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The suprachiasmatic nucleus (SCN) of the hypothalamus is a dominant circadian pacemaker in the mammalian brain controlling the rest-activity cycle and a series of physiological and endocrine functions to provide a foundation for the successful elaboration of adaptive sleep and waking behavior. The SCN is anatomically and functionally organized into two subdivisions: (1) a core that lies adjacent to the optic chiasm, comprises predominantly neurons producing vasoactive intestinal polypeptide (VIP) or gastrin-releasing peptide (GRP) colocalized with GABA and receives dense visual and midbrain raphe afferents, and (2) a shell that surrounds the core, contains a large population of arginine vasopressin (AVP)-producing neurons in its dorsomedial portion, and a smaller population of calretinin (CAR)-producing neurons dorsally and laterally, colocalized with GABA, and receives input from non-visual cortical and subcortical regions. In this paper, we present a detailed quantitative analysis of the organization of the SCN core and shell in the rat and place this in the context of the functional significance of the subdivisions in the circadian control of regulatory systems.
The pacemaker role of the suprachiasmatic nucleus in a mammalian circadian system was tested by neural transplantation by using a mutant strain of hamster that shows a short circadian period. Small neural grafts from the suprachiasmatic region restored circadian rhythms to arrhythmic animals whose own nucleus had been ablated. The restored rhythms always exhibited the period of the donor genotype regardless of the direction of the transplant or genotype of the host. The basic period of the overt circadian rhythm therefore is determined by cells of the suprachiasmatic region.
The suprachiasmatic nucleus (SCN) in rodents receives a dense innervation from serotonin neurons of the midbrain raphe. This projection overlaps the terminal field of the retinohypothalamic tract in the SCN core, the central part of the nucleus characterized by a population of vasoactive intestinal polypeptide (VIP)-containing neurons. To determine whether a similar pathway is present in primates, we carried out an immnunocytochemical investigation of the primate SCN using antisera against either serotonin (monkey) or the serotonin transporter (human). This demonstrated a dense serotonergic plexus over the SCN core in both species. As in rodents, the distribution of the serotonin innervation of the primate SCN overlaps that of the retinohypothalamic input and the VIP neuronal population. We also find a supraependymal plexus of serotonin axons in the third and lateral ventricles of the human and monkey brains that is similar in distribution, but less dense, than the one reported in rodents.
A subpopulation of retinal ganglion cells expresses the neuropeptide vasopressin. These retinal ganglion cells project predominately to our biological clock, the suprachiasmatic nucleus (SCN). Light-induced vasopressin release enhances the responses of SCN neurons to light. It also enhances expression of genes involved in photo-entrainment of biological rhythms.
Pacemaker cells within the hamster suprachiasmatic nucleus generate circadian rhythms. The suprachiasmatic nucleus is heavily innervated by serotonin axons originating in the median raphe nuclei. Consequently, serotonergic agonists and antagonists or agents that alter levels of serotonin in the synapse following transmission can modulate many aspects of circadian rhythmicity. Examples of the latter are some antidepressants and the stimulant amphetamine that bind to the serotonin transporter and block serotonin reuptake. It has been hypothesized that circadian rhythm dysfunction may be involved in depression, and that the efficacy of certain antidepressants in treating depression may involve an alteration of serotonin levels and certain circadian rhythm parameters. However, although the hamster is the behavioral model of choice for the study of circadian rhythms, the identification of serotonin transporters in this species has not been reported. Therefore, in this report we describe the distribution of the serotonin transporter in the hamster suprachiasmatic nucleus using immunohistochemical techniques. Our results demonstrate a dense labeling of the serotonin transporter throughout the ventral and medial regions of the suprachiasmatic nucleus, a pattern that overlaps the distribution of serotonergic afferents in this nucleus. Amphetamines and certain antidepressants may serve as substrates for this transporter and elicit chronopharmacological activity by elevating serotonin levels in the suprachiasmatic nucleus.
