pothalamic tnrct is tu pri-
mar-v afferent input to.tle SCN. It originates irt tlierrdfini from a srnall
sirlrset of retinal ganglioo cells and irutervates the eatire volume of the
SCN. although the spcific subregions of dre SCN that are most heavily
irrnenaterl vary among different species of mammals. Eadr retina s:eruls
a similar number of prqiuiors to each SCN. resulting in an aproxi-
uratel-v bilaterally baianced input- This is in contrast to the projections of
thlr visual system, rvhicfu tend to be heavill: weighted toward the contra-
lateral side- The de-ere of contralateralism of tlre visual syst'em is
inrersely related to the rsnrber of retinal ganglion cell axots crossing
orer at dre chi;rsmartic midline- rthich. in turn, is directly related to the
degree of visual fieltl binrrulanty. F-or examplq humans have for*'ard-
set e)'es and- theretbre- rvell-de.r.eloped binocuiar vision, allowing excel-
le'nt per-cepticn of deptfi o-f ficld at {he expense of a lvide visual fielJ-
Rrxlents. on the other lrand- ha'.'e laterally set eyes, resulting in iittle
overlap ofeach eye's visual field. This is rnanifested as a lorv
degree of binocularity, whfoh is reflected anatomically in the optic c*ti-
asm as a large number of axons crossing o'er the chiasruatic midline-
Hence, in rodents. a prqr:rderance of i,isual system projectiom targets
cen[al strucnrres in the csriralateral side of the brain. No such relation-
ships exist in the projecties of the retinohypothalamic.racl The lack of
contralateralism is consisenr rvith a system optimized for siryple irradi-
ance de.tection rather tlunvisual tracking-
The excitatory neuroransmitter, glutarnate, is the primary neu-
rotransmitter of the retinohypotbalamic tract, with pituitary a&.nylyl
cyclase activating peptide (PACAP) modulating glriumate's effect in
the SCN. Glutamate receplor antagonists can block the effeces of light
on the circadian axis, illusrradng the importance ofthis neurotransmir
ter in conveying photic infonnation from the retina tottre SCN.
The SCN also lec.eir.es afferents from the ipsilateral intergenicu-
late leaflet (IGL), a sutrnucteus of the lateral gedculate complex.
The IGt., in turn, receive-5-i1pr-11 directly from the retina, thus provid-
ing, a secondary indirectpathrvay fronr the i.etina to the SCN. Neu-
ropepride Y is the predominant transmitter of the IGL-Io-SCN
proj^ 'rion. Althou-eh lle func:l:rn nf the IGL is not well establislrd-
it is purported to be inv.rlved i:r '-'ncodi,,g environmental luminance.
Other. Iess understood projections to the SCN are known to exist.
N4ost prominent amosg rbese is a distinct serotonergic projection
iionr the midbrain raphe- Serotonin (-i-hydroxltryptamine [-5-HT]) is
kno*'n to modulate light's effect on SCN fLinction. Systernic adniini:;-
I ..1 3. Chronobiologv 163
tration of a 5-HT,u receptor agonist before the application t)f a li-sht
pulse attenuates light-induced phase shifts of circadian lcrcomotor
activity in hamsters and nice- Light-induced expression of Fo.s (an
irnmedate eariy gene) rvithin the SCN is also attenuated s'ith this ago-
nist. 5-[IT.r, a novel serotonin receptor'subclass, has aiso been irnp]i-
cated in mediating serotodn's nrodrllatlon of the glu&rmatergic input
to the SCN. Electron microscopy has been used to localize 5-HT,u
and 5-HTr -receptors in pre- and postsynaptic membranes u'ithin the
SCN- The behavioral data, in conjunction wi&'the pharmacological
and anatomical findings, hightight the impoftarce of serotonin in reg-
ulating ihe photic information reaching the SCN via the retinohlpo-
thalamic tract- It has been hypothesized that serotonin nla.v adjust the
gain of the circadian syslem's response to light.
Efferent Projections Most SCN efferent projections rernain
within the limits of tlre hypothalamus. The besrstudied projection
originating in &e SCN is the mtlltisynaptic projection to the pineal
of inhibitory GABAergic SCN neurons traverse lhe
glanrJ- A.rious
hypothalamus dorsally to the autonomic division of paraventricular
nucleus (PVN). The tonic activity of tbe PVN is soppressed during the
day, when the SCN firing rate is high, and is. uninhilited dqiry the
night, when the SCN is quiescent The P]/I'{ t91r$-1.q"*".ndiry
:pmjdction through Sre.medial f<irebrain buirdle to the
glutafnaterlic
intermedir:lateral cell column of the spinal cord at the upper thoracic
levels (f-1 and T:2)- Cholinergic preganglionic sympathetic neurons
propagate this signal by syrapsing bn adrenergic postganglionic sym-
pathetics within the superior cervical ganglion. These postganglionic
fibers finally'innen'ate pinealoc.vtes to stimulate melatonin synthesis-
Norepinephrine relea-se from the terminals of these fibers increases
intracellular cyclic adenosine monophosphate (cAMP) ler'els and'
consequently. the activity of mclatonin synthetic pathura;v. Melitonin
is not stored or released via a.secretory pathlt'ay. Its lipophilic n;rture
pemrits it to passively diffuse through membranes. Thus. the release of
rnelatonin is directly related to its rate of synthesis-
The action of norepinephrine is mediated through B- and cr-,-adre-
nergic receptors- p-Adrenergic receptors stimulate the producti'.rn of
c,A.IvIP, rvhereas the ctr-adrenereic receptors potentiate the action of
p-adrenergic receptors. The ultlnale outcome of this efferent path-
way is that increased rnelatonin synthesis occum ivhen SCN activity
is low. This antiphasic relationship is established by the GABAergic
sign-changing synapse at the PvN- Melatonin r.eceptors localized to
tte SCI.I are likelyio provide a feedback mechanism by rvhich the
antiphasic relationship between the SCN and pineal gland is main-
tained and possibly reinforced-
A sec-ond, iess understood efferent pathway from the SCN plays an
important role in the control of cortisol' Systemic cortisol levels
increase in respolse to $ress- Horvever, these levels also have a strong
circadian componert, being highest in the early rnorning in humans.
Peak cortisol levels occur at approximately 6 eU to 8 AM, just as rnela-
tonin levels approach baseline- This stress-independent colllponent
rvas identified through SCN-lesion studies in rodents that abolished
circadian rhythms of cortisol but left the acute response to stress
intact- An inhibitory GABAergic projection from the SCN to the
hyp,thalarnic PVN is the first element in the neural pathway regulat-
ing rhythmic cortisol levels. Arons ui this pioje-ction syrapse oii the
par.riceliutar neurons of tlre PVit that contain co(lcotropin-releasing
htinnone (CRH). The temiinals ol these CRH-containing neuron\
reside in the median eminence, where they relea:e CRH into the pitu-
itan'portal system and sdmulatc the rdiease of adrenocortico[ophic
horn.rone (ACTH) fronr the adenohypophysis. ACTH, h rurn- acts on
the zona fascictilata of the adrenal gland to release cortisol.
 ro* l. Neural Sciences

