In the olfactory bulb, granule neurons and periglomerular neurons inhibit many principal mitral and tufted cells (Figure 4A). In the hippocampus, adult-born dentate granule cells, while making a small number Pomalidomide of extremely potent, large mossy fiber connections with target CA3 pyramidal neurons, innervate tens of hilar

basket interneurons, each of which in turn inhibits hundreds of mature granule cells in the dentate gyrus (Figure 4B) (Freund and Buzsáki, 1996). Third, adult-born neurons also modify the local circuitry through selective activation of modulatory pathways. One recent study using an optogenetic approach has suggested that newborn neurons contact several distinct subtypes of local interneurons (Bardy et al., 2010), thus introducing dis-inhibition. In the dentate gyrus, granule cells are known to innverate hilar mossy cells, which in turn activate many mature dentate granule cells contralaterally (Figure 4B). Future studies will address this unified hypothesis with a better characterization of anatomical and functional connectivity of adult-born neurons and electrophysiological analysis of both adult-born neurons and network properties in behaving animals. We also need to understand the contribution of potential modulatory inputs to adult-born neurons from other brain regions, such as centrifugal inputs to the olfactory bulb and dopaminergic inputs

to the dentate gyrus (Mu et al., 2011). The field is poised to make major breakthroughs in understanding functions of adult neurogenesis in animal models, given the recent technical Erastin nmr advances. A number of sophisticated genetic models allow targeting of specific subtypes of neural progenitors or newborn neurons at specific maturation stages. Optogenetic approaches permit manipulating the activity PDK4 of adult-born neurons with exquisite spatial and temporal precision and without the complication of injury responses and homeostatic compensation associated with the physical elimination of adult neurogenesis. With a combinatorial approach

for analyses at cellular, circuitry, system, and behavior levels, future studies will clarify how adult neurogenesis may contribute to olfaction, learning, memory, and mood regulation. Furthermore, these studies may identify new functions of adult neurogenesis under physiological states and how aberrant neurogenesis may contribute to mental disorders, degenerative neurological disorders, and injury repair. The discovery of continuous neurogenesis in the adult mammalian brain has overturned a century old dogma and provided a new perspective on the plasticity of the mature nervous system. In the past decade, the field of adult neurogenesis has turned its focus from documenting and characterizing the phenomenon and its regulation to delineating underlying molecular mechanisms, stem cell regulation, neuronal development, and functional contributions. Many significant questions have been addressed and some basic principles have emerged.