Season dependent effects of urban environment on circadian clock of tree sparrow (Passer montanus).

Great efforts have been made recently to understand the effect(s) of urban environments on the circadian and seasonal physiology of wild animals, but the mechanisms involved remain largely unknown. Most laboratory studies and a few studies on animals in the wild suggest alterations occur in the physiological functions of organisms in urban habitats. Here, we addressed the effects of the interaction of seasons and urban environments on clock gene expression in three tissues of tree sparrows (Passer montanus). Tree sparrows (N = 30 per site per time of year) were procured from rural and urban habitats during periods corresponding to their three physiological states, i.e., June (longest photoperiod; reproductive phase), September (equinox photoperiod; refractory phase), and December (shortest photoperiod; sensitive phase). Birds (N = 5 per time per site per month) were sampled at six time points; ZT1, ZT5, ZT9, ZT13, ZT17, and ZT21 (ZT0 = sunrise time) and clock gene expression in the hypothalamus, pineal gland, and retina was studied. Our results show that there is persistence of the circadian clock in both rural and urban birds throughout the year. In urban birds Bmal1, Npas2, Per2, and Cry1 acrophases were advanced, compared to rural birds, while Clock acrophase was delayed, depending on the tissue and time of year. This difference could be because of changes in the availability, duration, and intensity of sunlight during different times of the year and/or differential photoreceptor sensitivities, differential physiological states, or a combination of all these factors. These important results reveal, for the first time in any species, season-dependent effects of an urban environment on the molecular machinery of the circadian clock.

Pineal-dependent increase of hypothalamic neurogenesis contributes to the timing of seasonal reproduction in sheep.

To survive in temperate latitudes, species rely on the photoperiod to synchronize their physiological functions, including reproduction, with the predictable changes in the environment. In sheep, exposure to decreasing day length reactivates the hypothalamo-pituitary-gonadal axis, while during increasing day length, animals enter a period of sexual rest. Neural stem cells have been detected in the sheep hypothalamus and hypothalamic neurogenesis was found to respond to the photoperiod. However, the physiological relevance of this seasonal adult neurogenesis is still unexplored. This longitudinal study, therefore aimed to thoroughly characterize photoperiod-stimulated neurogenesis and to investigate whether the hypothalamic adult born-cells were involved in the seasonal timing of reproduction. Results showed that time course of cell proliferation reached a peak in the middle of the period of sexual activity, corresponding to decreasing day length period. This enhancement was suppressed when animals were deprived of seasonal time cues by pinealectomy, suggesting a role of melatonin in the seasonal regulation of cell proliferation. Furthermore, when the mitotic blocker cytosine-b-D-arabinofuranoside was administered centrally, the timing of seasonal reproduction was affected. Overall, our findings link the cyclic increase in hypothalamic neurogenesis to seasonal reproduction and suggest that photoperiod-regulated hypothalamic neurogenesis plays a substantial role in seasonal reproductive physiology.

Melatonin inhibits hypothalamic gonadotropin-releasing hormone release and reduces biliary hyperplasia and fibrosis in cholestatic rats.

