Rusak 1979
Rusak 1979
Rusak 1979
I. INTRODUCTION
B. Historical Pempective
intervening decades. Rothmann (cited in 184) maintained that the 24-h rhythm
of sleep-wakefulness survived decortication in a dog. Kleitman and Camille (184)
on the other hand concluded that the diurnal sleep-wakefulness cycle of dogs
depended on the presence of a fu nctionally active cerebral cortex and noted
that decorticate dogs reverted to a polyphasic existence characteristic of young
puppies. Lemkuhl is cited (183) as demonstrating that extirpation of the cerebrum
dimini .shed.activity lev pelsand n.ormal periodicity in pigeons. Removal of various
parts of the nervous system of an insect (Carausius morosus) reportedly
disrupted the 24-h rhythm (100). Mason described disturbances in die1 cortisol
rhythms in monkeys after damage to the hippocampal-fornix system (232). The
daily rhythm in pituitary ACTH content was shown to persist after supratha-
lamic ablation of the mouse brain; lesions that included the thalamus and hypo-
thalamus interfered with this rhythm (123). Neither systematic nor conclusive
by modern criteria, this work did not progress to the stage of answering basic
questions about the role of the central nervous system (CNS) in CRs.
Beginning in the 1950’s the prevailing xeitgeist facilitated acceptance of a
preeminent role for the nervous systemin CR generation. Pittendrigh is quoted
as stating that “the elaborate chronometers of birds, bees, and crustaceans
are all in the nervous system and probably depend on neurological organiza-
tion for some of their unique complexity” (118). In a related vein Halberg et al.
(138) stated that “a hypothalamic oscillator . . . driven from within (by feed-
back) and triggered from without, may well control certain 24-h rhythms of the
body as a whole.” These prophetic speculations did not derive from a substantive
empirical base. One could reasonably defend the position that a localized center
for CRs was an oversimplification (141). The presence of CRs in organisms
without nervous systems and their reported persistence in in vitro preparations
of nonneural mammalian tissue (10) did little to encourage examination of the
CNS as the major source of circadian rhythmicity. Most prevalent perhaps
was the view expressed by Harker (141) that there is a basic 24-h rhythm
present in the cells of all animals and that any cell or group of cells could
constitute a circadian clock.
Most neurobiologists equipped to tackle the problem of neural participation
in CRs were largely unaware of the phenomena waiting to be explained;
unfortunately those chronobiologists conversant with the phenomenology were
not neurally inclined in their experimentation.
The current interest among neurobiologists in circadian phenomena is
attributable to several recent developments: the description of circadian
rhythmicity in isolated single neurons and in isolated eyes of the marine mollusk
Aplysia caZifomica (157, 376) and the identification of the suprachiasmatic
nuclei (SCN) of the mammalian hypothalamus as putative circadian oscillators
(252, 370). The reports of Harker (142, 143), which stipulated the cockroach
subesophageal ganglion as a source of CRs, were subsequently not substantiated
(see p. 471) but did much to stimulate research on the neural substrate of insect
CRs. Richter’s investigations (315,316) had earlier opened the modern era of re-
search on mammalian neural clocks.
II. ENTRAINMENT
that EOPs may have provided the receptors for entrainment of CRs prior to the
evolution of lateral eyes.
I. Invertebrates
Truman (393) and Brady (62) distinguish two classes of insect clocks that
differ in several respects, including the mechanisms of their entrainment by
light. One type is exemplified by the clock gating silkmoth eclosion (see p. 476);
the photoreceptor is extraocular and resides in a brain locus either closely
associated with or identical to that of the driving oscillator (394). The second
type is exemplified by the clock controlling cockroach activity rhythms (see
p. 471); it includes an ocular photoreceptor coupled neurally to a central oscillator
localized in each optic lobe of the brain (270, 271). In cockroaches, unlike silk-
moths, disconnection of the compound eyes from the brain prevents entrainment
(at least in moderate light intensities), so the clock mechanism does not appear
to be directly light sensitive (62).
Reports of extraocular or ocellar-mediated entrainment of behavioral
rhythms in roaches (e.g., 21) and related species may be predicated on inadequate
control procedures (62). However, in one orthopteran species [Ephippiger sp.
(94)] entrainment of activity seems to involve both extraocular (cephalic) photo-
receptors and the compound eyes. In addition, the silkmoths entrain flight
activity rhythms via a cephalic photoreceptor-clock complex, and neither the
eyes nor the ocelli are involved (395). The insects therefore present a diverse
array of entrainment mechanisms that cannot be described by a simple rule
relating to types of rhythm. Information on extraretinal entrainment in insects
has been reviewed in detail by Truman (395a).
Entrained crayf&h (Procambavw clarlcii) have a bimodal activity rhythm;
the activity peak that occurs early in the dark phase (D) is a typical CR entrain-
able via EOPs. Covering the eyes, bilateral ablation of the ommatidia, elimina-
tion of the lamina ganglionaris, or excision of the caudal ganglion are all con-
sistent with photic entrainment (288). Apparently EOPs are localized extra-
caudally and are not confined to the opticlobe, nor is the optic stalk necessary
for entrainment. Higher light intensities are needed to entrain the electro-
retinogram (ERG) when light impinges on the retina than when it falls on the
brain; extraretinally localized light is sufficient for entrainment. The EOPs have
not been localized and ablated, so it is not known whether the retinal pathway
is sufficient for entrainment. Page and Larimer (288) speculate that the EOPs
for locomotion and for the ERG are in the supraesophageal ganglion, although
they do not exclude other CNS regions (optic lobe) from participation. It re-
mains unclear whether there exist multiple extraretinal pathways for entrain-
ment and whether entrainment of different rhythms is mediated by separate EOPs.
Sensitivity of the median eyes to light in the scorpion (Androctones
austraZis) is under circadian control and undergoes a 3-log-unit peak-to-trough
change each cycle. The comparable change in the lateral eyes is only 0.3 log
units (117). In this strictly night-active species the receptors in the two eyes
and their associated visual systems supply the CNS with different afferent
information about the time course of ambient light. Fleissner (117) suggests
that the lateral eyes may provide information about the time course of dusk
whereas the median eyes could mediate dawn and dusk transition phases. Com-
parison of inputs e,manating from these different receptors could be of signifi-
cance for entrainment.
The locomotor activity of intact Aplysia is diurnal, with activity onset
preceding L,, in LD 12:12. Bilateral eye removal eliminates anticipation of the L
phase but still permits synchronization (not necessarily entrainment) of activity
to the onset of low light intensity. This photic response persists for over 90 days
and does not depend on social communication of intact with eyeless animals (212).
The fact that eye removal eliminates anticipation of the L phase suggests that
the eyes are part of the oscillator complex controlling activity (211,212). Photic
driving of activity after eye removal demands extraocular photoreceptors, as
does evidence that the rhythm of neural activity in the eye can be entrained
by an extraocular receptor (48), although the eye’s rhythm can also be entrained
directly by light in vitro (104). Extraocular receptors can also mediate entrain-
ment of activity rhythms in another mollusk, the slug Lirnux wuzximus (117).
The circadian oscillators in the two eyes ofA@ysia are not strongly coupled
(154) and photoreceptors in one eye are not effective in entraining the contra-
lateral eye (211). There are many photoreceptors inApZysia besides those in the
eye; these include receptors in the skin of the mantle, the abdominal and cerebral
ganglia, and the oral tentacles. Lickey et al. (211) suggest that entrainment
of the various circadian oscillators in this animal (and thereby mutual synchroni-
zation) is effected by the same external xeitgeber (light) and that a mechanism
of internal coupling between oscillators need not be invoked.
2. Amphibians
The frontal organ and the pineal body of most amphibian species retain
neural connections with the brain and have elements resembling the photo-
receptive cells of the lateral eyes (1). The pineal is sensitive to visible and ultra-
violet light. The frontal nerve that connects to the pineal and also innervates
the frontal organ responds to chromatic and achromatic light. These organs
are well constituted to serve as EOPs for entrainment (1).
Most amphibians are mainly nocturnal in their activity and in a number of
species CR entrainment persists in eyeless individuals. The frontal organ of frogs
may contain the photoreceptors for entrainment of CRs. In newts either the
EOP resides in the pineal body itself or the pineal is necessary for entrainment
for some other reason (1). Entrainment in some amphibians occurs via ocular
and extraocular receptors. Frogs are one of the very few vertebrates in which
pineal (frontal organ) involvement in entrainment has been established (1).
3. Reptiles
Potential EOPs in reptiles include the pineal organ and the parietal eye.
The pineal has modified or rudimentary photoreceptors whereas the parietal eye
has well-organized photoreceptors that resemble the cones of the lateral eyes.
Both organs give electrical responses to illumination (see review in 401). The
locomotor’rhythm can be entrained in lateral eye-ablated animals of seven dif-
ferent species (399). Entrainment persists in Scelopomcs olivaceus after com-
bined removal of the lateral eyes, parietal eyes, and pineal organ, although the
activity pattern is altered (399,401). At least some EOPs are capable of intensity
as well as wavelength discriminations (see 401). In some lizards lateral eye
removal has no apparent effect, suggesting that for some CRs entrainment may
be exclusively via EOPs. In S. oZivaceus EOPs have been localized to un-
specified portions of the brain (401).
The parietal eye of lizards has an ERG whose sensitivity varies with the
wavelength of the stimulating light. Engbretson and Lent (102) studied a prepa-
ration consisting of the parietal eye, parietal nerve, and pineal of the collared
lizard (Crotaphytus collaris) maintained in a natural photoperiod. Photo- and
chemoresponsiveness was nearly reversed during the two phases of the lizard’s
daily photoperiod. In the L. phase illumination of the eye produced a fourfold
increase in nerve impulse activity (an on-response); responsiveness to light was
modulated by chemical stimulation of the pineal and norepinephrine (NE)-
sensitive neurons in the pineal appeared to feed back to the parietal eye to
augment its light responsiveness. Illumination of the eye during the D phase did
not increase nerve activity, but activity tended to increase when the light
stimulus was terminated (an off-response). Application of NE to the pineal
during the D phase had little effect. Pineal efferent regulation of the visual
pathway has yet to be documented in other vertebrates; the absence of direct
neural connections between the pineal and retina (250) probably rules out
a strictly comparable mechanism in birds and mammals.
4. Birds
ments were relatively ineffective (419b). The authors present a cogent discussion
of problems associated with EOP localization studies, including the problem
of light transmission to sites remote from the site of implantation. These observa-
tions are not, sense strictu, relevant to the search for receptors involved in
entrainment but are worth considering because entrained CRs frequently medi-
ate the effects of photoperiods on the hypothalamic-hypophyseal-testicular axis.
The locomotor activity of enucleated sparrows (Passer domesticus) can be
entrained by ambient cycles of low light intensity (240). Photoreceptors in the
eye as well as EOPs in the brain mediate effects of light intensity on 7 of this
rhythm (240). Other work has established dermal light sensitivity in pigeon
embryos and neonates (147) but the role of these receptors in entrainment
remains to be documented.
Ocular photoreceptors contribute to the effects of light on the circadian
system of some birds; the light threshold for entrainment is lower in sighted
than in enucleated sparrows (240). The arrhythmicity observed in Passer in LL
also is dependent on the eyes.
The number of extraocular photoreceptors and their typology, sensitivity
to wavelength, and locus within the CNS are unknown. Studies of gonadal
condition in quail implanted with radioluminescent paint suggest at least some
localization of EOPs in the hypothalamus, optic lobe, and rhinencephalon (153).
Careful studies of CR entrainment after similar procedures are called for and
could substantially increase our understanding of EOP localization and function.
It would be fruitful to test for EOPs in areas of the avian CNS that receive
optic nerve projections. Specifically the anterior hypothalamic region, site of
termination of the retinohypothalamic tract (RHT) in several avian species
(55, 237), would be a likely starting point (see also 280-282).
Photic entrainment of pinealectomized Passer indicates the pineal is at
most one of many EOPs. In these birds light information from the eyes and
from the EOPs summates in producing entrainment (240).
