Allosteric activation and genetic antagonism of metabotropic glutamate receptor subtype 7 (mGluR7) : implications for stress-related physiology and behavior

Metabotropic glutamate receptor subtypes (mGluR1 to -8) act as pre- and postsynaptic regulators of neurotransmission in the central nervous system. Regulation of neurotransmission via metabotropic glutamate receptors has recently been implicated in the pathophysiology of anxiety and stress-related disorders including depression. Among metabotropic glutamate receptor subtypes, the group III metabotropic glutamate receptor subtype 7 (mGluR7) shows the highest evolutionary conservation (Flor et al., 1997; Makoff et al., 1996), which suggests that this receptor could play an important physiological role. Cryan et al. (2003) have demonstrated that mice with a targeted deletion of the gene for mGluR7 (mGluR7-/-) show antidepressant and anxiolytic-like effects in a variety of stress-related paradigms, including the forced swim stress and the stress-induced hyperthermia tests. Furthermore, the same group has recently developed mGluR7 knockdown using siRNA, which further supported the critical role of mGluR7 in anxiety- and stress-related behaviors (Thakker et al., 2005). Since the hypothalamic-pituitary-adrenal (HPA) axis regulates stress responses, it was investigated in this thesis whether the levels of selected mRNA transcripts and endocrine hormones were altered in mGluR7 deficient mice in the HPA axis. Over all, mGluR7-/- mice showed only moderately lower serum levels of corticosterone and adrenocorticotropic hormone (ACTH) compared to mGluR7+/+ mice. However, strong evidence has been found for up-regulation of glucocorticoid receptor (GR)-dependent feedback suppression of the HPA axis in mice with mGluR7 deficiency: (i) mRNA transcripts of GR were significantly higher in the hippocampus of mGluR7-/- animals, (ii) similar increases were seen for 5-HT1A receptor transcripts which are thought to be directly controlled by the GR transcription factor and finally (iii) mGluR7-/- mice showed elevated sensitivity to dexamethasone-induced suppression of serum corticosterone when compared with mGluR7+/+ animals. These results indicate that mGluR7 deficiency causes dysregulation of HPA axis parameters which may account, at least in part, for the phenotype of mGluR7-/- mice in animal models for anxiety and stress-related disorders. In addition, the data given here show that protein levels of brain-derived neurotrophic factor (BDNF) are elevated in the hippocampus of mGluR7-/- mice which will be discussed at the latter part of this thesis in the context of the stress-resistant phenotype found in those animals. It can be concluded that genetic ablation of mGluR7 in mice interferes at multiple sites in the neuronal circuitry and molecular pathways implicated in anxiety and stress-related disorders. Metabotropic glutamate receptor subtypes (mGluR1 to -8) act as pre- and postsynaptic regulators of neurotransmission in the central nervous system. Regulation of neurotransmission via metabotropic glutamate receptors has recently been implicated in the pathophysiology of anxiety and stress-related disorders including depression. Among metabotropic glutamate receptor subtypes, the group III metabotropic glutamate receptor subtype 7 (mGluR7) shows the highest evolutionary conservation (Flor et al., 1997; Makoff et al., 1996), which suggests that this receptor could play an important physiological role. Cryan et al. (2003) have demonstrated that mice with a targeted deletion of the gene for mGluR7 (mGluR7-/-) show antidepressant and anxiolytic-like effects in a variety of stress-related paradigms, including the forced swim stress and the stress-induced hyperthermia tests. Furthermore, the same group has recently developed mGluR7 knockdown using siRNA, which further supported the critical role of mGluR7 in anxiety- and stress-related behaviors (Thakker et al., 2005). Since the hypothalamic-pituitary-adrenal (HPA) axis regulates stress responses, it was investigated in this thesis whether the levels of selected mRNA transcripts and endocrine hormones were altered in mGluR7 deficient mice in the HPA axis. Over all, mGluR7-/- mice showed only moderately lower serum levels of corticosterone and adrenocorticotropic hormone (ACTH) compared to mGluR7+/+ mice. However, strong evidence has been found for up-regulation of glucocorticoid receptor (GR)-dependent feedback suppression of the HPA axis in mice with mGluR7 deficiency: (i) mRNA transcripts of GR were significantly higher in the hippocampus of mGluR7-/- animals, (ii) similar increases were seen for 5-HT1A receptor transcripts which are thought to be directly controlled by the GR transcription factor and finally (iii) mGluR7-/- mice showed elevated sensitivity to dexamethasone-induced suppression of serum corticosterone when compared with mGluR7+/+ animals. These results indicate that mGluR7 deficiency causes dysregulation of HPA axis parameters which may account, at least in part, for the phenotype of mGluR7-/- mice in animal models for anxiety and stress-related disorders. In addition, the data given here show that protein levels of brain-derived neurotrophic factor (BDNF) are elevated in the hippocampus of mGluR7-/- mice which will be discussed at the latter part of this thesis in the context of the stress-resistant phenotype found in those animals. It can be concluded that genetic ablation of mGluR7 in mice interferes at multiple sites in the neuronal circuitry and molecular pathways implicated in anxiety and stress-related disorders

