Neurobiology of Circadian Rhythm Regulation

Neurobiology of C irc adian
Rhythm Regulation
Alan M. Rosenwasser, PhDa,*, Fred W. Turek, PhDb
KEYWORDS
Circadian Pacemaker Suprachiasmatic nucleus Entrainment Clock genes
KEY POINTS
The suprachiasmatic nucleus (SCN) of the anterior hypothalamus has been firmly established as the
master circadian pacemaker in mammals.
The SCN circadian pacemaker is synchronized (entrained) by environmental light–dark cycles via
photoreceptors and neural pathways distinct from those mediating visual perception.
The cellular–molecular basis of circadian rhythm generation involves several circadian clock genes
expressed not only in the SCN but also throughout the brain and peripheral tissues and organs.
The SCN serves as a central pacemaker atop a hierarchically organized, anatomically distributed
circadian timing system and entrains downstream circadian clocks via neural and neuroendocrine
pathways.
System-wide circadian coordination is necessary for optimal physiologic function and maintenance
of physical and mental health.
IDENTIFICATION OF THE SUPRACHIASMATIC SUPRACHIASMATIC NUCLEUS: A NETWORK

NUCLEUS CIRCADIAN PACEMAKER OF CLOCK CELLS
The initial demonstrations that lesions of the su- Studies using a variety of in vitro models, including
prachiasmatic nucleus (SCN) severely disrupt or electrophysiological recording and optical moni-
abolish circadian rhythms in behavioral and endo- toring of SCN cell and tissue cultures, have pro-
crine functions were published in the early vided compelling evidence that circadian
1970s.1,2 Following these initial demonstrations, oscillation is fundamentally a cell-autonomous
extensive subsequent research involving lesions, process, expressed in many, but probably not
in vivo and in vitro electrophysiology, functional all, individual SCN neurons.4–7
metabolic mapping, fetal tissue transplant, and Nevertheless, individual SCN clock cells nor-
molecular analyses revealed that the SCN is mally interact to produce coherent circadian sig-
capable of autonomous, self-sustained circadian nals at the tissue (and behavioral) level.8–10
rhythmicity at both the single-cell and tissue levels. Despite the capacity of individual SCN neurons
These now-classic studies are summarized in the for autonomous rhythmicity, recent studies have
published report of a meeting held to evaluate revealed that neuronal network interactions in-
the state of SCN research on the 25th anniversary crease the frequency of rhythmic cells detected
of its discovery.3 in culture, as well as the amplitude of their
a
sleep.theclinics.com
Department of Psychology, School of Biology and Ecology, Graduate School of Biomedical Science and Engi-
neering, University of Maine, 5742 Little Hall, Orono, ME 04467, USA; b Department of Neurobiology, Center
for Sleep and Circadian Biology, Northwestern University, 2205 Tech Drive, Hogan Hall 2-160, Evanston, IL
60208, USA
* Corresponding author.
E-mail address: [email protected]
Sleep Med Clin 17 (2022) 141–150