A sec:ondaD, i:rhibitory parh\\,a-v to &e pVN via a vasoprassinereic posttranslarional modifications. For example, phosphorylation of
projecrion tfuoueh rhe dorsomedial hyporhaidrnus has ben impticaied
some of the PER proteins by casein kinase Ie is irnportant for rheir
in cortisol regularion- Analogous to the circuit controltiog pineal mela-
translocation into the nucleus. Other kinases, and presumably phos-
tonin, rhe circuit regularing cortisol conlains a single inhibitory syn-
phatases, are emerging as critical regulators of the circadian molecu_
apse- Accordingll" one .'vould expect a circadian cortisol secretion
Iar clockrvork. More g}obal reguiatory mechanisms, soch as histone
profile similar in phase and sr-,ape to thar of pineal meratonin. This is
acetilation or phosphorylation, are also likely to control &e rtq,th_
not the case, suggesting the presence of otlier factors trat may be mic expression and function of clock genes.
involved in shaping the circad-ian profile of cortisol- First among these
is the mechanism of informaiion rransfer- Although or" gglglpineal
circuii is exclusivery neural, the SCN-adrenar circuit im'oh,es &e stirn- RESETTING THE CIRCADIAN CLOCK
ulated release of horrnooes that are subject to the vagaries ofdiffirsion
Sensory Parameters In .humans and other mammals, light
and transport thrtrugh the circulati.n. Second. thc sensiti'it-v of the
perceired through rhe e,,es is the rnost bffective agent for enraining
, adrenal cortex io ACIH also exhibits a circadian r..ariation- Finatty, ir
(synchronizing) the circadian system to the 24-hour day. Bilateral
has been proposed that cortisol itself may feed back on the brain to
removal of the eyes renders an individual incapable ofresetting the
inhihit fp1{ and Ai.IH producti.n.
circadian clock, indicating that the photosensitive apparaus neces_
sary for resetting must be ocular. Ho*,ever, several lines of evidence
Molecular Clockwork As menrioned previously, isolated suggest that.this appararus is distinc.t ftom the rod andconc photore_
SCN neurons can generate cfcatlian rlryrlrrrrs. I-br decades, however, ceptors that arc requircd for vision.
the lack of knowledge regarding the inner clockwork of the circadian First, the photic seusitivities of the visual and circadian wstems dre
pacemaker forced invesLigarors to treat the SCN as a ..black quite different (Ftg- I.113)- The visual sysrem can be activated by
box.,,
Since the mid-r980s, progress in understanding rhythmic biochemi- intensities of light rangi4g from dim starlight to brighr ,Jaylight. This
cal processes has led to advances in the identification and character: dynarnlc range represents 4pproximately t+ log units of light inrensity
izatioa of the molecular gears of circadian pacemakers. A aohort .meastred in photons pe1 secgad pei. cm2- Thd d)rnaimic range of the
of
principal clock genes has bec.n identifie<J ir mammals since 1997. circadian system is only 3 log units, and the actiration tr*eshotd is
N{any of these motecular coluponents *,ere initially discovered much higher than rhe visual system. Additionally, the circadian system
in
the fruit fly, Drosophilo nvlanogoster_.leading to the discovery requires light stinruli of much longer ciuration to activare clock reset-
of
'marnrnalian orthologs- -the basic architecture of the circadian clock- ting thal thar reguired by the visual system to construct images.
*.ort is generallv conser'ed among species of ttre animal kingdom; These dift-erences in activation parameters are consistent with the
howevpr, some of the clrck genes have been tluplicated in differences in the photoreceptive tasks performed by these fimctionally
the mam-
nralian genorne. These tjuplications hare added another tevel distinct systerns- The principal task ofthe visuar system is to construct a
of
complexity and tbe possibility of partially r-edunrlanr functions- spatiorempor-al representation of the environment- In rhis sense, the
e1,e
The nrolecular clock-*rrrk .f the nraster crock i, the scN functions like a rno'ie camer4 acquiring a series of srilr shots that the
is virru-
allv iclentical to that of the peripheral stave oscillarors- The SCN are
so small that their size precludes irrost hiochemical analyses,
How_
e*er, intcsrigalors ha'e lreen able t. char**terize cl.ck proteins
from
abundant clock-containing peripheral tissues- such as liver,
io under_
stand the wt:rkings of tire cen.tral clock.in the SCN. From
these and
other studies. the follorving concepts are notr established.
Ttre mammalian circadian clock*,ork consists of interacting posi_
tive"-and negative transcripfional and translarional feedback
loops.
The expression of three hontologs of the Drosophik
Wnod ;;;
{P.erL, Per2, and perj) and rn o homologs of the ilrosophtta crlpto-
chromegene (Cryl and. Cr,-2) are positively regulared by +a'
the bin&ry (l,
of cLocK-N'IoPa (Mop3 is arso knowa ut sMeLD heterodimers
to E-box enhancers in the prornoters of these genes.
-E1
The products of or
the Per. and C1'genes translocate hack into the nucleus
and repress o
their orvn transcription- This series of ev,ents constitutes
the negative
feedback Iimb of the core osciilation.
In addition ro activaring the rranscnption of the per end Cry
genes, the CLOCK-IvIOP3 complex also activates
expression of the
orphan nuclear receptor g.ene; Re.r,-Erbc. The gene product
of Rer_
Erba in turn, translocates into the nucleus unJ ,.p."rr", franscrip_
ti.,n of the MOP-I gene through Rer,-ErbtROR..*ponr. -2
elements
in
the MOP-i gene promotei I\4Op3 subseqtrently heterodimerizes rvith rru 15
CLOCK an..i again a!.(rvales expression of the per, Crl,.
*Jnr> log.irradiance (photonsis/cm?i
.'irta qene.s, This derepression /or auiivation) i;f rlre l,iCp3 gene,
subsequent hereroclir:terizarion \.r,ith CLOCK.
and actii..;;-n of rire 1,.13-3, Craphical representaiion oi the response ranges of the
Per, Cry,. and Rey-Erbo- genes constirutes the posirive .ll!-Yr-,
vtsual and circ,rCr.rr
teedback limb svslents. The reSponse ranges oi sensitivity (xlaxis) and
of the corc oscillarttl. inlegratio.. ti,nr-, ,).-rxig of the circaiian anJ ;!"";s contained
The inreractions of clock proteins and rhe ranslocarions "";rl Ntte thatare
rvithin the bou.tj.:rres of their respective rectangres.
the circadian
of these systenr is ins(,rrrr'(:,c ro light and requires stimuli of lorrgcr
proteins [retr,veerr cellular courparttnents are duralions relative
tightll, regulated b;'- to the visual svsl*rrr

