Current Topic Workshop: Mathematical Neuroendocrinology

(August 9,2010 - August 13,2010 )

Organizers


Richard Bertram
Department of Mathematics, Florida State University
Arthur Sherman
National Institutes of Health

Neuroendocrinology is at the intersection of neuroscience and endocrinology. Of the many endocrine glands in the body, the one that is under the most direct neural control is the pituitary gland, which is located adjacent to the brain region called the hypothalamus. The anterior portion of the pituitary consists of several cell types, each of which is electrically excitable (like neurons) and which secretes a hormone when activated. Neurons within the hypothalamus act on pituitary cells to evoke hormone secretion at the proper times and under the proper physical stimuli. The pituitary hormones then act on other endocrine glands (like pineal, adrenal, ovaries, and testes) to influence secretion of hormones. All of the hormones influence neuron activity within the hypothalamus, closing the loop. Mathematical neuroendocrinology is a new field that uses mathematical modeling and analysis to help interpret neuroendocrine data and design new experiments. Models have been developed at the cellular and systems level.

This workshop is the second in a series (the first was held at AIM) and will continue dialogues and collaborations between mathematicians and experimentalists begun at AIM. One goal is to discuss problems in neuroendocrinology that can be addressed using mathematics. These discussions took place during the first meeting, but we now have a better feel for the types of problems of interest. Another goal is to bring young mathematicians and experimentalists who have never worked with mathematical biologists into the mathematical biology community to spur its growth.

Accepted Speakers

Ursula Kaiser
Division of Endocrinology, Diabetes, and Hypertension, Boston University
Yue-Xian Li
Departments of Mathematics and Zoology, University of British Columbia
Sue Moenter
see below in comments, University of Virginia
Michael Shipston
Centre for Integrative Physiology, University of Edinburgh
Richard Yamada
Department of Mathematics, University of Michigan
Monday, August 9, 2010
Time Session
09:00 AM
10:00 AM
Arturo Iglesias - Introduction to neuroendocrinology
Introduction to neuroendocrinology
10:30 AM
11:30 AM
Richard Bertram - An introduction to the analysis of biomathematical models
An introduction to the analysis of biomathematical models
Tuesday, August 10, 2010
Time Session
09:00 AM
10:00 AM
Stanko Stojilkovic - Signaling Within and Between Pituitary Cells
Secretory pituitary cells express numerous voltage-gated sodium, calcium, potassium, and chloride channels and fire action potentials spontaneously, accompanied with a rise in intracellular calcium and modulation of cyclic nucleotide signaling pathway. These cells also express several subtypes of extracellular ligand-gated ion channels, which activation leads to amplification of the pacemaking activity and facilitation of calcium influx and hormone release. Numerous G protein-coupled receptors expressed in these cells stimulate or silence electrical activity, cyclic nucleotide signaling and action potential-dependent calcium influx and hormone release. Other members of this receptor family can activate IP3 receptor channels in the endoplasmic reticulum, leading to a cell type-specific modulation of electrical activity. Pituitary cells also express gap junction channels, which could be of the potential relevance for intercellular signaling. The current knowledge on complex relationship between electrical activity and calcium/cyclic nucleotide signaling in pituitary cells will be presented. A work in progress on identification of channels contributing to the pacemaking depolarization will also be discussed.
10:30 AM
11:30 AM
Arthur Sherman - Modeling of Exocytosis in Endocrine and Neuroendocrine Cells
Secretion, whether from nerve terminals or hormone-secreting cells, is determined by the product of the number of release-ready vesicles and the probability of release per vesicle. The probability of release is in turn dependent on both the concentration of calcium seen by the vesicles and the affinity of the release mechanism for calcium. All of these factors vary in time, depend on conditions and history of stimulation, and vary among cell types. Vesicle trafficking to releases sites on the plasma membrane is regulated by calcium and also by metabolism, at least in insulin-secreting cells. It has long been known that vesicles differ in proximity to calcium channels, but recent evidence from many cell types supports the hypothesis that a subset of vesicles distant from channels may have enhanced sensitivity to calcium and play a larger role than previously thought. These issues will be discussed based on models in beta cells along with possible relevance for pituitary and hypothalamic neurons.
Wednesday, August 11, 2010
Time Session
09:00 AM
10:00 AM
Sue Moenter - Intrinsic and extrinsic contributors to gonadotropin-releasing hormone neuronal activity
The episodic release of gonadotropin-releasing hormone (GnRH) from nerve terminals in the hypothalamus is critical for encoding downstream pituitary response and thus fertility. Episodic release likely arises from the intersection of several components including intrinsic properties that generate repeating activity, synaptic inputs and the network interactions that bring about synchrony of neuronal activity. The current knowledge on these various aspects will be discussed. Preliminary work on how metabolic inputs that regulate fertility alter intrinsic properties will also be presented.
10:30 AM
11:30 AM
Yue-Xian Li - Viability of Autocrine Regulation in Synchronizing Diffusely Distributed Endocrine Neurons Producing Pulsatile Hormonal Signals
Reproduction in mammals is controlled by the pulsatile release of gonadotropin-releasing hormone (GnRH). About 800~2000 GnRH neurons participate in the generation of GnRH pulses. Their cell bodies are distributed in a scattered manner in designated areas of the hypothalamus. Although several experimental models including cultured hypothalamic tissues, placode-derived GnRH neurons, and GT1 cell lines have been developed and studied, a mechanistic explanation for the origin of GnRH pulsatility remains elusive. One major obstacle is identifying the mechanism for synchronizing scattered neurons. This talk is aimed at studying the viability of autocrine regulation in synchronizing GnRH neurons using mathematical models describing diffusely distributed GnRH neurons in two-dimensional space.