Short sleep is linked to disturbances in glucose metabolism and may induce a prediabetic condition. The biological clock in the suprachiasmatic nucleus (SCN) regulates the glucose rhythm in the circulation and the sleep-wake cycle. SCN vasopressin neurons (SCNVP) control daily glycemia by regulating the entrance of glucose into the arcuate nucleus (ARC). Thus, we hypothesized that sleep delay may influence SCN neuronal activity. We, therefore, investigated the role of SCNVP when sleep is disrupted by forced locomotor activity. After 2 h of sleep delay, rats exhibited decreased SCNVP neuronal activity, a decrease in the glucose transporter GLUT1 expression in tanycytes lining the third ventricle, lowered glucose entrance into the ARC, and developed hyperglycemia. The association between reduced SCNVP neuronal activity and hyperglycemia in sleep-delayed rats was evidenced by injecting intracerebroventricular vasopressin; this increased GLUT1 immunoreactivity in tanycytes, thus promoting normoglycemia. Following sleep recovery, glucose levels decreased, whereas SCNVP neuronal activity increased. These results imply that sleep-delay-induced changes in SCNVP activity lead to glycemic impairment, inferring that disruption of biological clock function might represent a critical step in developing type 2 diabetes.
In mammals, the hypothalamic suprachiasmatic nucleus (SCN) functions as the central circadian pacemaker, orchestrating behavioral and physiological rhythms in alignment to the environmental light/dark cycle. The neurons that comprise the SCN are anatomically and functionally heterogeneous, but despite their physiological importance, little is known about the pathways that guide their specification and differentiation. Here, we report that the stem/progenitor cell transcription factor, Sex determining region Y-box 2 (Sox2), is required in the embryonic SCN to control the expression of SCN-enriched neuropeptides and transcription factors. Ablation of Sox2 in the developing SCN leads to downregulation of circadian neuropeptides as early as embryonic day (E) 15.5, followed by a decrease in the expression of two transcription factors involved in SCN development, Lhx1 and Six6, in neonates. Thymidine analog-retention assays revealed that Sox2 deficiency contributed to reduced survival of SCN neurons during the postnatal period of cell clearance, but did not affect progenitor cell proliferation or SCN specification. Our results identify SOX2 as an essential transcription factor for the proper differentiation and survival of neurons within the developing SCN.
The suprachiasmatic nucleus (SCN) is generally considered the master clock, independently driving all circadian rhythms. We recently demonstrated the SCN receives metabolic and cardiovascular feedback adeptly altering its neuronal activity. In the present study, we show that microcuts effectively removing SCN-arcuate nucleus (ARC) interconnectivity in Wistar rats result in a loss of rhythmicity in locomotor activity, corticosterone levels, and body temperature in constant dark (DD) conditions. Elimination of these reciprocal connections did not affect SCN clock gene rhythmicity but did cause the ARC to desynchronize. Moreover, unilateral SCN lesions with contralateral retrochiasmatic microcuts resulted in identical arrhythmicity, proving that for the expression of physiological rhythms this reciprocal SCN-ARC interaction is essential. The unaltered SCN c-Fos expression following glucose administration in disconnected animals as compared to a significant decrease in controls demonstrates the importance of the ARC as metabolic modulator of SCN neuronal activity. Together, these results indicate that the SCN is more than an autonomous clock, and forms an essential component of a larger network controlling homeostasis. The present novel findings illustrate how an imbalance between SCN and ARC communication through circadian disruption could be involved in the etiology of metabolic disorders.
In mammals, circadian rhythms are driven by a pacemaker located in the suprachiasmatic nucleus (SCN), which is composed of multiple, single-cell oscillators. Isolated SCN tissue shows clear circadian oscillation in release of arginine vasopressin (AVP) in organotypic slice cultures. Previously, we reported that the oscillators in the dorsal SCN have shorter periods than those in the ventral part. Here, we examined whether a correlation between the period and the rostral-caudal co-ordination could exist. The rostral, central and caudal SCN were cultured separately and the periods of circadian rhythms of AVP release were measured. The rostral and caudal parts of the SCN showed shorter periods than the central SCN. Together with previous findings, it is suggested that the shorter period region originates from AVP containing areas, while the longer period region corresponds with vasoactive intestinal polypeptide (VIP) containing cells. In our VIP-immunoreactive slices, the application of VIP antagonists shortened the periods of the AVP-releasing rhythm. These data indicate that the oscillators in AVP cells have short periods and are entrained by VIP cells to form a single integrated rhythm.
