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Becker muscular dystrophy (BMD) is a hereditary disease characterized by dystrophin deletion that consequently induces muscle weakness, cardiac hypertrophy and cardiac failure; These conditions are similar to those in Duchenne muscular dystrophy. The circadian rhythm is a physiological phenomenon that is predominantly regulated by the transcription and translation of clock genes. Bmal1 (Brain and muscle Arnt-like protein 1) is one of the core clock genes, and its deficiency disturbs the circadian rhythm, results in cardiac hypertrophy and cardiac failure. Dystrophin expression under diurnal conditions and in Bmal1 deficiency is yet to be elucidated. In this study, we analyzed the heart and lungs sampled during a BMD autopsy. Macroscopical examination revealed a large heart and dilated cardiomyopathy. Microscopical examination revealed an undulated structure, as well as the degeneration, and necrosis of myocardial cells. We also analyzed dystrophin expression in tissues obtained from human autopsies and mice. In human autopsy cases, dystrophin expression was lower in the heart with BMD compared that in the heart with non-BMD hypertrophy. In the heart and muscle of control mice, dystrophin expression was higher at ZT0 than at ZT12. The dystrophin expression was found to be lower in heart-specific Bmal1 knockout mice compared to that in the control mice. Hence, our study indicated that BMD was closely associated with cardiac hypertrophy and cardiac failure, while dystrophin had a diurnal expression pattern in control mice that was regulated by Bmal1.

Mood disorders such as depression, anxiety, and bipolar disorder are highly associated with disrupted daily rhythms of activity, which are often observed in shift work and sleep disturbance in humans. Recent studies have proposed the REV-ERBα protein as a key circadian nuclear receptor that links behavioural rhythms to mood regulation. However, how the Rev-erbα gene participates in the regulation of mood remains poorly understood. Here, we show that the regulation of the serotonergic (5-HTergic) system, which plays a central role in stress-induced mood behaviours, is markedly disrupted in Rev-erbα

Disturbance of the daily cycles in sleep and wakefulness induced by conditions such as shift work and jet lag can increase the risk of affective disorders including anxiety and depression. The way such circadian disorganization disrupts the regulation of mood, however, is not well understood. More specifically, the impact of circadian disorganization on the daily rhythms of the neuronal function that controls mood remains unclear. We therefore investigated the effects of circadian disorganization on expression rhythms of clock genes as well as immediate early genes (IEGs) in several mood-controlling regions of the brain. To introduce circadian disorganization of behaviors, we exposed male C57BL/6J mice to chronic reversal of the light-dark cycle and we found a marked negative mood phenotype in these mice. Importantly, the most adverse effect of circadian disorganization on expression rhythms of clock and IEGs was observed in the prefrontal cortex (PFC) when compared to that in other mood-related areas of the brain. Dysregulation of molecular rhythms in the PFC is therefore suggested to be associated with the development of mood disorders in conditions including shift work and jet lag.

Smad3 has circadian expression; however, whether Smad3 affects the expression of clock genes is poorly understood. Here, we investigated the regulatory mechanisms between Smad3 and the clock genes Dec1, Dec2, and Per1. In Smad3 knockout mice, the amplitude of locomotor activity was decreased, and Dec1 expression was decreased in the suprachiasmatic nucleus, liver, kidney, and tongue compared with control mice. Conversely, Dec2 and Per1 expression was increased compared with that of control mice. In Smad3 knockout mice, immunohistochemical staining revealed that Dec1 expression decreased, whereas Dec2 and Per1 expression increased in the endothelial cells of the kidney and liver. In NIH3T3 cells, Smad3 overexpression increased Dec1 expression, but decreased Dec2 and Per1 expression. In a wound-healing experiment that used Smad3 knockout mice, Dec1 expression decreased in the basal cells of squamous epithelium, promoting wound healing of the mucosa. Finally, the migration and proliferation of Smad3 knockdown squamous carcinoma cells was suppressed by Dec1 overexpression but was promoted by Dec2 overexpression. Dec1 overexpression decreased E-cadherin and proliferating cell nuclear antigen expression, whereas these expression levels were increased by Dec2 overexpression. These results suggest Smad3 is relevant to circadian rhythm and regulates cell migration and proliferation through Dec1, Dec2, and Per1 expression.

