Objective
The locus coeruleus (LC) is the main noradrenergic centre of the brain and the most widely projecting central nervous system nucleus known. The LC has been proposed to play a role in the plasticity of the visual cortex (1), in attention and vigilance (2), as well as in the control of mood (3), memory acquisition (4) and selective attention (5). The LC is a major target of degenerative disorders such as Parkinson and Alzheimer disease and Down's syndrome (6-8). Finally, the LC plays a key role in triggering the opiate withdrawal syndrome (9) and is a prime model for studying the molecular basis of opiate habituation and deshabituation (10).
Whereas many studies have been devoted to the anatomy, pharmacology and electrophysiology of the LC, little is known of its ontogeny and cellular biology. The analysis of these aspects could provide important insights in its functioning and maintenance as well as inspire therapeutic strategies. Indeed, signals regulating the development of particular neuronal lineages are known to be important for the maintenance and plasticity of the differentiated phenotype under physiological and pathological conditions in the adult. For instance, neurotrophic factors that are survival factors for several classes of embryonic neurons also prevent lesion-induced degeneration of the same neurons in the adult. This proposal focusses on the molecular mechanisms involved in the determination of LC neurons and on their trophic dependency throughout embryonic and postnatal life.
The main immediate objectives are:
1. to reappraise the normal development of the LC (and noradrenergic centers A1 and A2) in the light of novel markers and concepts of neural tube regionalization;
2. to explore the transcriptional control of LC development and maintenance, in particular by the homoeodomain proteins Phox2a and Phox2b;
3. to study the requirements for survival and maintenance of the noradrenergic phenotype in vivo and in cultures of differentiated LC neurons, in particular the neurotrophic dependencies of LC neurons;
4. to establish conditions that would allow the generation of central noradrenergic neurons in vivo and in-vitro.
By taking a multi-disciplinary approach, combining studies on cultured cells with in vivo studies in both chick and mouse and exploiting the experimental advantages offered by each species, we ultimately hope to understand the sequence of events involved in the generation and maintenance of central noradrenergic neurons. We expect that our studies will lead to a better understanding of several diseases and dysfunctions of the LC and ultimately to the development of new therapeutic strategies for neuroprotection and for the prevention of opiate habituation and withdrawal syndromes. For instance, the understanding of the signalling involved in the generation of noradrenergic neurons may lead to transgenic models of specific noradrenergic deficiencies and to the development of engineered progenitor cell lines that may be of therapeutic interest for neurodegenerative diseases involving the LC.
Thus, our proposal complies with the objectives of the work programme in that the cellular and molecular mechanisms of LC development are investigated to provide a basis for the understanding of multiple dysfunctions of this important neural centre.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences neurobiology
- medical and health sciences basic medicine neurology dementia alzheimer
- medical and health sciences basic medicine anatomy and morphology
- medical and health sciences basic medicine neurology parkinson
- medical and health sciences basic medicine pharmacology and pharmacy
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Coordinator
60528 FRANKFURT AM-MAIN
Germany
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