Melatonin is a hormone produced by the pineal gland with increased circulating levels shown to inhibit biliary hyperplasia and fibrosis during cholestatic liver injury. Melatonin also has the capability to suppress the release of hypothalamic gonadotropin-releasing hormone (GnRH), a hormone that promotes cholangiocyte proliferation when serum levels are elevated. However, the interplay and contribution of neural melatonin and GnRH to cholangiocyte proliferation and fibrosis in bile duct-ligated (BDL) rats have not been investigated. To test this, cranial levels of melatonin were increased by implanting osmotic minipumps that performed an intracerebroventricular (ICV) infusion of melatonin or saline for 7 days starting at the time of BDL. Hypothalamic GnRH mRNA and cholangiocyte secretion of GnRH and melatonin were assessed. Cholangiocyte proliferation and fibrosis were measured. Primary human hepatic stellate cells (HSCs) were treated with cholangiocyte supernatants, GnRH, or the GnRH receptor antagonist cetrorelix acetate, and cell proliferation and fibrosis gene expression were assessed. Melatonin infusion reduced hypothalamic GnRH mRNA expression and led to decreased GnRH and increased melatonin secretion from cholangiocytes. Infusion of melatonin was found to reduce hepatic injury, cholangiocyte proliferation, and fibrosis during BDL-induced liver injury. HSCs supplemented with BDL cholangiocyte supernatant had increased proliferation, and this increase was reversed when HSCs were supplemented with supernatants from melatonin-infused rats. GnRH stimulated fibrosis gene expression in HSCs, and this was reversed by cetrorelix acetate cotreatment. Increasing bioavailability of melatonin in the brain may improve outcomes during cholestatic liver disease.NEW & NOTEWORTHY We have previously demonstrated that GnRH is expressed in cholangiocytes and promotes their proliferation during cholestasis. In addition, dark therapy, which increases melatonin, reduced cholangiocyte proliferation and fibrosis during cholestasis. This study expands these findings by investigating neural GnRH regulation by melatonin during BDL-induced cholestasis by infusing melatonin into the brain. Melatonin infusion reduced cholangiocyte proliferation and fibrosis, and these effects are due to GNRH receptor 1-dependent paracrine signaling between cholangiocytes and hepatic stellate cells.

The pineal gland: A model for adrenergic modulation of ubiquitin ligases.

INTRODUCTION: A recent study of the pineal gland of the rat found that the expression of more than 3000 genes showed significant day/night variations (The Hartley dataset). The investigators of this report made available a supplemental table in which they tabulated the expression of many genes that they did not discuss, including those coding for components of the ubiquitin proteasome system. Herein we identify the genes of the ubiquitin proteasome system whose expression were significantly influenced by environmental lighting in the Hartley dataset, those that were stimulated by DBcAMP in pineal glands in culture, and those that were stimulated by norepinephrine. PURPOSE: Using the Ubiquitin and Ubiquitin-like Conjugation Database (UUCA) we identified ubiquitin ligases and conjugases, and deubiquitinases in the Hartley dataset for the purpose of determining whether expression of genes of the ubiquitin proteasome pathway were significantly influenced by day/night variations and if these variations were regulated by autonomic innervation of the pineal gland from the superior cervical ganglia. METHODS: In the Hartley experiments pineal glands groups of rats sacrificed during the day and groups sacrificed during the night were examined for gene expression. Additional groups of rats had their superior cervical ganglia removed surgically or surgically decentralized and the pineal glands likewise examined for gene expression. RESULTS: The genes with at least a 2-fold day/night significant difference in expression included genes for 5 ubiquitin conjugating enzymes, genes for 58 ubiquitin E3 ligases and genes for 6 deubiquitinases. A 35-fold day/night difference was noted in the expression of the gene Sik1, which codes for a protein containing both an ubiquitin binding domain (UBD) and an ubiquitin-associated (UBA) domain. Most of the significant differences in these genes were prevented by surgical removal, or disconnection, of the superior cervical ganglia, and most were responsive, in vitro, to treatment with a cyclic AMP analog, and norepinephrine. All previously described 24-hour rhythms in the pineal require an intact sympathetic input from the superior cervical ganglia. CONCLUSIONS: The Hartley dataset thus provides evidence that the pineal gland is a highly useful model for studying adrenergically dependent mechanisms regulating variations in ubiquitin ligases, ubiquitin conjugases, and deubiquitinases, mechanisms that may be physiologically relevant not only in the pineal gland, but in all adrenergically innervated tissue.

Pinealectomy abolishes circadian behavior and interferes with circadian clock gene oscillations in brain and liver but not retina in a migratory songbird.

