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Functions of the Mineralocorticoid Receptor in the Hippocampus By
Functions of the Mineralocorticoid Receptor in the Hippocampus by Aaron M. Rozeboom A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Cellular and Molecular Biology) in The University of Michigan 2008 Doctoral Committee: Professor Audrey F. Seasholtz, Chair Professor Elizabeth A. Young Professor Ronald Jay Koenig Associate Professor Gary D. Hammer Assistant Professor Jorge A. Iniguez-Lluhi Acknowledgements There are more people than I can possibly name here that I need to thank who have helped me throughout the process of writing this thesis. The first and foremost person on this list is my mentor, Audrey Seasholtz. Between working in her laboratory as a research assistant and continuing my training as a graduate student, I spent 9 years in Audrey’s laboratory and it would be no exaggeration to say that almost everything I have learned regarding scientific research has come from her. Audrey’s boundless enthusiasm, great patience, and eager desire to teach students has made my time in her laboratory a richly rewarding experience. I cannot speak of Audrey’s laboratory without also including all the past and present members, many of whom were/are not just lab-mates but also good friends. I also need to thank all the members of my committee, an amazing group of people whose scientific prowess combined with their open-mindedness allowed me to explore a wide variety of interests while maintaining intense scientific rigor. Outside of Audrey’s laboratory, there have been many people in Ann Arbor without whom I would most assuredly have gone crazy. -
Circadian Disruption: What Do We Actually Mean?
HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Eur J Neurosci Manuscript Author . Author manuscript; Manuscript Author available in PMC 2020 May 07. Circadian disruption: What do we actually mean? Céline Vetter Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA Abstract The circadian system regulates physiology and behavior. Acute challenges to the system, such as those experienced when traveling across time zones, will eventually result in re-synchronization to the local environmental time cues, but this re-synchronization is oftentimes accompanied by adverse short-term consequences. When such challenges are experienced chronically, adaptation may not be achieved, as for example in the case of rotating night shift workers. The transient and chronic disturbance of the circadian system is most frequently referred to as “circadian disruption”, but many other terms have been proposed and used to refer to similar situations. It is now beyond doubt that the circadian system contributes to health and disease, emphasizing the need for clear terminology when describing challenges to the circadian system and their consequences. The goal of this review is to provide an overview of the terms used to describe disruption of the circadian system, discuss proposed quantifications of disruption in experimental and observational settings with a focus on human research, and highlight limitations and challenges of currently available tools. For circadian research to advance as a translational science, clear, operationalizable, and scalable quantifications of circadian disruption are key, as they will enable improved assessment and reproducibility of results, ideally ranging from mechanistic settings, including animal research, to large-scale randomized clinical trials. -
Familial Neurohypophyseal Diabetes Insipidus in 13 Kindreds and 2
3 181 G Patti, S Scianguetta and Familial centralQ1 diabetes 181:3 233–244 Clinical Study others insipidus Familial neurohypophyseal diabetes insipidus in 13 kindreds and 2 novel mutations in the vasopressin gene Giuseppa Patti1,*, Saverio Scianguetta2,*, Domenico Roberti2, Alberto Di Mascio3, Antonio Balsamo4, Milena Brugnara5, Marco Cappa6, Maddalena Casale2, Paolo Cavarzere5, Sarah Cipriani7, Sabrina Corbetta8, Rossella Gaudino5, Lorenzo Iughetti9, Lucia Martini5, Flavia Napoli1, Alessandro Peri7, Maria Carolina Salerno10, Roberto Salerno11, Elena Passeri8, Mohamad Maghnie1, Silverio Perrotta2 and Natascia Di Iorgi1 1Department of Pediatrics, IRCCS Istituto Giannina Gaslini Institute, University of Genova, Genova, Italy, 2Department of Women, Child and General and Specialized Surgery, University of Campania ‘Luigi Vanvitelli’, Naples, Italy, 3University of