The long term goal of this project is to elucidate the mechanisms that regulate functions of the noradrenergic locus coeruleus (LC) system. Our previous results defined afferents to the LC nucleus, and characterized LC dendrites that extend into specific extranuclear zones. However, these findings also generated new questions: (i) what are the inputs to extranuclear LC dendrites, (ii) what circuits are LC afferents a part of, and (iii) what LC output functions are regulated by these afferent circuits? The proposed experiments will answer these difficult but important questions using new anatomical technology and electrophysiology. LC neurons have extensive extranuclear dendrites, and the zones containing these distal dendrites receive numerous inputs that do not innervate the LC nuclear core. However, it has been difficult to identify which of these afferents terminate on LC dendrites vs. other elements in this region. We will retrogradely label afferents that specifically innervate extranuclear LC dendrites using the recently developed transsynaptic tract-tracer, pseudorabies virus (PRV). Dendritic afferents will be confirmed by ultrastructural analyses, and their impact on LC neuronal activity will be determined. In addition to direct afferents to LC neurons, it is important to determine inputs to these direct afferents, and thereby identify circuits that regulate LC function. We will map indirect afferents to the LC in a detailed time-course study of transsynaptic transport of PRV. For prominent indirect afferents, the relays to the LC will be identified and the influence of these afferent circuits on LC activity will be determined. Our preliminary results indicate that the suprachiasmatic nucleus (SCN) is a prominent indirect input to the LC. The SCN is the brain's circadian pacemaker, and controls among other rhythms circadian properties of sleep and waking. As the LC has long been implicated in arousal, we hypothesize that the SCN-LC circuit is a key neural substrate linking circadian and sleep-waking processes. We will test this hypothesis by manipulating SCN activity, recording the effects on EEG arousal, and testing the role of the LC and associated relay nuclei in the effects obtained. This will be the first analysis of a neural link between circadian and arousal processes. These studies will extend our analysis of afferent control of LC function to identify inputs to distal LC dendrites and circuits that regulate LC activity. They will also provide the first demonstration of afferent circuit regulation of an important LC output function, cortical arousal.
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