The models discussed here are developed based on experiments in GT1 cells as well as hypothalamic neurons in culture. These experiments revealed that GnRH neurons express GnRH receptors that allow GnRH to regulate its own secretion through an autocrine effect. GnRH binding to its receptors on GnRH neurons triggers the activation of three types of G-proteins of which two activates and one inhibits GnRH secretion (Krsmanovic et al, 2003, PNAS 100:2969). These observations suggest GnRH secreted by GnRH neurons serve as a diffusive mediator as well as an autocrine regulator. A mathematical model has been developed (Khadra-Li, 2006, Biophys. J. 91:74) and its robustness and potential applicability to GnRH neurons in vivo investigated (Li-Khadra, 2008, BMB 70:2103). In this talk, I will introduce some key experimental and modeling results of this rhythm-generating system, focusing on the effects of intracellular distance, rate of hormone secretion, and spatial distribution on the ability of diffusely distributed GnRH neurons to synchronize through autocrine regulation. Based on the modeling results, one plausible explanation for why GnRH neurons are distributed in a scattered manner is proposed.

(Results presented in here are based on works in collaboration with Anmar Khadra, Atsushi Yokoyama, and Patrick Fletcher.)
Thursday, August 12, 2010
Time Session
09:00 AM
10:00 AM
Ursula Kaiser - Differential Regulation of FSH(beta) Transcription by Changes in GnRH Pulse Frequency
The gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) play an integral role in the reproductive axis, translating neural and hormonal input into precisely regulated output to achieve normal sexual development and regulation of gonadal function. In recent years, considerable progress has been made in the elucidation of the molecular mechanisms underlying tissue-specific and tonic GnRH-dependent expression of the gonadotropin (beta)-subunit genes. However, little is known about the mechanisms essential in the differential control of gonadotropin gene expression by changes in GnRH pulse frequency. The focus of this presentation is to discuss mechanisms that contribute to the GnRH pulse frequency-dependent differential control of FSH(beta) gene expression. A major GnRH-responsive site within the FSH(beta) promoter is predominantly bound by cAMP response element binding protein (CREB) to stimulate FSH(beta) transcription. In turn, the transcriptional inhibitor, inducible cAMP early repressor (ICER), is expressed to a greater extent at high GnRH pulse frequencies and antagonizes the stimulatory transcriptional effects of CREB. The experimental data supporting this dynamic model of GnRH pulse frequency-dependent regulation of FSH(beta) transcription will be presented and ongoing studies to explore mechanisms essential in integrating the effects of the bZIP transcription factors, CREB and ICER, to ultimately govern the activation of FSH(beta) gene expression will be discussed.
10:30 AM
11:30 AM
Michael Shipston - Ion channels and the control of the hypothalamic pituitary-adrenal (HPA) axis: from molecules to models
Stress-related disorders represent one of the major health-care burdens in modern society. The neuroendocrine stress response is coordinated through the dynamic interplay between the brain and the endocrine regulation of the anterior pituitary and adrenal glands - the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is a classic example of homeostatic feed-forward and feedback loops working together to control system output and function.