Bmal1, a clock gene, is associated with depression, hypertrophy, metabolic syndrome and diabetes. Smad3, which is involved in the TGF-β signaling pathway, plays an important role in the regulation of tumor progression, fibrosis, obesity and diabetes. Our previous report showed that Smad3 has circadian expression in mouse livers. In the current study, we focused on the heart, especially on the myocardial stromal fibroblasts because the roles of Bmal1 and Smad3 in this tissue are poorly understood. Bmal1 and Smad3 have circadian expression in mouse hearts, and their circadian expression patterns were similar. Bmal1 expression decreased in the hearts of whole-body Smad3 knockout mice, whereas Smad3 expression had little effect on heart-specific Bmal1 knockout mice. Both Smad3 knockout and heart-specific Bmal1 knockout mice showed increases in p21, S100A4, CD206 and TNF-α expression in the myocardial stromal fibroblasts and macrophage compared to control mice. We also examined Smad3, Bmal1 and Dec1 expression in human tissue from old myocardial infarctions. Expression of Smad3, Bmal1 and Dec1 decreased in the stromal fibroblasts of tissue from old myocardial infarctions compared to control cases. On the other hand, p21, S100A4 and TNF-α increased in the stromal fibroblasts of tissue from old myocardial infarctions. Furthermore, expression of Smad3, Bmal1 and Dec1 decreased in TNF-α treated-NIH3T3 cells but expression of p21 and S100A4 increased. This new evidence suggests that Smad3 and Bmal1 regulate p21 and S100A4 expression in myocardial stromal fibroblasts through TNF-α.

Cardiac fibrosis is a major cause of cardiac dysfunction in hypertrophic hearts. Differentiated embryonic chondrocyte gene 1 (Dec1), a basic helix&ndash, loop&ndash, helix transcription factor, has circadian expression in the heart, however, its role in cardiac diseases remains unknown. Therefore, using Dec1 knock-out (Dec1KO) and wild-type (WT) mice, we evaluated cardiac function and morphology at one and four weeks after transverse aortic constriction (TAC) or sham surgery. We found that Dec1KO mice retained cardiac function until four weeks after TAC. Dec1KO mice also revealed more severely hypertrophic hearts than WT mice at four weeks after TAC, whereas no significant change was observed at one week. An increase in Dec1 expression was found in myocardial and stromal cells of TAC-treated WT mice. In addition, Dec1 circadian expression was disrupted in the heart of TAC-treated WT mice. Cardiac perivascular fibrosis was suppressed in TAC-treated Dec1KO mice, with positive immunostaining of S100 calcium binding protein A4 (S100A4), alpha smooth muscle actin (&alpha, SMA), transforming growth factor beta 1 (TGF&beta, 1), phosphorylation of Smad family member 3 (pSmad3), tumor necrosis factor alpha (TNF&alpha, ), and cyclin-interacting protein 1 (p21). Furthermore, Dec1 expression was increased in myocardial hypertrophy and myocardial infarction of autopsy cases. Taken together, our results indicate that Dec1 deficiency suppresses cardiac fibrosis, preserving cardiac function in hypertrophic hearts. We suggest that Dec1 could be a new therapeutic target in cardiac fibrosis.

