Seven principles in the regulation of adult neurogenesis.

Seven key elements describing the regulation of adult neurogenesis are proposed. (i) A distinction must be made between regulation and 'control' at the transcriptional level in order to appreciate the hierarchy of regulatory factors. (ii) The regulatory hierarchy comprises conceptual levels from behaviour to genes. Consequently, 'regulation' of neurogenesis can be confounded by confusing rather than integrating factors, levels and concepts. The immense spectrum of neurogenic regulators reflects the sensitivity of adult neurogenesis to many different types of stimuli, and provides a means of abstraction. (iii) Age per se does not seem to play a constant role in the modulation of this process, as the dramatic 'age-related' changes in adult neurogenesis only take place early in life. (iv) The regulatory hierarchy at any given time-point is corresponded by the directionality and sequential interdependence of different regulatory factors in the course of development. Regulation goes from non-specific to specific, and the following steps build on regulation at the previous ones. (v) This complexity is reflected at the genetic level in that adult neurogenesis is highly heritable and highly polygenic with single factors explaining little of the variance. (vi) As regulation is additive, there is an element of self-reinforcement in the regulation of adult neurogenesis, allowing the formation of regulatory reserves for situations of functional demand. (vii) The complexity of regulation makes adult neurogenesis sensitive to pathological disturbance at various levels, suggesting that different molecular events might result in similar and shared behavioural or functional phenotypes originating in the dentate gyrus.