The neurotrophic hypothesis and the cholinergic basal forebrain projection

Development of the nervous system is characterized by stages of cell proliferation, the formation of exuberant connections, cell death, maturation, and differentiation. During the development, an abundance of neurons are born and form connections, yet a much smaller number of these cells and connections are maintained into adulthood. The importance of trophic interactions mediated by diffusable agents during neural development was first proposed by Ramon y Cajal. The possibility that trophic agents mediate survival during the development has since been elaborated by others and formulated into the “neurotrophic hypothesis.” The general hypothesis provides a framework with which to contrast and compare trophic molecules in a detailed developmental process. Specifically, the neurotrophic hypothesis consists of three major tenets: (1) an overabundance of connections are formed during development; (2) projection neurons are dependent upon limiting amounts of a trophic molecule elaborated in the target tissue; (3) those neurons that compete successfully for the trophic molecule are maintained into adulthood, whereas the remainder undergo cell death. There exists a good deal of evidence supporting the neurotrophic hypothesis in the peripheral nervous system (PNS). Originally formulated in the context of the PNS, the neurotrophic hypothesis has been largely extrapolated to the central nervous system (CNS). Moreover, the theory has been extended to propose that (a) trophic molecules are necessary for the maintenance of adult neurons and (b) decreasing amounts of trophic support predicate cell death in aging and neurodegenerative disorders. This chapter explains the legitimacy of these extrapolations and the known role of neurotrophic factors in development, maintenance, and promotion of survival in the CNS— namely, in the cholinergic projection of the basal forebrain.