5. Mammals
because the CNS can effectively integrate visual input with afferent information
from other modalities (345). Perhaps most significant is the economy achieved
in reducing the number of receptors necessary for transducing photic informa-
tion. Where many functions are light dependent, as is true for mammals, a single
set of receptors can effectively and efficiently synchronize all rhythms if light
information is funneled through it to the central oscillator(s) (345).
I. Anatomy
tract (SAOT) runs with the POT and terminates in the midbrain tegmentum.
The inferior accessory optic tract (IAOT) of rats leaves the chiasm and courses
along the ventral part of the brain alongside fibers of the medial forebrain
bundle to terminate eventually in the MTN of the midbrain tegmentum. The
IAOT was originally thought to consist entirely of decussated retinal fibers
but is now known to contain uncrossed components as well (250). The IAOT
was recently described in the hamster (214) after earlier attempts to detect
it had failed (99).
The RHT is a bilateral projection that directly connects the retina with the
suprachiasmatic nuclei of the hypothalamus. The claim that the RHT of hamsters
projects to the ventromedial hypothalamus (301,302) has not been substantiated
(214). All modern anatomical investigations show it terminating only in the SCN.
This projection is discussed on p. 480.
The neurotransmitters involved in retinofugal pathways are not known.
The LGN and superior colliculus have high levels of cholinergic enzymes but
the optic nerves show little or no choline@ activity; it is unlikely that acetyl-
choline is involved in synaptic transmission, of direct optic projections of rats
either at the subcortical or cortical levels (44).
2. Function
rhythms of albino rats (251), nor was light entrainment of pineal enzyme rhythms
eliminated by similar lesions (251, 254). Ablation of the LGN also failed to
eliminate the nocturnal drinking rhythms of albino (369) and hooded (371) rats
in LD 12:12. Destruction of the POT and SAOT permitted these animals to re-
entrain their drinking rhythms at least as rapidly as controls after a 12-h phase
shift in the illumination cycle (369). These studies suffer from several shortcom-
ings, the most common being the small number of daily observations used to
characterize the rhythm (usually 3 per 24 h) and the use of data from groups of ani-
mals rather than from individuals to assess entrainment.
More thorough work has confirmed that rats with POT and SAOT transec-
tions entrain their activity rhythms to the LD cycle (91). Similar results have
been found with golden hamsters; steady-state entrainment of wheel running
appeared normal in hamsters bearing bilateral LGN lesions that interrupted
the POT and SAOT and variously damaged the hippocampus, fimbria of the
hippocampus, internal capsule, caudate nucleus, and putamen. However, the
rate of reentrainment after a 12-h phase shift of the LD cycle was far slower
than for neurologically intact controls (427). This first suggestion that the POT
might play some role in entrainment was confirmed and extended in a more
complete investigation (332) in which hamster POTS and SAOTs were lesioned
as they rose laterally out of the posterior border of the chiasm; the chiasm
itself was damaged, as were the supraoptic nuclei and portions of the lateral
hypothalamic area, amygdala, and hippocampus.
Some of the hamsters with complete bilateral POT damage had unusually
long active phases that extended into the L phase of the LD cycle or showed
a long phase lead of activity onset relative to the D phase. Reentrainment
of the activity rhythm after a 4-h delay in the LD cycle was much slower in the
POT-lesioned animals than in controls. In addition, the period of the free-
running activity rhythm in constant dim illumination was unusually long for the
lesioned animals. The long 7 in 0.2-1x illumination suggests that the ambient
illumination may have been perceived as more intense by the brain-damaged
animals. Damage to the POT frequently produces near total pupillary dilation
(mydriasis) and could cause retinal flooding with light (414). Other tests indicate
a seemingly paradoxical sensitivity to light after destruction of the POTS (369,
371). The 7 of the activity rhythm in POT-damaged hamsters was not tested
in DD to determine whether the oscillator or its sensitivity to light was affected
(332). Some hamsters with apparently comparable and complete POT lesions
entrained normally to the LD cycle and free-ran with normal 7 values in dim LL
(332). The basis for these individual differences is not known.
After POT lesions light may be less efficient at phase shifting either the
dawn or dusk components of the circadian activity rhythm. According to one
model (296) these components ordinarily are driven toward each other by light
striking their respective sensitive phases. The hypothesized change could ac-
count for the phase leads, late activity offsets, slow phase shifts, and long
active phases of the POT-damaged animals (330, 331).
All studies agree that “normal” steady-state entrainment can occur to a
greater or lesser extent after POT damage; all investigators so far also report
a complete loss or gross impairment in the POT-damaged animals’ ability to per-
form ,relatively simple discriminations based on light-intensity differences (78,
248, 332,427). Thus the intensity discrimination involved in entrainment appears
to be separable from that involved in learning other behavioral discriminations
based on intensity differences. A recent study (204) suggests that information
on light intensity and pattern may be coded in separate pathw ‘WS relative and
absolute intensity discriminations depend on different visual systems (204).
Normal entrainment of POT-damaged rats to LD cycles employing bright light
and absolute darkness does not imply that these animals would entrain normally
to all illumination cycles. In natural or artificial photoperiods where intensity
differences between the L and D phases are relative rather than absolute the
differences from controls might well be substantial.
b) Inferior accessory optic tracts. Bilateral transection of the IAOT was
reported to eliminate the response of the pineal enzyme hydroxyindole
0-methyltransferase (HIOMT) to light (248). This parameter varies with photo-
period but is not a true circadian rhythm; it provides a useful index of retinally
mediated light input to the pineal. Moore subsequently failed to replicate his
earlier findings (250); the pineal HIOMT response to light persists even when
the IAOT and POTSAOT are destroyed. Bilateral lesions of the MTN do elimi-
nate the HIOMT response to light (250). However, the latter effect is unlikely
to be due to interruption of the IAOT visual projection; more probably it reflects
destruction of descending sympathetic fibers to the pineal (250).
Reports that steady-state entrainment and phase shifting of rat drinking
rhythms survive interruption of the IAOT (369) also must be reevaluated. The
surgical procedures used in the earlier studies to accomplish bilateral IAOT
interruption were predicated on the then-current belief that the IAOT of the rat
is a completely decussated pathway. The demonstration of a clear uncrossed
IAOT component (250) means that the animals studied had one uncrossed IAOT
component intact. It is remotely possible that elimination of this remaining
tract would affect entrainment.
Lesions of the accessory optic system, with the qualification noted above,
do not interfere with the rat’s ability to perform discriminations based on visual
cues (427). In rhesus monkeys (Macaca mulatta) bilateral destruction of the
accessory optic system does not affect performance of a response based on dis-
crimination of total luminous flux. Visual input from the accessory visual system
is essential for these discriminations in monkeys subjected to visual cortical
ablations (290). Comparable data on species other than primates are lacking.
In primates, pathways such as the AOTs, in conjunction with the POTS, may be
sufficient for entraining circadian rhythms. Even in rodents destruction of the
RHT is consistent with some degree of entrainment (331), presumably mediated
by the POT/AOT projections.
c) Binocular mechanisms. Adult rats with one eye removed or occluded
show significantly lower D-to-L ratios in wheel-running activity and drinking
and are slower to reentrain these behaviors after a phase shift in the photo-
period (369,427). The magnitude of the differences between one-eyed and two-
eyed rats is exaggerated when the contrast between the L- and D-phase illumina-
tion intensity is reduced (427). Rats were maintained in a constantly illuminated
room; during alternating 12-h periods an opaque contact lens occluded first the
left eye and then the right eye. The drinking rhythm of these animals did not
entrain to this manipulation; although each eye received temporally patterned
visual input (12 h of light exposure followed by 12 h of darkness during occlu-
sion), the inputs to the two eyes were 180’ out of phase. This suggests central
algebraic summation of total luminous flux reaching the retinas occurs during
entrainment of CRs. Support for this conjecture comes from observations that
the drinking rhythms of rats can be entrained when one eye is constantly
illuminated and the second eye is exposed to a simulated LD cycle produced
by covering and uncovering the eye at 12-h intervals (427).
Each SCN nucleus receives RHT input from both eyes, with the majority
of RHT fibers originating in the contralateral eye (148, 247). There are no
functional asymmetries when animals process light with both eyes; however,
the input to the two SCN after unilateral enucleation is asymmetrical and this
may account for the decreased rate of reentrainment in unilateral enucleates
after photoperiod phase shifts (427). Removal of one eye at birth produces a
nearly equal distribution of remaining RHT fibers to the two SCN (366) and is
correlated with an elimination of entrainment differences between one- and two-
eyed animals (363).
C. Nonphdic Entrainment
1. Temperature
White-footed mice handled briefly during the active phases of free runs
manifested a 40.min delay in activity onset the next day (307). In isolation in LL
each of two monkeys had its own free-running feeding rhythm; when they were
placed together there was a high correlation in their feeding times (323).
Conspecific song acted as a weak xeitgeber for house sparrows (Passer
domesticus) (238a).
The activity of a family of beavers (Castor canadensis), presumed to be
in darkness under snow and ice cover, free-ran with 7 = 27 h (57). This may
indicate social entrainment of the group as a whole (mutual phase synchroniza-
tion) but all individuals may have had very similar free-running 7 values.
Again, this form of entrainment, if it occurs, is presumably most effective in the
absence of an LD cycle. However, separate male and female groups of red wolf-
coyote hybrids living under natural illumination showed differences in their
activity patterns that were largely eliminated when the mixed group was
reunited (324).
In an isolation chamber an LD cycle per se often is not sufficient to entrain
all human CRs (15). The addition of auditory cues produces entrainment; differ-
ent ranges of entrainment are possible for the activity and temperature rhythms
(15). Some blind people have a sleep-wakefulness cycle with 7 = 24.9 h (243);
some individuals complain of periodic sleep disorders that could reflect break-
aways from nonphotic entrainment (243).
However, there is also evidence that LD cycles do influence entrainment
of some human CRs (54). Lack of entrainment of isolated humans to LD cycles
may have resulted from a less rigorous application of the illumination cycle in
human than in animal studies (89a). Note also that the apparently unusual
sensitivity to social cues reported in humans may simply reflect inadequate
information on other social species (see above and discussion in 334). Humans
are unique in having the ability to increase light exposure beyond that available
during the solar day, but whether our entrainment mechanism has come to
differ significantly from that of other soci al mammals remains to be established.
3. Food availability
of the drinking free run when the animals are fist returned to ad libitum feeding
is reportedly determined by the phase of the previous deprivation cycle (380).
The data supporting this conclusion are not compelling and the instability of en-
trainment produced by the fmd-restriction schedule is notable (especially for
the urine-volume and K+-excretion rhythms). It remains to be established that
the feeding schedule itself is a xeitgeber with status equal to that of the LD
cycle. The persistence of urinary rhythms in monkeys deprived of food and
water or trained to eat every 2 h in LD 12:lZ (257) indicates that the LD cycle
may be sufficient for entrainment of the rhythms under study.
The LD cycle effectively and ordinarily entrains eating and drinking
rhythmsinallmammals so f%r studied (e.g., 334,380,425,428). Food-deprivation
schedules clearly are capable of influencing the expression of various rhythms
but the exotic nature of these manipulations makes it unlikely that they do so
normally. Free-feeding squirrel monkeys eat by day (317,257) and free-feeding
rats mainly by night (425). Neither species eats all its daily food in a single 3- to
4-h interval. Since eating and drinking rhythms are always entrained by the
LD cycle the ultimate control of all food-related rhythms is by the illumina-
tion cycle.
Temporally coded stimuli generated by food and water intake are secondary
xeitg&rs whose utility for temporal integration derives from their isomorphic
relation with the photoperiod. The presumed unidirectional nature of this rela-
tion (food intake cannot alter the LD cycle) argues for the primacy of photo-
period as xeitgeber.