brain can ifitfrfret as a dynamrc visual scene. Thus, information al*ut
the relatir,e positions of differni stimuli ivithin rhe visual field must
be
to motion u'ithin
nrainained throughout processing The ability det€ct
the visual 6eld also requires a relatively fast int'egration tirne analog<rus
to a fast Lrternaticnal Standards Organization (ISO) rating for a roll of
3-5-rnm fikrI. Thcse spatial ad tempordl requiremen8 can tre satis6ed
by a fine t*'edimeusioual may of narrow-capture' bighly sensitirt'
photorecefitive elerrents, sl& as tlre photoreceptor layer of the retina
that contains tberod and corelfutoreceptors.
By ooatrasllte task of &e photoreceptive input to the circadian
system is the Murementdambient illumination. Inessence, &e cir-
cadian photoreceptive systera rust-firnction as alight meter rather than
a camera Thergguirements of alight meter are different than those of a
carrera- Spatialilrformation ism
important and may, in fact, confouod
the sisEm. t udnous point *owces of ligh! such as the moon' could
prove coniising for n:rnow-capure photoreceptive elernents- If. hou'-
ever, the sysGm'used relatiwly insensitive, bload-capture photorecep
tive elements caPable of inr4rating large sectors of visual:pace. the
relative contribution of the ruma\ irradiance t<-r the total arubient irradi
ance would be minimized ald &rs u'ould not be mistaken for a dal'tirne
iight level. Theoretically, a &e' two-dimensional array of narrou-
caphfe,photorcceiTtive elixesb could sen'e in this cqpacity if ttre out-
put of the array were averaged Altemativell', ?1 aq?tglryglty {iltiac-r
coarse arfiry of relatively f#
-koad+apture phot*eCeptive. eleraelfis
would be optimal for wide spatial integration at a reduced absolute sen-
sitiviq'. Lighming could also potentialty baffie the circadian system
Arnbient lel'els of illuminatim driered by lightning can equal frose
levels of dayligbl Howevet tlr circadian system's insensitivity to
stimuli of short duration mrtially filters out this source of photic
noise. Thken together, ttre spaial and temporal stimulus pararnete$
rgquired to acti\ate.the circdian photic input system ensure ttnt only
relevant stimuli are confened o the central circadian pacemaker-
The different seRsory demards ofthe circadian and visual systcDri
raise the possibiiity that a ncxel photoreceptile apparatus subsen'es
light-mediated entrainrnent of the circ'adian system to the day-night
cycle. Visuatty blind ro&nts Srat have a genetically induced krss of rods
and cones remain capable of liglt-rnediated circadian clock resening-
Paradoxically,, the loss of rods and cones has no effect on the sensitivity
of *re circerlian system to Iighq daspite the fact thar these animaLs are
incapable of forming images- A similar sinration has been observed in
btind hrnnans. A subsed ofblid individuals retain the ability to photi-
cally regulate the rhythmic synbesis of melatonin.
Some blind individuals report no cognitive visua! perception,
show oo elecrophysiological evidence for ocular light detection as
determined by electroretinogran analysis, and exhibit no pupillary
light response- However, soure of these individuals continue to sholv
an acute suppression ofnocas-oal melatonin and a phaseshift in the
circadian rhythm of melatonia pnoduction. All too frequently, blind
inrlividuals are hilaterally enucleated and fitted with prosthetic eyes
'for purposes rangi'ng from surcepribility to ocular infections to rea-
sons of aesthetics. Perhaps some ofthese decisions should be recon-
sidered in light of the fact that the eyes may retain a function in
clock resetting despite being useless for'.'ision.
Extraocular Photoreceplion In recenr years, it has been
suggested that photic stimulation ofe.^traocular tissues is suiiicient to
shift tlre human circaciian cloc*- Specifically. blue light illuminatioi, of
highly varcularized tissue, suci as &e pc,plireal region behind the knee-
was shown io phase shift the nighd-r increase of melatonin' This remark-
able result was challenged by muttiple studies in humans and roderrts
that failed to replicate the original finding of extraocular circadian pho-
toreception. One such study inr'oliid expcsing bilaterallv enucleated
'I
.i3- Chronobiolog,v r65
hamsters to irradiances r'quir-alenr ro suniight levels at noon- These ani-
mals were also completely shat'ed to maximize trSx6utaneous trss-
rnission of light. Even these eitraordinary measures $'ere not sufficient
to demonstrate any evidence of extraocular cir'cadian photoreception in
&ese eyeless rodeats Subsequmtiy, a human study designed to repli-
caie the protocol of the original mlcly failed to repmduce .the results of
the initial rvork Currently, Ore mncepr of exraocular circadiao Photole-
ception in humans and other nununals is not widely accepted among
those investigating ensainment srecianisms.
NOVEI- CTASS OF RETINAL PHOTORECEPTOR
lntrinsically Photosensitive Retinal Canglion Cells
The findings from retinaIy dqg€nerat€ animal models and blind hurnans
indicate that photor€cepors other &an rods and aioes arc likely to be
involved in the photoregulatica ofthe circadian axis. Blue wavelengths
of light most effciently supg€ss grelatonin in humans. However, the
spectral profile of melatonin srpp.*sion does not match that of any of
the photopigments found in lalnal rods tx coues- A small subsa of
rodent retinal gangiion cells recen0y has beerr shourn to be intinsically
photosensitive. The specrral s€nsitiYity of tlrese cells matches the spec-
tral sensitivrly,of tlb circadian sysirem. Most compe[i4g'.lrowever, is
that the.intrinsicalty,$'rotoseasiri*eretinat gangliol qA[s:proj€.t'direcrly
io ttre SCN. tUey also prr-rject to rhe IGL and &i olivary pptectal
nuclei, other brain structures inlrrhoerJ in the interpretation of illunli-
nance information. The intrimically photosensitive cells cootain mel-
nnopsin, a photopigment initially discorered in the pigmented skin
cells (melanophores) of tad;roles and subsequently identified in huma:t
and nrouse retinas. The anatom:i;rnd physiology of melanopsin-contain-
ing retihal ganglion cells are c.onsistent rvith the previously descriired
characteristics expected of crelts im'olved in illuminance detection'
Namell', these cells zre ferr'in number.'fhey represent t to 2 penrnt of
all ot'the retinal gmgliur cells in the roderir retina- Thqse cells are also
disrributed over the enlire retinal eipanse. The dendritic arbors tlf
melanopsin-containiog retinal gangii(nI cells are vast- rvitharbors in thd
ruouse retina ranging frorn 400ro -5()0 lrnr in diameter. Melanopsin'irself
is locaiized to the plasma ntemhane of the cell body, axons, and den-
drites. The sizr of the receptil€ fields of these cells matches the size of
the tJendritic arbors, indicatingdrat *re entire arbor has the ability to ini-
tiate phototransduction and therefor=e i-c capable of spatially integiating
large sectors of the t'isual field. Ttre average :rouse eye is approxirnately
3 mm in diarneter. Therefore, a photoreceptor with a receptive field
diameter of 4O0 to 500 pm'is able to spatiall5r integr-ate 15 to 20 degrees
of visual space. By comparisoq the diameter of the full moon at its
highest point inthi sky is approximarely equivalent to t degree of the
human risual freld- Melanopsin-containing retinal ganglioo cetls are
clearly broad-cSpturg photorecePtors- Furthermore, because the den-
dritic arbors werlry, these cells form a photoreceptive net in the -ianer
rnammalian retina. This comptex of cells represi:n8 'tlre coarse array of
photoreceptire elements expected of an irradiance detector' In addition'
rhe activation pammeters of these cells parallel the parameters observed
for the circadian system as a whole- The melanopsin-confafuing gan-
glion cells are significantly less sensitive to light compared to the rod
and cone photoreceptors of the visual systenl and they require light
srimuli of relati,cly long duration to he acti\ated. Finally, these cells are
ma\imally scrrsilive to u,avelengths of light similar to those required t,
acutell' suppress noco,-ral mel;tonin le'':ls in hu::ans.
Function Although the anatontv arid physiology of melanopsin
retinal ganglion. cells are highly- suggestile thaf these celts function
as circadian photoreceptors. recetll studies provide the most compel-
Iing evidence. Mice with a targetcd disnrption of both copies of the
 166 1. Neural Sciences