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142 Rosenwasser & Turek
oscillation, and contribute to the overall robust- free-running conditions.21,22 Surprisingly, howev-
ness of SCN pacemaker function.11,12 er, unlike the original Clock mutation, Clock-null
Early studies suggested that SCN clock cells (knockout) mice express robust and persisting
could maintain intercellular synchrony in the circadian rhythms, with only a modest shortening
absence of sodium-dependent action poten- of circadian period23; it was subsequently found
tials,13,14 suggesting that gap junctions, glial that NPAS2 can substitute for CLOCK as a dimer-
coupling, calcium-dependent signaling, or local ization partner for BMAL1 within the SCN, thus
diffusible signals might be responsible for syn- maintaining circadian pacemaker function.24
chronizing the network of clock cells.15 In contrast, Regarding the Per genes, several distinct muta-
however, more recent studies have found that tions have been studied by different laboratories,
blocking action potentials in SCN tissue slices or but in general, Per1 or Per2 disruption shortens
cell cultures can disrupt intercellular phase syn- circadian period and reduces the robustness of
chrony,10 thus reviving interest in the possible syn- free-running rhythms.25,26 Similarly, Cry-mutant
chronizing role of synaptic transmission. Both mice also exhibit alterations in the free-running
g-aminobutyric acid (GABA) and vasoactive intes- period, whereas Cry1/Cry2 double mutants are
tinal peptide (VIP) neurotransmission, among other rendered arrhythmic.27,28 In contrast to other clock
signaling mechanisms, have now been implicated genes, the circadian clock function of Ck1e was
in the maintenance of coupling among SCN clock discovered by genetic analysis of a spontaneous
cells, as well as among subpopulations of SCN single-gene mutation that dramatically shortens
clock cells.16,17 free-running period in the hamster, originally called
the tau mutation.29 Cloning of the tau gene
MOLECULAR BASIS OF THE revealed its identity as Ck1e, and subsequent
SUPRACHIASMATIC NUCLEUS CIRCADIAN transgenic insertion of this allele into mice recapit-
PACEMAKER ulated the hamster short-period phenotype,
whereas deletion of Ck1e in mice lengthened the
A critical role for protein synthesis in the mamma- circadian period.30 More recently, mutations of
lian circadian pacemaker was established in the the Fxbl3 gene have been shown to lengthen the
late 1980s,18,19 and elucidation of the fundamental free-running period.31,32 Similar to Ck1e, Fxbl3 in-
molecular genetic oscillatory mechanism began in fluences circadian period by regulating the post-
earnest about 10 years later. The first mammalian translational stability of other clock proteins such
circadian clock gene, Clock, was identified in a as PER and CRY.33 Of course, for the molecular
forward-genetics mutagenesis screen,20 and this clock to drive circadian rhythmicity in physiology
discovery was followed quickly by the identifica- and behavior, clock gene expression must be
tion of several other core molecular clock compo- linked to intracellular signaling pathways regu-
nents, some of which were homologous to lating neuronal membrane potential and, ulti-
previously discovered circadian clock genes in mately, firing rate. Remarkably, recent research
the fruit fly.21,22 In addition to Clock, other recog- demonstrates that ionic events at the cell mem-
nized mammalian clock genes include the 3 period brane influence the molecular clock via some of
(Per) genes (Per1, Per2, and Per3), 2 cryptochrome the same intracellular signals that convey clock
genes (Cry1 and Cry2), Bmal1 (also known as signals to the membrane, and in some cases,
Arntl1 and Mop3), CK1e (Casein kinase 1 epsilon), these ionic currents may be necessary for self-
Rev-erba, and Fxbl3, all of which are expressed in sustainment of the molecular clock.34 Such re-
SCN neurons. The specific functions of these sults—at a minimum—serve to blur the distinction
various genes within the interlocking molecular between the core clock mechanisms and the so-
feedback loops that generate circadian signals at called hands of the clock.
the cellular level have been reviewed extensively In addition to their effects on circadian behavior,
elsewhere, and are not discussed here. some circadian clock gene mutations also affect
Mutations or deletions of any of these genes sleep–wake homeostasis, and several forms of af-
produce alterations in circadian phenotype at the fective behavior, suggesting possible molecular
behavioral level. The most devastating effects on links between the circadian, sleep regulatory,
clock function are seen in Bmal1-knockout mice, and motivational systems of the brain.35–37
which express immediate loss of rhythmicity in
the absence of a light–dark cycle.21,22 In contrast, FUNCTIONAL ARCHITECTURE OF THE
the original Clock mutation, which codes for a SUPRACHIASMATIC NUCLEUS
dominant-negative CLOCK protein, dramatically
lengthens free-running period and often leads to Although the SCN was initially characterized as
a gradual loss of rhythmicity under long-term being composed of distinct ventrolateral and
Neurobiology of Circadian Rhythm Regulation 143
