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The suprachiasmatic nucleus (SCN) of the hypothalamus is the principal circadian pacemaker in the mammalian brain and, as such, it generates circadian rhythms in rest and activity, core body temperature, neuroendocrine function, autonomic function, memory and psychomotor performance, and a host of other behavioral and physiological processes. The SCN is the central player in an important neural system, the circadian timing system (CTS).
1. Circadian Rhythms Are Adaptations To The Solar Cycle
The physical environment of living organisms presents extraordinarily diverse circumstances requiring complex adaptations. The most prominent, regularly recurring stimulus in the physical environment is the solar cycle of light and dark and, not surprisingly, nearly all species, plant and animal, have evolved daily rhythms in organismal functions and behavior in response to the solar cycle which enhance adaptation and survival. Such rhythms, when they have special properties, to be outlined below, are designated circadian rhythms. Circadian rhythms are found in nearly all living organisms, from prokaryotes through eukaryotes, from simple to higher plants, and simple invertebrates to the human. The nature of these rhythms is diverse but in mammals, the major subject of this research paper, the most evident expression of circadian function is the sleep–wake cycle. This rhythm, and associated rhythms in physiological and endocrine functions, are expressions of the activity of a specialized neural system, the CTS.
Mammals present two patterns of behavioral adaptation to the solar cycle. In those species in which olfaction and audition dominate the animals’ perception of their environment, the rest-activity (sleep– wake) rhythm is ‘nocturnal’; the animals are awake at night and sleep during the day. In animals in which vision is the major sensory modality, the rest-activity rhythm is diurnal with activity during the day and rest at night. The nocturnal pattern is typical of rodents and carnivores, for example, whereas the diurnal pattern is exempliﬁed by birds and primates.
2. Circadian Rhythms Have Two Principal Properties
Under normal conditions of the light-dark cycle, circadian rhythms have a period of exactly 24 hours. If photic cues are removed, however, by placing animals in constant darkness or constant light, the rhythms are maintained but with a period that diﬀers from 24 hours. In the ﬁrst circumstance, in which the period of the rhythm is the same as that of the solar cycle, the rhythm is said to be ‘entrained.’ When the period diﬀers from 24 hours in constant conditions, the rhythm is termed ‘free-running’ (Fig. 1). These two properties, entrainment and endogenous maintenance of free-running rhythmicity, provide us with insight into the necessary organization of the CTS. That is, the phenomenon of a free-run in the absence of environmental cues indicates that circadian rhythmicity is generated by a clock-pacemaker within the animal. Entrainment implies that photoreceptors and a visual pathway to the clock-pacemaker are necessary components of the system and the diverse functions under circadian control imply the presence of pathways from the clock-pacemaker to sites expressing eﬀector rhythms (Fig. 1). The eﬀect of circadian regulation is not to alter a function but to provide a temporal organization for its expression.
3. The SCN Is The Center Of The CTS
3.1 The SCN Is An Endogenous Circadian Pacemaker
The SCN is a small, paired hypothalamic nucleus that lies immediately about the optic chiasm and just lateral to the third ventricle in all mammals. Typically it is composed of small neurons that are compactly organized. There are four lines of evidence supporting the conclusion that the SCN is a circadian pacemaker.
3.1.1 The SCN Is The Site Of Termination Of The Retinohypothalamic Tract—An Essential Entrainment Pathway. For an explanation of this, see below.
3.1.2 Ablation Of The SCN Abolishes Circadian Rhythms. The initial studies of SCN ablation were performed in the early 1970s. Following these lesions, there is a complete loss of temporal organization of functions under circadian regulation. For example, SCN-lesioned animals show an arrhythmic pattern of sleep-wake behavior yet the amount of time spent awake is normal as is the amount of time spent in REM and non-REM sleep. Similarly, the rhythm in adrenal steroid secretion is lost but the total amount of steroid secreted is normal and responses to stress are maintained. Thus, in these and many other functions, the eﬀect of SCN lesions is only to alter the temporal organization of functions, not the functions themselves.
3.1.3 Circadian Rhythmicity Is Maintained In The SCN In Isolation In Vivo And In Vitro. In elegant experiments, Inouye and Kawamura were able to isolate the SCN from the rest of the brain in intact animals and record from SCN neurons in these animals. Although the animals were arrhythmic in behavior, and other brain areas lost rhythms in neuronal ﬁring, SCN neurons maintained a stable rhythm of ﬁring with high levels during the day and low levels at night, and the ﬁring rate rhythm free-runs in constant conditions. Subsequent studies by a number of investigators conﬁrmed these observations in SCNs maintained in vitro in the absence of the rest of the brain. This has not been found for other brain areas. Thus, the SCN is a unique brain area in that it maintains rhythmicity in isolation both from environmental cues and input from other brain areas.
3.1.4 Circadian Rhythmicity Is Restored In SCN-Lesioned Animals That Receive Transplants Of Fetal SCNs. In arrhythmic animals with SCN lesions, placement of small transplants of fetal hypothalamus containing the SCN into the third ventricle restores the circadian sleep–wake rhythm. The transplants must contain SCN tissue and be placed in the relative vicinity of the lesioned area to be eﬀective. It was unclear until recently how the transplants functioned but work by Silver and Lehman and co-workers, who were early leaders in the transplant studies, showed conclusively that the transplants can communicate with the rest of the brain through a humoral signal released into the cerebrospinal ﬂuid to diﬀuse into the adjacent brain, hypothalamus and thalamus. These data on transplantation of SCN provide the ﬁnal, conclusive evidence that the SCN is the principal circadian pacemaker.
