The prefrontal cortex is essential for a wide variety of higher functions, including attention and memory. Cholinergic neurons are thought to be of prime importance in the modulation of these processes. Degeneration of forebrain cholinergic neurons has been linked to several neurological disorders. The present study was designed to identify genes and networks in rat prefrontal cortex that are associated with learning and cholinergic-loss-memory deficit. Affymetrix microarray technology was used to screen gene expression changes in rats submitted or not to 192 IgG-saporin immunolesion of cholinergic basal forebrain and trained in spatial/object novelty tasks. Results showed learning processes were associated with significant expression of genes, which were organized in several clusters of highly correlated genes and would be involved in biological processes such as intracellular signaling process, transcription regulation, and filament organization and axon guidance. Memory loss following cortical cholinergic deafferentation was associated with significant expression of genes belonging to only one clearly delineated cluster and would be involved in biological processes related to cytoskeleton organization and proliferation, and glial and vascular remodeling, i.e., in processes associated with brain repair after injury. (C) 2011 Elsevier Inc. All rights reserved.