炭素-窒素結合に作用する微生物加水分解酵素の解析と医薬品中間体生産への応用

京都大学0048新制・課程博士博士(農学)甲第20451号農博第2236号新制||農||1051(附属図書館)学位論文||H29||N5072(農学部図書室)京都大学大学院農学研究科応用生命科学専攻(主査)教授 小川 順, 教授 三上 文三, 教授 栗原 達夫学位規則第4条第1項該当Doctor of Agricultural ScienceKyoto UniversityDFA

MUSCLE ARCHITECTURE AND THE RATIO OF JOINT TORQUE TO MUSCLE VOLUME OF TRICEPS SURAE MUSCLES IN YOUNG MEN AND WOMEN

INTRODUCTION: Muscle volume is a major determinant of joint torque (Fukunaga et al., 2001). However, it is not clear whether there are gender-differences in a relationship between joint torque and muscle volume. It is not clear also about muscle architecture, e.g., physiological cross-sectional area (PCSA) and fascicle length. We aim to compare 1) muscle architecture under the maximal voluntary contraction condition and muscle volume (MVTS) of the triceps surae muscles (TS), and 2) the relationship between MVC and MVTS, for young men and women

FORCE-LENGTH RELATIONSHIPS OF HUMAN GASTROCNEMIUS AND SOLEUS MUSCLES IN VIVO

INTRODUCTION: Synergistic muscle have different architecture, and therefore could have different force-length relationships for the same joint angle changes. Previous studies have failed to reveal the force-length relationships of synergistic muscles. The purpose of this study was to investigate the force-length relationships of the triceps surae muscles for humans in vivo

Regulating divergent transcriptomes through mrna splicing and its modulation using various small compounds

Human transcriptomes are more divergent than genes and contribute to the sophistication of life. This divergence is derived from various isoforms arising from alternative splicing. In addition, alternative splicing regulated by spliceosomal factors and RNA structures, such as the RNA G-quadruplex, is important not only for isoform diversity but also for regulating gene expression. Therefore, abnormal splicing leads to serious diseases such as cancer and neurodegenerative disorders. In the first part of this review, we describe the regulation of divergent transcriptomes using alternative mRNA splicing. In the second part, we present the relationship between the disruption of splicing and diseases. Recently, various compounds with splicing inhibitor activity were established. These splicing inhibitors are recognized as a biological tool to investigate the molecular mechanism of splicing and as a potential therapeutic agent for cancer treatment. Food-derived compounds with similar functions were found and are expected to exhibit anticancer effects. In the final part, we describe the compounds that modulate the messenger RNA (mRNA) splicing process and their availability for basic research and future clinical potential

Study of human Wharton’s duct structure and its relationship with salivary flow

Of all major salivary glands, the human submandibular gland secretes the largest amount of saliva. Along with the sublingual duct, the main duct (Wharton’s duct) is known to open into the sublingual caruncula; however, reports regarding this common opening structure are scarce and details unclear. The structure of Wharton’s duct opening is quite different from that of parotid duct (Stensen’s duct) opening in its overall size and diameter despite what is commonly noted in text books. About 85% of sialolith occurrences in humans is in the submandibular gland and duct, which causes local pain during swallowing in most cases. The details of Wharton’s duct’s inner structure is relatively unknown, and further investigation is necessary to understand its special characteristics and clinical applications. In this study, we observed the inner structure of the ducts’ common opening area by scanning electron microscopy and confirmed a large number of blood vessels present in the connective tissue layer just under the epithelium. In addition, we confirmed the presence of smooth muscle in the same area using smooth muscle actin antibody. These structural findings suggest that Wharton’s duct itself is likely responsible for the regulation of salivary flow

HAMAMATSU-ICG study: Protocol for a phase III, multicentre, single-arm study to assess the usefulness of indocyanine green fluorescent lymphography in assessing secondary lymphoedema