In songbirds, the pineal gland is part of the multi-oscillatory circadian timing system, with participating component oscillators in the eyes and hypothalamus. This study investigated the role of the pineal gland in development of the nighttime migratory restlessness (Zugunruhe) and generation of circadian gene oscillations in the retina, brain and liver tissues in migratory redheaded buntings (Emberiza bruniceps). Pinealectomized (pinx) and sham-operated buntings entrained to short days (8h light: 16h darkness, 8L:16D) were sequentially exposed for 10days each to stimulatory long days (13L: 11D) and constant dim light (LLdim; a condition that tested circadian rhythm persistence). Whereas activity-rest pattern was monitored continuously, the mRNA expressions of clock genes (bmal1, clock, npas2, per2, cry1, rorα, reverα) were measured in the retina, hypothalamus, telencephalon, optic tectum and liver tissues at circadian times, CT, 1, 6, 13, 17 and 21 (CT 0, activity onset) on day 11 of the LLdim. The absence of the pineal gland did not affect the development of long-day induced Zugunruhe but caused decay of the circadian rhythm in Zugunruhe as well as the clock gene oscillations in the hypothalamus, but not in the retina. Further, there were variable effects of pinealectomy in the peripheral brain and liver tissue circadian gene oscillations, notably the persistence of per 2 and cry1 (optic tectum), rorα (telencephalon) and npas2 (liver) mRNA oscillations in pinx birds. We suggest the pineal gland dependence of the generation of circadian gene oscillations in the hypothalamus, not retina, and peripheral brain and liver tissues in migratory redheaded buntings.

The benefits of four weeks of melatonin treatment on circadian patterns in resistance-trained athletes.

Exercise can induce circadian phase shifts depending on the duration, intensity and frequency. These modifications are of special meaning in athletes during training and competition. Melatonin, which is produced by the pineal gland in a circadian manner, behaves as an endogenous rhythms synchronizer, and it is used as a supplement to promote resynchronization of altered circadian rhythms. In this study, we tested the effect of melatonin administration on the circadian system in athletes. Two groups of athletes were treated with 100 mg day(-1) of melatonin or placebo 30 min before bed for four weeks. Daily rhythm of salivary melatonin was measured before and after melatonin administration. Moreover, circadian variables, including wrist temperature (WT), motor activity and body position rhythmicity, were recorded during seven days before and seven days after melatonin or placebo treatment with the aid of specific sensors placed in the wrist and arm of each athlete. Before treatment, the athletes showed a phase-shift delay of the melatonin circadian rhythm, with an acrophase at 05:00 h. Exercise induced a phase advance of the melatonin rhythm, restoring its acrophase accordingly to the chronotype of the athletes. Melatonin, but not placebo treatment, changed daily waveforms of WT, activity and position. These changes included a one-hour phase advance in the WT rhythm before bedtime, with a longer nocturnal steady state and a smaller reduction when arising at morning than the placebo group. Melatonin, but not placebo, also reduced the nocturnal activity and the activity and position during lunch/nap time. Together, these data reflect the beneficial effect of melatonin to modulate the circadian components of the sleep-wake cycle, improving sleep efficiency.

[Chronotropic properties of adaptogenic drugs].

Adaptogenic agents of hormonal (melatonin) and plant origin (ginseng and bilobil) produce optimizing effect on circadian rhythm of locomotion and on the temporal dynamics of forced swimming in intact and false-operated rats. Melatonin exhibits the most expressed impact on behavior of animals. After the removal of the pineal gland, these effects of investigated drugs were significantly decreased. It is suggested that the pineal gland may take part in the chronotropic activity of adaptogenic drugs.

[Circadian clock and non-visual functions: the role of light in humans]. / Horloge circadienne et fonctions non visuelles : rôle de la lumière chez l'Homme.

Hormonal secretion, cognitive performance, motor activity, metabolic processes, the sleep wake cycle and, most recently shown, cell division and ADN repair show a 24 h rhythmicity that is driven by the circadian timing system (the biological clock). Their appropriate activity over the 24 h requires appropriate entrainment of the circadian clock, which is achieved through the synchronizing effects of ocular light exposure. The activation of melanopsin-expressing ganglion cells in the retina depends on timing, quality, intensity, and history of light exposure. Inappropriate lighting leads to inappropriate synchronization of the clock, and activation of non-visual functions (mood, wakefulness, cognition, etc.). In turn, a deficit of circadian entrainment to the 24 h is responsible for alterations of a large number of functions, and leads to altered sleep, wake, mood, neurobehavioral processes and cell division, but also to pathologies. The crucial role of the circadian clock and the nature of the non-visual functions activated by light give rise to the concept that light is a biological need fundamental to health. Without an appropriate light hygiene, the clock receives an odd tempo, and it is cacophony!