dorsomedial subdivisions,38 this scheme has been rhythmicity, suggesting that rhythmic signals
recast to include SCN core and shell subnuclei, a from the core serve a permissive gate-like role in
concept that may better accommodate species sustaining oscillatory function in the shell.42
differences in the anatomic distribution of neuro-
peptides, afferent terminal fields, and gene LIGHT INPUT TO THE SUPRACHIASMATIC
expression patterns in the SCN.39 The SCN core NUCLEUS: THE RETINOHYPOTHALAMIC
is associated with a high concentration of VIP- TRACT
positive and gastrin-releasing peptide (GRP)–pos-
itive neurons, whereas the shell is associated with Although stimuli such as temperature, sound,
the presence of arginine vasopressin–positive food, and social cues seem to contribute to phase
neurons. Beyond this basic organization, however, control, the 24-h environmental light–dark cycle is
clear species differences have been noted, and it the primary cue for circadian entrainment in most
has been argued that the popular distinction be- mammalians (and other vertebrate taxa). A
tween SCN core and shell may be such an extreme specialized retinal projection system, referred to
oversimplification as to impede understanding of as the retinohypothalamic tract (RHT), is both
the functional organization of this critical necessary and sufficient for photic entrainment
structure.40,41 of the circadian pacemaker45,46 (Fig. 1). The RHT
Although the specific functions of chemically originates from a distinct subset of retinal ganglion
defined SCN cell populations are not fully known, cells, separate from those giving rise to the pri-
VIP and GRP neurons of the SCN core seem to mary visual pathways,47 and terminates mainly in
collate afferent signals relevant to pacemaker the SCN, as well as more sparsely in the anterolat-
entrainment, whereas vasopressinergic (or other) eral hypothalamus, subparaventricular zone, and
neurons of the SCN shell may have the primary re- supraoptic region.48,49 In addition, RHT axon col-
sponsibility of generation of self-sustaining circa- laterals also project to the thalamic intergeniculate
dian oscillations.42 A preeminent role for the SCN leaflet (IGL), which, as discussed later, is an impor-
core in pacemaker entrainment is supported by tant component of the circadian system.
findings that major SCN afferent systems Remarkably, retinally degenerate strains of
converge in the core subnucleus, administration mice, in which nearly all classic photoreceptors
of SCN core peptides such as VIP and GRP can (ie, rods and cones) are lost by early adulthood,
mimic both light-induced phase shifting and Per exhibit normal circadian responses to light.50
gene expression in the SCN in vivo and in vitro, More recently, similar findings have been reported
and light-evoked changes in SCN physiology and in genetically engineered mice with a total devel-
gene expression spreads over time from core to opmental absence of both rods and cones,
shell. Conversely, evidence for a preeminent role demonstrating conclusively that circadian light
of the SCN shell in pacemaking includes findings entrainment can be mediated by a novel, nonrod,
that the core projects robustly to the shell, but noncone photoreceptor system.51 Circadian
not vice versa, spontaneous circadian rhythmicity entrainment in the absence of rods and cones is
in neuronal activity, neuropeptide release, and maintained by a population of intrinsically photo-
gene expression is seen more reliably in the shell sensitive retinal ganglion cells that use the peptide
than in the core, and spontaneous rhythmicity in melanopsin as a photopigment.52,53 Nevertheless,
SCN gene expression seems to flow from the circadian entrainment is maintained in
most dorsomedial toward more central–lateral re- melanopsin-knockout mice54,55 and is only fully
gions over the course of the circadian cycle. On abolished when both classical and melanopsin-
the other hand, the view that SCN core and shell based photoreception is eliminated demonstrating
underlie discrete entrainment and pacemaking redundancy in the circadian photoreception sys-
functions is probably too simplistic because (1) tem in the retina.56–58
several arousal-related afferents of limbic and RHT terminals release the excitatory amino acid
brainstem origin target the SCN shell,39 (2) neurotransmitter, glutamate, which acts through
in vitro studies have revealed independent free- both W-methyl-D-aspartate (NMDA) and non-
running rhythmicity in the secretion of core and NMDA receptors and a variety of intracellular
shell peptides from the same tissue explant,43 signaling pathways to increase Per gene expres-
and (3) SCN core and shell can exhibit stable sion. These changes in gene expression, when
dissociation of rhythmic gene expression in vivo superimposed on the ongoing circadian
under certain conditions.44 Furthermore, studies transcription–translation cycle, correspond func-
using microlesions indicate that the integrity of tionally to phase shifts of the circadian oscil-
the SCN core is essential for the maintenance of lator.59–62 In addition to glutamate, RHT terminals
high-amplitude behavioral and molecular-level also release 2 identified peptide cotransmitters,
Fig. 1. Overview of functional neuroana-