Trieste, Trieste, Italy, 4Pediatrics Unit, Policlinico S. Orsola-Malpighi, Bologna, Italy, 5Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy, 6Unit of Endocrinology, Bambino Gesù Children’s Hospital, IRCCS, Roma, Italy, 7Endocrine Unit, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Firenze, Correspondence Ospedale Careggi Firenze, Firenze, Italy, 8Endocrinology and Diabetology Service, IRCCS Istituto Ortopedico Galeazzi, should be addressed University of Milan, Milan, Italy, 9Policlinico Universitario Modena, Modena, Italy, 10Department of Translational to M Maghnie or S Perrotta Medical Sciences-Pediatric Section, University of Naples Federico II, Naples, Italy, and 11SOD Endocrinologia, DAI Email Medico-Geriatrico, AOU Careggi Florence, Florence, Italy mohamadmaghnie@gaslini. *(G Patti and S Scianguetta contributed equally to this work) org or silverio.perrotta@ unicampania.it Abstract Background: Autosomal dominant neurohypophyseal diabetes insipidus (adNDI) is caused by arginine vasopressin (AVP) deficiency resulting from mutations in the AVP-NPII gene encoding the AVP preprohormone. -
A Murine Model of Autosomal Dominant Neurohypophyseal Diabetes Insipidus Reveals Progressive Loss of Vasopressin- Producing Neurons
A murine model of autosomal dominant neurohypophyseal diabetes insipidus reveals progressive loss of vasopressin- producing neurons Theron A. Russell, … , Jeffrey Weiss, J. Larry Jameson J Clin Invest. 2003;112(11):1697-1706. https://doi.org/10.1172/JCI18616. Article Endocrinology Familial neurohypophyseal diabetes insipidus (FNDI) is an autosomal dominant disorder caused by mutations in the arginine vasopressin (AVP) precursor. The pathogenesis of FNDI is proposed to involve mutant protein–induced loss of AVP-producing neurons. We established murine knock-in models of two different naturally occurring human mutations that cause FNDI. A mutation in the AVP signal sequence [A(–1)T] is associated with a relatively mild phenotype or delayed presentation in humans. This mutation caused no apparent phenotype in mice. In contrast, heterozygous mice expressing a mutation that truncates the AVP precursor (C67X) exhibited polyuria and polydipsia by 2 months of age and these features of DI progressively worsened with age. Studies of the paraventricular and supraoptic nuclei revealed induction of the chaperone protein BiP and progressive loss of AVP-producing neurons relative to oxytocin-producing neurons. In addition, Avp gene products were not detected in the neuronal projections, suggesting retention of WT and mutant AVP precursors within the cell bodies. In summary, this murine model of FNDI recapitulates many features of the human disorder and demonstrates that expression of the mutant AVP precursor leads to progressive neuronal cell loss. Find the latest version: https://jci.me/18616/pdf A murine model of autosomal See the related Commentary beginning on page 1641. dominant neurohypophyseal diabetes insipidus reveals progressive loss of vasopressin-producing neurons Theron A. -
And Low-Dose Melatonin Therapies
diseases Review Divergent Importance of Chronobiological Considerations in High- and Low-dose Melatonin Therapies Rüdiger Hardeland Johann Friedrich Blumenbach Institute of Zoology and Anthropology, University of Göttingen, 37073 Göttingen, Germany; [email protected] Abstract: Melatonin has been used preclinically and clinically for different purposes. Some applica- tions are related to readjustment of circadian oscillators, others use doses that exceed the saturation of melatonin receptors MT1 and MT2 and are unsuitable for chronobiological purposes. Conditions are outlined for appropriately applying melatonin as a chronobiotic or for protective actions at elevated levels. Circadian readjustments require doses in the lower mg range, according to receptor affinities. However, this needs consideration of the phase response curve, which contains a silent zone, a delay part, a transition point and an advance part. Notably, the dim light melatonin onset (DLMO) is found in the silent zone. In this specific phase, melatonin can induce sleep onset, but does not shift the circadian master clock. Although sleep onset is also under circadian control, sleep and circadian susceptibility are dissociated at this point. Other limits of soporific effects concern dose, duration of action and poor individual responses. The use of high melatonin doses, up to several hundred mg, for purposes of antioxidative and anti-inflammatory protection, especially in sepsis and viral diseases, have to be seen in the context of melatonin’s tissue levels, its formation in mitochondria, and detoxification of free radicals. Citation: Hardeland, R. Divergent Keywords: circadian; entrainment; inflammation; melatonin; mitochondria; receptor saturation Importance of Chronobiological Considerations in High- and Low-dose Melatonin Therapies. Diseases 2021, 9, 18. -
