The Ghrelin Receptor Regulates Dendritic Spines and the NMDA Receptor–Mediated Synaptic Transmission in the Hippocampus

Increasing evidence suggests the involvement of ghrelin (an orexigenic hormone) and its cognate receptor growth hormone secretagogue receptor (GHSR1a, also known as the ghrelin receptor) in extra‐hypothalamic functions such as hippocampal learning and memory. However, cellular and molecular mechanisms underlying the ghrelin‐regulated hippocampal neuron activity are poorly understood. In this chapter, we show the following: (1) ghrelin promoted phosphorylation of the N‐methyl‐d‐aspartate receptor (NMDAR) subunit 1 (GluN1) in a PKC/PKA‐dependent manner and amplified NMDAR‐mediated excitatory postsynaptic currents, (2) ghrelin stimulated phosphorylation of CREB (cAMP response‐element‐binding protein), and (3) ghrelin increased phalloidin binding to F‐actin, suggesting possible reorganization of dendritic spines; all occurred through the activation of GHSR1a in the CA1 pyramidal cell of the hippocampus in cultured slice preparations. Interestingly, the ghrelin’s effects on GluN1 and CREB phosphorylation were negatively modulated by exogenous application of endocannabinoids, 2‐arachidonoylglycerol (2‐AG), and anandamide (ANE), in type 1 cannabinoid receptor (CB1R)‐dependent and ‐independent manners, respectively. It is suggested that ghrelin and the ghrelin receptor regulate synaptic transmission and plasticity in the hippocampus, interacting with the endogenous cannabinoid system, which may be essential and necessary for successful acquisition of metabolic state–dependent learning and adaptive appetitive behavior

Ghrelin upregulates the phosphorylation of the GluN2B subunit of the NMDA receptor by activating GHSR1a and Fyn in the rat hippocampus

Ghrelin and its receptor GHSR1a have been shown to exert numerous physiological functions in the brain, in addition to the well-established orexigenic role in the hypothalamus. Earlier work indicated that ghrelin stimulated the phosphorylation of the GluN1 subunit of the NMDA receptor (NMDAR) and enhanced synaptic transmission in the hippocampus. In the present study, we report that the exogenous application of ghrelin increased GluN2B phosphorylation. This increase was independent of GluN2B subunit activity or NMDAR channel activity. However, it depended on the activation of GHSR1a and Fyn as it was blocked by D-Lys3-GHRP-6 and PP2, respectively. Inhibitors for G-protein-regulated second messengers, such as Rp-cAMP, H89, TBB, ryanodine, and thapsigargin, unexpectedly enhanced GluN2B phosphorylation, suggesting that cAMP, PKA, casein kinase II, and cytosolic calcium signaling may oppose to the effect of ghrelin on the phosphorylation of GluN2B. Our findings suggest that 1) GluN2B is likely a molecular target of ghrelin and GHSR1a-driven signaling cascades, and 2) the ghrelin-mediated phosphorylation of GluN2B depends on Fyn activation under complex negative regulation by other second messengers

Studies on liquid phase peptide synthesis by fragment condensation on a soluble polymer support

Thesis--University of Tsukuba, D.Sc.(B), no. 244, 1985. 3. 2

Metabolic Demand Stimulates CREB Signaling in the Limbic Cortex: Implication for the Induction of Hippocampal Synaptic Plasticity by Intrinsic Stimulus for Survival

Caloric restriction by fasting has been implicated to facilitate synaptic plasticity and promote contextual learning. However, cellular and molecular mechanisms underlying the effect of fasting on memory consolidation are not completely understood. We hypothesized that fasting-induced enhancement of synaptic plasticity was mediated by the increased signaling mediated by CREB (cAMP response element binding protein), an important nuclear protein and the transcription factor that is involved in the consolidation of memories in the hippocampus. In the in vivo rat model of 18 h fasting, the expression of phosphorylated CREB (pCREB) was examined using anti-phospho-CREB (Ser133) in cardially-perfused and cryo-sectioned rat brain specimens. When compared with control animals, the hippocampus exhibited up to a twofold of increase in pCREB expression in fasted animals. The piriform cortex, the entorhinal cortex, and the cortico-amygdala transitional zone also significantly increased immunoreactivities to pCREB. In contrast, the amygdala did not show any change in the magnitude of pCREB expression in response to fasting. The arcuate nucleus in the medial hypothalamus, which was previously reported to up-regulate CREB phosphorylation during fasting of up to 48 h, was also strongly immunoreactive and provided a positive control in the present study. Our findings demonstrate a metabolic demand not only stimulates cAMP-dependent signaling cascades in the hypothalamus, but also signals to various limbic brain regions including the hippocampus by activating the CREB signaling mechanism. The hippocampus is a primary brain structure for learning and memory. It receives hypothalamic and arcuate projections directly from the fornix. The hippocampus is also situated centrally for functional interactions with other limbic cortexes by establishing reciprocal synaptic connections. We suggest that hippocampal neurons and those in the surrounding limbic cortexes are intimately involved in the metabolism-dependent plasticity, which may be essential and necessary for successful achievement of adaptive appetitive behavior

FOOT MOVEMENT IN IMPACT PHASE OF INSTEP KICKING IN SOCCER

Ball impact technique is essential to produce a higher ball velocity in soccer instep kicking. However, to date only a few studies focused on foot kinematics during ball impact, in which plantar flexion motion of the foot was solely reported (Asai et al., 1995; Nunome et al., 2006). In this study, three-dimensional movement of the foot (plantar flexion / dorsal flexion, abduction / adduction, eversion / inversion) during ball impact was quantified to extract some movement characteristics releted to a higher ball velocity

Die Studien über Vitamin C in der Nebenniere. (III. Teil.)