Intake of melatonin increases tryptophan hydroxylase type 1 activity in aged rats: Preliminary study.

Pineal melatonin is important not only for synchronization of biological rhythms, but also in the ageing process as a potential drug to relieve oxidative damage. During ageing, the nocturnal melatonin production decreases resulting in an increased incidence of disorders. Present in vivo experiments were performed to study the effects of exogenous melatonin chronically administered to old rats on the pineal biosynthesis of melatonin and the precursor serotonin (5-HT) mediated by tryptophan hydroxylase type 1 (TPH-1). Accumulation of 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition was used as a measure of the TPH-1 activity. 5-HT and its metabolite 5-HIAA were also quantified by HPLC-ED. As expected, ageing resulted in worsening of different neurochemical parameters. However, chronic intake of melatonin (1mg/kg/day, diluted in drinking water, 4 weeks) increased TPH-1 activity and significantly improved the age-induced deficits in nocturnal melatonin content in the pineal gland. Results suggest that melatonin intake (or melatonin rich foods) may contribute to recover the pineal function preventing the nocturnal descent of 5-HT and melatonin biosynthesis that normally occur in pineal gland as a consequence of ageing.

Pineal oscillator functioning in the chicken--effect of photoperiod and melatonin.

The avian pineal gland, apart from the hypothalamic master clock (suprachiasmatic nuclei, SCN) and retina, functions as an independent circadian oscillator, receiving external photic cues that it translates into the rhythmical synthesis of melatonin, a biochemical signal of darkness. Functional similarity to the mammalian SCN makes the avian pineal gland a convenient model for studies on biological clock mechanisms in general. Pineal melatonin is produced not only in a light-dependent manner but also remains under the control of the endogenous oscillator, while the possible involvement of melatonin in maintaining cyclic expression of the avian clock genes remains to be elucidated. The aim of the present study was to characterize the diurnal profiles of main clock genes transcription in the pineal glands of chickens exposed to continuous light (LL) and supplemented with exogenous melatonin. We hypothesized that rearing chickens from the day of hatch under LL conditions would evoke a functional pinealectomy, influencing, in turn, pineal clock function. To verify this hypothesis, we examined the diurnal transcriptional profiles of selected clock genes as well as the essential parameters of pineal gland function: transcription of the genes encoding arylalkylamine N-acetyltransferase (Aanat), a key enzyme in melatonin biosynthesis, and the melatonin receptor (Mel1c), along with the blood melatonin level. Chickens hatched in summer or winter were maintained under LD 16:8 and 8:16, corresponding to the respective photoperiods, as the seasonal control groups. Another set of chickens was kept in parallel under LL conditions and some were supplemented with melatonin to check the ability of exogenous hormone to antagonize the effects evoked by continuous light. Twelve-day-old chickens were sacrificed every 3 h over a 24-h period and the mRNAs of selected clock genes, Bmal1, Cry1, Per3, E4bp4, together with those of Aanat and Mel1c, were quantified in the isolated pineal glands. Our results indicate that the profiles of clock gene transcription are not dependent on the duration of the light phase, while LL conditions decrease the amplitude of diurnal changes, but do not abolish them entirely. Melatonin supplied in drinking water to the birds kept in LL seems to desynchronize transcription of the majority of clock genes in the summer, while in the winter, it restores the pattern, but not the diurnal rhythmicity. Rhythmic expression of Bmal1 appears to provide a direct link between the circadian clock and the melatonin output pathway, while the availability of cyclic melatonin is clearly involved in the canonical transcription pattern of Per3 in the chicken pineal gland. Regardless of the experimental conditions, a negative correlation was identified between the transcription of genes involved in melatonin biosynthesis (Aanat) and melatonin signal perception (Mel1c receptor).

The bird circadian clock: insights from a computational model.