Illumination cycles may influence the circadian system of mammals via
several routes (332) and the system itself comprises a multiplicity of oscillators
(296, 331). However, the present evklence does not convincingly demonstrate
the existence of multiple, independent, nonphotic xeitgebem affecting the
circadian system. Rather, the illumination cycle appears to entrain a neural
oscillatory complex coupled to other oscillators that are not influenced directly
by photic input. The fact that a central oscillatory complex has exclusive access
to light information that it transmits to other systems does not necessarily
imply a strictly hierarchical coupling mechanism (258); feedback effects of
peripheral structures on central oscillators have been clearly demonstrated (426a).
A. Invertebmtes
I. Aplysia
axons run in the optic nerves; these tend to cluster near the base of the eye.
2) Centrifugal influences are exerted on each eye by the CNS of the intact
animal; this brain efference appears to include output from the contralateral eye.
3) Inhibitors of ribosomal protein synthesis phase-shift or disrupt rhythmicity
depending on dosage and pattern of administration. 4 ) The availability .of mono-
and divalent cations influences rhythm generation. Evidence to support these
conclusions is outlined below and in a recent review (211).
I) SITE OF GENERATION. The period of the CAP rhythm was reported
to decline in an apparently graded fashion as greater portions of the eye were
excised; when 2% of the eye remained, only short, ultradian rhythms were
expressed (165). Jacklet and Geronimo (165) concluded that the CAP circadian
rhythm reflected coupling among a large population of (ultradian) oscillators.
However, another study (352, 377, 378) reported no reduction in period when
only a very small portion of the base of the eye remained intact.
Jacklet (38, 160, 163) has reviewed his own and Sener’s (352) results and
has indicated some technical inadequacies in the performance and especially
the analysis of Sener’s experiments. Published records from these studies (378)
show the apparent persistence of a single circadian cycle of CAP frequency
in the grouped data obtained from 13 eyes reduced to a very small size. Results
presented in this way are of doubtful relevance to the present issue; at minimum,
it is premature to dismiss the claims of Jacklet and Geronimo (165) on the basis
of these results. Benson and Jacklet (39) provide additional indirect evidence
for the existence of a population of coupled oscillators on the basis of apparent
cold-induced splitting of the population rhythm.
Strumwasser (377,378) suggested that a small number of cells at the base
of the eye are specialized for circadian rhythm generation; these were claimed
to couple neurochemically to the selcondary neurons whose axons run in the
optic nerv ‘es and generate the CAPS. The hypothesis was based on the assertion
that spontaneous CAP generation is disrupted when neurosecretion is blocked
(16, 17). This conclusion is not supported by other studies that show a per-
sistence of rhythm generation and phase-shifting in culture media that should
block neurochemical transmission (105, 106, 161). Recordings in the studies
by Audesirk (16,17) were restricted to only brief sessions during the first cycle
after dissection; they do not provide substantial contradictions to the findings
of E&in and Jacklet. Although neurochemical transmission is not required for
generation of the CAP rhythm, a serotonergic mechanism appears to play a role
in phase control of the rhythm; addition of serotonin to the culture medium
can phase-shift the eye’s rhythm (85a).
Benson and Jacklet (38-41) have recently reported on the effects of DzO,
light, and temperature on properti .es of rhythms generated by isolated Apl ysia
eyes. These studies exemplify the value of the Aplysia eye preparation for the
analysis of both formal and physiological properties of rhythm generation;
we have not discussed them further because they relate mainly to formal prop-
erties and models of rhythm generation beyond the scope of this review.
II) CENTRAL INFLUENCES. Neural activity recorded from the eye in vitro
occurs in a more regular burst pattern against a lower background level of ac-
tivity, has a longer 7, and responds more slowly to phase shifts of the LD cycle
than the activity of the in vivo eye (104). Although the slower phase shift and
longer 7 are an effect of the culture medium (50, 104), the regular bursting
pattern against a quiet background is a consequen.ce of the loss of cerebral
efference via the optic nerve. Selective cooling of the cerebral ganglion to inhibit
its efference modifies these features of the in vivo preparation in the direction
of the in vitro eye (104).
Attached and isolated eyes entrain to white-light cycl .es, but only the at-
tach .ed eye en trains to red -light (RL) cycl es; optic nerve efference is crucial
for entrainment of the intact eye to RL cycles. This finding demands at least
an RL-sensitive extraocular receptor, but it could also be explained by the
existence of an extraocular RL-sensitive receptor-oscillator complex (48, 211).
The source of the efference to the eyes is not known; it sometimes differs
slightly in the two optic nerves. Stimulation of other cerebral nerves may inhibit
the efference, and very-low-intensity light restricted to one eye may inhibit
the efference in the contralateral optic nerve (104). Cerebral efference plays
a role in resetting the phase of eyes exposed to L + D transitions (300a).
In an intact Aplysia selective exposure of one eye to an LD cycle sufficient
to entrain its activity fails to entrain the activity of the contralateral unstimulated
eye; thus, the two eyes are not strongly coupled (154, 158, 211). However,
some experimental conditions reveal a functional interaction between the eyes.
Intact Aplysia were allowed to free run in DD or dim LL for variable lengths
of time, and the phase relation of the two eyes was then assessed bY excising
the eyes and recording independently from each in vitro. Pairs of eyes excised
after a few days in constant conditions were roughly synchronized; and even
after 8-28 days most pairs of eyes were still O-4 h out of phase; however,
a few at this time were lo-12 h out of phase. By 29-62 days 61% of pairs
were 9.5-12 h out of phase and the majority of the remainder were still 1.5-4.5 h
out of phase; none were separated in phase by 4.5-7.0 h (154). These findings
suggest that the eyes in vivo are weakly negatively coupled and tend to drive
each other into an antiphase relation when they are not subject to synchroniza-
tion by a common xeitgeber. Such a hypothesis is also consistent with prior
evidence that the eyes are not strongly, positively coupled (158, 211).
III) CHEMICAL INFLUENCES. Macromolecular synthesis and ion distribu-
tions are implicated in the generation of the circadian rhythm of CAPS by the
isolated Aplysia eye. Treatment for 12 h with either cycloheximide or puromycin
produced dose-dependent phase delays; 6-h pulses of puromycin yielded a phase-
response curve similar in form to that obtained with l-h light pulses, including
both delays and advances. These drugs reversibly inhibit protein synthesis;
actinomycin D and aflatoxin Bl both block RNA synthesis, and their application
produced an irreversible loss of the CAP rhythm in most eyes (325).
Jacklet (164) has applied 6-h pulses of lo- 5 M anisomycin, another inhibitor
of protein synthesis, to generate a PRC similar to that obtained with puromycin.
When tonically present in the medium at the same concentration, anisomycin
permitted CAP generation for 3 days at relatively low frequencies, but with no
evidence of a circadian rhythm. A lower concentration of anisomycin permitted
the expression of a few circadian cycles before the rhythm damped out, and a yet
lower one permitted continued circadian rhythmicity but with relatively long
7 values of 28 h rather than 26.5 h. Protein synthesis at ribosomes thus is of
considerable significance for rhythm generation, but it is not necessarily part
of the time-keeping mechanism. Proteins may well be required for the continued
operation of a circadian oscillator even if the synthetic. process itself is not
integral to the oscillation (164).
The isolated Aplysia eye offers an excellent opportunity for the manipula-
tion of the ionic milieu of a circadian oscillator and for tests of the proposition
that circadian timekeeping involves ionic flux across cellular membranes (274).
Increasing K+ concentrations in the culture medium for 6 h produced phase
shifts in the rhythm of CAP production whose amplitude and direction depended
on the phase of application. The resultant PRC for high K+ concentration
resembled that for l-h light pulses; moreover, phase shifts could be generated
similarly in a milieu that did not permit neurochemical transmission. E&in
(105) suggests that increased extracellular K+ might phase-shift neural oscil-
lators directly by depolarizing them.
Treatment of in vitro eyes with pulses of either lithium chloride or manga-
nese ions produced all-delay PRCs; treatment with a divalent ionophore, which
equalizes transmembrane distributions of divalent cations, produced a similar
all-delay PRC (106, 107). The phase-shifting capacity of the ionophore was
not affected by manipulating the extracellular concentrations of either Ca2+ or
w 2+, so transport of these ions across the external plasma membrane is not
critical. E&in and Corrent (107) suggest that the critical ion-distribution
changes occur at intracellular membranes, perhaps at the mitochondria. Chemi-
cal treatment to inhibit cellular respiration or other aspects of cellular energy
metabolism also produced all-delay PRCs, but treatment with an inhibitor of the
Na+-K+ pump produced a PRC similar to that produced by high concentrations
of K+. Ion distributions and energy metabolism, probably at an intracellular
membrane, therefore are implicated in rhythm generation; it is not yet possible
to discriminate among several possible models for ionic involvement in circadian
rhythmicity (106, 107).
c) Activity rhythms. Locomotor activity of Aplysia is predominantly
diurnal in LD cycles and free-runs with a circadian period in constant conditions
(159, 200, 378). Removal of the eyes (and their circadian oscillators) does not
eliminate the predominantly diurnal pattern of Aplysia activity in an LD cycle
(49), but it is not certain if this represents true entrainment or a form of
“masking’ (212). These findings are consistent with a “masking” effect and
do not prove that true extraocular entrainment is possible. However, the clear
evidence that at least some eyeless Aplysia generate circadian activity rhythms in
DD establishes the existence of extraocular oscillator(s) for activity (49, 211,212).
The role of the eye in rhythm generation is not clearly defined; Lickey et al.
(212) suggest that the eye is one of several oscillators involved in the control
2. Insects
in addition this study suffered from a lack of tests in constant conditions, the
presence of a temperature cycle in LD, and some uncertainty as to the ar-
rhythmicity of crickets so labeled (see 62).
Both locomotor activity and stridulation were studied in Teleogryllus com-
modus after cautery of the PI; crickets with residual stainable cells generated free-
running circadian rhythms, but with modified .7 values. Among those without
stainable material some were arrhy thmic in ac tivity and did not stridulate,
others were i nactive but stridulated rhythmically , and one cricket stridulated
rhythmically but locomoted arrhythmically (363). Since some animals with no
neurosecretory cells visible were rhyth .mic in one measure, the activity of these
cells does not seem to be necessary to rhythm generation; nor, on the basis of
evidence discussed below, does neurosecretion appear to be sufficient for ex-
pression of rhythmicity. The issue of neurosecretion aside, neural activity
of other cells in the PI may influence rhythm generation (221); the role of the
cricket protocerebrum isdiscussed in the next section.
Another approach to this question has been to correlate changes in the
anatomy or physiology of neural structures with rhythms in behavior. Since
acti vity and inn umerable other physiological functions vary with a daily rhythm,
the correlation is bound to be high; however, causal relations between various
rhyth ms have not been establishe d and the meaning of the correlation is far from
clear. Some ill ustrative examples include the rhythm of nu clear diameter in cells
in the nervous system of Droso@Za wzelarmgaster (312), peaks of neural activity
recorded from the PI of A. domesticus just prior to the anticipated peak
of locomotion (20), and a peak in RNA synthesis in neurosecretory cells of the PI
during the L phase in the same’species (88).
A further step has been taken in a study of Apis mellifica. The rate of
protein synthesis in the PI normally reaches a peak before the time of foraging
activity. When foraging was restricted to a brief period at an unusual time,
the rhythm of protein synthesis also shifted to anticipate activity (407). This
does not prove that the PI generates the rhythm or even that it is uniquely
involved in preparation for activity, since a parallel rhythm of low amplitude
is found in the corpora allata. However, the proliferation of such correlations,
if shown to be specific and to persist in constant conditions, would provide
evidence suggesting a role of the PI in generating the activity rhythm; such
evidence does not now exist.