Central to the control of the HPA axis is the coordinated activity of ion channels and cellular electrical excitability in the key nodes of the axis - hypothalamic neurones, anterior pituitary corticotrophs and adrenal cortical cells. However, while the inputs and outputs of each node are well understood how the electrical properties of these systems is controlled and whether disturbances in ion channel properties may underlie disease states associated with HPA axis dysfunction is very poorly understood. This talk is aimed at identifying some of the major challenges in understanding HPA axis function from both a physiological and modelling viewpoint and to stimulate new research avenues that should lead to improved predictive tools to understand HPA axis function in health and disease. Preliminary work exploiting an integrated approach to understand the complex interplay between multiple ion channels and their control of distinct nodes of the HPA axis will be discussed.
Friday, August 13, 2010
Time Session
09:00 AM
10:00 AM
Richard Yamada - Multi-Scale Mathematical Models of the Supra-Chiasmatic Nuclei
The master-clock in all mammals is the Supra-Chiasmatic Nuclei (SCN) which is the organ responsible for coordinating time-keeping in all cells within the organism. The SCN is composed of approximately 10,000 individual cells. Experimental evidence indicates that each cell in the SCN is an individual oscillator; inter-cellular coupling mechanisms (electrical and chemical) become important in synchronizing rhythms within a cellular network.