The bilaterally symmetrical suprachiasmatic nuclei (SCN) of the hypothalamus are the loci of the mammalian clock controlling circadian rhythms. Previous studies suggested that all regions of the SCN are equipotential as circadian rhythmicity is sustained after partial ablation, as long as approximately 25% of the nuclei are spared. In contrast to these results, we found that animals bearing partial lesions of the SCN that spared the subregion delimited by cells containing the calcium-binding protein calbindin-D28K (CaBP), sustained circadian locomotor rhythms. Furthermore, there was a correlation between the strength of the rhythm and the number of spared CaBP cells. Partial lesions that destroyed this region but spared other compartments of the SCN resulted in loss of rhythmicity. The next study indicates that transplants of half-SCN grafts that contain CaBP cells restore locomotor rhythms in SCN-lesioned host animals, whereas transplants containing SCN tissue but lacking cells of this subnucleus fail to restore rhythmicity. Finally, there was a correlation between the number of CaBP-positive cells in the graft and the strength of the restored rhythm. Taken together, the results indicate that pacemakers in the region of the CaBP subnucleus are necessary and sufficient for the control of locomotor rhythmicity and that the SCN is functionally heterogeneous.
The suprachiasmatic nucleus (SCN) of the hypothalamus is the master circadian clock in mammals. SCN neurons exhibit circadian Ca2+ rhythms in the cytosol, which is thought to act as a messenger linking the transcriptional/translational feedback loop (TTFL) and physiological activities. Transcriptional regulation occurs in the nucleus in the TTFL model, and Ca2+-dependent kinase regulates the clock gene transcription. However, the Ca2+ regulatory mechanisms between cytosol and nucleus as well as the ionic origin of Ca2+ rhythms remain unclear. In the present study, we monitored circadian-timescale Ca2+ dynamics in the nucleus and cytosol of SCN neurons at the single-cell and network levels. We observed robust nuclear Ca2+ rhythm in the same phase as the cytosolic rhythm in single SCN neurons and entire regions. Neuronal firing inhibition reduced the amplitude of both nuclear and cytosolic Ca2+ rhythms, whereas blocking of Ca2+ release from the endoplasmic reticulum (ER) via ryanodine and inositol 1,4,5-trisphosphate (IP3) receptors had a minor effect on either Ca2+ rhythms. We conclude that the in-phasic circadian Ca2+ rhythms in the cytosol and nucleus are mainly driven by Ca2+ influx from the extracellular space, likely through the nuclear pore. It also raises the possibility that nuclear Ca2+ rhythms directly regulate transcription in situ.
The role of the suprachiasmatic nuclei (SCN) in generating circadian rhythms in physiology and behavior is well established. Recent evidence based on clock gene expression indicates that the rodent SCN are composed of at least two functional subdivisions. In Syrian hamsters (Mesocricetus auratus), cells in a subregion of the caudal SCN marked by calbindin-D(28K) (CalB) express light-induced, but not rhythmic, clock genes (Per1, Per2, and Per3). In the SCN region marked by vasopressinergic cells and fibers, clock gene expression is rhythmic. Importantly, lesions of the CalB subregion that spare a significant portion of the SCN abolish rhythms in locomotor behavior. One possibility is that the CalB subregion is required to maintain SCN function necessary to support all behavioral and physiological rhythms. Alternatively, this subregion may control circadian rhythms in locomotor behavior, whereas other circadian responses in physiology and behavior are sustained by different SCN compartments. The present study sought to distinguish between these possibilities by examining the role of the CalB subregion in a battery of rhythms within an individual animal. The results indicate that lesions of the CalB subregion of the SCN abolish circadian rhythms in behavior (locomotion, drinking, gnawing), physiology (body temperature, heart rate), and hormone secretion (melatonin, cortisol), even when other SCN compartments are spared. Together, these findings suggest a novel fundamental property of SCN organization, with a subset of cells being critical for the maintenance of SCN function manifest in circadian rhythms in physiology and behavior.