III) OPTIC LOBES. Considerable evidence suggests that the optic lobes
contain the driving oscillators controlling circadian activity rhythms in cock-
roaches and crickets. Section of the optic nerves in cockroaches produced free-
running rhythms that could not be entrained (270), whereas separation of the
optic lobes from the protocerebrum by transecting the optic tracts rendered
Leucophaea mudenze arrhythmic (271). One finding suggested a humoral cou-
pling mechanism from the brain to the thoracic effecters: section of the circum-
esophageal connectives (CEC), which should interrupt the direct neural path
from brain to thoracic ganglia, failed to block rhythm generation. This claim
was later withdrawn (295); subsequent studies clearly demonstrate that a neural
just passive driving of the system. Two hypotheses are offered (311) to account
for these results: 1) there is a damped oscillator in the brain (protocerebrum?)
that can be entrained by a temperature cycle or coupled to a light-entrained
oscillator in the optic lobes or 2) a self-sustained oscillator in the brain depends
on some contribution of the optic lobes for its ability to express circadian
rhythms and for entrainment by light. Confirmation of the findings of this study
would require modification of the generally accepted model (described below)
for control of insect circadian rhythms.
The existence of a circadian mechanism outside the optic lobes is also im-
plied by a recent report describing the persistence of a circadian rhythm of endo-
cuticular growth in bilobectomized cockroaches (BLabems fuscus) maintained
in constant conditions (222a). The rhythm is reported to persist after either
optic-lobe extirpation or decapitation, both of which should render activity
arrhythmic. Interpretation of these findings must await a more complete report
demonstrating the absence of all daily environmental cycles (including tempera-
ture and relative humidity) and the persistence of a cuticular growth rhythm
in lesioned animals whose activity is simultaneously shown to be arrhythmic.
rv) GENERAL COMMENTS. Evidence on the role of neural and neurosecretory
systems in rhythm generation has been summarized in a model (61, 62). It de-
scribes a relatively simple wiring diagram for rhythm generation that is heuristi-
cally useful, but may not reflect the full complexity of contributions by inter-
mediate neural levels to circadian organization (62, 320). The model includes
a pair of light-entrained oscillators in the optic lobes, proximal to the medulla,
whose output reaches the protocerebrum via the optic tracts. The efference
from the protocerebrum is by way of the CEC, whose activity disinhibits the
spontaneously active SEG; the resultant excitation is conveyed via the ventral
nerve cord to the thoracic ganglia to release locomotion and stridulation. The
model can now be elaborated to include interactions between the optic-lobe oscil-
lators that influence the rhythm’s period (284) and the possible existence of
(damped) neural oscillators outside the optic lobes (222a, 311).
The model adequately accounts for the data; however, reservations about
the interpretation of lesion studies in mammals (p. 486) apply here as well.
The meaning of correlations between neural damage and behavioral deficits is
not self-evident. Localized neural damage may modify the function of neural
tissue remote from the lesion site in ways that may not be anatomically obvious
(348). Additionally, loss of rhythmicity might result from damage to systems
that are not themselves oscillators, but whose function is crucial to rhythm
generation (269). Finally, specific functions may be wrongly ascribed to anatomi-
cally salient neuropiles or tracts in the vicinity of effective lesions; the correla-
tion between anatomical and functional prominence may not be perfect (61,362).
A further complication in these anatomical analyses is the difficulty of deducing
the presence and functional status of neurosecretory cells from histological
preparations (see p. 472; 62).
Appropriate description and analysis of results obtained in studies of insect
behavioral rhythms pose a second challenge. Some physiological interventions
oscillator is not in the optic lobes and the brain does not couple to the abdominal
effecters via neural connectives. These conclusions are different from those
reached in studies of dictyopteran and orthopteran locomotor and stridulatory
rhythms (see p. 475).
Implantation of the (proto)cerebral lobes exclusive of the optic lobes per-
mitted rhythmic gating of eclosion in brainless pupae, although the gate was
relatively broad. These and earlier results indicated an important role for the
neurosecretory cells of the PI; implantation into brainless pupae of a wedge
of tissue containing these cells did not induce substantial rhythmicity, however.
On the other hand, implantation of the remainder of the brain permitted only
random emergence (394). A hormone originating in median neurosecretory cells
of the PI appears to trigger the sequence of events leading to eclosion; the clock
and the photoreceptor for this rhythm seem to reside in the protocerebrum.
Transfer of the median neurosecretory cells unfortunately does not resolve the
question of whether the clock is also localized in these cells, because the absence
of induced rhythmicity may reflect the absence of a photoreceptor (located else-
where in the protocerebrum) or surgical trauma to the cells (394).
Do the differences between the silkmoth clock mechanism and the cockroach
and cricket clocks represent phyletic differences or difference between clocks
that control daily rhythms (locomotion, stridulation) and unique, gated events
(eclosion) (62, 393)? Truman’s (395) study of flight rhythms in giant silkmoths
provided a partial answer to this question. Section of the CEC, excision of
the brain, and implantation of the excised brain into the abdomen produced high
activity levels and arrhythmicity. Extirpation of the SEG or section of the
ventral nerve cord caudal to the SEG produced essentially inactive moths.
Clearly, locomotor rhythmicity depends on a neural, rather than a humoral,
link from brain to effecters, as is typical of other species.
Entrainment of activity in silkmoths depends on neither the eyes nor the
optic lobes. Unilateral excision of the brain and removal of the contralateral
optic lobe still permit normal entrainment. The photoreceptors for entrainment
and the rhythm generator are in the protocerebrum. Activity in the saturnid
moths, unlike activity in crickets and cockroaches, may be controlled by a proto-
cerebral clock that is directly sensitive to light, yet the coupling of brain to
thoracic effecters is not humoral, but neural, in both groups (395). The silkmoth
eclosion clock, while also localized in the protocerebrum (PI?) and directly
entrained by light, is linked hormonally to the abdominal ganglia (394).
3. Crustaceans
P. bouti& (12, 27), but a full report of these studies indicated that low-
amplitude ERG rhythms persisted even after excision of the entire brain (26).
An earlier report (287) indicated that the ERG rhythm of P. clarkii survived
CEC section but was eliminated by optic-tract interruptions or lesions in the
midline of the supraesophageal ganglion. The importance of distinguishing
generation of rhythms from responses to ambient illumination is emphasized
by the finding that the proximal eye pigment showed no circadian migration
rhythm in DD after optic-tract section, but still responded appropriately to LD
cycles (287). The circadian rhythm of lateral eye ERG in Limulus polyphemus
is also under the control of optic nerve efferents from the brain; section of the
nerves eliminated the rhythm (24).
Pigment-dispersal rhythms in chromatophores of autotomized legs re-
portedly persisted in ES-ablated Uca pugilator in LL (409); in Processa edulis
the pigment-dispersal rhythm persisted with low amplitude for one cycle in LD,
but not in DD (275). The critical significance of test procedures cannot be
overemphasized.
The strongest generalizations permitted by the data are offered in Arechiga’s
(11) recent review. He concluded that the brain is important for the genera-
tion of some rhythms and for the control of sinus-gland secretions that may
in turn coordinate rhythms throughout the body; there seem to be several
independent sites of rhythm generation in the crustacean body remote from the
brain. Particular rhythms are likely controlled at several levels, but the rela-
tions among these mechanisms and their precise loci have yet to be elucidated.
B. Vertebates
I. Suprachiasmatic nuclei
volume of about 0.05 mm3 (133, 318). The highest cell density is in the ventro-
medial portion of the nuclei; dorsally, laterally, and caudally a gradual decline
in cell density produces quite indistinct boundaries in these directions (133,318).
The somata of SCN cells have scant amounts of cytoplasm surrounding the
nucleus and few dendrites, each branching only once or twice (196, 255, 385);
the densely packed somata are not separated by glial wrapping, at least in the
mouse (413). Dendrites of ventrally situated cells tend to be oriented parallel
to the chiasm, whereas those of more dorsal cells tend to be oriented parallel
to the ventricle (318,385). In Golgi stained sections axons may be seen to leave
the nuclei dorsocaudally, bending into the periventricular region and coursing
caudally along the ventricle (196, 385; see below).
The SCN contain a broad array of synaptic types and various synaptic
vesicle sizes and types, probably representing a variety of neurotransmitters
(133, 134, 223, 379). Most synapses are Gray type II (GTII: symmetrical,
axodendritic); another large proportion are asymmetrical GTI (axodendritic).
According to current conceptions of synaptic structure-function relations, about
one-third of the synapses in the SCN should be excitatory and two-thirds in-
hibitory (133). There also are a considerable proportion of axosomatic synapses
(GTII) and a small percentage of dendrodendritic synapses in the ventral half
of the nuclei (133, 134). Guldner (133) estimates that up to 2% of synapses
are dendrodendritic; using his most conservative estimate of 300 synapses/
neuron, 1% of synapses in the SCN will still represent a substanti al number
(~6 x 104). Some of these dendrodendritic synapses apparently are formed
by fine collateral branches of dendrites that loop back to terminate on their
dendrites of origin; their function is unknown (134a).
In the ventral portion of the nuclei Giildner (133) describes a complex
consisting of synapses in close proximity, not separated by glial wrapping,
but surrounded overall by astroglial lamellae. The SCN neurons contain special-
ized me mbrane structures, described as stacked or folded cisternae of the endo-
plasmic reticulum and lyin g near the cell mem brane (133, 223). The function
of these structures is not known; they have also been described in the arcuate
nucleus (223). The dendrites and somata of the SCN cells in females contain
more multivesiculated bodies than do those of males (133). Additional informa-
tion about the gross and fine anatomy of the SCN is given by Krieg (196),
Szentagothai et al. (385), and Guldner (133); ultrastructural development of the
SCN is described by Lenn et al. (210).
The pattern of vascularization of the suprachiasmatic region may be signifi-
cant to studies of SCN function. Major blood vessels enter this region from the
anterior margin of the optic chiasm and course caudally; few vessels pass dorsally
through the chiasm into the region of the SCN (207). Knife cuts or lesions
anterior to the SCN therefore may interfere with their vascular supply;although
revascularization eventually may occur, irreversible tissue damage could
already have been produced.
II) AFFERENTS AND EFFERENTS. Three major afferent pathways to the
SCN have been described. One, a projection from the midbrain raphe nuclei,
accounts for the high levels of serotonin found in the SCN (2,122,336). A second
projection from the ventral lateral geniculate nuclei (VLGN) reaches the SCN
either via the medial lemniscus or via the optic tract; the projection is bilateral
but heaviest to the ipsilateral side (313, 384). The third.major projection origi-
nates in the retina and reaches the SCN via the optic nerves and chiasm (148,
255). This retinohypothalamic tract has been extensively described and dis-
cussed in recent reports. Unlike other projections and anatomical features of the
SCN that are known almost exclusively from studies of rats, the RHT has been
described in representative mammals from many orders (76, 99, 148, 247, 388,
389,390); a retinohypothalamic projection is found in all vertebrate classes (98).
The common features of the mammalian RHT include a bilateral projection
that rises out of the chiasm, entering the SCN from its ventrolateral aspect,
terminating preferentially in the ventral and caudal portions of the nuclei,
where it forms both GTI and GTII synapses (134b). Interestingly, the projec-
tions from the raphe nuclei and the VLGN also terminate in the ventral portion
of the SCN. Possibly these several inputs are represented in the multisynaptic
complexes that are also confined to the ventral portion of the SCN (133). There
are unequal projections from each eye to the ipsilateral and contralateral SCN,
the contralateral side receiving the heavier projection in all species studied
except the chimpanzee (247, 390).
The RHT generally has been described as consisting of fine, unmyelinated
fibers rising out of the chiasm through the ventral SCN (244, 251); however,
one report describes the fibers as “myelinated” (413), and another describes
caudally entering fibers as turning to run rostrally into the ventromedial SCN
(230). Some RHT fibers have been traced to a region just posterior to the SCN
in the rat (230, 318) and in the chimpanzee (390); these may innervate SCN
dendrites that extend caudal to the SCN border as defined by cell type and
density of somata (251). The RHT may be formed by fine collaterals that branch
in the chiasm from larger, myelinated ganglion cell axons that continue in the
classic optic tracts (231, 244).
The ventrolateral cells that receive the heaviest RHT projection are larger
than and structurally different from the small, densely packed medial cells.