wiid-type mouse

Iguse lacking.rods, cones,

wild-type
-+-

.-E
E
75

=6'o
g,.cu
,tg

rL

08160
hours

1x.t0-s 1x10{ 1x1o-7 1x1t$ 1x105 FICURE 1.13-5 Wheel running activity records of a rvilcl-tv,pe mouse
1x10a *pyr".lrcking rods. conis, anr.i melanopsin. Top: Repiesentative
1ld,?
double piotted aoivity record of a wild-q,pe rnouse uncler ent;aining con-
irradiance at 4g0 nm (W/cmz) ditions of 12 hours of u4rite light (800 luii and l2 hours of clarknesi
tgrey
box). Bottorru Representative?ouble-plotted activih, records of a m6use
Metanopsin in rhe rnouse. Top: Retinal ganglion cells hckrng rcds, cones, and melanopsin under identical enfaining conditions.
rn a lat-mounted, mouse raina labeled by indirict inrmunbfluorescence rvrldtype mice consolidate their actir,ity to the da# pnase, anJ
=r,,T1.]:1 againsr melanopsin.'Nore the jhotoreceptive
Y\,r*r
Ihe trme ol activity onset is coincident with the light to dark transition,
Ill^1n."n1ibody net the
overlapping mice lacking rods, cones, and melanopsin contlnue to free run rvith an
:]T_*_ PI-IT dendriric arbors. (Courtesl, of Dr. Ana
Lastrucct.) Uottorn: Flrrence_respon:e reiationship in rvild-tylte period length of less than 24 hours. (Adapted {rom supplsrnqntary
anopsin null mice in respoose to a is_minute pulse
and rnel- 1!n;lc
data trom hnda S, Provencio l, Tu DC et al.: Mllanopsin is'required
of blue (4g0_nm for
rt/avetength) lrght at circadian time l5 hours- Melanopsin-null mice 191 ilgqe-forming
photic responses in blind nrice. _Tcrence. 2003;
exhibited.attenuated phase shifting of circadian lo.o.otor rhvthms 301:525.)
rela,
I:,."-tg,Ild-,ype
5ato I K, Castrucci Ail1, et al.: lrlelanopsin
f,";
siblings at.all irraliances resred. (Aciapiecl r,rra, S,
[OpnJ] requir.nreni for normai
lighrinduced circadian phase shifting. scii"'ie. iooi,zsa.zzl
s.l melanopsin gene does not completely abolish lieht-induced circa-
dian phase shifting; sonrc capacity for phase shitiing renrains. .l.he
photoreceptors mediating this resid,.:ai sensitivity are
likely to be rhe
lllanclsin genc shorv profounC deficits in rneir abilitv to phast rods or the cones: hoi,eyer, orr cannor r.xcluJe the possibilirr.
that
shift circadian locomotor rhyiirms irr response ir_r pulses of
light. an unrecognized class ofocular photorcceptor fulfills
rliis role.
These deficits rvere ob.serveci at all rrradiances lesred (Fig I
l.]_4). To tesl the conribution of rod and cone photoreceptors ro photo,
Thus, the photopigrnent melanopsin and. presumablr,, rhe
rerinal entrainment- melanopsin-null mice rvere crossed u,ith nrice
garglion cells containine melanopsin are reguireti for lacking
nor.ntal photic rods and cones- the piogen-y of rnis cross that iverc rodlcss.
regulation of circadian rbythms. perhaps the mosr srrrprisrng cone-
aspect Iess. and melanopsin-null rvere incapable of phoroerrtr.ainrnent.
of these "knock otrt" sturiies is that d.isrupting both copies even
of the ai hish irradiances of ambient light (Fig. I .I I j) Orher nonvisual
 'I
.1 3. Chronobiolog),

as the pho-
photophy.siotogy \vas alsc atnlished in these mice, such Clock Time
of the melatonin biosynthetic pathu'ay, the pupiilar-r'
ior"grlrtinn 6 9 12 1518 21 24 3 6 9 12 15 1821 i: : 6
light response, and the acute light-induced inhibition of activitl''
Fionr these studies, it can be concluded that at least partial func- I
Sleep
tional retlundancy exists for nonvisual photoreception between rods, 1-
ganglion cells'
corres, or both and themelanopsin-containing retinal 2

