The magnocellular neurons (MCNs) of the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus are the principal site of biosynthesis of prepropeptide precursor of the antidiuretic hormone vasopressin (VP). This precursor is processed during anterograde axonal transportation to terminals in the posterior pituitary gland, where biologically active VP is stored until released into the general circulation in response to physiological activation of the SON by osmotic cues. By binding to V2-type receptors located in the kidney, VP decreases the amount of water lost in urine. Osmotic activation of the SON is accompanied by a dramatic morphological and functional remodelling. We have sought to understand the mechanistic basis of this plasticity in terms of the differential expression of genes. To identify such genes, we adopted an unbiased global approach based on Suppressive Subtractive Hybridisation-Polymerase Chain Reaction (SSH-PCR) Using this method, we generated libraries of clones putatively differentially expressed in control vs dehydrated SON. In order to rapidly screen these libraries, 1152 clones were subjected to microarray analysis, resulting in the identification of 459 differentially expressed transcripts. cDNA clones corresponding 56 of these RNAs were sequenced, revealing many of them to be novel ESTs. Four transcripts were shown by in situ hybridisation (ISH) to be significantly up- or down-regulated in the SON following dehydration. These genes may represent novel effectors or mediators of SON physiological remodelling.