Im Anschluss an die I. und II. Mitteilungen hat nur der Verf. Untersuchungen an Kaninchen auf das Verhalten des Vitamin C (V.C) in der Nebenniere histologisch angestellt. Wenn man auf die Nebenniere die saure Losung von AgNO3 wirken liess und daraus dann Schnittpräaparate von Geweben anfertigte und die sog. V. C-Kornchen in diesen Praparaten untersuchte, so findet man, dass die Körnchen in der Zona reticularis am reichsten bzw. am dichtigsten verteilt sind, in der Zona fasciculata hingegen etwas geringer, und zwar am geringsten in der mittleren Schicht, etwas reichlicher in der äusseren, am reichsten in der inneren Schicht. In der Kapsel so wie in dem Mark sind die Körnchen kaum anzutreffen. In der Zona glomerulosa sind sie in der Regel nur spärlich vorhanden, gelegentlich treten sie aber in der inneren Schicht der Zona mässig in die Erscheinung. Die Körnchen vorringern sich auf den Reiz des Nervus vagus hin gleichmäassig, während sie sich bei dem durch den Nervus splanchnicus zugeleiteten Reiz vermehren. Diese Zunahme findet in den Abschnitten statt, wo die Kornchen von Anfang an physiologische reichlich vorhanden sind; bisweilen kommen sie auch in dem Mark zum Vorschein. Wenn man jedoch das Nikotin aufgestrichen hat, so kömmen trotz der Wirkung des gereizten Nervus splanchnicus fast keine quantitave Schwankungen der Körnchen zustande. Durch die Adrenalininjektion liefern die V. C-Körnchen das gleiche Bild wie bei dem Beiz des Nervus splanchnicus; durch die Atropininjektion erscheinen die Körnchen etwas dichter, durch die Pilokarpininjektion hingegen etwas locker. Die Eigenschaft der Körnchen bleibt bei ihnen quantitativen Schwankungen konstant. Diese histologischen Befunde des V.C stimmen mit den Ergebnissen chemischer Mengenbestimmung überein. Auf diese Weise hat der Verf. bei Kaninchen durch Anwendung histologische Methode die Innervation des Nervus vagus, splanchinicus und des Bauchsympathicus auf das Verhalten des V.C in der Nebenniere festgestellt und dadurch die Ergebnisse der I. und II. Mitteilungen bestätigt

Melatonin enhances vertical bone augmentation in rat calvaria secluded spaces

Background: Melatonin has many roles, including bone remodeling and osseointegration of dental implants. The topical application of melatonin facilitated bone regeneration in bone defects. We evaluated the effects of topical application of melatonin on vertical bone augmentation in rat calvaria secluded spaces. Material and Methods: In total, 12 male Fischer rats were used and two plastic caps were fixed in the calvarium. One plastic cap was filled with melatonin powder and the other was left empty. Results: Newly generated bone at bone defects and within the plastic caps was evaluated using micro-CT and histological sections. New bone regeneration within the plastic cap was increased significantly in the melatonin versus the control group. Conclusions: Melatonin promoted vertical bone regeneration in rat calvaria in the secluded space within the plastic cap

The magnetic field influence on magnetostructural phase transition in Ni2.19Mn0.81Ga

Magnetic properties of a polycrystalline alloy Ni$_{2.19}$Mn$_{0.81}$Ga, which undergoes a first-order magnetostructural phase transition from cubic paramagnetic to tetragonal ferromagnetic phase, are studied. Hysteretic behavior of isothermal magnetization $M(H)$ has been observed in a temperature interval of the magnetostructural transition in magnetic fields from 20 to 100 kOe. Temperature dependencies of magnetization $M$, measured in magnetic fields $H = 400$ and 60 kOe, indicate that the temperature of the magnetostructural transition increases with increasing magnetic field.Comment: Presented at the Second Moscow International Symposium on Magnetism (Moscow-2002

The Management of Constipation: Current Status and Future Prospects

Chronic constipation, a common condition, can have remarkably negative effects on a patient’s quality of life. Recent research has identified factors that may influence the prognosis of chronic constipation and suggests the need for adequate therapy. However, the major obstacles in this field were: (1) a small number of therapeutic options, (2) no clear diagnostic criteria, and (3) no effective method to collect information form the patients. These were due to the fact that bowel movement patterns vary widely among individuals, and also the functional constipation, including irritable bowel syndrome, is difficult to be distinguished from the chronic constipation. Recently, it has been demonstrated that the Rome IV diagnostic criteria of functional constipation and the Bristol stool form scale are useful for the objective evaluation and recording of stool. Based on these developments, and the increase of newly developed medicines the therapy for the constipation is significantly changing and therefore, if conventional therapy for chronic constipation is ineffective, switching of medicines is possible. Therefore, clinicians should update the information of these newly developed drugs available in clinics and diagnostic criteria. For this purpose, in this chapter, we have summarized the perspective on the current paradigm of treatment for chronic constipation focusing on recently introduced therapeutic drugs

生体分子分析のためのマイクロ流体デバイスの開発

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 船津 高志, 東京大学教授 浦野 泰照, 東京大学准教授 角田 誠, 東京大学准教授 大戸 梅治, 東京大学講師 前田 和哉University of Tokyo(東京大学