Publisher Summary The major central cholinergic systems include (1) the projection neurons of the medial septum and diagonal band of Broca (MS/DB) to the hippocampus; (2) the projection neurons of the nucleus basalis magnocellularis (NBM) to the amygdala and cerebral cortex; (3) the inter-neurons of the striatum. Although the basal forebrain projection neurons have been implicated in learning and memory, and the striatal inter-neurons in motor behaviors, it still is not clear how and to what extent the central cholinergic neurons are involved in specific behaviors. Similarly, relatively little is known about the cellular and molecular mechanisms that regulate animal behaviors mediated by the central cholinergic systems. Although acetylcholine (ACh) was the first neurotransmitter discovered in the central nervous system, it remains unclear how the synthesis, storage, and release of ACh are regulated, or how ACh neurochemistry might be altered by environmental stimuli or synaptic experience, both of which would impact on cholinergically mediated behaviors. The central cholinergic systems are particularly dysfunctional in Alzheimer's disease. Thus, our animal research on the regulation of central cholinergic transmission and behavior has focused on the deficits in the systems associated with senescence and the potential amelioration of age-related deficits by the administration of the neurotrophic protein, nerve growth factor (NGF). This chapter describes the current understanding of the regional regulation of ACh synthesis and release in young and old rats, and illustrates several correlations between age-related and NGF-induced alterations in cholinergic neurochemistry, electrophysiology, morphology, and behavior.