The transmission of information about the photic environment to the circadian clock involves a complex array of neurotransmitters, receptors, and second messenger systems. Exposure of an animal to light during the subjective night initiates rapid transcription of a number of immediate-early genes in the suprachiasmatic nucleus of the hypothalamus. Some of these genes have known roles in entraining the circadian clock, while others have unknown functions. Using laser capture microscopy, microarray analysis, and quantitative real-time PCR, we performed a comprehensive screen for changes in gene expression immediately following a 30 minute light pulse in suprachiasmatic nucleus of mice.
The circadian clock, located in the suprachiasmatic nucleus (SCN), receives a major afferent from the median raphe nucleus (MRN). In the Syrian hamster, only about 50% of the cells giving rise to this afferent contain serotonin. There is mixed evidence as to whether the serotonergic portion of this projection is involved in non-photic phase shifting of circadian locomotor rhythms. In order to better characterize the non-serotonergic projections, we conducted retrograde tract tracing using the beta subunit of cholera toxin combined with multi-label immunohistochemistry. Similar to previous findings, almost half of the retrogradely labeled cells contained serotonin. Additionally, approximately 30% of the retrogradely labeled cells contained vesicular glutamate transporter 3 (VGLUT3), but not serotonin. Surprisingly, some dorsal raphe cholera toxin labeling was also noted, particularly in animals with central-SCN injections. To determine if the non-serotonergic projections were important for non-photic phase shifts elicited by MRN stimulation, the MRN was electrically stimulated in animals pretreated with SCN injection of either the serotonin neurotoxin 5,7-dihydroxytryptamine or vehicle control. Intact animals phase advanced to midday electrical stimulation of the raphe while lesioned animals did not. Together, these results show that although some of the non-serotonergic raphe projections to the SCN contain VGLUT3, it is the serotonergic raphe innervation of the SCN that is critical for non-photic phase shifting elicited by MRN stimulation.
Many biochemical, physiological, and behavioral processes such as glucose metabolism, body temperature, and sleep-wake cycles show regular daily rhythms. These circadian rhythms are adjusted to the environmental light-dark cycle by a central pacemaker located in the suprachiasmatic nucleus (SCN) in order for the processes to occur at appropriate times of day. Here, we investigated the expression and function of a synaptic organizing protein, C1QL3, in the SCN. We found that C1ql3 is robustly expressed in the SCN. C1ql3 knockout mice have a reduced density of excitatory synapses in the SCN. In addition, these mice exhibited less consolidated activity to the active portions of the day and period lengthening following a 15-minute phase-delaying light pulse. These data identify C1QL3 as a signaling molecule that is highly expressed in SCN neurons, where it contributes to the formation and/or maintenance of glutamatergic synapses and plays a role in circadian behaviors, which may include circadian aftereffects.
Dopamine (DA) neurotransmission controls behaviors important for survival, including voluntary movement, reward processing, and detection of salient events, such as food or mate availability. Dopaminergic tone also influences circadian physiology and behavior. Although the evolutionary significance of this input is appreciated, its precise neurophysiological architecture remains unknown. Here, we identify a novel, direct connection between the DA neurons of the ventral tegmental area (VTA) and the suprachiasmatic nucleus (SCN). We demonstrate that D1 dopamine receptor (Drd1) signaling within the SCN is necessary for properly timed resynchronization of activity rhythms to phase-shifted light:dark cycles and that elevation of DA tone through selective activation of VTA DA neurons accelerates photoentrainment. Our findings demonstrate a previously unappreciated role for direct DA input to the master circadian clock and highlight the importance of an evolutionarily significant relationship between the circadian system and the neuromodulatory circuits that govern motivational behaviors.
