Objectif
PULSE NETWORKS aims to develop a biomathematical theory and computational model of the mechanisms underlying the two output patterns, pulsatile and graded, of an intensively studied but so far little modelled neural network - the oxytocin control system - performing two corresponding physiological functions. Pulsatile output is necessary for lactation and parturition, whereas graded output control sodium excretion from the kidney. Essential aspects of the network that complicate its study are that pulsatile output is dependent on the integrity of the neuronal network, and on stochastic synaptic input. On the other hand, the system output is more transparent than that of other intensively modelled neuronal systems, e.g. the hippocampus and the cortex, as it is coded by essentially low dimensional signals from the pituitary. Furthermore, there is now considerable knowledge of both cellular mechanisms and system performance. The system behaviour is so complex that mathematical models are the only means of critically evaluating and testing the underlying mechanisms. Therefore the time is now ripe tor constructing a mathematical theory, bringing together leading European experimenters and neuronal modellers. A second major emphasis of the project is to carry out further physiological experiments to plug the gaps in our knowledge highlighted by the modelling approach, and whose filling will be necessary for successful model building.
This project will be important (i) in terms of an improved understanding of the oxytocin control system; (ii) is of general neurobiological interest for the insights it provides about management of information by a dual mode neural network providing control of two separate physiological functions; and (iii) constitutes a paradigm for modelling neuroendocrine neural networks generally. Neuroendocrine systems control growth and metabolism, fluid and electrolyte balance, blood pressure and the physiological responses to stress and all aspects of reproduction, and are of key importance to health and welfare. This study will be of benefit through its impact on improved management of neuroendocrine disorders, and indirectly through the development of more effective models of hypothalamic pulse generators such as the luteinizing hormone and growth hormone pulse generators, that themselves could result respectively in improved contraceptive methods and improved quality of life for the elderly. Improved knowledge about the interaction between drugs and the OT pulse generator could have importance for drug therapy for pain relief in the later stages of pregnancy in humans.
The project complies with the requirements of Area 4.4 of the Biotechnology Programme because of the potential medical, welfare and commercial benefits for the KU; and also because it is an interdisciplinary project contributing to basic knowledge about how a dual function/dual mode neural network manages the information contained in the diversity of afferent inputs to produce a physiologically appropriate output, utilizing studies of intracellular mechanisms and intercellular communication and a range of mathematical and computational models.
The proposal is divided into 6 interrelated work packages. Work Package I comprises the development of a range of mathematical models of single oxytocin neurones which as far as possible reproduce the observed behaviour of single neurones, and which, when assembled into model networks, have the potential to reproduce the network behaviour. Work Package 2 comprises studies of basic cell mechanisms and properties, including the determinants of dendritic oxytocin secretion, the cellular actions of oxytocin when applied to the cell dendrites, and establishing the physiological impact of transmitters released during suckling. Work Package 3 comprises in vivo electrophysiological studies of the network mechanisms underlying bursting activity during functioning milk-ejection reflexes, in particular of the changes in the activity patterns leading up to bursts. and how these are modulated by a range of neurotransmitters which are known to affect bursting. The degree of synchronization between the four hypothalamic nuclei containing oxytocin neurones will also be characterized and quantified. Work Package 4 involves the construction of network models: assembling the single neurone models devised in Work Package I into networks which can burst in the manner observed experimentally. The first stage will utilize a network model which can be handled analytically. Work Package 5 will provide the specially tailored statistical techniques for analysing particularly the electrophysiological recordings from Work Package 3 (developing approximations that can be fitted, efficiently estimating their parameters) and implementing these methods on the experimental data. Work Package 6. A further important element is performing empirical tests of the mathematical models and predictions of models as they are constructed. This multi-disciplinary package involves design of biological experiments that most powerfully discriminate between alternative hypothetical mechanisms, carrying out the tests, and finally analysing and interpreting the results.
Champ scientifique (EuroSciVoc)
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CORDIS classe les projets avec EuroSciVoc, une taxonomie multilingue des domaines scientifiques, grâce à un processus semi-automatique basé sur des techniques TLN. Voir: Le vocabulaire scientifique européen.
- ingénierie et technologie génie électrique, génie électronique, génie de l’information ingénierie électronique système d’automatisation et de contrôle
- sciences naturelles sciences chimiques chimie inorganique métal alcalin
- sciences médicales et de la santé médecine clinique obstétrique
- sciences naturelles mathématiques mathématiques appliquées modèle mathématique
- sciences naturelles informatique et science de l'information intelligence artificielle intelligence de calcul
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Coordinateur
CB2 4AT Cambridge
Royaume-Uni
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