The ventrolateral portion receives a heavy homogenous RHT projection as as-
sessed autoradiographically, whereas the medial portion receives a patchy input
suggestive of encapsulated synaptic complexes (224). The ventral portion of the
medial SCN is also the site of the multisynaptic complexes described by
Guldner (133).
Several other projections to the SCN have also been tentatively identified.
The medial corticohypothalamic tract may carry a projection from the hippo-
campus to the SCN (196; Field, cited in 133), and anterior hypothalamic cells
lateral to the SCN may project into it (318). In addition, a variety of midbrain
and limbic structures may project to the SCN via the stria terminalis and the
periventricular tract (196, 225, 266, 385), and SCN dendrites may receive a
brainstem noradrenergic projection that surrounds the SCN (251). Some of
these supposed projections have been identified only in preparations with re-
pathways whose plasticity has been documented (see 347); the plasticity of other
SCN afferents has not been studied.
Very little is known about the efferents of the SCN. The fine axons of SCN
neurons are difficult to follow in Golgi preparations; they are seen to take a dorso-
caudal, periventricular route but their terminations have not been identified
(196,385). The difficulty of producing a highly localized microinjection of labeled
precursor into the tiny, deep-lying SCN has limited the use of autoradiography
for tracing its efferents.
Swanson and Cowan (383) radioactively labeled a single suprachiasmatic
nucleus in one rat and trace d the efferent pathw rays. Al .l projections w ‘ere ipsilat-
era1 to the injection site; none were rostra1 to the nucleus. One projection
coursed medially along the periventricular tract, dorsocaudal to the nucleus;
a second traveled along the ventral aspect of the hypothalamus, passing ventro-
lateral to the ventromedial nucleus. The latter pathway projected to the capsular
zone surrounding the ventromedial, dorsomedial, and arcuate nuclei, and some
fibers appeared to reach the internal lamina of the median eminence. Some of
these projections may represent fibers of passage, since no evidence was pre-
sented for the actual termination of fibers in these areas. The intensity of label-
ing in fine, branching axons falls toward background levels, making the distal
portion of the projection difficult to delineate (383).
General features of this projection were confirmed with the use of a reduced-
silver stain for degenerating fibers after SCN ablation in the “woodmouse”
(Apodemus?) (110). However, Buijs et al. (68) presented preliminary evidence
for thin, vasopressin-containing fibers that project rostrally from the SCN into
the periventricular preoptic area. Portions of the caudal projections have also
been confirmed physiologically (194, 225); in one study approximately 15%
of 200 SCN neurons recorded from by glass micropipettes could be activated
antidromically by stimulation in the hypophysiotropic area near the arcuate and
ventromedial hypothalamic nuclei (343).
b) Physiology. Nishino and colleagues (272,273) have used a transpharyn-
geal approach to record the electrical activity of single neurons in the rat SCN.
Spontaneously active units fired at rates that ranged from <1 to 20 spikes/s in
recording sessions of several hours duration. The firing of a number of single
units oscillated spontaneously from low, irregular rates to high, sustained rates
with periods in the range of 3-5 min. Single electrical pulses delivered to the
optic nerves did not influence the spontaneous activity of SCN neurons; the
optimal rate of optic n.erve stimulation was 5-10/s, and even then the latencies
of the units’ responses were considerabl .e. These results provide strong evidence
that small-caliber, unmyelinated fibers in the optic nerves form the retinal
projection to the SCN.
Optic nerve stimulation excited 40% of the units tested and inhibited 24%;
neurons lying as little as 150 pm apart could be oppositely affected by identical
stimulation parameters (273). Sawaki (343) reported that, although single pulses
delivered to the optic nerves affected few SCN units, trains of pulses at a rate
of about l/s were more effective. The majority of responsive units were excited
by the stim ulation regardless of whether it was delivered to the ipsilateral or
contralateral optic nerve (343). Light flashes to the eyes could also either increase
or decrease firing rates of SCN units, and again most units were excited by the
stimulation (273, 343).
Other studies with light stimulation of the eyes have confirmed that SCN
units have a high response threshold, show long latencies, and are more fre-
quently excited (37%) than inhibited (20%) by light (132a, 215a). It is not clear
whether the long latencies represent slow transmission in the RHT or a poly-
synaptic input reaching the SCN via a POT-VLGN-SCN circuit (334). Several
rats with LGN lesions were tested for SCN responses to light; nearly 60% of
cells recorded from intact rats responded to light, whereas less than 10% were
responsive in LGN-lesioned rats (132a). Two possible explanations for this loss
of responsiveness are that responses to light may in fact be mediated in large
part by a VLGN-SCN projection or that LGN lesions may cause degeneration
of axons forming the POT and of the fine collaterals to these main trunks that
form the RHT (see 231, 244). The condition of the RHT after LGN ablation
has not been described.
A few reports describe the effects of neurotransmitter application on SCN
activity. Both spontaneous and glutamate-induced electrical activity were de-
pressed after iontophoretic application of serotonin to neurons of the cat SCN.
Electrical stimulation of the median raphe also inhibited SCN neural activity (53).
Nishino and Koizumi (272) found that the majority of units tested were in-
hibited by the application of monoamines, with serotonin being more effective
than norepinephrine or dopamine; most cells were also excited by acetylcholine
and to a lesser extent by glutamate. Units that were excited by optic nerve
stimulation were generally more sensitive to the inhibitory effects of mono-
amines than were those inhibited by such stimulation.
The influence of neural activity in the SCN on the activity of other parts
of the nervous system has also been studied; electrical stimulation of the SCN
at high rates (20/s) produced strong inhibition of neural activity in the superior
cervical trunks (which innervate the pineal gland), whereas lower rates of
stimulation were less effective (273). Stimulation of the SCN at high rates also
inhibited spontaneous activity of lateral hypothalamic cells. Stimulation at a
lower rate did not inhibit firing of such units but did reduce the frequency with
which they oscillated spontaneously between low and high rates (191).
These studies establish the existence of connections between the SCN and
other neural structures; interpretations of the functional nature of these connec-
tions, based on such neurophysiological data, must be tentative. First, only
SCN neurons that are spontaneously active under particular experimental con-
ditions (e.g., urethan anesthesia) have so far been studied. It is not known
whether these neurons are typical of the SCN or constitute a functionally
distinct subset of the entire population. Second, the spontaneous activity of
neurons elsewhere in the mammalian nervous system varies systematically with
time of day (25, 169, 191, 346); in addition, the responsiveness of neural tissue
to various stimuli changes with time of day (191, 227, 346). Circadian rhythms
of spontaneous activity and responsiveness of SCN neurons have yet to be de-
scribed, but they very likely exist and modify the responses obtained under
particular recording conditions. In most studies the circadian phase at which
SCN neurons were studied was not reported.
Finally, the responsiveness of SCN neurons to stimuli such as light may
vary with other experimental conditions, including: the state of adaptation of
the eye, the phase of the neuron in its short-period oscillation in firing rate (191),
and the nature and duration of the test. The last condition might be especially
important; a system involved in the control of circadian rhythms might be
expected to respond differently to brief light flashes and to extended light inter-
ruptions at various circadian phases. Therefore, it remains an open question
whether the effects of light as an entraining agent acting on the SCN parallel the
effects of light on SCN neurons as so far described neurophysiologically. Con-
siderable work will be required to provide even partial answers to the questions
raised by these investigations.
Because the suprachiasmatic region has been implicated in the regulation
of reproduction (see below), there has been considerable interest in establishing
whether the SCN contain neurosecretory neurons. The identification of SCN
projections into the hypophysiotropic area and the median eminence of rats
(194, 343, 383) suggests a role for the SCN in reproduction but does not itself
imply neurosecretory activity in SCN neurons. Studies of female rabbits (reflex
ovulators) indicated an elaboration of neurosecretory material in some SCN
neurons after copulation (81). The only class of neurons that responded to the
copulation-derived stimuli was found near capillaries; in their active state these
neurons resembled classic neurosecretory units (magnocellular neurons with
active Golgi apparatus and dense-core vesicles). Ovariectomy of rabbits also
resulted in anatomical signs of increased activity of SCN neurons that may
represent the synthesis of gonadotropin-releasing hormone (80).
In male rats only a few scattered cells, also near capillaries, were Gomori
positive and neurosecretory; such cells, located peripherally in the SCN, were
also found scattered throughout the anterior hypothalamic region (223). The
parvicellular units comprising most of the SCN proper did not appear to be
neurosecretory and showed little or no response to either long-term castration
or colchicine treatment. The authors concluded that only the magnocellular units
were likely to secrete luteinizing hormone-releasing hormone (LHRH) and that
the role of the parvicellular units of the SCN in LHRH control must be indirect
(223). Other studies with immunohistological methods have also demonstrated
LHRH-containing neurons in the SCN of guinea pigs (28, 353) and female rats
(353). The SCN of the albino mouse has been described as made up of “secretory
neurons of the peptidergic type” (413).
There is other evidence for neurosecretion by SCN cells; vasopressin and
its carrier neurophysin have been localized in the rat and mouse SCN (68, 382,
405, 406, 422). There was great variability in the number of neurophysin-
containing cells in one study; single 5-pm sections through the SCN contained
used were appropriate only to determine that the dependent variable was not
normally rhythmic. This restricted view of the consequence of lesions, combined
with a limited assessment of neural damage, can generate misleading structure-
function correlations predicated on inadequate descriptions of both the struc-
tural and functional changes produced. These cautions should be considered in
evaluating the results and conclusions summarized below.
I) ADRENAL CORTICOSTERONE.Corticosterone levels in the blood of groups
of laboratory rats sacrificed at intervals throughout an LD cycle peak near the
time of the L + D transition; in blinded rats the corticosterone rhythm appears
to free-run with a constant phase relation to the activity cycle (124). This daily
rise in corticosterone release can be eliminated by knife cuts posterior to the
chiasm (and SCN) but not anterior to the SCN (5,132,252). Electrolytic lesions
centered on the SCN have effects similar to those of postchiasmatic cuts (198,
252, 304). Several possible effects of the lesions could produce such results:
1) The corticosterone peak could be phase-shifted; it may occur at unpredictable
phases in each rat or it may be shifted in all rats to a phase that is not sampled
by the experimental proced ure. 2) Entrainment might be lost so that cortico-
sterone peaks free-run with circadian periods that are obscured bY the grouped
data. 8) Entrainment might be lost so that the rhythm free-runs with a non-
circadian period. 4) Corticosterone might be secreted randomly or at a steady
low rate in all rats.
Support for hypothesis 3 is provided by Wilson and Critchlow (416); a knife
was used to separate the medial-basal hypothalamus from the chiasmatic region,
and repeated blood samples were taken from the tail veins of individual rats
at 4-h intervals for 44 consec utive hours . When corticosterone values were
grouped for each phase a flat CWV ‘e was generated at an intermediate level
of corticosterone. However, only one rat showed a flat individual curve over 44 h;
others produced excursions of corticosterone levels that were as great as those
found in controls. The conclusion (416) that individual rats do not show a free-
running circadian rhythm of corticosterone secretion is premature given that
the observation period was brief (by circadian standards) and that lesioned
animals were maintained in an LD cycle. Individual records showed single or
multiple daily peaks of corticosterone secretion that are consistent with free-
running ultradian rhythms or even with free-running circadian rhythms ob-
scured by exogenous effects associated with the LD cycle.
A second study (95, 96) also used tail-vein sampling Tom SCN-lesioned
rats at 4-h intervals over 24. or 36-h periods. Again, excursions in cortico-
sterone levels of normal amplitude were reported, and these were described
as “asynchronous and devoid of circadian rhythmicity.” However, it still re-
mains possible that these rats under constant conditions would show free-
running circadian or ultradian rhythms or randomly timed peaks. These alterna-
tive hypotheses can only be discriminated by further improvement in measure-
ment techniques and by the application of appropriate descriptive and inferential
statistics to the data.