MELATONIN and HUMAN RHYTHMS INTRODUCTION It Has
Chronobiology International, 23(1&2): 21–37, (2006) Copyright # 2006 Taylor & Francis Group, LLC ISSN 0742-0528 print/1525-6073 online DOI: 10.1080/07420520500464361 MELATONIN AND HUMAN RHYTHMS Josephine Arendt Centre for Chronobiology, School of Biomedical and Molecular Sciences, University of Surrey, Guildford, England Melatonin signals time of day and time of year in mammals by virtue of its pattern of secretion, which defines ‘biological night.’ It is supremely important for research on the physiology and pathology of the human biological clock. Light suppresses melatonin secretion at night using pathways involved in circadian photoreception. The melatonin rhythm (as evidenced by its profile in plasma, saliva, or its major metabolite, 6-sulphatoxymelatonin [aMT6s] in urine) is the best peripheral index of the timing of the human circadian pacemaker. Light suppression and phase-shifting of the melatonin 24 h profile enables the characterization of human circadian photore- ception, and circulating concentrations of the hormone are used to investigate the general properties of the human circadian system in health and disease. Suppression of melatonin by light at night has been invoked as a possible influence on major disease risk as there is increasing evidence for its oncostatic effects. Exogenous melatonin acts as a ‘chronobiotic.’ Acutely, it increases sleep propensity during ‘biological day.’ These properties have led to successful treatments for serveal circadian rhythm disorders. Endogenous melatonin acts to reinforce the functioning of the human circadian system, probably in many ways. The future holds much promise for melatonin as a research tool and as a therapy for various conditions. Keywords Melatonin, Light, Circadian and Circaanual Rhythms, Chronobiotic, Sleep, Sleep Disorders, Photoperiodism INTRODUCTION It has been nearly 50 yrs since Aaron Lerner identified melatonin and, after self-administration, reported that it made him feel sleepy (Lerner et al., 1958). -
Tumour-Specific Arginine Vasopressin Promoter Activation in Small-Cell
British Journal of Cancer (1999) 80(12), 1935–1944 © 1999 Cancer Research Campaign Article no. bjoc.1999.0623 Tumour-specific arginine vasopressin promoter activation in small-cell lung cancer JM Coulson, J Stanley and PJ Woll CRC Department of Clinical Oncology, University of Nottingham, City Hospital, Hucknall Rd, Nottingham NG5 1PB, UK Summary Small-cell lung cancer (SCLC) can produce numerous mitogenic neuropeptides, which are not found in normal respiratory epithelium. Arginine vasopressin is detected in up to two-thirds of SCLC tumours whereas normal physiological expression is essentially restricted to the hypothalamus. This presents the opportunity to identify elements of the gene promoter which could be exploited for SCLC- specific targeting. A series of human vasopressin 5′ promoter fragments (1048 bp, 468 bp and 199 bp) were isolated and cloned upstream of a reporter gene. These were transfected into a panel of ten cell lines, including SCLC with high or low endogenous vasopressin transcription, non-SCLC and bronchial epithelium. All these fragments directed reporter gene expression in the five SCLC cell lines, but had negligible activity in the control lines. The level of reporter gene expression reflected the level of endogenous vasopressin production, with up to 4.9-fold (s.d. 0.34) higher activity than an SV40 promoter. The elements required for this strong, restricted, SCLC-specific promoter activity are contained within the 199-bp fragment. Further analysis of this region indicated involvement of E-box transcription factor binding sites, although tumour-specificity was retained by a 65-bp minimal promoter fragment. These data show that a short region of the vasopressin promoter will drive strong expression in SCLC in vitro and raise the possibility of targeting gene therapy to these tumours. -
Familial Neurohypophyseal Diabetes Insipidus—An Update Jane H