It should be noted that the relari..,e contribution of the visual Photore- ee! 0
ceptors versus that of the melanopsin retinal ganglion cells appears yE
gB
to be different among the various nonvisual responses' Forexample' }L' -2

melanopsin plays a rather significant role in the phase shifting of cir-

;- E
I
cadian locomotor activiry hou'ever, the pupillary light response is ao

relativelv insensitive to the loss of melanopsin' Importantly' the ^4, 30 I

complete loss qf photic responses in melanopsin-null mice lacking 5q;

rods and cones demonstrates that no additional photopigments, such
as cryptcchronles, are required for nonvisual photic signaling' Thus,
9 f.;
;6"
20

10

0
.t
'-::--J
I

it appears that lmultiple photoreceptor systems subserv'e nonvisual

photoreception, a phenomenon observed across phylogeny'
9

rrf
The darvn ofair travgl has introduced society to the phenomenon
jet lag, a drauratic exar4ple of circadian desyncluony- Simply
!EI
E3 t
E
'|

0
,l,t"tl
stated, jet lag is the condition of one's circadian ciock being desyn- -t .,,-.. ',J
chronized from '.he local time. Shift work can also cause circadian 0-it

desynchrony- The invention.of arti-ficial lighting has pemritted the i=c

&F n I
manufacturing and service industries to \r'ork around the clock. As-a l€ E
.6Rb
0.0
I
F X--
result. shift rvorkers are conslantly erperiencing the effects of circa- t.5 -
dian desl'nchrony as they try to entrain to an ever-changing light-
-o-3 :
dark cycle. Sorne deleterious effects of shift work include elevated 360 -240 -120 0 120 240 360

stress. deficits in alertness, decreased cognitive function, and gastric
distress. Ahhough no therapy currently exists for jet lag or shift
s.ork. an etficacious treatrnent ultimately must involYe the appropri-
ate resetting of the clock. Such a treatment may fuclude tirqed
administration of light stimuli of spectrally optirnal rvavelengths- A
rnore ccmplete understanding of horv melanopsin-containing retinal
gan-qliru cells convert such stirnuli iltto neurai signals may present
investigators s'ith pharmacological entry points against rvhich chro-
nobiotic drugs can be designed.
SI EEP AND CIRCADIAN RHYTHMS
Sleep Regulation Resttul consolidated sleep is most appreci-
ated rvhen sleep disturbances are exPerienced. Steep is the inte$ated
producr of two oscillatory processes. The first proc€ss, frequently
referred to as the sleep lwmeostar, is an oscillation that stems from
the accumulation and dissipation of sleep debt- The biological sub-
sffates encodilg sleep debt are not kno'*n, although adenosine is
emerging as a primary candidate neuromodulator of the sleep
homeostat. The second oscillatory process is governed by the circa-
Circadia Phc ofCorc BodyTemPcratue
(dcgre)
'
FIGURE 1.13-6 Relative phase relationship of sleep in r'oun: ' :'-! to
other circadian phase markcrs. (From Diik DJ, Lockley S\M lnviir'r: :er'v: ''
tntegration of human sleep-rvake regulatiort and circadian 1[r';;1:;r:'
r\'' ./
Appl Pht'siol. 2002;92:852, rvith permission')
tors. This variability is parzlleled by physiology- Clinicali-' ti';:rral
preference can be quantiiied usrng the Horne-Ostberg (HO) ;litr'lion-
-"i'J ro
naire. In qualitative tenns, nanting, people or monting /a'i '
awaken earlier and experience the core body temperature mi:li:::.::in at
alr earlier clock time relative to night people ot night olrls' Sir''i' tlep-
rivation studies have shown that the homeostatic componenl ':l 'icep
is remarkably similar among individuals of similar age' (Ie 'irr--"'riJ Lre
noted that there is a well-established age-dependent declint: :r.: :leep
need.) Therefore, diurnal pref'-rence is dictated almost exclu j;r r:-'; by
the circadian component of sleep regulation-
Circadian Sleep Disorders Advanced sleep ph:+t i-vn-

dian clock and controls a daily rhyhm in sleep propensity or' con-
versely, arousal. These interacting oscillations can be dissociated by
housin-e subjects in a timeless environment for several weeks-
The circadian cycle in arousal (wakefulness) steadily increases
tfuoughout the day, reaching a maximum immediately before the cir-
cadiau increase in plasma nrelatonin (Fig. I.l3-6). Arousal subse-
qr:entlv decreases to coincide with the circadian trough in core body
temperature. Experiments imposing forced sleep schedules through-
Llut the circadian day have shou'n that an unintemrpted 8-hour bout
of slrep can only be obtained if sleep is initiated approximately 6
hours hefcrr.' thc temperature nadir. This nadrr typically occurs at
drome (ASPS) is a pathological extreme of &e rrroming laii' ;:i:'-'no-
rype- An autosomal-dominant familial form of ASPS tLnSPS)
recently .has been genetically characterized' Affl icted fanrii'r :: i€m-
bers exhibit a striking 4-hour ad'r'ance of the daily slt:i--'-t-'ake
rh1,thm. They typically fall asleep at approximately 7;3ti t
ri and
spontaneously awaken at approximately 4:30 au. Affected -:''ii' ;du-
als have a single nucleotide pol,'lnorphism in ihe gelre i'r-':Jing
hPER2. the human homolog of rhe mouse Per2 clock gene i i:i' ::de-
nine-to-guiutine nucleotide polymorphism results in serine-t' ''i'. ;ine
amino aciti .substitution ihat causes the mutant prot3in to
-'' ;;:effi-
.:ientll' phospltoryl:lted by casein l:irase Ie- an establishe : i)Do-

approx.irnatery 5.00 at'l to 6:00 ei'l- In healthy individuals, initiating
sleep tretrvecn I l:00 p;rl nnd 12:00 al'{ affbrus the highest probabil-
itv of geuing 8 solid hours ofsleep.
It should be stressed that diumal preferenc:e varies arnong individu-
als as a lunction oi age. endogenous circadian periods. and other fac-
nent of the circadian n:cl:cular clockrvork. Sinrilarly. deli' I -leep
i - :'net-
phase svndrome (DSPS) has been shor.v'n to be influenced
ics, A length polvrnorphisln in a repeat region of the &P/ri'' '-ene
appeais to be associated with diumal preference in DSPS ' ;' 'rnts,
the shorter allele heing associated lvith evening prtferetrce
 I5B 1. Neural Sciences