The circadian timekeeping system appears more complex in birds than in mammals. In mammals, the main pacemaker is centralized in the suprachiasmatic nuclei, whereas in birds, the pacemaker involves the interplay between the pineal and hypothalamic oscillators. In order to investigate the consequence of this complex mechanism, we propose here a mathematical model for the bird circadian clock. The model is based on the internal resonance between the pineal and hypothalamic oscillators, each described by Goodwin-like equations. We show that, consistently with experimental observations, self-sustained oscillations can be generated by mutual inhibitory coupling of the 2 clocks, even if individual oscillators present damped oscillations. We study the effect of constant and periodic administrations of melatonin, which, in intact birds, acts as the coupling variable between the pineal and the hypothalamus, and compare the prediction of the model with the experiments performed in pinealectomized birds. We also assess the entrainment properties when the system is subject to light-dark cycles. Analyses of the entrainment range, resynchronization time after jet lag, and entrainment phase with respect to the photoperiod lead us to formulate hypotheses about the physiological advantage of the particular architecture of the avian circadian clock. Although minimal, our model opens promising perspectives in modeling and understanding the bird circadian clock.

Impaired leukocyte trafficking and skin inflammatory responses in hamsters lacking a functional circadian system.

The immune system is under strong circadian control, and circadian desynchrony is a risk factor for metabolic disorders, inflammatory responses and cancer. Signaling pathways that maintain circadian rhythms (CRs) in immune function in vivo, and the mechanisms by which circadian desynchrony impairs immune function, remain to be fully identified. These experiments tested the hypothesis that the hypothalamic circadian pacemaker in the suprachiasmatic nucleus (SCN) drives CRs in the immune system, using a non-invasive model of SCN circadian arrhythmia. Robust CRs in blood leukocyte trafficking, with a peak during the early light phase (ZT4) and nadir in the early dark phase (ZT18), were absent in arrhythmic hamsters, as were CRs in spleen clock gene (per1, bmal1) expression, indicating that a functional pacemaker in the SCN is required for the generation of CRs in leukocyte trafficking and for driving peripheral clocks in secondary lymphoid organs. Pinealectomy was without effect on CRs in leukocyte trafficking, but abolished CRs in spleen clock gene expression, indicating that nocturnal melatonin secretion is necessary for communicating circadian time information to the spleen. CRs in trafficking of antigen presenting cells (CD11c(+) dendritic cells) in the skin were abolished, and antigen-specific delayed-type hypersensitivity skin inflammatory responses were markedly impaired in arrhythmic hamsters. The SCN drives robust CRs in leukocyte trafficking and lymphoid clock gene expression; the latter of which is not expressed in the absence of melatonin. Robust entrainment of the circadian pacemaker provides a signal critical to diurnal rhythms in immunosurveilliance and optimal memory T-cell dependent immune responses.

[The role of retinal-hypotalamic-pineal system in pro- and antioxidant processes in the gingival tissues of adult male albino rats].

The aim of this study is to evaluate the effects of pineal gland functional state on the prooxydant processes and antioxidant system in the gingival tissues. Male rats were assigned into one of the following groups in accordance with the duration of photoperiod: 1) control--natural daylight; 2) permanent darkness for 14 days; 3) permanent light for 14 days. The following parameters were measured in gingival tissues and the blood serum: 1) prooxidant factors (dieneconjugates--DC and malonic dialdehyde--MD); 2) antioxidant enzymes (superoxide dismutase--SOD and catalase). The present findings indicate that the gingival tissue of rats reacts to the changes in the duration of photoperiod by peroxidation and activity of antioxidant enzymes. The antioxidant-prooxidant index under dark conditions (high function of the pineal gland) was lower than under condition of permanent light ("physiological" pinealectomy). Different durations of photoperiod change the intensity of free radical oxidation and the activity of antioxidant enzymes at the systemic level (blood serum) and much more at the organ level (tissues of gingiva). Our data suggest that the gingival tissues possess rather powerful protective antioxidant system, which depends on the functional state of the pineal gland.

A review on the effect of the photoperiod and melatonin on interactions between ghrelin and serotonin.

