What good is an old brain in a young body – a strategy for regenerating the neocortex - Jean Hébert
The neocortex is the seat of our highest cognitive functions. Neocortical projection neurons, the principle neurons of the neocortex, become dysfunctional with age and can be lost due to neurodegeneration or insults such as stroke or trauma. The highly plastic nature of neocortical neuronal networks suggests that they could in theory withstand a slow turnover of neurons over time without significantly compromising function or memory. Therefore cell replacement may be a viable approach to rejuvenating the neocortex. We have recently shown that endogenous stem or precursor cells have little or no ability to replace projection neurons when they are lost in the adult neocortex (Diaz et al., April 2013, J. Neuroscience). Moreover, previous attempts at replacing these projection neurons using several types of transplanted neural stem or precursor cells have not provided viable strategies. One limitation of previous attempts is that the transplanted cells remained primarily in the transplant site or only migrated a short distance away from it. Therefore, to achieve the goal of functionally integrating new projection neurons throughout broad areas of the neocortex and to minimize the number of injection sites, a novel strategy is required that takes into account cell dispersion. Our goal is to develop an approach for introducing new, widely dispersed, projection neurons in the adult neocortex, providing a paradigm for testing whether they can functionally integrate. One way in which we are attempting to accomplish this is by using embryonic cells that are inherently migratory when transplanted into the adult mouse neocortex. However, because these particular migratory precursor cells generate interneurons rather than projection neurons, we engineer them with lentiviruses with which we can induce expression of transcription factors that will reprogram them to the desired fate once they have dispersed.