COBRE: UMMC: GALANIN IN LOCUS COERULEUS - VENTRAL TEGMENTAL AREA AXONS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The noradrenergic locus coeruleus (LC) and serotonergic dorsal raphe (DR) nucleus are two brainstem centers that have been implicated in major depressive disorder. These systems are widely projecting and have the potential to globally impact brain function. Despite the broad distribution of norepinephrine (NE)- and serotonin (5HT)-containing axons within the CNS, a number of studies indicate that subpopulations of LC and DR neurons can be discriminated on the basis of neurochemical content and target specificity. This suggests that under certain behavioral or physiological conditions, subgroups of LC and DR neurons may selectively influence the activity of particular neuronal circuits. The lab has pursued this concept by examining the innervation of structures associated with the ascending trigeminal somatosensory system by LC and DR. In these investigations it was revealed that the major output from one LC nucleus is organized with respect to the crossed trajectory of this modality specific pathway, and that there is a propensity for individual LC neurons to send axon collaterals to neuronal ensembles engaged in similar sensory functions. Other recent findings indicate that cortical nitric oxide synthase (NOS)-containing axons originate from discrete clusters of DR neurons located primarily along the ventral midline. State-of-the-art tract tracing, immunohistochemical, and electron microscopic techniques are also being utilized in current studies which are aimed at exploring the role of the neuropeptide, galanin (Gal), in depression. A major focus of this work is to explore an existing hypothesis which states that LC-derived Gal may negatively impact dopamine output from the ventral tegmental area (VTA) and contribute to symptomatology observed in depression, i.e. decreased motor activity and decreased appreciation of pleasurable stimuli. More specifically, the lab is interested in defining the chemoarchitecture of the LC-VTA projection, and characterizing the synaptic organization of LC-VTA axon terminals relative to mesolimbic and mesocortical projection neurons. On-going work is also directed toward examining the effect of enhanced levels of LC activity on Gal and dopamine-beta-hydroxylase (DBH) expression. Since animal models of depression manifest increased levels of LC activity and suicide victims demonstrate elevated levels of LC tyrosine hydroxylase, it stands to reason that depression-related increases in LC activity may alter the synthesis and availability of Gal and NE in LC terminals. This issue and the possibility that dysregulation of LC firing may modify the synaptic relationship between LC and VTA, are being examined in studies where levels of LC activation are manipulated and correlated with changes in Gal- and DBH-positive VTA fiber density, morphology, and ultrastructure.