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ABSTRACT: The two major classes of activity-dependent neuroplasticity predict different consequences of activity alteration on circuit response. Hebbian plasticity (positive feedback) posits that alteration of neuronal activity causes a parallel response within a circuit. In contrast, homeostatic plasticity (negative feedback) predicts that altering neuronal activity results in compensatory responses within a circuit. The relative roles of these modes of plasticity in vivo are unclear, since neuronal circuits are difficult to manipulate in the intact organism. In this study, we tested the in vivo effects of activity deprivation in the superior cervical ganglion-pineal circuit of adult rats, which can be noninvasively silenced by exposing animals to constant light. We demonstrated that total deprivation of sympathetic activity markedly decreased the presence of axonal proteins in the pineal and reduced the density and thickness of sympathetic axonal arbors. In addition, we demonstrated that sympathetic inactivity eliminated pineal function and markedly decreased pineal expression of neurotrophins. Administration of β-adrenergic agonist restored the expression of presynaptic and postsynaptic proteins. Furthermore, compensatory axonal growth through collateral sprouting, normally seen following unilateral denervation of the pineal, was profoundly impaired in the absence of neural activity. Thus, these data suggest that sympathetic axonal terminals are maintained by neural activity that induces neurotrophins, which may act through a retrograde mechanism to preserve the integrity of axonal arbors via a positive feedback loop. Conversely, by using Hebbian-like neuroplasticity, silent yet intact circuits enter a hibernation mode marked by reduction of presynaptic axonal structures and dramatically reduced postsynaptic expression of neurotrophins.
Journal of Neuroscience 09/2011; 31(36):12708-15. · 7.11 Impact Factor
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ABSTRACT: Sleep disorders are important risk factors for stroke; conversely, stroke patients suffer from sleep disturbances including disruptions of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep and a decrease in total sleep. This study was performed to characterize the effect of stroke on sleep architecture of rats using continuous electroencephalography (EEG) and activity monitoring. Rats were implanted with transmitters which enabled continuous real time recording of EEG, electromyography (EMG), and locomotor activity. Baseline recordings were performed prior to induction of either transient middle cerebral artery (MCA) occlusion or sham surgery. Sleep recordings were obtained for 60 h after surgery to identify periods of wakefulness, NREM, and REM sleep before and after stroke. Spectral analysis was performed to assess the effects of stroke on state-dependent EEG. Finally, we quantified the time in wake, NREM, and REM sleep before and after stroke. Delta power, a measure of NREM sleep depth, was increased the day following stroke. At the same time, there was a significant shift in theta rhythms to a lower frequency during REM and wake periods. The awake EEG slowed after stroke over both hemispheres. The EEG of the ischemic hemisphere demonstrated diminished theta power specific to REM in excess of the slowing seen over the contralateral hemisphere. In contrast to rats exposed to sham surgery which had slightly increased total sleep, rats undergoing stroke experienced decreased total sleep. The decrease in total sleep after stroke was the result of dramatic reduction in the amount of REM sleep after ischemia. The suppression of REM after stroke was due to a decrease in the number of REM bouts; the length of the average REM bout did not change. We conclude that after stroke in this experimental model, REM sleep of rats is specifically and profoundly suppressed. Further experiments using this experimental model should be performed to investigate the mechanisms and consequences of REM suppression after stroke.
Experimental Neurology 08/2011; 232(2):168-75. · 4.70 Impact Factor
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ABSTRACT: Serotonin N-acetyltransferase (AANAT) catalyzes the conversion of serotonin to N-acetylserotonin, which is the immediate precursor for formation of melatonin. Although it is known that AANAT is degraded via the proteasomal proteolysis, detailed mechanisms are not defined. In this paper, we tested the in vivo role of proteasome inhibition on AANAT activity and melatonin release and examined the amino acid residues in AANAT that contribute to the proteasome degradation. We have shown that inhibition of proteasome activities in vivo in the intact pineal gland fails to prevent the light-induced suppression of melatonin secretion. Furthermore, in cell lines stably expressing AANAT, inhibition of proteasomal proteolysis, which resulted in a large accumulation of AANAT protein, similarly failed to increase AANAT enzyme activity proportional to the amount of proteins accumulated. Site-directed mutagenesis analysis of AANAT revealed that the AANAT degradation is independent of lysine and the two surface cysteine residues. Deletion analysis of N-terminus identified the second amino acid leucine (L2) as the key residue that contributes to the proteasomal proteolysis of AANAT protein. These results suggest that rat AANAT protein is degraded via the N-end rule pathway of proteasomal proteolysis and the leucine at the N-terminus appears to be the key residue recognized by N-end rule pathway.