There is no firm evidence for an exogenous “masking’ effect of the LD cycle
adequately assessed the correlation between behavioral effects and the physio-
logical and anatomical sequelae of the lesions (cf. 348). The degree of “nocturnal-
ity” that survives SCN destruction does not itself provide any evidence for a
role for the SCN in generating circadian rhythms; only continuous, long-term
recordings in constant conditions can provide adequate evidence on this point.
The original report of the effects of SCN lesions on wheel-running activity
rhythms of rats described a reduction of total activity and a redistribution of
activity throughout the LD cycle (370). The loss of nocturnality has since been
confirmed in other studies in which the SCN of rats were destroyed or isolated
(132, 304, 367), but no further assessment has been attempted of the nature
of the changes in activity rhythms produced by SCN destruction.
Parallel studies in golden hamsters that have included several months of ac-
tivity recording in constant conditions (dim LL) after SCN lesions have yielded
some similar results and some that differ considerably from those obtained with
rats. Some hamsters with complete or near-complete lesions of the SCN distrib-
uted their wheel-running in brief bursts throughout the day; power spectral anal-
ysis revealed no significant periodicities in the data. Other hamsters produced very
noisy activity records that contained significant ultradian periodicities (ca. 8- and
12-h rhythms) as established by power spectral analysis. Still other lesioned
hamsters generated ultradian rhythms that were easily detected both by eye
and by statistical methods (330, 331). Another report has described SCN-
lesioned hamsters as “arrhythmic” under constant conditions; this assessment
was based on visual inspection of records and was not supported by any further
analysis. The assessment is also not well supported by the two published activity
records from this study (373).
It is agreed that normal circadian rhythms of activity do not occur in rats
or hamsters after SCN lesions, but it does not follow that such animals are
“arrhythmic.” In fact, many lesioned hamsters generate very prominent
ultradian rhythms that may provide clues to the normal function of the SCN.
In some cases ultradian rhythms develop out of the dissociation of previously
coupled rhythmic elements. The normal function of the SCN may be to provide
an internal source of integration for a variety of rhythmic components; apparent
“arrhythmicity” may be the result of a complete dissociation of these elements,
whereas ultradian rhythms may reflect partial dissociation and perhaps mutual
coupling among components. Conditions that permit the expression of ultradian
rhythms or of arrhythmicity are not known; perhaps very large lesions that
damage regions adjacent to the SCN are conducive to arrhythmicity. In one
study the quality of entrainment surviving SCN destruction correlated posi-
tively with the degree of preservation of tissue at the anterior SCN-preoptic
suprachiasmatic (POSC) border (330, 331). The largest lesions destroyed both
the POSC and the SCN regions; these produced some of the most severe disrup-
tions of entrainment and rhythmicity. The involvement in rhythm generation
of the suprachiasmatic region immediately adjacent to the SCN proper deserves
further study (see p. 502).
Neural control of circadian organization may vary between rats and hamsters,
but since published studies are not strictly comparable this question must await
clarification. The possibility that detailed, long-term studies will yield similar
results across species is reinforeed by several recent reports. One described
8-h activity rhythms in mice (A&s muscuZus) after SCN destruction (403).
Other reports have described ultradian rhythms in several behaviors after SCN
lesions in rats (see below). Finally, one study has found circa 8- and 12-h
rhythms in wheel-running activity as well as other behaviors in SCN-lesioned
rats (387a).
IV) SLEEP CYCLES. The sleep-wakefulness cycle of nocturnal rodents can
be described as a sequence of episodes of waking, slow-wave sleep (SWS),
and paradoxical sleep (PS) that is repeated throughout the day, but with more
sleep episodes occurring in L and more waking occurring in D periods. This
pattern may be partly under exogenous control (“masking”) since D periods
can trigger PS episodes (218) whereas L periods may suppress PS (115). Never-
theless, there apparently is a true circadian rhythm in the distribution of sleep
episodes that persists under constant conditions (97a, 245).
The effects of SCN manipulations on sleep cycles have been studied in rats
entrained to LD cycles, with results not completely consistent across studies.
The L-versus-D difference in total sleep time was abolished immediately after
SCN ablation (156). Blinded rats developed an apparently free-running sleep
waking cycle that retained normal internal sleep structure; total sleep time and
relative proportions of sleep stages were both normal in blinded and in lesioned
rats. This last point was also made by Coindet et al. (84), who reported that PS
was distributed evenly in L and D periods after an SCN lesion. In their study
SWS remained concentrated in L after SCN lesions, although the L:D sleep
ratio was reduced compared with control levels. Interpretation of these findings
is difficult because results for SCN-lesioned rats were pooled on the grounds
that they were all “in phase”; the meaning of that phrase is not made clear.
Stephan and Nunez (367) attempted to isolate the SCN using a “core knife”
that produced considerable damage to many parts of the brain; interpretation is
difficult because control recordings yielded unusual sleep cycles (apparently
because of inadequate adaptation to the recording apparatus). In lesioned rats
the L:D distribution of sleep approached 50%, but 3 of 6 lesioned rats clearly
concentrated PS in the D phase. Whether this residual PS rhythm or the residual
SWS rhythm (84) is endogenous or imposed by the LD cycle has not been
established.
Another study recorded sleep cycles of female rats for 8-10 days in LD
14:lO after SCN lesions. The sleep records showed a flat distribution of SWS
across the LD cycle, but PS seemed to peak late in the ,L phase. A larger
anterior hypothalamic lesion that destroyed the SCN flattened both rhythms
in a single rat; no statistical analyses of the data were presented (419a).
Interestingly, lesions in other neural structures often produced sharp peaks
of PS in the D phase (419a); the extensive neural damage caused by the “core
knife” used in the study by Stephan and Nunez (367) also resulted in PS con-
centration in the D phase in some rats. However, the many procedural and
during their inactive phases; the consequences of these stimuli persist and are
acted on in the succeeding active phase.
Free runs in eating and drinking rhythms in LL were documented for some
recovered LHA rats and occurred as well in blind LHA rats (327). The
redistribution of behavior to the D phase thus is not due to destruction of a
circadian alimentation clock. Nor is changed sensitivity to light a plausible
explanation, since redistribution of behavior to the active phase occurs in
peripherally enucleated rats with LHA damage (328). The most likely conclusion
is that postdeprivation food and water intakes and responsiveness to injected
NaCl are “modulated according to the phase of an endogenous oscillator” (328).
What remains to be discovered is the nature of the change induced by the lesions
that can alter the influence of the circadian system and decrease plasticity of
regulated behaviors.
b) Ventromedial and dorsomedial hypothalamus. Rats fed ad libitum gain
weight during D, lose weight during L, and undergo D- and L-phase cycles
of lipogenesis and lipolysis (173, 205). Damage to the VMH reverses the die1
weight rhythms and interferes with the lipogenesis-lipolysis cycle (173, 205).
The nocturnal drinking rhythm of rats is attenuated but not eliminated
by VMH damage (125, 173). A nearly equal distribution of food intake is re-
corded in the L and D phases after VMH damage (42, 173); this contrasts with
the robust nocturnal feeding observed in neurologically intact rats (425).
Integrity of the VMH may be required for the expression of the die1 feeding
rhythm. It is highly unlikely that the disturbances are in any way directly
related to impaired entrainment to the LD cycle. Hyperinsulinemia and pe-
ripheral metabolic changes consequent to VMH destruction (120, 205) most
likely override the normal circadian organization and entrainment of feeding.
In addition VMH lesions may interrupt critical SCN efferents to motor systems
involved in feeding.
Lesions of the dorsomedial hypothalamus also attenuate the nocturnal
feeding rhythms of rats (42). Both VMH and DMH damage eliminate diurnal
fluctuations in plasma corticosterone concentrations (35). The lack of multiple
sampling from individual animals and the possibility of free runs in hormone
secretion during exposure to the LD cycle are recognized by several authors
as procedural shortcomings (e.g., 35); in these studies, rhythm elimination
might also reflect interruption of SCN efferents (381, 383).
c) Miscellaneous structures. Slusher (359) was among the first to report
elimination of diurnal differences in rat plasma corticosterone levels after
hypothalamic damage; her effective lesions were in the anterior periventricular
zone and appeared to include the SCN or its immediately caudal efferents.
Damage to the fornix was originally thought to eliminate the rat die1 cortico-
sterone rhythm (246), but subsequent work demonstrated that the effect was
transitory and normal entrainment was recovered by the third postoperative
week (206). Fornix transection, hippocampal ablation, and destruction of the
septal nuclei each allows retention of the entrained corticosterone rhythm
in individual lesioned animals (416, 417). The septum and fornix cannot be the
source of the anterior connections to the medial basal hypothalamus necessary
for the expression of entrained corticosterone cycles in rats, although the fornix
may play a more significant role in primates (113, 232).
Corticosterone content of the rat preoptic area, hippocampus, mesencepha-
lon, amygdala, and anterior pituitary undergoes die1 variation similar to that
of plasma corticosterone (208). Hypothalamic corticosterone content also varies
rhythmically with peaks and troughs out of phase with those of the plasma and
of the other brain regions measured. Frontal deafferentation eliminates the
rhythms in corticosterone content of the hypothalamus and preoptic area (208).
Allen and Allen (4) report an absence of plasma corticosterone rhythms after
transection at T3 of the rat spinal cord. This surprising finding may reflect
nonspecific postsurgical trauma rather than involvement of the spinal cord
in entrainment or mediation of adrenal corticosterone secretion.
The midbrain raphe nuclei are sites of serotonin-containing perikarya that
project to the SCN (2) and presumably are responsible for these nuclei having
high serotonin concentrations (122, 336). Raphe lesions substantially reduce
forebrain (including SCN) serotonin content (193, 199, 222). A transitory de-
crease in the L:D ratio of locomotor activity was observed after dorsal or com-
bined dorsal and medial lesions of the raphe nuclei (178). Block and Zucker (52)
also noted that an increased proportion of daily wheel running occurred during
the L phase in LD 12:12 after damage to these nuclei. The lesions were less
effective in interfering with the normal L:D distribution of drinking behavior (52)
and also failed to alter the rhythm of pineal NAT activity (254) or of adrenal
corticosterone (326). The assessment of reentrainment of wheel-running activity
after a phase shift in the photoperiod was complicated by the loss of a well-defined,
stable, phase-reference point after raphe damage (52). Clearly raphe lesions
neither eliminate nor drastically impair steady-state entrainment and phase
shifting of several CRs. It is less certain whether this type of neural damage
affects more subtle parameters of circadian organization and entrainment.
In constant dim light, raphe-lesioned rats were more active at all phases than
controls but still generated free-running circadian rhythms with periods com-
parable to those of control rats (52). Large reductions in forebrain serotonin
and the elimination of the raphe projection to the SCN are therefore consistent
with the generation and expression of CRs; such evidence supports the claim
that the SCN constitute an endogenous neural oscillator.
Removal of the superior cervical ganglion (SCG) eliminates entrained
rhythms in pineal NAT and serotonin. This is a consequence of pineal denerva-
tion and is not attributable to interference with visual pathways for entrain-
ment (250). The behavior of the rat feeding rhythm after SCG removal is less
readily explained in terms of pineal denervation, since SCG ablation but not
pinealectomy retards the rate of phase shifting from an LL free run to entrain-
ment to an LD cycle (30). Baum (30) suggests that postganglionic fibers from
the SCG modify neural activity in hypothalamic regions that synchronize
the feeding rhythm. The paradigm used in this study (shifts from LL to LD)
permits only the most tentative conclusions since the animals’ circadian phases
were not equated in the experimental and control groups at the time the LD
cycle was imposed.
d) NewaL rhythms. We have emphasized the role of neural structures
in regulation of CRs and have neglected the many neural parameters that
themselves undergo diurnal fluctuations. The list of CNS rhythms is long and
growing rapidly. Ziegler and co-workers (421) cite studies showing anterior and
lateral hypothalamic, spinal cord, midbrain, caudate, brainstem, and frontal
cortex variations in norepinephrine content and report a diurnal rhythm of
norepinephrine in monkey cerebrospinal fluid. Significant diurnal variations in
serotonin occur in the amygdala and midbrain of rats (358) and in the telencepha-
lon of hamsters, gerbils, and guinea pigs (292). Many rat brain regions show
cyclic fluctuations in dopamine content (358).