tomic pathways in the mammalian circa-
dian system. Major SCN afferent systems
originating in the retina and raphe
nuclei also target the intergeniculate
leaflet (IGL) of the thalamus, which itself
projects to the SCN. Retinal projections
to the SCN and IGL mediate photic input
to the circadian system, whereas raphe
projections to the SCN and IGL mediate
the effects of certain nonphotic, behav-
ioral state–related signals. Furthermore,
raphe-IGL-SCN circuits also modulate
and integrate photic and nonphotic
signaling to the SCN pacemaker. SCN
outputs mainly target the hypothalamus
and diencephalon and seem to include
both neural efferents and secreted para-
crine signals. 5-HT, 5-hydroxy-trypt-
amine; GLU, glutamate; NPY,
neuropeptide Y; PACAP, pituitary adenyl cyclase-activating peptide; PK, prokineticin; SP, substance P; VP, arginine
vasopressin; VIP, vasoactive intestinal polypeptide.
substance P (SP) and pituitary adenyl cyclase– naturalistic lighting conditions (eg, regimens
activating peptide (PACAP). SP seems to play an including twilight transitions, seasonally changing
important role in RHT transmission because selec- photoperiod, or simulated moonlight), relative to
tive SP antagonists block light-induced phase the square-wave light–dark cycles commonly
shifting and immediate-early gene expression used in the laboratory.72
in vivo, as well as glutamate receptor–mediated In addition to providing a secondary, indirect
phase shifting in vitro, whereas SP administration source of photic signaling to the circadian clock,
can itself induce circadian phase shifts.63–65 In the IGL also plays a preeminent role in the regula-
contrast, PACAP administration has been reported tion of the circadian system by nonphotic, arousal-
either to antagonize or to mimic the effects of related stimuli. Thus, IGL lesions abolish the
glutamate on circadian phase shifting and Per phase-shifting effects of novelty-induced wheel
gene expression in vitro, depending on the dose running and benzodiazepine administration in
and the circadian phase of administration.66–68 hamsters, as well as the period-shortening effect
of running-wheel access in rats and the entrain-
OTHER FUNCTIONAL INPUTS TO THE ment effect of scheduled daily treadmill activity in
SUPRACHIASMATIC NUCLEUS mice.73–78 More recently, evidence has been pre-
sented that IGL neurons may mediate the effects
An additional major SCN afferent system arises of metabolic signals on the SCN pacemaker.79,80
from the IGL, a distinct retinorecipient region of A third major afferent system converging mainly
the lateral geniculate complex, intercalated be- on the SCN core originates from the serotonergic
tween the dorsal and ventral lateral geniculate midbrain raphe, especially the median raphe nu-
nuclei69–71 (see Fig. 1). The projection from the cleus81–84 (see Fig. 1). In addition, ascending sero-
IGL to the SCN is referred to as the geniculohypo- tonergic projections originating in the dorsal raphe
thalamic tract (GHT), and GHT neurons release nucleus innervate the IGL, providing a second
both neuropeptide Y and GABA. Retinal signals route for serotonergic regulation of the SCN circa-
are conveyed to the IGL in part by axon collaterals dian pacemaker.81,82 As for the IGL itself, exten-
of RHT neurons,72 and GHT and RHT terminal sive evidence has implicated serotonergic
fields are largely coextensive within the SCN projections to the SCN and IGL in modulation of
core. Thus, the IGL/GHT system provides a sec- photic effects on the circadian pacemaker, as
ondary, indirect pathway by which light signals well as in the mediation of nonphotic effects on
can reach the circadian pacemaker. Although the the pacemaker. These effects seem to be medi-
IGL is clearly not necessary for photic entrainment, ated via 5-hydroxytryptamine (5-HT)1A and 5-HT7
lesions of the IGL/GHT system result in subtle receptors within the SCN, the IGL, and the raphe
modifications in the photic control of circadian nuclei and by 5-HT1B receptors located presynap-
phase and period.70,71 Furthermore, the IGL may tically on RHT terminals.85–89
have a significant role in entrainment under more
In addition to the RHT, GHT, and 5-HT projec- locomotor but not neuroendocrine rhythms to
tions, several other identified pathways provide SCN-lesioned arrhythmic hosts.97 Several diffus-
afferent input to the circadian system, including ible candidate molecules have now been impli-
noradrenergic projections from the locus coeru- cated as circadian output signals, including
leus, cholinergic projections from the basal fore- prokineticin-2, tumor necrosis factor-a, and
brain and pontine tegmentum, and histaminergic vasopressin.97
