Regulation of Adult Neurogenesis 2.0 – Beyond Signaling Pathways and Transcriptional Regulators

Abstract

The discovery of adult neurogenesis added a new layer of complexity to our understanding of the mechanisms underlying plasticity in the adult mammalian brain. After more than five decades of research, studies in adult rodents combining genetic and pharmacologic manipulations of neurogenesis with behavioral analyses have now convincingly proven that the life-long generation of new neurons in the dentate gyrus of the hippocampus, in the subven-tricular zone/olfactory bulb system, and potentially in the hypothalamus, is critical for neural circuit plastic-ity and for adaptation of the organism to a changing environment. Furthermore, analyses of preclinical models for human diseases not only suggest that perturbation of adult neurogenesis contributes to the pathogenesis of cognitive impairment and emotional symptoms in ageing, neurodegenerative and neurode-velopmental diseases but also raise the possibility that ameliorating neurogenesis deficits may be of con-siderable therapeutic benefit. Boosted by the proof that substantial generation of neurons occurs in some areas of the postnatal and adult human brain [1–4], there is an ever-increasing interest in determining the precise physiological function of the new neurons and in deciphering the molecular and cellular mech-anisms underlying their life-long generation in the adult brain. The origin of new neurons are neural stem/ precursor cells (NSPCs) that are either quiescent or slowly proliferating. NSPCs give rise to neurons through a complex sequence of proliferation, differ-entiation and maturation steps that culminate in the functional integration of the neuron into an existing neural circuit. The adult-born neuron's ability to pow-erfully modulate neural circuit function is not solely explained by its addition to the circuit, but also by its electrophysiological properties and connectivity, which are at least for a limited time highly distinct from the properties of its embryonically generated counterparts. Transplantation experiments conducted around the turn of the millennium were the first to demonstrate that signals provided by the surrounding cells are critical regulators of adult neurogenesis leading to the concept that interaction of NSPCs with a neu-rogenic microenvironment or neurogenic niche is central for regulating neurogenesis. While the neu-rogenic niche concept originally focused on the role of the niche to permit neuronal differentiation of NSPCs, later experiments revealed that the environ-mentally derived signals are involved in the control of