isrls are caprble ofsynchronizjng physiology to the seasonal cycle to

Day Night
maximize surival. For exampie, pr=ecise seasonal cycles in reproduc_
tion are seen throughoul the plant and animal kingdorns. l_arge mam_
mals that rypically have lorg gestation periods, such as sheep,
conceile in rhe fall when the nighs are long and the days are short, io
birth occurs during the relatively mild season of spring. These ani*als
are referred b u,shofi.da); breetlerc- Conversell,, rnammals with ges_
tation periods of only a few weeks, such as hamsters, conceive and
give birttr &ning spring and sumloer, when the days are long and the
nights are dmrt- Hence, these animals are.referred to as long_day
brced'ers. Like circadian rhythrns, many cf these yearly (circannual)
rhythms terd ro persist in the absence of seasonal cues u,ith endoge-
nous periods ofapproximarely I year.
t'Natural"
human Melatonin and Seasonality The nrosr reliable environ-
sleep mental paramrter providing a faithful representation of the solar day
is the day-night cycle. Similarly, the most reliable environmental
parameter reflecting the progression through the scasons is the
change in daylength, the fraction ofthe 24_hour day between suri-
rise aad sunsel [n seasonally breeding animals, day length is physio_
Iogic.ally esoded through the melatonin profile. As Oesi.iha
previously, rDdatonin levels are elevated durLg the nighr A long
night, rych as rhdt experienced during the shorr day lengths of win_
ter' results ia an elevated melatbnin profire of rerativery ro,g dura-
tion- A short snnrner night, by contrast, results in a short duration of
elevated melatonin. This seasonal signal is interpreted by the repro-
ductive axis, resulting in an appropriate reproductive response.
Modern Melatonin's,$Ie in tansducing day length was elucidared by pinea_
fiuman lectomizing masonally breeciiirg animals, thereby removing the pri-
sleep mary endogeoous source of melatonin. Melatonin was then infused
in profiles mimicking long d4ys or short days. The duration oi ele_,
------d vated melatonin u'as the primary determinant of seasonal .reprodui_
o'Il';''t tive status, even *,hen the infused profile was adminisrere.d under a
conflicting day tength- Variations in bther parameters, such as the
,'. Change of sleiep sliucrure iri response to arriircial iight_ amplitude of the melatonin profile, the amount of total melatonin
,t]-CYTI _11
r?9.. lotrl sieep tinre is reduced,.and periods oi rluict rr.:rkefulncss'are synthesized, or rhe phase relationship of the profile to thc iight_dark
abolisherl.by_extending rla,rtinre into nighttime throlgh arriii<_ial lighting.
(Fronr WehrT,{ Moul DE, Barbaro G, etil.,
cycle, are of timited importance.in producing a humoral signal that
Conse^,riion of phr.,tolierioS_
responsive mechanisms in humans. Am I physio!.1993;265:R846, transduces day length.
rvith
permission.) Reproductine response.s. to changing day length can be dramatic.
d: Siberian hamsrer (Phodopus
tdays srrr.goiur) maintained in long
is reproductively competent and typicalty has a testicular
The advent of the Iight bulb has extended rhe human tjav into weight of approximately 250 mg per testis. Under short days, how_
rhe
natural night- This encroachment on the night, although increasing ever, thq testes r€gress to'approximately l5 mg per testis, represent_
productivity, has affected hurnan sleep patrems (Fig l. l3_7). Typi_ ing a 94 perc€nt decrease in testicular mass. The same degree of
cal use of artificial Iights results in a singlq consolidaretl bour of regression is observed in response to melatonin infusions that mirnic
sleep Iasting approximately 8 hours. This patr.em of sleep is short days. Communication of the hormimalSi transduced day length
uncom_
mon among most other mammals, which typically experience
more
to the repr<rductive axis is likely to be mediated, at least partialll,,
fractured sleep. Huinan sleep under more natu.al phoroperiods, ttnough melatonin receptors in the pars tuberalis ol the piruitary
where the duration of the night is longer, becomes dec:ompresscd. gland. The exac[ mechanism remains unknou,n. but activation
of
Specifically, a bimodal distribution of sleep is obsen.ed: bours these receptorsis hypothesized to indirectly regulate an unidentified
of
sleep occur in early and lare night, periods if qufa it.t*e_fulncss factor put:itively named. tuberalin- Tuberalin, in furn- controls gene
are
interspersed betu'een the two primary.bouts of sleep. .l his expression and prolactin release from lactotrophs in rhe adenohypo-
natural
sleep pauern is more sinrilar to the sleep patterns of orher
manrnrals_
physis of the piruirary.

SIASONATITY Seasonaiity in Hurnans Whether hurnans are rrutv seasonal

The l/-hour period of the Earth,s r.tation around its exi) r\ r.r,ii,.1,rc_
ing. Howevel the Earth's aris is rihed 23-45 degrees iiorn rlrt
ptaue If
rts own o.bit around the sun (&e ecliptic). As alesult.
lhe r(,littrve pro-
yttnion of daytime to nighttime within the 24-hour asrrorrorrrrcai
tlav
\ranes as the Earth proceeds through its oibit ol-the
sun. \{;rn,. ,rrlan-
is still a point of considerable debate. -several lines trf evidence e;,ist
that suggesi tbe presence of a residual tendency torvard seasonality.
A peak in &e rate of suicide occurs in the summer; rhis peak is
cross-cultural- Birth rates also tend to shotv a sea-sonal variation;
a
small but disinguishable peak in the rate of births occur-s in
sprins
and summer- This pattem, hotvever, is itself variable arrtj is heavilv
 1.I3. ChronobiologY 169