Familial Neurohypophyseal Diabetes Insipidus—An Update Jane H. Christensen* and Søren Rittig† Although molecular research has contributed significantly to our knowledge of familial neurohypophyseal diabetes insipidus (FNDI) for more than a decade, the genetic back- ground and the pathogenesis still is not understood fully. Here we provide a review of the genetic basis of FNDI, present recent progress in the understanding of the molecular mechanisms underlying its development, and survey diagnostic and treatment aspects. FNDI is, in 87 of 89 kindreds known, caused by mutations in the arginine vasopressin (AVP) gene, the pattern of which seems to be largely revealed as only few novel mutations have been identified in recent years. The mutation pattern, together with evidence from clinical, cellular, and animal studies, points toward a pathogenic cascade of events, initiated by protein misfolding, involving intracellular protein accumulation, and ending with degener- ation of the AVP producing magnocellular neurons. Molecular research has also provided an important tool in the occasionally difficult differential diagnosis of DI and the opportunity to perform presymptomatic diagnosis. Although FNDI is treated readily with exogenous administration of deamino-D-arginine vasopressin (dDAVP), other treatment options such as gene therapy and enhancement of the endoplasmic reticulum protein quality control could become future treatment modalities. Semin Nephrol 26:209-223 © 2006 Elsevier Inc. All rights reserved. KEYWORDS neurohypophyseal diabetes -
Dark-Phase Light Contamination Disrupts Circadian Rhythms in Plasma Measures of Endocrine Physiology and Metabolism in Rats
Comparative Medicine Vol 60, No 5 Copyright 2010 October 2010 by the American Association for Laboratory Animal Science Pages 348–356 Dark-Phase Light Contamination Disrupts Circadian Rhythms in Plasma Measures of Endocrine Physiology and Metabolism in Rats Robert T Dauchy,1,* Erin M Dauchy,1 Robert P Tirrell,2 Cody R Hill,1 Leslie K Davidson,2 Michael W Greene,2 Paul C Tirrell,2 Jinghai Wu,2 Leonard A Sauer,2 and David E Blask1 Dark-phase light contamination can significantly disrupt chronobiologic rhythms, thereby potentially altering the endocrine physiology and metabolism of experimental animals and influencing the outcome of scientific investigations. We sought to de- termine whether exposure to low-level light contamination during the dark phase influenced the normally entrained circadian rhythms of various substances in plasma. Male Sprague–Dawley rats (n = 6 per group) were housed in photobiologic light-exposure chambers configured to create 1) a 12:12-h light:dark cycle without dark-phase light contamination (control condition; 123 µW/cm2, lights on at 0600), 2) experimental exposure to a low level of light during the 12-h dark phase (with 0.02 , 0.05, 0.06, or 0.08 µW/cm2 light at night), or 3) constant bright light (123 µW/cm2). Dietary and water intakes were recorded daily. After 2 wk, rats underwent 6 low-volume blood draws at 4-h intervals (beginning at 0400) during both the light and dark phases. Circadian rhythms in dietary and water intake and levels of plasma total fatty acids and lipid fractions remained entrained during exposure to either control conditions or low-intensity light during the dark phase. -
Role of Melatonin in the Regulation of Human Circadian Rhythms and Sleep
Journal of Neuroendocrinology, 2003, Vol. 15, 432–437 Role of Melatonin in the Regulation of Human Circadian Rhythms and Sleep C. Cajochen, K. Kra¨ uchi and A. Wirz-Justice Center for Chronobiology, Psychiatric University Clinic, Basel, Switzerland. Key words: chronobiotic, soporific, EEG power density, thermoregulation, sleepiness. Abstract The circadian rhythm of pineal melatonin is the best marker of internal time under low ambient light levels. The endogenous melatonin rhythm exhibits a close association with the endogenous circadian component of the sleep propensity rhythm. This has led to the idea that melatonin is an internal sleep ‘facilitator’ in humans, and therefore useful in the treatment of insomnia and the readjustment of circadian rhythms. There is evidence that administration of melatonin is able: (i) to induce sleep when the homeostatic drive to sleep is insufficient; (ii) to inhibit the drive for wakefulness emanating from the circadian pacemaker; and (iii) induce phase shifts in the circadian clock