Journal of Pineal Research 03/2010; 48(3):290-6. · 5.79 Impact Factor
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ABSTRACT: Melatonin is a hormone secreted from the pineal gland specifically at night and contributes to a wide array of physiological functions in mammals. Melatonin is one of the most well understood output of the circadian clock located in the suprachiasmatic nucleus. Melatonin synthesis is controlled distally via the circadian clock located in the suprachiasmatic nucleus and proximally regulated by norepinephrine released in response to the circadian clock signals. To understand melatonin synthesis in vivo, we have performed microdialysis analysis of the pineal gland, which monitors melatonin as well as the precursor (serotonin) and intermediate (N-acetylserotonin) of melatonin synthesis in freely moving animals in realtime at high resolution. Our data revealed a number of novel features of melatonin production undetected using conventional techniques, which include (1) large inter-individual variations of melatonin onset timing; (2) circadian regulation of serotonin synthesis and secretion in the pineal gland; and (3) a revised view on the rate-limiting step of melatonin formation in vivo. This article will summarize the main findings from our laboratory regarding melatonin formation in mammals.
Reviews in Endocrine and Metabolic Disorders 12/2009; 10(4):237-43. · 3.17 Impact Factor
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ABSTRACT: Pineal melatonin release exhibits a circadian rhythm with a tight nocturnal pattern. Melatonin synthesis is regulated by the
master circadian clock within the hypothalamic suprachiasmatic nucleus (SCN) and is also directly inhibited by light. The
SCN is necessary for both circadian regulation and light inhibition of melatonin synthesis and thus it has been difficult
to isolate these two regulatory limbs to define the output pathways by which the SCN conveys circadian and light phase information
to the pineal. A 22-h light–dark (LD) cycle forced desynchrony protocol leads to the stable dissociation of rhythmic clock
gene expression within the ventrolateral SCN (vlSCN) and the dorsomedial SCN (dmSCN). In the present study, we have used this
protocol to assess the pattern of melatonin release under forced desynchronization of these SCN subregions. In light of our
reported patterns of clock gene expression in the forced desynchronized rat, we propose that the vlSCN oscillator entrains
to the 22-h LD cycle whereas the dmSCN shows relative coordination to the light-entrained vlSCN, and that this dual-oscillator
configuration accounts for the pattern of melatonin release. We present a simple mathematical model in which the relative
coordination of a single oscillator within the dmSCN to a single light-entrained oscillator within the vlSCN faithfully portrays
the circadian phase, duration and amplitude of melatonin release under forced desynchronization. Our results underscore the
importance of the SCN′s subregional organization to both photic input processing and rhythmic output control.
Proceedings of the National Academy of Sciences 10/2009; 106(41):17540-17545. · 9.68 Impact Factor
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ABSTRACT: Small laboratory animals have provided significant information about melatonin regulation, yet most of these organisms are nocturnal and regulate melatonin synthesis by mechanisms that diverge from those of humans. For example, in all rodents examined, melatonin secretion occurs with a time lag of several hours after the onset of darkness; in addition, arylalkylamine N-acetyltransferase (AANAT), the key enzyme in melatonin synthesis, displays dynamic transcriptional activation specifically at night in all rodents studied to date. In ungulates and primates including humans, on the other hand, melatonin secretion occurs immediately during the early night and is controlled by circadian posttranscriptional regulation of AANAT. We hypothesize that the diurnal Octodon degus (an Hystricognath rodent) could serve as an improved experimental model for studies of human melatonin regulation. To test this, we monitored melatonin production in degus using pineal microdialysis and characterized the regulation of melatonin synthesis by analyzing degu Aanat. Degu pineal melatonin rises with little latency at night, as in ungulates and primates. In addition, degu Aanat mRNA expression displays no detectable diurnal variation, suggesting that, like ungulates and primates, melatonin in this species is regulated by a posttranscriptional mechanism. Compared with AANAT from all rodents examined to date, the predicted amino acid sequence of degu AANAT is phylogenetically more closely related to ungulate and primate AANAT. These data suggest that Octodon degus may provide an ideal model system for laboratory investigation of mechanisms of melatonin synthesis and secretion in diurnal mammals.