After a brief overview of modeling approaches in this field, we will review current strategies for quantitative modeling of the SCN at the cellular and intra-cellular level. In particular we will discuss models which have studied the roles of molecular noise and inter-cellular coupling mechanisms in the SCN network; these model's results will be compared to experimental data. Ultimately we would like to understand the role of the SCN at the organismal level. We conclude with a general discussion/direction of the issues/questions in the next stage of SCN modeling.
Name Email Affiliation
Aggarwal, Nitish aggarwal.46@osu.edu Biology and Mathematics, The Ohio State University
Banerjee, Sayanti banerjee.35@osu.edu Mathematics, The Ohio State University
Bertram, Richard bertram@sb.fsu.edu Department of Mathematics, Florida State University
Bonnefont, Xavier Xavier.Bonnefont@igf.cnrs.fr Department of Endocrinology, Centre National d''Etudes Spatiales
Boulant, Jack boulant.1@osu.edu Physiology & Cell Biology, The Ohio State University
Ciccone, Nick nciccone@partners.org Brigham and Women's Hospital, Harvard Medical School
Clment, Frdrique Frederique.Clement@inria.fr Universit'e de Paris XII (Paris-Val-de-Marne)
Cruz, Maytee maytee_ca@yahoo.com School of Human Evolution, Arizona State University
Dean II, Dennis ddean@rics.bwh.harvard.edu Division of Sleep Medicine, Boston University
Diekman, Casey diekman@umich.edu Bioinformatics, University of Michigan
Duan, Wen wdua004@ec.auckland.ac.nz Mathematics Department, University of Auckland
Eya, Arlene arleneeya@yahoo.com Dept. of Biological Sciences, University of the Philippines
Fletcher, Patrick patrick.allen.fletcher@gmail.com Department of Mathematics, Florida State University
Freeman, Mark freeman@neuro.fsu.edu Department of Biological Sciences, Florida State University
Glanowska , Kasia kmg5v@virginia.edu University of Virginia School of Medicine
Gou, Jia jia_g@math.ubc.ca Department of Mathematics, University of British Columbia
Gutierrez, Juan j.gutierrez@math.miami.edu
Helena, Cleyde chelena@neuro.fsu.edu Neuroscience Program, Florida State University
Iglesias, Arturo iglesiasa@neuro.fsu.edu Department of Biological Sciences, Florida State University
Kaiser , Ursula UKAISER@partners.org Division of Endocrinology, Diabetes, and Hypertension, Boston University
Khadra, Anmar khadraa@mail.nih.gov National Institutes of Health
Kim, Jung Eun jkim@math.ohio-state.edu Mathematics, The Ohio State University
Kolli, Jaya jkolli@rossmed.edu.dm Clinical Medicine, University of the West Indies
Kucka, Marek hsugr@mail.nih.gov Endocrinology and Reproduction Research Branch, NICHD
Le Tissier, Paul pletiss@nimr.mrc.ac.uk Division of Molecular Neuroendocrinology, International Institute for Applied Systems Analysis
Lee, Euiwoo ewlee@ssu.ac.kr Mathematics, Korea Advanced Institute of Science and Technology (KAIST)
Leng , Gareth sarah.matheson@ed.ac.uk Centre for Integrative Physiology, University of Edinburgh
Li, Yue-Xian yxli@math.ubc.ca Departments of Mathematics and Zoology, University of British Columbia
Magill, John magill@psicorp.com Principal Research Engineer, Physical Sciences Inc.
McCobb , David dpm9@cornell.edu Dept. of Neurobiology and Behavior, Cornell University
Meijer , Onno o.meijer@lacdr.leidenuniv.nl Division of Medical Pharmacology, Rijksuniversiteit te Leiden
Moenter, Sue smm4n@virginia.edu see below in comments, University of Virginia
Olmez, Fatih olmez@math.osu.edu Mathematics, The Ohio State University
Pararai, Mavis pararaim@iup.edu Mathematics Department, Indiana University of Pennsylvania
Selgrade, Jim selgrade@math.ncsu.edu Department of Mathematics, North Carolina State University
Sherman , Arthur asherman@nih.gov National Institutes of Health
Shipston, Michael mike.shipston@ed.ac.uk Centre for Integrative Physiology, University of Edinburgh
Sinkala, Zachariah zsinkala@mtsu.edu Mathematical Sciences, Middle Tennessee State University
Stojilkovic, Stanko hsugr@mail.nih.gov Endocrinology & Reproduction Research, National Institutes of Health
Stredney, Don don@osc.edu Research Dept., Ohio Supercomputer Group
Tabak, Joel joel@neuro.fsu.edu Department of Biological Sciences, Florida State University
Tomaiuolo, Maurizio mtomaiuolo@bio.fsu.edu Neuroscience Program, Florida State University
Toporikova, Natalia ntoporikova3@mail.gatech.edu Laboratory for Neuroengineering, Georgia Institute of Technology
Tsaneva-Atanasova , Krasimira K.Tsaneva-Atanasova@bristol.ac.uk Department of Mathematics, University of Auckland
Vidal, Alexandre alx.vidal@gmail.com Department of Mathematics, Université d'Evry Val d'Essonne
Walker, Jamie jamie.walker@bristol.ac.uk Engineering Mathematics, University of Bristol
Wohleb, Eric eric.wohleb@osumc.edu Molecular Virology, Immunology, and Medical Genetics (MVIMG), The Ohio State University
Yamada, Richard yryamada@umich.edu Department of Mathematics, University of Michigan
Zeeman, Mary Lou mlzeeman@bowdoin.edu Department of Mathematics, Bowdoin College
An introduction to the analysis of biomathematical models
An introduction to the analysis of biomathematical models
Introduction to neuroendocrinology
Introduction to neuroendocrinology
Differential Regulation of FSH(beta) Transcription by Changes in GnRH Pulse Frequency
The gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) play an integral role in the reproductive axis, translating neural and hormonal input into precisely regulated output to achieve normal sexual development and regulation of gonadal function. In recent years, considerable progress has been made in the elucidation of the molecular mechanisms underlying tissue-specific and tonic GnRH-dependent expression of the gonadotropin (beta)-subunit genes. However, little is known about the mechanisms essential in the differential control of gonadotropin gene expression by changes in GnRH pulse frequency. The focus of this presentation is to discuss mechanisms that contribute to the GnRH pulse frequency-dependent differential control of FSH(beta) gene expression. A major GnRH-responsive site within the FSH(beta) promoter is predominantly bound by cAMP response element binding protein (CREB) to stimulate FSH(beta) transcription. In turn, the transcriptional inhibitor, inducible cAMP early repressor (ICER), is expressed to a greater extent at high GnRH pulse frequencies and antagonizes the stimulatory transcriptional effects of CREB. The experimental data supporting this dynamic model of GnRH pulse frequency-dependent regulation of FSH(beta) transcription will be presented and ongoing studies to explore mechanisms essential in integrating the effects of the bZIP transcription factors, CREB and ICER, to ultimately govern the activation of FSH(beta) gene expression will be discussed.
Viability of Autocrine Regulation in Synchronizing Diffusely Distributed Endocrine Neurons Producing Pulsatile Hormonal Signals
Reproduction in mammals is controlled by the pulsatile release of gonadotropin-releasing hormone (GnRH). About 800~2000 GnRH neurons participate in the generation of GnRH pulses. Their cell bodies are distributed in a scattered manner in designated areas of the hypothalamus. Although several experimental models including cultured hypothalamic tissues, placode-derived GnRH neurons, and GT1 cell lines have been developed and studied, a mechanistic explanation for the origin of GnRH pulsatility remains elusive. One major obstacle is identifying the mechanism for synchronizing scattered neurons. This talk is aimed at studying the viability of autocrine regulation in synchronizing GnRH neurons using mathematical models describing diffusely distributed GnRH neurons in two-dimensional space.