Aim Our previous findings suggest that the nucleus of the solitary tract (NTS), a pivotal region for regulating the set point of arterial pressure, exhibits abnormal inflammation in pre-hypertensive and spontaneously hypertensive rats (SHRs), with elevated anti-apoptotic and low apoptotic factor levels compared with that of normotensive Wistar-Kyoto (WKY) rats. Whether this chronic condition affects neuronal growth and plasticity in the NTS remains unknown. To unveil the characteristics of the neurodevelopmental environment in the NTS of SHRs, we investigated the expression of neurotrophic factors transcripts in SHRs. Methods RT(2) Profiler PCR Array targeting rat neurotrophins and their receptors was used to screen for differentially expressed transcripts in the NTS of SHRs compared to that of WKY rats. Protein expression and physiological functions of some of the differentially expressed transcripts were also studied. Results Gene and protein expressions of glial cell line-derived neurotrophic factor family receptor alpha-3 (Gfrα-3) factor were both upregulated in the NTS of adult SHRs. Gene expressions of corticotropin-releasing hormone-binding protein (Crhbp), interleukin-10 receptor alpha (Il-10ra) and hypocretin (Hcrt) were downregulated in the NTS of adult SHRs. The Gfrα-3 transcript was increased and the Hcrt transcript was decreased in the NTS of young pre-hypertensive SHRs, suggesting that these profiles are not secondary to hypertension. Moreover, microinjection in the NTS of hypocretin-1 decreased blood pressure in adult SHRs. Conclusion These results suggest that altered neurotrophic factors transcript profiles may affect the normal development and function of neuronal circuitry that regulates cardiovascular autonomic activity, thereby resulting in manifestations of neurogenic hypertension in SHRs.

The daily rhythm of glucose metabolism is governed by the circadian clock, which consists of cell-autonomous clock machineries residing in nearly every tissue in the body. Disruption of these clock machineries either environmentally or genetically induces the dysregulation of glucose metabolism. Although the roles of clock machineries in the regulation of glucose metabolism have been uncovered in major metabolic tissues, such as the pancreas, liver, and skeletal muscle, it remains unknown whether clock function in non-major metabolic tissues also affects systemic glucose metabolism. Here, we tested the hypothesis that disruption of the clock machinery in the heart might also affect systemic glucose metabolism, because heart function is known to be associated with glucose tolerance. We examined glucose and insulin tolerance as well as heart phenotypes in mice with heart-specific deletion of Bmal1, a core clock gene. Bmal1 deletion in the heart not only decreased heart function but also led to systemic insulin resistance. Moreover, hyperglycemia was induced with age. Furthermore, heart-specific Bmal1-deficient mice exhibited decreased insulin-induced phosphorylation of Akt in the liver, thus indicating that Bmal1 deletion in the heart causes hepatic insulin resistance. Our findings revealed an unexpected effect of the function of clock machinery in a non-major metabolic tissue, the heart, on systemic glucose metabolism in mammals.

Aim The nucleus tractus solitarii (NTS) is a central brainstem structure that plays an important role in regulating cardiovascular homeostasis. In this study, we examined whether H1 receptors in the NTS can control the baroreceptor reflex function by modulating synaptic transmission. Methods Cardiac baroreceptor reflex function was assessed before and after the microinjection of 2-pyridylethylamine (10–25 nmol), a histamine H1 receptor-specific agonist, into the NTS of urethane-anaesthetized Wistar rats. The cardiovascular responses induced by l-glutamate microinjection into the NTS were also examined before and after the NTS administration of 2-pyridylethylamine. Results Nucleus tractus solitarii microinjections of 2-pyridylethylamine significantly inhibited the gain of the cardiac baroreceptor reflex and bradycardiac/depressor responses induced by l-glutamate microinjection into the NTS. These findings suggest that histamine H1 receptors regulate the cardiac baroreceptor reflex in a post-synaptic manner to inhibit barosensitive NTS neurons. Conclusion Taken together with our previous findings, the present results provide further evidence that histamine may play a role within the NTS in regulating cardiovascular homeostasis.

Understanding how the 24-hour blood-pressure rhythm is programmed has been one of the most challenging questions in cardiovascular research. The 24-hour blood-pressure rhythm is primarily driven by the circadian clock system, in which the master circadian pacemaker within the suprachiasmatic nuclei of the hypothalamus is first entrained to the light/dark cycle and then transmits synchronizing signals to the peripheral clocks common to most tissues, including the heart and blood vessels. However, the circadian system is more complex than this basic hierarchical structure, as indicated by the discovery that peripheral clocks are either influenced to some degree or fully driven by temporal changes in energy homeostasis, independent of the light entrainment pathway. Through various comparative genomic approaches and through studies exploiting mouse genetics and transgenics, we now appreciate that cardiovascular tissues possess a large number of metabolic genes whose expression cycle and reciprocally affect the transcriptional control of major circadian clock genes. These findings indicate that metabolic cycles can directly or indirectly affect the diurnal rhythm of cardiovascular function. Here, we discuss a framework for understanding how the 24-hour blood-pressure rhythm is driven by the circadian system that integrates cardiovascular and metabolic function.