Journal of Pineal Research 07/2009; 47(1):75-81. · 5.79 Impact Factor
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ABSTRACT: The central circadian pacemaker is a remarkably robust regulator of daily rhythmic variations of cardiovascular, endocrine, and neural physiology. Environmental lighting conditions are powerful modulators of circadian rhythms, but regulation of circadian rhythms by disease states is less clear. Here, we examine the effect of ischemic stroke on circadian rhythms in rats using high-resolution pineal microdialysis.
Rats were housed in LD 12:12 h conditions and monitored by pineal microdialysis to determine baseline melatonin timing profiles. After demonstration that the circadian expression of melatonin was at steady state, rats were subjected to experimental stroke using two-hour intralumenal filament occlusion of the middle cerebral artery. The animals were returned to their cages, and melatonin monitoring was resumed. The timing of onset, offset, and duration of melatonin secretion were calculated before and after stroke to determine changes in circadian rhythms of melatonin secretion. At the end of the monitoring period, brains were analyzed to determine infarct volume.
Rats demonstrated immediate shifts in melatonin timing after stroke. We observed a broad range of perturbations in melatonin timing in subsequent days, with rats exhibiting onset/offset patterns which included: advance/advance, advance/delay, delay/advance, and delay/delay. Melatonin rhythms displayed prolonged instability several days after stroke, with a majority of rats showing a day-to-day alternation between advance and delay in melatonin onset and duration. Duration of melatonin secretion changed in response to stroke, and this change was strongly determined by the shift in melatonin onset time. There was no correlation between infarct size and the direction or amplitude of melatonin phase shifting.
This is the first demonstration that stroke induces immediate changes in the timing of pineal melatonin secretion, indicating that cortical and basal ganglia infarction impacts the timing of melatonin rhythms. The heterogeneous direction and amplitude of melatonin shifts suggests that the upstream regulation of hypothalamic timekeeping is likely anatomically diffuse and mechanistically complex. Finally, our study exemplifies the use of pineal microdialysis to evaluate the effect of neurological diseases on circadian function.
Journal of Circadian Rhythms 11/2008; 6:9.
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ABSTRACT: Serotonin (5-hydroxytryptamine, 5-HT), a precursor for melatonin production, is produced abundantly in the pineal gland of all vertebrate animals. The synthesis of 5-HT in the pineal gland is rate limited by tryptophan hydroxylase 1 (TPH1) whose activity displays a twofold increase at night. Earlier studies from our laboratory demonstrate that pineal 5-HT secretion exhibits dynamic circadian rhythms with elevated levels during the early night, and that the increase is controlled by adrenergic signaling at night. In this study, we report that (a) 5-HT total output from the pineal gland and TPH1 protein levels both display diurnal rhythms with a twofold increase at night; (b) stimulation of cAMP signaling elevates 5-HT output in vivo; (c) 5-HT total output and TPH1 protein content in rat pineal gland are both acutely inhibited by light exposure at night. Consistent with these findings, molecular analysis of TPH1 protein revealed that (a) TPH1 is phosphorylated at the serine 58 in vitro and in the night pineal gland; and (b) phosphorylation of TPH1 at this residue is required for cAMP-enhanced TPH1 protein stability. These data support the model that increased nocturnal 5-HT synthesis in the pineal gland is mediated by the phosphorylation of TPH1 at the serine 58, which elevates the TPH1 protein content and activity at night.
Journal of Pineal Research 09/2008; 45(4):506-14. · 5.79 Impact Factor
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ABSTRACT: Our laboratory has pioneered long-term microdialysis to monitor pineal melatonin secretion in living animals across multiple circadian cycles. There are numerous advantages of this approach for rhythm analysis: (1) we can precisely define melatonin onset and offset phases; (2) melatonin is a reliable and stable neuroendocrine output of the circadian clock (versus behavioral output which is sensitive to stress or other factors); (3) melatonin measurements can be performed extremely frequently, permitting high temporal resolution (10 min sampling intervals), which allows detection of slight changes in phase; (4) the measurements can be performed for more than four weeks, allowing perturbations of the circadian clock to be followed long-term in the same animals; (5) this is an automated process (microdialysis coupled with on-line HPLC analysis), which increases accuracy and bypasses the labor-intensive and error-prone manual handling of dialysis samples; and (6) our approach allows real-time investigation of circadian rhythm function and permits appropriate timely adjustments of experimental conditions. The longevity of microdialysis probes, the key to the success of this approach, depends at least in part on the methods of the construction and implantation of dialysis probes. In this article, we have detailed the procedures of construction and surgical implantation of microdialysis probes used currently in our laboratory, which are significantly improved from our previous methods.