projections from the posterior hypothalamus.90,91
Similar to serotonergic projections, noradrenergic MULTIOSCILLATOR NATURE OF THE
and cholinergic projections also innervate the CIRCADIAN SYSTEM
IGL, providing an alternate pathway by which
these transmitter systems could alter SCN func- The evidence reviewed earlier in this study amply
tion. However, unlike the RHT, GHT, and 5-HT pro- justifies the use of the term pacemaker to describe
jections to the SCN, which form generally the SCN’s role in circadian rhythmicity. Neverthe-
overlapping terminal fields in the SCN core, norad- less, the larger circadian system is now known to
renergic, cholinergic, and histaminergic SCN in- be composed of a multiplicity of circadian oscilla-
puts preferentially target the SCN shell. Beyond tors distributed widely in the brain and body.
these systems, a recent review concluded that Although extensive physiologic studies conducted
the SCN receives direct monosynaptic projections in the premolecular era revealed several varieties
from at least 35 distinct brain areas,41 revealing of rhythmic dissociation and disruption that
enormous potential for circadian pacemaker mod- strongly implied the existence of a multioscillatory
ulation by a wide range of extrinsic and intrinsic circadian system,98 these studies provided little
stimuli. evidence regarding the anatomic localization and
distribution of the circadian system.
SUPRACHIASMATIC NUCLEUS OUTPUT After the elucidation of the core clock genes, it
PATHWAYS soon became apparent that the expression of
these genes was not restricted to the SCN but
Perhaps surprisingly, first-order SCN efferents was in fact widely distributed in the brain and pe-
innervate a relatively small number of target areas riphery. Nevertheless, it was generally believed
concentrated mainly in the diencephalon and that non-SCN cellular oscillators were highly
basal forebrain.92,93 These SCN targets then relay damped and possessed little or no capacity for
circadian timing signals to autonomic and neuro- self-sustainment in the absence of periodic SCN
endocrine systems, as well as to central structures input. More recently, however, the finding that
regulating affective, sensory, and motor pro- circadian clock genes express persistent rhythmi-
cesses, as well as to sleep-regulatory brain re- cally in several surgically isolated brain re-
gions.94 SCN efferents emerge from both the gions99,100 and in numerous cultured peripheral
core and shell subnuclei and release several neu- tissues and cell types101,102 has provided compel-
rotransmitters and peptides including GABA, ling evidence for a whole-body, anatomically
glutamate, and vasopressin (see Fig. 1). Remark- distributed network of cellular- and tissue-level
ably, anatomically distinct populations of SCN circadian clocks. Thus, the current conception of
neurons seem to innervate specific efferent tar- the circadian system is that the SCN pacemaker
gets, providing multiple waves of neuronal signals entrains rhythmicity in downstream central and
that regulate circadian phase in a target-specific peripheral clocks via neural and neuroendocrine
manner. Despite earlier evidence that neuronal ef- signals, as well as less directly via its control of
ferents were exclusively responsible for conveying rhythmic feeding, activity, and body tempera-
SCN output signals,95 it now appears that the SCN ture,103 which in turn entrain other behavioral,
regulates certain rhythmic processes via diffusible physiologic, and cellular rhythms (Fig. 2). In this
paracrine signals. Evidence for a diffusible SCN way, a broad network of direct and indirect con-
output signal was first suggested by the finding trols ensures that the SCN and other central and
that surgical isolation of the hamster SCN within peripheral clocks maintain specific, and presum-
a hypothalamic island abolished SCN-dependent ably optimal, phase relationships with the external
neuroendocrine responses but allowed for persist- and internal environment, resulting in the overall
ing locomotor activity rhythms in the same ani- temporal coordination of the system.
mals.96 The hypothesis for paracrine signaling What is the advantage of a distributed system of
from the SCN in the regulation of rhythmic pro- independent circadian clocks, as opposed to a
cesses was strengthened considerably by the passive system that strongly depends on SCN sig-
finding that transplant of SCN tissue encased nals for the sustainment of periodicity? Perhaps
within a semipermeable capsule could restore the advantage lies in the ability of such a system
certain natural circumstances. Of course, such