We performed genome-wide mutagenesis in C57BL/6J mice using N-ethyl-N-nitrosourea to identify mutations causing high blood glucose early in life and to produce new animal models of diabetes. Of a total of 13 new lines confirmed by heritability testing, we identified two semi-dominant pedigrees with novel missense mutations (Gck(K140E) and Gck(P417R)) in the gene encoding glucokinase (Gck), the mammalian glucose sensor that is mutated in human maturity onset diabetes of the young type 2 and the target of emerging anti-hyperglycemic agents that function as glucokinase activators (GKAs). Diabetes phenotype corresponded with genotype (mild-to-severe: Gck(+/+)Gck(P417R/+), Gck(K140E)(/+)Gck(P417R/P417R), Gck(P417R/K140E), and Gck(K140E/K140E)) and with the level of expression of GCK in liver. Each mutant was produced as the recombinant enzyme in Escherichia coli, and analysis of k(cat) and tryptophan fluorescence (I(320/360)) during thermal shift unfolding revealed a correlation between thermostability and the severity of hyperglycemia in the whole animal. Disruption of the glucokinase regulatory protein-binding site (GCK(K140E)), but not the ATP binding cassette (GCK(P417R)), prevented inhibition of enzyme activity by glucokinase regulatory protein and corresponded with reduced responsiveness to the GKA drug. Surprisingly, extracts from liver of diabetic GCK mutants inhibited activity of the recombinant enzyme, a property that was also observed in liver extracts from mice with streptozotocin-induced diabetes. These results indicate a relationship between genotype, phenotype, and GKA efficacy. The integration of forward genetic screening and biochemical profiling opens a pathway for preclinical development of mechanism-based diabetes therapies.

OBJECTIVES The brainstem nucleus of the solitary tract (nucleus tractus solitarii, NTS) is a pivotal region for regulating the set-point of arterial pressure, the mechanisms of which are not fully understood. Based on evidence that the NTS exhibits O2-sensing mechanisms, we examined whether a localized disturbance of blood supply, resulting in hypoxia in the NTS, would lead to an acute increase in arterial pressure. METHODS Male Wistar rats were used. Cardiovascular parameters were measured before and after specific branches of superficial dorsal medullary veins were occluded; we assumed these were drainage vessels from the NTS and would produce stagnant hypoxia. Hypoxyprobe-1, a marker for detecting cellular hypoxia in the post-mortem tissue, was used to reveal whether vessel occlusion induced hypoxia within the NTS. RESULTS Following vessel occlusion, blood flow in the dorsal surface of the medulla oblongata including the NTS region showed an approximately 60% decrease and was associated with hypoxia in neurons located predominantly in the caudal part of the NTS as revealed using hypoxyprobe-1. Arterial pressure increased and this response was pronounced significantly in both magnitude and duration when baroreceptor reflex afferents were sectioned. CONCLUSION These results suggest that localized hypoxia in the NTS increases arterial pressure. We suggest this represents a protective mechanism whereby the elevated systemic pressure is a compensatory mechanism to enhance cerebral perfusion. Whether this physiological mechanism has any relevance to neurogenic hypertension is discussed.