Pharmacology Biochemistry and Behavior 09/2008; 90(2):148-55. · 2.53 Impact Factor
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ABSTRACT: The mammalian clock regulates major aspects of energy metabolism, including glucose and lipid homeostasis and mitochondrial oxidative metabolism. The biochemical basis for coordinated control of the circadian clock and diverse metabolic pathways is not well understood. Here we show that PGC-1alpha (Ppargc1a), a transcriptional coactivator that regulates energy metabolism, is rhythmically expressed in the liver and skeletal muscle of mice. PGC-1alpha stimulates the expression of clock genes, notably Bmal1 (Arntl) and Rev-erbalpha (Nr1d1), through coactivation of the ROR family of orphan nuclear receptors. Mice lacking PGC-1alpha show abnormal diurnal rhythms of activity, body temperature and metabolic rate. The disruption of physiological rhythms in these animals is correlated with aberrant expression of clock genes and those involved in energy metabolism. Analyses of PGC-1alpha-deficient fibroblasts and mice with liver-specific knockdown of PGC-1alpha indicate that it is required for cell-autonomous clock function. We have thus identified PGC-1alpha as a key component of the circadian oscillator that integrates the mammalian clock and energy metabolism.
Nature 06/2007; 447(7143):477-81. · 36.28 Impact Factor
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ABSTRACT: We have recently reported dynamic circadian rhythms of serotonin (5-HT, 5-hydroxytryptamine) output in the pineal gland of rat, which precedes the onset of N-acetylserotonin (NAS) and melatonin secretion at night. The present study was aimed at investigating in detail the relationship between 5-HT onset (5HT-on) and melatonin onset (MT-on) in multiple strains of rats and comparing them with those of hamsters.
Animals were maintained in chambers equipped with light (250 lux at cage levels) and ventilation in a temperature-controlled room. Following surgical implantation of a microdialysis probe in the pineal gland, animals were individually housed for on-line pineal microdialysis and for automated HPLC analysis of 5-HT and melatonin. Animals were under a light-dark cycle of 12:12 h for the duration of the experiments.
All animals displayed dynamic 5-HT and melatonin rhythms at night. In all cases, 5HT-on (taken at 80% of the daily maximum levels) preceded MT-on (taken at 20% of the daily maximum levels). Within the same animals, 5HT-on as well as MT-on across multiple circadian cycles exhibited minimum variations under entrained conditions. Large inter-individual variations of both 5HT-on and MT-on were found in outbred rats and hamsters under entrained conditions. In comparison, inbred rats displayed very small individual variations of 5HT-on and MT-on. Importantly, we have uncovered a species-specific relationship of 5HT-on and MT-on. 5HT-on of rats, regardless of the strain, preceded MT-on of the same rats by 50 min. In contrast, 5HT-on of hamsters led MT-on by as much as 240 min. Thus, while a constant relationship of 5HT-on and MT-on exists for animals of the same species, the relative timings of 5HT-on and MT-on differ between animals of different species.
These results suggest that both 5-HT and melatonin could serve as reliable markers of the circadian clock because of their day-to-day precision of onset timings within the same animals or within individuals of the same strain or same species. The results also demonstrate that data for MT-on cannot be compared directly between different species, and that 5HT-on may be a more reliable circadian marker when data from animals of different species are compared.
Journal of Circadian Rhythms 02/2006; 4:12.