plasticity may become maladaptive when humans
choose to chronically disconnect their feeding
and/or sleep–wake cycles from the SCN, as so
often occurs in the current 24/7 society.
THE CIRCADIAN TIMING SYSTEM IN HEALTH

AND DISEASE
This new picture of the circadian timing system
has raised important questions about the potential
adverse health effects that may be associated with
a loss of normal synchronization between and
among central and peripheral oscillations. Thus,
circadian disruption at the molecular and systemic
levels has been linked to sleep disorders, obesity
and diabetes, heart disease, cancer, and psychiat-
ric disorders.103–106 Given estimates that approxi-
mately 10% to 20% of the entire genome is
expressed rhythmically in any given tissue or or-
Fig. 2. The multioscillatory circadian timing system in- gan,107,108 many other mechanisms linking circa-
cludes a large number of autonomously rhythmic dian synchrony and desynchrony to health and
circadian clock cells distributed within both central disease will undoubtedly emerge in the next few
and peripheral tissues. The circadian pacemaker re- years and beyond.
sides in the SCN, is entrained by light–dark cycles Circadian dysregulation certainly occurs quite
and other environmental stimuli, and in turn, serves
often in humans, who can over-ride their circadian
to entrain and synchronize peripheral clocks. Some
clock and exert substantial volitional control over
peripheral tissues can exhibit persistent autonomous
rhythmicity, whereas others may be damped in the their sleep–wake and feeding cycles. Under such
absence of periodic SCN signals. Together, SCN and circumstances, abnormal phase relationships are
non-SCN central neural oscillators result in rhythmic expressed between sleep–wake behaviors (and
behavior (such as food intake and motor activity), other rhythmic processes tightly linked to sleep
autonomic nervous system (ANS) function, and hypo- or wake states, as well as feeding or fasting states)
thalamic–pituitary–adrenal (HPA) axis hormone secre- and the circadian clock (and rhythmic processes
tion. These behavioral and physiologic rhythms in tightly linked to those behavioral processes).
turn can give rise to other rhythmic signals (eg, Although the internal desynchronies that occur
glucose availability, corticosterone levels, and body
with jet lag and shift work may be the most
temperature) that serve to maintain phase synchrony
dramatic, they are not the only examples of real-
among peripheral oscillators, probably in a tissue-
specific manner. In turn, the activity of peripheral world circadian disruption. Indeed, social con-
oscillators may give rise to rhythmic signals (eg, pe- straints, work schedules, and the use of artificial
ripheral hormones, autonomic afferents, and meta- lighting may result in the widespread occurrence
bolic signals) that contribute to the synchronization of social jet lag even in people living under rela-
of the SCN pacemaker and other central oscillators. tively stable entrained conditions but who phase
shift their sleep and feeding times on weekends
and holidays relative to the weekdays.109 Regard-
to display a degree of plasticity in internal phase less of work or travel schedules, humans in the
relationships under certain environmental condi- modern, round-the-clock society are certainly
tions, such as when sleep and wakefulness occur becoming less strictly diurnal, opposing millions
at abnormal clock times or when feeding is of years of evolutionary selection.
restricted to atypical temporal windows. Under
such conditions, a system of largely self- SUMMARY
sustaining clocks can maintain largely undamped
rhythmicity at the cellular and tissue levels. Thus, The SCN contains a master circadian pacemaker
although temporal coordination throughout the that entrains, coordinates, and contributes to the
circadian system is generally assumed to be phys- sustainment of a large population of cellular- and
iologically optimal, the overall circadian system tissue-level circadian clocks located throughout
may be designed to allow downstream oscillators the brain and body. Furthermore, the SCN itself
to display adaptive phase adjustments under contains a large number of normally coupled, but
potentially autonomous, cellular oscillators that 6. Colwell CS. Circadian modulation of calcium levels
interact to underlie its pacemaker function. These in cells in the suprachiasmatic nucleus. Eur J Neu-
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The author has nothing to disclose.
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Neurobiology of Circadian Rhythm Regulation

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Neurobiology of C irc adian

IDENTIFICATION OF THE SUPRACHIASMATIC SUPRACHIASMATIC NUCLEUS: A NETWORK

Sleep Med Clin 17 (2022) 141–150

Fig. 1. Overview of functional neuroana-

certain natural circumstances. Of course, such

THE CIRCADIAN TIMING SYSTEM IN HEALTH

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