These many rhythms tell us little about the neural bases for circadian
rhythms. They represent additional parameters that may facilitate study of
neural regulatory mechanisms for CRs. As such they have various drawbacks;
they are less easily quantified than any of a number of behavioral variables
and do not lend themselves to long-term study in individual animals. The vast
majority of these rhythms must reflect oscillations in remotely located neural
pacemakers and are not likely to be part of the basic oscillatory network.
Various neural structures generate rhythms of spontaneous electrical
activity and of responsiveness to neural input. The lateral hypothalamus is a
particularly well-explored area: single neurons in the rat LHA cycle spon-
taneously over several minutes from low to high firing rates; stimulation of
other neural structures may change the firing rate, eliminate the oscillation,
or simply slow the oscillation without changing the mean firing rate (191).
Neurons in the LHA also show longer period fluctuations in activity (346);
single units respond with opposite sign to identical stimulation of the splanchnic
nerve at different phases of the daily cycle (191). Another study demonstrated
either increases or decreases in food intake of rats depending on the time of day
at which norepinephrine was injected into the LHA (227).
Such examples could be multiplied; they raise intriguing questions about
the kinds of information conveyed by cycles of neural activity to other portions
of the nervous system. If the instantaneous firing rate carries information in the
nervous system, how do ultradian and circadian changes in spontaneous firing
rate (346), chemical sensitivity (227), and synaptic efficacy (25) influence infor-
mation transmission? These interesting observations do not bear on the issue of
rhythm generation, however, unless the observed rhythms can be shown to
persist in isolation or to be significant to generation of circadian rhythms else-
where. In one study, isolating a hypothalamic island, including the SCN, from
the rest of the brain eliminated circadian rhythms of multiple-unit activity in
several brain regions; rhythms within the hypothalamic island survived the
operation (180b). It will be important to determine if rhythms in other parts
of the hypothalamus persist after separation from the SCN.
and they can influence rhythm amplitude and sensitivity to other stimuli (236).
The presence of corticosterone, for example, can determine physiological and
behavioral responses to prolactin in all major vertebrate classes (236). The most
striking example is the phase relation between corticosterone and prolactin as
a determinant of the onset of gonadal development, migratory restlessness,
and direction of migratory flight in Zonotrichia a&co2Eis (236). In adrenalec-
tomized monkeys cortisol entrains the urinary K+-excretion rhythm without
changing feeding rhythms (258). Since the LD cycle ordinarily entrains corticoid
rhythms in humans and other animals (236), it ultimately entrains most if not all
bodily rhythms in complex multicellulars. As noted by Scharrer (345), this is a
parsimonious solution to a potentially difficult problem of synchronization of
many oscillators with different or even identical xeitgebers.
4. Pineal gland
by these findings is that the pineal drives remotely based CRs through hormonal
rather than neural channels (240,306). Implants of melatonin, a putative pineal
hormone, produce arrhythmicity or significant changes in 7 in the Passer loco-
motor rhythm (397), ftiher implying a hormonal link between the pineal and
other oscillators.
The role of the pineal as an avian clock is brought into question by the ob-
servation by Rutledge and Angle (335) of normal free-running circadian organi-
zation in the perch hopping of Sturnus vulgaris recorded 6 mo after pinealec-
tomy. Histological confirmation of the total absence of pineal tissue is claimed;
if this can be confirmed, it would establish that the pineal is not the oscillator
in this species.
The preliminary report of a disruption in the Passer locomotor rhythm
after lesions in the vicinity of the SCN (386) creates some problems for a pineal-
clock hypothesis, although the pineal could still function as a driving oscillator
whose coupling with driven oscillators is mediated by the hypothalamus. This is
plausible because the SCN and other parts of the hypothalamus are prime
target tissues for melatonin of pineal origin (306). Rhythms in melatonin secre-
tion (306) may entrain nervous structures to generate a variety of bird CRs.
b) Reptiles. Removal of the pineal and parietal eyes of the lizard SC-
ohvaceus exposed to LL produced large changes in 7 in about half the animals,
arrhythmicity in most of the remaining animals, and, in a single animal, splitting
of the activity rhythm into two components with different 7 values (400).
Pinealectomy and not parietalectomy appears responsible for these effects. The
persistence of circadian rhythmicity in pinealectomized lizards housed in DD
(400) argues against the view that the pineal is a master oscillator; however,
Underwood’s study (400) supports the more conservative claim that the pineal
is a coupling device or part of the effector apparatus for circadian rhythmicity.
c) Mammals. The pineal functions as a neuroendocrine transducer, con-
verting neural into hormonal signals; it receives neural input from superior
cervical postganglionic fibers that terminate in the proximity of pinealocyte
processes (250). After superior cervical ganglionectomy pineal rhythms are
abolished, including the L:D variation in the number of granulated pinealocytes
(37). Transection of the human spinal cord above C8 eliminates diurnal variations
in melatonin excretion (185) and pineal rhythms can also be abolished by a variety
of surgical procedures within the CNS, each probably the equivalent of a central
sympathectomy (250, 340). These arrhythmicities, far from establishing the
pineal as a clock, suggest that its secretory rhythms are dependent on periodic
input originating elsewhere.
Although the pineals of a number of mammalian species exhibit CRs (329)
in no instance has pineal removal interfered with normal circadian organization.
The pineal does not function as a master circadian clock in the few mammals
where this proposition has been tested (303). The pronounced effects of the
pineal on reproductive rhythms of photoperiodic mammals are more readily
attributable to pineal antigonadal activity (309) than to pineal-induced changes
in circadian organization.
I. General features
Welsh (411) speculated in 1938 that “the same internal mechanism which
is responsible for maintaining, in the rat, an estrous cycle of definite dura-
tion . . . may be, in part responsible for the maintenance of 24 h cycles of
muscular activity.” Observations by Everett and Sawyer (109) also suggested
that a neural signal generated at circadian intervals is essential to ovulation.
Drugs injected during a critical period, which in individual rats is as short as
30-45 min daily (130), delay ovulation by 24 h. The positioning of the daily
critical period is completely controlled by the LD cycle, further implicating the
circadian system (7).
Exposure to LL lengthens the period of the A&s musculus estrous cycle (74)
and shortens cycle length in the baboon Papio cynocephalus (137). Although
free runs were not established for these species, the findings are in accord with
the circadian rule for nocturnal and diurnal species, respectively, and provide
circumstantial evidence for clock control of estrous and menstrual cycles,
Alleva et al. (6) first demonstrated that a mammalian estrous cycle is regu-
lated by a biological clock. Hamsters exposed to an LD 16:8 photoperiod had
estrous cycles with 7 = 96 h; in LL the onset of heat free-ran with 7 significantly
greater than 96 h. The latter finding has been replicated with hamsters main-
tained in constant dim illumination (116).
More recent work has definitively established a circadian link to the hamster
estrous cycle. The period of the estrous cycle under free-running conditions
is four times the period of the concurrently recorded circadian activity rhythm.
Disruptions of the circadian system produced by exposing the animal to LL
invariably also interfere with normal estrous cycles (116). These findings compel
one of two conclusions: either the hamster estrous cycle is subject to regulation
by the same circadian clock that times the activity rhythm or the two rhythms
are generated by separate but closely coupled oscillators.
Fitzgerald and Zucker (116) suggest that the stimulus for the ovulatory
surge of gonadotropins in this species is generated by a circadian system that
includes the SCN. Evaluation of this hypothesis is dif%ult because the estrous
cycle is dependent on many variables involving different levels of organization,
some entirely unrelated to biological clocks. Interpretation of findings involving
brain lesions, the main source of relevant data, is hazardous because of the
compactness, close proximity, and overlap of the neural systems that 1) manu-
facture gonadotropin-releasing hormones (GnRH), 2) generate circadian
rhythms, and 3) serve as target tissues for positive-feedback effects of ovarian)
steroids. Because of notable species differences we consider the involvement
of the SCN separately for each of several mammals. A complete catalogue of
relevant studies is beyond the scope of this review; our bias has been to cite
recently published reports that contain references to the older literature.
3. Neural substrates
The most meaningful data are the concentrations of releasing hormones in the
portal vasculature during the stages of the estrous cycle. The dynamic methods
of assessing LHRH content currently in use often yield inconsistent or contra-
dictory information. For example, despite very substantial elevation of serum
LH in OVX rats and the greater LH-releasing activity in their portal plasma,
Eskay et al. (103) failed to observe an increase in LHRH concentration in portal
plasma of long-term OVX rats. Some of these discrepancies may reflect sam-
pling difficulties (failure to detect temporally restricted LHRH surges) and others
surely are due to the conditions under which blood sampling is accomplished
(surgical trauma and long-term deep anesthesia). The single most germane
observation is that of Sarkar et al. (341), who report a proestrous LHRH
surge in portal blood of rats. The anesthetic used in their study blocks neither
the spontaneous LH surge nor ovulation; nor does it stimulate LH release.
These data indicate that the LH surge begins shortly after the GnRH surge
is detectable in portal plasma and suggest that LH surges are at least in part
dependent on estrogen-stimulation of LHRH release.
Luteinizing hormone-releasing hormone has been localized in the organum
vasculosum lamina terminalis (OVLT), in the median eminence, and in other
hypothalamic nuclei (see 66, 101, 186). The OVLT is a circumventricular organ
present at the most rostra1 part of the third ventricle in the rat (see 410).
Its medium-sized neurons with neuropile richly vascularized by a capillary
plexus are surrounded by catecholaminergic neurons in the immediately adja-
cent periventricular nucleus and in the diagonal-band nucleus (249). Lesions
restricted to the OVLT (339), which presumably do not disturb general circadian
organization, completely block the estrogen-plus-progesterone-induced FSH
and LH surges. Samson and McCann (339) suggest that rostra1 LHRH-
containing elements are necessary for the positive-feedback effects of steroids
on LH release and that axonal transport of LHRH from the OVLT to the median
eminence (ME) constitutes a significant portion of ME LHRH. Anterior
hypothalamic deafferentation either through or caudal to the SCN decreases
LHRH content of the medial basal hypothalamus and increases LHRH content
in the POA (176). Perikarya containing LHRH have also been localized to the
SCN region (66,353). S&al6 et al. (353) suggest that LHRH in the ME originates
from cells within the SCN. This hypothesis is not consistent with the small
decreases in ME LHRH after SCN lesions (175), nor with the report that
LHRH was not detectable in the SCN of females killed on the morning of
proestrus (189). Very few LHRH-positive nerve fibers are found within hypo-
thalamic islands after complete MBH isolation; the arcuate nucleus of deaffer-
ented animals has no positive-staining LHRH cells (353). It appears likely that
rhythmic release of LHRH is eliminated in deafferented animals and that the
amount of LHRH reaching the portal vasculature is greatly reduced after
lesions that interfere with the OVLT and perhaps other rostra1 hypothalamic
structures. The LHRH of rostra1 hypothalamic origin denied access to the portal
system may be secreted into the general circulation; its dilution in the plasma
would diminish or eliminate its significance for LH release. This sequence
of events could account for the discrepancy between normal serum LHRH
levels and depressed serum LH and FSH levels (176).
IV) INFLUENCE OF ESTROGENS.Estrogen treatments that induce diurnal
surges of serum FSH and LH have no significant effect on preoptic-region
GnRH content of control or hypothalamically deafferented rats (176). This
should not be interpreted to mean that gonadotropin surges do not reflect
differences in GnRH release induced by estradiol. There are marked regional
brain differences in LHRH responsiveness to estradiol (189), the OVLT being
insensitive and the ME sensitive to manipulation of estrogen levels (176, 189).
Other data (341) also imply that estrogens increase the release of GnRH.
Estradiol benzoate decreases the amount of serum LHRH and increases the
amount of this hormone in the MBH of brain-damaged and control animals (176).