The daily rhythm of mammalian energy metabolism is subject to the circadian clock system, which is made up of the molecular clock machinery residing in nearly all cells throughout the body. The clock genes have been revealed not only to form the molecular clock but also to function as a mediator that regulates both circadian and metabolic functions. While the circadian signals generated by clock genes produce metabolic rhythms, clock gene function is tightly coupled to fundamental metabolic processes such as glucose and lipid metabolism. Therefore, defects in the clock genes not only result in the dysregulation of physiological rhythms but also induce metabolic disorders including diabetes and obesity. Among the clock genes, Dec1 (Bhlhe40/Stra13/Sharp2), Dec2 (Bhlhe41/Sharp1), and Bmal1 (Mop3/Arntl) have been shown to be particularly relevant to the regulation of energy metabolism at the cellular, tissue, and organismal levels. This paper reviews our current knowledge of the roles of Dec1, Dec2, and Bmal1 in coordinating the circadian and metabolic pathways.

The hypothalamic neuronal circuits that modulate energy homeostasis become mature and functional during early postnatal life. However, the molecular mechanism underlying this developmental process remains largely unknown. Here we use a mouse genetic approach to investigate the role of gamma-protocadherins (Pcdh-gammas) in hypothalamic neuronal circuits. First, we show that rat insulin promoter (RIP)-Cre conditional knockout mice lacking Pcdh-gammas in a broad subset of hypothalamic neurons are obese and hyperphagic. Second, specific deletion of Pcdh-gammas in anorexigenic proopiomelanocortin (POMC) expressing neurons also leads to obesity. Using cell lineage tracing, we show that POMC and RIP-Cre expressing neurons do not overlap but interact with each other in the hypothalamus. Moreover, excitatory synaptic inputs are reduced in Pcdh-gamma deficient POMC neurons. Genetic evidence from both knockout models shows that Pcdh-gammas can regulate POMC neuronal function autonomously and non-autonomously through cell-cell interaction. Taken together, our data demonstrate that Pcdh-gammas regulate the formation and functional integrity of hypothalamic feeding circuitry in mice.

Recent gene array and molecular studies have suggested that an abnormal gene expression profile of interleukin-6 (IL-6) in the nucleus tractus solitarii (NTS), a pivotal region for regulating arterial pressure, may be related to the development of neurogenic hypertension. However, the precise functional role of IL-6 in the NTS remains unknown. In the present study, we have tested whether IL-6 affects cardiovascular control at the level of the NTS. IL-6 (1, 10, and 100 fmol) was microinjected in the NTS of Wistar rats (280–350 g) under urethane anesthesia. Although the baseline levels of arterial pressure and heart rate did not change following IL-6 injections, the cardiac baroreflex in response to increased arterial pressure was dose-dependently attenuated. In addition, IL-6 (100 fmol) microinjections also attenuated l-glutamate-induced bradycardia at the level of the NTS. Immunohistochemical detection of IL-6 in naïve rats demonstrated that it was predominantly observed in neurons within the brain stem, including the NTS. These findings suggest that IL-6 within the NTS may play an important role for regulating cardiovascular control via modulation of input signals from baroreceptor afferents. Whether the abnormal gene expression of IL-6 in the NTS is associated in a causal way with hypertension remains to be resolved.

Although both α1- and α2-adrenergic receptors (ARs) are known to be expressed in the nucleus of the solitary tract (NTS), the functional significance of these receptors is still not fully established. In this study, we microinjected α1- and α2-AR agonists into the NTS of urethane-anaesthetized Wister rats to study the cardiovascular effects in response to their activation. When the α1-AR agonist phenylephrine was microinjected into the area where barosensitive neurons are dominantly located (baro-NTS), mean arterial pressure (MAP) and heart rate (HR) were significantly elevated. When tested in the area where chemosensitive neurons are dominantly located (chemo-NTS), however, MAP and HR were significantly decreased. Pretreatment with the non-specific α-AR antagonist phentolamine into the NTS inhibited the phenylephrine-induced cardiovascular responses. In contrast, microinjection of the α2-AR agonist clonidine into either the baro-NTS or the chemo-NTS decreased MAP and HR; they were also inhibited by the α2-adrenergic antagonist yohimbine. Moreover, we immunohistochemically identified that cardiovascular responses induced by α1-ARs may be mediated by NTS neurons while those induced by α2-ARs may be mediated by astrocytes located in the barosensitive and chemosensitive areas of the NTS. These results suggest that both types of α-AR expressed in the NTS may be involved in regulating cardiovascular homeostasis via modulation of input signals from baroreceptor and chemoreceptor afferents; however, cardiovascular responses produced by stimulation of α1-ARs are strictly location specific within the NTS.