geographic factors' lnterest- B- Full rentissions (orachange lrorn depression to matda or hy'oo-
influericed hY unknowa cultural and
of fu spring-summer birth rate peak has dimin- niania] also occur at a characteristic tiue of the year-
,fr" amplitude
C, Trvo major depressirrc episodes nreeting criteria A and B have
ingf:,,
islr"a ut societies have beconie indusrialized' have
during long occurred in the last 2 years, an<l no lonseasonal episodes
The decompressed bimodal structui€ oi hurnan sleep
that tbe lengtb of natural sleep is related to the occurred in rhe saroe luiod-
oights indicates the
tn" nigbt. Potentially, a two-oscillator system could frmc- D- Seas.tnal nrajor depressive episodes suhstantially outnumber
tJig*, of
proper sleep pafferns during changing photoperiods' nonseasona! episodes over the individual's lifetime'
iioito *rinruin
oscillator that
Su"h u propoted system would consist of an evening
(dusk) morning oscilla-
tracksthe uansition frerday to night and a
Winter SAD The most prevalent form of SAD has an onset itr
ior that tracks $e transition from night to day (dawn)' Therelative the late fall and early uinter aod remits in the late spring and early
encode the chang-
phase differences betrveen these oscillators may summer. This conCitioa is frequently refened to as Hia'€r SAD'win'
ing ary lengths associred with the passing ofthe seasons' Biologi-
ter depressittn, or ttle *iater blues- S-vnlptorns at1'pical of major
.i "r,ia"n"" [or a two-oscillalor system exists in rodens aad
depression can.preseot sith winter SAD. These include' but are not
hunrans- : restricted to. a signifcant increase in weight, hyperphagia' an
Ttre nielatonin profile of maay vertebrates, including some in,:rea.se rather than desease in sleep, a heightened sensitivity
to
peaks' ln rodens' Most
humans, is bimodal. wiih evening and morning interpersonal rejection, aad a leaden feeling in the extremities-
metabolic and electro@ysiological sudies of the SCN typically
distinct, hou.ever, is a eaving forcarbohydrates-
bra! in &e plane' Resulrs of gen-
have been done in slices cut coronal Survevs indicate the prevalence of rvinter SAf) among the
electrophysiological studies conducted in brain slices cut ir
the hori- 4 and 9 percent' Women are four tirrtes
eral populadon to be betcteeil
fre-
zontalplane have prov-rded new iasightr The action potential as men to be affocte{ and as much as 20 perc'ent of the
as likel-l'
pop-
quencl in SCN neu(Es &orn horizontally cut preparatiom is ulation may have subsyadromal features' Rates of SAD *" t]lglp
UimoJrt, with peaks in &e early and late subjective day' Further- higher among relatives of rbose s'ith a confirmed diagnosis of
SAD'
more, the interpeak int€rvd varie-s as a funclion of the photgpgriod Th"is could U- ;t*iArr;;i-:"
. a'gene'dic infl uence or environmental
in which the animal rlas housed- These studies lehd credeirce to il fl ue nees. given shued environrnental exposur r: arnong families'
long-standing suspicious &at rhe SCN of seasonally breeding marn- The goltl standard trEdltr€nt for winter SAD is light therapy' A
nrals and, perhaps, norseasonal mammals harbor a monring and typic:rl prescription for light therapy involves 45 to 90 minutes
daily
evening cscillaror that iilteract to convey day length information' .*pnrrru to a broad spec*um'-ultravioiet-tiltered' \Yhite light source
In seasonalty reproductive mammals' the duration of the nightly of retatively high irradiaoce (5,000 to 10.000 lux)' Recent studies
increase in nretatonin effectively enco&s day lengt'h
(or, more accu- in con-
har,e suggesred that a c.rynbination treatrnent of light therapy
rately, night length). By contras! in the vast rnajority of hurrans' the junction ,vith cognitive{ehaviorat therapy maV b1 more efficacious
duration olelevated rnelatoqin is invariant throughout the year- ihan light therapy alone- Monoamine oxidase inhibirors (MAOfs)
Recent stu<lies have shorun that healthy men living in their usual
.home har.ealsobeenusedsrccessfullytotreatri,interSAD.Theantide-
environrnellt had rvinter and sumnler melatonin profiles that pressant elfecr of photorherapy in u'inter SAD pat'ients has
given rise
rvere indistinguishable" Horvever' healthy men enrolled in a carefully t.r s"ternl hyporheses regarrling the etiology of the disorder' One
controlled photoperiod exPeriment gave surprisingly diffbrent hypothesis proposes that SAD parients experietrce Ihe consequences
results. In this cohort, iong nights elicired an extended period of oi a .hronicaltl' pluse &layert circadian clock' suggesting ihat the
melatonin elevation. &aversely, short nights produced a cofl1- aberrirnt phase angte bet*een the clock and the environment
is caus-
pressed period of elevared melatonin. In essence, humans retain the s1i1,g 1lf v,'inter SAD- Co$istest with this h-vpothesis is that the ofispt
capacityto encode day lcngth' although this capacity is masked by of the nightly release of melatouin is delayed among some winter
the self-imposed artificial lighting regimens of modern society' It SaO patienri relative to healthy controls (Fig' I' 13-8)' However'
the
should be noted &at a small lercentage of individuals residing in onsetofrnelatoninincreaseisnotphaseshiftedre,Iativetocontrols.
their usual environme.nt €xhibits meiatonin profiles that trrck day In essence. these patie*ts have a tonger duration of elevated srelato-
Iength, much like seasorally breeding manunals' Of partrcular ioter- nin rhat increases at the sasre clock time as that of controls
but srays
estL male patients experiencing SAD, some of wbom exhibit this elevaled longer, thus impinging on the morning hours' Although
spparent seasorralitY- these data are not coirsi3terrt with the phase delay hypothesis'
they
of morning bright light therapy that
may explain the effectiveness
profile of winter
SEASONAL AFFECTIVE DISORDER AND would acutelY suPpress the extended melatonin
CIRCADIAN RHYTTIMS SAD patients. It should be noted *rat the sculpting of the melatonin
profile by rnornilg light exposure cannot entirely explain the proven
SAD is the most overt sranifestation of seasonalily in humans' It is ,u...r, of phototherapy- In some rvinter SAD patiens' bright light
characterized by recurrent major depressive episodes followed by atilninistered during the evening is also antidepressant' In tact'
somq
periods of remission thai occur on a seasonal basis' SAD is not cate- phtxotherapy treatment paradigms prescribe morning and evening
edition of
lorized as a distinct mood disorder in the fourth revised light erposures.
the Diagnostic arul Snfisical Manual of Mental Duordars (DSIv{- -l-he
success iherapy administered at various clock times
oilight
IV-TR) Rather, once the diagnostic criteria for a rn'tjor depressive sirggestc that winr'r SAD may not haYe a circadian-based
etiology'
"ulr..rrlut. g v"i:ler
-pisode have beerr rrlel, then it can be determined rvhether the 'eo- A ri hypothesis proposes that Paiie rris experiencin
son.al pattem specifer:nteria are present, thus in'licating diagno-
' SAD are generaii-' less scrrsitive to iight tharr ltealthv counterpails'
sis of SAD. The SAD specifier criteria are Such phoric insensitivity 'r,r'ould become apparent during the
dccr.'ased light levels of late fall and early rvinter' depriring
repres- dlese
A. Regular ternporal relarionship between the onset of major off depnession-
(unrelated obvi- indii'itluats of the threshold r.f light required to stave
sive episodes and a particulartime ofthe i'ear tr-
ous season-related psychosocial stressors)"
Accorriinull'. daity suppiementation of lighr through bright photo-
 170 1. Neural Scit nces