The models discussed here are developed based on experiments in GT1 cells as well as hypothalamic neurons in culture. These experiments revealed that GnRH neurons express GnRH receptors that allow GnRH to regulate its own secretion through an autocrine effect. GnRH binding to its receptors on GnRH neurons triggers the activation of three types of G-proteins of which two activates and one inhibits GnRH secretion (Krsmanovic et al, 2003, PNAS 100:2969). These observations suggest GnRH secreted by GnRH neurons serve as a diffusive mediator as well as an autocrine regulator. A mathematical model has been developed (Khadra-Li, 2006, Biophys. J. 91:74) and its robustness and potential applicability to GnRH neurons in vivo investigated (Li-Khadra, 2008, BMB 70:2103). In this talk, I will introduce some key experimental and modeling results of this rhythm-generating system, focusing on the effects of intracellular distance, rate of hormone secretion, and spatial distribution on the ability of diffusely distributed GnRH neurons to synchronize through autocrine regulation. Based on the modeling results, one plausible explanation for why GnRH neurons are distributed in a scattered manner is proposed.

(Results presented in here are based on works in collaboration with Anmar Khadra, Atsushi Yokoyama, and Patrick Fletcher.)
Intrinsic and extrinsic contributors to gonadotropin-releasing hormone neuronal activity
The episodic release of gonadotropin-releasing hormone (GnRH) from nerve terminals in the hypothalamus is critical for encoding downstream pituitary response and thus fertility. Episodic release likely arises from the intersection of several components including intrinsic properties that generate repeating activity, synaptic inputs and the network interactions that bring about synchrony of neuronal activity. The current knowledge on these various aspects will be discussed. Preliminary work on how metabolic inputs that regulate fertility alter intrinsic properties will also be presented.
Modeling of Exocytosis in Endocrine and Neuroendocrine Cells
Secretion, whether from nerve terminals or hormone-secreting cells, is determined by the product of the number of release-ready vesicles and the probability of release per vesicle. The probability of release is in turn dependent on both the concentration of calcium seen by the vesicles and the affinity of the release mechanism for calcium. All of these factors vary in time, depend on conditions and history of stimulation, and vary among cell types. Vesicle trafficking to releases sites on the plasma membrane is regulated by calcium and also by metabolism, at least in insulin-secreting cells. It has long been known that vesicles differ in proximity to calcium channels, but recent evidence from many cell types supports the hypothesis that a subset of vesicles distant from channels may have enhanced sensitivity to calcium and play a larger role than previously thought. These issues will be discussed based on models in beta cells along with possible relevance for pituitary and hypothalamic neurons.
Ion channels and the control of the hypothalamic pituitary-adrenal (HPA) axis: from molecules to models
Stress-related disorders represent one of the major health-care burdens in modern society. The neuroendocrine stress response is coordinated through the dynamic interplay between the brain and the endocrine regulation of the anterior pituitary and adrenal glands - the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is a classic example of homeostatic feed-forward and feedback loops working together to control system output and function.