Contexte: Sema4D/CD100 est un type de semaphorine de classe 4 qui joue des roles cruciaux dans le guidage des cones de croissance dans les neurones en developpement. Sema4D est largement exprime dans tout le systeme nerveux central de l'embryon chez la souris et il est localise selectivement aux oligodendrocytes et a la myeline du cerveau apres la naissance. Cependant, il n'y a pas de preuve directe de l'implication de Sema4D dans le developpement du reseau neuronal qui est crucial pour le fonctionnement neurocomportemental. Dans cette etude, nous avons examine si un deficit en Sema4D entraine un developpement comportemental anormal. Methodes: Des souris de phenotype sauvage et des souris deficientes en Sema4D ont ete soumises a des analyses comportementales, dont le test du champ ouvert, de l'adhesive tape removal, du rotarod et du labyrinthe aqueux. Resultats: Les tests de champ ouvert ont montre que les souris ayant un deficit en Sema4D avaient une activite locomotrice accrue et passaient un pourcentage moindre du temps dans le centre du champ. Dans les tests de l'adhesive tape removal et du rotarod, qui evaluent la coordination motrice et l'equilibre, les souris ayant un deficit en Sema4D ont presente une performance significativement superieure, ce qui est en faveur d'un comportement moteur facilite. Les souris ayant un deficit en Sema4D et les souris de type sauvage ont appris avec succes la tâche du labyrinthe aqueux qui consistait a localiser une plate-forme de sauvetage dissimulee et ont egalement fait preuve d'une memoire precise de la position de la plate-forme lorsque le test etait repete apres avoir retire la plate-forme. De plus, la vitesse de nage des souris ayant un deficit en Sema4D etait significativement superieure a cette des souris de type sauvage, ce qui est en faveur d'un comportement moteur accelere. Couclusion: Nos analyses comportementales chez la souris ont demontre que les souris ayant un deficit en Sema4D ont une activite motrice accrue, ce qui est en faveur du role crucial que joue Sema4D dans le processus de developpement nerveux des structures centrales, soit un role facilitant sur le comportement moteur chez la souris.

This paper focuses on balance sheet adjustments across the recent boom–bust cycles in the Pacific region along with structural changes in sectoral balance sheets and policy environments. Comparing empirical regularities across industrial as well as East Asian countries over the past decades, our analysis shows that asset price busts and concurrent macroeconomic developments in East Asia share some common patterns, identified using event analysis, with industrial economies. Regarding the macroeconomic impact of asset market price busts, we generally observed qualitatively similar features between industrial countries and East Asian emerging markets. Major differences between the two groups appear in the magnitude of swings and the speed of recoveries of the key macroeconomic variables. Negative impacts on investment were stronger in East Asia, but quicker recoveries were their features, whereas private consumption was commonly rather robust to asset market turmoil.

The discovery of an internal temporal clockwork that coordinates behavior and metabolism according to the rising and setting of the sun was first revealed in flies and plants. However, in the past decade, a molecular transcription-translation feedback loop with similar properties has also been identified in mammals. In mammals, this transcriptional oscillator programs 24-hour cycles in sleep, activity and feeding within the master pacemaker neurons of the suprachiasmatic nucleus of the hypothalamus. More recent studies have shown that the core transcription mechanism is also present in other locations within the brain, in addition to many peripheral tissues. Processes ranging from glucose transport to gluconeogenesis, lipolysis, adipogenesis and mitochondrial oxidative phosphorylation are controlled through overlapping transcription networks that are tied to the clock and are thus time sensitive. Because disruption of tissue timing occurs when food intake, activity and sleep are altered, understanding how these many tissue clocks are synchronized to tick at the same time each day, and determining how each tissue 'senses time' set by these molecular clocks might open new insight into human disease, including disorders of sleep, circadian disruption, diabetes and obesity.