[} Healthy lden in Phctopenod Eperirent

A basic tener irr the development of pharnracological rreatmcnts
is that a dose dependence nrust erisl to implicate the efl-ectiveness of
the drue in uLresricrn. Sinrilarlv, a dose or fluence dependence should
t5O be otrserved u,itJr respect to tleatmetrl of rvinter SAD [,ith bright
E

440 phototherap-,-. Severai studies attempting to documenr a fluence-

:= response relationship in the treament of winrer SAD have provided
9;
E the field with conflicting data N{oriover, light rherap},. like orher
=P20 photobiological responses, should show a war.elength dependence
that reflects the spectral sensitivity of the photopigments mediating
rE 'lo
that response. Several investigators have attempted to establish the
relative efficac\., of colored-light .treatments. Taken together. these
studies have provided equivocal results rvilh no clear range of rvave-
lengths proving to be most effectir.e.
It has been proposed thar u'ioter SAD parients do nct experience
an inherent insensitivitv ro hght but rather lail to respond appropri-
ately to light. Several plrr.siological responses r<; light har.e been
J
tested among SAD patients. and no.striking de{icits in photorespon-
j siveness u,ere obscned r'elative to healthy controls. Light exposure,
o however, elicits a myriad of biologica! responses. some of rvhich are
E
subtle. Studies comparing the photoresponsiveness of SAD and con-
E
e trol subjects ire far titrrn cornprehensive.
E Ip general, it ca.nnor be denied. that phototherap_V has prove.n to be
an bffective treatment for rvinter SAD. .The mechanisnrs hv rvhich
bright light anleliorare.s the syinptoms ol rhis clisease remnin
unknown. Expcrirnentally, ir has proven diflicult to selet't an appro-
priate control tteatnlent to assess the contributi<rn ol tltc placebo
pl Uen Win Sm in Us,.rl Enviroonent cffect oflight therapy. SAD patients tend to be educared rbout rheir
malady and the avirilrrble trcatnient prradigms, nuking experimental
J
design difficult and subsequent inrerpretarion of results necessarily
E cautious.
>'
-=
o.
-d NONSEASONAT DEPRESSION AND
= CIRCADIAN RHYTHMS
E=
Aberrations in dre tirning :rnd alnount of slecp are lrequenllv part of
the svmptomologt, of depression. incJrrding nonseasonal tlepression-
For example, the ci.cadian phase angle, of sleep onsel can vary in
bipolar i disorder, depenciing on the state; depression causes a phase
Hours Relative to onsel of Secretifii
delay, whereas mania results in a phase advance. In addition. sleep
disturbances can coltribure ro the pathogenesis of the rlisea_se. A
FICURE t.13-a Seasonal rariation in melatonin profiles of healthy men
and men with seasonal afl'ective disorder (SAD). AiThe melatonin piofiles
curious phenomenon related to depression and sleep is that totai
oj neilttrf m91 sleep deprivation can provide a transient antidepressant effecr in a
Try as a hrncrion of rhe experimenrally controlled phorope-
riod. Winter-like long nighrs produce a longer profiie of ele,,ated melatonin majority (approximatel-v 60 percent) of depressed parienls. No dif-
relative to sumrner-like.short nights. B: Fleahl-ry men did not shorv a sea- ference Was observed tretrveerr medicated and nonmedicated patients
sonal va:.iation of the melatonin profile rrhen ihey had been living under
in the efficacy of sleep deprivatioo treatment.
the lighting cycle of their usual environment- G Bycontrast, men ,"iih SaO
exhibited a seasonal variarion of the melatonin profilc when they had been Relapse occurs atier the follorving nigbt of sleep. Ever-r short,
living uniJer the lighting qcle of their usual environnrent- (From W,ehr TA, daytime naps can cause relapse. This tendency of nap-inducecl
Duncan \,1C Jr, Sher L, ct al.: A circadian signal of change of season in relapse varies as a function of time of day during which the nap is
patients with seasonal aifecrive disorder Arch Gen psych.'200t ;5g: t t OB, taken. Early morning appears to be a critical time durin-e r..,hich naps
with permission.)
have a high tendenc), of c:rusing relapse. Using rhis inlbrmarion. a
treatment paradigm rvas developed conrb.ining total sleep depriva-
tion, a phase advance of the sleep schedule. aud slolv reseuing Io rhe
therapy would be expec:ted to ercecd this theoretical threshold. Thjs originai sleep schedule.
h;'pothesis predicts that the incidence of rvinter SAD among blind Pai;:nts who have just initiated a regimen or'antidepression tned-
individuals '.r,ould be much irrghe. ihan rhar c:.perienced arnons the ication are sleep deprived lirr one rrieht and are allorverJ to sleep on
sighted population. Thi: correlation has nor been observetl. Hou,- the frllowin; day ti.,,,r -5:00 pivr to midnighr- This. .nstitures a 6-
ever. it
shoulC be remer-nher,:or tl;at :t ponio:r crf the btind population hour phase advanc: ;:lative ttt the sleep schedule obserr.ed betbre
abilit't. de tt:r.r liqhr lo; purposes of melatoni,
still retains a residual the uight of sleep deprivarion. Sleep c.rnset aDd off.set lrre sutrse-
suppression and circadiarr plilse shiltine. despite an inabiliry to con- quentlv delayeo I hour e,rch dav for I rveek rintil a convenlional bed-
struct visual irnages. h rnLrst be emphasized rhar a lack ol cognirir,e time oi 1l:00 pi; to 6:00 rrrt is achieved. This paradigm ensures rhat
vision should not be equared ri'irh a din.rinished or abolished capacitv sleep is avoided ciurin.s tlre cr irical rnorning perio<l u,hen rela;rse te n-
to detect gross environrnental iilrulinltnce chanqes_ dency is hrgh, lt iilso protides an acute antidepressanl t-.fti:ct riuring