Trends in Neurosciences
The hypothalamic integrator for circadian rhythms
Introduction
It has been known for nearly half a century that large lesions of the mediobasal hypothalamus cause loss of circadian rhythms of locomotor activity, feeding and drinking [1] but the location of the biological clock was not pinned down until 1972. A key series of experiments in that year established that the suprachiasmatic nucleus (SCN) receives the bulk of the retinal input to the hypothalamus 2, 3, and that lesions of the SCN cause loss of circadian rhythms 4, 5. Subsequent work showed that the individual neurons of the SCN contain a genetically driven clock mechanism, with a transcriptional–translational feedback loop that ensures a nearly 24 h cycle [6]. This cycle is then synchronized to the external light–dark cycle by input to the SCN from retinal ganglion cells that act as irradiance detectors (their slow responses are proportional to the light level) [7].
Although the events that control the SCN clock cycle have been delineated in considerable detail over the past decade, the mechanisms that convert that clock signal into patterning of a wide variety of physiological and behavioral rhythms have remained obscure. However, recent work has begun to identify the key pathways and neurotransmitters that are involved in this process. This review will focus on those mechanisms.
Section snippets
Output from the SCN
The projections from the SCN in rats were first shown by Swanson and Cowan in 1975 using autoradiographic tracing [8], and in more detail by Watts and colleagues in 1987 [9]. These same projections can be identified conveniently in sections through the SCN region that have been stained immunohistochemically for either arginine vasopressin (AVP) or vasoactive intestinal polypeptide (VIP), which are contained in many of the output neurons [10].
The SCN provides three major output pathways. One
Which SCN targets regulate circadian cycles of specific functions?
Early lesion studies of the circadian system primarily used methods that damage both neuronal cell bodies and axons passing through or near the lesion site (e.g. electrolytic lesions, mechanical lesions or colchicine injections). Unfortunately, the complex interweaving of cell groups and fiber pathways present in the hypothalamus made the results of such studies difficult to interpret. The roles played by SCN targets in circadian control of specific functions have been reassessed recently by
Why have such a complicated, three-stage integrator?
This model for a hypothalamic circadian integrator allows the brain much more flexibility in sculpting circadian rhythms than would a simpler mechanism. For example, melatonin secretion, which is under the simplest type of monosynaptic regulation from the SCN to central effector neurons in the paraventricular nucleus, is hard-wired to the circadian clock in the SCN [31]. The SCN is more active during the light cycle, and its GABAergic neurons presumably inhibit the paraventricular premotor
Experimental manipulation of circadian patterns by restricted feeding
It is possible to manipulate the circadian rhythms of a wide range of behaviors and physiological functions by restricting the timing of food availability during the day [41]. When rats, which are typically nocturnal, are allowed access to food only during the middle of the light cycle, they quickly adapt to eating during the day (Figure 3b). Interestingly, they become active about an hour before the food is actually presented and reduce locomotor activity during the dark cycle, thus shifting
Summary
Within the past few years, the outline of the hypothalamic circadian integrator has finally begun to emerge. We now recognize that different functions can be controlled directly by the SCN clock (e.g. release of melatonin), or can be regulated by systems that are one synaptic relay (e.g. body temperature) or two synaptic relays (e.g. and feeding, locomotor activity, wake–sleep cycles and corticosteroid secretion) from the clock. The role of this complex integrator is now understood as allowing
References (43)
- et al.
Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat
Brain Res.
(1972) Direct projection from the suprachiasmatic nucleus to hypophysiotrophic corticotropin-releasing factor immunoreactive cells in the paraventricular nucleus of the hypothalamus demonstrated by means of Phaseolus vulgaris-leucoagglutinin tract tracing
Brain Res.
(1995)Morphological correlates of circadian rhythm restoration induced by transplantation of the suprachiasmatic nucleus in hamsters
Exp. Neurol.
(1994)Ventrolateral preoptic nucleus contains sleep-active, galaninergic neurons in multiple mammalian species
Neuroscience
(2002)- et al.
Efferent connections of the parabrachial nucleus in ths rat
Brain Res.
(1980) Sleep and activity: their relation to the 24-hour clock
Res. Publ. Assoc. Res. Nerv. Ment. Dis.
(1967)- et al.
A retinohypothalamic projection in the rat
J. Comp. Neurol.
(1972) An autoradiographic and electron microscopic study of retino-hypothalamic connections
Z. Zellforsch. Mikrosk. Anat.
(1972)- et al.
Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions
Proc. Natl. Acad. Sci. U. S. A.
(1972) - et al.
Coordination of circadian timing in mammals
Nature
(2002)
A broad role for melanopsin in nonvisual photoreception
J. Neurosci.
The efferent connections of the suprachiasmatic nucleus of the hypothalamus
J. Comp. Neurol.
Efferent projections of the suprachiasmatic nucleus: II. Studies using retrograde transport of fluorescent dyes and simultaneous peptide immunohistochemistry in the rat
J. Comp. Neurol.
Anatomical demonstration of the suprachiasmatic nucleus–pineal pathway
J. Comp. Neurol.
Afferents to the ventrolateral preoptic nucleus
J. Neurosci.
The suprachiasmatic nucleus projects to posterior hypothalamic arousal systems
NeuroReport
A diffusible coupling signal from the transplanted suprachiasmatic nucleus controlling circadian locomotor rhythms
Nature
Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling
Science
Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus
Nature
Effects of suprachiasmatic transplants on circadian rhythms of neuroendocrine function in golden hamsters
Endocrinology
Cited by (443)
Open Questions Regarding the Efficacy, Mechanisms, and Moderators of Treatments for Circadian Sleep-Wake Disruption in People With Dementia
2024, American Journal of Geriatric PsychiatryCircadian rhythms and physiological processes
2023, Encyclopedia of Sleep and Circadian Rhythms: Volume 1-6, Second EditionTranslational approaches to influence sleep and arousal
2022, Brain Research BulletinDorsal clock networks drive temperature preference rhythms in Drosophila
2022, Cell ReportsCitation Excerpt :Spontaneous internal desynchronization suggests that locomotor activity rhythms and BTR are experimentally dissociated (Lavie, 2001). Locomotor activity rhythms and the BTR are controlled by different output pathways from the suprachiasmatic nucleus (Saper et al., 2005); however, the underlying mechanisms controlling BTR remain largely unclear. At least two factors determine BTR.
Diurnal Variation of Brain Activity in the Human Suprachiasmatic Nucleus
2024, Journal of Neuroscience