This chapter examines the role of structural change in productivity growth in Japan, focusing on her recent lost decades, with reference to the United States. As a matter of fact, Japan and the US have shown quite contrasting performances in terms of aggregate productivity growth before and after the early 1990s (Figure 3.1). Jorgenson and Nomura (2007) state as follows: Before 1990: “The rapid closing of 3.7 per cent per year in the US-Japan gap in GDP per capita during 1960–1990 was achieved by 2.1 per cent annual growth in relative input per capita and 1.6 per cent annual reduction in the TFP[total factor productivity] gap.” But after 1990, “Japanese total factor productivity, relative to the US, fell from 86.1 in 1990, to 81.7 in 2000, and 79.5 in 2004, reflecting the sharp acceleration in US TFP growth after 1995 and the more modest recovery of Japanese TFP growth.”

The idea of regional financial cooperation in East Asia was without doubt created by the Asian economic crisis in 1997. This paper examines policy options for crisis prevention with respect to exchange rate regimes, external debt management and domestic financial sector restructuring in the broader context of external and domestic financing for growth in East Asia. Putting the regional financial cooperation in this context, the paper argues that the cooperation will complement to strengthen the present and future international financial architecture, but that there is no strong rationale for this regional financial cooperation should, nor would lead to a monetary union.

The tuberomammillary nucleus (TMN) of the posterior hypothalamus has a high density of histaminergic neurons, the projection fibers of which are present in many areas of the brain, including the nucleus tractus solitarius (NTS), which controls arterial pressure (AP). In this study, we investigated whether the TMN–NTS pathway is involved in central cardiovascular regulation. Bicuculline, a gamma‐aminobutyric acid type A (GABAA) receptor antagonist, was microinjected into the ventral TMN of anesthetized rats and its effects on AP and heart rate (HR) were observed. We also evaluated the effect of cetirizine, an H1 receptor antagonist, microinjected into the NTS on cardiovascular responses induced by electrical stimulation of the TMN. Both AP and HR increased following bicuculline microinjection into the ventral TMN. Similar pressor and tachycardic responses were observed after electrical stimulation of the ventral TMN. Microinjection of cetirizine into the NTS partially inhibited the pressor response but had no effect on HR. Finally, the treadmill test was associated with a high level of c‐Fos expression in both ventral TMN and NTS neurons. These results suggest that the TMN–NTS pathway is involved in regulation of AP, presumably under a high‐arousal phase, such as that during exercise.

Cardiac function is highly dependent on oxidative energy, which is produced by mitochondrial respiration. Defects in mitochondrial function are associated with both structural and functional abnormalities in the heart. Here, we show that heart-specific ablation of the circadian clock gene Bmal1 results in cardiac mitochondrial defects that include morphological changes and functional abnormalities, such as reduced enzymatic activities within the respiratory complex. Mice without cardiac Bmal1 function show a significant decrease in the expression of genes associated with the fatty acid oxidative pathway, the tricarboxylic acid cycle, and the mitochondrial respiratory chain in the heart and develop severe progressive heart failure with age. Importantly, similar changes in gene expression related to mitochondrial oxidative metabolism are also observed in C57BL/6J mice subjected to chronic reversal of the light-dark cycle; thus, they show disrupted circadian rhythmicity. These findings indicate that the circadian clock system plays an important role in regulating mitochondrial metabolism and thereby maintains cardiac function.

We studied the effect of Agrp (agouti-related peptide) on LH (luteinizing hormone) and PRL (prolactin) surges in ovariectomized rats primed with estradiol and progesterone. The rats displayed characteristic LH and PRL surges that were completely abolished by starving. Injection of either 1 nmol or 3 nmol Agrp (83-132), a potent antagonist of the orexigenic MC3 and MC4 receptors, completely prevented both the LH and PRL surges. We also investigated the effects of either a single or double injection of anti-Agrp serum to fasted animals, which were without LH and PRL surges. A single injection of the antiserum was without effect, but the rats that received double injection of anti-Agrp serum partially reinstated both the LH and PRL surges. Although the onset of LH and PRL surges was significantly delayed in the double treated group, the highest levels of the surges for both hormones were statistically indistinguishable compared with the control group. These data give a clear indication that endogenous Agrp may be involved in LH and PRL surges during starvation, providing further evidence that the melanocortin system is important for these hormonal surges in female rats.

