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This thesis describes efforts at the interface of chemistry and neuroscience to design and characterize fluorescent probes capable of tracing neurotransmitters from individual release sites in brain tissue. As part of the Fluorescent False Neurotransmitters (FFNs) program, small organic fluorophores have been developed that undergo uptake into specific presynaptic release sites and synaptic vesicles by utilizing the native protein machinery, which can then be released during neuronal firing. The most advanced generation of FFNs are pH-sensitive, and display an increase in fluorescence when released from the acidic vesicular lumen into the extracellular space, called a “FFN Flash.” In Chapter 2, the utility of the dopamine-selective and pH-sensitive functionality of FFN102 to study the mechanisms that regulate changes in pre-synaptic plasticity, a critical component of neurotransmission was explored. This included using the FFN flash to quantitatively trace dopamine release, changes in the release probability of individual release sites, and changes in vesicular loading that can affect quantal size. The second goal of this thesis research, as detailed in Chapters 3 and 4, sought to expand the substrate scope of the FFN program to neurotransmitter systems other than dopamine. Described in Chapter 3, is the identification of a fluorescent phenylpyridinium, APP+, with excellent labeling for dopamine, norepinephrine, and serotonin neurons, however, the properties of the probe were found to be ill-suited for measuring neurotransmitter release. As a result, it was concluded that this class of compounds was not suitable for generating viable FFN leads. In contrast, Chapter 4 highlights the design, synthesis, and screening towards generating the novel noradrenergic-specific FFN, FFN270. This probe was further tested for application in acute murine brain slices where it labeled noradrenergic neurons, and was demonstrated to release upon stimulation. This chapter also describes the application of this compound in a series of in vivo experiments, where the ability to measure norepinephrine release from individual release sites was demonstrated in a living animal for the first time. This work opens the possibility for many exciting future FFN experiments studying the presynaptic regulation of neurotransmission in vivo.

In a multi-gear and multi-species artisanal fishery, the level of technical interactions (i.e. the competitive externalities resulting from a shared exploitation of common resources or fishing grounds) among various fishing units is high. Assessing these technical interactions is of great importance for fishery management, as any control applied to one fishing unit may have positive or negative effects on others. The magnitude and direction of these effects cannot be easily measured, unless all fishing units and species in the fishery are considered simultaneously. Technical interactions are particularly important in the complex artisanal fisheries of the English Channel. Using a bioeconomic model of the English Channel that incorporates all the major fishing units (the BECHAMEL model), we describe a method for measuring and classifying the technical interactions due to the competition for resource (stock externalities). The results are used to develop a typology of metiers and fleets based on their overall level of interaction for the resource. We also define fleets and metiers as structuring, dependent, intermediate or autonomous., Au sein d’une pêcherie multi-engins et plurispécifique, le niveau d’interactions techniques existant entre différentes unités de pêche (flottilles ou métiers) peut être élevé. La mesure de ces interactions techniques est capitale en termes de gestion, car une mesure de gestion appliquée à une unité de pêche aura des conséquences, positives ou négatives, sur les autres unités. Cependant l’amplitude et le sens de ces interactions sont difficiles à mesurer, car toutes les unités de pêche et les ressources intervenant dans la pêcherie doivent être prises en compte simultanément. Les interactions techniques sont particulièrement importantes dans la pêcherie artisanale de la Manche. A partir d’un modèle bioéconomique intégrant l’essentiel des unités de pêche de la Manche (le modèle Bechamel), nous décrivons une méthode pour mesurer et classifier les interactions techniques issues de la compétition pour la ressource (externalités de stock). Les résultats sont utilisés pour développer une typologie des flottilles et métiers à partir de leur niveau global d’interaction. En fonction de ce critère, on définit des flottilles et métiers dits structurants, dépendants, intermédiaires ou autonomes.

This paper presents the structure and examples of results from a bioeconomic model that stimulates the fisheries of the English Channel. The main purpose of the model is to study the consequences of various management alternatives on the economic situation of UK, French and Belgian fleets fishing in the area, and on exploited resources. Considering the large number of technical interactions, the whole Channel may be regarded as one large multi-country, multi-gear and multi-species fishery. The model describes this feature through the link between three entities : fleets, "métiers", and species caught. The empirical basis of the model is composed of UK, French and Belgian data concerning stocks, fleets and landings, and two economic sample surveys of UK and French fleets. The different modules (effort module, biological module and economic module) are described. A simple simulation is run, and the model reliability is discussed. The model presented in this paper is part of the EU funded project "Bioeconomic modelling of the fisheries of the English Channel" (FAIR CT-96-1993)., Cet article présente la structure et des exemples de résultats d'un modèle de simulation bioéconomique des pêcheries de la Manche. L'objectif principal de ce modèle est d'étudier les conséquences de différentes alternatives de gestion sur la situation économique des flottilles anglaises, françaises et belges travaillant sur cette zone et sur les stocks exploités. En raison d'un grand nombre d'interactions techniques, la Manche peut être vue comme une unique pêcherie internationale, multimétiers et plurispécifique. Le modèle décrit cette complexité à travers les liens entre trois entités : la flottille, le "métier" et le stock exploité. La base empririque du modèle est composée des données françaises, anglaises et belges de production et d'effort, et de deux enquêtes économiques sur les flottilles anglaises et françaises. Les différents modules (module d'effort, de production/biologie et d'économie) sont décrits. Une simulation simple est analysée, et la validité du modèle est discutée. Le modèle présenté dans ce papier fait partie du projet européen "Modélisation bioéconomique des pêcheries de la Manche" (FAIR CT-96-1993).

Norepinephrine is a monoamine neurotransmitter with a wide repertoire of physiological roles in the peripheral and central nervous systems. There are, however, no experimental means to study functional properties of individual noradrenergic synapses in the brain. Development of new approaches for imaging synaptic neurotransmission is of fundamental importance to study specific synaptic changes that occur during learning, behavior, and pathological processes. Here, we introduce fluorescent false neurotransmitter 270 (FFN270), a fluorescent tracer of norepinephrine. As a fluorescent substrate of the norepinephrine and vesicular monoamine transporters, FFN270 labels noradrenergic neurons and their synaptic vesicles, and enables imaging synaptic vesicle content release from specific axonal sites in living rodents. Combining FFN270 imaging and optogenetic stimulation, we find heterogeneous release properties of noradrenergic synapses in the somatosensory cortex, including low and high releasing populations. Through systemic amphetamine administration, we observe rapid release of cortical noradrenergic vesicular content, providing insight into the drug’s effect.