From early neuronal polarity to establishment of neuronal connections in adult Neurogenesis.
The correct establishment of neuronal connections into neuronal circuitry is essential for the proper organization of the nervous systems.Such connections are generated through polarization of newly generated neurons beginning with the specification of a single axon among equally potential neurites (Figure 1 A and B). Along thisprocess, growth cones located at the leading edges of undifferentiated neurites detect and respond to environmental cues that guide one, and only one of them to growth over the other attaining final axonal identity. These polarizing cues, include contact-mediated or secreted molecules acting over the fated axon.It is clear that individual polarity cues can function activating a plethora of various events including the differential expression of receptors and protein complexes,the selective accumulation of polarity regulators and cross talk between intracellular signaling cascades,at the growth coneof the fated axon.Of these instructive cues, the neurotrophins are perhaps the best candidates.
Aim of the project.Although there is considerable indication for the role of neurotrophins in neuronal polarity, the precise molecular mechanisms that underlie neurotrophin signal transduction in axonal specification remain unresolved. So far, we report that the pan-neurotrophin receptor p75NTRis akey polarity regulator that localizes asymmetrically in differentiating neurons in response to neurotrophinsand it transduces polarity signals for specification of the future axon.
In the next three years we will investigate the role of p75NTR in transducing signals for axonal specificationboth in vitro and in vivo.
Figure 1 - A Coronal section of the mouse hippocampus showing adult-generated neurons transduced with GFP-retrovirus (green) in the granule cell layer (gcl), extending dendrites in the molecular layer (ml) of the dentate gyrus and axons through the hilus (hl) toward the CA3 area. Scale bar is 100 µm. Sample tracings of newborn neurons from confocal images (in 2D projection) are shown at different times post-injection (dpi).
Figura 1 - B Upper panels show confocal images of GFP-expressing newborn neuron as in A.
Adult neurogenesis in mammals has been observed in the subgranule zone in the dentate gyrus of the hippocampus. Once generated, the vast majority of neurons in the dentate gyrus remain located on the hilar side of the granule layer and integrate into the existing neuronal network by receiving afferent input from perforate path fibres, and providing efferent output to pyramidal CA3 cells.
While new neurons have been regarded to enter the pre-existing circuitry via a stereotypical sequence of morphological and functional transitions, a lifelong description of this process is largely unknown.
Aim of the project
The lifelong genesis of new neurons is well documented in many animal species including humans,yet the fate of these new neurons and their functions are largely unknown.In the next three years we will investigate how continuous generation of new neurons in old animals stabilizes cognitive and memory performances as well as the mood state of the animals.