Since the MBH is the final common pathway for LHRH transportto the pituitary
this may reflect estrogen-stimulated increases in releasing-hormone concentra-
tions in the portal vasculature. Additional evidence suggests that rhythmic
LHRH release can account for LH surges: pulsatile LHRH infusion produces
pulsatile LH release in OVX rats not treated with estrogens, whereas constant
LHRH infusion leads to a steady increase in plasma LH devoid of pulsatile
characteristics (349).
Pituitary responsiveness to LHRH is greatly augmented by ovarian hor-
mones (85,203). There is a 50-fold increase in rat pituitary sensitivity to LHRH
during proestrus, measured by the amount of LH release. Ovariectomy on the.
day preceding proestrus (diestrus III) abolishes this effect (203). Similar results
have been obtained in vitro; preincubation of a primary culture of rat adeno-
hypophyseal cells with estradiol substantially decreased the concentration of
LHRH required for stimulation of LH release. This effect was detectable after
10 h and maximal after 24 h of incubation. Luteinizing hormone-releasing hor-
mone also induced responses in culture in the complete absence of estradiol
and the maximal LH response to LHRH was not increased by estrogen
treatment (93).
Given in a sequence of two injections spaced 1 h apart, LHRH greatly
increased LH secretion at proestrus; by comparison LH output was only slightly
augmented at other stages of the estrous cycle (75). Evidently in the presence
of estrogen conditioning LHRH sensitized the pituitary to subsequent LHRH
treatment (3, 75). This massive pituitary sensitization to LHRH permits the
modest proestrous increase in GnRH concentration in portal plasma to pro-
duce the LH surge (341).
Single injections of EB produce multiple LH surges at approximately 24-h
intervals in OVX rats in several different photoperiods (202). Only a single
surge is observed during a normal estrous cycle, in part because.progesterone
inhibits estradiol-stimulated LH release (119). Under physiological conditions
increased progesterone secretion that accompanies the LH surge likely pre-
vents subsequent surges until a new cohort of follicles has developed sufficient
estrogenic capabili .ty (11.9). The patterning and amoun .ts of estrad .iol secreted
during the normal cycle also may impose li .mits on the number of surges.
information
FIG. 1. Features of the system for the circadian timing of the rat estrous cycle. 1) Light-dark
information is relayed via the retinohypothalamic tract to the SCN where it entrains circadian
oscillators. 2) Neurons of the SCN generate circadian rhythms. Projections from the SCN to the
median eminence (383) and probably to the arcuate nucleus (262) impose circadian rhythmicity
on cellular activities of these neural structures. A neurogenic stimulus, generated by the SCN
on a circadian basis, determines the time of release of LHRH (and other releasing hormones)
from the median eminence into the primary capillary plexus of the hypophyseal portal system.
Because it drives many circadian oscillations, the SCN also mediates the diurnal rhy thm of estradiol
secretion (177, 268). 3) Estradiol (E2) acts via negative-feedback mechanisms on the medial basal
hypothalamus-median eminence complex to inhibit LH release. 4) Subsequently E, increases the
release of ME LHRH into the portal vasculature (341) and sensitizes the pituitary to LHRH
(85, 203). The temporal coordination of a) increased LHRH release, b) increased pituitary sensi-
tivity to LHRH, and c) LHRH sensitization of pituitary to subsequent LHRH release (3, 75)
depends on periodic influences from the SCN. Together these events produce the LH surge.
5) Ovarian progesterone fist enhances the estrogen-induced surge but then inhibits the LH release
apparatus*( 119) and restricts the LH surge to 1 day of the cycle. Insufficient estrogenic conditioning
of neural and hypophyseal tissue also prevents transduction of the daily SCN signal into daily LH
surges. AC, anterior commissure; AH, anterior hypothalamic area; AP, anterior pituitary; ARC,
arcuate nucleus; LHRH, luteinizing hormone-releasing hormone; ME, median eminence; OC, optic
chiasm; OVLT, organum vasculosum lamina terminalis; POA, preoptic area; RHT, retinohypotha-
lamic tract; SCN, suprachiasmatic nuclei. [This model is an elaboration and revision of an earlier
version proposed for the hamster estrous cycle (116). ]
356). In this species, unlike the rat and hamster, ovulation and relatively
normal estrous cycles occur in the absence of neural influences from more
rostra1 hypothalamic structures.
The participation of circadian rhythms in the organization of the guinea pig
cycle has never been established; moreover, the time of ovulation and the onset
of behavioral estrus clearly are not entrained to the LD cycle in ways com-
parable to those reported for rats and hamsters. In guinea pigs exposed to
natural photoperiods the onset of heat occurs at every phase of the solar day
(420). Given these considerations, the persistence of estrous cycles after elimina-
tion or disruption of normal circadian organization attendant on various neural
interventions is neither surprising nor necessarily problematic for the model
developed on the basis of rat studies.
d) Monkeys. Complete deafferentation of the MBH, interrupting neural
connections from the SCN and POA to the median eminence, has no significant
effect on mean plasma gonadotropin levels nor on circhoral patterns of LH
release of OVX lMacaca muZattu (187). Estrogen-induced LH surges also sur-
vive these manipulations. Knobil and co-workers (187, 188) conclude that a
preoptic neural signal is not required for the production of the LH surge. These
data appear to be contradicted by a study (277) in which spontaneous ovulation
and estrogen-induced LH surges were blocked by lesions of the ventralmost
POA, anterior hypothalamic area (AHA), and SCN. Norman et al. (277) suggest
that destruction of only the SCN-MBH pathways, leaving other projections
intact, may inhibit subsequent LH release and could account for the absence
of ovulation or positive-feedback effects of estrogens. A more recent study (188)
has failed to replicate some of these findings. Evidence in favor of SCN partici-
pation in ovulation comes from two other sources. Three of four monkeys with
anterior disconnections rostra1 to the SCN but only one of three with cuts caudal
to the SCN ovulated spontaneously; six of these seven animals generated LH
surges in response to estrogen treatment (195). Monkeys with hypothalamic
islands that included the SCN continued to cycle, whereas one of the animals
with a disconnection caudal to the SCN stopped cycling and failed to respond
to estrogen injections with an LH surge (113). Perhaps in the absence of
exogenous steroids more or different neural circuitry is necessary for spon-
taneous expression of the LH surge than when such steroids are present.
The dispensability of structures rostra1 to the MBH for estrogen-mediated
LH surges was established definitively in a recent study (150). After complete
ablation of the septum, anterior commissure, POA, SCN, all of the OVLT,
most of the supraoptic nuclei, and variable portions of the dorsal hypothalamic
nuclei, EB-treated OVX monkeys generated LH and FSH discharges similar
to those observed in control animals. In monkeys LHRH immunoreactive
perikarya are found in a continuum from the septal-preoptic region to the pre-
mammillary nuclei caudally; reactive axons in the ME have their cell bodies
in the MBH. There is an apparent lack of organization of LHRH elements in the
hypothalamus; they are scattered over a wide area with no distinct, well-
organized fiber tracts (357). Even the major LHRH projections are diffuse and
(167) and not, as in rats, at a specific time of day entrained by the LD cycle (166).
This diminishes the significance of circadian organization of the estrous cycle,
unless secretion of estradiol under physiological conditions is subject to circadian
control. In common with rats and hamsters and unlike rhesus monkeys (187)
a single injection of EB produces multiple LH discharges 16-27 h apart (180).
The hypothalamic control of ovulation cycles and the participation of SCN and
POA in sheep circadian and estrous rhythms remain to be established. Sheep
are particularly interesting in this context because it is not unlikely that circadian
rhythms mediate the seasonal breeding cycle (216, 337); sheep may represent
an intermediate form of organization in which the influence of day length on
seasonal reproduction is mediated by hypothalamic circadian oscillators but
timing of ovulation and behavioral receptivity within a breeding season is not
dependent on circadian organization.
Damage to neural structures other than the SCN also can eliminate the
annual testicular cycle of hamsters. Knife cuts that partially or totally isolate
the MBH are effective, as are pinealectomy or superior cervical ganglionectomy
(308, 310). Some of these procedures do not interfere with the SCN nor with
the generation of nonpineal CRs. Interpretation of these results is problematic
because integrity of the pineal, especially its neural innervation, is essential
for expression of the annual testicular cycle. These findings can be accounted
for in several different ways. 1) The SCN lesions eliminate the nocturnal peak
of pineal NAT activity (250, 251, 254); if melatonin is the primary pineal anti-
gonadal agent, the loss of sufficient melatonin production may be the functional
equivalent of a pinealectomy. 2) The phasing of the pineal’s hormone secretion
relative to the LD cycle may be crucial to its antigonadal activity (387). The
loss of light-controlled pineal rhythms after RHT-SCN destruction may prevent
antigonadal effects even in the presence of sufficient melatonin. 3) The SCN
lesions may remove hypothalamic inhibitory influences and result in increased
prolactin secretion (46). Prolactin is capable in part of protecting the hamster
gonad from the regressive effects of short days (29). 4) The SCN may be part
of the target tissue (67, 152a) on which pineal hormones act to induce testicular
regression (but see 46b).
At present one cannot choose among these possibilities. It seems likely that
neural control of pineal CRs play a crucial role in photoperiodic time measure-
ment and that the SCN regulate male reproductive cycles in some mammals
in ways yet to be specified.
V. PROSPECTUS
tion on coupling to and among neural oscillators because these processes are
central to unders tanding the neural mechanisms controlling circadian rhythmic-
ity. Coupling refers to the production or modification of rhythmicity in one
system by another. This subsumes: 1) mechanisms for entrainment of oscil-
lators by exteroceptive inputs, 2) the (mutual) interaction of oscillators and
of their constituent osci .Ilatory units, and 8) the efferent influence of central
oscillators on neural and endocrine effecters. Such coupling is likely to be
achieved by a variety of neurophysiological mechanisms; study of these mecha-
nisms may yield new principles of neural function and of circadian organization.
Questions awaiting experimental attention include the following:
I) Virtually no information is available about the neurophysiological basis
for the influence of a remote photoreceptor (e.g., the mammalian retina) on
central oscillators, nor is there any evidence for how a photoreceptor-oscillator
complex (e.g., the ApZysia eye) influences other oscillators and effecters. Since
agents other than light (e.g., temperature, hormones) can influence central
oscillators, questions about access of exteroceptive stimuli to oscillators must
be extended to these agents; this analysis should also consider how and where
these inputs are transduced into neural afference to central oscillators.
2) Several lines of evidence indicate that metazoans comprise a multilevel
complex of oscillators both within and outside the nervous system (10,14,15,51,
154, 165, 258, 284, 296, 331). -Although dissociations may occur in some condi--
tions, normally these oscillators are adaptively integrated through some corn-
binati .on of mutual and hierarchical coupling. The neurophysiological basis for
these interactions among oscillators is unknown . Presumably some combination
of the information-transmission mechanisms familiar to neurophysiologists
serves these functions; the elucidation of which mechanisms permit one oscilla-
tor to influence the ‘period icity of another is likely to provide useful insights
into the molecular basis of rhythm generation in the nervous system.
3) Studies of the control of neural and endocrine effecters by central oscil-
lators (perhaps through intermediary damped oscillators) may prove a source
of new principles of neural integration in relation to control of behavior and
physiology. Even the necessarily brief review we have provided (p. 496) of the
generally ignored dynamic aspects of neurophysiological function indicates that
a rich field of study awaits exploration.
We thank Eric Bittmsn, Julian Davidson, Gail Eskes, Bruce Goldman, Phyllis Johnston, and
Werner Loher for their advice and for criticism of portions of the manuscript. We are grateful
to Claire Almada, Nancy Beattie, Colleen Clattenburg, Gary Dupis, Darlene Frost, Carol McVicar,
and Becky Phillips for bibliographic and secretarial help. Preparation of the manuscript was sup-
ported by a grant from the National Research Council of Canada and by Grant I-ID-02982 from the
National Institute of Child Health and Human Development.
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