such that the circadian phase of increased sleep propensity occurs at a new, desired time. Therefore, exogenous melatonin can act as soporific agent, a chronohypnotic, and/or a chronobiotic. We describe the role of melatonin in the regulation of sleep, and the use of exogenous melatonin to treat sleep or circadian rhythm disorders. entrained (6, 7) and in sighted subjects with non 24-sleep–wake Endogenous melatonin and the circadian sleep–wake cycle syndrome (8, 9). Even more impressive are the results cycle and thermoregulation obtained from studies using the forced desynchrony protocol to Under entrained conditions, the phase relationship between the separate out circadian- and wake-dependent components of beha- endogenous circadian rhythm of melatonin and the sleep–wake viour. -
Central Diabetes Insipidus (CDI) 15035X Mutations
Central Diabetes Insipidus (CDI) 15035X Mutations Clinical Use Clinical Background • Differentiate inherited CDI from CDI is an acquired or autosomal acquired CDI dominant inherited disorder character- • Screen for CDI carrier status in at- ized by polyuria, polydipsia, a low risk individuals urinary specific gravity, and high risk of severe dehydration. Arginine Reference Range vasopressin (AVP), also known as Negative (no mutations detected) antidiuretic hormone (ADH), is absent. CDI stems from the degenera- Interpretive Information tion or destruction of cells in the posterior pituitary, the site of AVP Mutation present production. Thus, it is also referred to • Central diabetes insipidus (affected as pituitary, neurohypophyseal, or or carrier) neurogenic diabetes insipidus. The disorder typically presents in infancy or early childhood, although late-onset cases have been reported. Although rare, inherited CDI can be caused by mutations in the AVP gene on chromosome 20. Prepro-AVP, the initial protein product of the AVP gene, undergoes several post-transla- tional steps to yield AVP, neurophysin, and glycoprotein. When mutations in the AVP gene are present, cytotoxic products that lead to destruction of the secretory neurons are generated. Since more than 30 relevant mutations have been identified, gene sequencing is the method of choice for diagnosis of the inherited form. After identifica- tion of a mutation in an affected indi- vidual, genetic testing can be used to evaluate other family members. Method • Polymerase chain reaction (PCR) and DNA sequencing • Analytical specificity: mutations in 3 exons of the AVP gene Specimen Requirements 5 mL room temperature whole blood 3 mL minimum Collect blood in a lavender-top (EDTA) or yellow-top (ACD solution B) tube. -
Photoperiodic Responses on Expression of Clock Genes, Synaptic Plasticity Markers, and Protein Translation Initiators the Impact of Blue-Enriched Light
Photoperiodic Responses on Expression of Clock Genes, Synaptic Plasticity Markers, and Protein Translation Initiators The Impact Of Blue-Enriched Light Master report Jorrit Waslander, s2401878 Behavioral Cognitive Neuroscience research master, N-track University of Groningen, the Netherlands Internship at: Bergen Stress and Sleep Group, University of Bergen, Norway Date: 13-7-2018 Internal supervisor, University of Groningen: P. (Peter) Meerlo External supervisor, University of Bergen: J. (Janne) Grønli Daily supervisor, University of Bergen: A. (Andrea) R. Marti Photoperiodic Responses in the PFC Table of Contents Summary ................................................................................................................................................. 3 Introduction ............................................................................................................................................. 5 Research Objective .............................................................................................................................. 8 Hypotheses .......................................................................................................................................... 8 Methods ................................................................................................................................................ 10 Experimental procedure .................................................................................................................... 10 Ethics ............................................................................................................................................