Introduction Secondary lymphoedema of the extremities is an important quality-of-life issue for patients who were treated for their malignancies. Indocyanine green (ICG) fluorescent lymphography may be helpful for assessing lymphoedema and for planning lymphaticovenular anastomosis (LVA). The objective of the present clinical trial is to confirm whether or not ICG fluorescent lymphography using the near-infrared monitoring camera is useful for assessing the indication for LVA, for the identification of the lymphatic vessels before the conduct of LVA, and for the confirmation of the patency of the anastomosis site during surgery. Methods and analysis This trial is a phase III, multicentre, single-arm, open-label clinical trial to assess the efficacy and safety of ICG fluorescent lymphography when assessing and treating lymphoedema of patients with secondary lymphoedema who are under consideration for LVA. The primary endpoint is the identification rate of the lymphatic vessels at the incision site based on ICG fluorescent lymphograms obtained before surgery. The secondary endpoints are 1) the sensitivity and specificity of dermal back flow determined by ICG fluorescent lymphography as compared with 99mTc lymphoscintigraphy—one of the standard diagnostic methods and 2) the usefulness of ICG fluorescent lymphography when confirming the patency of the anastomosis site after LVA. Ethics and dissemination The protocol for the study was approved by the Institutional Review Board of each institution. The trial was filed for and registered at the Pharmaceuticals and Medical Devices Agency in Japan. The trial is currently on-going and is scheduled to end in June 2020

徳島県の訪問看護提供状況

This survey aimed to clarify the current status of providing nursing services and the characteristics of visiting nursing stations (VNSs), which were classified by the size of VNS in Tokushima Prefecture. A questionnaire survey was conducted from January to March 2015 among all 71 VNSs in the prefecture. The questionnaire included questions regarding the implementation framework of home nursing, actual situations of service provision, conditions of patients, and issues and challenges of home care in Tokushima Prefecture. Of 71 VNSs, 34 responded to the questionnaire（response rate, 47.9％）. The proportion of VNSs that provided complicated medical procedures was low ; e.g., 27.6％ of VNSs provided self-peritoneal dialysis at home, 48.3％ provided services for narcotic pain control, and 58.6％ provided total parenteral nutrition. Home visits for patients with mental illnesses were provided significantly more by large size VNSs Home visits were frequently provided for households located far from VNSs, thus raising concerns regarding the workload of nurses and the convenient use of VNSs by clients. For patients to comfortably live in local areas that are familiar to them, it was considered that correcting the uneven geographical distribution of VNSs might be important

Monoblock Craniofacial Internal Distraction in a Child with Pfeiffer Syndrome: A Case Report

A 7-yr-old boy visited our surgical center with Pfeiffer syndrome type 1, presenting with macrocrania, broad big toe and thumb, exophthalmos, tongue protrusion, malocclusion with midfacial retrusion, mild respiratory difficulty due to minor upper airway obstruction, and developmental delay. He also exhibited anthrophobia with a passive character. The patient was treated with internal monoblock distraction osteogenesis to increase the intracranial and intraorbital volumes, and the nasal and pharyngeal airway spaces using two modular mid-facial internal distractors. For distraction, the latency period was 1 week, the daily activation of 1.0 mm was 20 days (total advancement 20 mm at the midline), and the consolidation period was 3 months. The follow-up computed tomography 12 months after surgery showed expansion of the brain and proper ossification in the distracted area. The patient also showed aesthetically good cranial contours, improved tongue and eyeball protrusion, no respiratory difficulty, and improved learning. We suggest that the internal distraction may last longer than an external type, resulting in a better bone fusion rate and successful expansion of craniofacial bones

Receptor subtype‐dependent galanin actions on gamma‐aminobutyric acidergic neurotransmission and ethanol responses in the central amygdala

The neuropeptide galanin and its three receptor subtypes (GalR1‐3) are expressed in the central amygdala (CeA), a brain region involved in stress‐ and anxiety‐related behaviors, as well as alcohol dependence. Galanin also has been suggested to play a role in alcohol intake and alcohol dependence. We examined the effects of galanin in CeA slices from wild‐type and knockout (KO) mice deficient of GalR2 and both GalR1 and GalR2 receptors. Galanin had dual effects on gamma‐aminobutyric acid (GABA)‐ergic transmission, decreasing the amplitudes of pharmacologically isolated GABAergic inhibitory postsynaptic potentials (IPSPs) in over half of CeA neurons but augmenting IPSPs in the others. The increase in IPSP size was absent after superfusion of the GalR3 antagonist SNAP 37889, whereas the IPSP depression was absent in CeA neurons of GalR1 × GalR2 double KO and GalR2 KO mice. Paired‐pulse facilitation studies showed weak or infrequent effects of galanin on GABA release. Thus, galanin may act postsynaptically through GalR3 to augment GABAergic transmission in some CeA neurons, whereas GalR2 receptors likely are involved in the depression of IPSPs. Co‐superfusion of ethanol, which augments IPSPs presynaptically, together with galanin caused summated effects of ethanol and galanin in those CeA neurons showing galanin‐augmented IPSPs, suggesting the two agents act via different mechanisms in this population. However, in neurons showing IPSP‐diminishing galanin effects, galanin blunted the ethanol effects, suggesting a preemptive effect of galanin. These findings may increase understanding of the complex cellular mechanisms that underlie the anxiety‐related behavioral effects of galanin and ethanol in CeA.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92021/1/j.1369-1600.2011.00360.x.pd