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ABSTRACT: Circadian rhythms are self-sustaining oscillations that free-run in constant conditions with a period close to 24 h. Overt circadian rhythms have been studied mostly using onset phase as the marker for the underlying pacemaker. Using in vivo online pineal microdialysis, the authors have performed detailed analysis of free-running profiles of rat pineal secretory products, including N-acetylserotonin (NAS) and melatonin that have precisely defined onsets and offsets. When rats entrained in LD 12:12 were released into constant darkness (DD), both onset and offset phases of melatonin and NAS free-run. However, while onsets free-run with a period closer to a day (FRP(on) = 24-24.17 h) at the beginning, offset phases free-run with significantly larger FRPs (free-running periods) (FRP(off) = 24.24-24.42 h). This asymmetric free-running of onset and offset of NAS and melatonin in DD resulted in a 60- to 120-min increase of secretion duration of both NAS and melatonin. The rate of expansion of melatonin duration was 10 to 15 min per circadian cycle. The expansion of melatonin secretion duration ended for some within 4 days, while others were still expanding by the end of 10th day in DD. These results revealed that upon release into DD, the pacemaker's oscillation is initially driven by 2 forces, free running and decompression, before reaching a stable state of free running, and suggest that the circadian pacemaker may be an elastic structure that can decompress and compress under varying photic conditions. They also illustrate the importance of using both onset and offset of a given rhythm as phase markers, as compression/decompression, and transient disparity between FRP(on) and FRP(off) may be a common phenomenon of the circadian pacemaker.
Journal of Biological Rhythms 11/2005; 20(5):430-40. · 2.93 Impact Factor
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ABSTRACT: Circadian rhythms are endogenously generated by a central pacemaker and are synchronized to the environmental LD cycle. The rhythms can be resynchronized, or reentrained, after a shift of the LD cycle, as in traveling across time zones. The authors have performed high-resolution mapping of the pacemaker to analyze the reentrainment process using rat pineal melatonin onset (MT(on)) and melatonin offset (MT(off)) rhythms as markers. Following LD (12:12) delays of 3, 6, and 12 h, MT(on) was phase locked immediately, whereas MT(off) shifted rapidly during the initial 1 through 3 cycles. In all animals, the MT(off) shifted beyond their expected phase positions in the new LD cycle, which resulted in a transient expansion of melatonin secretion duration for several cycles. It took MT(off) only 1, 2, or 3 cycles to complete most of the required phase shifts after 3, 6, or 12 h of the LD cycle delays, respectively. However, the final stabilization of phase relationships of both MT(on) and MT(off) required at least 6 cycles for rats experiencing a 3-h LD delay and much longer for the rest. These results reaffirmed the notion that both onset and offset phases of melatonin rhythms are important markers for the pacemaker and demonstrated that the reentrainment of the central pacemaker to a delay shift of the LD cycle is a 3-step process: an immediate phase lock of onset and a rapid delay shift of offset rhythms, overshoot of the offset, and, finally, a slow adjustment of both onset and offset phases. This study represents the 1st detailed analysis of the pacemaker behavior during reentrainment using melatonin and supports the notion that the eventual adaptation of the circadian pacemaker to a new time zone is a time-consuming process.
Journal of Biological Rhythms 11/2005; 20(5):441-50. · 2.93 Impact Factor
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ABSTRACT: Circadian melatonin production in the pineal gland and retina is under the control of serotonin N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase. Because NAT activity varies diurnally, it has been considered both the melatonin rhythm-generating enzyme and the rate-limiting enzyme of melatonin synthesis. In rats with dramatically reduced NAT activity due to a H28Y mutation in NAT, melatonin levels remained the same as in wildtype controls, suggesting that NAT does not determine the rate of melatonin production at night. Using a combination of molecular approaches with a sensitive in vivo measurement of pineal diurnal melatonin production, we demonstrate that (i) N-acetylserotonin (NAS), the enzymatic product of NAT, is present in vast excess in the night pineals compared with melatonin; (ii) the continuous increase in NAT protein levels at late night does not produce a proportional increase in melatonin; and (iii) an increase in NAS in the same animal over several circadian cycles do not result in corresponding increase in melatonin output. These results strongly suggest that NAT is not the rate-limiting enzyme of melatonin formation at night.
Journal of Pineal Research 09/2005; 39(1):91-6. · 5.79 Impact Factor
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ABSTRACT: This study describes the development of a new technique for long-term measurement of daily 5-hydroxytryptamine (5-HT) and melatonin contents in the pineal gland of freely moving rats. The technique features a number of novel improvements over previous protocols. It allows visualization of the pineal gland for accurate targeting of the guide cannula, which minimizes bleeding; incurs no direct injury to the surrounding brain tissues; and causes no interference with the sympathetic innervation from the superior cervical ganglia. Robust releases of melatonin and indole precursors were continuously monitored quantitatively and reproducibly for more than 2 wk in the same animal. In addition, effects of pharmacological agents on in vivo pineal circadian rhythms can be studied reproducibly over time, and gene expression profiles can be correlated with physiological consequences in single animals. Using these approaches, it is found that beta-adrenergic activation leads to decreased release of 5-HT, and that increased cAMP signaling in vivo results in activation of N-acetyltransferase gene induction and melatonin production. These studies will enhance the understanding of signaling pathways that regulate pineal 5-HT and melatonin synthesis and secretion.