Ghrelin and serotonin, which exhibit rhythmic secretion profiles under feeding/fasting conditions, are sensitive to increases and decreases in the day length and form a close web of interrelationships in the regulation of energy homeostasis. Ghrelin and serotonin are biochemically and functionally linked to the suprachiasmatic nucleus, which is a circadian pacemaker, and melatonin, which is an internal transducer of photic environmental changes. Ghrelin and serotonin might be candidates for integrating photic and nonphotic signals, such as light and food availability in the central nervous system. The mechanisms that convert a light signal into a variety of physiological and behavioral rhythms remain unknown. However, we know that the conversion of light signals is necessary to maximize an animal's chances of survival and reproduction.

Detection of nighttime melatonin level in Chinese Original Quiet Sitting.

BACKGROUND/PURPOSE: Some research has shown that melatonin levels increase after meditation practices, but other research has shown that they do not. In our previous functional magnetic resonance imaging study, we found positive activation of the pineal body during Chinese Original Quiet Sitting (COQS). To find other supporting evidence for pineal activation, the aim of this study was to evaluate the effect of COQS on nighttime melatonin levels. METHODS: Twenty subjects (11 women and 9 men, aged 29-64 years) who had regularly practiced daily meditation for 5-24 years participated in this study. All subjects served alternately as participants in the mediation and control groups. COQS was adopted in this study. Tests were performed during two nighttime sessions. Saliva was sampled at 0, 10, 20, 30, 45, 60 and 90 minutes after COQS and tested for level of melatonin. Time period effect analysis and mixed effect model analysis were preceded by paired t test analysis. RESULTS: In the meditation group (n = 20), the mean level of melatonin was significantly higher than the baseline level at various times post-meditation (p < 0.001). Within the control group (n = 20), the mean level of melatonin at various times was not significantly different compared with baseline (p>0.05). These results suggested that the melatonin level was statistically elevated in the meditation group and almost unchanged in the control group after nighttime meditation. The urine serotonin levels detected by measuring 5-hydroxy-indole-3-acetic acid levels were also studied, but no detectable difference between the groups was found. CONCLUSION: Our results support the hypothesis that meditation might elevate the nighttime salivary melatonin levels. It suggests that COQS can be used as a psychophysiological stimulus to increase endogenous secretion of melatonin, which in turn, might contribute to an improved sense of well-being.

Biological clocks and regulation of seasonal reproduction and migration in birds.

Timekeeping is important at two levels: to time changes in physiology and behavior within each day and within each year. For the former, birds have a system of at least three independent circadian clocks present in the retina of the eyes, the pineal gland, and the hypothalamus. This differs from the situation in mammals in which the input, pacemaker, and output are localized in different structures. Each bird clock interacts with at least one other clock, and together, they appear to form a centralized clock system that keeps daily time. These clocks have a powerful endogenous component, and the daily light-dark cycle entrains them to 24 h. The timing and duration of life history stages that make up annual cycle of an individual must also be controlled by some form of timekeeping. However, evidence for the existence of an equivalent endogenous circannual clock is less clear. Environmental cues, particularly photoperiod, appear to have a more direct role than simply entraining the clock to calendar time. For example, the timing of migration is probably greatly influenced by photoperiod, but its manifestation each day, as Zugunruhe, appears to be under circadian control. Migration involves marked changes in physiology to cope with the energetic demands. There is still much that we do not know about how organisms' timekeeping systems respond to their natural environment, particularly how salient signals from the environment are perceived and then transduced into appropriately timed biological functions. However, given that changes in environmental input affects the clock, increasing human disturbance of the environment is likely to adversely affect these systems.

[The historical background of the pineal gland: I. From a spiritual valve to the seat of the soul]. / El devenir histórico de la glándula pineal: I. De válvula espiritual a sede del alma.

INTRODUCTION: Throughout history, the special anatomical location of the pineal gland in the central nervous system has given rise to a number of physiological hypotheses regarding the functional role of this organ. DEVELOPMENT: In classical ancient times, the pineal body (conarium) was considered to be a sort of valve-like sphincter that regulated the flow of the spiritus animalis at the ventricular level. But it was not until the 17th century that the pineal gland finally reached its highest levels of physiological significance, when Rene Descartes considered it to be the anatomical structure that housed the seat of the soul. CONCLUSIONS: The Cartesian hypotheses regarding the pineal gland did not arouse much interest in the scientific community of the time, and attention to this organ dwindled from then until the 20th century, when its neuroendocrinological nature was finally confirmed.