3.1.5 SCN Neurons Are Circadian Oscillators. There are two potential mechanisms by which the SCN might generate circadian rhythms. The ﬁrst is that individual SCN neurons are born as circadian oscillators that are then coupled to make a pacemaker. The second is that circadian function arises as an emergent property of coupled SCN neurons which are not themselves oscillators. The SCN is formed embryologically from precursor cells located in the diencephalic germinal epithelium. As these precursor cells divide, the newly formed neurons migrate from the germinal epithelium to form the SCN. In the rat, the most extensively studied species, SCN neurons are formed in late prenatal life with the process completed by three days before birth. At 2 days before birth, the SCN is very primitive and contains no synapses, indicating that its neurons do not participate in a neural network. Nonetheless, a circadian rhythm in glucose utilization appears in the SCN on that day, and this is not generated by maternal inﬂuences, or other fetal inﬂuences, indicating that SCN neurons have become rhythmic and, hence, at least a subset must be individual circadian oscillators. Subsequently, the neurons are coupled through neural connections to make a pacemaker. The validity of this interpretation of SCN organization is shown by other studies in which individual SCN neurons, isolated in tissue culture, exhibit circadian rhythms in ﬁring rate. This type of pacemaker organization is also consonant with observations on invertebrate pacemakers.
3.1.6 Circadian Function In The SCN Is Genetically Determined And Generated Through Protein Inter-Actions. Data presented over many years have established that circadian rhythmicity is a genetically-determined function. Among the studies contributing to this understanding are experiments in Neurospora and Drosophila that have indicated the existence of clock genes. Beginning in the mid-1980s, clock genes were cloned and analyzed, largely by Dunlap and his co-workers for Neurospora and by Hall, Rosbash, and Young for Drosophila. This work shows that circadian rhythmicity, at the molecular-cellular level, is the expression of clock genes producing proteins that, in turn, regulate expression of the clock genes, that is, the clock mechanism can be viewed as a simple feedback loop. This ﬁeld is evolving very rapidly at present and recent ﬁndings indicate that there is a substantial conservation of function from invertebrates to mammals. Homologues of the Drosophila clock genes are present in the mammalian SCN and cycle in a pattern similar to that in Drosophila. This work will continue to expand rapidly and we should expect a reasonably complete understanding of the molecular-cellular events underlying circadian rhythmicity in the mammalian SCN to be elucidated in the near future.
3.2 The SCN Is Coupled To Eﬀector Systems By Neural Pathways
The major output of the SCN is to hypothalamus and thalamus with very limited projections to basal forebrain. Within this context, the densest projections are to anterior hypothalamus for the control of body temperature and autonomic function and to the paraventricular and arcuate nuclei for neuroendocrine regulation and to the posterior hypothalamus and thalamus for behavioral state regulation. Thus, these projections form the basis circadian control of eﬀector systems. A scheme for this is shown diagrammatically in Fig. 2.
4. The SCN In Nonmammalian Vertebrates
There appears to be an SCN, or an SCN homologue, in the brains of all vertebrates. The function of the SCN, however, diﬀers in nonmammalian vertebrates in comparison to mammals. As described above, the SCN is the circadian pacemaker responsible for the temporal organization of behavior into 24-hour sleep-wake cycles in virtually all mammals. Relatively little work has been done on ﬁsh, amphibia, and reptiles but birds have been studied extensively. In avian species there are three patterns of organization of the circadian timing system. The ﬁrst, represented by the domestic chicken, is somewhat similar to mammals. The SCN is the pacemaker responsible for the temporal organization of behavior but the pineal is capable of independent circadian activity. The second, represented by passerine species, diﬀers in that the pineal is the principal pacemaker but the pineal acts through eﬀects on the SCN, that is, if the pineal is removed from animals in constant conditions, the animals become arrhythmic and transplantation of the pineal to the anterior chamber of the eye restores rhythmicity. If the SCN is ablated in animals with intact pineals, behavioral rhythmicity is lost even though the pineal continues to put out a rhythmic signal. The third variation, seen in some quail species, is characterized by three structures, the pineal, SCN, and retina being capable of generating rhythmicity. Thus, in avian species, the SCN, the pineal or the retina are potential circadian pacemakers. This is of interest in that recent data indicate that the mammalian retina is capable of generating intrinsic circadian rhythms and there is some evidence that mammals can exhibit a very limited amount of circadian function in the absence of the SCN. This is only evident in specialized environmental situations and, under usual circumstances, SCN-lesioned animals do not recover circadian function and remain arrhythmic throughout their lives.
The adaptation of animals to their environment is characterized by a temporal organization of behavior into cycles of rest (sleep) and activity. In mammals, this temporal organization of behavior, facilitated by a precise temporal organization of physiological, neural, and endocrine processes is established by a small, paired hypothalamic nucleus, the suprachiasmatic nucleus. The suprachiasmatic nucleus is comprised of individual neuronal oscillators coupled to constitute a network that functions as a circadian pacemaker. The precise output of the pacemaker is modulated by photic and nonphotic neural aﬀerents to provide maximal adaptation. This output acts predominantly through connections to hypothalamus and, to a lesser extent, to thalamus and basal forebrain. Although limited, these connections orchestrate the precise pattern of behavioral and physiological processes that represent the circadian contribution to adaptation.
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