Journal of Pineal Research 10/2003; 35(2):118-24. · 5.79 Impact Factor
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ABSTRACT: The 3-O-sulfotransferases (3OSTs) catalyze the addition of sulfate groups at the 3-OH site of glucosamine in heparan sulfate proteoglycans, which serve as critical mediators of various biological functions. We demonstrate that the 3OST2 isoform is expressed at high levels in the rat pineal specifically during the daylight hours. The dramatic diurnal rhythm of 3OST2 is regulated by central clock-controlled activities of the superior cervical ganglion, persists in constant darkness, and is inducible by light at nighttime. Importantly, 3OST2 transcription is blocked by beta-adrenergic agonists that activate the pineal melatonin formation and is induced by beta-adrenergic antagonists, which block melatonin production in vivo. Because of the inverse expression and regulation patterns of 3OST2 with serotonin N-acetyltransferase, the enzyme controlling the melatonin rhythm in the pineal, we tested the effects of forced expression of 3OST2 in the night pineals on N-acetyltransferase gene expression and melatonin production and found that, surprisingly, 3OST2 expression at night fails to interfere with melatonin synthesis. These data suggest 3OST2 may serve a unique function in the pineal that may be independent of melatonin formation.
Journal of Biological Chemistry 06/2003; 278(18):16315-9. · 4.77 Impact Factor
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ABSTRACT: Using on-line microdialysis, we have characterized in vivo dynamics of pineal 5-hydroxytryptamine (5-HT; serotonin) release. Daily pineal 5-HT output is triphasic: (i) 5-HT levels are constant and high during the day; (ii) early in the night, there is a novel sharp rise in 5-HT synthesis and release, which precedes the nocturnal rise in melatonin synthesis; and (iii) late in the night, levels are low. This triphasic 5-HT production persists in constant darkness and is influenced strongly by intrusion of light at night. We demonstrate that both diurnal 5-HT synthesis and 5-HT release are activated by sympathetic innervation from the superior cervical ganglion and show that these processes are controlled by distinct receptors. The increase in 5-HT synthesis is controlled by beta-adrenergic receptors, whereas the increase in 5-HT release is mediated by alpha-adrenergic signaling. On the other hand, the marked decrease in 5-HT content and release late at night is a passive process, influenced by the extent of melatonin synthesis. In the absence of melatonin synthesis, the late-night decline in 5-HT release is prevented, reaching levels roughly twice as high as that of the day value. In summary, our results demonstrate that 5-HT levels display marked circadian rhythms that depend on adrenergic signaling.
Proceedings of the National Academy of Sciences 05/2002; 99(7):4686-91. · 9.68 Impact Factor
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ABSTRACT: The mammalian clock regulates major aspects of energy metabolism, including glucose and lipid homeostasis and mitochondrial oxidative metabolism(1,2). The biochemical basis for coordinated control of the circadian clock and diverse metabolic pathways is not well understood. Here we show that PGC-1 alpha (Ppargc1a), a transcriptional coactivator that regulates energy metabolism(3-9), is rhythmically expressed in the liver and skeletal muscle of mice. PGC-1 alpha stimulates the expression of clock genes, notably Bmal1 (Arntl) and Rev-erba (Nr1d1), through coactivation of the ROR family of orphan nuclear receptors. Mice lacking PGC-1 alpha show abnormal diurnal rhythms of activity, body temperature and metabolic rate. The disruption of physiological rhythms in these animals is correlated with aberrant expression of clock genes and those involved in energy metabolism. Analyses of PGC-1 alpha-deficient fibroblasts and mice with liver-specific knockdown of PGC-1 alpha indicate that it is required for cell-autonomous clock function. We have thus identified PGC-1 alpha as a key component of the circadian oscillator that integrates the mammalian clock and energy metabolism. Peer Reviewed http://deepblue.lib.umich.edu/bitstream/2027.42/62918/1/nature05767.pdf
Nature.
