ABSTRACT
CRTD-Center for Regenerative Therapies Dresden, Technische Universität Dresden, 01307 Dresden, Germany. *Corresponding author: gerd.kempermann@crt-dresden.de
List of abbreviations after the text.
The inevitable opening quote of perhaps too many reviews on adult neurogenesis is: “In the adult centers, the nerve paths are something fi xed, and immutable: everything may die, nothing may be regenerated”. This famous phrase is usually taken as the origin of the so-called “no new neurons” dogma, supposedly postulated by Ramón y Cajal in 1928, even though in the original text it is immediately followed by the more forward-looking assertion that it was for the science of the future to “…change, if possible, this harsh decree”. Although it is still true to state that the adult brain is essentially a non-regenerative organ, our understanding of its capacity for plasticity and repair has now grown signifi cantly. The fi rst person to “change the harsh decree” was Joseph Altman, who in the 1960’s fi rst proposed that the generation of new neurons (neurogenesis) would occur in the adult hippocampus (Altman and Das, 1965) and olfactory bulb (Altman, 1969) using tritiated thymidine (which incorporates into the DNA of dividing cells). The results received wide interest at the time but ended
up as an idiosyncrasy, because the lack of neuron-specifi c markers made it impossible to conclusively identify these newly born cells as neurons, and their origin remained unclear. Altman had speculated that “some precursor cell” must be responsible for the generation of these new neurons (Altman and Das, 1965) but could not identify it. Almost 15 years later, Michael Kaplan was the fi rst to combine proliferation (based on incorporation of [3H]-thymidine) with confi rmation of cell type (by electron microscopy) to prove that the proliferating cells in the hippocampus and olfactory bulb identifi ed by Altman became neurons (Kaplan and Hinds, 1977). Public perception started to change when, in the 1980s, Nottebohm and colleagues demonstrated that new neurons are continuously produced each season when canaries learned new songs (Goldman and Nottebohm, 1983). They showed that the size of a particular nucleus in the song system, the higher vocal center (HVC) of male canaries, changes seasonally with song learning (Nottebohm, 1981). In addition, testosterone could increase the size of the HVC in females (Nottebohm, 1980) by increasing the survival of the newborn neurons (Rasika et al., 1994), an effect that is mediated by brain derived neurotrophic factor (BDNF) (Rasika et al., 1999). This link to behavior and learning was intriguing and added a large amount of mechanistic detail. Technological advances in the fi eld subsequently became available to allow multiple approaches to confi rm adult neurogenesis. Importantly, these adult-born neurons were shown to display the electrophysiological properties of mature neurons that were functionally integrated into the existing neuronal circuitry (Paton and Nottebohm, 1984). Confi rmation that the newly born cells become neurons was also achieved in adult rats by co-expression of the neuronal marker neuron-specifi c enolase (Cameron et al., 1993). Finally, the early 1990s saw two major advances in the fi eld. The rediscovery of adult neurogenesis in the rodent hippocampus (Gould et al., 1992) and olfactory bulb (Lois and Alvarez-Buylla, 1993), together with the identifi cation of the underlying stem cell population in the two neurogenic regions, the subventricular zone (SVZ) (Reynolds and Weiss, 1992; Richards et al., 1992) and hippocampus (Palmer et al., 1995; Palmer et al., 1997), generated a renewed vigor in the fi eld, and the race was on to identify adult neurogenesis in other species. In 1998, a groundbreaking study by Peter Eriksson cemented the importance of adult neurogenesis by demonstrating that new neurons are also produced in the brains of humans (Eriksson et al., 1998). The role of stem cells in adult neurogenesis was by now obvious (Alvarez-Buylla and Lois, 1995) and the conceptual link between adult neurogenesis and the emerging fi eld of neural stem cells was publicized in an important review by Fred H. Gage in 1995 (Gage et al., 1995).