Recent evidence suggests that nitric oxide (NO), a free radical gas, plays an important role in regulating the function of a variety of neuroendocrine systems. With respect to the hypothalamo-pituitary-gonadal axis, a stimulatory effect of NO on the release of gonadotropin-releasing hormone (GnRH) from rat hypothalamus has been demonstrated in vitro. However, no previous study has reported NO-stimulated secretion of GnRH from in vivo hypothalamus, and also the precise cellular site of action of NO within the GnRH neuronal system remains to be elucidated. In the present study, utilizing the push-pull perfusion technique of rat hypothalamus, we examined the effect of L-arginine (L-Arg), an NO donor, on the release of GnRH, neuropeptide Y and cyclic GMP (c-GMP), which is a pivotal second messenger molecule of the NO system. For comparison, we also examined the effect of carbon monoxide (CO), another putative gaseous neurotransmitter, using hematin, a CO donor. During the period of 11.00–18.00 h, we collected blood and hypothalamic perfusates from ovariectomized adult rats that had been implanted with an estradiol capsule 2 days before. During the entire period of observation, L-Arg (1.0 or 10 mM), hematin (10 or 100 µM) or artificial cerebrospinal fluid alone (as the control) was infused into the medial preoptic area (MPOA) where there are cell bodies of GnRH neurons, or the median eminence-arcuate nucleus complex (ME-ARC) where axon terminals of GnRH neurons are localized. Although 10 mM of L-Arg significantly stimulated GnRH and c-GMP, but not neuropeptide Y, levels in both the MPOA and ME-ARC, GnRH and c-GMP in the ME-ARC were already increased by 1.0 mM of L-Arg. By contrast, both concentrations of hematin were without effect at either site of the hypothalamus. This study is the first to demonstrate that NO is capable of stimulating GnRH release from rat hypothalamus in vivo. Our data also suggests that both cell bodies and axon terminals of GnRH neurons may be sites of action of NO. Our data do not support a previous study by other investigators that reported a stimulatory effect of CO on the GnRH release.

In order to know more about the in vivo secretion of various cytokines from the human pituitary, this study measured the concentrations of interleukin (IL)-1alpha, IL-1beta, IL-2, IL-6, tumor necrosis factor-alpha and IL-1 receptor antagonist (ra) in both the peripheral blood and the cavernous sinus (CS) plasma from six patients with Cushing's disease before and after an intravenous bolus injection of human corticotropin-releasing hormone (CRH, 100 microg). As a routine procedure for the diagnosis of Cushing's disease, adrenocorticotropin (ACTH) levels were also determined in the same samples. In four of the six patients, unstimulated levels of IL-1ra in the CS ipsilateral to the ACTH-secreting adenoma were higher than those in the peripheral blood, with a ratio ofor = 1.5:1, even though CRH was without effect on the cytokine's concentration in the CS. In contrast, no consistent data were obtained for any of the remaining five cytokines. These results demonstrate for the first time that the in vivo release of IL-1ra is detectable in at least some corticotroph adenomas, and also suggest a possible role of the cytokine in physiological and pathophysiological processes occurring in the human pituitary.

This paper examines the role of structural change in productivity growth in Japan, focusing on her recent "lost decades", with reference to the United States. Japan is now known to have a sharp slowdown in productivity growth in the 1990s, when we find a slowdown in intra-industry productivity growth is the main cause. We also find that the contribution of inter-industry reallocation of employment is almost zero in the 1990s and even significantly negative in the 2000s. Interestingly, the same holds true in the US, too. We will argue that structural change or the lack of it may not be responsible for the lost decades in Japan, and that these contrasting outcomes between Japan and the US come from a common factor.