Seasonal biology: avian photoreception goes deep.

The avian hypothalamus senses light directly, allowing endocrine physiology to synchronise to seasonal day-length changes. New data implicate the photopigment VA-opsin in this deep brain photoreception.

The sunspot theory of schizophrenia: further evidence, a change of mechanism, and a strategy for the elimination of the disorder.

The Gestational Zinc Deficiency Theory suggests that the schizophrenia is caused by a spectrum of damage, produced in utero, to zinc dependent fetal organs such as the brain, pancreas, pineal, testes etc. One problem encountered by the theory is how such deficiency could occur given that the disorder is fairly uniformly distributed across the planet. The original explanation, that seasonal variation in zinc availability was responsible is unconvincing and a search for clues led to an investigation of the Recency Theory which argues that schizophrenia was unknown before 1750 and that an "epidemic of insanity" began around 1780 and stabilized around 1900. The Sunspot Theory arose from the realization that Juckett and Rosenberg's finding of a strong correlation between solar activity and longevity might, with some modification, explain both changes in the incidence of the disorder and the origin of the maternal zinc deficiency. The twenty year shift required to give optimal correlation was explained by these authors as being caused by ionizing radiation induced changes to developing fetal germinal cells. In the sunspot theory it was suggested that the correlation between solar activity and schizophrenia incidence was due to changes in maternal zinc metabolism following microwave induced stress. In this article it will be shown that that mechanism was incorrect. A far better explanation is provided by assuming that geomagnetic field induced loss of pineal activity in the mother during pregnancy permanently affects pineal entrainment in the fetus. In addition it is shown that the loss of correlation between solar activity and longevity during the 1800 to 1830 period identified by Juckett and Rosenberg explains a hitherto inexplicable decline, between 1877 and 1887, in the rising graph of schizophrenia incidence. Finally, the hypothesis, if correct suggests that a strategy based on zinc and melatonin supplements given to at risk parents may go some way to eliminating the disorder.

Mucosal strengthening activity of central and peripheral melatonin in the mechanism of gastric defense.

This review summarizes the involvement of centrally and peripherally applied melatonin, a major hormone of pineal gland, in the mechanism of gastric mucosal integrity, gastroprotection and ulcer healing. Melatonin was originally shown to attenuate gastric mucosal lesions but the controversy exists in the literature as to whether melatonin derived from the pineal gland, considered as the major source of this indole or rather that locally generated from L-tryptophan within gastric mucosa, plays predominant role in the mechanism of gastrointestinal integrity. Both, intragastric (i.g.) and intracerebroventricular (i.c.v.) administration of melatonin and its precursor, L-tryptophan to rats without or with removed pineal gland by pinealectomy attenuates in the dose-dependent manner the formation of on gastric lesions induced by topical irritants and water immersion restraint stress (WRS). Melatonin accelerated the gastric ulcer healing and this was accompanied by the rise in gastric blood flow (GBF), the plasma melatonin and gastrin levels, the mucosal generation of PGE(2) and luminal NO content. Pinealectomy, which suppresses the plasma melatonin levels, markedly aggravated the gastric lesions induced by WRS. Concurrent supplementation of pinealectomized animals with melatonin or L-tryptophan, the melatonin precursor, attenuated the lesions induced by WRS. Treatment with luzindole, an antagonist of Mel(2) receptors, or with L-NNA, the NO-synthase inhibitor, significantly attenuated melatonin- and L-tryptophan-induced protection and the acceleration of ulcer healing and the accompanying increase in the GBF and luminal content of NO. We conclude that 1) exogenous melatonin and that released from the L-tryptophan attenuate lesions induced by topical irritant such as ethanol and WRS via interaction with MT(2) receptors and due to an enhancement of gastric microcirculation, probably mediated by NO and PG derived from cNOS, iNOS and COX-2 overexpression and activity, and 2) the pineal gland plays an important role in the limitation of WRS-induced gastric lesions and acceleration of ulcer healing via releasing melatonin predominately at night time, that exerts gastroprotective and ulcer healing actions.