Central to the control of the HPA axis is the coordinated activity of ion channels and cellular electrical excitability in the key nodes of the axis - hypothalamic neurones, anterior pituitary corticotrophs and adrenal cortical cells. However, while the inputs and outputs of each node are well understood how the electrical properties of these systems is controlled and whether disturbances in ion channel properties may underlie disease states associated with HPA axis dysfunction is very poorly understood. This talk is aimed at identifying some of the major challenges in understanding HPA axis function from both a physiological and modelling viewpoint and to stimulate new research avenues that should lead to improved predictive tools to understand HPA axis function in health and disease. Preliminary work exploiting an integrated approach to understand the complex interplay between multiple ion channels and their control of distinct nodes of the HPA axis will be discussed.
Signaling Within and Between Pituitary Cells
Secretory pituitary cells express numerous voltage-gated sodium, calcium, potassium, and chloride channels and fire action potentials spontaneously, accompanied with a rise in intracellular calcium and modulation of cyclic nucleotide signaling pathway. These cells also express several subtypes of extracellular ligand-gated ion channels, which activation leads to amplification of the pacemaking activity and facilitation of calcium influx and hormone release. Numerous G protein-coupled receptors expressed in these cells stimulate or silence electrical activity, cyclic nucleotide signaling and action potential-dependent calcium influx and hormone release. Other members of this receptor family can activate IP3 receptor channels in the endoplasmic reticulum, leading to a cell type-specific modulation of electrical activity. Pituitary cells also express gap junction channels, which could be of the potential relevance for intercellular signaling. The current knowledge on complex relationship between electrical activity and calcium/cyclic nucleotide signaling in pituitary cells will be presented. A work in progress on identification of channels contributing to the pacemaking depolarization will also be discussed.
Multi-Scale Mathematical Models of the Supra-Chiasmatic Nuclei
The master-clock in all mammals is the Supra-Chiasmatic Nuclei (SCN) which is the organ responsible for coordinating time-keeping in all cells within the organism. The SCN is composed of approximately 10,000 individual cells. Experimental evidence indicates that each cell in the SCN is an individual oscillator; inter-cellular coupling mechanisms (electrical and chemical) become important in synchronizing rhythms within a cellular network.

After a brief overview of modeling approaches in this field, we will review current strategies for quantitative modeling of the SCN at the cellular and intra-cellular level. In particular we will discuss models which have studied the roles of molecular noise and inter-cellular coupling mechanisms in the SCN network; these model's results will be compared to experimental data. Ultimately we would like to understand the role of the SCN at the organismal level. We conclude with a general discussion/direction of the issues/questions in the next stage of SCN modeling.
video image

Introduction to neuroendocrinology
Arturo Iglesias Introduction to neuroendocrinology

video image

An introduction to the analysis of biomathematical models
Richard Bertram An introduction to the analysis of biomathematical models

video image

Modeling of Exocytosis in Endocrine and Neuroendocrine Cells
Arthur Sherman Secretion, whether from nerve terminals or hormone-secreting cells, is determined by the product of the number of release-ready vesicles and the probability of release per vesicle. The probability of release is in turn dependent on both the concentra

video image

Differential Regulation of FSH(beta) Transcription by Changes in GnRH Pulse Frequency
Ursula Kaiser The gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) play an integral role in the reproductive axis, translating neural and hormonal input into precisely regulated output to achieve normal sexual development and regulati