Introduction to neuroendocrinology
An introduction to the analysis of biomathematical models
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.
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.
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.
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.