The main goal of this project is to study the regulation of nicotinic acetylcholine receptors (nAChRs) in the CNS by neuregulins, a new family of neurotrophic factors that are present in cholinergic neurons throughout central and peripheral nervous system. We will also determine if neuregulin induced change in the number of distribution of functional nAChRs alters synaptic transmission in the circuits described. Neuregulins will be studied in vitro by adding them to neuronal cell cultures, and they will be studied in vivo in mutant mice that exhibit diminished neuregulin expression. To maximize the generality of our results, we will study neurons dissociated from the Medial Habenula (MHb), the Interpeduncular Nucleus (IPN), the Substantia Nigra, (SN), and the Ventral Tegmental Area (VTA). Each region offers advantages for studies of nAChR regulation. In each case, the nuclei can be dissected easily from embryos and neonatal animals, the cells can be maintained in spars cell culture, a subpopulation of the neurons receive cholinergic synaptic inputs, and the neurons express a diverse array of nAChRs. In vitro cell culture experiments are described in the three Specific Aims. In vivo studies that utilize fresh slices prepared from normal and mutant mice are described in Collaborations. We emphasize microelectrode recordings of ACh induced currents because we want to study regulation of functional receptors. However, ligand binding and receptor subunit gene expression will be used to confirm and extend results in some cases. In each series of experiments, we will begin with the relatively well studied MHb-IPN system, but results will be extended to Septal-MHb, and PPT-SN/VTA interactions.
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