Glycogen synthase kinase 3 (GSK3) is a serine-threonine kinase that regulates mammalian circadian rhythms at the behavioral, molecular and neurophysiological levels. In the central circadian pacemaker, the suprachiasmatic nucleus (SCN), inhibitory phosphorylation of GSK3 exhibits a rhythm across the 24 h day. We have recently shown that GSK3 is capable of influencing both the molecular clock and SCN neuronal activity rhythms. However, it is not known whether GSK3 regulates the response to environmental cues such as light. The goal of this study was to test the hypothesis that GSK3 activation mediates light-induced SCN excitability and photic entrainment. Immunofluorescence staining in the SCN of mice showed that late-night light exposure significantly increased GSK3 activity (decreased pGSK3β levels) 30-60 min after the light-pulse. In addition, pharmacological inhibition of GSK3 blocked the expected light-induced excitability in SCN neurons; however, this effect was not associated with changes in resting membrane potential or input resistance. Behaviorally, mice with constitutively active GSK3 (GSK3-KI) re-entrained to a 6-h phase advance in the light-dark cycle in significantly fewer days than WT control animals. Furthermore, the behavioral and SCN neuronal activity of GSK3-KI mice was phase-advanced compared to WT, in both normal and light-exposed conditions. Finally, GSK3-KI mice exhibited normal negative-masking behavior and electroretinographic responses to light, suggesting that the enhanced photic entrainment is not due to an overall increased sensitivity to light in these animals. Taken together, these results provide strong evidence that GSK3 activation contributes to light-induced phase-resetting at both the neurophysiological and behavioral levels.
The suprachiasmatic nucleus (SCN) generates circadian rhythms of behavior and hormone secretion in mammals, and integrates responses to light and nonphotic stimuli to synchronize such rhythms with the external environment. Previous studies have demonstrated a close association between the induction of the immediate early gene (IEG) c-fos in the SCN by light and phase shifts of circadian rhythms induced by light, but nonphotic stimuli (e.g., arousal), which also cause phase shifts, do not increase c-fos expression in the SCN. Because c-fos is now known to be a member of a large family of IEGs which can regulate transcription and thus cellular function, the aim of the current study was to determine whether induction of another member of this immediate early gene family, fosB, is associated with photic and nonphotic phase shifts. An antiserum that recognizes a unique peptide sequence derived from FosB was produced so that the expression of fosB could be investigated in cells within the SCN by immunocytochemical detection of its protein product. The regional distribution of FosB-immunoreactive (ir) cells in the SCN of Syrian and Siberian hamsters was broadly similar to that for c-Fos-ir cells. However, whereas c-fos expression in the SCN was constitutively low, but could be massively induced by light at particular circadian phases, FosB-ir cells were present at all circadian phases studied, irrespective of photic stimulation, and light only produced marginal increases in the number of FosB-ir cells compared with nonstimulated controls. Moreover, blockade of glutamatergic neurotransmission by pretreatment of hamsters with the NMDA receptor antagonist MK801 significantly reduced photic induction of c-Fos-ir cells, but did not influence the number of FosB-ir cells in the SCN. Finally, an arousing nonphotic stimulus known to cause phase advances in wheel-running behavior in Syrian hamsters did not alter significantly the number of FosB-ir cells in the SCN. These observations indicate that light and nonphotic stimuli are not potent regulators of fosB expression in the SCN. However, because fosB and c-fos can be present in the SCN at the same time after a light pulse, these studies indicate the potential for interactions with each other and with members of the Jun family in the regulation of the circadian timing system.
Glycemia is maintained within very narrow boundaries with less than 5% variation at a given time of the day. However, over the circadian cycle, glycemia changes with almost 50% difference. How the suprachiasmatic nucleus, the biological clock, maintains these day-night variations with such tiny disparities remains obscure. We show that via vasopressin release at the beginning of the sleep phase, the suprachiasmatic nucleus increases the glucose transporter GLUT1 in tanycytes. Hereby GLUT1 promotes glucose entrance into the arcuate nucleus, thereby lowering peripheral glycemia. Conversely, blocking vasopressin activity or the GLUT1 transporter at the daily trough of glycemia increases circulating glucose levels usually seen at the peak of the rhythm. Thus, biological clock-controlled mechanisms promoting glucose entry into the arcuate nucleus explain why peripheral blood glucose is low before sleep onset.
Previous studies indicate that light information reaches the suprachiasmatic nucleus (SCN) through a subpopulation of retinal ganglion cells that contain both glutamate and pituitary adenylyl cyclase activating peptide (PACAP). While the role of glutamate in this pathway has been well studied, the involvement of PACAP and its receptors are only beginning to be understood. Speculating that PACAP may function to modulate how neurons in the suprachiasmatic nucleus respond to glutamate, we used electrophysiological and calcium imaging tools to examine possible cellular interactions between these co-transmitters.
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